CN102603731A - New quinolone derivative - Google Patents

Abstract

The invention relates to a quinolone derivative with superior antibacterial activity. The derivative shows excellent antibacterial activity and has a wide antibacterial spectrum, and especially has very strong activity in resisting Gram-positive bacteria. The invention also relates to a preparation method of the quinolone derivative, and a pharmaceutical composition containing the quinolone derivative or its salt, ester or solvate as active ingredients, as well as application of the quinolone derivative or its salt, ester or solvate in preparing antibacterial agent medicines.

Description

One type of Novel Quinolone verivate

Technical field

The present invention relates to as medicine, veterinary drug, aquatic products medication and the useful quinolones synthetic antibacterial agents of bacterinertness preservatives.That is to say, the present invention relates to formula quinolone parent nucleus hThe limit (or gThe limit) or be equivalent to its position thick with 5-, 6-, 7-, 8-, 9-or 10-unit's ring (shown in (I)).With different to the known quinolones antiseptic-germicide a little less than the gram positive bacterial strain activity, it has shown excellent anti-microbial activity, the pharmacokinetics performance that also has very wide antimicrobial spectrum and improve greatly:

（Ⅰ）

Wherein

R1 is any substituted alkyl, thiazolinyl, naphthenic base, alkoxyl group, amino, alkylamine, dialkylamine, aryl or aralkyl;

Each independently is Q-R7 for R2, R3 and R4;

Q is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R7 is Wasserstoffatoms or NR8R9, or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

Each independently is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl for R8 and R9;

R8 and R9 are any substituted thiazolinyl together or are arbitrarily made with 3-, 4-, 5-, the assorted naphthenic ring of 6-or 7-unit;

R5 is halogen atom, hydroxyl or any substituted alkoxyl group;

R10 is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R2 and R3 are any substituted thiazolinyl together or are arbitrarily made with 3-, 4-, 5-, the assorted naphthenic ring of 6-or 7-unit;

R3 and R4 are any substituted thiazolinyl together or are arbitrarily made with 3-, 4-, 5-, the assorted naphthenic ring of 6-or 7-unit;

R4 and R5 are any substituted thiazolinyl together or are arbitrarily made with 3-, 4-, 5-, the assorted naphthenic ring of 6-or 7-unit;

R6 is Wasserstoffatoms or any substituted alkyl;

Each independently is nitrogen-atoms or carbon atom for A and B, and condition is when A is N, no R10; When B is N, no R5;

N is 1,2 or 3; M is 0,1 or 2;

X is C, N, O or S.

The invention still further relates to the as above preparation method of formula I compound or its salt, ester or the solvolyte of definition; With contain formula I compound or its salt, ester or solvolyte pharmaceutical composition as activeconstituents, and formula I compound or its salt, ester or solvolyte in preparation as the purposes in the antiseptic-germicide medicine.

Background technology

Gram positive organism is the main pathogenic bacterium that cause multiple disease.Along with antibiotics being widely used clinically, its resistance constantly increases, and has become at present one of most thorny issue clinically.Compare with gram-negative bacteria, gram positive organism lacks complicated infiltration mechanism and effluxes passage, thereby antimicrobial therapy is more effective to its infection usually.However; Along with streptococcus pneumoniae and staphylococcus; Especially methicillin-resistant gold Portugal bacterium (MRSA) is to beta-lactam and the chemical sproof continuous increase of macrolide antibiotics, and the treatment that the gram positive organism sexuality is dyed has become one of important topic that the clinicist need often face.In addition, although make the purulence suis at present to PCs still sensitivity, to the general resistance of macrolide antibiotics.Enterococcus spp is to the intrinsic resistance of many microbiotic, and developed into drug resistance of vancomycin especially at present.

Quinolone has become and has tackled the most effectively one of antibacterials of many infection at present clinically.Be the main direction of year quinolone area research surplus in the of nearly ten how in the activity that keeps to gram-negative bacteria improving on the outstanding active basis anti-gram positive organism (particularly staphylococcus and streptococcus pneumoniae).In recent years, the Novel Quinolone kind is come out successively, makes the antimicrobial spectrum of such medicine expand to gram positive organism from traditional gram-negative bacteria thus.Meanwhile, the quinolone persister that is separated to clinically also shows a rising trend.The research work of Given this, developing the quinolones of the low again novel structure of existing anti-gram positive organism clinical efficacy and resistance selectivity extensively launches.

Before more than 40 year, people are surprised to find that at antimalarial drug---isolated a kind of by product has faint activity to some gram-negative bacteria in chloroquine (chloroquine) building-up process.Through the structural modification to this by product, first Comprecin was born in 1962---Nalidixic Acid (nalidixic acid).These article have certain clinical efficacy to gram-negative coccus property urinary tract infections.The seventies in 20th century, W-4565 (oxolinicacid) and pipemidic acid (pipemidic acid), first 7-piperazinyl quinolone) etc. come out one after another.These first-generation quinolones do not have activity to gram positive organism, only limit to treatment clinically by the microbial urinary tract infections of most of gram-negatives.

As first introduce in the C-6 position fluorine atom quinolone---the anti-microbial activity of R-802 (flumequine) obviously improves.This prompting: the suitable modification to mother nucleus structure perhaps can improve the activity of this type medicine to gram positive organism.Early 1980s, Koga etc. combine the constitutional features of R-802 and pipemidic acid, successfully develop the norfloxicin (norfloxacin) with 6-fluoro-7-piperazinyl structure, and the fluoroquinolone New Times has been opened in the appearance of this medicine.In the period of after this surplus in the of short ten, pefloxacin (pefloxacin, 6), enoxacin (enoxacin; 7), fleroxacin (fleroxacin, 8), CIPROFLOXACIN USP 24 (ciprofloxacin, 9), lomefloxacin (1omefloxacin; 10), Ofloxacine USP 23 (ofloxacin, 11) and levofloxacin a large amount of outstanding kinds such as (1evofloxacin, 12) constantly occur; And all inherited the constitutional features of 6-fluoro-7-piperazinyl, some drugs wherein is widely used so far clinically.The antimicrobial spectrum of these medicines obviously enlarges, and comprises gram-negative bacteria and gram positive organism, and the absorption in gi tract is good, and Plasma Concentration is high, is used to the therapy system sexuality clinically and dyes.It is active that these early stage fluoroquinolones have outstanding anti-gram-negative bacteria, streptococcus pneumoniae only had medium activity, so be not enough to tackle respiratory tract infection; And the bacterial drug resistance that constantly occurs therebetween also makes its activity to golden Portugal bacterium weaken greatly.

