CN102603731B - One class Novel Quinolone derivative - Google Patents

Abstract

The present invention relates to a kind of Carbostyril derivative with superior anti-microbial activity, which show excellent anti-microbial activity, also have very wide antimicrobial spectrum, especially there is very strong resisting gram-positive bacteria active; The invention still further relates to the preparation method of this Carbostyril derivative, with containing this Carbostyril derivative or its salt, ester or the solvate pharmaceutical composition as activeconstituents, and this Carbostyril derivative or its salt, ester or solvate are used as the purposes in antiseptic-germicide medicine in preparation.

Description

One class Novel Quinolone derivative

Technical field

The present invention relates to as the useful quinolones synthetic antibacterial agents of medicine, veterinary drug, aquatic products medication and germ resistance preservatives.That is, the present invention relates to formula quinolone parent nucleus hlimit (or glimit) or be equivalent to thick and 5-, 6-, 7-, 8-, 9-or 10-ring (such as formula (I) Suo Shi) in its position.Different to the active weak known methods for quinolones antibacterial agents of gram positive bacterial strain, which show excellent anti-microbial activity, the pharmacokinetics performance also having very wide antimicrobial spectrum and greatly improve:

（Ⅰ）

Wherein

R1 is the alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkylamine, dialkylamine, the aryl or aralkyl that replace arbitrarily;

R2, R3 and R4 are each is independently Q-R7;

Alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl that Q is hydrogen atom or replaces arbitrarily;

R7 is hydrogen atom or NR8R9, or the alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replace arbitrarily;

Alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl that R8 and R9 is each to be independently hydrogen atom or to replace arbitrarily;

For the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit together with R8 with R9;

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

Alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl that R10 is hydrogen atom or replaces arbitrarily;

For the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit together with R2 with R3;

For the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit together with R3 with R4;

For the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit together with R4 with R5;

The alkyl that R6 is hydrogen atom or replaces arbitrarily;

A and B is each is independently nitrogen-atoms or carbon atom, and condition is when A is N, without R10; When B is N, without 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 preparation method of formula I compound or its salt as defined above, ester or solvate, with containing formula I compound or its salt, ester or the solvate pharmaceutical composition as activeconstituents, and formula I compound or its salt, ester or solvate are used as the purposes in antiseptic-germicide medicine in preparation.

Background technology

Gram positive organism is the Main Pathogenic Bacteria causing various diseases.Along with antibiotics widely using clinically, its resistance constantly increases, and has become at present one of most thorny issue clinically.Compared with gram-negative bacteria, gram positive organism lacks complicated infiltration mechanism and outer row's passage, and thus antimicrobial therapy is usually more effective to its infection.However, along with streptococcus pneumoniae and staphylococcus, especially Methicillin-resistant Staphylococcus aureus (MRSA) is to the continuous increase of beta-lactam and macrolide antibiotics resistance, the treatment of gram positive organism sexuality dye become clinicist often need faced by one of important topic.In addition, although it is still responsive to Penicillin antibiotics at present to make Streptococcus pyogenes, to the general resistance of macrolide antibiotics.Enterococcus spp to the intrinsic resistance of many microbiotic, and has developed into drug resistance of vancomycin at present especially.

Quinolone has become current and has tackled one of the most effective antibacterials of many infectious diseases clinically.How the activity basis to the outstanding activity of gram-negative bacteria being improved anti-gram positive organism (particularly staphylococcus and streptococcus pneumoniae) is being kept to be the Main way of nearly more than ten years quinolone area research.In recent years, 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 mediated quinolone resistance strain be separated to clinically also shows a rising trend.Given this, the research work of developing the quinolones of existing anti-gram positive organism clinical efficacy and the low again novel structure of resistance selectivity extensively launches.

Before more than 40 year, people are surprised to find that at antimalarial drug---in chloroquine (chloroquine) building-up process, isolated a kind of by product has faint activity to some gram-negative bacteria.By the structural modification to this by product, be born in 1962 first Comprecin---Nalidixic Acid (nalidixicacid).These product have certain clinical efficacy to gram-negative cocci urinary tract infections.20 century 70s, W-4565 (oxolinicacid) and pipemidic acid (pipemidicacid), first 7-piperazinyl quinolone) etc. come out one after another.These first-generation quinolones do not have activity to gram positive organism, are only limitted to treatment clinically by the microbial urinary tract infections of most of Grain-negative.

As first C-6 position introduce fluorine atom quinolone---the anti-microbial activity of flumequine (flumequine) significantly improves.This prompting: perhaps can improve the activity of this kind of medicine to gram positive organism to the suitable modification of mother nucleus structure.Early 1980s, Koga etc. are in conjunction with the constitutional features of flumequine and pipemidic acid, and successfully develop the norfloxicin (norfloxacin) with 6-fluoro-7-piperazinyl structure, the appearance of this medicine opens the fluoroquinolone New Times.Between more than ten after this short years, Pefloxacin (pefloxacin, 6), enoxacin (enoxacin, 7), fleroxacin (fleroxacin, 8), Ciprofloxacin (ciprofloxacin, 9), lomefloxacin (1omefloxacin, 10), Ofloxacine USP 23 (ofloxacin, 11) and levofloxacin (1evofloxacin, 12) etc. a large amount of outstanding kind constantly occurs, and all inheriting the constitutional features of the fluoro-7-piperazinyl of 6-, some drugs wherein widely uses so far clinically.The antimicrobial spectrum of these medicines obviously expands, and comprises gram-negative bacteria and gram positive organism, and absorption is in the gastrointestinal tract good, and Plasma Concentration is high, is used to transplantation in treating systemic clinically and infects.It is active that these early stage fluoroquinolones have outstanding anti-gram-negative bacteria, only has medium activity, therefore be not enough to tackle respiratory tract infection to streptococcus pneumoniae; And the bacterial drug resistance constantly occurred therebetween also makes it greatly weaken the activity of S. aureus L-forms.

