CN102452986B - N-formyl hydroxylamine compounds, preparation method thereof, and purposes thereof - Google Patents
N-formyl hydroxylamine compounds, preparation method thereof, and purposes thereof Download PDFInfo
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Abstract
The invention relates to N-formyl hydroxylamine compounds, a preparation method thereof, and purposes thereof. The invention provides compounds represented by a formula I, enantiomers thereof, or racemic mixtures thereof. In the formula, X is O, NH, or S; R1 is H, C1-C5 straight chain or branched chain alkyl; R2 and R3 are independent H, C1-C5 straight chain or branched chain alkyl, -OR', -SR', - halogen, -CN, -CONR', -COOR' or COR', wherein R' is H, C1-C5 straight chain or branched chain alkyl. The invention also provides a method for preparing the compounds, medicine compositions containing the compounds, and purposes of the compounds. The compounds provided by the invention can be used for preventing and/or treating infectious diseases, and can be used for preparing antibacterial medicines.
Description
Technical field
The invention belongs to medical technical field, particularly, the present invention relates to N-formyl hydroxylamine compound as peptide deformylase (PDF) inhibitor and its production and use.
Background technology
In China, the incidence of infection is higher, in recent years, be widely used due to antibiotic, resistant organism rolls up and spreads, make new antibiotic market life shorter and shorter, in the urgent need to strengthening antibiotic rational use of drug to reduce the generation of resistant organism, also should accelerate the antibiotic exploitation of novel texture simultaneously.
Peptide deformylase (Peptide deformylase; PDF) be to be a kind ofly present in prokaryotic organism as the metallopeptidase in bacterium; peptide piptonychia acidylate by its catalysis is the necessary process in intestinal bacteria and most bacterial metabolism, and this process does not exist in the plastosome of Mammals and fungi.Therefore, design take this process as target spot or synthetic PDF enzyme inhibitors class new antibiotic becomes a tempting target.In to the screening of PDF inhibitor, it is found that BB-3497 is a kind of strong PDF inhibitor of synthetic, a series of derivatives are synthesized out subsequently.
Bibliographical information have PDF to suppress active compound to have following a few class: N-formyl azanol class BB-3497 (Clements, J.M.et al. (2001) Antimicrob.Agents Chemother.45 (2), 563-570; Cynamon, M.H.et al. (2004) J.Antimicrob.Chemother.53 (2), 403-405); Non-peptide class (Jayasekera, M.M.K.et al. (2000) Arch.Biochem.Biophys.381,313-316); Hydroxamic acid (Apfel, C.et al. (2000) J.Med.Chem.43,2324-2331; Apfel, C.et al, (2001) J.Med.Chem.44,1847-1852); Peptide aldehydes (Durand, D.J.et al. (1999) Arch.Biochem.Biophys.367 (2), 297-302), other (Huntington, K.M.et al. (2000) Biochemistry.39 (15), 4543-4551).But also there is no at present medicine listing.Because PDF extensively distributes in bacterium, PDF inhibitor likely becomes extensive pedigree antibiotic, therefore, is the research direction of good new antibacterials.
In Chinese patent application 200810053273.7, disclose a kind of hydroxamic acid derivatives, Preparation Method And The Use containing 1,3-, bis-assorted five-membered ring fused benzenes, wherein the structural formula of the disclosed hydroxamic acid derivatives that contains 1,3-, bis-assorted five-membered ring fused benzenes is as follows:
But the polarity of hydroxamic group is large in this structural formula, easily change.
Summary of the invention
Large in order to improve the polarity of the hydroxamic group in hydroxamic acid structure, easily the shortcoming of change, the invention provides a kind of N-formyl hydroxylamine compound, the preparation method of this compound, the pharmaceutical composition that comprises this compound and the purposes of this compound.
One object of the present invention is, finds the antibacterials of new texture from new mechanism, and the compound shown in a kind of formula I or its enantiomorph or racemic mixture are provided.
Another object of the present invention is, the preparation method of above-claimed cpd is provided.
Another object of the present invention is, a kind of pharmaceutical composition that comprises above-claimed cpd or its enantiomorph or racemic mixture is provided.
A further object of the present invention is, provides above-claimed cpd or its enantiomorph or racemic mixture to prevent and/or treat the purposes in the medicine of infectious diseases in preparation.
The technical scheme that the present invention realizes above-mentioned purpose is as follows:
On the one hand, the invention provides the compound shown in a kind of formula I or its enantiomorph or racemic mixture,
Wherein, X is O, NH or S; R
1for H, C
1-C
5straight or branched alkyl; R
2and R
3be H, C independently
1-C
5straight chained alkyl ,-OR ' ,-SR ' ,-halogen ,-CN ,-CONR ' ,-COOR ' or-COR ', wherein, R ' is H, C
1-C
5straight or branched alkyl.
Preferably, in formula I, X is O, NH or S; R
1for H, sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-or the tertiary butyl; R
2and R
3be independently H, methyl, ethyl, n-propyl, sec.-propyl, hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, first sulfydryl, second sulfydryl, fluorine, chlorine, bromine ,-CN ,-COOR ', CONR ' or-COR ', wherein, R ' is methyl, ethyl, n-propyl or sec.-propyl.