Gram positive organism had certain active early stage FQNS

Pharmaceutical Chemist is to fluoroquinolone parent nucleus C-5, and system has been carried out and structural modification widely in C-7 and C-8 position, and the anti-gram positive organism activity of such medicine is improved constantly.Introducing amino in the C-5 position then is one of structure of modification strategy the earliest.This measure makes that such antibiotic anti-gram positive organism activity is generally improved, like Sparfloxacin (sparfloxacin, 13).The C-5 bit substituent of grepafloxacin (grepafloxacin, 14) is a methyl, and its anti-gram positive organism activity is superior to CIPROFLOXACIN USP 24.Said two devices significantly improves the activity of many gram positive organisms (especially streptococcus pneumoniae), and the activity to anerobes also has certain improvement simultaneously.Although it is superior to CIPROFLOXACIN USP 24 to staphylococcic activity, but still not satisfactory; Its raising to the activity against staphylococci of anti-the quinolones also only has learning value, also is not enough to produce significant clinical meaning.Regrettably, these 2 kinds are all former thereby used or withdraw from market by strict restriction because of toxicology soon after listing.After this 7-N-METHYL PIPERAZINE base-8-BAY 128039 of exploitation---Gatifloxacin (gatifloxacin, 15) further improves the active of gram positive organism, simultaneously anti-anaerobic activity also be improved significantly.In recent years; Introducing pyrrolidyl in the C-7 position makes such medicine significantly improve the activity of gram positive organism; Like PD 127391 (clinafloxacin, 16), Tosulfloxacin (tosufloxacin, 17), Sitafloxacin (sitafloxacin; 18) and SB 265805 (gemifloxacin, 19) demonstrated fully this constitutional features.In addition, introduce the dicyclo amido in the C-7 position, like Moxifloxacin (moxifloxacin, 20) and trovafloxacin (trovafloxacin, 21), its anti-gram positive organism activity is significantly improved, lipotropy obviously strengthens, and the transformation period obviously prolongs.

Other position substituting groups are optimized one 6 fluorine atoms of C (this fluorine atom is considered to relevant with genotoxicity) that make on the removal fluoroquinolone parent nucleus become possibility; And the quinolones of new generation that has been born thus; Be non-FQNS or remove FQNS that its first representative is Jia Nuosha star (garenoxacin, BMS-284756; T-3811ME, 22).One of constructional feature of these article is that its C one 8 bit substituents are difluoro-methoxy, is not methoxyl group, and the improvement of its bacteriostatic activity and fungicidal activity is considered to relevant with this substituent introducing.The Jia Nuosha star is effective especially to the GPC that comprises golden Portugal bacterium, is that its activity is superior to CIPROFLOXACIN USP 24, Ofloxacine USP 23, levofloxacin and Moxifloxacin to methicillin-sensitivity property and the best quinolone antibiotic of resistance activity against staphylococci.

Gram positive organism had outstanding active Novel Quinolone class medicine

The substruction of quinolone drug effect group is 1,4 dihydro-4-oxo pyridine-3-carboxylic acid, its C-5, the thick and aromatic ring in C-6 position.Has R on the nitrogen-atoms of 1-position ₁, substituting group is that anti-microbial activity institute is essential, C-3 position carboxyl and C-4 position carbonyl be considered to quinolone molecule and DNA combine most importantly, do not see this 2 other feasible substituent reports of positions connection so far as yet.So it also is that anti-microbial activity is necessary that C-3 position carboxyl and C-4 position carbonyl are considered to.Very approaching in view of C-2 position and combining site, this connects any substituting group all will hinder the quinolone molecule undoubtedly near target site and cause its active reduction.

In recent years; The Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly, through to N-1 on the parent nucleus, C-5; C-6; The structure of modification of C-7 and C-8 bit substituent and ingenious collocation have obtained the active quinolone antibiotic that obviously improves to gram positive organism, thereby improve the activity of its anti-gram positive organism.

To N-1 bit substituent structure of modification.Prior art research shows that the substituting group on the quinolone parent nucleus N-1 position is necessary for hydrophobic group, because it is not only controlling the activity of quinolone, and its pharmacokinetics character is also had certain influence.Cyclopropyl is one of best substituting group on this of generally acknowledging so far; N one 1 bit substituents of great majority QNS that gone on the market and that researching and developing are cyclopropyl, like CIPROFLOXACIN USP 24, Sparfloxacin, grepafloxacin, Gatifloxacin, PD 127391, SB 265805, Moxifloxacin and Jia Nuosha star.In addition, connect on the N-1 position cyclopropyl of Sitafloxacin a fluorine atom [suitable-(1R, 2s)-2-fluorine cyclopropyl], and also can improve its activity during this 2,4 difluorobenzene base, like Tosulfloxacin and trovafloxacin to gram positive organism and anerobes.The another kind that Ofloxacine USP 23 and levofloxacin have embodied on this position replaces form, promptly introduces a condensed ring through N-1 and C-8 position and forms the parent nucleus that three ring a pair of horses going side by sides are closed, and its oxygen heterocyclic 3-position connects methyl.This structure is that of cyclopropyl successfully substitutes group, but the activity of its S-isomer (levofloxacin) is 100 times of corresponding R-isomer.

To C-5 bit substituent structure of modification.Research shows, when the bigger substituting group (like halogen and methoxyl group) of volume was introduced in the C-5 position, the active of quinolone significantly reduced, possibly be such group with the active combining site of C-3 and C-4 position between have the event that interacts; And the substituting group of medium volume then can obviously improve its external activity to gram positive organism like the introducing of amino (Sparfloxacin), methyl (grepafloxacin) or hydroxyl etc.Though it is active that the substituting group on this position is believed to be helpful in the anti-gram positive organism of quinolones; But its influence also will be depended on N-1 to a great extent; Substituting group on C-7 and the C-8 position; Because its C-5 position of nearly all quinolone (like CIPROFLOXACIN USP 24, Ofloxacine USP 23, levofloxacin, Gatifloxacin, PD 127391, Sitafloxacin, SB 265805, Moxifloxacin, trovafloxacin and Jia Nuosha magnitude) only connects a Wasserstoffatoms; Wherein a lot of N-1 bit substituents is a cyclopropyl, but the activity of their anti-gram positive organisms is far from each other.Wherein, the anti-microbial activity of PD 127391, Sitafloxacin, SB 265805, Moxifloxacin and Jia Nuosha star obviously is better than other quinolones.This shows the result that the anti-gram positive organism activity of quinolones is substituting group comprehensive action on each position.

To C-6 bit substituent structure of modification.The anti-microbial activity that fluorine atom can obviously strengthen quinolone is introduced in the C-6 position.Obtained first fluoroquinolone-R-802 through introducing fluorine atom to parent nucleus C-6 position, the success of this research has disclosed the anti-gram positive organism activity that is expected to improve such medicine through the transformation to the basic structure of quinolone first.The introducing of C-6 position fluorine atom has significantly strengthened the quinolone molecule to the restraining effect of dna gyrase and to the perviousness of bacterial cell; Therefore being considered to quinolone, to have an outstanding anti-microbial activity necessary; So, the most basic mother nucleus structure of such drug research during the 6-fluoroquinolone has just become subsequently surplus in the of 20 year.Simultaneously, the 6-that also occurs recent years goes fluoroquinolone to cause people's very big concern.Preliminary study result shows that compare with corresponding fluoroquinolone, 6-goes the genotoxicity level of fluoroquinolone to obtain reduction.It is reported that the outstanding representative-Jia Nuosha star of non-fluoroquinolone all is better than new fluoroquinolone Moxifloxacin to the activity of susceptibility and resistance gram positive organism.According to another report, 6-nitro and 6-aminoquinolone have better activity to GPC.As far as the 6-aminoquinolone, its activity depends on the substituting group on C-7 and the C-8 position to a great extent.The active determination in vitro result shows that similar with fluoroquinolone, methyl or methoxy is introduced in the C-8 position of 6-nitro and 6-aminoquinolone can improve its anti-gram positive organism activity.