To gram positive organism, there is certain active early stage fluoroquinolones

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 C-5 position is then one of structure of modification strategy the earliest.This measure makes such antibiotic anti-gram positive organism activity generally be improved, as Sparfloxacin (sparfloxacin, 13).The C-5 bit substituent of grepafloxacin (grepafloxacin, 14) is methyl, and its anti-gram positive organism activity is better than Ciprofloxacin.The activity of said two devices to many gram positive organisms (especially streptococcus pneumoniae) significantly improves, and also has certain improvement to the activity of anerobe simultaneously.Although it is better than Ciprofloxacin to staphylococcic activity, but still not satisfactory; It also only has learning value to the raising of the activity against staphylococci of resistance to quinolones, is also not enough to produce significant clinical meaning.Regrettably, these 2 kinds are all strictly limited because of toxicological concerns soon and use or withdraw from market after listing.After this develop 7-methylpiperazine base-8-BAY 128039---Gatifloxacin (gatifloxacin, 15) improves further to the activity of gram positive organism, simultaneously anti-anaerobic activity also be improved significantly.In recent years, introducing pyrrolidyl in C-7 position makes the activity of such medicine to gram positive organism significantly improve, as Clinafloxacin (clinafloxacin, 16), Tosulfloxacin (tosufloxacin, 17), Sitafloxacin (sitafloxacin, 18) and gemifloxacin (gemifloxacin, 19) fully demonstrated this constitutional features.In addition, dicyclo amido is introduced in C-7 position, as Moxifloxacin (moxifloxacin, 20) and trovafloxacin (trovafloxacin, 21), its anti-gram positive organism activity is significantly improved, lipotropy obviously strengthens, and the transformation period obviously extends.

Being optimized other position substituting groups makes C mono-6 fluorine atoms (this fluorine atom is considered to relevant to genotoxicity) removed on fluoroquinolone parent nucleus become possibility, and the quinolones of new generation that has been born thus, i.e. non-fluoride halide glass class or go fluoroquinolones, its first representative is Jia Nuosha star (garenoxacin, BMS-284756, T-3811ME, 22).One of constructional feature of these product is its C 1 bit substituent is difluoro-methoxy, not methoxyl group, and it is relevant that its bacteriostatic activity and the improvement of fungicidal activity are considered to introducing substituent to this.Jia Nuosha star is effective especially to the gram positive coccus comprising S. aureus L-forms, and be the quinolone antibiotic to methicillin-susceptible and resistance activity against staphylococci the best, its activity is better than Ciprofloxacin, Ofloxacine USP 23, levofloxacin and Moxifloxacin.

Gram positive organism is had to the New fluoroquinolone of outstanding activity

The basic structure of quinolone pharmacophore is Isosorbide-5-Nitrae dihydro-4-oxo pyridine-3-carboxylic acid, the thick and aromatic ring in its C-5, C-6 position.1-position nitrogen-atoms has R ₁, substituting group by anti-microbial activity required, C-3 position carboxyl and C-4 position carbonyl be considered to quinolone molecule and DNA in conjunction with most important, there is not yet these 2 positions so far and connect other feasible substituent reports.Therefore C-3 position carboxyl and C-4 position carbonyl are considered to also be that anti-microbial activity is necessary.In view of C-2 position and combining site closely, this connects any substituting group and quinolone molecule will be hindered all undoubtedly close to target site and cause it active to reduce.

In recent years, the Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly, by to N-1 on parent nucleus, C-5, C-6, the structure of modification of C-7 and C-8 bit substituent and ingenious collocation, obtain the quinolone antibiotic significantly improved the activity of gram positive organism, thus improve the activity of its anti-gram positive organism.

To N-1 bit substituent structure of modification.Prior art research shows, the substituting group on quinolone parent nucleus N-1 position is necessary for hydrophobic group, because it not only controls the general activity of quinolone, and also has a certain impact to its pharmacokinetics.Cyclopropyl be generally acknowledge so far this on one of best substituting group, N 1 bit substituent of quinolones that is that great majority have gone on the market and that researching and developing is cyclopropyl, as Ciprofloxacin, Sparfloxacin, grepafloxacin, Gatifloxacin, Clinafloxacin, gemifloxacin, Moxifloxacin and Jia Nuosha star.In addition, the N-1 position cyclopropyl of Sitafloxacin connects a fluorine atom [cis-(1R, 2s)-2-fluorine cyclopropyl], and this position connects 2, also its activity to gram positive organism and anerobe can be improved, as Tosulfloxacin and trovafloxacin during 4-difluorophenyl.The another kind that Ofloxacine USP 23 and levofloxacin embody on this replaces form, namely introduces a condensed ring by N-1 and C-8 position and forms the parallel parent nucleus closed of three rings, and the 3-position of its oxa-ring 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 volume larger substituting group (as halogen and methoxyl group) is introduced in C-5 position, the activity of quinolone significantly reduces, may be exists between such group and C-3 and C-4 position active binding site interact former; And the substituting group of medium volume, the introducing as amino (Sparfloxacin), methyl (grepafloxacin) or hydroxyl etc. then can significantly improve its external activity to gram positive organism.Although the anti-gram positive organism that the substituting group on this is believed to be helpful in quinolones is active, but its impact also will depend on N-1 to a great extent, substituting group on C-7 and C-8 position, because nearly all quinolone (as Ciprofloxacin, Ofloxacine USP 23, levofloxacin, Gatifloxacin, Clinafloxacin, Sitafloxacin, gemifloxacin, Moxifloxacin, trovafloxacin and Jia Nuosha magnitude) its C-5 position only connects a hydrogen atom, wherein a lot of N-1 bit substituents is cyclopropyl, but the activity of their anti-gram positive organisms is far from each other.Wherein, the anti-microbial activity of Clinafloxacin, Sitafloxacin, gemifloxacin, Moxifloxacin and Jia Nuosha star is obviously better than other quinolones.This shows that the anti-gram positive organism activity of quinolones is the result of substituting group comprehensive action in each position.

