CN102443015A - 7-substituted quinoline carboxylic acid derivatives, preparation method and application thereof in antibiosis and antituberculosis - Google Patents
7-substituted quinoline carboxylic acid derivatives, preparation method and application thereof in antibiosis and antituberculosis Download PDFInfo
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Abstract
The invention discloses 7-substituted quinoline carboxylic acid derivatives, a preparation method and application thereof in antibiosis and antituberculosis. 7-(1-substituted-3-amino-1-tetrahydro pyrrole[3, 4-c] pyrrolyl) quinoline carboxylic acid derivatives are compounds, medical salts, physiologically hydrolysable esters, hydrates or isomers represented in the FORMULA I and having unexpected strong anti-bacterial and anti-tubercular activities; compared with the quinolone anti-bacterial and anti-tubercular medicaments in the market, the derivatives have more superior broad-spectrum anti-bacterial activities and anti-tubercular activities and have good prospects in preparing anti-bacterial medicaments or anti-tubercular medicaments.
Description
Technical field
The invention belongs to the medical chemistry field, be specifically related to a kind of 7-substd quinolines carboxylic acid derivative and preparation method thereof, with and in the purposes aspect antibiotic and the antitubercular agent.
Background technology
QNS has become a big class through the development in surplus 40 years and has been widely used in clinical wide spectrum, efficient, hypotoxic anti-infective chemotherapeutics.But it is, also undesirable to anerobes, mycoplasma and chlamydial activity because it is relatively poor to gram-positive bacteria activity.And owing to they are widely used, even abuse, its resistant organism is increased sharply; Methicillin-resistant gold Portugal bacterium (MRSA) particularly; The continuous appearance that methicillin-resistant form staph (MRSE) and vancomycin-resistant enterococcus (VRE) infect comprises the appearance of clinical general resistance mycobacterium tuberculosis strain, has become one of thorny problem that the clinicist faces; People press for its structure are transformed and modified; Search out antimicrobial spectrum more extensively reach antibiotic, tuberculosis is active stronger, especially stronger to these resistant organism activity antibiotic and antitubercular agent of Novel Quinolone class is to tackle these increasing drug-fast bacteria infections.
Document [Activity vs Mycobacterium tuberculosis:B.Ji et al, Antimicrob.Ag.Chemother.42,2066 (1998)] has reported that the very strong tuberculosis of Moxifloxacin is active, and it is clinical to have got into the III phase at present.
Summary of the invention
The objective of the invention is to have excellent antibacterial and the active compound of tuberculosis in order to provide; The contriver has carried out extensive studies, and design has been synthesized the 7-position and had various substituent Pyrrolidines [3,4-c] pyrazol-1-yl carbostyril compound; And the antibiotic and tuberculosis of having measured it is active; The final discovery, 7-(1-replacements-3-amino-1-Pyrrolidine [3,4-c] pyrazolyl) carbostyril compound has beyond thought antibiotic by force and tuberculosis is active to the wide spectrum pathogenic bacterium; And antitubercular agent antibiotic with the quinolones that has gone on the market compared, and it is active to have more superior broad spectrum antibiotic activity and tuberculosis.
Another object of the present invention is in order to provide a kind of 7-position to have the preparation method of various substituent Pyrrolidines [3,4-c] pyrazol-1-yl carbostyril compound.
A further object of the invention provides above-mentioned 7-position and has the purposes of various substituent Pyrrolidines [3,4-c] pyrazol-1-yl carbostyril compound aspect the antibiotic or antitubercular agent of preparation.
The object of the invention can reach through following measure:
Compound shown in the formula I and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer,
In the formula,
A is CH, CF, CCl, COCH
3, COCHF
2, CCH
3Or N;
R
1Be C
1～C
3Alkyl, FCH
2CH
2-, cyclopropyl, phenyl or halogenophenyl, perhaps from A to R
1Constitute C-O-CH
2-CH (CH
3The bridged bond of)-structure;
R
2Be H, NH
2Or CH
3
R
3Be C
1～C
6Alkyl, aryl, C
3～C
6The substituted C of naphthenic base, aryl
1-C
6Alkyl or C
4～C
6Through thiazolinyl.