C-7 bit substituent structure of modification.The antimicrobial spectrum of C-7 bit substituent and quinolone, bioavailability and untoward reaction etc. are closely related.Cyclammonium base (like piperazinyl and pyrrolidyl) is that modal substituting group is gone up in this position.Non-substituted piperazinyl quinolone (like norfloxicin, enoxacin or CIPROFLOXACIN USP 24) has outstanding activity to gram-negative bacteria; And can improve its oral absorption simultaneously when introducing methyl on the piperazine ring and anti-gram positive organism active, but the active raising of anti-gram positive organism is accompanied by the active reduction of Pseudomonas aeruginosa sometimes.C-7 bit substituent like pefloxacin, fleroxacin, Ofloxacine USP 23 and levofloxacin is a 4-N-METHYL PIPERAZINE base; The C-7 bit substituent of lomefloxacin, grepafloxacin and Gatifloxacin is a 3-N-METHYL PIPERAZINE base; The C-7 bit substituent of Sparfloxacin is 3,5 lupetazin bases.Above-mentioned these 7-N-METHYL PIPERAZINE base quinolones and other 7-piperazinyl quinolones compare gram positive organism and all have higher activity, and be sure of because it has the event of stronger perviousness to bacterial cell.

Another kind of common C-7 bit substituent is the amino-pyrroles alkyl; The introducing of this group often makes quinolone stronger than the anti-gram positive organism activity of corresponding 7-piperazinyl quinolone; And it is active not only can to improve its anti-gram positive organism when on pyrrolidine ring, introducing methyl, and helps to overcome some physical properties of quinolones and the deficiency of pharmacokinetics properties.The C-7 bit substituent of PD 127391 and Tosulfloxacin is 3-amino-pyrroles alkyl, and the C-7 bit substituent of Sitafloxacin is spiral shell-amino-pyrroles alkyl, and the C-7 bit substituent of SB 265805 is 3-aminomethyl-4-methoxy imino-1-pyrrolidyl.Wherein the anti-streptococcus pneumoniae activity of SB 265805 is significantly improved.The C-7 bit substituent of DW286 (23, the SB 265805 analogue) is 3-aminomethyl-3-methyl-4-methoxyimino-1-pyrrolidyl, i.e. methyl of extra introducing in the 3-position of SB 265805 side chain, and its anti-gram positive organism activity is superior to SB 265805.The size of the alcoxyl imido grpup on the pyrrolidine ring of C-7 position and lipotropy have remarkably influenced to the anti-microbial activity and the pharmacokinetics character of fluoroquinolone.Along with the increase of alkyl, anti-gram positive organism activity also strengthens thereupon, but the activity of anti-gram-negative bacteria reduces.After macoradical (like benzyl etc.) substituted the alkyl in the alcoxyl imido grpup, though still can keep anti-microbial activity, its pharmacokinetics character and physics and chemistry flight of steps leading to a palace hall matter were then barely satisfactory.

Pyrrolidine ring thick again with or screw togather a ring and form 7-dicyclo amido fluoroquinolone, these Wyovins all can be regarded the verivate of tetramethyleneimine as.Wherein, The C-7 position side chain of Moxifloxacin is the diazabicyclo structure; The side chain of trovafloxacin and CFC-222 (24) is the azabicyclo structure that is connected with an amino, and the side chain of Sitafloxacin is the twin nuclei that screws togather a cyclopropyl in the 4-position of 3-amino-pyrrolidine.The C-7 position side chain that adds new fluoroquinolone such as PD 127391, Tosulfloxacin and SB 265805 in addition all contains a tetramethyleneimine skeleton, and they generally have very outstanding anti-microbial effect to gram positive organism.

Go in the fluoroquinolone at 6-; The C-7 position side chain of PGE 9262932 (25) and PGE 4175997 (26) is 3-aminoalkyl-1-pyrroles's cyclic group; The two is similar with trovafloxacin; All have broad spectrum antibiotic activity, its anti-gram positive organism activity is stronger than trovafloxacin, but to the activity of enterobacteriaceae a little less than trovafloxacin.The Jia Nuosha star is different with the structure of FQNS and above-mentioned 2 non-fluoroquinolones; Its C-7 position side chain is not that cyclammonium base but one are contained the pulsating 5-isoindoline of aromatic structure base; This compound is keeping gram-negative bacteria on the outstanding active basis; To a lot of gram positive organisms, especially streptococcus pneumoniae had very outstanding anti-microbial activity.

From the composition optimizes angle analysis, the 7-cyclammonium base of quinolone has very big modification space, and the position that allows in the quinolone molecule to connect macoradical also has only the C-7 position.For example, the 4-position N of 7-piperazine ring goes up the quinolone series that connects macoradical and has potential anti-microbial activity (particularly to gram positive organism), and some compound wherein is better than its parent compound 7-piperazinyl quinolone to staphylococcic activity.Think that in view of the above the macoradical that the C-7 position connects does not hinder the infiltration of quinolone molecule to bacterial cell.As everyone knows; The character of C-7 bit substituent is to influence the bioactive important factor of quinolone, this type N-substituted piperazinyl quinolone to the activity of gram positive organism why make moderate progress possibly be quinolone molecule with this structure in gram positive organism, accumulate more easily so.

To C-8 bit substituent structure of modification.It is active that the naphthyridines ketone (like Tosulfloxacin, SB 265805 and trovafloxacin) that the quinolone (like CIPROFLOXACIN USP 24 and grepafloxacin) of many C-8 position unsubstituted and C-8 position are nitrogen-atoms has good anti-gram positive organism.The C-8 bit substituent has certain influence to the oral pharmacokinetics character that changes quinolone, the aspects such as selectivity that enlarge antimicrobial spectrum and reduction medicament-resistant mutation.Halogen atom is introduced in the C-8 position, methyl or methoxy can improve quinolones to the GPC external activity of (even comprising early stage fluoroquinolone persister), simultaneously anerobes is also demonstrated good antibacterial activity.Early stage research shows; Fluoro (like lomefloxacin and Sparfloxacin) and chloro (like PD 127391 and Sitafloxacin) are the best C-8 bit substituents that improves the quinolones anti-microbial activity; But also there are phototoxicity and some unacceptable untoward reaction simultaneously, so present people have abandoned the halogenated new drug layout strategy of 8-.Subsequently, not only strengthened activity, made phototoxicity and cytotoxicity reduce to bottom line again gram positive organism and anerobes through a large amount of 8-BAY 128039s of researching and developing out (Gatifloxacin and Moxifloxacin).

In recent years, the Novel Quinolone of succeeding in developing successively constantly improves to the activity of gram positive organism, and this might make the dream of " chemical sproof development is led in the exploitation of new drug " come true in the near future.Structure activity study shows; Through structure of modification to quinolone; C-6 particularly, the modification of C-7 and C-8 bit substituent can increase medicine action target spot number on the type in bacterial cell; Weaken the effect of efflux protein (efflux pump) simultaneously, thereby reduce the frequency of occurrences of quinolone resistance gram-positive bacterial strain.

Though the Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly; In the hope of passing through to N-1 on the parent nucleus; C-5, C-6, the structure of modification of C-7 and C-8 bit substituent and ingenious collocation; Thereby obtain the active quinolone antibiotic that obviously improves, to improve the activity of its anti-gram positive organism to gram positive organism.But at the quinolone parent nucleus hThe limit (or gThe limit) or be equivalent to the thick carbostyril compound in its position and do not see any research and report as yet with 5-, 6-, 7-, 8-, 9-or 10-unit ring.

