CN100497331C - 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same - Google Patents
7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same Download PDFInfo
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- CN100497331C CN100497331C CNB2007101456083A CN200710145608A CN100497331C CN 100497331 C CN100497331 C CN 100497331C CN B2007101456083 A CNB2007101456083 A CN B2007101456083A CN 200710145608 A CN200710145608 A CN 200710145608A CN 100497331 C CN100497331 C CN 100497331C
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a 7-(4-ketoxime-3-amino-1-piperidine) new quinolyl carboxylic acid derivation, the preparation process and the medical use as well as antimicrobials and feed additives containing the derivations thereof, in particular to a new fluoroquinolone formate derivation. A 4-ketoxime-3-amino-1-piperidine are on the fluoroquinolone nucleus 7-position of the derivation, a methoxyl is on 8-position, and a cyclopropyl is on 1-position. Compared with the prior fluoroquinolone antibacterial drugs, the derivation has more excellent Gram positive bacteria activity and extended-spectrum antibacterial activity.
Description
Technical field
The invention belongs to the medical chemistry field, relate to and have active new quinaldinic acid derivative of excellent antibacterial and preparation method thereof, and the antibacterial combination that contains them; Particularly, the present invention relates to 7-(4-oximido-3-amino-piperidino) new quinaldinic acid derivative.
Background technology
Quinolones develops into the anti-infective chemotherapeutics that has become a class wide spectrum, efficient, low toxicity now from Nalidixic Acid (nalidixic acid, J.Med.Chem.1962,5,1063) in 1962.Because they are widely used, even abuse, its resistant organism is increased sharply, methicillin-resistant gold Portugal bacterium (MRSA) particularly, the continuous appearance of methicillin-resistant form staph (MRSE) and vancomycin-resistant enterococcus (VRE) infection has become one of thorny problem that the clinicist faces, people press for that to search out antimicrobial spectrum wider, anti-microbial activity is stronger, and especially stronger to these resistant organism activity Novel Quinolone class antimicrobial drug is to tackle these increasing drug-fast bacteria infections.
Japanese scholar in 1988 discloses the synthetic and biological activity (JP:122722/1988 that the 7-position has the fluoroquinolone compounds of 3-substituted-amino-piperidino; JP:310418/1988), outstanding representative wherein is the Q-35 (balofloxacin) of having succeeded in developing and having ratified to go on the market, and it has active preferably to the gram-positive microorganism that comprises MRSA.Its shortcoming is a poorly water-soluble, thus can only make oral preparations, thus limited its widespread use.
Korea S scholar in 1994 discloses the synthetic and biological activity (KR:13604/1994 that the 7-position has the fluoroquinolone compounds of 3-oximido-4-aminomethyl-1-pyrrolidyl; KR:39915/1994; KR:39930/1994; CN:1114959A/1996), outstanding representative wherein is to have succeeded in developing and by the FDA approval gemifloxacin (gemifloxacin) in U.S.'s listing, it is except having broad spectrum of activity, its outstanding advantage is other Comprecins that the activity to streptococcus pneumoniae is better than having gone on the market, its shortcoming is not strong to common clinically golden Portugal bacterium (comprising increasing MRSA) activity, thereby has limited its range of application clinically.
2006, scholars such as Yang Yushe disclose the 7-position and have had 7-[3-amino (or aminomethyl)-4-oximido-piperidino] the synthetic and biological activity (CN1850823A) of carbostyril compound, and each substituting group in its general formula carried out widely definition, but wherein only specifically having enumerated the 1-position is 1 of cyclopropyl, 8-naphthyridines based compound.
In order to overcome above-mentioned existing in prior technology defective, the inventor has carried out extensive studies, by when 3-amino (or 3-aminomethyl)-4-oximido piperidines-1-bases with different replacements are introduced in the 7-position of quinolone skeleton, other locational substituting groups of conversion quinolone skeleton (comprise that the 1-position is Et, CH
2CH
2F, 2-fluorophenyl, 2,4 difluorobenzene base, cyclopropyl; The 5-position is H, NH
2, Me; The 8-position is N, CH, CCl, CF, COMe, COCHF
2, CMe or 1-position and 8-position be connected to
Deng), and the pharmacologically active of mensuration gained compound.The final discovery, having only the 1-position of bibliographical information different from the past is cyclopropyl, the 5-position is a hydrogen, the 8-position is a methoxyl group, the 7-position is that the Novel Quinolone derivative of 3-amino-4-oximido-piperidino just has beyond thought strong anti-microbial activity to the wide spectrum pathogenic bacterium, compare with the carbostyril family antibacterial drugs that has gone on the market, it significantly has more superior resisting gram-positive bacteria activity and broad spectrum of activity, is gemifloxacin and baloxacin 4～32 times to the activity of the golden Portugal bacterium that comprises MRSA and MRSE especially.
Summary of the invention
The object of the present invention is to provide a kind of new by general formula (I) expression the quinolone carboxylic acid compounds and pharmaceutical salts, physiology hydrolyzable ester, hydrate or isomer,
Wherein:
R
1Represent C
1～C
6Alkyl or cycloalkyl; Or benzyl or substituted benzyl; Or phenyl or substituted-phenyl;
R
2, R
3Can be identical, also can be different, represents H separately, C
1-C
6-alkyl; amino protecting group etc.; these amino protecting groups have: formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formyl radical, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl, isobutyl boc and trichloro-ethoxycarbonyl, 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.
In the piperidines moieties of the general formula that the present invention relates to (I) compound, the carbon atom that links to each other with amino or aminomethyl is a unsymmetrical carbon, therefore can R or S or R and S blended form exist, the present invention includes all these isomer and mixture.
For general formula of the present invention (I) compound, because the existence of 4-position oximido in the piperidines moieties, therefore general formula (I) compound can E or the configuration form of Z or E and Z mixture exist, general formula of the present invention (I) compound comprises all these isomer and mixture.Wherein, preferred E formula configuration.
Formula of the present invention (I) compound is at pharmaceutically acceptable non-toxic salt.Comprise and mineral acid, the salt that example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid etc. form, with organic acid, salt as formation such as acetate, trifluoroacetic acid, citric acid, toxilic acid, oxalic acid, succsinic acid, phenylformic acid, tartrate, fumaric acid, amygdalic 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 as methylsulfonic acid, tosic acid etc.Also their an alkali metal salt of conversion processes, alkaline earth salt, silver salt, barium salt etc. routinely.
The ester class of formula of the present invention (I) compound not only comprises and replacing or unsubstituted fatty ester, especially 1-6 carbon atom, as lower alkyl esters such as methyl esters, and comprise by intravital chemical hydrolysis or enzymic hydrolysis, at least can partly be converted into the ester class of formula (I) compound, as acetyl oxygen methyl esters, pivalyl oxygen methyl esters, the 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 of the present invention (I) compound also can solvate (as hydrate) form exist, therefore, these solvates (as hydrate) are also included within the The compounds of this invention.
The present invention specifically comprises following compound, and their pharmaceutical salts, physiology hydrolyzable ester, hydrate or isomer:
1-cyclopropyl-6-fluoro-7-(3-amino-4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-methylamino--4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-amino-4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-methylamino--4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-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:
R representative has or does not have the aliphatics carboxyl of 2-6 the carbon atom that heteroatoms replaces in formula (II), (IV) compound, or is the aromatic carboxyl of 7-11 carbon atom, the R in formula (II '), (II), (IV), (I) compound
1, R
2, R
3Definition as the aforementioned; X represents halogen atom, is preferably fluorine and chlorine.
