CN1011310B - Process for producing 1,4-dihydro-4-oxo-1,8-dinaphihyridine derivatives - Google Patents

Abstract

The present invention relates to a new 1, 4-dihydro-4-oxo-1, 8-naphthyridine derivative with substituted or unsubstituted aryl on 1-position and a fluorine atom or a substituted or unsubstituted cyclic amino on 7-position, salts thereof, a producing process thereof and antibacterium medicines containing the compounds.

Description

Process for producing 1,4-dihydro-4-oxo-1,8-dinaphihyridine derivatives

The present invention relates to one new replacement arranged on the 1-position or unsubstituted aryl and a replacement arranged on the 7-position or unsubstituted cyclic amino 1,4-dihydro-4-oxygen-1, the production method of 8-naphthyridines derivatives and salt thereof.

Nalidixic acid, minaline (Piromidicacid), up to the present pipemidic acid (Pipemidic acid) and analogue thereof have been widely used as the synthetic antibacterials.But these medicines are gratifying to the treatment disease aspect none that is difficult to treat that Pseudomonas aeruginosa and gram positive bacterium infected.Therefore, the compound of various pyrrolidone carboxylic-acids develops, and is 1-ethyl-6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-3-quinolyl carboxylic acid (norfloxacin) or analogue, as the surrogate of the synthesising bacteria anti-reflecting medicine of routine.These compounds have the excellent antibacterial activity that anti-various gram negative bacteriums comprise Pseudomonas aeruginosa, but the anti-microbial activity of resisting gram-positive bacterium is dissatisfied.Therefore, development has not only just become the thing of serious hope to gram negative bacterium but also to the synthesising bacteria anti-reflecting medicine that gram positive bacterium has a broad-spectrum antimicrobial.

In these cases, the present inventor as the result of broad research, finds that 1,4 new dihydro-4-oxygen-1,8 naphthyridines derivatives and salt thereof can address the above problem.

The purpose of the present invention research provides one new 1,4-dihydro-4-oxygen-1, the production method of 8 naphthyridines derivativess and salt thereof, they have good character, as, strong resisting gram-positive bacterium and anti-gram negative bacterium anti-microbial activity are arranged, can resist the bacterium that antibiotic is had resistance especially, when oral or haemoconcentration height during without the intestines and stomach administration, very safe.

According to this invention, provide with logical formula I represent 1, the production method of 4-dihydro-4-oxygen-1,8 naphthyridines derivatives:

R in the formula ¹The protecting group of representing a hydrogen atom or a carboxyl, R ²Represent a replacement or unsubstituted aryl, R ^3bA replacement of expression or its salt of unsubstituted cyclic amino and one, it is characterized in that the represented compound or its salt of compound or its salt that formula II is represented and formula III reacts,

R wherein ^3aThe expression halogen atom, R ¹And R ²Definition the same,

R ^3b-H [Ⅲ]

R wherein ^3bDefinition the same, and as required, remove protecting group and with the product salify.

The present invention will be elaborated as follows.

In leading to formula I or (II) represented compound and salt thereof, carboxyl-protecting group R ¹Comprise, as, the group of formation ester, these groups can be used catalytic reduction under the condition of gentleness, and chemical reduction or other treatment process are sloughed, and form its very easy in vivo sloughing of group of ester; Contain organosilyl group, contain the group of organophosphorus and contain their very easy sloughing when water or alcohol are handled of group of organotin; And the group of other various known formation esters.

In these carboxyl-protecting groups, best protecting group comprises, as, open at Japanese patent application Kokai() carboxyl-protecting group described in numbers 80,665/84.

R ²Aryl comprise that as, phenyl, naphthyl and similar group, this aryl can be replaced by one or more substituting groups, substituting group can be selected from halogen atom, as, fluorine, chlorine, bromine, iodine etc.; Alkyl, as, straight or branched C ₁-C ₁₀Alkyl such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group etc.; Hydroxyl; Alkoxyl group, as, straight or branched C ₁-C ₁₀Alkoxyl group such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy, heptan the oxygen base, octyloxy etc., cyano group; Amino; Amido, as, C ₁-C ₄Amido such as formamido group, kharophen, propionamido, butyrylamino etc., and three alkylhalide groups, as, three halogen-C ₁-C ₄-alkyl such as trifluoromethyl, trichloromethyl etc.

