CN103145631A - Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof - Google Patents
Antibacterial derivative of quinoxaline-1,4-dioxide and application in animal production thereof Download PDFInfo
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- 0 C/C(/C(C(CCc1c(C)c(*)c(*)c(*)c1*)=O)[N+](c1c(C)cc(C)c(*)c1)[O-])=C\*[O-] Chemical compound C/C(/C(C(CCc1c(C)c(*)c(*)c(*)c1*)=O)[N+](c1c(C)cc(C)c(*)c1)[O-])=C\*[O-] 0.000 description 1
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Abstract
The invention discloses an antibacterial derivative of quinoxaline-1,4-dioxide and an application in animal production thereof. The derivatives of quinoxaline-1,4-dioxide shown in formulas 1, 2, 3, 4, 5 or 6 and salts thereof have high antibacterial activities, are low in toxicity or non-toxic to beasts and birds and have higher antibacterial activities and higher safety compared with the quinoxaline derivatives of the varieties in the market at present; and therefore, the derivatives can serve as a growth promoter for feed, the animal growth is promoted, and the derivatives have good application prospects in the breeding industry.
Description
Technical field:
The present invention relates to the quinoxaline-1 of new germ resistance, the derivative of 4-dioxide with and application in the animal fowl growth regulator of the prevention of preparation cultivated animals Important Infectious Diseases and treatment articles and cultivated animals.
Background technology:
Although Chinese patent 97110620.7(applying date 1997.4.21) (publication number CN1197068A) described 3-methyl-2-phenylethylene keto-Kui Evil woodss-1,4-dioxide (Quinocetone, quinocetone) compound and synthetic method, but at Monats hefte fuer Chemie, 1995, vol.126, #11p.1217 – 1224 has specifically disclosed this compound structure.
US Patent No. 3344022,3371090,3344022,3644360,4128642,4100284,4303657,4317824, the patents such as 4343942,4684649 have been described the derivative of a series of Kui Evil woods-Isosorbide-5-Nitrae-dioxide as treatment of animals medication and growth stimulant.
De quinoxaline animal growth stimulant such as carbadox (carbadox) are used in the U.S. and Chinese market approval at present, and there is serious general toxicity in olaquindox (olaquinodox), three intoxicatings and activity problems.(mequindox Maquidox) also exists serious toxicity and activity problems to the methlacetylquinoxalinediode that goes on the market in Chinese market, is an active reactive molecule simultaneously.
Summary of the invention:
The purpose of this invention is to provide have good anti-microbial activity, to the livestock and poultry low toxicity or nontoxic, can be as animal fowl growth regulator, promote growth of animals or poultry De quinoxaline-1, the derivative of 4-dioxide or its salt.
Quinoxaline-1 of the present invention, the derivative of 4-dioxide or its salt is characterized in that, quinoxaline-1, the structural formula of the derivative of 4-dioxide suc as formula 1 or formula 2 shown in, its Chinese style 1 and formula 2 be cis-trans-isomer each other
Formula 1
Formula 2
R in formula 1 and formula 2
1-R
5Be selected from-OH ,-CH
3, C
1To C
6Alkane, phenyl ring, hydrogen, benzyl, halogen ,-O-CH
3,-NO
2, R
6, R
7Group be selected from hydrogen, halogen ,-O-CH
3
Described halogen is preferably F or Cl.
Further preferred, the R in formula 1 and formula 2
6, R
7Be-H R
1Be-H R
2Be-F or-CH
3, R3, R4, R5 are-H.
Quinoxaline-1 of the present invention, the derivative of 4-dioxide or its salt is characterized in that, and quinoxaline-1, the structural formula of the derivative of 4-dioxide are suc as formula 3, shown in formula 4, formula 5 or formula 6, and its Chinese style 3, formula 4, formula 5 and formula 6 be cis-trans-isomer each other
Formula 3
Formula 4
Formula 5
Formula 6
R in formula 3, formula 4, formula 5 and formula 6
1To R
4Group is selected from-OH ,-CH
3, C
1To C
6Alkane, hydrogen, halogen ,-O-CH
3
Described halogen is preferably F or Cl.