The method that among the present invention formula (II ') compound is converted into formula (II) compound earlier is a currently known methods, and can easily realize transforming (seeing EP:0352123, CN:1059527A etc.) by existing disclosed method.
The compound of general formula (IV) can prepare like this:
Make the compound of represented compound of general formula (II) and general formula (III) expression carry out condensation.
In reaction, can be by in the presence of solvent and add suitable alkali, or without solvent, satisfy the demand with excessive formula (III) compound, in room temperature to 200 ℃, have or do not have under the pressure condition stirring reaction formula (II) compound and formula (III) compound 0.5-10 hour, come preparation formula (IV) compound.Formula (III) compound of available free form of mixtures or itself and the formed salt of example hydrochloric acid, Hydrogen bromide or trifluoroacetic acid in this reaction.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine or the hexamethyl-phosphoramide of using.
This reaction is generally carried out in the presence of acid acceptor.In this case, in order to improve the reaction efficiency of more expensive reaction substrate formula (II) compound, using excessive reactant formula (III) compound, for example, is to wait mole to 10 times of molar weights to relative initiator, preferred equimolar amount to 5 times molar weight.When using excess reactant formula (III) compound, unreacted formula (III) compound that stays after the reaction is recyclable and be reused for reaction.The acid acceptor that is preferred for this reaction comprises mineral alkali, as sodium bicarbonate, yellow soda ash, salt of wormwood, sodium hydride, Potassium monofluoride etc., organic bases is as 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] octanes (DABCO) etc.
Can the hydrolysis boric acid ester when general formula (IV) compound is removed amino protecting group, come preparation formula (I) compound with this.Usually hydrolysis in basic solvent (for example, solution in methyl alcohol, ethanol, tetrahydrofuran (THF), diox or water such as triethylamine, ammoniacal liquor, sodium bicarbonate, salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide), or (for example, the solution in water, alcohol, tetrahydrofuran (THF), dioxane, 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.
Routine is used for organic chemistry filed and that be easy to remove after reaction and does not decompose any protecting group of target compound structure, can be used as amino protecting group suitable in formula (III) compound.The object lesson that can be used for the protecting group of this purpose comprises formyl radical, ethanoyl, trifluoroacetyl group, replacement or unsubstituting phenenyl formyl radical, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, isobutyl boc, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, replacement or not substituted benzyl oxygen carbonyl, replacement or not substituted benzyl, trityl, THP trtrahydropyranyl, 5-methyl-2-oxo-1,3-oxa-ring penta-4-alkene methyl, alkyloyloxyethyl methyl, alpha-aminoalkyl acyl group etc.
After reaction is finished, if having amino protecting group, can remove by hydrolysis, solvolysis or reduction in the formula of formation (I) compound according to the relevant nature of protecting group.For example, formula (IV) compound in solvent under 0～150 ℃ of temperature, handle in the presence of organic acid or mineral acid or the alkali slough protecting group in the hydrolysis of boron ester and formula (I) compound.The acid that can be used for this purpose can relate to mineral acid, example hydrochloric acid, Hydrogen bromide, phosphoric acid etc., and organic acid is as acetate, trifluoroacetic acid, formic acid, toluenesulphonic acids etc.Or lewis acid, as boron tribromide, aluminum oxide etc.The alkali that is used for this purpose can use the oxyhydroxide of basic metal or alkaline-earth metal, as sodium hydroxide, hydrated barta etc.Alkaline carbonate is as yellow soda ash, lime carbonate etc.Alkali metal alcoholates, as sodium methylate, sodium ethylate etc., or sodium acetate etc.Reaction can be carried out in solvent, for example water or organic solvent, as ethanol, tetrahydrofuran (THF), dioxan, ethylene glycol, acetate etc., or the mixture of this organic solvent and water, as needs, this reaction also can be carried out under no any solvent condition.
In addition; when protecting group be p-toluenesulfonyl, benzyl, trityl, during to methoxy-benzyl, benzyloxycarbonyl, to methoxyl group benzyloxy base carbonyl, trichlorine ethoxy carbonyl, β-iodo ethoxy carbonyl etc., these groups can be by also removing originally effectively.Though removing the reduction reaction conditions of protecting group changes along with the character of relevant protecting group; but hydrogen stream is generally used in this reduction; in inert solvent; in the presence of catalyzer such as platinum, palladium, Raney nickel etc., under 10-150 ℃ of temperature, carry out, or in ammoniacal liquor, under-50 ℃ to-10 ℃ temperature, carry out with sodium Metal 99.5 or metallic lithium.
Be known compound as formula (II/) compound of initiator in the present invention, and can make easily by known method in the existing publication that (EP 230295; EP 241206; J.Med.Chem.1995,38 (22): 4478).
According to the method shown in the following reaction scheme 2, can prepare formula (III) compound of another initiator of the present invention.
Reaction scheme 2:
Wherein gained compound (10), (11), (12), (13) are formula (III) compound.
P represents amino protecting group.R
1, R
2With the definition of protecting group as mentioned above.
Method shown in the following specific explanations reaction scheme.
At first with 1-benzyl-4-oxo-piperidines-3-carboxylic acid, ethyl ester hydrochloride adds organic bases in solvent such as ethanol such as triethylamine makes reaction system be weakly alkaline, use then reductive agent as: POTASSIUM BOROHYDRIDE is carried out reduction reaction and is got (1).Formed (1); at room temperature with ammoniacal liquor react acid amides (2); compound (2) is prepared into amine (3) with clorox through the Hofmann rearrangement reaction in the presence of alkali such as sodium hydroxide; obtain (4) with the amido protecting radical reaction then, gained (4) is sloughed benzyl through the 5%Pd/C reduction and is made (5).And then obtain (6) with the amino protecting group reagent react.Compound (6) carries out oxidation with oxygenant such as chromium trioxide-sulfuric acid (Jones ' reagent) and gets carbonyl compound (7).Gained (7) generates oxime compounds (8) with reactions such as alcoxyl amine hydrochlorate such as methoxamine hydrochloride, ethoxy amine hydrochlorides.Compound (8) carries out alkylated reaction with alkylating agent such as methyl-sulfate or methyl iodide and gets compound (9) in the presence of alkali.1-position protecting group according to the difference of protecting group character, had both optionally been sloughed in compound (8) and (9), obtained compound (12) and (10) respectively.Also can two protecting groups slough simultaneously, then obtain compound (13) and (11) respectively.
The present invention also provides and contains formula (I) compound as defined above, or on its pharmacodynamics acceptable salt as the antimicrobial compound of activeconstituents.The weight ratio of the quinolone carboxylic acid derivatives that pharmaceutical composition contains in composition is 0.1-99.9%, and the weight ratio of medicine acceptable carrier in composition is 0.1-99.9%.Pharmaceutical composition exists to be fit to medicinal dosage form.Medicinal preparation is tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, sucks agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, suppository, ointment, plaster, creme, sprays, aerosol, drops, patch.
Pharmaceutical composition of the present invention, as dosage form, the significant quantity of the invention compound that contains in every dose is 0.1mg-1000mg, described every dose refers to, and each preparation unit is as every of tablet, capsular every, also can refer to each taking dose, as take 100mg at every turn.