Preferably, described compound is:
N-(benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-tolimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-methoxyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-oxyethyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-itrile group benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-methoxycarbonyl benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-chloro benzimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5,6-benzoxazole dimethyl-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(6-methylbenzothiazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(6-first aminocarbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide; Or
N-(6-first carbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide.
On the other hand, the invention provides a kind of preparation method of above-claimed cpd, this preparation method comprises the steps:
(1) compound shown in formula III and 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid is at catalyzer, for example 4,6-dimethoxy-2-chloro-1,3, under the effect of 5-triazine (CDMT) and/or N-methylmorpholine (NMM), with organic solvent, for example methylene dichloride is solvent, under room temperature, react the compound shown in production II at 0 ℃; And
(2) compound shown in formula II step (1) being generated is with reductive agent, for example, with H
2reduce with 10%Pd/C, with organic solvent, for example ethanol is solvent, under room temperature, reacts deprotection, obtains the compound shown in formula I;
Wherein, R
1, R
2and R
3there is the implication of aforementioned definitions.
Another aspect, the invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises above-claimed cpd or its enantiomorph or racemic mixture.
Preferably, described pharmaceutical composition also comprises one or more pharmaceutically acceptable carriers, vehicle and/or thinner.
Preferably, described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
Preferably, described pharmaceutical composition is tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the little pin of injection, injection freeze-dried powder or infusion solutions.
Again on the one hand, the invention provides above-claimed cpd or its enantiomorph or racemic mixture and prevent and/or treat in preparation the medicine of infectious diseases, for example purposes in antibacterials.
Below will describe the present invention.
Compound of the present invention has the structure shown in formula I:
Wherein, X can be O, NH or S; R
1for H, C
1-C
5straight or branched alkyl; R
2and R
3can be H, C independently
1-C
5straight chained alkyl ,-OR ' ,-SR ' ,-halogen ,-CN ,-CONR ' ,-COOR ' or-COR ', wherein, R ' can be for containing H, C
1-C
5straight or branched alkyl.R
2and R
3can adopt identical or different substituting group.
Preferably, in formula I, X can O, NH or S; R
1can be H, sec.-propyl, methyl, ethyl, n-propyl, normal-butyl, isobutyl-or the tertiary butyl; R
2and R
3can be H, methyl, ethyl, n-propyl, sec.-propyl, hydroxyl, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, first sulfydryl, second sulfydryl, fluorine, chlorine, bromine ,-CN ,-COOR ', CONR ' or-COR ', wherein, R ' can be methyl, ethyl, n-propyl or sec.-propyl.R
2and R
3can adopt identical or different substituting group.
The example of compound of the present invention is as follows:
N-(benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-tolimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-methoxyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-oxyethyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-itrile group benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-methoxycarbonyl benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5-chloro benzimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(5,6-benzoxazole dimethyl-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(6-methylbenzothiazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide;
N-(6-first aminocarbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide; And
N-(6-first carbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide.
Compound shown in formula I of the present invention can exist with optically active isomer, racemic modification or diastereomeric form, the present invention includes all enantiomorphs and composition thereof.
The preparation method of the compounds of this invention comprises the steps:
(1) compound shown in formula III and 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid is at catalyzer, for example 4,6-dimethoxy-2-chloro-1,3, under the effect of 5-triazine (CDMT) and/or N-methylmorpholine (NMM), with organic solvent, for example methylene dichloride is solvent, under room temperature, react the compound shown in production II at 0 ℃; And
(2) compound shown in formula II step (1) being generated is with reductive agent, for example, with H
2reduce with 10%Pd/C, with organic solvent, for example ethanol is solvent, under room temperature, reacts deprotection, obtains the compound shown in formula I;
Wherein, R
1, R
2and R
3there is the implication of aforementioned definitions.
Wherein, compound shown in formula III can adopt any methods known in the art to obtain, the for example compound shown in formula III is 1, the aminated compounds of 3-bis-assorted five-membered ring fused benzenes, it can adopt disclosed method in Chinese patent application 200810053273.7 to prepare, particularly, can adopt following reaction preparation:
In above reaction formula, R is suitable amido protecting group, R
1, R
2and R
3there is the implication of aforementioned definitions, THF: tetrahydrofuran (THF), HOBt:1-hydroxyl-benzo-triazole; DCC:N, N '-dicyclohexyl carbimide.
Wherein, 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid also can adopt any methods known in the art to obtain, for example 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid can adopt and be prepared as follows route and obtain:
In above-mentioned reaction, reaction conditions is: (a) BuBr, NaOEt, r.f.; (b) NaOH, EtOH/H
2o, r.t.; (c) HCHO, pyridine, ACN; (d) EtOH, 98%H
2sO
4, r.f.; (e) KOH, MeOH, r.t.; (f) DBU, ACN, N
2, r.f.; (g) LiOHH
2o, MeOH/H
2o, r.t.
