CN102531946A - 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof - Google Patents
3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN102531946A CN102531946A CN2012100020701A CN201210002070A CN102531946A CN 102531946 A CN102531946 A CN 102531946A CN 2012100020701 A CN2012100020701 A CN 2012100020701A CN 201210002070 A CN201210002070 A CN 201210002070A CN 102531946 A CN102531946 A CN 102531946A
- Authority
- CN
- China
- Prior art keywords
- hydroxybenzamide
- oxygen base
- fluoro
- mol ratio
- ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses a 3-methoxybenzamide (MBA) derivant, which is disclosed in the following structural formula (1), wherein R1 is chlorine or bromine, R2 and R3 are independently fluorine or hydrogen, and n is an integer of 1-5. According to the 3-MBA derivant, a hydrophobic halogenated hydrocarbon side chain of which the length is 3-7 atoms is introduced on the C-3 site of 3-MBA to discover the optimal length of the hydrocarbon side chain introduced on C-3 of the 3-MBA. Meanwhile, a chlorine atom and a bromine atom with better lipid solubility are introduced into the tail end of the side chain so as to enhance the antibacterial activity of the derivant. In order to improve the target and the antibacterial activity of a compound, fluorine atoms are introduced onto the C-2 site and the C-6 site of the 3-MBA. The experiment proves that the compound disclosed by the invention can be used for specifically inhibiting the activity of various pathogenic bacteria even drug resistant bacteria, such as staphylococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus, staphylococcus saprophyticus, bacillus subtilis, bacillus anthracis and the like.
Description
Technical field
The present invention relates to 3-methoxy benzamide verivate and preparation method thereof and application.
Background technology
At present the mankind have have researched and developed polytype antibacterials, use more have penicillium mould and cephalosporins, tetracyclines, aminoglycoside, Macrolide, chloromycetin, quinolones, trimethoprim and paraxin etc.More than the mechanism of action of several kinds of antiseptic-germicides have nothing in common with each other.In whole 20th century, antibacterials play crucial effects for human existence and development.
But in recent years, along with antiseptic-germicide widespread use is clinically particularly abused, and lack correct guidance, drug-resistance of bacteria increases year by year always.Occur multiple resistant organism in recent years, microbiotic commonly used has clinically been produced resistance.More common resistant organism comprises: methicillin-resistant staphylococcus aureus (MRSA), multidrug resistant streptococcus aureus (MDRSA), penicillin resistant streptococcus pneumoniae and multidrug resistant faecium etc.More than several kinds of resistant organism serious threats human existence; More severe is; Traditional screening method based on cell levels has been difficult to find new microbiotic, so research and development anti-microbial activity antibacterials strong, that have novel antibacterial mechanism are extremely urgent.It was gratifying; Progress along with science and technology; People deepen continuously to the understanding of microbiotic mechanism of action, bacterial growth and reproduction mechanisms and bacterial resistance mechanism, and this sets up and use for people based on the screening model of molecular level and lays a good foundation to find new antibiotic.
The binary fission of bacterium is that bacterial reproduction is necessary, in the binary fission process of bacterium, has the division indispensable protein of a plurality of high conservatives.These division indispensable proteins do not exist in Mammals, and only specificity exists in bacterium.Based on above advantage, the binary fission that suppresses bacterium has become antibiotic approach very likely.At present, people mainly concentrate on FtsZ (the thread temperature sensitive albumen Z) albumen the research that suppresses bacterium binary fission.In the division of all bacteriums must albumen, the FtsZ conservative property was higher, and specificity is stronger, and in bacterium binary fission process, plays a role as initial albumen, and the binary fission of bacterium is played crucial effects.Since finding for the first time in 1998, people have done a large amount of work to FtsZ albumen.At present, FtsZ has become has one of the antibacterials of research and development prospect action target spot most.
The antibacterials screening model of existing multiple target FtsZ is set up so far, and multiple suppressor factor to FtsZ comes to light, but in the majority with natural product.The target FtsZ small molecules lead compound of having found at present is less, and so far, 3-MBA (3-methoxy benzamide) is the lead compound that meets " patent medicine five yuan then " most, also is the most promising target lead compound of generally acknowledging.Through existing structure activity relationship data and by the area of computer aided medicinal design, it has been established that, carries out in the cohesive process at 3-MBA and FtsZ albumen; The BM group of 3-MBA plays crucial targeting, and BM can combine with crack on the FtsZ albumen, and this crack is between the H7 of FtsZ target spot spiral and one of carbon tip; And adjoin five amino acid residue: R191; Q192, N263, V307 and T309.In addition, the C-3-O of 3-MBA can form hydrogen bonded with R191 and two binding sites of Q192.In sum, the BM group of 3-MBA and C-3-O are active necessary groups, can't modify.But the C-3-OH of 3-MBA is very potential structural modification site, the rational structure modification is carried out in this site be expected to develop the 3-MBA verivate that the antimicrobial agent activity significantly strengthens and have good pharmacokinetic properties.
Up to the present, the 3-MBA related patent U.S. Patent No. of having reported has only one (to see world patent WO 2007107758; Chinese patent: CN 200780009959.X), this patent is introduced a series of phenyl ring and quaternary, heterocyclic side chains such as five yuan at three of 3-MBA, and has measured the anti-microbial activity that verivate is directed against subtilis and streptococcus aureus.But this patent has significant limitation.For example; First: though this patent has been introduced heterocyclic side chains such as a series of phenyl ring, quaternary and five yuan at C-3-OH; But the distance of terminal heterocycle and parent nucleus is single, and most of heterocycles and the parent nucleus methylene radical of only being separated by is not explored the optimum length of terminal heterocycle and parent nucleus; The second, up-to-date research shows that possibly there are potential hydrogen bonded site in C-3 position side chain and FtsZ targeted integration zone at 3-MBA, and this possibly be the important breakthrough point that research and development have the 3-MBA verivate of higher anti-microbial activity and wider antimicrobial spectrum.But patent WO 2007107758 emphasis are introduced a series of heterocyclic substituted three side chain terminal, do not explore the hydrogen bonded site that possibly exist.The 3rd, this patent has been described the building-up process of compound emphatically, and is less in the work of doing aspect the evaluated biological activity of compound.For example, when carrying out compound anti-microbial activity mensuration (MIC mensuration), only carried out comprehensive determination of activity, do not measured the anti-microbial activity of other pathogenic bacterium, can't reflect the antimicrobial spectrum of compound to this a kind of bacterium of ATCC29213.What is more important, this patent have been ignored the key property of FtsZ, and that is exactly: extensively there is and exists less otherness in FtsZ in streptococcus aureus.