To C-6 bit substituent structure of modification.The anti-microbial activity that fluorine atom obviously can strengthen quinolone is introduced in C-6 position.Obtain first fluoroquinolone-flumequine by introducing fluorine atom to parent nucleus C-6 position, the anti-gram positive organism that the success of this research discloses first by being expected to improve such medicine to the transformation of quinolone basic structure is active.The introducing of C-6 position fluorine atom significantly enhances the restraining effect of quinolone molecule to DNA gyrase and the perviousness to bacterial cell, therefore being considered to quinolone, to have outstanding anti-microbial activity necessary, so 6-fluoroquinolone has just become the most basic mother nucleus structure of such drug research in more than 20 years subsequently.Meanwhile, the 6-also occurred recent years goes fluoroquinolone to arouse great concern.Preliminary Results shows, and compared with corresponding fluoroquinolone, 6-goes the genotoxicity level of fluoroquinolone to obtain reduction.It is reported, the activity of outstanding representative-Jia Nuosha star to susceptibility and resistance gram positive organism of non-fluoride halide glass is all better than new fluoroquinolone Moxifloxacin.According to another report, 6-nitro and 6-aminoquinolone have better activity to gram positive coccus.For 6-aminoquinolone, its general activity depends on the substituting group on C-7 and C-8 position to a great extent.Active determination in vitro result shows, similar to fluoroquinolone, and the C-8 position of 6-nitro and 6-aminoquinolone is introduced methyl or methoxy and can be improved its anti-gram positive organism activity.

C-7 bit substituent structure of modification.Antimicrobial spectrum, the bioavailability and untoward reaction etc. of C-7 bit substituent and quinolone are closely related.Cyclammonium base (as piperazinyl and pyrrolidyl) is modal substituting group on this position.Non-substituted piperazinyl quinolone (as norfloxicin, enoxacin or Ciprofloxacin) has outstanding activity to gram-negative bacteria, and can improve its oral absorption and anti-gram positive organism activity when piperazine ring being introduced methyl, but the raising of anti-gram positive organism activity is sometimes along with the reduction to Pseudomonas aeruginosa activity simultaneously.C-7 bit substituent as Pefloxacin, fleroxacin, Ofloxacine USP 23 and levofloxacin is 4-methylpiperazine base, the C-7 bit substituent of lomefloxacin, grepafloxacin and Gatifloxacin is 3-methylpiperazine base, the C-7 bit substituent of Sparfloxacin is 3,5 lupetazin bases.These 7-methylpiperazine base quinolones above-mentioned 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 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 introducing methyl on pyrrolidine ring, and contribute to overcoming some physical properties of quinolones and the deficiency of pharmacokinetics aspect.The C-7 bit substituent of Clinafloxacin 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 gemifloxacin is 3-aminomethyl-4-methoxy imino-1-pyrrolidyl.Wherein the anti-Streptococcus pneumoniae activity of gemifloxacin is significantly improved.DW286(23, gemifloxacin analogue) C-7 bit substituent be 3-aminomethyl-3-methyl-4-methoxyimino-1-pyrrolidyl, namely additionally introduce a methyl in the 3-position of gemifloxacin side chain, its anti-gram positive organism activity is better than gemifloxacin.Size and the lipotropy of the alcoxyl imido grpup on the pyrrolidine ring of C-7 position have remarkably influenced to the anti-microbial activity of fluoroquinolone and pharmacokinetics.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 (as benzyl etc.) substitutes the alkyl in alcoxyl imido grpup, though still can anti-microbial activity be kept, its pharmacokinetics and physics and chemistry flight of steps leading to a palace hall matter then barely satisfactory.

Pyrrolidine ring thicker and or screw togather ring and form 7-dicyclo amido fluoroquinolone, these Wyovins all can regard the derivative of tetramethyleneimine as.Wherein, the C-7 position side chain of Moxifloxacin is diazabicyclo structure, trovafloxacin and CFC-222(24) side chain be connected with an amino azabicyclo structure, and the side chain of Sitafloxacin is the twin nuclei screwing togather a cyclopropyl in the 4-position of 3-amino-pyrrolidine.Add that the C-7 position side chain of the new fluoroquinolone such as Clinafloxacin, Tosulfloxacin and gemifloxacin is all containing a tetramethyleneimine skeleton in addition, they generally have very outstanding anti-microbial effect to gram positive organism.

Go in fluoroquinolone at 6-, PGE9262932(25) C-7 position side chain and PGE4175997(26) is 3-aminoalkyl-1-pyrroles cyclic group, the two is similar to trovafloxacin, all there is broad spectrum antibiotic activity, its anti-gram positive organism activity comparatively trovafloxacin is stronger, but to the activity of enterobacteriaceae a little less than trovafloxacin.Jia Nuosha star is different from the structure of fluoroquinolones and above-mentioned 2 non-fluoride halide glass, its C-7 position side chain is not cyclammonium base but a 5-isoindoline base containing aromatic structure segment, this compound is keeping on the basis to the outstanding activity of gram-negative bacteria, to a lot of gram positive organism, especially to streptococcus pneumoniae, there is very outstanding anti-microbial activity.

From composition optimizes angle analysis, the 7-cyclammonium base of quinolone has very large modification space, and allows the position connecting macoradical also to only have C-7 position in quinolone molecule.Such as, the quinolone series 4-position N of 7-piperazine ring connecting macoradical has potential anti-microbial activity (particularly to gram positive organism), and some compound is wherein better than its parent compound 7-piperazinyl quinolone to staphylococcic activity.Think accordingly, the macoradical that C-7 position connects does not hinder quinolone molecule to the infiltration of bacterial cell.As everyone knows, the character of C-7 bit substituent affects the bioactive important factor of quinolone, this kind of N-substituted piperazinyl quinolone to the activity of gram positive organism why make moderate progress may be have the quinolone molecule of this structure easier accumulate in gram positive organism therefore.