A among the present invention is preferably CH, CF, CCl, COCH
3, COCHF
2Or N; Further be preferably CH, CF, CCl or N.
R among the present invention
1Be preferably C
1～C
3Alkyl, FCH
2CH
2-, cyclopropyl, halogen monosubstituted phenyl, halogen di-substituted-phenyl or halogen tri-substituted phenyl, perhaps from A to R
1Constitute C-O-CH
2-CH (CH
3The bridged bond of)-structure; Further be preferably C
1～C
3Alkyl, FCH
2CH
2-, cyclopropyl, MONO FLUORO BENZENE base, difluorophenyl or trifluorophenyl, perhaps from A to R
1Constitute C-O-CH
2-CH (CH
3The bridged bond of)-structure (be mother in the compound encircle the quinoline ring become the pyrido-benzoxazine ring).
R among the present invention
2Be preferably H or NH
2Most preferably be H.R
3Be preferably C
1～C
6Alkyl further is preferably C
1～C
3Alkyl most preferably is methyl.
The pharmaceutical salts of formula I compound of the present invention; Promptly in pharmaceutically acceptable atoxic pharmaceutical salts; Comprise and mineral acid; The salt that example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc. form is with organic acid, like the salt of formation such as acetate, trifluoroacetic acid, Hydrocerol A, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, racemic melic acid, xitix or oxysuccinic acid; And amino acids formed salt such as L-Ala, aspartic acid, Methionin or and sulfonic acid, the salt that forms like methylsulfonic acid, tosic acid etc.Also can be by their an alkali metal salt of conventional conversion processes, alkaline earth salt, silver salt, barium salt etc.
The physiology hydrolyzable ester of formula I compound of the present invention; Comprise not only replacing or unsubstituted fatty ester that 1～6 carbon atom especially is like lower alkyl esters such as methyl esters; And comprise through intravital chemical hydrolysis or enzymic hydrolysis; At least can partly be converted into the ester class of this formula (I) compound, like acetyl oxygen methyl esters, pivalyl oxygen methyl esters, ethoxycarbonyl 2-ethoxyethyl acetate, cholinesterase, amino ethyl ester (as: diformazan ammonia ethyl ester or 1-piperazinyl ethyl ester), 5-2,3-indanyl ester, phthalidyl ester and hydroxy alkyl ester (as: 2-hydroxyl ethyl ester or 2; 3-two hydroxypropyl acrylates), 5-methyl-2-oxo-1,3-dioxane penta-4-alkene methyl ester.
Formula I compound of the present invention also can be with solvolyte, and like the form existence of hydrate, therefore, these solvolytes (like hydrate) are also included within the compound of the present invention.
The isomer of formula I compound of the present invention, particularly optical isomer, like the optical isomer on 3,5,6,7 or 8 on the quinoline ring, perhaps the substituent optical isomer on Pyrrolidine and the pyrazoles ring all is included within the compound of the present invention.
Compound in formula I compound of the present invention and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or the isomer is preferably selected from following compound:
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid;
1-(2, the 4-difluoro) phenyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid;
1-ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-(2-fluorine) ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
9-fluoro-10-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-3 (S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid.
The invention still further relates to the preparation method of formula (I) compound, shown in reaction scheme 1, formula (I) but compound through type (II) compound and formula (III) compound or its salt react and prepare.
Reaction scheme 1:
A, R in reaction scheme 1
1, R
2And R
3Like aforesaid definition; X represents halogen atom, is preferably fluorine and chlorine.