But pharmaceutical composition of the present invention can use solid carrier when solid that is prepared into pulvis, tablet dispersion powder, capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation.Spendable solid carrier is preferably one or more materials that are selected from thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, the swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5% to 70% micronize activeconstituents.Suitable solid carrier comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose gum, Xylo-Mucine, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet and capsule are represented best oral solid formulation.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injection formulations of parenteral administration can be water or water-propylene glycol solution form, regulates its degree of oozing such as grade, and pH etc. make the physiological condition that is suitable for live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can add an amount of tinting material, seasonings, stablizer and thickening material again by activeconstituents is dissolved in the water, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to prepare in viscous substance such as natural and synthetical glue, methylcellulose gum, Xylo-Mucine and other the known suspension agent and be suitable for oral aqueous suspensions.
In order to be easy to administration and dosage homogeneous, it is particularly advantageous that the said medicine preparation is mixed with dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, and each unit contains the activeconstituents of the good predetermined amount of the calculating that produces desired result of treatment.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in the pipe or the bottle in ointment, gel or creme.
Though the amount of contained activeconstituents can change in the dosage unit form, generally, be adjusted in the 1-800mg scope according to the effectiveness of selected activeconstituents.
When formula of the present invention (I) active compound is used as the medicine of treatment infectation of bacteria, preferably give the amount of 6-14mg/kg body weight in the fs.But dosage can change along with the seriousness of the infection of patient's needs, desire treatment, selected compounds etc.
Those skilled in the art can determine to be suitable for the preferred dose of certain situation according to a conventional method.Generally, the amount of begin treatment is lower than the optimal dose of activeconstituents, increases dosage then gradually, up to reaching optimum therapeuticing effect.For simplicity, total per daily dose can be divided into several parts, divides administration for several times.
As mentioned above, The compounds of this invention has stronger anti-microbial activity and wide antimicrobial spectrum to the various pathogenic microorganisms that comprise Gram-negative bacteria and gram-positive microorganism.The compounds of this invention is to gram positive bacterial strain, especially to the anti-microbial activity of the Staphylococcus that comprises MRSA, MRSE quinolones antiseptic-germicide gemifloxacin (gemifloxacin) and the baloxacin (balofloxacin) far above nearest listing.
The anti-microbial activity of The compounds of this invention is by measuring its institute to reference culture, clinical strain separated and to the minimum inhibition concentration of the tolerance bacterial strain of some antiseptic-germicides (MIC mg/L) measures.In this experiment recently among two Comprecin gemifloxacin of new listing and baloxacin and the CN1850823A representative compounds of two structure proximates compare medicine.Minimal 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......128cg/ml, use multiple spot inoculator inoculation experiments bacterium (105cfu/ point) in the plate after the culture medium solidifying, put 35 ℃ of constant temperature culture observations after 18 hours, the concentration of contained drug minimum is minimum inhibitory concentration (MIC) in the plate of asepsis growth.
Table 1 has been listed in the application's formula (I) compound antibacterial activity in vitro of four representation compounds to various gram positive bacterial strains, and with two Comprecin gemifloxacin of nearest new listing and baloxacin and CN1850823A in the representative compounds of two structure proximates compare.By table 1 as seen, the application's formula (I) compound is the Comprecin gemifloxacin of new in recent years approval listing and 2-32 times of baloxacin to the external activity of these gram-positive microorganisms, is representative compounds 8-128 times of two structure proximates among the CN1850823A.Beat all especially is that the application's formula (I) compound also shows than gemifloxacin and the outstanding a lot of activity of baloxacin increasing clinically MRSA and MRSE.
Table 1
A
*Be 41 compounds of the embodiment among the CN1850823A, 7-(3-amino-4-first oximido-piperidino)-6-fluoro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid;
B
*Be 1 compound of the embodiment among the CN1850823A, 7-(3-methylamino--4-first oximido-piperidino)-6-fluoro-1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid.
The pharmacokinetics aspect of performance is compared with known quinolone compounds, and The compounds of this invention has suitable water-soluble, therefore can be absorbed well in vivo, show very high bioavailability, the suitable antiseptic-germicide that is used as.
Table 2 has provided solvability in the water of the representative embodiment 17 that selects in the application's formula (I) compound, and compares with the quinolones baloxacin of new approval listing recently.By table 2 as seen, compound of the present invention water-soluble is 6 times of baloxacin.Therefore, they not only can make oral preparations, also can make the treatment that injection is used to infect disease easily.
Table 2
| The embodiment compound | 17 | Baloxacin |
| Solubleness in the water (μ g/ml) | 1676.66 | 300.77 |
Oral acute toxicity test
For measuring the oral acute toxicity of The compounds of this invention, embodiment 18 and 19 compounds have been carried out acute toxicity test, to contain the embodiment 18 of different concns and the oral male mice that awards of solution of 19 compounds, dosage is the 0.1ml/10g body weight, the dead mouse that counts respectively after 7 days is measured, and calculates the medium lethal dose (LD of each compound with the Bliss program
50).The results are shown in Table 3.
The oral acute toxicity of the mouse of table 3 experimental compound
| Experimental compound | LD 50(mg/kg) |
| Embodiment 18 | >4000 |
| Embodiment 19 | >4000 |
Experimental result shows that these toxicity of compound are very low, is fit to very much medicinal.
Owing to have oximido in the 7-bit substituent in the The compounds of this invention, so molecular configuration exists Z type or two kinds of possibilities of E type, 7-position side chain compound is done monocrystalline X-diffraction analysis show, 7-of the present invention (4-oximido-3-amino-piperidino) carbostyril compound is to exist with E formula configuration.It below is the monocrystalline X-ray diffraction analytical data of embodiment ten compounds
Single crystal structure is analyzed
One, diffraction experiment
The sample crystal is the water white transparency column, and the used crystallographic dimension of diffraction analysis is 0.10 * 0.10 * 1.0mm, belongs to oblique system, and spacer is P2
1/ n, unit cell parameters: a=13.058 (3), b=10.916 (2),
β=99.08 (3) °.Unit cell volume
Molecule number Z=8 in the structure cell.
Collect diffracted intensity data, MoK α radiation, graphite monochromator with MAC DIP-2030K face detection instrument, collimator tube ф=0.90mm, crystal and IP plate distance are 100mm, pipe is pressed 50kV, pipe stream 80mA, ω scanning, maximum 2 θ angles are 50.0 °, sweep limit is 0-180 °, and the backswing angle is 6 °, is spaced apart 6 °, sweep velocity is 0.9 °/min, and each picture scanning 1 time amounts to picked-up 30 images, independent point diffraction is 3649, but view-point (| F|
2〉=2 σ | F|
2) be 2870.
Two, Structure Calculation
On microcomputer, resolve crystalline structure with direct method (shelxs-97), obtain 18 non-hydrogen atom positions from E figure, crossover uses method of least squares and difference Fourier method to obtain other non-hydrogen atom position, with least-squares refinement structural parameter and differentiation atomic species, obtain whole hydrogen atoms position with geometric calculation and difference Fourier method, final reliable factor R
1=0.0804, wR
2=0.2304, S=1.066.Final definite asymmetry unit stoichiometric equation is [C
7H
17N
3O
1(HCl)
2]
2, the molecular weight that calculates individual molecule is 230.14, calculates crystalline density 1.278g/cm
3
Figure 1 shows that the monomolecular relative configuration figure of compound, Fig. 2 is the superimposed figure of bimolecular, and Fig. 3 is the ellipsoid figure of A, B molecule, and Fig. 4 is that molecule is along the axial structure cell accumulation graph of a.Table 4 is the atomic coordinate parameter and the equivalent temperature factor, and table 5 is for becoming interatomic bond distance of key and bond angle value.