To C-8 bit substituent structure of modification.The quinolone (as Ciprofloxacin and grepafloxacin) of many C-8 positions unsubstituted and C-8 position are that the naphthyridones (as Tosulfloxacin, gemifloxacin and trovafloxacin) of nitrogen-atoms has good anti-gram positive organism activity.C-8 bit substituent has a certain impact to the oral pharmacokinetic character changing quinolone, the aspect tool such as selectivity that expands antimicrobial spectrum and reduce medicament-resistant mutation.Halogen atom is introduced in C-8 position, methyl or methoxy can improve the external activity of quinolones to gram positive coccus (even comprising early stage Fluoroquinolones Resistant Strains), also demonstrates good anti-microbial activity to anerobe simultaneously.Early stage research shows, fluoro (as lomefloxacin and Sparfloxacin) and chloro (as Clinafloxacin and Sitafloxacin) are the best C-8 bit substituents improving quinolones anti-microbial activity, but also there is phototoxicity and some unacceptable untoward reaction, therefore people have abandoned the new drug design strategy of 8-halo at present simultaneously.Subsequently, not only increase the activity to gram positive organism and anerobe by the 8-BAY 128039 (Gatifloxacin and Moxifloxacin) researched and developed in a large number, make again phototoxicity and cytotoxicity be down to bottom line.

In recent years, the activity of the Novel Quinolone succeeded in developing successively to gram positive organism constantly improves, and the dream that this likely makes " development of resistance is led in the exploitation of new drug " comes true in the near future.Structure activity study shows, by the structure of modification to quinolone, particularly C-6, the modification of C-7 and C-8 bit substituent, the action target spot number of medicine in bacterial cell on type Ⅱ topoisomerase can be increased, weaken the effect of efflux protein (efflux pump) simultaneously, thus reduce the frequency of occurrences of mediated quinolone resistance gram-positive bacterial strain.

Although the Pharmaceutical Chemist in the whole world has synthesized ten hundreds of Novel Quinolone compounds targetedly, to passing through N-1 on parent nucleus, C-5, C-6, the structure of modification of C-7 and C-8 bit substituent and ingenious collocation, thus obtain the quinolone antibiotic that the activity of gram positive organism is significantly improved, to improve the activity of its anti-gram positive organism.But at quinolone parent nucleus hlimit (or glimit) or be equivalent to the thick and carbostyril compound that is 5-, 6-, 7-, 8-, 9-or 10-ring in its position and there is not yet any research and report.

Therefore, under these backgrounds, based on above prior art, investigator of the present invention conducts extensive research, by quinolone parent nucleus hlimit (or glimit) or be equivalent to thick and 5-, 6-, 7-, 8-, 9-or 10-ring in its position, and measure the pharmacologically active of the compound formed, carry out the carbostyril compound of Development of New Generation, they comprise endurance strain to wide spectrum pathogenic bacterium and demonstrate strong anti-microbial activity, also have the pharmacokinetics performance improved further.As a result, our early start works out and has found at quinolone parent nucleus hlimit (or glimit) or be equivalent to the compound or its salt of general formula (I) or the solvate of thick and 5-, 6-, 7-, 8-, 9-or 10-ring in its position, they demonstrate strong anti-microbial activity, and it is a very safe compound, and this completes the present invention.

Summary of the invention

Infectious diseases is the second disease killer threatening human health.Resistance still constantly occurs, and increases in hospital and community, decreases the therapeutic choice of patient, adds hospital stays and medical expense.As a result, need substitute and improve antibacterials to treat resistance pathogenic bacteria.

Quinolones is the synthetic drugs of a class wide spectrum, efficient, low toxicity.Early stage quinolones has stronger anti-microbial activity to Gram-negative bacteria, but lower to gram-positive bacteria activity.Although the quinolones of fresh market is as Gatifloxacin (Drug, 1999,58 (4): 683) and Moxifloxacin (external medicine-microbiotic fascicle, 2002,23 (6): 274) anti-microbial activity makes moderate progress, but in general, the activity of resisting gram-positive bacteria needs to be strengthened further, needs to strengthen the anti-microbial activity of some specific bacteria as streptococcus pneumoniae, faecalis etc. simultaneously.Therefore, expect clinically to have the higher medicine of validity.In addition, known to taking the side effects such as the side effect of bringing out spasm or phototoxicity together with non-steroidal anti-inflammatory drugs, also need to develop the higher quinolones synthetic antibacterial agents of security.

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

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

（Ⅰ）

Wherein:

R ¹for the alkyl, thiazolinyl, cycloalkyl, alkoxyl group, amino, alkylamine, dialkylamine, the aryl or aralkyl that replace arbitrarily;

R ², R ³and R ⁴each is independently Q-R ⁷;

Alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl that Q is hydrogen atom or replaces arbitrarily;

R ⁷for hydrogen atom or NR ⁸r ⁹, or the alkyl, aryl, aralkyl, heterocyclic radical or the Heterocyclylalkyl that replace arbitrarily;

R ⁸and R ⁹each alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl being independently hydrogen atom or replacing arbitrarily;

R ⁸and R ⁹together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit;

R ⁵for halogen atom, hydroxyl or any alkoxyl group replaced;

R ¹⁰for hydrogen atom or any alkyl, aryl, aralkyl, heterocyclic radical or Heterocyclylalkyl replaced;

R ²and R ³together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit;

R ³and R ⁴together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit;

R ⁴and R ⁵together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit;

R ⁶for hydrogen atom or any alkyl replaced;

A and B is each is independently nitrogen-atoms or carbon atom, and condition is when A is N, without R ¹⁰; When B is N, without R ⁵;

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

X is C, N, O or S.

As defined above, have excellent antibacterial activity, wide antimicrobial spectrum and superior pharmacokinetics performance, in 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 atom.Preferred alkyl is methyl, ethyl, propyl group and butyl, particularly methyl and ethyl.Preferred thiazolinyl comprises vinyl, propenyl and butenyl.When alkyl is a part (moieties as aralkyl) of other group, preferably contain to 6, particularly to 4 carbon atom.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, especially 6-10 carbon atom.Preferred aryl comprises phenyl, naphthyl, anthryl, phenanthryl, pyrans, particularly phenyl or naphthyl, especially phenyl.When aryl is a part (aryl moiety as aralkyl) of other group, preferred phenyl, naphthyl, phenanthryl or pyrans, particularly phenyl or naphthyl, especially phenyl.