Can be in reaction through in the presence of solvent and add suitable alkali (acid acceptor), at 20-200 ℃, have or do not have under the pressure condition stirring reaction formula (II) compound and formula (III) compound or with its salt 0.5～10 hour, come preparation formula (I) compound.Formula (III) compound or itself and the formed salt of example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid of available free form in this reaction.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred acetonitrile, N, DMSO 99.8MIN., pyridine or the HMPT of using.
This reaction is generally carried out in the presence of acid acceptor.Under this situation, in order to improve the reaction efficiency of more expensive initiator formula (II) compound, use excessive reactant formula (III) compound, for example to relative initiator for waiting mole to 10 times of molar weights, the preferred mole that waits is to 5 times of molar weights.When using excess reactant formula (III) compound, the unreacted mixture that stays after the reaction is recyclable and be reused for reaction.The acid acceptor (alkali) that is preferred for this reaction comprises mineral alkali; Like sodium hydrogencarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride etc., organic bases is like triethylamine, diisopropylethylamine, pyridine, N; N-Dimethylamino pyridine, N; N-dimethylamino-aniline, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) etc.
Formula of the present invention (I) compound also can prepare through method shown in the reaction scheme 2.
Reaction scheme 2: in the presence of solvent and acid acceptor, carried out condensation reaction 0.5～10 hour at 0～150 ℃ of following formula IV compound and (III) compound, the formula V compound; Then the formula V compound is reacted in basic solvent or acid solvent, remove boron-containing group, get formula (I) compound;
Reaction scheme further is following:
The R representative has or does not have the aliphatics carboxyl of substituted 2～6 carbon atoms of heteroatoms in formula (IV), (V) compound, or is the aromatic carboxyl of 7～11 carbon atoms, A, R
1, R
2And R
3Like aforesaid definition; X represents halogen atom, is preferably fluorine and chlorine.
It is currently known methods that formula of the present invention (II) compound is converted into formula (IV) compound earlier, and can easily realize transforming (seeing EP:0352123, CN:1059527A etc.) by existing disclosed method.
The compound of logical formula V can prepare like this:
Make the compound of represented compound of general formula (IV) and general formula (III) expression carry out condensation.
General formula (III) compound is with the same in reaction scheme 1, and in reaction scheme 2, this step reaction can be used formula (III) compound of free cpds form, or itself and the salt of hydrochloric acid, Hydrogen bromide or trifluoroacetic acid formation.
In reaction, can be through in the presence of solvent and acid acceptor, at 0～150 ℃, have or do not have under the pressure condition stirring reaction formula (IV) compound and formula (III) compound 0.5～10 hour, prepare the formula V compound.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects, preferably use acetonitrile, N, DMSO 99.8MIN., pyridine or HMPT.
This reaction is generally carried out in the presence of acid acceptor.Under this situation, in order to improve the reaction efficiency of more expensive initiator formula (IV) compound, use excessive reactant formula (III) compound, for example, for waiting mole to 10 times of molar weights, the preferred mole that waits is to 5 times of molar weights to relative initiator.When using excess reactant formula (III) compound, the unreacted mixture that stays after the reaction is recyclable and be reused for reaction.The acid acceptor that is preferred for this reaction comprises mineral alkali; Like sodium hydrogencarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride etc., organic bases is like triethylamine, diisopropylethylamine, pyridine, N; N-Dimethylamino pyridine, N; N-dimethylamino-aniline, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO) etc.
Logical formula V compound can come preparation formula (I) compound through the hydrolysis boric acid ester.Usually hydrolysis in basic solvent (for example; Solution in methyl alcohol, ethanol, THF 、 diox or water such as triethylamine, ammoniacal liquor, sodium hydrogencarbonate, salt of wormwood, yellow soda ash, sodium hydroxide); Or (for example, the solution in water, alcohol, THF 、 diox, chloroform, methylene dichloride such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid, Hydrogen bromide) reaction under 0～150 ℃ realized in 0.5～10 hour in acidic solution.