Further preferred, the R in formula 3, formula 4, formula 5 and formula 6
1, R
2, R
3, R
4Be-H; Or R
1, R
3Be-F R
2, R
4Be-H.
The present invention also provides suc as formula 1, De quinoxaline-1 shown in formula 2, formula 3, formula 4, formula 5 or formula 6, and the derivative of 4-dioxide or its salt are in preparation Animal diseases prevention or medicine or the application in the preparation animal feed additive for promoting growth.
Described animal is the animals such as pig, chicken, duck, goose, beef cattle, milk cow, sheep, fish, shrimp, fox, ermine or racoon dog of each growth phase.
Described promoting animal growth feed is perfect compound feed, interpolation is the De quinoxaline-1 suc as formula 1, shown in formula 2, formula 3, formula 4, formula 5 or formula 6, and the derivative of 4-dioxide or its salt consumption during as feed additive for promoting growth is 5～500ppm of perfect compound feed quality.
Described quinoxaline-1, the salt of the derivative of 4-dioxide can be hydrochloride.
Of the present invention suc as formula 1, shown in formula 2, formula 3, formula 4, formula 5 or formula 6 the De quinoxaline-1, the derivative of 4-dioxide or its salt have good anti-microbial activity, to livestock and poultry low toxicity or nontoxic, its quinoxaline derivative than the kind of having gone on the market at present has the security of stronger anti-microbial activity and Geng Gao, therefore can be as animal fowl growth regulator, promote growth of animals or poultry, have extraordinary application prospect in the cultivation industry.
Embodiment
Following examples are to further illustrate of the present invention, rather than limitation of the present invention.
Embodiment 1:2-(3-(3-fluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-002, preparation as shown in Equation 7)
Formula 7
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0OC.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 3-fluorobenzaldehyde (2.23g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3-fluorobenzene) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.
Cis-trans-isomer split process: TLC(DCM100%) show three points; and product solvability in DCM is relatively good; get this product silica gel column chromatography separation of 5 grams (300 order silica gel divide) DCM:MeOH=100:1～10:1 and obtain yellow cotton-shaped solid; about 4.5 grams (E)-2-(3-(3-fluorophenyl) acryl)-3-Jia based quinoxaline 1; the 4-dioxide, yield 90%.Therefore infer that this compound trans structure is greater than 90%.
NMR:δH(CDCl3,400MHz)8.7(1H,d),8.57(1H,d),7.86(2H,m),7.58(1H,d),7.37(2H,m),7.29(1H,m),7.15(2H,m),2.57(3H,s).
δH(DMSO,400MHz)8.5(1H,d,Ar-H,J=9.6Hz),8.4(1H,d,Ar-H,J=9.2Hz),7.99(2H,m),7.8(1H,d,=CH,J=16.4Hz),7.64(1H,d,Ar-H,J=10Hz),7.57(1H,d,Ar-H,J=8Hz),7.48(1H,m),7.3(2H,m,=CH and Ar-H),2.35(3H,s).
Embodiment 2:2-(3-(2-chloro-6-fluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-010, preparation as shown in Equation 8)
Formula 8
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 2-chloro-6-fluorobenzaldehyde (2.84g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(2-chloro-6-fluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.67(1H,d),8.58(1H,d),7.92(3H,m),7.4(1H,d),7.3(2H,m),7.0(1H,m),2.59(3H,s).
Embodiment 3:2-(3-(4-fluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-003, preparation as shown in Equation 9)
Formula 9
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 3-fluorobenzaldehyde (2.23g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(4-fluorobenzene) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.66(1H,d),8.57(1H,d),7.89(2H,m),7.58(3H,m),7.0(3H,m),2.57(3H,s).