Aralkyl can be arbitrarily by alkyl that aryl replaces.Aralkyl is containing preferred 7-30, more preferably 7-24, particularly 7-18, especially 7-11 carbon atom, and particularly preferred aralkyl is phenmethyl, menaphthyl, anthracene methyl, luxuriant and rich with fragrance methyl and pyrans methyl.Especially preferred aralkyl is phenmethyl.

Cycloalkyl can be cyclic hydrocarbon groups saturated arbitrarily, containing 3-12, and preferred 3-8, a particularly 3-6 carbon atom.Preferred cycloalkyl is cyclopropyl, cyclopentyl and cyclohexyl, particularly cyclopropyl.

Heteroaryl can be monocycle or the polycyclic system of fragrance arbitrarily, containing at least one heteroatoms.Preferably, heteroaryl is 5-to 18-unit, particularly 5-to 14-unit, and especially 5-to 10-unit aromatic ring system, containing at least one heteroatoms, is selected from oxygen, sulphur and nitrogen-atoms.Preferred heteroaryl comprises pyridyl, pyranyl, mercapto pyranyl, pyrryl, furyl, thienyl, indyl, pseudoindoyl, indolizine 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 arbitrary monocycle or polycyclic system, containing at least one heteroatoms, can be unsaturated or fractional saturation or completely saturated.Here term " heterocycle " comprises above-mentioned heteroaryl and nonaromatic heterocycles base.Preferred heterocyclic radical is 3-to 18-unit, more preferably 3-to 14-unit, particularly 3-to 10-unit, more especially 3-to 6-unit, and especially 5-to 6-ring system, containing 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 is for morpholinyl, morpholine sulfonic group, tetrahydro isoquinolyl and tetrahydrofuran base.

Heterocyclylalkyl can be arbitrarily by alkyl that heterocyclic radical replaces.Preferred heterocyclic moiety is 3-to 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 foregoing substituents is designated as, the random substituting group occurred can be appoint one or more at medicament research and development and/or for a change activity, stability, bioavailability or other characteristic and normally used substituting group in modified compound structure.These substituting groups comprise halogen atom, nitro, cyano group, hydroxyl, cycloalkyl, 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 aforesaid random substituting group representative or comprise an alkyl substituent, this alkyl substituent can be line style or branched chain type and containing 12, preferably 6, most preferably 4 carbon atoms.Cycloalkyl can comprise 3-8, a 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 comprising halogen atom, as alkylhalide group, can comprise and appoint one or more halogen atom.

Preferred random substituting group comprises halogen atom, nitro, cyano group, hydroxyl, C _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 random substituting group comprises halogen atom, nitro, cyano group, hydroxyl, C _1-4alkyl, C _1-4haloalkyl, C _1-4alkoxyl group, C _1-4halogenated alkoxy.Most preferably halogen atom.

Formula I compound of the present invention can form pharmacy acceptable salt or ester or solvate, these salt comprise the salt with inorganic salt example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc., with organic carboxyl acid as acetic acid, trifluoroacetic acid, lemon is calculated, toxilic acid, oxalic acid, amber are calculated, the salt of phenylformic acid, tartrate, fumaric acid, amygdalic acid, xitix or oxysuccinic acid, or with the salt of sulfonic acid as methylsulfonic acid, tosic acid etc., and with the common known and salt of conventional other acid be used in carbostyril compound technical field.These acid salt can be prepared by method for transformation routinely.

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 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 respectively as defined above.

As shown in reaction scheme 1, the method for the preparation of formula (I) compound comprises the following steps:

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

2) formula (II-a) compound and Y-R ¹condensation in the basic conditions, obtain formula (II-b) compound, wherein Y is halogen atom, is preferably bromine atoms or atomic iodine;

3) formula (II-b) compound is in the basic conditions through hydrolysis or HOR ⁵alcoholysis obtains formula (I) compound.

As shown in reaction scheme 2, the method for the preparation of formula (I) compound comprises the following steps:

1) formula III compound and barkite are obtained by reacting formula (III-a) compound, wherein R ¹²represent methyl or ethyl;

2) formula (III-a) compound successively with ortho-formiate and NH ₂r ¹be obtained by reacting formula (III-b) compound;

3) formula (III-b) compound is closed ring in the basic conditions and obtain formula (III-c) compound;

4) by formula (III-c) compound hydrolysis or HOR ⁵alcoholysis obtains formula (I) compound.

Above-mentioned synthetic method will be more specifically explained in following Preparations.

The third aspect, the present invention also provides containing formula as defined above (I) compound or its pharmaceutically acceptable salt or solvate as activeconstituents, and the antimicrobial compound of pharmaceutically acceptable carrier.When this combination is used for clinical object, to be combined the solid, semisolid or the liquid pharmaceutical formulation that are made into oral, parenteral and use or locally use with pharmaceutically acceptable carrier by formula (I) compound or its pharmaceutically acceptable salt or solvate.

Embodiment

synthesis

Invention compound, comprises its salt, hydrate and solvate, can use known method or prepare with process like known class, as used reaction scheme below.Discovery changes or revises inessential parameter and can reach equifinality by professional and technical personnel.

citing

Following example, only for illustration of the present invention, is not used in restriction the present invention.

embodiment 11-cyclopropyl-10-fluorin-4-oxygen generation-Isosorbide-5-Nitrae, the preparation of 6,7,8,9-hexahydropyridine also [3,4-g] quinoline-3-carboxylic acid

The preparation of the chloro-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid of the fluoro-7-of (a) 6-.