Formula (II) compound as initiator is a known compound in the present invention, and can easily make by known method in the existing publication.For example: L.A.Mitscher etc., J.Med.Chem.30,2283 (1987); J.Med.Chem.31,503 (1988); D.T.W.Chu etc., J.Med.Chem.29,2633 (1986); J.M.Domagala etc., J.Med.Chem.34,1142 (1991); D.Bouzard etc., J.Med.Chem.35,518 (1992); J.M.Domagala etc., J.Med.Chem.31,991 (1988) etc.
The present invention also protects the midbody of preparation I compound, i.e. the salt that forms of compound shown in the formula III or itself and hydrochloric acid, Hydrogen bromide or trifluoroacetic acid,
In the formula, R
3Definition as stated.
Compound shown in the formula III can prepare according to the method shown in the reactions route 3:
Reaction scheme 3:
Wherein the gained compound is formula (III) compound.
P represents amino protecting group; R
3Like aforesaid definition.Described amino protecting group comprises formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formamido-, p-toluenesulfonyl, methoxy or ethoxy or uncle's fourth oxygen or trichloro-ethoxycarbonyl or fluorenylmethyloxycarbonyl, replacement or not substituted benzyl oxygen carbonyl, alkyl acyl-oxygen methyl, replacement or not substituted benzyl, trityl, tetrahydrofuran base, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alpha-aminoalkyl acyl group.
Amino initiator and R through protection (like Boc)
3NHNH
2In ethanol, react compound (1), deaminize protection base obtains compound (III).
Compound and pharmaceutical salts thereof shown in the formula I of the present invention, physiology hydrolyzable ester, hydrate or isomer can be applied to prepare antibacterials or antitubercular agent aspect, and its using dosage and existing xacin-series medicine are similar.This compounds has beyond thought strong antibiotic and tuberculosis is active, and antitubercular agent antibiotic with the quinolones that has gone on the market compared, and has more superior broad spectrum antibiotic activity and tuberculosis activity.
Embodiment
Following examples are used to explain the present invention, but are not used for limiting scope of the present invention.
Embodiment 1, amino Pyrrolidine [3, the 4-c] pyrazole hydrochloride of 1-methyl-3-
N
2Protection down, 1-tertbutyloxycarbonyl-3-cyanic acid-4-pyrrolidone (4.20g, 0.02mol), the 40% methyl hydrazine aqueous solution (2.32g, 0.02mol) and the mixture of ethanol (100ml) react 6h in stirring at room.React the solvent evaporated that finishes, the gained resistates is dissolved in methylene dichloride (50ml), uses the saturated common salt water washing, anhydrous magnesium sulfate drying.Filter, the resistates after concentrating is dissolved in methyl alcohol (50ml), feeds exsiccant HCl gas, and TLC follows the tracks of until reacting completely.The solid that filtration is separated out, vacuum-drying get off-white color solid 0.80g (yield 23.0%).
1HNMR(400MHz，DMSO-d
6)δppm：3.45(3H，s，CH
3)，4.19(2H，s，CH
2)，4.43(2H，s，CH
2)
MS(ESI，m/z)：139(M
++1)
Embodiment 2,1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (11g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) reacts 8h in stirring at room.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets off-white color solid 1.26g (yield 83.4%).
1HNMR (400MHz, DMSO-d
6) δ ppm:1.15～1.29 (4H, m, cyclopropyl CH
2CH
2), 3.53 (3H, s, CH
3), 3.70～3.77 (1H, m, cyclopropyl CH), 4.68～5.000 (4H, m, 2 * CH
2), 8.11 (1H, d, J=12.8Hz, 5-H), 8.65 (1H, s, 2-H).
MS(ESI，m/z)：385(M
++1)
Embodiment 3,1-(2, the 4-difluoro) phenyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-(2, the 4-difluoro) phenyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (1.34g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) reacts 9h in stirring at room.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets white solid 1.66g (yield 91.1%).