In addition, R ^3bThe ring amino one or more Sauerstoffatom that has at least a nitrogen-atoms also to have to add as the heteroatoms of Cheng Huan, and comprise that 5-or 6 yuan of rings are amino as the 1-pyrrolidyl, piperazinyl, 1-piperazinyl, morpholinyl etc.Above-mentioned ring amino can be replaced by one or more substituting groups, and these substituting groups can be selected from following base, alkyl, as, straight or branched C ₁-C ₄Alkyl such as methyl, ethyl, n-propyl, isobutyl-, the sec-butyl and the tertiary butyl; Amido; Aminoalkyl, as, ammonia C ₁-C ₄Alkyl such as aminomethyl, 2-aminoethyl, 3-aminopropyl etc.; Hydroxyalkyl, as, hydroxyl C ₁-C ₄Alkyl such as methylol, 2-hydroxyethyl, 3-hydroxypropyl etc.; Hydroxyl; Alkenyl, as, C ₂-C ₄Alkenyl such as vinyl, allyl group etc.; Acyl group is as C ₁-C ₄Acyl group such as formyl radical, ethanoyl, propionyl, butyryl radicals etc.; Alkylamino, as, C ₁-C ₄Alkylamino such as methylamino-, ethylamino, n-propylamine base, isopropylamino etc.; Dialkylamino, as, two-C ₁-C ₄Alkylamino such as dimethylamino, diethylin, two-just-third amino, first and second amino etc.; Cyano group; Oxo group; Arylalkylamino, as, aryl-C ₁-C ₄Alkylamino such as benzyl amino, benzene ethylamino etc.; Amido.As, C ₁-C ₄Amido such as acetyl ammonia, propionamido, butyrylamino etc.; Carbalkoxy, as, C ₁-C ₄Carbalkoxy such as methoxycarbonyl, ethoxycarbonyl, oxygen carbonyl just-third, the different third oxygen carbonyl etc.; And N-acyl group-N-alkylamino, as, N-ethanoyl N-alkylamino, the nitrogen-atoms in these groups in the alkylamino is by C ₁-C ₄Acyl group such as ethanoyl, propionyl, propionamido, butyrylaminos etc. replace.

And, R ^3aHalogen atom comprise, as, fluorine, chlorine and bromine.

In the compound of representing with logical formula I, with those R ²Phenyl and R for the fluorine replacement ^3bFor the compound that replaces or do not get 1-pyrrolidyl or 1-piperazinyl better, those R ²Be 2,4 difluorobenzene base and R ^3bFor 3-amino-pyrrolidyl is better.

Being included in base with the salt of the compound of logical formula I or (II) representative is amino etc. and the common salt that become at acidic group such as carboxyl etc.The salt that is become on base comprises, as, with ore deposit acid example hydrochloric acid, the salt that sulfuric acid etc. became; With organic acid such as oxalic acid, formic acid, trichoroacetic acid(TCA), the salt that trifluoroacetic acid etc. became; With sulfonic acid such as methylsulphonic acid, right-toluenesulphonic acids, the salt that naphthene sulfonic acid etc. became.The salt that is become on acidic group comprises, as, with basic metal such as sodium, the salt that potassium etc. became; With alkaline-earth metal such as calcium, the salt that magnesium etc. became; Ammonium salt; With nitrogenous organic base such as PROCAINE HCL, PHARMA GRADE, two-benzyl amine, N-benzyl-β-styroyl amine, 1-ephedrine, N, the two benzyl ethylene diamines of N-, triethylamine, Trimethylamine 99, tributylamine, pyridine, N, accelerine, N-methyl piperidine, N-methylmorpholine, diethylamine, the salt that dicyclohexylamine etc. became.R ^3bSalt comprise with the represented compound base of formula I on salt.

If with logical formula I, (II), compound of (III) expression and salt thereof have isomer (as, optical isomer, geometrical isomer, tautomer etc.), the present invention includes all isomer, crystallized form and hydrate forms thereof.

Method of the present invention will be explained as follows in detail: the compound or its salt of logical formula I representative is to get by leading to the represented compound or its salt reaction of represented compound or its salt of formula II and logical formula III.

Used solvent can be any solvent of reactionlessness to be comprised aromatic hydrocarbon such as benzene, toluene, dimethylbenzene etc. in the reaction, ethers such as diox, tetrafluoro furans, phenylmethylether, ethylene glycol diethyl ether etc., halogenated hydrocarbon polymer such as methylene dichloride, chloroform, ethylene dichloride etc.; Acid amides such as N, dinethylformamide, N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Alcohols such as methyl alcohol, ethanol etc.; Nitrile such as acetonitrile etc.; Though be not limited to these solvents.But these solvents can use also two or more solvent use separately.The amount of the compound or its salt that logical formula III is represented is best excessive, preferably each mol is the compound of representative with general formula [II], or the compound or its salt of its salt shown in the molar logical formula III of 2-5, the consumption of the compound or its salt shown in logical formula III is about the 1-1.3 mol, then each mol is with the compound or its salt of general formula [II] representative, with enough once molar sour binding reagents.The acid binding reagents comprises organic or mineral alkali such as triethylamine.1,8-azo two ring [5,4,0] undecyl 7-alkene (DBU), tert.-butoxy potassium, salt of wormwood, yellow soda ash, sodium hydride etc.

Reaction is carried out at 0 ℃-150 ℃ usually, is preferably in 50 ℃-100 ℃ and carries out, and the reaction times is generally 5 minutes to 30 hours, preferably 30 minutes to 3 hours.

If R ¹The protecting group of expression carboxyl can be hydrolyzed into the free carboxy acid in the presence of common acid that is used for hydrolysis or alkali, hydrolysis reaction carries out at 0 ℃-100 ℃ usually, is preferably in 20 ℃-100 ℃ reactions 5 minutes to 50 hours, preferably 5 minutes to 4 hours.Further; if desired; can will transform salify or ester by salt-forming reaction or known esterification itself with the represented compound or its salt of general formula [I]; if with the compound or its salt of logical formula II or (III) representative beyond reactive site, also have active group (as; hydroxyl, amino etc.), then available usual method is protected active group before reaction; after question response is complete, slough protecting group again.