Summary of the invention
To above-mentioned prior art; To present 3-MBA derivative antibacterial active low with become problems such as the property of medicine is relatively poor; And the hydrogen bonded site that possibly exist on the C-3 position of exploration 3-MBA and the optimum length of C-3 position side chain; Seminar of the present invention has designed and synthesized a series of expection activity compounds-3-methoxy benzamide verivate preferably by area of computer aided medicinal design means such as (CADD), and the present invention also provides its preparation method.
The present invention realizes through following technical scheme:
3-methoxy benzamide verivate, structural formula is as shown in the formula shown in (I):
Wherein, R
1Be chlorine or bromine; R
2And R
3Be fluorine or hydrogen independently; N is 1~5 integer.
Preferably, said 3-methoxy benzamide verivate is meant following compound:
1) 3-[(2-bromotrifluoromethane) oxygen base] BM
2) 3-[(3-bromopropyl) oxygen base] BM
3) 3-[(4-brombutyl) oxygen base] BM
4) 3-[(5-bromine amyl group) oxygen base] BM
5) 3-[(6-bromine hexyl) oxygen base] BM
6) 3-[(3-chloropropyl) oxygen base] BM
7) 3-[(4-chlorobutyl) oxygen base] BM
8) 3-[(5-chlorine amyl group) oxygen base] BM
9) 3-[(6-chlorine hexyl) oxygen base] BM
10) 3-[(2-bromotrifluoromethane) oxygen base]-2, the 6-difluorobenzamide
11) 3-[(3-bromopropyl) oxygen base]-2, the 6-difluorobenzamide
12) 3-[(4-brombutyl) oxygen base]-2, the 6-difluorobenzamide
13) 3-[(5-bromine amyl group) oxygen base]-2, the 6-difluorobenzamide
14) 3-[(6-bromine hexyl) oxygen base]-2, the 6-difluorobenzamide
15) 3-[(3-chloropropyl) oxygen base]-2, the 6-difluorobenzamide
16) 3-[(5-chlorine amyl group) oxygen base]-2, the 6-difluorobenzamide
17) 3-[(4-chlorobutyl) oxygen base]-2, the 6-difluorobenzamide.
The preparation method of said 3-methoxy benzamide verivate, as follows:
(1) works as R
1Be bromine, R
2And R
3When being hydrogen, the preparation method is: the 3-hydroxybenzamide is placed N, in dinethylformamide or the acetonitrile, in the presence of Anhydrous potassium carbonate or soda ash light, add bromo alkane, 55~65 ℃ were reacted 14~17 hours, generated the compound of general formula (I); Wherein, 3-hydroxybenzamide and N, the ratio of dinethylformamide or acetonitrile is 1mmol: 11~14mL; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate or soda ash light is 1: 1.5~2.0; The mol ratio of 3-hydroxybenzamide and bromo alkane is 1: 4~5;
(2) work as R
1Be chlorine, R
2And R
3When being hydrogen, the preparation method is: the 3-hydroxybenzamide is placed N, in the dinethylformamide, add catalyzer Soiodin and Anhydrous potassium carbonate, add chloroparaffin then, 55 ℃~65 ℃ were reacted 16~18 hours, generated the compound of general formula (I); Wherein, 3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5~3.0mL; The mol ratio of 3-hydroxybenzamide and Soiodin is 1: 0.2~0.3; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate is 1: 1.8~2.0; The mol ratio of 3-hydroxybenzamide and chloroparaffin is 1: 4~5;
(3) work as R
1Be bromine, R
2And R
3When being fluorine, the preparation method is: with 2,6-two fluoro-3-hydroxybenzamides place N, in dinethylformamide or the acetonitrile, in the presence of Anhydrous potassium carbonate, add bromo alkane, and 50~60 ℃ were reacted 7~10 hours, generated the compound of general formula (I); Wherein, 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 11~15mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 2.0~3.0; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and bromo alkane is 1: 4~5;
(4) work as R
1Be chlorine, R
2And R
3When being fluorine, the preparation method is: with 2,6-two fluoro-3-hydroxybenzamides place N, in the dinethylformamide, add catalyzer Soiodin and Anhydrous potassium carbonate, add chloroparaffin, and 50~60 ℃ were reacted 7~10 hours, generated the compound of general formula (I); Wherein, 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5~3.0mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Soiodin is 1: 0.2~0.3; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 2.0~3.0; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and chloroparaffin is 1: 4~5.
Preferably, in the said step (1), 3-hydroxybenzamide and N, the ratio of dinethylformamide (DMF) or acetonitrile is 1mmol: 11mL; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate or soda ash light is 1: 1.5.
Preferably, in the said step (1), reaction solvent is DMF.
Preferably, in the said step (2), 3-hydroxybenzamide and N, the ratio of dinethylformamide (DMF) is 1mmol: 2.5mL; The mol ratio of 3-hydroxybenzamide and Soiodin is 1: 0.3; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate is 1: 1.8.
Preferably, in the said step (3), 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide (DMF) is 1mmol: 11mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 3.
Preferably, in the said step (3), reaction solvent is DMF.
Preferably, in the said step (4), 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide (DMF) is 1mmol: 2.5mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Soiodin is 1: 0.2; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 3.
Said 3-hydroxybenzamide is prepared by the 3-hydroxy-benzoic acid, number is CN200780009959.X at Chinese patent, and publication number is to mention in the patent of 101404989A.Said 2,6-two fluoro-3-hydroxybenzamides can directly be bought from the market and obtain.