1H?NMR(400MHz，DMSO-d
6)δppm：3.48(3H，s，CH
3)，3.84～4.25(4H，m，2×CH
2)，7.33～7.36(1H，m，ph-H)，7.70(1H，s，ph-H)，7.78～7.85(1H，m，ph-H)，8.06(1H，d，J＝12.8Hz，5-H)，8.73(1H，s，2-H)。
MS(ESI，m/z)：457(M
++1)
Embodiment 4,1-ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-ethyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (1.06g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) is in 60 ℃ of stirring reaction 72h.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets yellow solid 1.2g (yield 77.0%).
1H?NMR(400MHz，DMSO-d
6)δppm：1.46(3H，t，J＝6.4Hz，NCH
2 CH 3 )，3.53(3H，s，CH
3)，4.58(2H，q，J＝6.4Hz，N
CH 2 CH
3)，4.70～4.77(4H，m，2×CH
2)，7.81(1H，d，J＝14.4Hz，5-H)，8.90(1H，s，2-H)。
MS(ESI，m/z)：390(M
++1)
Embodiment 5,1-(2-fluorine) ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-(2-fluorine) ethyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (1.10g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) is in 60 ℃ of stirring reaction 72h.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets yellow solid 1.10g (yield 68.0%).
1H?NMR(400MHz，DMSO-d
6)δppm：3.50(3H，s，CH
3)，4.74～4.85(4H，m，2×CH
2)，4.88～4.95(4H，m，CH
2CH
2F)，7.80(1H，d，J＝14.4Hz，5-H)，8.74(1H，s，2-H)。
MS(ESI，m/z)：408(M
++1)
Embodiment 6,1-cyclopropyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (1.10g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) is in 60 ℃ of stirring reaction 72h.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets yellow solid 1.10g (yield 69%).
1HNMR (400MHz, DMSO-d
6) δ ppm:1.10～1.14 (4H, m, cyclopropyl CH
2CH
2), 3.50 (3H, s, CH
3), 4.05～4.10 (1H, m, cyclopropyl CH), 4.60～4.84 (4H, m, 2 * CH
2), 7.73 (1H, d, J=14.0Hz, 5-H), 8.61 (1H, s, 2-H).
MS(ESI，m/z)：402(M
++1)
Embodiment 7,1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Embodiment 1 compound (0.72g, 4.0mmol), 1-cyclopropyl-6,7-two fluoro-8-difluoro-methoxies-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (1.26g, 4.0mmol), the mixture of triethylamine (1ml) and acetonitrile (30ml) is in 60 ℃ of stirring reaction 72h.The solid that filtration is separated out, water is washed till neutrality, and vacuum-drying gets yellow solid 0.86g (yield 47.2%).
1HNMR (400MHz, DMSO-d
6) δ ppm:1.00～1.17 (4H, m, cyclopropyl CH
2CH
2), 3.49 (3H, s, CH
3), 4.02～4.08 (1H, m, cyclopropyl CH), 4.53～4.70 (4H, m, 2 * CH
2), 6.90 (1H, t, J=73.6Hz, OCHF
2), 7.87 (1H, d, J=13.6Hz, 5-H), 8.73 (1H, s, 2-H).
MS(ESI，m/z)：450(M
++1)
Embodiment 8,1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Boric acid (1.24g, 20.0mmol), propionic anhydride (9.1ml, 70.1mmol), in 100 ℃ of stirring reaction 25min; Reaction 0.5h under 150 ℃ reduces to 105 ℃ again, adds 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester (0.42g; 1.3mmol), reaction 3.5h reduces to room temperature, in the impouring frozen water; Filter, ethanol is washed, and vacuum-drying gets the faint yellow solid product.