Embodiment 4:2-(3-(2-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-007, preparation as shown in Equation 10)
Formula 10
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add Benzaldehyde,2-methoxy (2.45g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(2-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.69(1H,d),8.58(1H,d),7.89(3H,m),7.58(1H,d),7.41(1H,m),7.2(1H,s),6.98(1H,m),6.9(1H,d),3.83(3H,s),2.57(3H,s).
Embodiment 5:2-(3-(3-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-008, preparation as shown in Equation 11)
Formula 11
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add m-methoxybenzaldehyde (2.45g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.68(1H,d),8.58(1H,d),7.89(2H,m),7.56(1H,d),7.3(1H,m),7.14(3H,m),6.97(1H,m),3.81(3H,s),2.57(3H,s).
Embodiment 6:2-(3-(2,6-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-011, preparation as shown in Equation 12)
Formula 12
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 2; 6-difluorobenzaldehyde (2.56g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(2,6-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.67(1H,d),8.58(1H,d),7.89(2H,m),7.78(1H,d),7.4(1H,d),7.36(1H,m),6.95(2H,m),2.58(3H,s).
Embodiment 7:2-(3-(2-fluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-001, preparation as shown in Equation 13)
Formula 13
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 2-fluorobenzaldehyde (2.23g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(2-fluorobenzene) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.68(1H,d),8.59(1H,d),7.86(2H,m),7.78(1H,d),7.64(1H,m),7.4(1H,m),7.2(2H,m),7.1(1H,m),2.58(3H,s).
Embodiment 8:2-(3-(4-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-009, preparation as shown in Equation 14)
Formula 14
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 4-methoxybenzaldehyde (2.45g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(4-(3-methoxyphenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.67(1H,d),8.58(1H,d),7.89(2H,m),7.52(3H,m),7.0(1H,d),6.97(2H,d),3.84(3H,s),2.57(3H,s).
Embodiment 9:2-(3-(4-chloro-phenyl-) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-014, preparation as shown in Equation 15)
Formula 15
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 4-chlorobenzaldehyde (2.52g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(4-chloro-phenyl-) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.65(1H,d),8.58(1H,d),7.89(2H,m),7.75(3H,m),7.36(2H,d),7.1(1H,d),2.56(3H,s).
Embodiment 10:2-(3-(3,4-dichlorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-016, preparation as shown in Equation 16)
Formula 16
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 3; 4-dichlorobenzaldehyde (3.13g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3,4-dichlorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.65(1H,d),8.58(1H,d),7.89(2H,m),7.67(1H,s),7.55(1H,d),7.48(1H,d),7.40(1H,d),7.1(1H,d),2.57(3H,s).
Embodiment 11:2-methyl-3-(3-p-methylphenyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-017, preparation as shown in Equation 17)
Formula 17
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add p-tolualdehyde (2.16g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-methyl-3-(3-p-methylphenyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.67(1H,d),8.58(1H,d),7.89(2H,m),7.55(1H,d),7.46(2H,d),7.23(2H,d),7.1(1H,d),2.56(3H,s),2.4(3H,s).
Embodiment 12:2-(3-(3,4-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-020, preparation as shown in Equation 18)
Formula 18
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 3; 4-difluorobenzaldehyde (2.56g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3,4-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.65(1H,d),8.58(1H,d),7.89(2H,m),7.54(1H,d),7.44(1H,m),7.3(1H,s),7.2(1H,m),7.07(1H,d),2.57(3H,s)
Embodiment 13:2-methyl-3-(3-o-tolyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-018, preparation as shown in Equation 19)
Formula 19
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add o-toluylaldehyde (2.16g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-methyl-3-(3-o-tolyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.68(1H,d),8.58(1H,d),7.99(1H,d),7.88(2H,m),7.66(1H,d),7.33(1H,m),7.22(2H,m),7.1(1H,d),2.59(3H,s),2.4(3H,s).