The compound that obtains like this can be with common separation and pure system measure, and as column chromatography, recrystallization extracts or the like.

The production method of initial compounds of the present invention will be described below.

Initial compounds of the present invention can be produced according to following production route:

R in the formula ^1aExpression and R ¹Identical carboxyl-protecting group; R ¹, R ²And R ^3aIdentical with top determined implication.

The salt of the compound that general formula [V] is represented is identical with the salt of the compound of general formula [II] representative.

(ⅰ) represented compound of general formula [V] and salt thereof can be correspondingly by with general formula [IV] represented compound and acetal such as N, N-diethyl formamido group dimethylacetal, N, reactions such as N-dimethylformamide base diethyl acetal, and then with general formula, R ²-NH ₂(R ²Identical with top determined implication) represented amine reaction and getting.

The used solvent of above-mentioned reaction can be from being any solvent to reactionlessness, and they comprise aromatic hydrocarbon such as benzene, toluene, dimethylbenzene etc.; Ethers such as diox, tetrafluoro furans, phenylmethylether, glycol dimethyl ether etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform, ethylene dichloride etc.; Amine such as N, dinethylformamide, N, N-dimethyl ethanoyl etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Certainly be not limited to these.These solvents can use separately also and can two or more solvent use.Each mol with the amount of the used acetal of the represented compound of general formula [IV] with 1 mol or more mostly be, especially about 1,0-1,3 mol are for well.Reaction is carried out at 0 ℃-100 ℃ usually, carry out better wanting 20 minutes to 50 hours usually at 50 ℃-80 ℃, with 1-3 hour for well, each mol is a mol or more with the amount of the represented used amine of compound of general formula [IV].Reaction is carried out at 0 ℃-100 ℃ usually, carries out to good at 10 ℃-60 ℃, reacted usually 20 minutes to 30 hours, with 1-5 hour for well.

Another kind method is, with general formula [IV] representative compound in the presence of aceticanhydride with ethyl orthoformate or original acid A ester reaction, then with general formula R ²-NH ₂Be the amine and the reactant salt thereof of representative, can obtain compound and salt thereof with general formula [V] expression.

(ⅱ) will can correspondingly obtain compound or its salt with the represented compound or its salt of general formula [V] having in the presence of the alkali or in the presence of the alkali-free, carrying out ring-closure reaction (preferably heating) with general formula [II] expression.

Any the solvent of reactionlessness all be can be used as the solvent of this reaction, comprise, as, acid amides such as N, dinethylformamide, N,N-dimethylacetamide etc.; Ethers is a diox, phenylmethylether, diglyme etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc., or the like, limit to these though have more than.These solvents can use separately, also two or more solvent can be used.Alkali comprises, as, sodium bicarbonate, salt of wormwood, tert.-butoxy potassium, sodium hydride etc.Each mol is advisable with 0.5 to 5 mol by the represented compound of general formula [V] or the amount of their the used alkali of salt.Reaction is carried out at 20 ℃ to 160 ℃ usually, and preferably at 100 ℃ to 150 ℃, the reaction times is generally 5 minutes to 30 hours, best 5 minutes to 1 hour.

The compound or its salt of general formula [II] or [V] expression, wherein R ¹Or R ^1aThe representation carboxy protecting group if desired, can be hydrolyzed into the free carboxy acid in the presence of common acid that is used for hydrolysis or alkali, hydrolysis reaction is preferably in 20 ℃～100 ℃ reactions 5 minutes to 50 hours, best 5 minutes to 4 hours usually at 0 ℃～100 ℃.Further; the represented compound or its salt of general formula [II] or [V] transforms salify or ester by salt-forming reaction or known esterification itself; if with the compound or its salt of general formula [II] or [V] representative beyond reactive site, also have active group (as; hydroxyl; amino etc.); then available usual method with the active group protection, after question response is finished, is sloughed protecting group again before reaction.

The compound that obtains like this can be with common separation and purifying measure, and as column chromatography, recrystallization extracts or the like.

Anti-microbial activity and acute toxicity typical compound according to the present invention is illustrated as follows.

1. anti-microbial activity

Experimental technique

According to Japanese chemotherapy can will standard method [chemotherapy (Chemo Therapy) 29(1), 76-79(1981)], 37 ℃ of heart infusion broth nutrient solutions, the bacterial solution of cultivating 20 hours (cultured solution of broth by Eiken Kagaku produce) is inoculated into the heart infusion agar substratum that contains medicine and cultivated 20 hours at 37 ℃, can be observed bacterial growth after this, the minimum concentration of measuring bacteria growing inhibiting is a minimum inhibitory concentration MTC(mcg/ml), the amount of inoculated bacteria is 10 ⁴Cell/dish (10 ⁶Cells/ml), the minimum inhibitory concentration MTC value of following test compound is shown in Table 1.

Used symbol has following meaning in table 1:

* 1: produce the penicillinase bacterium

* 2: produce the cephalosporinase bacterium

* 3: inoculation scale: 10 ⁸Cells/ml

Me: methyl

Et: ethyl

N-Pr: n-propyl

I-Pr: sec.-propyl

2. acute toxicity

Measuring medium lethal dose (LD) for mouse vein administration (the purebred mouse of ICR, male, body weight: 18-24 restrains) with above-mentioned the 5th, 6, No. 12 test compounds is 200 milligrams/kilogram or more.