Chloro-for fluoro-for 56.0g6-7-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid (preparation method's reference EuropeanJournalofOrganicChemistry, 2006,4398) is dissolved in 300ml Glacial acetic acid, stirs.The glacial acetic acid solution 200ml of the nitric acid (d=1.52) of 42.0ml is slowly dripped at 0 ~ 5 DEG C.Insulated and stirred 2 hours at reaction solution 0 ~ 10 DEG C.React complete, under low temperature, add 600ml frozen water, separate out a large amount of solid product, filter.Filter cake water and normal heptane wash twice, the dry crude product obtaining the chloro-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid of the fluoro-7-of 50.0g6-for 8 hours under vacuum.Without the need to refining, be directly used in lower step and feed intake.

The preparation of the fluoro-7-carboxymethyl of (b) 6--8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid

Sodium hydride solid (containing mineral oil) 3.1g is suspended in 100ml anhydrous tetrahydrofuran solution, slowly drips the anhydrous tetrahydrofuran solution 100ml of 18.7g oxalic acid diethyl ester.Stir 2 hours at 20 ~ 25 DEG C.The tetrahydrofuran solution 150ml of the chloro-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid of the fluoro-7-of 45.0g6-is dripped under room temperature.Insulated and stirred 12 hours, pours into reaction solution in frozen water, divides phase of anhydrating.Organic phase anhydrous sodium sulfate drying, concentrates and obtains brown oil.Add the sodium hydroxide solution that 250ml mass concentration is 4.0% under room temperature, be slowly warming up to 60 ~ 70 DEG C, insulated and stirred 2 hours.Be down to 20 ~ 25 DEG C, be about 2 with 1N salt acid for adjusting pH, separate out a large amount of yellow solid.Filter, dry, obtain the fluoro-7-carboxymethyl of yellow 6--8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid crude product 32.2g.Purity >=87.0%.

The preparation of (c) 6-cyano group-7-carboxymethyl-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid

Add the fluoro-7-carboxymethyl of 31.0g6--8-nitro-1 in the reactor successively; 4-dihydro-4-Oxoquinoline-3-carboxylic acid; 9.5g cuprous cyanide (must not be excessive); the N of 25ml absolute; dinethylformamide; 125 ~ 135 DEG C are slowly warming up to, insulated and stirred 3 hours (must be noted that during operation that prussic acid is poisoned) under nitrogen gas stream protection.Reaction solution cooling down, adds 300ml methylene dichloride and 300ml water successively.There is slight emulsification, after filtering breakdown of emulsion, stratification.Organic phase is washed, concentrated.Obtain semi-solid state product methylene dichloride and normal heptane crystallization.Obtain faint yellow solid product 6-cyano group-7-carboxymethyl-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid fine work, purity >=94.5%.

(d) 1-cyclopropyl-10-amino-4-oxo-Isosorbide-5-Nitrae, the preparation of 6,7,8,9-hexahydropyridine also [3,4-g] quinoline-3-carboxylic acid dihydrochloride.

In hydriding reactor, 25.0g6-cyano group-7-carboxymethyl-8-nitro-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid is dissolved in the mixed solution of 250ml methyl alcohol and 20.3ml concentrated hydrochloric acid, adds the platinum oxide of 0.5g10% under protection of inert gas.Inject hydrogen, room temperature reaction 3 hours under 45psi pressure condition.Decompression is lower steams except methyl alcohol, obtain 6-aminomethyl-7-acyl methyl-8-amino-1, the crude product of 4-dihydro-4-Oxoquinoline-3-carboxylic acid dihydrochloride, adds 300ml purified water, is slowly warming up to 75 ~ 85 DEG C, insulation reaction 4 hours, filtered while hot, add dichloromethane extraction (300ml × 2) after filtrate cooling, organic phase is dry, concentrated, obtain brown oil.Be directly used in lower step to feed intake.

(e) 1-cyclopropyl-10-fluorin-4-oxygen generation-Isosorbide-5-Nitrae, the preparation of 6,7,8,9-hexahydropyridine also [3,4-g] quinoline-3-carboxylic acid

In the reactor of polytetrafluoro material, add 1-cyclopropyl-10-amino-4-oxo-Isosorbide-5-Nitrae, 6,7,8,9-hexahydropyridine is [3,4-g] quinoline-3-carboxylic acid dihydrochloride 15.0g also, and less than 0 DEG C adds 80mlHF/ pyridine (70%) solution, reaction solution left at room temperature all dissolves to raw material, is cooled to-78 DEG C, adds 3.04g Sodium Nitrite, 0 DEG C is slowly warming up under stirring, insulated and stirred 30 minutes, is then slowly warming up to 60 DEG C, insulated and stirred 30 minutes.After cooling with frozen water by above-mentioned reaction solution cancellation.Add saturated solution of sodium bicarbonate cold in right amount, reaction solution with dichloromethane extraction (200ml × 3), organic phase anhydrous sodium sulfate drying, steaming desolventizes, resistates uses column chromatography (eluent is methylene dichloride and methyl alcohol), obtains 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.

the preparation of the fluoro-10-cyclopropyl of embodiment 211--7-oxo-2,3,4,5,7,10-six hydrogen-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-8-carboxylic acid

The preparation of the fluoro-7-bromine oxethyl of (a) 1-cyclopropyl-8--4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester

8.4g sodium hydride (60% mineral oil) is suspended in 150ml anhydrous tetrahydrofuran solution, the tetrahydrofuran solution 50ml of 24.9g2-bromoethanol is slowly dripped under room temperature, stir after 2 hours, the chloro-4-oxo-1 of the fluoro-7-of 62.0g1-cyclopropyl-8-is dripped under room temperature, the tetrahydrofuran solution 100ml of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, stirring reaction 12 hours at reaction solution 30 ~ 35 DEG C, react complete, reaction solution concentrates, add 300ml methylene dichloride and 150ml water, separatory, organic phase anhydrous sodium sulfate drying, concentrate and obtain red oil 55.8g, be directly used in the next step.