Embodiment 1 compound (0.36g, add 2.0mmol) and behind acetonitrile (15ml) the suspension-s stirring at room 0.5h of triethylamine (1ml) above-mentioned gained solid (0.84g, 2.0mmol), 60 ℃ of stirring reaction 72h.Remove solvent under reduced pressure, resistates is dissolved in 5% aqueous sodium hydroxide solution, and stirring at room reaction 0.5h filters, and filtrating transfers pH to neutral with 3% hydrochloric acid.Filter, the filter cake washing, vacuum-drying gets product 0.21g (yield 26.0%).
1H NMR (400MHz, CDCl
3) δ ppm:1.03～1.28 (4H, m, cyclopropyl CH
2CH
2), 3.70 (3H, s, CH
3), 3.76 (3H, s, OCH
3), 4.06～4.09 (1H, m, cyclopropyl CH), 4.67～4.80 (4H, m, 2 * CH
2), 7.91 (1H, d, J=13.6Hz, 5-H), 8.84 (1H, s, 2-H).
MS(ESI，m/z)：414(M
++1)
Embodiment 9,9-fluoro-10-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-3 (S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid
Boric acid (1.24g, 20.0mmol), (9.1ml 70.1mmol), in 100 ℃ of stirring reaction 25min, reacts 0.5h down in 150 ℃ to propionic anhydride again; Reduce to 105 ℃, add 9,10-two fluoro-3 (S)-methyl-7-oxos-2,3-dihydro-7H-pyrido [1,2; 3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester (0.36g, 1.3mmol), reaction 3.5h reduces to room temperature; In the impouring frozen water, filter, ethanol is washed, and vacuum-drying gets the faint yellow solid product.
Embodiment 1 compound (0.72g, add 4.0mmol) and behind acetonitrile (15ml) the suspension-s stirring at room 0.5h of triethylamine (1ml) above-mentioned gained solid (1.62g, 4.0mmol), 60 ℃ of stirring reaction 72h.The solid that filtration is separated out is dissolved in 5% aqueous sodium hydroxide solution with it, and stirring at room reaction 0.5h filters, and filtrating transfers pH to neutral with 3% hydrochloric acid.Filter, the filter cake washing, vacuum-drying gets product 0.47g (yield 29.0%).
1H?NMR(400MHz，CDCl
3)δppm：1.41～1.46(3H，m，CH
3)，3.50(3H，s，NCH
3)，4.30～4.33(1H，m，CH)，4.49～4.87(6H，m，3×CH
2)，7.56(1H，d，J＝14.0Hz，5-H)，8.89(1H，s，2-H)。
MS(ESI，m/z)：400(M
++1)
Experimental example 1
It is active that this experimental example is to study the antibiotic and tuberculosis of The compounds of this invention.
Antibiotic and the tuberculosis of The compounds of this invention is active to be that (MIC mg/L) realizes to the minimum inhibitory concentration of reference culture, clinical isolates strain through measuring it.
The bacterium minimum inhibitory concentration is measured as follows: adopt plate doubling dilution and Denlay multiple spot inoculator to carry out drug sensitive experiment, experimental bacteria increases bacterium with nutrient broth and angry heart immersion liquid; Become various desired concns with the doubling dilution of MH meat soup behind the medicine dissolution; Add respectively in right amount in plate; The MH nutrient agar dissolves quantitative injection the in back and contains mixing in the soup plate; The final concentration of medicine is respectively 0.03,0.06,0.125......128 μ g/ml, in the plate after the culture medium solidifying with multiple spot inoculator inoculation experiments bacterium (10
5The cfu/ point), put 35 ℃ of constant temperature culture observations after 18 hours, the minimum concentration of contained drug is minimum inhibitory concentration (MIC) in the plate of asepsis growth.