Said 3-hydroxybenzamide obtains through following preparation method:
(1) convert the 3-hydroxy-benzoic acid to the 3-hydroxybenzoyl chloride: with the 3-hydroxy-benzoic acid is starting raw material, is solvent with toluene, adds sulfur oxychloride, reflux 4.5~5 hours, and vacuum concentration generates the 3-hydroxybenzoyl chloride; Wherein, the mol ratio of 3-hydroxy-benzoic acid and sulfur oxychloride is 1: 1.5~1.9, and the usage ratio of 3-hydroxy-benzoic acid and toluene is 1mmol: 0.83~0.90mL;
(2) the 3-hydroxybenzoyl chloride with above-mentioned preparation places anhydrous tetrahydro furan;-5 ℃~-10 ℃ coolings; Slowly dropwise drip saturated strong aqua, make reaction solution slowly be increased to room temperature after 15~25 minutes in reaction under-5 ℃~-10 ℃; At room temperature stir 18h~20h, generate the 3-hydroxybenzamide; Wherein, the ratio of 3-hydroxybenzoyl chloride and THF is 1mmol: 0.37~0.40mL; The ratio of 3-hydroxybenzoyl chloride and saturated strong aqua is 1mmol: 0.37~0.40mL.
Said 3-hydroxybenzoyl chloride, 3-hydroxybenzamide, 2, the structural formula of 6-two fluoro-3-hydroxybenzamides as shown in the formula (II), (III) (IV) shown in:
Preferably, in the above-mentioned steps (1), the mol ratio of 3-hydroxy-benzoic acid and sulfur oxychloride is 1: 1.5, and the usage ratio of 3-hydroxy-benzoic acid and toluene is 1mmol: 0.83mL.
Preferably, in the above-mentioned steps (2), the ratio of 3-hydroxybenzoyl chloride and THF is 1mmol: 0.37mL, and the ratio of 3-hydroxybenzoyl chloride and saturated strong aqua is 1mmol: 0.37mL.
Among the above-mentioned preparation method: preferred 25 ℃ of said room temperature; Must there be water treatment before the uses such as solvent for use toluene, THF, DMF, acetonitrile.Synthetic route is as shown in Figure 1.
It is the hydrophobic side chains of 3 to 7 atoms that the present invention introduces length in the C-3 position of 3-MBA.The optimum length of hydrophobic side chain is introduced in the C-3 position that this patent has been explored at 3-MBA, and introduces fat-soluble better chlorine atom and bromine atoms in side chain terminal, has improved compound and has penetrated biomembranous ability, thereby the anti-microbial activity of verivate is enhanced.In order further to improve the target property and the anti-microbial activity of compound, introduce a series of halogen atoms in C-2 and the C-6 position of 3-MBA, finally find and introduce fluorine atom with higher anti-microbial activity.Antibacterial activity test result shows that the activity of the part verivate that this patent is related is superior to the activity of verivate in the Chinese patent (CN 200780009959.X).What is more important, the compound that relates in this patent has identical anti-microbial activity to responsive type with the resistance streptococcus aureus:
(1) activity (MIC=16 μ g/mL) of the active best anti-responsive type streptococcus aureus of compound (MSSAATCC 25923) is 256 times of lead compound 3-MBA;
(2) activity (MIC=16 μ g/mL) of active best compound methicillin-resistant staphylococcus aureus resistance (MRSA ATCC 29213) is 256 times of lead compound 3-MBA;
(3) activity (MIC=16 μ g/mL) of the active best anti-common drug-resistant type streptococcus aureus of compound is 256 times of lead compound 3-MBA.
Discover through above-mentioned, because the C-3 side chain of 3-MBA combines with hydrophobic pathway on the FtsZ target spot, so than hydrophilic side-chains, the 3-MBA verivate of introducing hydrophobic side chains has higher anti-microbial activity in the C-3 position.And if suitable at the length and the group of the C-3 position of 3-MBA introducing side chain, C-3 position side chain possibly form hydrogen bonded with the water repellent region on the FtsZ target spot; Therefore, 3-methoxy benzamide verivate of the present invention can be used as antibacterials, or is used to prepare the medicine of bacterial-infection resisting.
The present invention is based on following discovery: the 3-methoxy benzamide verivate of introducing hydrophobic side chains in the C-3 position can specificity suppresses the activity of various pathogens even resistant organism, for example streptococcus aureus, staphylococcus epidermidis, staphylococcus haemolyticus, Staphylococcus saprophyticus, subtilis, anthrax bacillus etc.Further amplify, can tentatively conclude through ne ar optics, the compound that the present invention relates to through with the FtsZ targeted integration, suppressed the activity of FtsZ, and then suppressed the binary fission of bacterium, thus the performance anti-microbial activity.Compared with prior art; The novelty of this patent is: 1. 3 at 3-MBA introduce hydrophobicity halogenated alkane side chain; This side chain lengths extends to the length of seven carbon atoms from three carbon atoms; Measure through a series of anti-microbial activities, desk study at 3 optimum lengths of introducing hydrophobic side chains of 3-MBA.2. in order to improve the fat-soluble and anti-microbial activity of compound, this patent is introduced halogen atom in side chain terminal; In order further to improve the target property and the anti-microbial activity of compound, introduce a series of halogen atoms in C-2 and the C-6 position of 3-MBA, final discovery has the fluorine atom of high anti-microbial activity.Anti-microbial activity is measured (MIC) and is shown; The activity of the anti-three kinds of streptococcus aureuses (comprising the responsive type streptococcus aureus, methicillin-resistant staphylococcus aureus and common drug-resistant type streptococcus aureus) of compound that this patent activity is best is 256 times of lead compound 3-MBA.3. seminar of the present invention has carried out comprehensive anti-microbial activity to synthetic compound and has measured, and comprises three kinds of streptococcus aureuses and five kinds of streptococcus pneumoniaes.Test through anti-microbial activity (MIC); Confirm that FtsZ extensively exists in multiple streptococcus aureus; And otherness is less, has also found some problems, for example; Most 3-MBA verivates are to the active relatively poor of streptococcus pneumoniae or do not have activity, and this discovery is consistent with the pharmacology pertinent literature of delivering in the recent period.