The preparation of the fluoro-10-cyclopropyl of (b) 11--7-oxo-2,3,4,5,7,10-six hydrogen-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-8-carboxylate hydrochloride

The oily matter obtained in (a) being dissolved in 250ml massfraction is in the dehydrated alcohol of the ammonia of 15% ~ 20%, stir 10 hours at 0-10 DEG C, reaction is finished, concentrating under reduced pressure at reaction solution 35 ~ 40 DEG C, add 250ml purified water, appropriate dilute hydrochloric acid after resistates cooling, then add 12.0g paraformaldehyde, slowly be warming up to 70 ~ 80 DEG C, insulation reaction 2 hours.Reacting liquor while hot is filtered, and filtrate lets cool, and adds 450ml methylene dichloride, is about 8, separatory under room temperature by strong aqua adjust ph, and aqueous phase has 400ml methylene dichloride to extract once again, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtains brown semi-solid state product.

The preparation of the fluoro-10-cyclopropyl of (c) 11--7-oxo-2,3,4,5,7,10-six hydrogen-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-8-carboxylic acid

The semi-solid state product obtained in (b) is dissolved in 240ml ethanol, the sodium hydroxide solution of 80.0ml2% is dripped at 0 ~ 5 DEG C, insulated and stirred 3 hours, then stirring at room temperature is risen to 1 hour, under reaction solution reduced pressure, ethanol is steamed and remove, 260ml methylene dichloride is added after cooling, with appropriate 1N salt acid for adjusting pH value to 6.6 ~ 7.2, organic phase activated carbon decolorizing 2 times, anhydrous sodium sulfate drying, concentrated about 1/3rd volumes, add normal heptane 320ml, stir 8 hours, separate out a large amount of faint yellow solid, filter, filter cake normal heptane washs, obtain 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.

the fluoro-1-cyclopropyl of embodiment 313--4-oxo-Isosorbide-5-Nitrae, the preparation of 6,7 – tetrahydrochysene-benzo [Isosorbide-5-Nitrae] oxazepine Zhuos also [6,7-g] quinoline-3-carboxylic acid

The preparation of (a) 7-(2-amino-benzene oxygen)-1-cyclopropyl-8-fluorin-4-oxygen generation-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester

4.1g sodium hydride (60% mineral oil) is suspended in 150ml anhydrous tetrahydrofuran solution, the tetrahydrofuran solution 150ml of 41.8g2-t-butoxycarbonyl amino phenol is dripped under room temperature, insulated and stirred 3 hours, the chloro-4-oxo-1 of the fluoro-7-of slow dropping 62.0g1-cyclopropyl-8-, the tetrahydrofuran solution 100ml of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, stirring reaction 8 hours at reaction solution 30 ~ 35 DEG C, react complete, reaction solution concentrates, add 300ml methylene dichloride and 150ml water, separatory, organic phase anhydrous sodium sulfate drying, concentrate and obtain red oil 65.8g, be directly used in the next step.

The fluoro-1-cyclopropyl of (b) 13--4-oxo-Isosorbide-5-Nitrae, the preparation of 6,7 – tetrahydrochysene-benzo [Isosorbide-5-Nitrae] oxazepine Zhuos also [6,7-g] quinoline-3-carboxylic acid ethyl ester

The oily matter obtained in (a) is dissolved in 250ml dehydrated alcohol, appropriate dilute hydrochloric acid, 12.0g paraformaldehyde, is slowly warming up to 70 ~ 80 DEG C, insulation reaction 5 hours.Reacting liquor while hot is filtered, and filtrate lets cool, and adds 450ml methylene dichloride, is about 8, separatory under room temperature by ammoniacal liquor adjust ph, and aqueous phase has 400ml methylene dichloride to extract once again, merges organic phase, with anhydrous sodium sulfate drying, concentrated, obtains reddish-brown semi-solid state product.Be directly used in the next step.

The fluoro-1-cyclopropyl of (c) 13--4-oxo-Isosorbide-5-Nitrae, the preparation of 6,7 – tetrahydrochysene-benzo [Isosorbide-5-Nitrae] oxazepine Zhuos also [6,7-g] quinoline-3-carboxylic acid

The semi-solid state product obtained in (b) is dissolved in 250ml ethanol, the sodium hydroxide solution of 80.0ml2% is dripped at 0 ~ 5 DEG C, insulated and stirred 3 hours, then stirring at room temperature is risen to 1 hour, under reaction solution reduced pressure, ethanol is steamed and remove, 260ml methylene dichloride is added after cooling, with appropriate 1N salt acid for adjusting pH value to 6.6 ~ 7.2, organic phase activated carbon decolorizing 1 time, anhydrous sodium sulfate drying, concentrated about 1/3rd volumes, add normal heptane 320ml, stir 8 hours, separate out a large amount of faint yellow solid, filter, filter cake normal heptane washs, obtain off-white color solid product.Purity >=97.4%, total recovery is 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 fluoro-1-cyclopropyl of embodiment 414--4-oxo-10H-1, the preparation of 4,6,8,9,11,12-seven hydrogen piperazine also [1,2-a]-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-3-carboxylic acid

Fluoro-7-(3, the 4-dibromo propoxy of (a) 1-cyclopropyl-8-) preparation of-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester

8.4g sodium hydride (60% mineral oil) is suspended in 150ml anhydrous tetrahydrofuran solution, slowly 43.6g3 is dripped under room temperature, the tetrahydrofuran solution 60ml of 4-dibromo-propanol, stir after 4 hours, the fluoro-7-(3 of 62.0g1-cyclopropyl-8-is dripped under room temperature, 4-dibromo propoxy)-4-oxo-1, the tetrahydrofuran solution 100ml of 4-dihydroquinoline-3-carboxylic acid, ethyl ester, stirring reaction 8 hours at reaction solution 30 ~ 35 DEG C, react complete, reaction solution concentrates, add 300ml methylene dichloride and 150ml water, separatory, organic phase anhydrous sodium sulfate drying, concentrate and obtain red oil 55.8g, be directly used in the next step.