Therefore, under these backgrounds, based on above prior art, investigator of the present invention has carried out extensive studies, through at the quinolone parent nucleus hThe limit (or gThe limit) or be equivalent to its position thick with 5-, 6-, 7-, 8-, 9-or 10-unit ring; And measure the pharmacologically active of formed compound; Come the carbostyril compound of Development of New Generation; They comprise that to the wide spectrum pathogenic bacterium endurance strain demonstrates the intensive anti-microbial activity, also have further improved pharmacokinetics performance.As a result, our early start works out and has found at the quinolone parent nucleus hThe limit (or gThe limit) or be equivalent to the compound or its salt or the solvolyte of the thick general formula (I) with 5-, 6-, 7-, 8-, 9-or 10-unit ring in its position, they demonstrate the intensive anti-microbial activity, and it is a compound as safe as a house, and have accomplished the present invention thus.

Summary of the invention

Infection is second the disease killer who threatens human health.Resistance still constantly occurs, and in hospital and community, increases, and has reduced patient's treatment and has selected, and has increased hospital stays and medical expense.As a result, need to substitute and improve antibacterials and treat the resistance pathogenic bacteria.

QNS is the synthetic drugs of one type of wide spectrum, efficient, low toxicity.Early stage QNS has stronger anti-microbial activity to Gram-negative bacteria, but lower to gram-positive bacteria activity.Though the QNS such as the Gatifloxacin (Drug that go on the market recently; 683) and Moxifloxacin (external medicine-microbiotic fascicle, 2,002 1999,58 (4):; 23 (6): anti-microbial activity 274) makes moderate progress; The activity of resisting gram-positive bacteria remains further to be strengthened, and need strengthen the anti-microbial activity to some specific bacteria such as streptococcus pneumoniae, faecalis etc. simultaneously but in general.Therefore, the higher medicine of validity appears in expectation clinically.In addition, known owing to take spinoffs such as the spinoff of bringing out spasm or phototoxicity with non-steroidal anti-inflammatory drugs, also need develop the higher quinolones synthetic antibacterial agents of security.

Have now found that some substituted Carbostyril derivative is used as antimicrobial compounds, particularly resisting gram-positive and negative bacterium with its pharmaceutically acceptable salt and ester.

The present invention provides the compound of formula I, or its pharmaceutically acceptable salt or ester or solvolyte

（Ⅰ）

Wherein:

R ¹Be any substituted alkyl, thiazolinyl, naphthenic base, alkoxyl group, amino, alkylamine, dialkylamine, aryl or aralkyl;

R ², R ³And R ⁴Each independently is Q-R ⁷

Q is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R ⁷Be Wasserstoffatoms or NR ⁸R ⁹, or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R ⁸And R ⁹Each independently is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R ⁸And R ⁹Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ⁵Be halogen atom, hydroxyl or any substituted alkoxyl group;

R ¹⁰Be Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R ²And R ³Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ³And R ⁴Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ⁴And R ⁵Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ⁶Be Wasserstoffatoms or any substituted alkyl;

Each independently is nitrogen-atoms or carbon atom for A and B, and condition is when A is N, no R ¹⁰When B is N, no R ⁵

N is 1,2 or 3; M is 0,1 or 2;

X is C, N, O or S.

As above defined, have excellent anti-microbial activity, wide antimicrobial spectrum and superior pharmacokinetics performance, in the formula I compound, alkyl or alkenyl, except as otherwise noted; It can be linear or side chain; Can comprise to 12, preferably to 6, especially to 4 carbon atoms.Preferred alkyl is methyl, ethyl, propyl group and butyl, particularly methyl and ethyl.Preferred thiazolinyl comprises vinyl, propenyl and crotonyl.When alkyl is the part (like the moieties of aralkyl) of other group, preferably contain to 6, particularly to 4 carbon atoms.Preferred moieties is methyl and ethyl.

Aryl can be the hydrocarbon group of fragrance arbitrarily and comprise 6-24, preferred 6-18, more preferably 6-16, particularly 6-14, an especially 6-10 carbon atom.Preferred aryl groups comprises phenyl, naphthyl, anthryl, phenanthryl, pyrans, particularly phenyl or naphthyl, especially phenyl.When aryl is the part (like the aryl moiety of aralkyl) of other group, preferred phenyl, naphthyl, phenanthryl or pyrans, particularly phenyl or naphthyl, especially phenyl.

Aralkyl can be arbitrarily by the substituted alkyl of aryl.Aralkyl contains preferred 7-30, more preferably 7-24, particularly 7-18, an especially 7-11 carbon atom, and preferred especially aralkyl is a phenmethyl, menaphthyl, anthracene methyl, luxuriant and rich with fragrance methyl and pyrans methyl.Especially preferred aralkyl is a phenmethyl.

Naphthenic base can be any saturated ring-type hydrocarbon group, contains 3-12, preferred 3-8, a particularly 3-6 carbon atom.Preferred naphthenic base is cyclopropyl, cyclopentyl and cyclohexyl, particularly cyclopropyl.

Heteroaryl can be the monocycle or the polycyclic system of fragrance arbitrarily, contains at least one heteroatoms.Preferably, heteroaryl is 5-to a 18-unit, and particularly the first aromatic nucleus system of 5-to 14-unit, especially 5-to 10-contains at least one heteroatoms, is selected from oxygen, sulphur and nitrogen-atoms.Preferred heteroaryl comprises pyridyl, pyranyl, mercapto pyranyl, pyrryl, furyl, thienyl, indyl, pseudoindoyl, pyrrocoline base, imidazolyl, pyriconyl, pyrans ketone group, pyrimidyl, pyrazinyl, oxazolyl, thiazolyl, purine radicals, quinolyl, isoquinolyl, quinoxalinyl, pyridazinyl, benzofuryl, benzoxazolyl and acridyl.Preferred heteroaryl comprises pyridyl, thienyl and furyl, especially 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl and 2-furyl.

Heterocyclic radical can be monocycle or polycyclic system arbitrarily, contains at least one heteroatoms, can be unsaturated or fractional saturation or saturated fully.The term here " heterocycle " comprises above-mentioned heteroaryl and nonaromatic heterocycles base.Preferred heterocyclic radical is 3-to a 18-unit, and more preferably 3-to 14-unit, particularly 3-to 10-unit are more especially 3-to 6-unit, and especially 5-to 6-unit member ring systems contains at least one heteroatoms, is selected from oxygen, sulphur and nitrogen-atoms.Preferred heterocyclic group comprises the heteroaryl of above-mentioned name, and pyranyl, piperidyl, pyrrolidyl, indolinyl, iso-dihydro-indole-group 、 alkyl dioxin, piperazinyl, morpholinyl, mercapto are for morpholinyl, morpholine sulfonic group, tetrahydro isoquinolyl and tetrahydrofuran base.

Heterocyclylalkyl can be arbitrarily by the substituted alkyl of heterocyclic radical.Preferred heterocyclic moiety is 3-to a 18-unit, more preferably 3-to 14-unit, particularly 3-to 10-unit, the especially above-mentioned heterocyclic radical of 5-to 10-unit; Moieties is C _1-6Alkyl, preferred C _1-4Alkyl, especially methyl.