Description of drawings
Fig. 1 is a synthetic route synoptic diagram of the present invention.
Embodiment
Below in conjunction with embodiment the present invention is further described.
Terminological interpretation:
DMF:N, dinethylformamide;
THF: THF;
MgSO
4: sal epsom;
The 3-MBA:3-methoxy benzamide;
R
f: than transplanting.
The preparation of embodiment 1 3-hydroxybenzamide
3-hydroxy-benzoic acid (10g, 72.4mmol, 1.0 equivalents) is suspended in the toluene (60ml), slowly adds THIONYL CHLORIDE 97 (7.8ml, 108.6mmol, 1.5 equivalents) under the room temperature.This solution is heated to backflow, kept 4.5 hours.Afterwards, make reaction solution be cooled to room temperature and vacuum concentration.Residue is dissolved in the THF (27ml), is cooled to-5 ℃, slowly dropwise drips saturated concentrated ammonia solution (28ml), makes reaction mixture slowly be increased to room temperature, at room temperature stirs 18 hours.With the reaction mixture vacuum concentration, the gained solid suspension is also filtered in water.The solid of collecting washs three times with pure water (about 20ml), and vacuum-drying then obtains the 3-hydroxybenzamide (6.94g, 70.0%) of pale solid form, and fusing point 165-167 ℃, R
f=0.12 (developping agent is a petrol ether/ethyl acetate, 1: 2).MS(ESI)m/z?calcd.For?C
7H
7NO
2?137.0;found(M+H
+)138.3.
Embodiment 2 usefulness bromoalkanes make the general method of 3-hydroxybenzamide generation alkylated reaction
A) with K
2CO
3(2.07g, 15mmol, 1.5 equivalents) join in the suspension-s of 3-hydroxybenzamide (1.37g, 10mmol, 1.0 equivalents) in DMF (110ml).With this mixed solution stir about 15 minutes at room temperature, add glycol dibromide (7.51g, 40mmol, 4 equivalents) then.The gained mixed solution was stirred 16 hours down at 60 ℃.Afterwards, make reaction solution be cooled to room temperature, any undissolved solid of elimination is also extremely dried with filtrate evaporated under reduced pressure.The residue of evaporate to dryness is dissolved in the ETHYLE ACETATE, uses K continuously
2CO
3Solution (purpose is to remove the not 3-hydroxybenzamide of complete reaction), saturated nacl aqueous solution washing.Use MgSO
4Dry organic layer, reduction vaporization is to smaller size smaller.With solid separation and purification on silicagel column of evaporate to dryness, obtain the required compound (target compound 1) (1.57g, 64.5%) of white solid form; Mp 127-130 ℃; TLC R
f=0.26 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.99(s,1H),7.49-7.36(m,4H),7.12(dd,1H,J=8.4Hz,J=1.8Hz),4.37(t,2H,J=5.4Hz),3.83(t,2H,J=5.4Hz).MS(ESI)m/zcalcd.for?C
9H
10BrNO
2243.0;found(M+H
+)244.3.
B) adopt and embodiment 2a) identical method, but replace glycol dibromide with 1,3 dibromopropane, obtain 3-[(3-bromopropyl) oxygen base] BM (target compound 2) white solid, yield 63.5%; Mp 128-131 ℃; TLC R
f=0.29 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.96(s,1H),7.48-7.34(m,4H),7.10(dd,1H,J=7.8Hz,J=1.8Hz),4.13(t,2H,J=6.0Hz),3.68(t,2H,J=6.0Hz),2.27(quintet,2H,J=6.0Hz).MS(ESI)m/z?calcd.for?C
10H
12BrNO
2257.0;found(M+H
+)258.1.
C) adopt and embodiment 2a) identical method, but replace glycol dibromide with 1,4 dibromobutane, obtain 3-[(4-brombutyl) oxygen base] BM (target compound 3) white solid, yield 65.46%; Mp 110-113 ℃; TLC R
f=0.31 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.96(s,1H),7.45-7.33(m,4H),7.08(dd,1H,J=8.1Hz,J=2.4Hz),4.04(t,2H,J=6.6Hz),3.62(t,2H,J=6.6Hz),1.98(quintet,2H,J=6.6Hz),1.85(quintet,2H,J=6.6Hz).MS(ESI)m/z?calcd.for?C
11H
14BrNO
2271.0;found(M+H
+)272.1.
D) adopt and embodiment 2a) identical method, but replace glycol dibromide with 1,5 dibromo pentane, obtain 3-[(5-bromine amyl group) oxygen base] BM (target compound 4) white solid, yield 68.9%; Mp 90-92 ℃; TLC R
f=0.47 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.95(s,1H),7.45-7.23(m,4H),7.07(dd,1H,J=8.4Hz,J=2.4Hz),4.01(t,2H,J=6.6Hz),3.57(t,2H,J=6.6Hz),1.88(quintet,2H,J=7.2Hz),1.76(quintet,2H,J=6.6Hz),1.58-1.52(m,2H).MS(ESI)m/z?calcd.forC
12H
16BrNO
2285.0;found(M+H
+)286.3.
E) adopt and embodiment 2a) identical method, but replace glycol dibromide with 1,6 dibromo-hexane, obtain 3-[(6-bromine hexyl) oxygen base] BM (target compound 5) white solid, yield 55.4%; Mp 109-112 ℃; TLC R
f=0.49 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.95(s,1H),7.44-7.33(m,4H),7.07(dd,1H,J=8.1Hz,J=1.5Hz),4.00(t,2H,J=6.6Hz),3.55(t,2H,J=6.6Hz),1.84-1.82(m,2H),1.74-1.72(m,2H),1.46-1.44(m,4H).MS(ESI)m/z?calcd.?for?C
13H
18BrNO
2299.1;found(M+H
+)300.5.