When compound of the present invention was used as medicine or medicament, the carrier of being used always in its normal and common medicament preparation combined, and makes tablet by usual method, capsule, pulvis, syrup, particle, suppository, ointment, injection etc.Administration number of times can suitably change according to patient's symptom, and normally oral or parenteral canal drug administration (as injection, drop, rectal administration, adult 0.1-100 milligram/kg/day, once or divide for several times.

The present invention will reduce reference example, and example and preparation example are set forth in down.

Used symbol has following meaning in reference example and the example:

Me: methyl, Et: ethyl, n-Pr: n-propyl,

Ipr: sec.-propyl, Ac: ethanoyl, : allyl group,

N: propylidene.

Reference example 1

2 of 21 grams, 6-two chloro-5-fluorine Yan acid are dissolved in 210 milliliters the chloroform, add thionyl (two) chlorine of 23.8 grams and the N of 0.1 gram in gained solution, the N-dimethylformamide.The gained mixture was 70 ℃ of reactions 2 hours.The thionyl chloride pressure reducing and steaming of solvent and surplus, gained residue are dissolved in 21 milliliters the tetrahydrofuran (THF).The magnesium ethylate diethyl malonates of 25.1 grams are dissolved in 110 milliliters the tetrahydrofuran (THF).Solution is chilled to-40 ℃ to-30 ℃, under uniform temp, in 30 minutes, will prepare in advance 2, the tetrahydrofuran solution of 6 two chloro-5-fluorine nicotinoyl chlorines splashes in this solution, reaction mixture stirred one hour under uniform temp, after solution temperature is raised to room temperature gradually, the pressure reducing and steaming solvent, in the residue that obtains like this, add 200 milliliters of chloroforms and 100 ml waters, with 6N hydrochloric acid pH value is transferred to 1, tell organic layer, use 50 ml waters successively, the saturated common salt washing of 50 milliliter 5% sodium bicarbonate aqueous solution and 50 milliliters, anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent adds 50 ml waters and 0.15 tosic acid that restrains in gained oily product, after, the gained mixture split stirring reaction 2 hours 100 ℃ of plays again.Reaction mixture is with 100 milliliters of chloroform extraction.Organic layer is washed anhydrous magnesium sulfate drying, pressure reducing and steaming solvent with 50 milliliters saturated common salt; the gained residue gets (2 of 23.5 grams with the pure system of column chromatography (WAKO silica gel C-200, toluene wash-out); 6 two chloro-5-fluoro-Yan acyl groups) ethyl acetate, fusing point 64-65 ℃.

Infrared spectra (Potassium Bromide) centimetre: ^νC=0 1650,1630, and 1620.

Nuclear magnetic resonance spectrum (CDCl ₃) the δ value

1.25（1.29H;t，J＝7H），1.33（1.71H，t，J＝7H），

4.07（1.14H，S），4.28（2H，q，J＝7H），5.82（0.43H，S），

7.80（1H，d，J＝7H），12.62（0.43H.S）。

Reference example 2

8.8 gram (2.6-two chloro-5-fluoro-Yan acyls) ethyl acetate are dissolved in 40 milliliters the benzene, add the N of 4.5 grams then, N-dimethylformamide base dimethylacetal, mixture was 70 ℃ of reactions 1.5 hours then.After this, the 2,4 difluorobenzene amine of 4.1 grams are added in the above-mentioned reaction mixture, reactant was room temperature reaction 4 hours.Pressure reducing and steaming solvent, the residue pure system of column chromatography (WAKO silica gel C-200; Elutriant: chloroform), get 9.0 gram 2-(2,6-two chloro-5-fluoro-Yan acyl groups)-and 3-(2,4-two fluoroanilino)-ethyl propenoate, fusing point 138-139 ℃.

Infrared spectra (Potassium Bromide) centimetre: ^νC=0 1690,

Nuclear magnetic resonance spectrum (CDCl ₃) the δ value:

1.08（3H，t，J＝7H），4.10（2H，q，J＝7H），

6.77-7.40（4H，m，），8.50（1H，d，J＝13H）

12.70（1H，d，J＝13H）

With being shown in table 2 with the resulting compound of quadrat method.

Reference example 3

9.0 the 2-(2 of gram, 6 two chloro-5-fluorine Yan acyl groups)-and 3-(2,4 two fluoroanilino) ethyl propenoate is dissolved in 90 milliliters N, in the N-methylformamide, the sodium bicarbonates of 3.6 grams added in the above-mentioned solution, and then, mixture was 120 ℃ of reactions 20 minutes.Afterwards, remove solvent under reduced pressure, the resistates of gained is dissolved in 50 milliliters of chloroforms.Gained solution is washed with 30 ml waters and 30 ml waters and 30 milliliters of saturated common salt aqueous solution successively, uses anhydrous magnesium sulfate drying then.The pressure reducing and steaming solvent, the crystalline material of gained is washed with 30 milliliters of diethyl ether, gets 7.0 gram 7-chloro-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxo 1,8 naphthyridine-3-carboxylic acid, ethyl ester, fusing point 220-222 ℃.