Embodiment 14:2,2-(imido methylene radical) two (2-hydrazino-1-thiazolinyl) two (1-methyl isophthalic acid-thiazolinyl) two (quinoxaline Isosorbide-5-Nitrae-dioxide) (YST-003-021, preparation as shown in Equation 20)
Formula 20
The preparation of step 1:2-(dimethoxy-methyl) quinoxaline Isosorbide-5-Nitrae-dioxide
Pyruvic aldehyde dimethyl acetal (71g, 0.6mol, 1eq) with Pyrrolidine (43g, 0.6mol, 1eq) being dissolved in the DCM of about 200ml, ice bath is cooled to 0 ° of C, benzofuraxan (82g afterwards, 0.6mol DCM solution 1eq) drips under stirring in 1 hour, keeps simultaneously the temperature of solution at 0 ° of C.Continue reaction 4 hours after being added dropwise to complete under ice bath, TLC shows that raw material benzofuraxan primitive reaction is complete.Be spin-dried for solvent DCM, get thick liquid, ice bath is lowered the temperature by product, add sherwood oil in reaction flask, have solid to separate out, filter with sand core funnel, filter cake obtains faint yellow solid (2-(dimethoxy-methyl) quinoxaline Isosorbide-5-Nitrae-dioxide) 66g with ethanol (250ml*3) washing.Yield: 46.6%.
1H NMR(CDCl
3,400MHz):δ8.6(2H,m),δ8.5(1H,s),δ7.8(2H,d),δ5.9(1H,s),δ3.5(6H,s).
Step 2:
Concentrated hydrochloric acid 200ml, methyl alcohol 1700ml and 2-(dimethoxy-methyl) quinoxaline Isosorbide-5-Nitrae-dioxide (70g, 296.7mmol, 2eq) join in reaction flask, and room temperature mechanical is stirred to 2-(dimethoxy-methyl) quinoxaline Isosorbide-5-Nitrae-dioxide and dissolves fully.Add afterwards two amido guanidinesalt hydrochlorates (18.5g, 148.3mmol, 1eq), 2 days TLC of room temperature reaction show that raw material reaction is incomplete, are heated to 40～50 ° of C and continue reaction one day, and TLC shows that the raw material primitive reaction is complete.There is yellow solid to separate out, suction strainer, solid methanol wash, then wash away a small amount of unreacted raw material completely with DCM, be spin-dried for, obtain 76g yellow solid [2,2-(imido methylene radical) two (2-hydrazino-1-thiazolinyl) two (1-methyl isophthalic acid-thiazolinyl) two (quinoxaline Isosorbide-5-Nitrae-dioxide)].HPLC:95.7%
1H NMR(DMSO,400MHz):δ9.6(2H,s),δ9.1(3H,d),δ8.5(4H,m),δ7.98(4H,m).
Embodiment 15:2-(3-(3,5-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-029, preparation as shown in Equation 21)
Formula 21
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 2; 6-difluorobenzaldehyde (2.56g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(2,6-difluorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)8.5(1H,d),8.4(1H,d),7.99(2H,m),7.8(1H,d),7.5(2H,d),7.36(2H,m),2.36(3H,s).
Tolyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-042, preparation as shown in Equation 22) between embodiment 16:2-methyl-3-(3-
Formula 22
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add a toluic aldehyde (2.16g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets tolyl acryl) quinoxaline Isosorbide-5-Nitrae-dioxide between product 2-methyl-3-(3-.Suitable anti-split process: reference example 1.
NMR:δH(CDCl3,400MHz)8.65(1H,d),8.58(1H,d),7.89(2H,m),7.55(1H,d),7.37(2H,d),7.27(2H,m),7.1(1H,d),2.56(3H,s),2.35(3H,s).
NMR:δH(DMSO,400MHz)8.65(1H,d),8.58(1H,d),7.99(2H,m),7.8(1H,d,=CH,J=16.4Hz)7.55(2H,s),7.27(2H,m),7.1(1H,d,=CH,J=16.4Hz),2.36(3H,s),2.29(3H,s).