Replaced at random when aforementioned substituting group is designated as, the substituting group that occurs at random can be arbitrary or a plurality of normally used substituting group in medicament research and development and/or for a change active, stability, bioavailability or other characteristic and in the modified compound structure.These substituting groups comprise halogen atom, nitro, cyanic acid, hydroxyl, naphthenic base, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino radical, di alkylamino group, formyl radical, carbalkoxy, carboxyl, aldehyde radical, alkane sulfydryl, alkyl sulphinyl, alkyl sulphonyl, alkyl azochlorosulfonate, carbamyl, alkylamino radical, aryl and aralkyl.

When the representative of aforesaid substituting group at random or comprise an alkyl substituent, this alkyl substituent can be line style or branched chain type and contain 12, preferred 6, and 4 carbon atoms most preferably.Naphthenic base can comprise 3-8, preferred 3-6 carbon atom.Aryl or aryl moiety can contain 6-10 carbon atom, preferred phenyl.Halogen atom can be fluorine, chlorine, bromine or iodine atom and any group that comprises halogen atom, like alkylhalide group, can comprise arbitrary or a plurality of halogen atom.

Preferably substituting group comprises halogen atom, nitro, cyanic acid, hydroxyl, C at random _1-6Alkyl, C _1-6Haloalkyl, C _1-6Alkoxyl group, C _1-6Halogenated alkoxy, amino, C _1-6Alkylamino radical, two (C _1-6Alkyl) amido, formyl radical, C _1-6Carbalkoxy, carboxyl, C _1-6Aldehyde radical, C _1-6Alkane sulfydryl, C _1-6Alkyl sulphinyl, C _1-6Alkyl sulphonyl, carbamyl, C _1-6Alkylamino radical.Preferred substituting group at random comprises halogen atom, nitro, cyanic acid, hydroxyl, C _1-4Alkyl, C _1-4Haloalkyl, C _1-4Alkoxyl group, C _1-4Halogenated alkoxy.Halogen atom most preferably.

Formula I compound of the present invention can form pharmacy acceptable salt or ester or solvolyte; These salt comprise the salt with inorganic salt example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc.; Salt with organic carboxyl acid such as acetate, trifluoroacetic acid, lemon calculation, toxilic acid, oxalic acid, amber calculation, phenylformic acid, tartrate, fumaric acid, racemic melic acid, xitix or oxysuccinic acid; Or with the salt of sulfonic acid such as methylsulfonic acid, tosic acid etc., and with common known and conventional other sour salt that are used for the carbostyril compound technical field.Can be by these acid salt of conventional conversion processes.

Second aspect the invention still further relates to the preparation method of formula I compound.

Formula (I) compound is according to preparation shown in following reaction scheme 1 or the reaction scheme 2.

Reaction scheme 1

Reaction scheme 2

Wherein: R ¹, R ², R ³, R ⁴, R ⁵, A, B, n, m, X as above define respectively.

Shown in reaction scheme 1, the method that is used for preparing formula (I) compound comprises the following steps:

1) formula II compound and EMME carry out condensation, obtain formula (II-a) compound, wherein R ¹¹Represent methylidene or ethyl;

2) formula (II-a) compound and Y-R ¹Condensation under alkaline condition, obtain formula (compound of II-b), wherein Y is a halogen atom, is preferably bromine atoms or iodine atom;

3) formula (compound of II-b) under alkaline condition through hydrolysis or HOR ⁵Alcoholysis obtains formula (I) compound.

Shown in reaction scheme 2, the method that is used for preparing formula (I) compound comprises the following steps:

1) reaction of formula III compound and barkite obtains formula (III-a) compound, wherein R ¹²Represent methylidene or ethyl;

2) formula (compound of III-a) successively with ortho-formiate and NH ₂R ¹Reaction obtains the formula (compound of III-b);

3) (ring obtains the formula (compound of III-c) to the compound of III-b) in alkaline condition ShiShimonoseki with formula;

4) with formula (III-c) compound hydrolysis or HOR ⁵Alcoholysis obtains formula (I) compound.

In following preparation example, will more specifically explain above-mentioned compound method.

The third aspect, the present invention also provides and contains as above defined formula (I) compound or its pharmaceutically acceptable salt or solvolyte as activeconstituents, and the antimicrobial cpd of pharmaceutically acceptable carrier.When this combination is used for clinical purpose, but through type (I) compound or its pharmaceutically acceptable salt or solvolyte combine with pharmaceutically acceptable carrier it is made into solid, semisolid or the liquid pharmaceutical formulation that oral, non-stomach and intestine use or use the part.

 

Embodiment

Synthetic

The invention compound comprises its salt, hydrate and solvate, can use known method or with process preparation like the known class, as use following reaction scheme.The professional and technical personnel will find to change or revise inessential parameter to reach equifinality.

 

For example

Following example only is used to explain the present invention, is not used in qualification the present invention.

Embodiment 1 1-cyclopropyl-10-fluoro-4-oxo-1,4,6,7,8, the 9-hexahydropyridine is the preparation of [3,4-g] quinoline-3-carboxylic acid also

(a) 6-fluoro-7-chloro-8-nitro-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid.

With 56.0g 6-fluoro-7-chloro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (preparation method is with reference to European Journal of Organic Chemistry, 2006,4398) is dissolved in the 300ml Glacial acetic acid min. 99.5, stirs.0～5 ℃ of glacial acetic acid solution 200ml that slowly drips the nitric acid (d=1.52) of 42.0ml down.0～10 ℃ of following insulated and stirred of reaction solution 2 hours.Reaction finishes, and low temperature adds the 600ml frozen water down, separates out a large amount of solid products, filters.Filter cake water and normal heptane washed twice, drying obtained 50.0g6-fluoro-7-chloro-8-nitro-1, the bullion of 4-dihydro-4-Oxoquinoline-3-carboxylic acid in 8 hours under the vacuum.Need not to make with extra care, directly being used for down, the step feeds intake.

(b) 6-fluoro-7-ethyloic-8-nitro-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid

3.1g is suspended in the 100ml anhydrous tetrahydrofuran solution with sodium hydride solid (containing MO), slowly drips the anhydrous tetrahydrofuran solution 100ml of 18.7g oxalic acid diethyl ester.20～25 ℃ were stirred 2 hours down.Drip 45.0g 6-fluoro-7-chloro-8-nitro-1 under the room temperature, the tetrahydrofuran solution 150ml of 4-dihydro-4-Oxoquinoline-3-carboxylic acid.Insulated and stirred 12 hours is poured reaction solution in the frozen water into, divides the phase of anhydrating.Organic phase is used anhydrous sodium sulfate drying, concentrates to obtain brown oil.Adding 250ml mass concentration is 4.0% sodium hydroxide solution under the room temperature, slowly is warming up to 60～70 ℃, insulated and stirred 2 hours.Reduce to 20～25 ℃, regulate pH with 1N hydrochloric acid and be about 2, separate out a large amount of yellow solids.Filter, drying promptly gets xanchromatic 6-fluoro-7-ethyloic-8-nitro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid bullion 32.2g.Purity >=87.0%.

(c) 6-cyanic acid-7-ethyloic-8-nitro-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid

In reactor drum, add 31.0g 6-fluoro-7-ethyloic-8-nitro-1 successively; 4-dihydro-4-Oxoquinoline-3-carboxylic acid; 9.5g cuprous cyanide (must not be excessive), the absolute anhydrous N of 25ml, dinethylformamide; The nitrogen gas stream protection slowly is warming up to 125～135 ℃ down, insulated and stirred 3 hours (must be noted that the prussic acid murder by poisoning during operation).Reaction solution cooling cooling adds 300ml methylene dichloride and 300ml water successively.Slight emulsification is arranged, behind the filtration breakdown of emulsion, standing demix.The organic phase washing concentrates.Obtain the semi-solid state product with methylene dichloride and normal heptane crystallization.Obtain faint yellow solid product 6-cyanic acid-7-ethyloic-8-nitro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid elaboration, purity >=94.5%.