Infrared spectra (Potassium Bromide) centimetre ^-1: ^νC=0 1730,1690.

Nuclear magnetic resonance spectrum (CDCl ₃) the δ value:

1.36（3H，t，J＝7Hz），4.30（2H，q，J＝7Hz），6.80-7.60（3H，m），8.27（1H，d，J＝7Hz），8.42（1H，s）.

With the compound shown in can table 3 with quadrat method.

Example 1

(1) with the 3.5 7-chloro-6-fluoro-1-(2 that restrain; 4 difluorophenyls)-1; 4-dihydro-4-oxygen-1; 8-naphthyridine 3-carboxylic acid, ethyl ester is dissolved in 35 milliliters the chloroform; 1.5 the triethylamine of gram N-ethanoyl piperazine and 1.6 grams adds in the above-mentioned solution; the gained mixture was 60 ℃ of reactions one hour; then, pressure reducing and steaming solvent, the gained residue pure system of column chromatography [WAKO silica gel C-200; elutriant: chloroform: ethanol 2 30: the 1(volume ratio)]; obtain the 7-(4-ethanoyl-1-piperazinyl of 3.5 grams)-6-fluoro-1-(2,4 difluorophenyls)-1,4-dihydro-4-oxygen-1; 8-naphthyridine-3-carboxylic acid, ethyl ester, fusing point 207-209 ℃.

Infrared spectra (Potassium Bromide) centimetre ^-1: ^νC=0 1730,1695.

Nuclear magnetic resonance spectrum (CDCl ₃) the δ value:

1.38（3H，t，J＝7Hz），2.05（3H，s），3.53（8H，br）

4.30（2H，q，J＝7Hz），6.80-7.75（3H，m），8.00（1H，d，J＝13Hz），8.30（1H S）.

With obtaining the compound shown in the table 4 with quadrat method.

(2) with the 2.5 7-(4-ethanoyl-1-piperazinyls that restrain)-6-fluoro-1-(2; the 4-difluorophenyl)-1; 4-dihydro-4-oxygen-1; 8-naphthyridine 3-carboxylic acid, ethyl ester is dissolved in 25 milliliters the 6N hydrochloric acid; gained vlil two hours; then, reaction mixture is chilled to room temperature, transfers PH to 12 with the sodium hydroxide of 1N; and then to transfer to PH with acetic acid be 6.5; the crystallization of separating out is filtered and is collected, with 30 milliliters of washings, drying; get the 6-fluoro-1-(2 of 1.8 grams; 4 difluorophenyls)-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8 naphthyridine-3-carboxylic acid.

Nuclear magnetic resonance spectrum (trifluoracetic acid-d ₁) the δ value:

3.30-4.50（8H，M），7.00-7.85（3H，M），

8.33（1H，d，J＝13Hz），9.21（1H，S）

Can obtain at the compound shown in the table 5 with same procedure.

Example 2

(1) dissolving 0.50 gram 7-chloro-6-fluoro-1-(2 in 5 milliliters of chloroforms, the 4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, in gained solution, add 0-20 gram 3-kharophen tetramethyleneimine and 0.15 gram triethylamine, after this gained mixture was reacted 1 hour at 60 ℃.Underpressure distillation removes and desolvates then, residue obtained with column chromatography [WAKO silica gel C-200, elutriant: chloroform: ethanol=30: the 1(volume ratio)] refining fusing point is 233-235 ℃ 7-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-diaza naphthyridines-3-carboxylic acid, ethyl ester 0.5 gram.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1725,1700

Nuclear magnetic resonance spectrum (CDCl ₃) the δ value:

6.75-7.60（4H，M），7.93（1H，d，J＝8Hz），

8.24（1H，S）

Obtain listed compound in the table 6 with similarity method.

(2) dissolving 0.25 gram 7-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl in 2.5 milliliters of 6N hydrochloric acid)-and 6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained vlil 2 hours.Then, reaction mixture is cooled to room temperature, with the 1N-aqueous sodium hydroxide solution its PH is adjusted to 12, is adjusted to 6.5 with acetic acid again.The crystallization filter collection of separating out with 2 milliliters of washings, drying, gets 0.18 gram 7-(3-amino-1-pyrrolidyl)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-diaza naphthyridines-3-carboxylic acid

Nuclear magnetic resonance spectrum (trifluoroacetic acid TFA-d ₁) the δ value:

2.25-2.85（2H，M），3.37-4.69（5H，M），

6.93-7.81（3H，M），8.22（1H;d，J＝11Hz），

9.16（1H，S）

Obtain listed compound in the table 7 with similarity method.