Three, interpretation of result
The result shows: sample is the piperidines oxime compounds, and the systematic naming method of molecule shown in Figure 1 is: 4-first oximido-3-methylamino piperidine dihydrochloride.Hexa-atomic piperidine ring is chair conformation, encircle outer C=N key and be E formula configuration, two hydrochloric acid respectively with molecule in N
3And N
1Form sat linkage.Contain two molecule A, B that conformation is identical in an asymmetry unit in the structure cell.Molecular arrangement belongs to the second space-like group under the crystalline state, so should not have optically active.Molecular memory is got in touch at sat linkage: N
1A... Cl
1A:
N
3A... Cl
2A:
N
1B... Cl
1B:
N
3B... Cl
2B:
The average salt key assignments is:
Molecule maintains it in the spatial stable alignment with sat linkage and Van der Waals force under the crystalline state.
Table 4: atomic coordinate and equivalent temperature factor table
Table 5: bond distance's value and bond angle value table
N(IA)-C(4A) 1.492(7) N(1B)-C(4B) 1.488(6)
N(1A)-C(3A) 1.498(6) N(1B)-C(3B) 1.493(6)
N(1A)-H(11A) 0.9000 N(1B)-H(11C) 0.9000
N(1A)-H(11B) 0.9000 N(1B)-H(11D) 0.9000
N(2A)-C(1A) 1.283(6) N(2B)-C(1B) 1.291(6)
N(2A)-O(1A) 1.397(5) N(2B)-0(1B) 1.396(5)
N(3A)-C(7A) 1.493(6) N(3B)-C(7B) 1.485(6)
N(3A)-C(2A) 1.497(7) N(3B)-C(2B) 1.496(7)
N(3A)-H(13C) 0.9000 N(3B)-H(13A) 0.9000
N(3A)-H(13D) 0.9000 N(3B)-H(13B) 0.9000
O(1A)-C(6A) 1.426(6) 0(1B)-C(6B) 1.437(6)
C(1A)-C(5A) 1.504(6) C(1B)-C(5B) 1.500(7)
C(1A)-C(2A) 1.506(6) C(1B)-C(2B) 1.509(6)
C(2A)-C(3A) 1.527(7) C(2B)-C(3B) 1.522(7)
C(2A)-H(2AB) 0.9800 C(2B)-H(2BB) 0.9800
C(3A)-H(3AB) 0.9700 C(3B)-H(3BB) 0.9700
C(3A)-H(3AC) 0.9700 C(3B)-H(3BC) 0.9700
C(4A)-C(5A) 1.523(8) C(4B)-C(5B) 1.525(7)
C(4A)-H(4AA) 0.9700 C(4B)-H(4BA) 0.9700
C(4A)-H(4AB) 0.9700 C(4B)-H(4BB) 0.9700
C(5A)-H(5AA) 0.9700 C(5B)-H(5BA) 0.9700
C(5A)-H(5AB) 0.9700 C(5B)-H(5BB) 0.9700
C(6A)-H(6AA) 0.9600 C(6B)-H(6BA) 0.9600
C(6A)-H(6AB) 0.9600 C(6B)-H(6BB) 0.9600
C(6A)-H(6AC) 0.9600 C(6B)-H(6BC) 0.9600
C(7A)-H(7AA) 0.9600 C(7B)-H(7BA) 0.9600
C(7A)-H(7AB) 0.9600 C(7B)-H(7BB) 0.9600
C(7A)-H(7AC) 0.9600 C(7B)-H(7BC) 0.9600
C(4A)-N(1A)-C(3A) 113.4(4) N(2A)-O(1A)-C(6A) 109.8(4)
C(4A)-N(1A)-H(11A) 108.9 N(2A)-C(1A)-C(5A) 127.6(4)
C(3A)-N(1A)-H(11A) 108.9 N(2A)-C(1A)-C(2A) 116.0(4)
C(4A)-N(1A)-H(11B) 108.9 C(5A)-C(1A)-C(2A) 116.3(4)
C(3A)-N(1A)-H(11B) 108.9 N(3A)-C(2A)-C(1A) 109.5(4)
H(11A)-N(1A)-H(11B) 107.7 N(3A)-C(2A)-C(3A) 112.1(4)
C(1A)-N(2A)-O(1A) 110.8(4) C(1A)-C(2A)-C(3A) 110.0(4)
C(7A)-N(3A)-C(2A) 115.0(4) N(3A)-C(2A)-H(2AB) 108.4
C(7A)-N(3A)-H(13C) 108.5 C(1A)-C(2A2-H(2AB) 108.4
C(2A)-N(3A)-H(13C) 108.5 C(3A)-C(2A)-H(2AB) 108.4
C(7A)-N(3A)-H(13D) 108.5 N(1A)-C(3A)-C(2A) 111.0(4)
C(2A)-N(3A)-H(13D) 108.5 N(1A)-C(3A)-H(3AB) 109.4
H(13C)-N(3A)-H(13D) 107.5 C(2A)-C(3A)-H(3AB) 109.4
N(1A)-C(3A)-H(3AC) 109.4 N(2B)-O(1B)-C(6B) 108.7(4)
C(2A)-C(3A)-H(3AC) 109.4 N(2B)-C(1B)-C(5B) 128.3(4)
H(3AB)-C(3A)-H(3AC) 108.0 N(2B)-C(1B)-C(2B) 114.4(4)
N(1A)-C(4A)-C(5A) 111.3(4) C(5B)-C(1B)-C(2B) 117.3(4)
N(1A)-C(4A)-H(4AA) 109.4 N(3B)-C(2B)-C(1B) 108.9(4)
C(5A)-C(4A)-H(4AA) 109.4 N(3B)-C(2B)-C(3B) 112.1(4)
N(1A)-C(4A)-H(4AB) 109.4 C(1B)-C(2B)-C(3B) 110.6(4)
C(5A)-C(4A)-H(4AB) 109.4 N(3B)-C(2B)-H(2BB) 108.4
H(4AA)-C(4A)-H(4AB) 108.0 C(1B)-C(2B)-H(2BB) 108.4
C(1A)-C(5A)-C(4A) 110.0(4) C(3B)-C(2B)-H(2BB) 108.4
C(1A)-C(5A)-H(5AA) 109.7 N(1B)-C(3B)-C(2B) 111.4(4)
C(4A)-C(5A)-H(5AA) 109.7 N(1B)-C(3B)-H(3BB) 109.3
C(1A)-C(5A)-H(5AB) 109.7 C(2B)-C(3B)-H(3BB) 109.3
C(4A)-C(5A)-H(5AB) 109.7 N(1B)-C(3B)-H(3BC) 109.3
H(5AA)-C(5A)-H(5AB) 108.2 C(2B)-C(3B)-H(3BC) 109.3
O(1A)-C(6A)-H(6AA) 109.5 H(3BB)-C(3B)-H(3BC) 108.0
O(1A)-C(6A)-H(6AB) 109.5 N(1B)-C(4B)-C(5B) 111.6(4)
H(6AA)-C(6A)-H(6AB) 109.5 N(1B)-C(4B)-H(4BA) 109.3
O(1A)-C(6A)-H(6AC) 109.5 C(5B)-C(4B)-H(4BA) 109.3
H(6AA)-C(6A)-H(6AC) 109.5 N(1B)-C(4B)-H(4BB) 109.3
H(6AB)-C(6A)-H(6AC) 109.5 C(5B)-C(4B)-H(4BB) 109.3
N(3A)-C(7A)-H(7AA) 109.5 H(4BA)-C(4B)-H(4BB) 108.0
N(3A)-C(7A)-H(7AB) 109.5 C(1B)-C(5B)-C(4B) 110.6(4)
H(7AA)-C(7A)-H(7AB) 109.5 C(1B)-C(5B)-H(5BA) 109.5
N(3A)-C(7A)-H(7AC) 109.5 C(4B)-C(5B)-H(5BA) 109.5
H(7AA)-C(7A)-H(7AC) 109.5 C(1B)-C(5B)-H(5BB) 109.5
H(7AB)-C(7A)-H(7AC) 109.5 C(4B)-C(5B)-H(5BB) 109.5
C(4B)-N(1B)-C(3B) 113.0(4) H(5BA)-C(5B)-H(5BB) 108.1
C(4B)-N(1B)-H(11C) 109.0 O(1B)-C(6B)-H(6BA) 109.5
C(3B)-N(1B)-H(11C) 109.0 O(1B)-C(6B)-H(6BB) 109.5
C(4B)-N(1B)-H(11D) 109.0 H(6BA)-C(6B)-H(6BB) 109.5
C(3B)-N(1B)-H(11D) 109.0 0(1B)-C(6B)-H(6BC) 109.5
H(11C)-N(1B)-H(11D) 107.8 H(6BA)-C(6B)-H(6BC) 109.5
C(1B)-N(2B)-0(1B) 110.9(4) H(6BB)-C(6B)-H(6BC) 109.5
C(7B)-N(3B)-C(2B) 115.6(4) N(3B)-C(7B)-H(7BA) 109.5
C(7B)-N(3B)-H(13A) 108.4 N(3B)-C(7B)-H(7BB) 109.5
C(2B)-N(3B)-H(13A) 108.4 H(7BA)-C(7B)-H(7BB) 109.5
C(7B)-N(3B)-H(13B) 108.4 N(3B)-C(7B)-H(7BC) 109.5
C(2B)-N(3B)-H(13B) 108.4 H(7BA)-C(7B)-H(7BC) 109.5
H(13A)-N(3B)-H(13B) 107.4 H(7BB)-C(7B)-H(7BC) 109.5
Brief description of drawings:
Fig. 1 is unit molecule (A) the relative configuration figure of the embodiment of the present application 10 compounds
Fig. 2 is the superimposed figure of bimolecular (A, B) of the embodiment of the present application 10 compounds
Fig. 3 a is the A molecule ellipsoid figure of the embodiment of the present application 10 compounds
Fig. 3 b is the B molecule ellipsoid figure of the embodiment of the present application 10 compounds
Fig. 4 is that the molecule of the embodiment of the present application 10 compounds is along the axial structure cell accumulation graph of a
Embodiment