(b) 1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group) preparation of-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester dihydrochloride

Add the oil product that (a) obtains in the reactor successively, 12.0g quadrol, 550ml anhydrous ethyl acetate; 60.g anhydrous sodium bicarbonate, is warming up to backflow under nitrogen protection, insulation reaction 48 hours; reaction solution lets cool, and filter, filter cake 50ml anhydrous ethyl acetate washs.Merge organic phase, with saturated common salt water washing (150ml × 2), organic phase adds 45ml purified water, and under fully stirring, control temperature drips concentrated hydrochloric acid at 5 ~ 10 DEG C, and adjust ph is about 3, separates out a large amount of white solid.Filter, filter cake ethyl acetate is washed, and dries, obtains 1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group)-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester dihydrochloride 41.9g.Purity >=91.0%

The fluoro-1-cyclopropyl of (c) 14--4-oxo-10H-1, the preparation of 4,6,8,9,11,12-seven hydrogen piperazine also [1,2-a]-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-3-carboxylic acid ethyl ester

By 36.0g1-cyclopropyl-8-fluoro-7-(2-piperazine methoxyl group)-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester dihydrochloride, 10.2g paraformaldehyde, 450ml dehydrated alcohol adds in reactor, is slowly warming up to backflow, and reaction solution becomes clarification gradually.Insulation reaction 3 hours, filtered while hot, reaction solution concentrating under reduced pressure, add 400ml methylene dichloride and 400ml purified water, the sodium hydrogen carbonate solution with 10% is adjusted to neutrality at 0 ~ 10 DEG C, aqueous phase with 400ml dichloromethane extraction once, merge organic phase.Concentrated after adding activated carbon decolorizing, obtain oil product 34.4g.Be directly used in the next step.

The fluoro-1-cyclopropyl of (d) 14--4-oxo-10H-1, the preparation of 4,6,8,9,11,12-seven hydrogen piperazine also [1,2-a]-[Isosorbide-5-Nitrae] oxazepine Zhuo also [6,7-g] quinoline-3-carboxylic acid

The oily matter obtained in (c) is dissolved in 250ml ethanol, the sodium hydroxide solution of 80.0ml2% is dripped at 0 ~ 5 DEG C, insulated and stirred 3 hours, then stirring at room temperature is risen to 1 hour, under reaction solution reduced pressure, ethanol is steamed and remove, 260ml methylene dichloride is added after cooling, with appropriate 1N salt acid for adjusting pH value to 6.5 ~ 7.0, organic phase activated carbon decolorizing 1 time, anhydrous sodium sulfate drying, concentrated about 1/3rd volumes, add normal heptane 320ml, stir 8 hours, separate out a large amount of faint yellow solid, filter, filter cake normal heptane washs, and obtains off-white color solid product.Purity >=98.4%, total recovery is 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

Antibacterial activity in vitro is tested

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

Minimal inhibitory concentration measures as follows: (1) prepares the agar plate that a series of pastille concentration gradient is successively decreased.(2), after being diluted by the bacteria suspension of 0.5 Maxwell standard opacity tube, draw with multi-point inoculator the bacterium liquid prepared and be inoculated in agar plate surface, each bacterial plaque Chinese bacterium number is about 104CFU.Inoculation order first inoculates without medicine contrast flat board, then dull and stereotyped to high drug level from low drug level.(3), after bacterium liquid inoculated by agar plate, agar plate is inverted into 35 DEG C ± 2 DEG C incubators and hatches 24h, observed and recorded MIC result.

MIC result interpretation standard: according to CLSI/NCCLS standard, is 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 with escherichia coli ATCC25922, streptococcus aureus ATCC29213, hemophilus influenzae ATCC49247 for Quality-control strains, and all experiments all judges whether to meet CLSI/NCCLS quality control standard with the MIC of Quality-control strains.

Test compound of the present invention is selected in test medication, and numbering is as table 2; The contrast medicine Ciprofloxacin (CPFX) selected in test, levofloxacin (LVFX), Moxifloxacin (MFLX) fasten city's sales item.

Following table lists 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
Bacteroides 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
								Chlamydia pneumoniae	1	1	0.1252	0.1252	0.0626	1	1
Tubercule bacillus	2	1	0.1252	0.0626	0.1252	1	2

Claims (8)

1. following (I) compound or its salt of representing

Wherein, A and B respectively represents carbon atom;

R ¹the cycloalkyl that representative replaces arbitrarily, R ²and R ³together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit; R ³and R ⁴together for the thiazolinyl that replaces arbitrarily or be arbitrarily made with the assorted naphthenic ring of 3-, 4-, 5-, 6-or 7-unit;

R ⁵represent halogen atom;

R ⁶the alkyl representing hydrogen atom or replace arbitrarily;

R ¹⁰represent hydrogen atom;

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

X is C, N, O or S;

The substituting group of described any replacement is selected from halogen atom, nitro, cyano group, hydroxyl, amino, carboxyl or C _1-6aldehyde radical;

Described alkyl is the alkyl of 1-12 carbon atom; Described thiazolinyl is the thiazolinyl of 2-12 carbon atom, and described cycloalkyl is the saturated cyclic hydrocarbon group of 3-12 carbon atom.

2. compound or its salt, wherein R as claimed in claim 1 ¹for cyclopropyl, R ⁵for fluorine atom, R ⁶for hydrogen atom, R ¹⁰for hydrogen atom, the compound represented by formula (I) is following formula: compound:

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

4. a compound or its salt, it is the compound or its salt shown in following formula:

5. a compound or its salt, it is the compound or its salt shown in following formula:

6. a compound or its salt, it is the compound or its salt shown in following formula:

7. the pharmaceutical composition that the compound or its salt according to any one of claim 1-6 containing medicine effective content is formed as activeconstituents and pharmaceutical carrier.

8. the compound according to any one of claim 1-6 or composition according to claim 7 are for the preparation of the purposes of medicine being used as antiseptic-germicide.