Will obtain containing different replace 1, aminated compounds and 2-[(N-benzyloxy-N-formyl radical amino of 3-bis-assorted five-membered ring fused benzenes) methyl] caproic acid carries out coupling (for example carrying out under the catalysis of CDMT, NMM), then with for example H
2with after 10%Pd/C reduction deprotection, just obtained a series of target compound.
Compound of the present invention or its enantiomorph or racemic mixture, can be prepared into pharmaceutical composition with one or more pharmaceutically acceptable carriers, vehicle and/or thinner, these pharmaceutical compositions can comprise solid orally ingestible, liquid oral medicine, injection etc.These pharmaceutical compositions can be tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the little pin of injection, injection freeze-dried powder or infusion solutions.
In the time of oral administration, pharmaceutical composition can be mixed with tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, solution or capsule, prepares combination of oral medication and can adopt lactose or starch to do carrier; Adopt gelatin, Xylo-Mucine, methylcellulose gum, polyvinylpyrrolidone etc. to make suitable bonding agent or become granular agent; Disintegrating agent can be selected starch or Microcrystalline Cellulose; Suitable antiadhesives and lubricant can be talcum powder, santocedl, stearin, calcium stearate or magnesium etc.
Can adopt any known prior art to carry out pharmaceutical compositions.For example; can prepare tablet by compacting wet granular; activeconstituents and carrier can be optionally and disintegrating agent composition mixture; the aqueous solution of this mixture and tackiness agent, alcoholic solution or in suitable equipment, carry out granulating containing water-alcohol solution; dried particles, adds other disintegrating agent, lubricant and antisticking agent to carry out compressing tablet subsequently.
Compound of the present invention or its enantiomorph or racemic mixture prevent and/or treat the medicine of infectious diseases, for example purposes in antibacterials in preparation.
Particularly, compound of the present invention can be with injection form administration, although dosage can change according to treatment target, administering mode, symptom and other factors.In the time of parenterai administration, composition of the present invention can be made injection formulations.Compound of the present invention is effective in quite wide dosage range.In adult's treatment, dosage range, at 0.1mg/kg-50mg/kg, is taken once or several times.The actual dosage of taking compound should be determined according to relevant situation by doctor, these situations comprise the person's of being treated physical state, route of administration, age, body weight, the individual reaction of patient to medicine, severity of patient's symptom etc., therefore above-mentioned dosage range also limits the scope of the invention never in any form.
Compared with prior art, N-formyl hydroxylamine compound of the present invention is at room temperature deposited stable, has the better stability as medicine.
Embodiment
Below in conjunction with embodiment, the present invention is described further.These embodiment are intended to help to set forth the content of invention rather than limit the scope of the invention.
embodiment 12-[(N-benzyloxy-N-formyl radical amino) methyl] preparation of caproic acid
The present embodiment is the raw material for the preparation of the compounds of this invention: 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid.
The preparation of acetoxime: add water 20mL in 100mL round-bottomed flask, oxammonium hydrochloride 6.95g (0.1mol), stirs and make dissolution of solid, splash into acetone 6.38g (0.11mol), room temperature reaction 1.5 hours, ice-water bath is cooling, add in batches sodium hydroxide 4.0g (0.1mol), stir 0.5 hour, extracted with diethyl ether (30mL × 3), dry, steam except ether, obtain white solid 6.79g, yield 93%, m.p.61-62 ℃.
The preparation of oxygen benzyl acetone oxime: 8.0g (0.348mol) sodium Metal 99.5 is added in 150mL dehydrated alcohol, cooling after sodium Metal 99.5 is all dissolved.25.4g (0.348mol) acetoxime is dissolved in to 100mL dehydrated alcohol gained solution and is added drop-wise in sodium ethylate, stir 1 hour.Again 44.1g (0.348mol) benzyl chloride is slowly added drop-wise in reaction mixture.React after 5 hours, steam except partial solvent, add 20mL water, extracted with diethyl ether (100mL × 3), combining extraction liquid, after being dried, removes solvent under reduced pressure, obtains 53.9g oxygen benzyl acetoxime, productive rate 95%.
1HNMR(300MHz，CDCl
3)：δ＝1.75(s，6H)，4.857(s，2H)，7.25(s，5H)。
The preparation of oxygen benzyl hydroxylamine hydrochloride: 20.0g oxygen benzyl acetone oxime is joined in 25mL concentrated hydrochloric acid in batches to heating in water bath to 60 ℃ reaction 3 hours.Flask is distilled on rotatory evaporator, steam except most of solvent will have a large amount of solids and separate out, suction filtration, and washing solid by a little ethanol and ethyl acetate, concentrated mother liquor, has again solid and separates out, obtain altogether 16.7g oxygen benzyl hydroxylamine hydrochloride, yield 85%, m.p.232-235 ℃.
The preparation of N-benzyloxy methane amide: add 10.0g (62.7mmol) oxygen benzyl hydroxylamine hydrochloride, 120mL ethanol, 5.0g (0.125mol) sodium hydroxide in 250mL round-bottomed flask, 23.2g (313.5mmol) ethyl formate, stirring at room temperature 1 day, removes most of solvent under reduced pressure, divides three extractions with 120mL ether, 1mol/L salt acid elution, saturated common salt water washing, dry, remove solvent under reduced pressure, obtain colourless liquid 6.6g, yield 70%.