In the following example, will more specifically explain the present invention.But should be understood that the following example to be intended to the present invention is described and scope of the present invention is not constituted any restriction.
Embodiment 1,4-hydroxyl-1-benzyl-piperidines-3-carboxylic acid, ethyl ester
The ice bath cooling is down to 1-benzyl-4-oxo-piperidines-3-carboxylic acid, ethyl ester (6.0g, 20mmol) and in the solution of 95% ethanol (20ml) drip triethylamine (1.4ml), add POTASSIUM BOROHYDRIDE (1.7g then in batches, 27mmol), in the reaction 2h hypsokinesis entry, dichloromethane extraction, washing, drying, concentrating under reduced pressure get faint yellow oily thing 3.1g, productive rate 58.4%.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.298(3H，s，CH
3)，1.782～1.915(2H，m，C
5-2H)，2.357～2.791(5H，m，C
2-2H，C
3-1H，C
6-2H)，3.727～4.391(5H，m，phCH
2，C
4-1H，CH
2CH
3)，7.132～7.268(5H，m，ph-5H)。
MS(FAB，m/z)：264(M
++1)。
Embodiment 2,4-hydroxyl-1-benzyl-piperidines-3-methane amide
Embodiment 1 compound (5.5g 13.8mmol) adds ammoniacal liquor (20ml), stirring at room 12h, and behind the concentrating under reduced pressure, the chloroform dissolving, washing, anhydrous magnesium sulfate drying filters, and concentrating under reduced pressure gets colorless oil product 4.8g, productive rate 65.4%.
1HNMR(300MHz，DMSO+D
2O)δ ppm：1.592～1.599(2H，s，C
5-2H)，2.343～2.523(5H，m，C
2-2H，C
3-1H，C
6-2H)，3.436～3.499(2H，m，ph CH
2)，4.020(1H，s，C
4-1H)，4.821(1H，s，OH)，6.953(1H，s，NH)，7.222～7.331(5H，m，ph-5H)，7.382(1H，s，NH)。
MS(FAB，m/z)：235(M
++1)。
Embodiment 3,3-amino-4-hydroxy-1-benzyl-piperidines
Method one: under ice bath cooling, in the mixing solutions of 12% clorox (25.9ml) and water (5ml), add in batches sodium hydroxide (6.8g, 0.17mol), adding embodiment 2 compound (3.0g behind the 10min, 12.9mmol), stirring at room is reacted half an hour, is warming up to 70 ℃ of reaction 3h, reduces to room temperature, transfer about pH=9, dichloromethane extraction, washing, drying, solvent evaporated gets colorless oil 1.33g, yield 50%.
Method two: embodiment 2 compound (3.0g, 12.9mmol) be dissolved in 6% the NaOH solution (10ml), the clorox (25.9ml) of dropping 12% under the ice bath cooling conditions, stirring at room 0.5h is heated to 70 ℃ of reaction 3h, reduce to room temperature, transfer about pH=9 dichloromethane extraction, washing, drying, solvent evaporated get colorless oil 1.38g.Yield 52%.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.671～1.699(2H，m，C
5-2H)，2.453～2.749(5H，m，C
2-2H，C
3-1H，C
6-2H)，3.436～3.690(3H，m，ph CH
2，C
4-1H)，7.297～7.427(5H，m，ph-5H)。
MS(ESI，m/z)：207(M
++1)。
Embodiment 4,4-hydroxyl-3-(N-tertbutyloxycarbonyl) amino-1-benzyl-piperidines
(7.0g, 34.0mmol) in water-soluble (15ml), transfer pH with sodium hydroxide is about 8.5 to embodiment 3 compounds, adds diox (20ml), adds di-t-butyl pyrocarbonate (BOC in batches
2O) (19.0g), keeping pH is about 8.5,60 ℃ of reaction 1h, and concentrating under reduced pressure adds water (30ml), methylene dichloride (3 * 20ml) extractions, anhydrous magnesium sulfate drying filters, and the pressure reducing and steaming solvent gets colorless oil product 8.6g, productive rate 80%.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.424(9H，s，BOC)，1.615～2.180(5H，m，NH-BOC，C
5-2H，C
6-2H，)，2.648～2.887(2H，m，C
2-2H)，3.441～3.544(4H，m，C
3-1H，C
4-1H，ph CH
2)，7.257～7.315(5H，m，ph-5H)。
MS(ESI，m/z)：319(M
++1)。
Embodiment 5,4-hydroxyl-3-(N-tertbutyloxycarbonyl) amino-piperadine
Embodiment 4 compounds (0.50g, 1.6mmol), 5%Pd/C (1g), dehydrated alcohol (50ml) normal pressure hydrogenation reaction 3h filters, and concentrating under reduced pressure gets colorless oil product 0.32g, productive rate 91%.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.430(9H，s，BOC)，1.665～1.700(2H，m，C
5-2H)，2.732～3.076(4H，m，C
6-2H，C
2-2H)，3.721～4.087(2H，m，C
3-1H，C
4-1H)，7.241～7.374(5H，m，ph-5H)。MS(ESI，m/z)：217(M
++1)。
Embodiment 6,4-hydroxyl-3-(N-tertbutyloxycarbonyl) amino-1-tertiary butyloxycarbonyl phenylpiperidines
(5.2g, 24mmol) in water-soluble (15ml), transfer pH with sodium hydroxide is about 8.5 to embodiment 5 compounds, adds diox (20ml), adds BOC in batches
2O (7.0g), keeping pH is about 8.5,60 ℃ of reaction 1h, concentrating under reduced pressure, add water (40ml), and methylene dichloride (3 * 20ml) extractions, anhydrous magnesium sulfate drying filters, concentrate the back and add sherwood oil, separate out white solid product 6.5g, productive rate 85.5%, mp:113～116 ℃.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.445～1.786(20H，m，2×BOC，C
5-2H)，3.24～3.96(6H，m，C
2-2H，C
3-1H，C
4-2H，C
6-2H)，4.931～4.954(1H，m，NH-BOC)。
MS(FAB，m/z)：317(M
++1)。
Embodiment 7,3-(N-tertbutyloxycarbonyl) amino-1-tertbutyloxycarbonyl-4-piperidone
(4.1g dropwise drips Jones reagent (9.9ml) in acetone soln 13.0mmol), drip to finish, and continues to stir 0.5 hour under the equality of temperature to finish reaction to embodiment 6 compounds down in the ice bath cooling.Add amount of methanol in reaction solution, after the color for the treatment of solution transfers green to by redness, filter, filtrate decompression boils off solvent, and residual solution is dissolved with chloroform, and saturated common salt is washed to water layer not to be had till the obvious green.The anhydrous magnesium sulfate drying organic phase is filtered, and boils off solvent and gets the product crude product, and VLC method (with ethyl acetate and sherwood oil gradient elution) is separated and obtained white solid product 3.5g, yield 85.6%, mp:114～117 ℃.