Tubercule bacillus activity test method: instrument and reagent: BacT/Alert system, mycobacterium culturing bottle (MB).Trial drug preparation: Rifampin (RIF) solvent absolute ethyl alcohol, diluent zero(ppm) water, vazadrine (INH), Tibutol (EMB), Moxifloxacin, CIPROFLOXACIN USP 24 (CIP) solvent, the equal zero(ppm) water of diluent; The ultimate density 0.12-128ug/ml of medicine in each culturing bottle.The preparation of former times of bacteria suspension: after the positive reaction of MB bottle, break up bacterium (in 36 hours) to positive MB bottle concussion; Former times of bacteria suspension of the preparation of 1% former times of bacteria suspension: 0.1ml adds in the 10mlMB bottle.The interpretation standard growth control has dual mode; A kind of is that direct growth is controlled, and as operation index, bacterial concentration is a former times of bacteria suspension; Another kind is 1% growth control; Bacterial concentration is 1% former times of bacteria suspension, as interpretation Rifampin (RIF), and vazadrine (INH), Tibutol (EMB), Moxifloxacin, CIPROFLOXACIN USP 24 (CIP) result's index.
The result judges:
1.GC bottle appears and included medicine bottle in positive back two days and also be positive, and representes that this medicine is invalid.
2.GC bottle presents the positive two days later, contains medicine bottle and just is positive (generally not being), representes this susceptibility sense.
Table 1 has been listed some representation compounds in the application's the formula I compound to the antibacterial activity in vitro of various gram-positive microorganisms and negative bacterium, and compares with two Comprecin Moxifloxacins, CIPROFLOXACIN USP 24s.
Table 1MIC (ug/ml)
Each compound of table 2 embodiment and 4 kinds of antibacterials are to the MIC (ug/ml) of mycobacterium tuberculosis
| Antibacterials | H37Rv ATCC27294 | Tubercule bacillus (clinical strain MDR926) |
| The vazadrine | 0.12 | 64.0 |
| Rifampin | 2.0 | ＞256.0 |
| Tibutol | 1.0 | 128.0 |
| Moxifloxacin | 0.25 | 1.0 |
| Embodiment 5,8 | 0.120.25 | 0.51.0 |
| Embodiment 4,7, and 9 | 0.251 | 14 |
| Embodiment 2,3, and 6 | 12 | 48 |
H37Rv ATCC27294 standard Quality Control bacterial strain
The clinical general Resistant strain of tubercule bacillus (clinical strain MDR926)
The American National clinical laboratory stdn council (Clinical and Laboratory StandardsInstitute, CLSI are adopted in this test; Formerly NCCLs) agar doubling dilution (the Two-fold agar dilution method that recommends; Performance Standards for Antimicrobial Susceptibility Testing) measure respectively tried thing to the minimum inhibitory concentration of test strain (The minimum inhibitory concentration, MIC).
Under the experiment condition, compound of the present invention is to the golden bacterium MRSA of Portugal, the MSSA of this test, form staph MRSE, and MSSE and streptococcus pneumoniae all have anti-microbial effect, and the MIC value of most bacterial strains is at 0.5-16ug/ml.
Each compound to the anti-microbial effect of examination gram positive organism basic with the Moses, encircle third quite or more excellent, and to tubercule bacillus, particularly the general resistance bacillus of clinical drug-resistant has great activity.
Claims (14)
1. compound and pharmaceutical salts thereof shown in the formula I, physiology hydrolyzable ester, hydrate or isomer,
In the formula,
A is CH, CF, CCl, COCH
3, COCHF
2, CCH
3Or N;
R
1Be C
1～C
3Alkyl, FCH
2CH
2-, cyclopropyl, phenyl or halogenophenyl, perhaps from A to R
1Constitute C-O-CH
2-CH (CH
3The bridged bond of)-structure;
R
2Be H, NH
2Or CH
3
R
3Be C
1～C
6Alkyl, aryl, C
3～C
6The substituted C of naphthenic base, aryl
1-C
6Alkyl or C
4～C
6Thiazolinyl.
2. compound according to claim 1 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said A is CH, CF, CCl or N.