Embodiment 17:2-(3-(3-chloro-phenyl-) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-043, preparation as shown in Equation 23)
Formula 23
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add m chlorobenzaldehyde (2.52g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3-chloro-phenyl-) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Productive rate is 64.7%.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)8.5(1H,d),8.4(1H,d),7.9(2H,m),7.8(2H,d),7.79(1H,d),7.5(1H,m),7.34(1H,s).7.3(1H,s),2.35(3H,s).
Embodiment 18:2-(3-(3,5-xylyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-044, preparation as shown in Equation 24)
Formula 24
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 3; 5-dimethylbenzaldehyde (2.41g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3,5-xylyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)8.5(1H,d),8.4(1H,d),7.99(2H,m),7.6(1H,d),7.36(2H,s),7.16(1H,d),7.1(1H,s),2.3(3H,s),2.2(6H,s).
Embodiment 19:2-(3-(3,5-dichlorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-045, preparation as shown in Equation 25)
Formula 25
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 3; 5-dichlorobenzaldehyde (3.13g; 18mmol, 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-(3-(3,5-dichlorophenyl) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(CDCl
3,400MHz)8.67(1H,d),8.59(1H,d),7.93(2H,m),7.5(4H,m),7.1(1H,d),2.58(3H,s).
Embodiment 20:2-methyl-3-(3-(pyridin-3-yl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-046, preparation as shown in Equation 26)
Formula 26
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add pyridine-3-formaldehyde (1.92g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-methyl-3-(3-(pyridin-3-yl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz),δ8.8(1H,s),δ8.6(2H,m),δ8.4(1H,d),δ8.2(1H,d),δ8.0(2H,m),δ7.9(1H,d),δ7.47(1H,m),δ7.4(1H,d),δ2.36(3H,s).
Embodiment 21:2-methyl-3-(3-(pyridin-4-yl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-047, preparation as shown in Equation 27)
Formula 27
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add Pyridine-4-Carboxaldehyde (1.92g; 18mmol; 1.2eq) stirred 20 minutes under ice bath, TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Add approximately 100mL water in reaction solution, extracting and demixing is spin-dried for organic phase and gets crude product, and crude product gets 2-methyl-3-with methanol wash, and (Isosorbide-5-Nitrae-the dioxide productive rate is 39.1% to 3-(pyridin-4-yl) acryl) quinoxaline.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)δ8.68(3H,s),δ8.58(1H,d),δ7.9(2H,m),δ7.6(1H,d),δ7.4(2H,d),δ7.3(1H,m).δ2.6(3H,d).
Embodiment 22:2-(3-(3-ethylbenzene) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-049, preparation as shown in Equation 28)
Formula 28
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 3-ethylbenzene formaldehyde (2.4g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, and TLC shows two points, and silica gel chromatographic column separates to get 2-(3-(3-ethylbenzene) acryl)-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(CDCl
3,400MHz)8.66(1H,d),8.59(1H,d),7.89(2H,m),7.59(1H,d),7.39(2H,s),7.3(2H,m),7.1(1H,d),2.65(2H,m),2.57(3H,s),1.23(3H,m).
Embodiment 23:2-methyl-3-(3-(3-oil of mirbane) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-051, preparation as shown in Equation 29)
Formula 29
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 3-nitrobenzaldehyde (2.72g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 10～15 minutes and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing, is spin-dried for solvent and gets product 2-methyl-3-(3-(3-oil of mirbane) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)δ8.54(1H,d),δ8.5(1H,s),δ8.4(1H,d),δ8.2(2H,d),δ8.0(3H,m),δ7.7(1H,m),δ7.4(1H,d),δ2.5(3H,s).