(d) 1-cyclopropyl-10-amino-4-oxo-1,4,6,7,8, the 9-hexahydropyridine is the preparation of [3,4-g] quinoline-3-carboxylic acid dihydrochloride also.

With 25.0g6-cyanic acid-7-ethyloic-8-nitro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid is dissolved in the mixed solution of 250ml methyl alcohol and 20.3ml concentrated hydrochloric acid in the hydrogenation still, and protection of inert gas adds the platinum oxide of 0.5g 10% down.Inject hydrogen, room temperature reaction is 3 hours under the 45psi pressure condition.Decompression is steamed down and is removed methyl alcohol, obtains 6-aminomethyl-7-acyl methyl-8-amino-1, the bullion of 4-dihydro-4-Oxoquinoline-3-carboxylic acid dihydrochloride; Add the 300ml purified water, slowly be warming up to 75～85 ℃, insulation reaction 4 hours; Filtered while hot, filtrating cooling back adds dichloromethane extraction (300ml * 2), and organic phase is dry; Concentrate, obtain brown oil.Directly being used for down, the step feeds intake.

(e) 1-cyclopropyl-10-fluoro-4-oxo-1,4,6,7,8, the 9-hexahydropyridine is the preparation of [3,4-g] quinoline-3-carboxylic acid also

In the reactor drum that gathers the tetrafluoro material, add 1-cyclopropyl-10-amino-4-oxo-1,4,6; 7,8, the 9-hexahydropyridine is [3,4-g] quinoline-3-carboxylic acid dihydrochloride 15.0g also; Add 80ml HF/ pyridine (70%) solution below 0 ℃, leave standstill under the reaction solution room temperature to raw material and all dissolve, be cooled to-78 ℃, add the 3.04g Sodium Nitrite; Stir down and slowly be warming up to 0 ℃, insulated and stirred 30 minutes slowly is warming up to 60 ℃ then, insulated and stirred 30 minutes.Cooling back with frozen water with above-mentioned reaction solution cancellation.Add an amount of cold saturated solution of sodium bicarbonate, reaction solution is with dichloromethane extraction (200ml * 3), and organic phase is used anhydrous sodium sulfate drying; Steaming desolventizes; Resistates uses column chromatography (eluent is methylene dichloride and methyl alcohol), obtains the faint yellow solid product, purity >=98.0%.Total recovery is 11.7%.EI-Ms(M+1)=303.2。 ¹H-NMR(400MHz,DMSO)：1.19(2H),1.35(2H),2.03(1H),2.94(2H),3.48(2H),3.76(2H),4.23(1H),7.69(1H),8.90(1H),11.05(1H)。Ultimate analysis: C, 63.54; H, 5.02; N, 9.30 results and C ₁₆H ₁₅FN ₂O ₃Theoretical value is consistent.

 

Embodiment 2 11-fluoro-10-cyclopropyl-7-oxos-2,3,4,5,7,10-six hydrogen-[1,4] oxa-azatropylidene is the preparation of [6,7-g] quinoline-8-carboxylic acid also

(a) 1-cyclopropyl-8-fluoro-7-bromine oxethyl-4-oxo-1, the preparation of 4-EEDQ-3-carboxylic acid, ethyl ester

8.4g sodium hydride (60% MO) is suspended in the 150ml anhydrous tetrahydrofuran solution, slowly drips the tetrahydrofuran solution 50ml of 24.9g ethylene bromohyrin under the room temperature, stir after 2 hours; Drip 62.0g1-cyclopropyl-8-fluoro-7-chloro-4-oxo-1, the tetrahydrofuran solution 100ml of 4-EEDQ-3-carboxylic acid, ethyl ester, 30～35 ℃ of following stirring reactions of reaction solution 12 hours under the room temperature; Reaction finishes, and reaction solution concentrates, and adds 300ml methylene dichloride and 150ml water; Separatory; Organic phase is used anhydrous sodium sulfate drying, concentrates and obtains red oil 55.8g, directly is used for step reaction down.

(b) 11-fluoro-10-cyclopropyl-7-oxo-2,3,4,5,7,10-six hydrogen-[1,4] oxa-azatropylidene is the preparation of [6,7-g] quinoline-8-carboxylic acid, ethyl ester hydrochloride also

The oily matter that obtains in (a) is dissolved in the absolute ethyl alcohol that the 250ml massfraction is 15%～20% ammonia, and 0-10 ℃ was stirred 10 hours down, and reaction is finished; 35～40 ℃ of following concentrating under reduced pressure of reaction solution; Resistates cooling back adds the 250ml purified water, and an amount of Hydrogen chloride adds the 12.0g Paraformaldehyde 96 then; Slowly be warming up to 70～80 ℃, insulation reaction 2 hours.Reacting liquor while hot is filtered, and filtrating is put cold, adds the 450ml methylene dichloride, regulates the pH value with strong aqua under the room temperature and is about 8, and separatory, water have the 400ml methylene dichloride to extract once again, merge organic phase, use anhydrous sodium sulfate drying, concentrate, and obtain brown semi-solid state product.

(c) 11-fluoro-10-cyclopropyl-7-oxo-2,3,4,5,7,10-six hydrogen-[1,4] oxa-azatropylidene is the preparation of [6,7-g] quinoline-8-carboxylic acid also

The semi-solid state product that obtains in (b) is dissolved in 240ml ethanol, 0～5 ℃ of sodium hydroxide solution that drips 80.0ml2% down, insulated and stirred 3 hours rose to stirring at room 1 hour then; Under the reaction solution reduced pressure ethanol steamed and remove, the cooling back adds the 260ml methylene dichloride, and with an amount of 1N salt acid for adjusting pH value to 6.6～7.2, organic phase is with activated carbon decolorizing 2 times; Anhydrous sodium sulfate drying concentrates about 1/3rd volumes, adds normal heptane 320ml; Stirred 8 hours, and separated out a large amount of faint yellow solids, filter; Filter cake washs with normal heptane, obtains the faint yellow solid product, purity >=96.0%.Total recovery is 8.3%.EI-Ms(M+1)=319.2。 ¹H-NMR(400MHz,DMSO)：1.17(2H),1.25,(2H),2.32(1H),2.90(2H),3.76(2H),4.26(2H),4.33(1H),7.12(1H),8.81(1H),11.12(1H)。Ultimate analysis: C, 60.41; H, 4.76; N, 8.82 results and C ₁₆H ₁₅FN ₂O ₄Theoretical value is consistent.

Embodiment 3 13-fluoro-1-cyclopropyl-4-oxos-1,4, the also preparation of [6,7-g] quinoline-3-carboxylic acid of 6,7 – tetrahydrochysene-benzo [1,4] oxa-azatropylidenes

(a) 7-(2-amino-benzene oxygen)-1-cyclopropyl-8-fluoro-4-oxo-1, the preparation of 4-EEDQ-3-carboxylic acid, ethyl ester

4.1g sodium hydride (60% MO) is suspended in the 150ml anhydrous tetrahydrofuran solution, drips the tetrahydrofuran solution 150ml of 41.8g 2-t-butoxycarbonyl amino phenol under the room temperature, insulated and stirred 3 hours; Slowly drip 62.0g 1-cyclopropyl-8-fluoro-7-chloro-4-oxo-1, the tetrahydrofuran solution 100ml of 4-EEDQ-3-carboxylic acid, ethyl ester, 30～35 ℃ of following stirring reactions of reaction solution 8 hours; Reaction finishes, and reaction solution concentrates, and adds 300ml methylene dichloride and 150ml water; Separatory; Organic phase is used anhydrous sodium sulfate drying, concentrates and obtains red oil 65.8g, directly is used for step reaction down.