1H?NMR(300MHz，CDCl
3)：δ＝4.65(m，2H)，7.16-7.18(m，2H)，7.21-7.24(m，2H)，7.27(s，1H)，7.98，8.21(s，1H)。
The preparation of 2-diethyl butylmalonate: add dehydrated alcohol 150mL in 500mL flask with three necks,round bottom, sodium Metal 99.5 8.0g (0.35mol), treat that sodium reacts completely, be chilled to room temperature, slowly splash into 52.9g (0.33mol) diethyl malonate, react 1 hour, then add 45.2g (0.33mol) bromination of n-butane, add rear backflow 2 hours.Remove most of ethanol under reduced pressure, add 70mL water, isolate organic phase, ethyl acetate aqueous phase extracted (50mL × 2), merge organic phase, dry, remove ethyl acetate under reduced pressure, underpressure distillation, collect 105-110 ℃/1.3kpa cut, obtain colourless liquid 46.7g, yield 65%.
1H?NMR(300MHz，CDCl
3)：δ＝0.86-0.93(t，3H)，1.24-1.40(m，10H)，1.85-1.93(m，2H)，3.27-3.34(t，3H)，4.15-4.24(q，4H)。
The preparation of 2-butyl malonic acid: add water 30mL in 500mL round-bottomed flask, ethanol 120mL, potassium hydroxide 30g (0.54mol), stirs potassium hydroxide is dissolved completely, add 43.2g (0.2mol) 2-diethyl butylmalonate, reflux 3 hours.Steam except most of solvent, add 70mL water, be placed in ice-water bath, be adjusted to PH < 2 with 5mol/L hydrochloric acid, ethyl acetate extraction (120mL × 3), merge organic phase, washing, saturated common salt water washing, dry, steaming desolventizes and obtains white solid 31.1g, yield 90%, m.p.105-107 ℃.
The preparation of 2-butylacrylic acid: add 2-butyl malonic acid 19.5g (0.122mol) in tri-mouthfuls of round-bottomed flasks of 250mL, ethanol 110mL, 37% formalin 47mL, stirs and makes dissolution of solid, slowly splash into piperidinyl-1 2.3g (0.145mol), within 20 minutes, add.Stir 1 hour, be heated to 72 ℃, react half an hour, reheat and reflux 2 hours.Steam except most of solvent, ethyl acetate extraction (80mL × 3), 5mol/L salt acid elution organic layer, saturated common salt water washing, dry, remove ethyl acetate under reduced pressure, add 150mL normal hexane, be placed in refrigerator overnight, filter, remove normal hexane under reduced pressure and obtain purer 2-butylacrylic acid 2.8g, yield 82%.
1H?NMR(300MHz，CDCl
3)：δ＝0.92(t，J＝7.2Hz，3H)，1.29-1.39(m，2H)，1.41-1.53(m，2H)，2.28-2.39(m，2H)，5.65(d，J＝1.2Hz，1H)，6.29(d，J＝1.2Hz，1H)，11.90(br，1H)。
The preparation of 2-butylacrylic acid ethyl ester: add 2-butylacrylic acid 10.0g (78.1mmol) in 100mL round-bottomed flask, dehydrated alcohol 50mL, vitriol oil 1mL, reflux 8 hours, steam except most of solvent, extract at twice saturated NaHCO with 100mL methylene dichloride
3washing, saturated common salt water washing, dry, remove solvent under reduced pressure, obtain colourless liquid 9.75g, yield 80%.
1H?NMR(300MHz，CDCl
3)：δ＝0.84-0.92(t，J＝8.1Hz，3H)，1.25-1.27(t，J＝7.2Hz，3H)，1.31-1.57(m，6H)，4.11-4.23(m，2H)，5.58(s，1H)，6.11(s，1H)。
2-[(N-benzyloxy-N-formyl radical amino) methyl] preparation of ethyl hexanoate: in 150mL round-bottomed flask, add 10.0g (66.2mmol) N-benzyloxy methane amide; 15.5g (99.3mmol) 2-butylacrylic acid ethyl ester; 50mL acetonitrile; DBU 10.1g (66.2mmol), N
2protection; reflux 7 hours; remove most of solvent under reduced pressure, add 100mL methylene dichloride to extract at twice, 1mol/L salt acid elution; saturated common salt water washing; dry, steaming desolventizes, and silicagel column separates (sherwood oil: ethyl acetate: methylene dichloride=6: 1: 1); obtain 17.4g colourless liquid, yield 85%.
1H?NMR(300MHz，CDCl
3)：δ＝0.88(t，J＝6.9Hz，3H)，1.20-1.28(m，7H)，1.48-1.60(m，2H)，2.70(m，1H)，3.24-4.20(m，4H)，4.70-4.97(m，2H)，7.38(s，5H)，7.94，8.15(s，1H)。
2-[(N-benzyloxy-N-formyl radical amino) methyl] preparation of caproic acid: in 150mL round-bottomed flask, add 5.0g (16.3mmol) 2-[(N-hydroxy-n-formyl radical amino) methyl] ethyl hexanoate; 50mL methyl alcohol; 25mL water, 0.75g (17.9mmol) LiOHH
2o, stirring is spent the night, and adds suitable quantity of water, dichloromethane extraction (20mL × 2).Water layer uses 1mol/L hcl acidifying to PH < 3, dichloromethane extraction (70mL × 3), saturated common salt water washing, dry, the concentrated product that obtains, silicagel column separates (sherwood oil: ethyl acetate: methylene dichloride=6: 1: 1, add a small amount of formic acid), obtain micro-yellow liquid 3.39g, yield 75%.