Example 3

(1) suspension 0.50 gram 7-chloro-6-fluoro-1-(2 in 15 milliliters of 6N hydrochloric acid, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8 naphthyridine-3-carboxylic acid, ethyl ester, suspension reflux 3 hours.Then, reaction mixture dilutes with 50 ml waters, with each 50 milliliters of chloroform extraction three times.United extraction liquid is with 100 milliliters of saturated sodium-chloride washings, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and the gained crystal material is washed with 15 milliliters of ether, gets 0.40 gram 7-chloro-6-fluoro-1-(2, the 4-difluorophenyl) 1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point 244-248 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1720

Nuclear magnetic resonance spectrum (d ₆-dimethyl sulfoxide (DMSO)) δ value:

7.26-8.56（3H，m），8.86（1H，d，J＝7H2），9.18（1H，S）

(2) suspension 0.30 gram 7-chloro-6-fluoro-1-(2 in 3 milliliters of dimethyl sulfoxide (DMSO), the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8 naphthyridines-3-carboxylic acid, then 0.25 gram N methyl piperazine is added in the gained suspension, after this, gained suspension was reacted 30 minutes at 60 ℃.Then, underpressure distillation removes desolvates, and adds 30 ml waters in residue obtained.The PH of gained mixture is adjusted to 12 with 10% aqueous sodium hydroxide solution, is adjusted to 7 with acetic acid again.The crystal material that leaching settles out with 5 milliliters of washings, obtains 0.24 gram 6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-7-(4-methyl isophthalic acid-piperazinyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point 208-209 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1730

Nuclear magnetic resonance spectrum (trifluoroacetic acid-d ₁) the δ value:

3.30（3H，S），3.45-5.25（8H，m），

7.12-8.10（3H，m），8.49（1H，d，J＝13Hz），

9.38（1H，S）

Example 4

Dissolving 2.0 gram 6-fluoro-1 in 5 milliliter of 47% bromine hydracid, 4-dihydro-1-(4-methoxyl group-2-aminomethyl phenyl)-7-(4-methyl isophthalic acid-piperazinyl) 4-oxygen-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained solution was 120-125 ℃ of reaction 2 hours.Reaction mixture is adjusted to PH13 with 10% aqueous sodium hydroxide solution, is adjusted to 6.5 with acetic acid again.The crystallization that filter collection settles out, with 10 milliliters of washings, 1.8 restrain 6-fluoro-1,4-dihydro-1-(4-hydroxy-2-methyl phenyl)-7-(4-methyl isophthalic acid-piperazinyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point＞280 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1725, the 1700(shoulder)

Nuclear magnetic resonance spectrum (trifluoroacetic acid-d ₁) the δ value:

2.08（3H，S），3.12（3H，S）2.88-5.12（8H，m）

6.93-7.62（3H，m），9.25（1H，S），

9.43（1H，d，J＝13Hz）

Obtain listed compound in the table 8 with similarity method

Example 5

Dissolving 0.40 gram 6-fluoro-1 in 10 milliliter of 47% bromine hydracid, 4-dihydro-1-(4-p-methoxy-phenyl)-the 7-(1-pyrrolidyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained solution was 120 ℃ to 125 ℃ reactions 2 hours.The PH of reaction mixture is adjusted to 13 with the 10% hydroxide aqueous solution, is adjusted to 6.5 with acetic acid then.The crystallization that the filter collection is separated out with 4 milliliters of washings, gets 0.30 gram 6-fluoro-1,4-dihydro-1-(4-hydroxy phenyl)-the 7-(1-pyrrolidyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point 263-265 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1725,1705

Nuclear magnetic resonance spectrum (trifluoroacetic acid-d ₁) the δ value

1.54-2.40（4H，m），3.14-4.14（4H，m），

6.95-7.69（4H，m），8.09（（1H，d，J＝12Hz），

9.14（1H，S）

Obtain down routine compound with similarity method:

6-fluoro-1,4-dihydro-1-(4-hydroxy phenyl)-7-(3-hydroxyl-1-pyrrolidyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid.

Fusing point: 180-183 ℃

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1725,1705

Example 6

At 0.1 gram 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxygen-1 adds 2 milliliters of 1N-aqueous sodium hydroxide solutions and two milliliters of ethanol in 8-naphthyridine-3-carboxylic acid, ethyl ester, and gained solution was 40 ℃ to 50 ℃ reactions 10 minutes.In reaction mixture, add acetic acid subsequently and regulate its PH to 6.5.Subsequently, mixture is with each 5 milliliters of twice of chloroform extraction.Extracting solution merges, and washes with 5 ml waters and 5 milliliters of saturated sodium-chloride water solutions in succession, uses anhydrous magnesium sulfate drying then.Underpressure distillation removes desolvates, and the gained crystal material is washed with 2 milliliters of ether, 0.08 restrain 7-(4-acetyl-1-piperazinyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point＞280 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1730

Nuclear magnetic resonance spectrum (d-dimethyl sulfoxide (DMSO)) δ value:

2.05（3H，S），3.57（8H，bs），

7.13-7.80（4H，m），8.13（1H，d，J＝13Hz），

8.70（1H，S）

Obtain listed compound in the table 9 with similarity method.