Embodiment 3 usefulness alkyl chloride make the 3-hydroxybenzamide that alkylating general method take place
A) 3-hydroxybenzamide (1.37g, 10mmol, 1.0 equivalents) is dissolved among the DMF (25ml), adds K
2CO
3(2.48g, 18mmol, 1.8 equivalents) and NaI (0.45g, 3mmol, 0.3 equivalent).With above-mentioned suspension-s stir about 5 minutes, add 1,3-propylene dichloride (4.52g, 40mmol, 4 equivalents).The gained mixed solution slowly is heated to 60 ℃, kept 18 hours, stop heating.Reaction solution is cooled to room temperature, and any undissolved solid of elimination is also extremely dried with filtrate evaporated under reduced pressure.The residue of evaporate to dryness is dissolved in the ETHYLE ACETATE, uses K continuously
2CO
3Solution, saturated nacl aqueous solution washing.Use MgSO
4Dry organic layer, reduction vaporization is to smaller size smaller.With solid separation and purification on silicagel column of evaporate to dryness, obtain the required compound (target compound 6) (1.22g, 56.9%) of white solid form; Mp 125-128 ℃; R
f=0.32 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.99(s,1H),7.48-7.35(m,4H),7.10(dd,1H,J=7.8Hz,J=1.8Hz),4.14(t,2H,J=6.0Hz),3.81(t,2H,J=6.6Hz),2.19(quintet,2H,J=6.6Hz).MS(ESI)m/zcalcd.for?C
10H
12ClNO
2213.1;found(M+H
+)214.3.
B) adopt and embodiment 3a) identical method, but replace 1 with 1,4 dichlorobutane, the 3-propylene dichloride obtains 3-[(4-chlorobutyl) oxygen base] BM (target compound 7) white solid, yield 53.6%; Mp 106-108 ℃; TLC R
f=0.34 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.95(s,1H),7.45-7.33(m,4H),7.08(dd,1H,J=7.8Hz,J=1.8Hz),4.05(t,2H,J=6.0Hz),3.72(t,2H,J=6.0Hz),1.92-1.82(m,4H).MS(ESI)m/z?calcd.for?C
11H
14ClNO
2227.1;found(M+H
+)228.4.
C) adopt and embodiment 3a) identical method, but replace 1 with 1,5 dichloropentane, the 3-propylene dichloride obtains 3-[(5-chlorine amyl group) oxygen base] BM (target compound 8) white solid, yield 52.4%; Mp 87-90 ℃; TLC R
f=0.35 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.95(s,1H),7.46-7.33(m,4H),7.07(dd,1H,J=8.4Hz,J=2.4Hz),4.01(t,2H,J=6.0Hz),3.67(t,2H,J=6.6Hz),1.82-1.73(m,4H),1.55(quintet,2H,J=7.8Hz).MS(ESI)m/z?calcd.for?C
12H
16ClNO
2241.1;found(M+H
+)242.3.
D) adopt and embodiment 3a) identical method, but replace 1 with 1,6 dichloro hexane, the 3-propylene dichloride obtains 3-[(6-chlorine hexyl) oxygen base] BM (target compound 9) white solid, yield 49.8%; Mp 104-106 ℃; TLC R
f=0.42 (petrol ether/ethyl acetate, 1: 2).
1H?NMR(600MHz,DMSO-d
6,δppm):7.95(s,1H),7.44-7.32(m,4H),7.07(dd,1H,J=8.1Hz,J=1.8Hz),4.00(t,2H,J=6.6Hz),3.65(t,2H,J=6.6Hz),1.76-1.72(m,4H),1.45(quintet,4H,J=3.6Hz).MS(ESI)m/z?calcd.for?C
13H
18ClNO
2255.1;found(M+H
+)256.3.
Embodiment 4 usefulness bromoalkanes make 2, the general method of 6-two fluoro-3-hydroxybenzamide generation alkylated reactions
A) with K
2CO
3(4.14g, 30mmol, 3.0 equivalents) join 2, in the suspension-s of 6-two fluoro-3-hydroxybenzamides (1.73g, 10mmol, 1.0 equivalents) in DMF (110ml).With this mixed solution stir about 15 minutes at room temperature, add glycol dibromide (7.51g, 40mmol, 4.0 equivalents) then.The gained mixed solution was stirred 10 hours down at 60 ℃.Afterwards, make reaction solution be cooled to room temperature, any undissolved solid of elimination is also extremely dried with filtrate evaporated under reduced pressure.The residue of evaporate to dryness is dissolved in the ETHYLE ACETATE, uses K continuously
2CO
3Solution, saturated nacl aqueous solution washing.Use MgSO
4Dry organic layer, reduction vaporization is to smaller size smaller.Residue is separation and purification on silicagel column, gets the required compound (target compound 10) (1.46g, 52.1%) of white solid form; Mp 89-93 ℃; R
f=0.34 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.14(br?s,1H),7.86(br?s,1H),7.27-7.23(m,1H),7.08(dt,1H,J=8.7Hz,J=1.8Hz),4.39(t,2H,J=5.4Hz),3.81(t,2H,J=5.4Hz).MS(ESI)m/z?calcd.for?C
9H
8BrF
2NO
2279.0;found(M+H
+)280.4.
B) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1,3 dibromopropane, obtain 3-[(3-bromopropyl) oxygen base]-2,6-difluorobenzamide (target compound 11) white solid; Yield 50.3%; Mp 83-84 ℃; TLC R
f=0.35 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.13(br?s,1H),7.85(br?s,1H),7.27-7.23(m,1H),7.07(dt,1H,J=9.0Hz,J=1.8Hz),4.15(t,2H,J=6.0Hz),3.66(t,2H,J=6.6Hz),2.25(quintet,2H,J=6.0Hz).MS(ESI)m/z?calcd.for?C?
10H
10BrF
2NO
2293.0;found(M+H
+)294.3.
C) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1,4 dibromobutane, obtain 3-[(4-brombutyl) oxygen base]-2,6-difluorobenzamide (target compound 12) white solid; Yield 55.2%, mp 67-69 ℃; TLC R
f=0.37 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.12(br?s,1H),7.84(br?s,1H),7.24-7.20(m,1H),7.06(dt,1H,J=9.0Hz,J=1.2Hz),4.08(t,2H,J=6.0Hz),3.61(t,2H,J=6.6Hz),1.99-1.94(m,2H),1.87-1.82(m,2H).MS(ESI)m/z?calcd.for?C
11H
12BrF
2NO
2307.0;found(M+H
+)308.4.
D) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1,5 dibromo pentane, obtain 3-[(5-bromine amyl group) oxygen base]-2,6 difluorobenzamides (target compound 13) white solid, yield 52.4%; Mp 84-87 ℃; TLC R
f=0.38 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.12(br?s,1H),7.84(br?s,1H),7.23-7.19(m,1H),7.05(dt,1H,J=9.0Hz,J=1.2Hz),4.04(t,2H,J=6.6Hz),3.56(t,2H,J=6.6Hz),1.89-1.85(quintet,2H,J=6.6Hz),1.77-1.72(quintet,2H,J=6.0Hz),1.56-1.51(m,2H).MS(ESI)m/z?calcd.for?C
13H
16BrF
2NO
2321.0;found(M+H
+)322.3.
E) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1,6 dibromo-hexane, obtain 3-[(6-bromine hexyl) oxygen base]-2,6 difluorobenzamides (target compound 14) white solid, yield 51.3%; Mp 78-80 ℃; TLC R
f=0.40 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.11(br?s,1H),7.83(br?s,1H),7.23-7.19(m,1H),7.05(dt,1H,J=9.0Hz,J=1.2Hz),4.03(t,2H,J=6.6Hz),3.54(t,2H,J=6.6Hz),1.83-1.81(m,2H),1.73-1.71(m,2H),1.44-1.43(m,4H).MS(ESI)m/z?calcd.?forC
13H
16BrF
2NO
2335.0;found(M+H
+)336.6.
F) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1-bromo-3-chloropropane, obtain 3-[(3-chloropropyl) oxygen base]-2,6-difluorobenzamide (target compound 15) white solid, yield 55.7%; Mp 104-106 ℃; TLC R
f=0.35 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.13(br?s,1H),7.85(br?s,1H),7.27-7.23(m,1H),7.07(dt,1H,J=9.0Hz,J=1.2Hz),4.16(t,2H,J=6.6Hz),3.79(t,2H,J=6.6Hz),2.18(quintet,2H,J=6.6Hz).MS(ESI)m/z?calcd.for?C
10H
10ClF
2NO
2249.0;found(M+H
+)250.2.
G) adopt and embodiment 4a) identical method, but replace glycol dibromide with 1-bromo-5-chloropentane, obtain 3-[(5-chlorine amyl group) oxygen base]-2,6-difluorobenzamide (target compound 16) white solid, yield 56.2%; Mp 82-85 ℃; TLC R
f=0.40 (methylene chloride, 20: 1).
1H?NMR(600MHz,DMSO-d
6,δppm):8.11(br?s,1H),7.83(br?s,1H),7.23-7.19(m,1H),7.05(dt,1H,J=9.0Hz,J=1.2Hz),4.04(t,2H,J=6.6Hz),3.66(t,2H,J=6.6Hz),1.81-1.72(m,4H),1.56-1.51(m,2H).MS(ESI)m/z?calcd.for?C
12H
14ClF
2NO
2277.1;found(M+H
+)278.5.
Embodiment 5 usefulness alkyl chloride make 2, the general method of 6-two fluoro-3-hydroxybenzamide generation alkylated reactions
With 2,6-two fluoro-3-hydroxybenzamides (1.73g, 10mmol, 1.0 equivalents) are dissolved among the DMF (25ml), add K
2CO
3(4.14g, 30mmol, 3.0 equivalents) and NaI (0.30g, 2mmol, 0.2 equivalent).With stir about under the above-mentioned suspension-s room temperature 5 minutes, add 1,4-dichlorobutane (5.08g, 40mmol, 4.0 equivalents).The gained mixed solution slowly is heated to 60 ℃, kept 10 hours.Stop heating, reaction solution is cooled to room temperature, and any undissolved solid of elimination is also extremely dried with filtrate evaporated under reduced pressure.The residue of evaporate to dryness is dissolved in the ETHYLE ACETATE, uses K continuously
2CO
3MgSO is used in solution, saturated nacl aqueous solution washing
4Dry organic layer, reduction vaporization is to smaller size smaller.Residue is separation and purification on silicagel column, gets the required compound (target compound 17) (1.27g, 48.2%) of white solid form; Mp 70-73 ℃; R
f=0.38 (methylene chloride, 20: 1).
1HNMR(600MHz,DMSO-d
6,δppm):8.12(br?s,1H),7.84(br?s,1H),7.24-7.20(m,1H),7.06(dt,1H,J=9.0Hz,J=1.8Hz),4.08(t,2H,J=6.0Hz),3.72(t,2H,J=6.6Hz),1.90-1.81(m,4H).MS(ESI)m/z?calcd.for?C
11H
12ClF
2NO
2263.1;found(M+H
+)264.2.
The anti-microbial activity of the substituted 3-MBA verivate of experimental example C-3 position hydrophobicity halogenated alkane
Adopt the test tube doubling dilution to measure the antibacterial activity in vitro of part target compound to responsive type streptococcus aureus (MSSA ATCC25923), methicillin-resistant staphylococcus aureus (MRSA ATCC 29213) and common drug-resistant type streptococcus aureus.Measure the result and see table 1:
The antibacterial activity in vitro MIC value (μ g/mL) of table 1C-3 substituted 3-MBA verivate of position hydrophobic side chains and lead compound 3-MBA
Wherein, 1~7 successively the representative compound be (target compound 1~7 among the corresponding embodiment):
3-[(2-bromotrifluoromethane) oxygen base] BM
3-[(3-bromopropyl) oxygen base] BM
3-[(4-brombutyl) oxygen base] BM
3-[(5-bromine amyl group) oxygen base] BM
3-[(6-bromine hexyl) oxygen base] BM
3-[(3-chloropropyl) oxygen base] BM
3-[(4-chlorine amyl group) oxygen base] BM.