1H?NMR(300MHz，CDCl
3)：δ＝0.87(t，J＝7.2Hz，3H)，1.30(m，4H)，1.49-1.61(m，2H)，2.74(m，1H)，3.24-3.85(m，2H)，4.75-4.97(m，2H)，7.27-7.41(m，5H)，7.99-8.16(m，1H)，10.91(br，1H)。
embodiment 2the preparation of 2-aminomethyl benzimidazole
The present embodiment is the raw material for the preparation of the compounds of this invention: 2-aminomethyl benzimidazole, it is the one in the compound shown in formula III.
The chemical equation of the present embodiment is as follows:
In 100mL round-bottomed flask, add 1.05g (9.72mmol) O-Phenylene Diamine, 1.71g (9.72mmol) N-t-butoxycarbonyl glycine, 30mL THF, stirring is dissolved substrate completely, be cooled to 0 ℃, add 2.41g (11.7mmol) DCC in batches, add rear ice bath and react half an hour, room temperature reaction spends the night.Filter, boil off solvent, silicagel column roughing out (methylene dichloride: methyl alcohol=25: 1) obtain product 2.24g, productive rate 86.9%.
Gained solid is dissolved in 15mL Glacial acetic acid, is heated to 72 ℃, react 8 hours, remove most of acetic acid under reduced pressure, add 100mL methylene dichloride to extract at twice, saturated NaHCO
3washing, saturated common salt water washing, dry, the concentrated product that obtains, silicagel column separates (methylene dichloride: methyl alcohol=30: 1), obtain white solid 1.72g, yield 82.4%, m.p.181-183 ℃.
1H?NMR(300MHz，CDCl
3)：δ＝1.45(s，9H)，2.13(s，1H)，4.54(d，J＝6.3Hz，2H)，6.12(br，1H)，7.25(d，J＝16.2Hz，2H)，7.57(d，J＝16.2Hz，2H)；IR(KBr，v/cm
-1)3343，1686，1529，1286，1173，736。
The methanol solution that above-mentioned white solid is dissolved in to 20mL 2mol/L HCl, stirring is spent the night, and steaming desolventizes, and filters, and ether washs, and obtains the hydrochloride 1.25g of white solid 2-aminomethyl benzimidazole, yield 95%; Remove hydrogenchloride with organic bases triethylamine and obtain 2-aminomethyl benzimidazole.
embodiment 3n-(benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] preparation of hexanamide
The present embodiment is a kind of preparation method in compound shown in formula I.
In 50mL round-bottomed flask, add 1.0g (5.72mmol) CDMT and 1.45g (5.20mmol) 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid is dissolved in dry methylene chloride (30mL); cryosel is bathed the lower 683mg (6.76mmol) of dropping N-methylmorpholine; react after 4 hours; add 764mg (5.20mmol) 2-aminomethyl benzimidazole (one in III); cryosel was bathed lower reaction after 2 hours, and room temperature reaction spends the night.Remove by filter precipitation, with a small amount of washed with dichloromethane precipitation, merge washing lotion and filtrate, use successively 0.5mol/L hydrochloric acid, saturated NaHCO
3, saturated common salt water washing, concentrating under reduced pressure after anhydrous sodium sulfate drying, by this crude product with silicagel column separate (methylene dichloride: methyl alcohol=20: 1) white solid 1.96g (one of II), yield 89%, m.p.114-117 ℃.
1H?NMR(300MHz，CDCl
3)：δ＝0.82(t，J＝6.3Hz，3H)，1.25-1.44(m，5H)，1.64(br，1H)，2.64(br，1H)，3.66-3.90(m，2H)，4.36-4.42(dd，J＝4.5Hz，15.0Hz，1H)，4.71(br，3H)，7.21-7.30(m，6H)，7.51(br，3H)，7.96(s，1H)；IR(KBr，v/cm
-1)：3320，2929，1658，1541，1442，1125.