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.377～1.504(18H，m，2×BOC)，2.451～3.062(4H，m，C
4-2H，C
6-2H)，4.271～4.762(3H，m，C
2-2H，C3-1H)，5.389(1H，br，NH)。
MS(FAB，m/z)：314(M
+)。
Embodiment 8,3-(N-tertbutyloxycarbonyl) amino-1-tertbutyloxycarbonyl-4-first oximido piperidines
Embodiment 7 compounds (0.5g, 1.59mmol) with methoxy amine hydrochlorate (0.4g, 4.78mmol) in pyridine in 70 ℃ the reaction 3h, boil off solvent, with the acetic acid ethyl dissolution residual solution, successively with the hydrochloric acid of 1M, saturated NaHCO
3The aqueous solution and washing, the anhydrous magnesium sulfate drying organic phase is filtered, and boils off solvent and gets thick product, and VLC method (with ethyl acetate and sherwood oil gradient elution) is separated and is obtained white solid product 0.53g, yield 97%.mp：114～116℃。
1H NMR(300MHz，CDCl
3)δ ppm：1.441～1.527(18H，s，2×BOC)，1.632～3.075(5H，m，C
3-1H，C
5-2H，C
6-2H)，3.866(3H，s，OCH
3)，4.185～4.311(2H，m，C
2-2H)，5.347～5.363(1H，m，NH-BOC)。MS(EI，m/z)：343(M
+)。
Embodiment 9,3-(N-methyl-N-tertbutyloxycarbonyl) amino-1-tertbutyloxycarbonyl-4-first oximido piperidines
In the exsiccant there-necked flask, add NaH (0.14g, 5.83mmol), ice bath cooling drips tetrahydrofuran (THF) (THF) (10ml) down, (1.00g 2.9mmol) is dissolved in the solution of THF (10ml) to drip embodiment 8 compounds then.Holding temperature is reacted 0.5h below 10 ℃, and (0.82g 5.8mmol) is dissolved in the solution of THF (5ml) to drip methyl iodide then.In system, drip methyl alcohol behind the reaction 3h, do not produce, add water (50ml), methylene dichloride (3 * 20ml) extractions, saturated common salt water washing, anhydrous sodium sulfate drying to there being bubble.Behind the concentrating under reduced pressure thick product, VLC method (with ethyl acetate and sherwood oil gradient elution) separate white solid product, productive rate 98%.mp：112～113℃。
1H NMR(300MHz，CDCl
3+D
2O)δ ppm：1.359(18H，s，2×BOC)，1.579(1H，s，C
4-1H)，2.165(1H，s，C
4-1H)，2.885(3H，s，NHCH
3)，2.964～3.385(3H，m，C
6-2H，C
3-1H)，3.832(3H，s，OCH
3)，3.894～4.009(2H，m，C
2-2H)。
MS(EI，m/z)：357(M
+)。
Embodiment 10,3-methylamino--4-first oximido piperidine hydrochlorate
Under the ice bath cooling, Acetyl Chloride 98Min. (5ml) is slowly added in the methyl alcohol (10ml), after half an hour, adding embodiment 9 compounds (1.0g, 2.9mmol), room temperature reaction 1h, remove solvent under reduced pressure, add ethyl acetate (10ml), stir 0.5 hour after-filtration, drying, get white solid product, productive rate 90%.mp：198～200℃。
1H NMR(300MHz，D
2O)δ ppm：2.396～2.484(1H，m，C
3-1H)，2.899(3H，s，NHCH
3)，3.180～3.255(1H，m，C
3-1H)，3.329～3.390(1H，m，C
2-1H)，3.518～3.575(1H，m，C
6-1H)，3.639～3.686(1H，m，C
2-1H)，4.991(3H，s，OCH
3)，4.413(1H，dd，J＝4.8Hz，12.8Hz，C
6-1H)，4.456～4.500(1H，m，C
3-1H)。
MS(FAB，m/z)：158(M
++1)。
Embodiment 11,3-amino-4-first oximido piperidine hydrochlorate
Under the ice bath cooling, Acetyl Chloride 98Min. (5ml) is slowly added in the methyl alcohol (10ml), after half an hour, adding embodiment 8 compounds (1.0g, 4.6mmol), room temperature reaction 1h removes solvent under reduced pressure, adds ethyl acetate (10ml), stirs 0.5 hour after-filtration, drying gets 0.53g, productive rate 84%.mp：178～181℃。
1H NMR(300MHz，D
2O)δ ppm：2.373～2.461(1H，m，C
3-1H)，3.158～3.234(1H，m，C
3-1H)，3.281～3.342(1H，m，C
2-1H)，3.535～3.591(1H，m，C
6-1H)，3.653～3.701(1H，m，C
2-1H)，4.002(3H，s，OCH
3)，4.010(1H，d，J＝4.2Hz，C
6-1H)，4.478(1H，dd，J＝5.6Hz，12Hz，C
3-1H)。
MS(FAB，m/z)：144(M
++1)。
Embodiment 12,3-(N-tertbutyloxycarbonyl) amino-1-tertbutyloxycarbonyl-4-second oximido piperidines
Embodiment 7 compounds (1.00g, 3.18mmol) same ethoxy amine hydrochloride (0.31g, 3.20mmol) in pyridine in 70 ℃ of reaction 3h, operation is with the preparation of embodiment eight compounds, white solid product, productive rate 92%.mp：74～75.5℃。
1H NMR(400MHz，CDCl
3+D
2O)δ ppm：1.227～1.262(3H，m，CH
2CH
3)，1.532(18H，s，2×BOC)，2.141(1H，br，C
5-1H)，2.810(1H，br，C
5-1H)，3.012～3.045(2H，m，C
6-1H)，3.863～3.895(1H，br，C
3-1H)，4.080～4.167(2H，m，CH
2CH
3)，4.294～4.311(2H，br，C
2-1H)。
MS(ESI，m/z)：358(M
++1)。
Embodiment 13,3-(N-methyl-N-tertbutyloxycarbonyl) amino-1-tertbutyloxycarbonyl-4-second oximido piperidines
With the method for embodiment 9 compounds,, get the oily product, productive rate 93.40% with the same iodomethane reaction of embodiment 12 compounds.