Example 7

At 0.10 gram 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(3-hydroxyl-1-pyrrolidyl)-4-oxygen-1, add 2 milliliters of 1N aqueous sodium hydroxide solutions and 2 milliliters of ethanol in 8-naphthyridine-3-carboxylic acid, ethyl ester, the gained mixture was 40 ℃ to 50 ℃ reactions 10 minutes.In reaction mixture, add acetic acid subsequently and regulate its PH to 6.5.Mixture is with each 5 milliliters of twice of chloroform extraction then.Extracting solution merges, and with 5 ml waters and 5 milliliters of saturated sodium-chloride water solution washings, uses anhydrous magnesium sulfate drying then in succession.Underpressure distillation removes desolvates, and the gained crystal material is washed to such an extent that 0.08 restrain 6-fluoro-1-(4-fluorophenyl with 2 milliliters of ether)-1,4-dihydro-7-(3-hydroxyl-1-pyrrolidyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, fusing point＞280 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1730

Nuclear magnetic resonance spectrum (d ₆-dimethyl sulfoxide (DMSO)) δ value:

1.92-2.52（2H，m），3.22-5.00（5H，m），

6.97-7.60（4H，m），8.01（1H，d，J＝11Hz），

9.00（1H，S）

With similarity method can table 10 in listed compound.

Example 8

Dissolving 0.25 gram 6-fluoro-1 in 2.5 milliliters of concentrated hydrochloric acids, 4-dihydro-1-(4-hydroxy-2-methyl phenyl)-and 4-oxygen-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid adds 20 milliliters of ethanol then in gained solution, the gained mixture was in stirring at room 15 minutes.The crystallization that leaching is separated out is washed with 5 milliliters of ethanol, gets 0.2 gram 6-fluoro-1,4-dihydro-1-(4-hydroxy-2-methyl phenyl)-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride.Fusing point＞280 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1725(shoulder), 1705

With similarity method can table 11 in listed compound

Example 9

Dissolving 2.0 gram 7-(3-amino-1-pyrrolidyls in 20 milliliters of concentrated hydrochloric acids)-and 6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid is added on 20 milliliters of ethanol in the gained solution in room temperature then, stirs 15 minutes.The crystallization that leaching is separated out with 40 milliliters of washing with alcohol, gets 1.4 gram 7-(3-amino-1-pyrrolidyls)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid hydrochloride, fusing point 247-250 ℃ (decomposition).

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1730

Example 10

At 0.3 gram 7-(4-ethoxycarbonyl-2-methyl-piperazinyl)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1 adds 5 milliliters of 1N-aqueous sodium hydroxide solutions and 5 milliliters of ethanol in 8-naphthyridine-3-carboxylic acid, ethyl ester, the gained mixture was 90 ℃ of reactions 2 hours.In reaction mixture, add acetic acid then its PH is adjusted to 6.5.The crystallization that leaching settles out washes dry then 0.2 gram 6-fluoro-1-(2, the 4-difluorophenyl of getting with water)-1,4-dihydro-7-(2-methyl isophthalic acid-piperazinyl)-4-oxygen-1,8-naphthyridine-3-carboxylic acid, ethyl ester, fusing point 230-239 ℃.

Infrared spectra (Potassium Bromide) cm ^-1: ^νC=0 1730,

Nuclear magnetic resonance spectrum (trifluoroacetic acid-d ₁) the δ value:

1.50（3H，S），3.20-5.15（7H，m），

7.00-7.90（3H，m），8.35（1H，d，J＝13H），

9.20（1H，S）

Example 11

Suspension 1.0 gram 3-amino-pyrrolidine dihydrochlorides add 2.06 gram triethylamines and make into solution in gained suspension in 20 milliliters of ethanol.Then with 2.0 gram 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid, ethyl ester is added in the solution in the time more than 15 minutes at 30 ℃, and the gained mixture was same thermotonus 3 hours.After reaction finishes, add 30 ml waters in reaction mixture, the crystallization filter collection of separating out is with 4 milliliters of washings.The gained crystal material is suspended in 13 milliliters of 6N hydrochloric acid, gained suspension reflux 2 hours.Subsequently, with the reaction mixture cooling, the crystallization that leaching is separated out is washed twice with each 2 milliliters.Get 7-(3-amino-1-pyrrolidyl)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid hydrochloride.

Infrared spectra (Potassium Bromide) cm ^-1: ^νC=0 1730

Example 12

10 gram 7-(3-amino-1-pyrrolidyls suspend in 75 milliliters of ethanol and 75 ml waters)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid.Add 5.2 in 40 ℃ and restrain tosic acid list hydrates in gained suspension, the gained mixture stirred 30 minutes in uniform temp.Continue it, make reaction mixture be chilled to 15 ℃, the crystallization that leaching is separated out, mixed solvent washing with 5 milliliters of ethanol and 5 ml waters, get 12.8 gram 7-(3-amino-1-pyrrolidyls)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid tosic acid list hydrate salt, fusing point 258-260 ℃

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1735

Nuclear magnetic resonance spectrum (dimethyl sulfoxide (DMSO)-d ₆) the δ value:

，3.12-4.30（5H，M），

2.27（S）

6.92-8.17（8H，M），8.79（1H，S）

Obtain following compounds with similarity method:

7-(3-amino-1-pyrrolidyl)-and 6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid oxalate.Fusing point (℃): 250-253.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1730

Example 13

Be dissolved at 1.6 gram methylsulphonic acids and add 5.00 gram 7-(3-amino-1-pyrrolidyls in the solution of 25 milliliters of acetic acid)-6-fluoro-1-12.4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid, after this, gained suspension in stirring at room to forming solution.In solution after this,, added 100 milliliters of ethanol in 30 minutes in 40 ℃-45 ℃.Subsequently, this reaction mixture is cooled to room temperature and stirred 30 minutes.The crystallization that leaching is separated out is given a baby a bath on the third day after its birth time with 20 milliliters of ethanol at every turn, 3.12 gram 7-(3-amino-1-pyrrolidyls)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid methyl sulfonate, fusing point＞300 ℃.