By 0.8g (1.96mmol) N-(benzimidazolyl-2 radicals-yl) methyl-2-[(N-benzyloxy-N-formyl radical amino) methyl] hexanamide (one in II) is dissolved in 20mL dehydrated alcohol; add the Pd/C (moisture 65%) of 200mg massfraction 10%; hydrogenation under normal temperature and pressure; after 3 hours, TLC detects, and reacts completely.Filter, concentrate to obtain white solid, silicagel column separates (methylene dichloride: methyl alcohol=20: 1), obtain white solid 0.57g (one in I), yield 92%, m.p.85-86 ℃.IR(KBr)cm
-1：3279(-NH-)，2956，2930(CH，aliphatic)，1655(＞C＝O)，1540(-C＝C-)，1384(-CHO)，743(-Ar-)；
1H?NMR(300MHz，DMSO，δppm)：0.82-0.83(t，3H，J＝3.6Hz，CH
3)，1.23-1.44(m，6H，CH
2)，2.64-2.73(m，1H，CH)，3.39-3.80(m，2H，CH
2)，4.29-4.76(m，2H，CH
2)，7.14-7.19(m，2H，Ar-H)，7.51(m，2H，Ar-H)，7.87(brs，0.49H，CHO)，8.30(brs，0.51H，CHO)；HRMS(ESI)：[M+H]
+calcd?m/z319.1771，found?319.1761.
embodiment 4-13
According to the preparation method who is similar to embodiment 3, select the different III that replace to replace 2-aminomethyl benzimidazole, can make respectively different I.
The nuclear-magnetism measurement result of compound prepared by embodiment 4-13 is as follows:
N-(5-tolimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.82-0.84 (t, 3H, J=4.2Hz, CH
3), 1.23-1.48 (m, 6H, CH
2), 2.39 (s, 3H, CH
3), 2.61-2.72 (m, 1H, CH), 3.38-3.80 (m, 2H, CH
2), 4.24-4.76 (m, 2H, CH
2), 6.96-7.01 (m, 1H, Ar-H), 7.29 (m, 1H, Ar-H), 7.37-7.39 (m, 1H, Ar-H), 7.87 (brs, 0.49H, CHO), 8.30 (brs, 0.51H, CHO).
N-(5-methoxyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.84 (t, 3H, CH
3), 1.23-1.47 (m, 6H, CH
2), 2.58-2.72 (m, 1H, CH), 3.35-3.77 (m, 4H, CH
2), 4.24-4.73 (m, 2H, CH
2), 6.77-6.81 (m, 1H, Ar-H), 6.99 (m, 1H, Ar-H), 7.37-7.40 (d, 1H, J=8.7Hz, Ar-H), 7.87 (brs, 0.5H, CHO), 8.30 (brs, 0.50H, CHO).
N-(5-oxyethyl group benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.84 (t, 3H, CH
3), 1.23 (m, 5H, CH
2), 1.31-1.36 (t, 3H, J=13.8Hz, CH
3), 1.44 (m, 1H, CH
2), 2.62-2.72 (m, 1H, CH), 3.35-3.79 (m, 2H, CH
2), 4.00-4.02 (m, 2H, CH
2), 4.24-4.73 (m, 2H, CH
2), 6.78 (m, 1H, Ar-H), 6.98 (m, 1H, Ar-H), 7.36-7.39 (d, 1H, J=8.1Hz, Ar-H), 7.87 (brs, 0.49H, CHO), 8.30 (brs, 0.51H, CHO).
N-(5-itrile group benzimidazolyl-2 radicals-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.79-0.83 (t, 3H, J=13.2Hz, CH
3), 1.21-1.38 (m, 6H, CH
2), 2.66-2.74 (m, 1H, CH), 3.38-3.77 (m, 2H, CH
2), 4.41-4.67 (m, 2H, CH
2), 7.55-7.57 (m, 1H, Ar-H), 7.66-7.69 (m, 1H, Ar-H), 8.05 (m, 1H, Ar-H), 7.86 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
N-(5-methoxycarbonyl benzo imidazoles-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.80-0.82 (t, 3H, J=6.3Hz, CH
3), 1.22-1.44 (m, 6H, CH
2), 2.67-2.74 (m, 1H, CH), 3.41-3.80 (m, 2H, CH
2), 3.86 (s, 3H, CH
3), 4.38-4.71 (m, 2H, CH
2), 7.59-7.62 (m, 1H, Ar-H), 7.82-7.84 (m, 1H, Ar-H), 8.12 (m, 1H, Ar-H), 7.87 (brs, 0.55H, CHO), 8.31 (brs, 0.46H, CHO).
N-(5-chloro benzimidazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1hNMR (300MHz, DMSO, δ ppm): 0.79-0.82 (t, 3H, J=6.9Hz, CH
3), 1.22-1.43 (m, 6H, CH
2), 2.64-2.73 (m, 1H, CH), 3.35-3.78 (m, 2H, CH
2), 4.33-4.68 (m, 2H, CH
2), 7.19 (m, 1H, Ar-H), 7.50-7.56 (m, 2H, Ar-H), 7.86 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
N-(5,6-benzoxazole dimethyl-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.82-0.84 (t, 3H, J=6.9Hz, CH
3), 1.24-1.43 (m, 6H, CH
2), 2.21-2.35 (s, 6H, CH
3), 2.67-2.74 (m, 1H, CH), 3.38-3.79 (m, 2H, CH
2), 4.28-4.70 (m, 2H, CH
2), 6.90-7.14 (m, 2H, Ar-H), 7.87 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
N-(6-methylbenzothiazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.80-0.83 (t, 3H, J=6.9Hz, CH
3), 1.23-1.46 (m, 6H, CH
2), 2.35 (s, 3H, CH
3), 2.66-2.75 (m, 1H, CH), 3.35-3.76 (m, 2H, CH
2), 4.25-4.76 (m, 2H, CH
2), 7.13 (m, 1H, Ar-H), 7.34 (m, 1H, Ar-H), 7.58 (m, 1H, Ar-H), 7.87 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
N-(6-first aminocarbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.79-0.83 (t, 3H, J=6.9Hz, CH
3), 1.23-1.44 (m, 6H, CH
2), 2.63 (s, 3H, CH
3), 2.63-2.72 (m, 1H, CH), 3.34-3.74 (m, 2H, CH
2), 4.26-4.76 (m, 2H, CH
2), 7.16 (m, 1H, Ar-H), 7.35 (m, 2H, Ar-H), 7.87 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
N-(6-first carbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide:
1h NMR (300MHz, DMSO, δ ppm): 0.81-0.84 (t, 3H, J=6.9Hz, CH
3), 1.24-1.46 (m, 6H, CH
2), 2.45 (s, 3H, CH
3), 2.65-2.74 (m, 1H, CH), 3.36-3.74 (m, 2H, CH
2), 4.25-4.74 (m, 2H, CH
2), 7.09 (m, 1H, Ar-H), 7.38 (m, 2H, Ar-H), 7.87 (brs, 0.51H, CHO), 8.30 (brs, 0.49H, CHO).