1H NMR(400MHz，CDCl
3+D
2O)δ，ppm：1.157～1.196(3H，m，CH
2CH
3)，1.451(18H，s，2×BOC)，2.141～2.510(2H，m，C
5-2H)，2.740(3H，m，NHCH
3)，3.002～3.079(2H，m，C
6-1H)，3.698～3.734(1H，m，C
3-1H)，3，971～4.042(2H，m，CH
2CH
3)，4.184～4.217(2H，m，C
2-1H)。
MS(ESI，m/z)：372(M
++1)。
Embodiment 14,3-methylamino--4-second oximido piperidine hydrochlorate
With the method for embodiment 10 compounds,, get white solid product, productive rate 95.10% with the same Acetyl Chloride 98Min. of embodiment 13 compounds/methyl alcohol reaction.mp：198～199℃。
1H NMR(400MHz，D
2O)δ，ppm：1.299(3H，t，J＝6.8Hz，CH
2CH
3)，2.870～2.878(3H，m，NHCH
3)，4.258(3H，q，J＝10.8Hz，CH
2CH
3)，2.395～4.345(7H，m，C
2-2H，C
3-1H，C
5-2H，C
6-2H)。
MS(ESI，m/z)：172(M
++1)。
Embodiment 15,3-amino-4-second oximido piperidine hydrochlorate
With the method for embodiment 10 compounds,, get white solid product, productive rate 94.37% with the same Acetyl Chloride 98Min. of embodiment 12 compounds/methyl alcohol reaction.Mp:192 ℃ of distillation.
1H NMR(400MHz，D
2O)δ，ppm：1.297(3H，t，J＝6.8Hz，CH
2CH
3)，2.374～2.463(1H，m，C
3-1H)，3.150～3.226(1H，m，C
3-1H)，3.297(1H，t，J＝12Hz，C
3-1H)，3.562～3.698(2H，m，C
6-2H)，3.989(1H，dd，J＝5.2Hz，12Hz，C
2-1H)，4.249(2H，q，J＝3.4Hz，CH
2CH
3)，4.466(1H，dd，J＝5.2Hz，12.8Hz，C
2-1H)。
MS(ESI，m/z)：156(M
++1)。
Embodiment 16,1-cyclopropyl-6-fluoro-7-(3-amino-4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Boric acid (1.5g, 24.2mmol), diacetyl oxide (11ml, 84.9mmol), in 100 ℃ of stirring reaction 15min, react 0.5h down in 160 ℃ again, reduce to 110 ℃, add 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester (0.50g, 1.55mmol), reaction 3h, reduce to room temperature, in the impouring frozen water, filter, ethanol is washed, and vacuum-drying gets the faint yellow solid product.Get the gained solid (0.50g, 1.08mmol) with embodiment 11 compounds (0.50g, 2.34mmol), in acetonitrile (15ml), under room temperature, reacted 2 days, remove solvent under reduced pressure, 60 ℃ of reaction 0.5h in the aqueous sodium hydroxide solution in 6% (15ml), filter, the acetic acid with 30% transfers pH to neutral, continues to stir 30min, filter, washing, dry back DMF/EtOH recrystallization gets product 0.27g, productive rate 60.0%, mp: 280 ℃.
1H NMR (400MHz, CDCl
3) δ ppm:1.011～1.244 (4H, m, cyclopropyl CH
2CH
2), 2.418～4.023 (15H, m, 2 * OCH
3, 2 '-2H, 3 '-1H, 5 '-2H, 6 '-2H, cyclopropyl 1H), 7.847 (1H, d, J=11.6Hz, 5-H), 8.822 (1H, s, 2-H).
MS(ESI，m/z)：419(M
++1)。
Embodiment 17,1-cyclopropyl-6-fluoro-7-(3-methylamino--4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With the preparation method of embodiment 16 compounds, earlier 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid be converted into boron ester inner complex again with the reaction of embodiment ten compounds, must product, productive rate 36%, mp:179～181 ℃.
1H NMR (400MHz, CDCl
3+ D
2O) δ ppm:0.946～1.059 (4H, m, cyclopropyl CH
2CH
2), 2.437 (3H, s, NHCH
3), 2.711～2.897 (2H, m, 5 '-2H), 3.246～3.732 (8H, m, 2 '-2H, 6 '-2H, OCH
3, cyclopropyl 1H), 3.856～4.016 (4H, m, NOCH
3, 3 '-1H), 7.909 (1H, d, J=12Hz, 5-H), 8.822 (1H, s, 2-H).
MS(ESI，m/z)：433(M
++1)。
Embodiment 18,1-cyclopropyl-6-fluoro-7-(3-amino-4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With the preparation method of embodiment 16 compounds, earlier with 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1, the inner complex that 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester is converted into the boron ester reacts with embodiment 15 compounds again, product, productive rate 57.17%, mp:179～181 ℃.
1H NMR (400MHz, CDCl
3+ D
2O) δ ppm:0.993～1.235 (4H, m, cyclopropyl CH
2CH
2), 1.283 (3H, t, J=10.6Hz, OCH
2CH
3), 2.476～3.698 (7H, m, cyclopropyl 1H, 2 '-2H, 5 '-2H, 6 '-2H), 3.745 (3H, s, OCH
3), 3.992～4.027 (1H, m, 3 '-1H), 4.088 (2H, q, J=17.7Hz, OCH
2CH
3), 7.911 (1H, d, J=11.6Hz, 5-H), 8.824 (1H, s, 2-H).
MS(ESI，m/z)：433(M
++1)。
Embodiment 19,1-cyclopropyl-6-fluoro-7-(3-methylamino--4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and its hydrochloride
With the preparation method of embodiment 16 compounds, earlier with 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1, the inner complex that 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester is converted into the boron ester again with the reaction of embodiment ten Four Modernizations compounds, just during aftertreatment, in and the solid of after-filtration without the DMF/EtOH recrystallization, be dissolved in again in the 6%NaOH aqueous solution but adopt, filter, filtrate neutralizes with acetic acid, leaches solid, dry, promptly get the monohydrate of product, productive rate 40.68%, mp:188～189.5 ℃.
| C 22H 27FN 4O 5H 2O | C | H | N |
| Calculated value | 56.89 | 6.29 | 12.06 |
| Measured value | 56.98 | 6.19 | 12.17 |
1H NMR (400MHz, CDCl
3+ D
2O) δ ppm:0.948～1.308 (7H, m, cyclopropyl CH
2CH
2, OCH
2CH
3), 2.437 (3H, s, NHCH
3), 2.728～2.916 (2H, m, 5 '-2H), 3.287～4.132 (11H, m, 2 '-2H, OCH
2CH
3, 6 '-2H, 3 '-1H, OCH
3, cyclopropyl 1H), 7.913 (1H, d, J=11.8Hz, 5-H), 8.822 (1H, s, 2-H).