Claims (9)
2. 3-methoxy benzamide verivate according to claim 1 is characterized in that: said 3-methoxy benzamide verivate is specially one of following compound:
1) 3-[(2-bromotrifluoromethane) oxygen base] BM
2) 3-[(3-bromopropyl) oxygen base] BM
3) 3-[(4-brombutyl) oxygen base] BM
4) 3-[(5-bromine amyl group) oxygen base] BM
5) 3-[(6-bromine hexyl) oxygen base] BM
6) 3-[(3-chloropropyl) oxygen base] BM
7) 3-[(4-chlorobutyl) oxygen base] BM
8) 3-[(5-chlorine amyl group) oxygen base] BM
9) 3-[(6-chlorine hexyl) oxygen base] BM
10) 3-[(2-bromotrifluoromethane) oxygen base]-2, the 6-difluorobenzamide
11) 3-[(3-bromopropyl) oxygen base]-2, the 6-difluorobenzamide
12) 3-[(4-brombutyl) oxygen base]-2, the 6-difluorobenzamide
13) 3-[(5-bromine amyl group) oxygen base]-2, the 6-difluorobenzamide
14) 3-[(6-bromine hexyl) oxygen base]-2, the 6-difluorobenzamide
15) 3-[(3-chloropropyl) oxygen base]-2, the 6-difluorobenzamide
16) 3-[(5-chlorine amyl group) oxygen base]-2, the 6-difluorobenzamide
17) 3-[(4-chlorobutyl) oxygen base]-2, the 6-difluorobenzamide.
3. the preparation method of claim 1 or 2 described 3-methoxy benzamide verivates is characterized in that:
(1) works as R
1Be bromine, R
2And R
3When being hydrogen, the preparation method is: the 3-hydroxybenzamide is placed N, in dinethylformamide or the acetonitrile, in the presence of Anhydrous potassium carbonate or soda ash light, add bromo alkane, 55~65 ℃ were reacted 14~17 hours, generated the compound of general formula (I); Wherein, 3-hydroxybenzamide and N, the ratio of dinethylformamide or acetonitrile is 1mmol: 11~14mL; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate or soda ash light is 1: 1.5~2.0; The mol ratio of 3-hydroxybenzamide and bromo alkane is 1: 4~5;
(2) work as R
1Be chlorine, R
2And R
3When being hydrogen, the preparation method is: the 3-hydroxybenzamide is placed N, in the dinethylformamide, add catalyzer Soiodin and Anhydrous potassium carbonate, add chloroparaffin then, 55 ℃~65 ℃ were reacted 16~18 hours, generated the compound of general formula (I); Wherein, 3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5~3.0mL; The mol ratio of 3-hydroxybenzamide and Soiodin is 1: 0.2~0.3; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate is 1: 1.8~2.0; The mol ratio of 3-hydroxybenzamide and chloroparaffin is 1: 4~5;
(3) work as R
1Be bromine, R
2And R
3When being fluorine, the preparation method is: with 2,6-two fluoro-3-hydroxybenzamides place N, in dinethylformamide or the acetonitrile, in the presence of Anhydrous potassium carbonate, add bromo alkane, and 50~60 ℃ were reacted 7~10 hours, generated the compound of general formula (I); Wherein, 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 11~15mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 2.0~3.0; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and bromo alkane is 1: 4~5;
(4) work as R
1Be chlorine, R
2And R
3When being fluorine, the preparation method is: with 2,6-two fluoro-3-hydroxybenzamides place N, in the dinethylformamide, add catalyzer Soiodin and Anhydrous potassium carbonate, add chloroparaffin, and 50~60 ℃ were reacted 7~10 hours, generated the compound of general formula (I); Wherein, 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5~3.0mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Soiodin is 1: 0.2~0.3; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 2.0~3.0; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and chloroparaffin is 1: 4~5.
4. preparation method according to claim 3 is characterized in that: in the said step (1), and 3-hydroxybenzamide and N, the ratio of dinethylformamide or acetonitrile is 1mmol: 11mL; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate or soda ash light is 1: 1.5.
5. preparation method according to claim 3 is characterized in that: in the said step (2), and 3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5mL; The mol ratio of 3-hydroxybenzamide and Soiodin is 1: 0.3; The mol ratio of 3-hydroxybenzamide and Anhydrous potassium carbonate is 1: 1.8.
6. preparation method according to claim 3 is characterized in that: in the said step (3), and 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 11mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 3.
7. preparation method according to claim 3 is characterized in that: in the said step (4), and 2,6-two fluoro-3-hydroxybenzamide and N, the ratio of dinethylformamide is 1mmol: 2.5mL; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Soiodin is 1: 0.2; 2, the mol ratio of 6-two fluoro-3-hydroxybenzamides and Anhydrous potassium carbonate is 1: 3.
8. preparation method according to claim 3 is characterized in that: said 3-hydroxybenzamide obtains through following preparation method:
Convert the 3-hydroxy-benzoic acid to the 3-hydroxybenzoyl chloride: with the 3-hydroxy-benzoic acid is starting raw material, is solvent with toluene, adds sulfur oxychloride, reflux 4.5~5 hours, and vacuum concentration generates the 3-hydroxybenzoyl chloride; Wherein, the mol ratio of 3-hydroxy-benzoic acid and sulfur oxychloride is 1: 1.5~1.9, and the usage ratio of 3-hydroxy-benzoic acid and toluene is 1mmol: 0.83~0.90mL;
The 3-hydroxybenzoyl chloride of above-mentioned preparation is placed anhydrous tetrahydro furan;-5 ℃~-10 ℃ coolings; Slowly dropwise drip saturated strong aqua, make reaction solution slowly be increased to room temperature after 15~25 minutes in reaction under-5 ℃~-10 ℃; At room temperature stir 18h~20h, generate the 3-hydroxybenzamide; Wherein, the ratio of 3-hydroxybenzoyl chloride and THF is 1mmol: 0.37~0.40mL; The ratio of 3-hydroxybenzoyl chloride and saturated strong aqua is 1mmol: 0.37~0.40mL.