embodiment 14the biological activity determination of the compounds of this invention
Experiment material: substratum: microorganism identification medium pH 7.9 ± 0.1 Beijing three medicine scientific and technological development company lot numbers: 020425.Bacterial classification: standard gold staphylococcus aureus CMCC 26112, standard klebsiella pneumoniae CMCC 46117, above bacterial classification is all purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
The preparation of sample: accurate weighing sample 1.6mg, after first dissolving with 1-2mL DMSO, is diluted to 5mL by stroke-physiological saline solution; Obtain 2mL with 0.22 μ m diameter membrane filtration degerming, then be diluted to 5mL with aseptic broth culture, obtain concentration and be: the liquid of 128 μ g/mL, then carries out doubling dilution with broth culture and obtains concentration and be: 64,32,16,8, the liquid of 4,2 μ g/mL is for subsequent use.
The preparation of bacterium liquid: the lyophilized powder of the standard gold staphylococcus aureus of preservation, standard bacillus canalis capsulatus is got to a little with transfering loop, draw gently in M-H nutrient agar (autoclaving solidifies rear) plate, cultivate after 48h, grow moistening, fresh bacterium colony.Get in a little sterile saline that enters 3-5mL with transfering loop, carry out than after turbid with 0.5,1 Maxwell turbidity pipe, the bacterium liquid of getting 150 μ l enters in the broth culture of 15mL, and in bacterium liquid, bacterium reaches 10
5, for subsequent use.
The mensuration of sample: add respectively the broth culture of 200 μ l and the bacterium liquid of 200 μ l in contrast on 96 orifice plates, in other holes, add respectively the different concns sample of compound sample of the present invention and 1 control sample (each sample repeats 2 times) to be 100 μ l, and bacterium liquid 100 μ l, medicine final concentration is respectively 32,16,8,4,2,1 μ g/mL.Take the clarification minimum concentration observed as MIC, result is as table 1.
The In Vitro Bacteriostatic (MIC, μ g/mL) of table 1 compound
From upper table 1, the compound obtaining in embodiment 3,7,9 and 11, has stronger restraining effect (MIC < 1 μ g/mL) to standard gold staphylococcus aureus (gram-positive microorganism) in vitro.
embodiment 15:the preparation of tablet
Every tablet of tablet containing 10mg activeconstituents is prepared as follows:
Formula consumption/sheet
The compound 10mg of embodiment 3
Microcrystalline Cellulose 35mg
Starch 45mg
Polyvinylpyrrolidone 4mg
Carboxymethyl starch sodium salt 4.5mg
Magnesium Stearate 0.5mg
Talcum powder 1mg
Amount to 100mg
Preparation method: get 50 amounts, activeconstituents (being the compound of embodiment 1), starch and Mierocrystalline cellulose are sieved, and fully mix, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular in 50-60 ℃ dry, by carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
embodiment 16:the preparation of injection liquid
Formula:
The compound 100mg of embodiment 7
Sorbityl monododecanoate 100mg
Citric acid 100mg
Distilled water 200ml
Preparation method: take NaOH adjust pH as 7.0-7.5, add 0.1% activated carbon, stir 30 minutes under room temperature, filter, by 50 milliliters of packing of every ampulla, 120 ℃ of high-temperature sterilizations obtain injection liquid for 30 minutes, and specification is 25mg.
embodiment 17:the preparation of capsule
Every capsule is prepared as follows containing the capsule of 100mg activeconstituents:
Formula consumption/capsule
The compound 100mg of embodiment 10
Starch 45mg
Polyoxyethylene dehydration sorb 1mg
Carboxymethyl starch sodium salt 2mg
Magnesium Stearate 2mg
Amount to 150.0mg
Preparation method: get 50 amounts, activeconstituents and starch are sieved, and fully mix, polyvinylpyrrolidonesolution solution is mixed with above-mentioned powder, sieve, make wet granular dry in 50-60 ℃, by carboxymethyl starch sodium salt, Magnesium Stearate sieves in advance, is then encased in capsule.