(b) 13-fluoro-1-cyclopropyl-4-oxo-1,4, the also preparation of [6,7-g] quinoline-3-carboxylic acid ethyl ester of 6,7 – tetrahydrochysene-benzo [1,4] oxa-azatropylidenes

The oily matter that obtains in (a) is dissolved in the 250ml absolute ethyl alcohol, an amount of Hydrogen chloride, the 12.0g Paraformaldehyde 96 slowly is warming up to 70～80 ℃, insulation reaction 5 hours.Reacting liquor while hot is filtered, and filtrating is put cold, adds the 450ml methylene dichloride, regulates the pH value with ammoniacal liquor under the room temperature and is about 8, and separatory, water have the 400ml methylene dichloride to extract once again, merge organic phase, use anhydrous sodium sulfate drying, concentrate, and obtain reddish-brown semi-solid state product.Directly be used for step reaction down.

(c) 13-fluoro-1-cyclopropyl-4-oxo-1,4, the also preparation of [6,7-g] quinoline-3-carboxylic acid of 6,7 – tetrahydrochysene-benzo [1,4] oxa-azatropylidenes

The semi-solid state product that obtains in (b) is dissolved in 250ml ethanol, 0～5 ℃ of sodium hydroxide solution that drips 80.0ml2% down, insulated and stirred 3 hours rose to stirring at room 1 hour then; Under the reaction solution reduced pressure ethanol steaming is removed, the cooling back adds the 260ml methylene dichloride, with an amount of 1N salt acid for adjusting pH value to 6.6～7.2; Organic phase is with activated carbon decolorizing 1 time, and anhydrous sodium sulfate drying concentrates about 1/3rd volumes; Add normal heptane 320ml, stirred 8 hours, separate out a large amount of faint yellow solids; Filter, filter cake washs with normal heptane, obtains the off-white color solid product.Purity >=97.4%, total recovery are 13.2%.EI-Ms(M+1)=367.4。 ¹H-NMR(400MHz,DMSO)：1.31-1.39,(4H),4.02(1H),4.17(1H),4.36(2H),6.73(1H),6.92-6.99(2H),7.22?(1H),7.26(1H),8.62(1H),?11.42(1H)。Ultimate analysis: C, 65.60; H, 4.153; N, 7.64 results and C ₂₀H ₁₅FN ₂O ₄Theoretical value is consistent.

The also also preparation of [6,7-g] quinoline-3-carboxylic acid of [1,2-a]-[1,4] oxa-azatropylidene of embodiment 4 14-fluoro-1-cyclopropyl-4-oxo-10H-1,4,6,8,9,11,12-seven hydrogen piperazines

(a) 1-cyclopropyl-8-fluoro-7-(3, the 4-dibromo propoxy)-4-oxo-1, the preparation of 4-EEDQ-3-carboxylic acid, ethyl ester

8.4g sodium hydride (60% MO) is suspended in the 150ml anhydrous tetrahydrofuran solution, slowly drips 43.6g 3, the tetrahydrofuran solution 60ml of 4-dibromo-propanol under the room temperature; Stir after 4 hours, drip 62.0g1-cyclopropyl-8-fluoro-7-(3, the 4-dibromo propoxy)-4-oxo-1 under the room temperature; The tetrahydrofuran solution 100ml of 4-EEDQ-3-carboxylic acid, ethyl ester, 30～35 ℃ of following stirring reactions of reaction solution 8 hours, reaction finishes; Reaction solution concentrates, and adds 300ml methylene dichloride and 150ml water, separatory; Organic phase is used anhydrous sodium sulfate drying, concentrates and obtains red oil 55.8g, directly is used for step reaction down.

(b) 1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group)-4-oxo-1, the preparation of 4-EEDQ-3-carboxylic acid, ethyl ester dihydrochloride

In reactor drum, add the oily product that (a) obtains, 12.0g quadrol, 550ml anhydrous ethyl acetate successively; 60.g be warming up to backflow under the anhydrous sodium bicarbonate, nitrogen protection, insulation reaction 48 hours; Reaction solution is put cold, filters, and filter cake washs with the 50ml anhydrous ethyl acetate.Merge organic phase, with saturated common salt water washing (150ml * 2), organic phase adds the 45ml purified water, fully stirs down, and controlled temperature drips concentrated hydrochloric acid down at 5～10 ℃, regulates the pH value and is about 3, separates out a large amount of white solids.Filter, filter cake washs with ETHYLE ACETATE, and oven dry obtains 1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group)-4-oxo-1,4-EEDQ-3-carboxylic acid, ethyl ester dihydrochloride 41.9g.Purity >=91.0%

(c) the also also preparation of [6,7-g] quinoline-3-carboxylic acid ethyl ester of [1,2-a]-[1,4] oxa-azatropylidene of 14-fluoro-1-cyclopropyl-4-oxo-10H-1,4,6,8,9,11,12-seven hydrogen piperazines

With 36.0g1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group)-4-oxo-1,4-EEDQ-3-carboxylic acid, ethyl ester dihydrochloride, the 10.2g Paraformaldehyde 96, the 450ml absolute ethyl alcohol adds in the reactor drum, slowly is warming up to backflow, and reaction solution becomes clarification gradually.Insulation reaction 3 hours, filtered while hot, the reaction solution concentrating under reduced pressure adds 400ml methylene dichloride and 400ml purified water, and the sodium hydrogen carbonate solution with 10% is adjusted to neutrality under 0～10 ℃, and water with the 400ml dichloromethane extraction once merges organic phase.Concentrate after adding activated carbon decolorizing, obtain oily product 34.4g.Directly be used for step reaction down.

(d) the also also preparation of [6,7-g] quinoline-3-carboxylic acid of [1,2-a]-[1,4] oxa-azatropylidene of 14-fluoro-1-cyclopropyl-4-oxo-10H-1,4,6,8,9,11,12-seven hydrogen piperazines

The oily matter that obtains in (c) is dissolved in 250ml ethanol, 0～5 ℃ of sodium hydroxide solution that drips 80.0ml2% down, insulated and stirred 3 hours rose to stirring at room 1 hour then; Under the reaction solution reduced pressure ethanol steaming is removed, the cooling back adds the 260ml methylene dichloride, with an amount of 1N salt acid for adjusting pH value to 6.5～7.0; Organic phase is with activated carbon decolorizing 1 time, and anhydrous sodium sulfate drying concentrates about 1/3rd volumes; Add normal heptane 320ml, stirred 8 hours, separate out a large amount of faint yellow solids; Filter, filter cake washs with normal heptane, obtains the off-white color solid product.Purity >=98.4%, total recovery are 9.7%.EI-Ms(M+1)=374.1。 ¹H-NMR(400MHz,DMSO)：1.33-1.36,(4H),1.91(1H?),2.67-2.73(4H),2.78(2H),3.36(1H),3.67(2H),4.12(1H),4.46(2H),7.04(1H),8.60(1H)，11.21(1H)。Ultimate analysis: C, 61.11; H, 5.43; N, 11.26 and C ₁₉H ₂₀FN ₃O ₄Theoretical value is consistent.