9. claim 1 or the 2 described 3-methoxy benzamide verivates application in the preparation antibacterials.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100020701A CN102531946A (en) | 2012-01-05 | 2012-01-05 | 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2012100020701A CN102531946A (en) | 2012-01-05 | 2012-01-05 | 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN102531946A true CN102531946A (en) | 2012-07-04 |
Family
ID=46340128
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2012100020701A Pending CN102531946A (en) | 2012-01-05 | 2012-01-05 | 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102531946A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461585A (en) * | 2014-09-09 | 2016-04-06 | 香港理工大学 | 3-aminobenzamide derivatives as beta-lactam auxiliary antibiotics, and preparation method and application thereof |
CN108689835A (en) * | 2018-07-10 | 2018-10-23 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 3- hydroxybenzoyl chlorides |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN87103300A (en) * | 1986-05-01 | 1987-11-11 | 菲泽有限公司 | Antiarrhythmic and preparation method thereof |
CN1143358A (en) * | 1994-03-09 | 1997-02-19 | 钮卡斯尔大学风险投资有限公司 | Benzamide analogs, useful as parp (ADP-ribosyltransferase, ADRPT) DNA repair enzyme inhibitors |
WO2006103045A1 (en) * | 2005-03-31 | 2006-10-05 | Ucb Pharma S.A. | Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses |
CN101404989A (en) * | 2006-03-23 | 2009-04-08 | 普罗利西斯有限公司 | Antibacterial agents |
-
2012
- 2012-01-05 CN CN2012100020701A patent/CN102531946A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN87103300A (en) * | 1986-05-01 | 1987-11-11 | 菲泽有限公司 | Antiarrhythmic and preparation method thereof |
CN1143358A (en) * | 1994-03-09 | 1997-02-19 | 钮卡斯尔大学风险投资有限公司 | Benzamide analogs, useful as parp (ADP-ribosyltransferase, ADRPT) DNA repair enzyme inhibitors |
WO2006103045A1 (en) * | 2005-03-31 | 2006-10-05 | Ucb Pharma S.A. | Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses |
CN101404989A (en) * | 2006-03-23 | 2009-04-08 | 普罗利西斯有限公司 | Antibacterial agents |
Non-Patent Citations (3)
Title |
---|
DAVID J. HAYDON, ET AL.: "An Inhibitor of FtsZ with Potent and", 《SCIENCE》 * |
LLOYD G. CZAPLEWSKI, ET AL.: "Antibacterial alkoxybenzamide inhibitors of the essential bacterial cell division protein FtsZ", 《BIOORGANIC & MIDICINAL CHEMISTRY LETTERS》 * |
PIOTR KOWALSKI, ET AL.: "Evalution of 1-Arylpiperazine Derivative of Hydrosybenzamides as 5-HT1A and 5-HT7 Serotonin Receptor Ligands: An Experimental and Molecular Modeling Approach", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105461585A (en) * | 2014-09-09 | 2016-04-06 | 香港理工大学 | 3-aminobenzamide derivatives as beta-lactam auxiliary antibiotics, and preparation method and application thereof |
CN108689835A (en) * | 2018-07-10 | 2018-10-23 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 3- hydroxybenzoyl chlorides |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106083891B (en) | The manufacture method of compound with hiv integrase inhibitory activity | |
JP4859672B2 (en) | 1-isopropyl-2-oxo-1,2-dihydropyridine-3-carboxamide derivatives having 5-HT4 receptor agonist activity | |
TW202304911A (en) | Pyridinamide compound | |
Chandra et al. | Synthesis and in vitro antimicrobial studies of medicinally important novel N-alkyl and N-sulfonyl derivatives of 1-[bis (4-fluorophenyl)-methyl] piperazine | |
Sridhar et al. | Synthesis of quinoline acetohydrazide-hydrazone derivatives evaluated as DNA gyrase inhibitors and potent antimicrobial agents | |
TW200902678A (en) | Compound wherein substituted bipyridyl group is connected with pyridoindole ring structure through phenylene group, and organic electroluminescent device | |
TW200804371A (en) | Organic compounds | |
JP2021521190A (en) | A novel method for synthesizing deuterated amides and deuterated sulfonamides | |
Keng Yoon et al. | Antituberculosis: synthesis and antimycobacterial activity of novel benzimidazole derivatives | |
TW201026699A (en) | 5-amino-2-(1-hydroxy-ethyl)-tetrahydropyran derivatives | |
TW201018682A (en) | Heterocyclic biaryl derivative, and pde inhibitor comprising same as active ingredient | |
KR100550078B1 (en) | Quinolonecarboxylic acid derivatives or salts thereof | |
CN102164919B (en) | Oxazolidinyl antibiotics | |
CA3081423A1 (en) | Antibacterial compounds | |
Kong et al. | Synthesis of fluorinated carbazoles via C–H arylation catalyzed by Pd/Cu bimetal system and their antibacterial activities | |
TW200418840A (en) | Process for preparing ARIPIPRAZOLE | |
CN105503898B (en) | A kind of nitrogenous heterocyclic artemisinin derivative and preparation method thereof | |
CN102531946A (en) | 3-methoxybenzamide (MBA) derivant as well as preparation method and application thereof | |
Pettit et al. | Antineoplastic agents 491.1 synthetic conversion of aaptamine to isoaaptamine, 9-demethylaaptamine, and 4-methylaaptamine | |
FR2969150A1 (en) | NOVEL INDOLIC MOLECULES DEMONSTRATING ANTIBACTERIAL ACTIVITIES IN A VARIETY OF GRAM-NEGATIVE AND POSITIVE BACTERIA INCLUDING MULTI-DRUG-RESISTANT BACTERIA | |
EP2994466A1 (en) | Antibacterial phthalide derivatives | |
WO2024001650A1 (en) | Metal iridium complex and use thereof | |
CN102834394B (en) | Bicyclic quinolone compounds, preparation methods and uses thereof | |
JP5191053B2 (en) | Ethanol or 1,2-ethanediol cyclohexyl antibiotic derivatives | |
Mohammed et al. | Design, synthesis and pharmacological evaluation of sulfanilamide-ciprofloxacin conjugates utilizing hybridization approach as new antibacterial agents |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120704 |