Infrared spectra (Potassium Bromide) Cm ^-1: ^νC=0 1735

Get following compounds with similarity method:

7-(3-amino-1-pyrrolidyl)-and 6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid.

Fusing point (℃): 220～230

Infrared spectra (Potassium Bromide) cm ^-1: ^νC=0 1735

Formulation examples 1

With 50 gram 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid and 49 gram crystalline celluloses, 50 gram W-Gums and 1 gram Magnesium Stearate mix, and this mixture is pressed and is formed 1000 platypelloid type tablets.

Formulation examples 2

With 100 gram 6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid mixes with 50 gram W-Gums, and the gained mixture is loaded in 1000 capsules and makes capsule.

Formulation examples 3

With 50 gram 7-(3-amino-1-pyrrolidyls)-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid and 49 gram crystalline celluloses, 50 gram W-Gums and 1 gram Magnesium Stearate mix, and this mixture is pressed into 1000 flat-section tablets.

Formulation examples 4

With 100 gram 7-(3-amino-1-pyrrolidyls)-1-(2, the 4-trifluorophenyl)-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid mixes with 50 gram W-Gums, and the gained mixture is loaded in 1000 capsules and makes capsule.

Claims (21)

1, a kind of preparation be expressed from the next 1,4-dihydro-4-oxygen-1, the method for 8-naphthyridines derivatives or its salt: (seeing left image)

R wherein ¹Represent hydrogen atom or carboxyl-protecting group, R ²Representative can be selected from the phenyl of the substituting group replacement of following group by at least one: halogen atom, alkyl, hydroxyl, alkoxyl group, cyano group, amino, amido and tri haloalkyl, R ^3bRepresentative can be selected from 1-pyrrolidyl, piperidino-(1-position only), 1-piperazinyl or the morpholino base of the substituting group replacement of following group by at least one; Alkyl, amino, hydroxyalkyl, hydroxyl, alkenyl, acyl group, alkylamino, dialkylamino, amido, carbalkoxy and N-acyl group-N-alkylamino is characterized in that the compound or its salt that will be expressed from the next:

R wherein ^3aRepresent halogen atom, R ¹And R ²Define the same, and the compound or its salt that is expressed from the next reaction:

R ^3b_H

R wherein ^3bDefine the same.

2, method according to claim 1, the wherein R in the starting compound general formula ²The phenyl that representative is replaced by a halogen atom at least.

3, method according to claim 2, the wherein R in the starting compound general formula ²Represent the 4-fluorophenyl.

4, method according to claim 2, the wherein R in the starting compound general formula ²Represent the 2,4 difluorobenzene base.

5, method according to claim 1, the wherein R in the starting compound general formula ^3bRepresentative can be selected from the 1-pyrrolidyl of the substituting group replacement of following group by at least one: amino, hydroxyl, alkylamino, dialkylamino, amido and N-acyl group-N-alkylamino.

6, method according to claim 5, the wherein R in the starting compound general formula ^3bRepresentative is by the 1-pyrrolidyl of amino or amido replacement.

7, method according to claim 6, the wherein R in the starting compound general formula ²The phenyl that representative is replaced by a halogen atom at least.

8, method according to claim 7, the wherein R in the starting compound general formula ²Represent the 4-fluorophenyl.

9, method according to claim 7, the wherein R in the starting compound general formula ²Represent the 2,4 difluorobenzene base.

10, method according to claim 1, the wherein R in the starting compound general formula ^3bRepresent 3-amino-1-pyrrolidyl.

11, method according to claim 10, the wherein R in the starting compound general formula ²The phenyl that representative is replaced by a halogen atom at least.

12, method according to claim 11, the wherein R in the starting compound general formula ²Represent the 4-fluorophenyl.

13, method according to claim 11, the wherein R in the starting compound general formula ²Represent the 2,4 difluorobenzene base.

14, method according to claim 1, the wherein R in the starting compound general formula ^3bRepresentative can be selected from the 1-piperazinyl of the substituting group replacement of following group by at least one: alkyl, hydroxyalkyl, alkenyl, acyl group and carbalkoxy.

15, method according to claim 14, the wherein R in the starting compound general formula ^3bRepresent the 1-piperazinyl.

16, method according to claim 15, the wherein R in the starting compound general formula ²The phenyl that representative is replaced by a halogen atom at least.

17, method according to claim 16, the wherein R in the starting compound general formula ²Represent the 4-fluorophenyl.

18, method according to claim 16, wherein R ²Represent the 2,4 difluorobenzene base.

19, method according to claim 1, wherein be to use 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid or its salt obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid or its salt.

20, method according to claim 1, wherein be to use 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid or its salt obtain 1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxygen-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid or its salt.

21, method according to claim 1, wherein be to use 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxygen-1,8-naphthyridine-3-carboxylic acid or its salt obtain 7-(3-amino-1-pyrrolidyl)-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-two fluoro-4-oxygen-1,8-diazine-3-carboxylic acid or its salt.