3. compound according to claim 1 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said R
1Be C
1～C
3Alkyl, FCH
2CH
2-, cyclopropyl, halogen monosubstituted phenyl, halogen di-substituted-phenyl or halogen tri-substituted phenyl, perhaps from A to R
1Constitute C-O-CH
2-CH (CH
3The bridged bond of)-structure.
4. compound according to claim 1 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said R
2Be H or NH
2
5. compound according to claim 1 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said R
3Be C
1～C
6Alkyl.
6. compound according to claim 5 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said R
3Be C
1～C
3Alkyl.
7. compound according to claim 1 and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer is characterized in that said compound is selected from:
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid;
1-(2, the 4-difluoro) phenyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid;
1-ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-(2-fluorine) ethyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6,8-two fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-difluoro-methoxy-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
9-fluoro-10-(1-methyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-3 (S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid.
8. the preparation method of compound shown in the described formula I of claim 1 and pharmaceutical salts, physiology hydrolyzable ester, hydrate or isomer; It is characterized in that with formula (II) compound and formula (III) compound or with its salt; In the presence of solvent and acid acceptor; And 20～200 ℃, have or do not have under the pressure reaction 0.5～10 hour, formula (I) compound; Reaction equation is following:
X is a halogen in the formula.
9. the preparation method of compound and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer shown in the formula I according to claim 8 is characterized in that said solvent is acetonitrile, N, DMSO 99.8MIN., pyridine or HMPT; Said acid acceptor is sodium hydrogencarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride, triethylamine, diisopropylethylamine, pyridine, N; N-Dimethylamino pyridine, N; N-dimethylamino-aniline, 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene or 1,4-diazabicyclo [2.2.2] octane.
10. the preparation method of compound shown in the described formula I of claim 1 and pharmaceutical salts, physiology hydrolyzable ester, hydrate or isomer; It is characterized in that in the presence of solvent and acid acceptor; Carried out condensation reaction 0.5～10 hour at 0～150 ℃ of following formula (IV) compound and (III) compound, the formula V compound; Then the formula V compound is reacted in basic solvent or acid solvent, remove boron-containing group, get formula (I) compound; Reaction equation is following:
In
formula
X is a halogen.
11. the preparation method of compound and pharmaceutical salts thereof shown in the formula I according to claim 10, physiology hydrolyzable ester, hydrate or isomer is characterized in that said solvent is acetonitrile, N, DMSO 99.8MIN., pyridine or HMPT; Said acid acceptor is sodium hydrogencarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride, triethylamine, diisopropylethylamine, pyridine, N; N-Dimethylamino pyridine, N; N-dimethylamino-aniline, 1; 8-diazabicyclo [5.4.0] 11 carbon-7-alkene or 1,4-diazabicyclo [2.2.2] octane; Said basic solvent is triethylamine, ammoniacal liquor, sodium hydrogencarbonate, salt of wormwood, yellow soda ash or the sodium hydroxide solution in methyl alcohol, ethanol, THF 、 diox or water; Said acid solvent is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or the Hydrogen bromide solution in water, alcohol, THF 、 diox, chloroform or methylene dichloride.
12. the application aspect the preparation antibacterials of compound and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer shown in the described formula I of claim 1.
13. the application aspect the preparation antitubercular agent of compound and pharmaceutical salts thereof, physiology hydrolyzable ester, hydrate or isomer shown in the described formula I of claim 1.
14. a midbody for preparing the described formula I compound of claim 1, it is the salt that compound shown in the formula III or itself and hydrochloric acid, Hydrogen bromide or trifluoroacetic acid form,
In the formula,
R
3Be C
1～C
6Alkyl, aryl, C
3～C
6The substituted C of naphthenic base, aryl
1-C
6Alkyl or C
4～C
6Thiazolinyl.
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|---|---|---|---|---|
| CN106831795A (en) * | 2017-01-16 | 2017-06-13 | 石家庄学院 | Quinolone isoalantolactone derivative and its preparation and application |
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2010
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