Described the present invention in detail with reference to embodiment above, to those skilled in the art, should be understood that, above-mentioned embodiment should not be understood to limit scope of the present invention.Therefore, can make various changes and improvements to embodiment of the present invention without departing from the spirit and scope of the present invention.
embodiment 18:the mensuration of the compounds of this invention stability
Study on the stability method: sample is placed in weighing bottle in right amount, the about 1mm of thickness of sample, uncovered being placed under 40 ℃, the condition of RH75%, the impurity of observing sample after 10 days changes.
HPLC condition determination: using octadecylsilane chemically bonded silica (5 μ granularity) is weighting agent, moving phase is water: methyl alcohol=88: 12 (regulating pH value to 7.1 left and right of moving phase with 0.3% Glacial acetic acid+3.0ml triethylamine), detection wavelength is 215nm, and the resolution of sample main peak and adjacent impurity peaks should meet the requirements.Adjusting methanol content according to different samples makes sample peak between 5-10 minute.
Measuring method: get compound of the present invention and existing (R)-2-butyl-N prepared by embodiment 3, embodiment 9
4-hydroxy-n
1-[1-(S)-(benzimidazolyl-2 radicals-yl)-2-methyl] propyl succinimide acid amides (being control sample 1) and (R)-2-butyl-N
4-hydroxy-n
1-(the chloro-benzoxazole-2-of 5-yl) methyl succinic diamide (being control sample 2) (prepared by embodiment 1 and embodiment 11 referring to Chinese patent application 200810053273.7), add moving phase dissolving and make the need testing solution that approximately contains 100 μ g in every 1ml, measure contrast solution 20 μ l injection liquid chromatographies, record 2 times to principal constituent peak retention time of color atlas, investigate foreign matter content in sample with normalization method.Measurement result is in table 2.
The Stability Determination result of table 2 test sample
Can be found out by upper table 2, compound of the present invention place before and after impurity level be more or less the same, and the product of prior art was placed after 10 days, impurity level obviously increases, this illustrates compared with the sample of compound of the present invention and prior art to have good stability.
Claims (13)
1. the compound shown in formula I or its enantiomorph or a racemic mixture,
Wherein, X is O, NH or S; R
1for H, C
1-C
5straight or branched alkyl; R
2and R
3be H, C independently
1-C
5straight chained alkyl ,-OR ' ,-SR ' ,-halogen ,-CN ,-CONR ' ,-COOR ' or-COR ', wherein, R ' is H, C
1-C
5straight or branched alkyl; It is characterized in that, described compound is:
N-(6-methylbenzothiazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide; Or
N-(6-first aminocarbonyl benzoxazole-2-yl) methyl-2-[(N-hydroxy-n-formyl radical amino) methyl] hexanamide.
2. a preparation method for compound claimed in claim 1 or its enantiomorph or racemic mixture, is characterized in that, the preparation method of described compound comprises the steps:
(1) compound shown in formula III and 2-[(N-benzyloxy-N-formyl radical amino) methyl] caproic acid under the effect of catalyzer, take organic solvent as solvent, under room temperature, react the compound shown in production II at 0 ℃; And
(2) compound shown in formula II step (1) being generated reduces with reductive agent, take organic solvent as solvent, under room temperature, reacts deprotection, obtains the compound shown in formula I; Wherein, R
1, R
2and R
3there is implication as defined in claim 1.
3. preparation method according to claim 2, is characterized in that, in step (1), described catalyzer is 4,6-dimethoxy-2-chloro-1,3,5-triazines (CDMT) and/or N-methylmorpholine (NMM).
4. according to the preparation method described in claim 2 or 3, it is characterized in that, in step (1), described organic solvent is methylene dichloride.
5. according to the preparation method described in claim 2 or 3, it is characterized in that, in step (2), described reductive agent is H
2and 10%Pd/C.
6. according to the preparation method described in claim 2 or 3, it is characterized in that, in step (2), described organic solvent is ethanol.
7. a pharmaceutical composition, this pharmaceutical composition comprises compound claimed in claim 1 or its enantiomorph or racemic mixture.
8. pharmaceutical composition according to claim 7, is characterized in that, described pharmaceutical composition also comprises one or more pharmaceutically acceptable carriers, vehicle and/or thinner.
9. according to the pharmaceutical composition described in claim 7 or 8, it is characterized in that, described pharmaceutical composition is solid orally ingestible, liquid oral medicine or injection.
10. according to the pharmaceutical composition described in claim 7 or 8, it is characterized in that, described pharmaceutical composition is tablet, capsule, sugar-coat agent, granule, dry powder doses, oral solution, the little pin of injection, injection freeze-dried powder or infusion solutions.
11. pharmaceutical compositions according to claim 10, is characterized in that, described tablet is dispersible tablet, enteric coated tablet, chewable tablet or orally disintegrating tablet.
12. compounds claimed in claim 1 or its enantiomorph or racemic mixture prevent and/or treat the purposes in the medicine of infectious diseases in preparation.
13. purposes according to claim 12, is characterized in that, described medicine is antibacterials.
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