Biological assay

The antibacterial activity in vitro test

The agar dilution of use standard is measured the ability of formula (I) formula (II) and its pharmaceutically acceptable salt, solvate and verivate resisting gram-positive and negative Pseudomonas.

Minimal inhibitory concentration is measured as follows: the agar plate that a series of pastille concentration gradients of (1) preparation are successively decreased.(2) after the bacteria suspension dilution with 0.5 Maxwell standard opacity tube, draw the bacterium liquid for preparing with the multiple spot inoculator and be inoculated in agar plate surface, each bacterial plaque Chinese bacterium number is about 104CFU.Inoculation is that the no medicine contrast of inoculation earlier is dull and stereotyped in proper order, and is then dull and stereotyped to high drug level from low drug level.(3) after agar plate has been inoculated bacterium liquid, agar plate is inverted into 35 ℃ ± 2 ℃ incubators hatches 24h, observed and recorded MIC result.

MIC is interpretation standard as a result: according to the CLSI/NCCLS standard, be judged to be the minimum inhibitory concentration (MIC) of this medicine to this strain bacterium with the minimum concentration of asepsis growth plate.Experiment is the Quality Control bacterial strain with escherichia coli ATCC25922, streptococcus aureus ATCC29213, hemophilus influenzae ATCC49247, and all experiment all judges whether to meet the CLSI/NCCLS quality control standard with the MIC of Quality Control bacterial strain.

Test compound of the present invention is selected in the test medication for use, and numbering is like table 2; The contrast medicine CIPROFLOXACIN USP 24 of selecting for use in the test (CPFX), levofloxacin (LVFX), Moxifloxacin (MFLX) are fastened city's sales item.

Following table is listed the MICs (μ g/mL) of part of compounds of the present invention and contrast medicine:

?	CPFX	LVFX	MFLX	No.A1	No.A2	No.A3	No.A4
								MSSA	2	1	0.0626	0.0626	0.1252	0.5	1
Methicillin-resistant staphylococcus aureus	8	2	0.5	0.2504	0.5	2	4
								Staphylococcus epidermidis	1	1	0.5	0.5	0.5	2	2
Streptococcus pneumoniae	4	1	0.1252	0.2504	0.2504	2	2
								Faecalis	2	2	0.2504	0.1252	0.2504	2	1
Bacillus coli	0.1252	0.0626	0.1252	0.1252	0.0626	0.2504	0.5
								Klebsiella pneumonia	0.2504	0.2504	0.0626	0.2504	0.1252	0.2504	0.2504
Emplastic serratia	0.0313	0.0313	0.0313	0.0313	0.0626	0.5	0.1252
								Pseudomonas aeruginosa	0.2504	0.5	0.5	0.5	0.5	1	1
Hemophilus influenzae	0.1252	0.1252	≤0.0313	0.0626	0.1252	0.1252	0.2504
								Proteus vulgaris	≤0.0313	0.0626	0.0626	0.0626	0.1252	0.2504	0.5
Bacteroide fragilis	2	1	0.5	0.5	0.5	1	0.5
								Legionella pneumophilia	0.1252	0.0626	≤0.0313	0.0626	≤0.0313	0.2504	0.5
Mycoplasma pneumoniae	0.5	0.5	0.0626	≤0.0313	0.0626	0.5	0.5
								CPN	1	1	0.1252	0.1252	0.0626	1	1
Tubercule bacillus	2	1	0.1252	0.0626	0.1252	1	2

Claims (15)

1. the compound of following formula (I) representative, or its salt, ester or solvolyte,

（ Ⅰ）

Wherein

A and B respectively represent independently nitrogen-atoms or carbon atom, and condition is when A is N, no R ¹⁰When B is N, no R ⁵

R ¹Represent any substituted alkyl, thiazolinyl, naphthenic base, alkoxyl group, amino, alkylamine, dialkylamine, aryl or aralkyl;

R ², R ³And R ⁴Each represents independently Q-R ⁷, wherein Q is Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl, R ⁷Represent Wasserstoffatoms or NR ⁸R ⁹, or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

R ⁸And R ⁹Each represents independently Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl; R ⁸And R ⁹Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ²And R ³Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit; R ³And R ⁴Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit; R ⁴And R ⁵Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit;

R ⁵Represent halogen atom, hydroxyl or any substituted alkoxyl group;

R ⁶Represent Wasserstoffatoms or any substituted alkyl;

R ¹⁰Represent Wasserstoffatoms or any substituted alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl;

N is 1,2 or 3; M is 0,1 or 2;

X is C, N, O or S.

2. compound as claimed in claim 1, its salt, ester or solvolyte, wherein A and B respectively represent carbon atom.

3. like each described compound, its salt, ester or solvolyte, wherein R among the claim 1-2 ¹Represent any substituted alkyl, naphthenic base, alkoxyl group, aryl or aralkyl, R ⁵Represent halogen atom, R ⁶Represent Wasserstoffatoms or any substituted alkyl, R ¹⁰Represent Wasserstoffatoms or any substituted alkyl, aryl, aralkyl.

4. like each described compound, its salt, ester or solvolyte, wherein R among the claim 1-3 ¹Be cyclopropyl, R ⁵Be fluorine atom, R ⁶Be Wasserstoffatoms, R ¹⁰Be Wasserstoffatoms, formula ( I)Represented compound is a following formula: compound:

。

5. like each described compound, its salt, ester or solvolyte among the claim 1-4, it is characterized in that, formula ( I)Middle R ², R ³And R ⁴Each represents Q-R ⁷, wherein Q is a Wasserstoffatoms, R ⁷Be Wasserstoffatoms.

6. like each described compound, its salt, ester or solvolyte among the claim 1-4, it is characterized in that, formula ( I)In R ²And R ³Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit.

7. like each described compound, its salt, ester or solvolyte among the claim 1-4, it is characterized in that, formula ( I)Middle R ³And R ⁴Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit.

8. like each described compound, its salt, ester or solvolyte among the claim 1-4, it is characterized in that, formula ( I)Middle R ⁴And R ⁵Together for any substituted thiazolinyl or be arbitrarily made with 3-, 4-, 5-, 6-or the assorted naphthenic ring of 7-unit.

9. compound as claimed in claim 1, its salt, ester or solvolyte, it is the compound shown in the following formula or its salt, its ester or its solvolyte:

。

10. compound as claimed in claim 1, its salt, ester or solvolyte, it is the compound shown in the following formula or its salt, its ester or its solvolyte:

。

11. compound as claimed in claim 1, its salt, ester or solvolyte, it is the compound shown in the following formula or its salt, its ester or its solvolyte:

。

12. compound as claimed in claim 1, its salt, ester or solvolyte, it is the compound shown in the following formula or its salt, its ester or its solvolyte:

。

13. contain the described formula of the claim 1 of medicine effective content ( I)Compound, its salt, ester or solvolyte are as the pharmaceutical composition of activeconstituents or pharmaceutical carrier.

14. the compsn described in claim 13, its Chinese style ( I)Be each described compound, its salt, ester or solvolyte among the claim 9-12.

15. be used to prepare purposes as the medicine of antiseptic-germicide like each described compound among the claim 1-14.