MS(ESI，m/z)：447(M
++1)。
With this product (3.50g, 7.5mmoL), 50% ethanol (10mL), concentrated hydrochloric acid (0.5mL) is stirring and refluxing 0.5h together, puts the cold refrigerator overnight that is placed on, and leaches solid, ethanol is washed, drying, the hydrochloride of this product.
| C 22H 27FN 4O 5HCl | C | H | N | Cl |
| Calculated value | 54.71 | 5.84 | 11.60 | 7.34 |
| Measured value | 54.82 | 5.81 | 11.75 | 7.53 |
Also can make its mesylate, lactic acid salt similarly.
Embodiment 20, coating tablet
The label prescription:
Embodiment 16 compound 10.0g
Lactose 50.0g
Starch 40.0g
Hydroxypropylcellulose 4.0g
10% polyvidone is an amount of
Magnesium Stearate 0.5g
Get mentioned component and mix, the whole grain that sieves after the granulation, dry, compressing tablet is made 100 labels.
Coating fluid prescription:
Opadry (Opadry) 5g, an amount of dressing of 80% ethanol.
Embodiment 21, capsule
Prescription:
Embodiment 17 compound 100g
Starch 10g
Sodium starch glycolate 20g
Low-substituted hydroxypropyl cellulose 10g
Tween 80 is an amount of
Polyvinylpyrrolidone 5% ethanol liquid is an amount of
Sodium lauryl sulphate 8g
1000 of No. 0 gastric-dissolved capsules
Make 1000 capsules
The preparation method:
Get the recipe quantity supplementary material, sieve respectively, add 5% polyvinylpyrrolidone alcohol liquid and tween 80 system softwood,, under 15 ℃ of room temperatures, dry with the granulation of 20 mesh sieves, add sodium lauryl sulphate, mix, by the 0.27g/S gastric-dissolved capsule of packing into No. 0, sample examination, the stripping limit is Q=80%, and content should be 90-110% of labelled amount.
The preparation of embodiment 22, injection
Get 1 gram embodiment, 18 compounds, add an amount of water for injection and make dissolving, add poloxamer 10 grams, add sodium-chlor 4 grams, dextran 10 grams add glucose 4 grams, N.F,USP MANNITOL 5 grams, mix, add 1000 milliliters of waters for injection, make 10 bottles of intravenous injections.
Claims (9)
1, compound and pharmaceutical salts thereof, hydrate or its isomer shown in the formula (I):
In the formula:
R
1Represent C
1～C
6Alkyl or cycloalkyl;
R
2, R
3Can be identical, also can be different, and it represents H, C separately
1-C
6-alkyl, amino protecting group;
Wherein said amino protecting group is selected from formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, tertbutyloxycarbonyl, isobutyl boc, trichloro-ethoxycarbonyl, fluorenylmethyloxycarbonyl, carbobenzoxy-(Cbz), alkyl acyl-oxygen methyl, benzyl or trityl.
2, compound and pharmaceutical salts thereof, hydrate or its isomer shown in the formula as claimed in claim 1 (I), it is:
1-cyclopropyl-6-fluoro-7-(3-amino-4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-methylamino--4-first oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-amino-4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid;
1-cyclopropyl-6-fluoro-7-(3-methylamino--4-second oximido) piperidines-1-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid.
3, compound and pharmaceutical salts thereof, hydrate or its isomer shown in the formula as claimed in claim 1 (I) is characterized in that, it is the configuration form of E configuration, Z configuration or E and Z mixture.
4, a kind of method for preparing compound shown in the described formula of claim 1 (I) and pharmaceutical salts, hydrate or its isomer, it comprises the steps:
(1) salt that formula (II) compound and formula (III) compound or it and acid are formed
In the formula, X is a halogen atom, and R represents to have or do not have the aliphatics carboxyl of 2-6 carbon atom of heteroatoms replacement, or the aromatic carboxyl of 7-11 carbon atom;
In the formula, R
1, R
2, R
3Definition is with claim 1;
In solvent, have in the presence of the acid acceptor, in proper temperature reaction down, production (IV) compound,
In the formula, R represents to have or do not have the aliphatics carboxyl of 2-6 carbon atom of heteroatoms replacement, or the aromatic carboxyl of 7-11 carbon atom, R
1, R
2And R
3Definition is with claim 1;
(2) under proper temperature, formula (IV) compound is placed basic solvent, or its boron-containing group is removed in reaction in acid solvent, get formula (I) compound;
When (3) needing, formula (I) compound that obtains is converted into its pharmaceutical salts, hydrate or isomer.
5, method as claimed in claim 4 is characterized in that, described basic solvent is the aqueous solution or the alcoholic solution or the pure water mixed solution of triethylamine, yellow soda ash, sodium bicarbonate, salt of wormwood, sodium hydroxide or potassium hydroxide.
6, method as claimed in claim 4 is characterized in that, described acid solvent is trifluoroacetic acid, hydrochloric acid, sulfuric acid, acetic acid or the hydrobromic aqueous solution or pure water mixed solution.
7, the antibacterial combination that contains each described formula (I) compound or pharmaceutically acceptable salt thereof of claim 1-3, hydrate or isomer.
8, antibacterial combination as claimed in claim 7 is characterized in that, said composition is the antibacterial combination that can be used for gi tract or parenteral administration.
As claim 7 or 8 described antibacterial combinations, it is characterized in that 9, said composition is tablet, capsule, paste, injection, powder injection, suppository, creme or drops.
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| CNB2007101456083A CN100497331C (en) | 2007-09-03 | 2007-09-03 | 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same |
| PCT/CN2008/001526 WO2009030106A1 (en) | 2007-09-03 | 2008-08-25 | 7-(4-oximino-3-amino-1-piperidyl)quinolinecarboxylic acid derivatives and their preparation methods |
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|---|---|---|---|
| CNB2007101456083A CN100497331C (en) | 2007-09-03 | 2007-09-03 | 7-(4-oxime-3-amino-1-piperidine) quinoline carboxylic acid derivative and method for making same |
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| CN101812052B (en) * | 2010-03-18 | 2012-10-03 | 中国医学科学院医药生物技术研究所 | Quinoline carboxylic acid derivative containing isatin substitute and preparation method thereof |
| CN101863876B (en) * | 2010-04-23 | 2012-12-12 | 中国医学科学院医药生物技术研究所 | Fluoroquinolone comprising 7-(3-amino-4-oximido)-1-piperidyl substitutional group and application of composition thereof |
| CN101974578B (en) * | 2010-10-21 | 2014-06-11 | 杭州师范大学 | Method for preparing quinolone type carboxylic acid intermediate through complex enzyme catalytic hydrolysis |
| CN103086955B (en) * | 2013-02-19 | 2014-10-15 | 中国医学科学院医药生物技术研究所 | Preparation method of 3-amino-4-alkoxyimino piperidine |
| CN103467448B (en) * | 2013-09-18 | 2015-04-15 | 浙江司太立制药股份有限公司 | 7-(3-amino-4-alcoxylimido-1-piperidyl)-1-[(1R, 2S)-2-fluoro-cyclopropyl] quinolone carboxylic acid compounds and preparation methods thereof |
| CN103739591B (en) * | 2014-01-02 | 2015-07-15 | 浙江司太立制药股份有限公司 | 7-(3-acylamino-4-oxyiminomethyl-1-piperidyl) fluoroquinolone carboxylic acid and preparation method thereof |
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| CN1850823A (en) * | 2006-05-19 | 2006-10-25 | 中国科学院上海药物研究所 | Quinolone compound containing oximino, and its preparing method and use |
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| CN101117336A (en) | 2008-02-06 |
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