Embodiment 24:2-methyl-3-(3-(naphthalene-2-yl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-058, preparation as shown in Equation 30)
Formula 30
Get sodium hydroxide (0.6g, 15mmol, 1eq) and 100mL methyl alcohol and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein; keep simultaneously the temperature of solution at 0 ° of C, add 2-naphthaldehyde (2.8g, 18mmol; 1.2eq) stir under ice bath and had solid to separate out in 1 hour and TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Filter, filter cake washs with methyl alcohol (100mL*3), but assorted point is arranged, and column chromatography for separation gets product 2-methyl-3-(3-(naphthalene-2-yl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(CDCl
3,500MHz)8.55(1H,d),8.4(1H,d),8.2(1H,s),7.94～8.03(6H,m),7.89(1H,d),7.5(2H,m),7.3(1H,d),2.4(3H,s).
Embodiment 25:2,2-(imido methylene radical) two (2-hydrazino-1-thiazolinyl) two (1-methyl isophthalic acid-thiazolinyls) two (6-Jia oxygen based quinoxaline Isosorbide-5-Nitrae-dioxide) (YST-003-056, as shown in Equation 31)
3,3'-(1E, 1'E)-2, the preparation of 2'-(iminomethylene) bis (hydrazin-2-yl-1-ylidene) bis (methan-1-yl-1-ylidene) bis (6-me thoxyquinoxaline1,4-dioxide)
The preparation of step 1:3-methoxyl group benzo furazan (formula 32)
Potassium hydroxide (1.23g; 22mmol; 1.1eq) be dissolved in approximately in 40 milliliters of ethanol; 4-methoxyl group-2-N-methyl-p-nitroaniline (3.36g afterwards; 20mmol, 1eq) add wherein, under nitrogen protection; chlorine bleach liquor (40mL; 66mmol, 3eq) be added drop-wise in this mixing solutions normal-temperature reaction 2 hours; TLC(PE:EA=5:1) show that raw material 4-methoxyl group-2-N-methyl-p-nitroaniline reacts completely; and there is solid to separate out, filters the filter cake washed with dichloromethane; be spin-dried for organic phase and obtain 3-methoxyl group benzo furazan, yield 50%.
The preparation of step 2:2-(dimethoxy-methyl)-7-Jia oxygen based quinoxaline Isosorbide-5-Nitrae-dioxide
3-methoxyl group benzo furazan (1.4g, 8.4mmol, 1eq), pyruvic aldehyde dimethyl acetal (2g, 17mmol, 2eq) and Pyrrolidine (1.2g, 17mmol, 2eq) be dissolved in approximately in 30 milliliters of Isosorbide-5-Nitrae-dioxane, this mixed solution is warming up to 50～60 ° of C reactions approximately 1 hour, and TLC shows that the raw material primitive reaction is complete.Add entry and methylene dichloride in reaction solution, extraction, layering is spin-dried for organic phase, adds afterwards sherwood oil to have solid to separate out, and filters, the filter cake methanol wash is spin-dried for filter cake and gets product 2-(dimethoxy-methyl)-7-first oxygen based quinoxaline Isosorbide-5-Nitrae-dioxide.NMRδH(CDCl3,400MHz)8.51(2H,d),7.87(1H,s),7.4(1H,d),5.9(1H,s),4.0(3H,s),3.55(6H,s).
Step 3:
3,3'-(1E, 1'E)-2, the preparation of 2'-(iminomethylene) bis (hydrazin-2-yl-1-ylidene) bis (methan-1-yl-1-ylidene) bis (6-methoxyquinoxaline1,4-dioxide)
The 2-(dimethoxy-methyl)-7-Jia oxygen based quinoxaline Isosorbide-5-Nitrae-dioxide (1.5g, 5.6mmol, 2eq) be dissolved into the 10mL concentrated hydrochloric acid, in 12mL methyl alcohol, then add two amido guanidinesalt hydrochlorate (0.35g, 2.8mmol, 1eq), room temperature reaction spends the night, and in solution, yellow solid is separated out, suction filtration, the filter cake methanol wash is spin-dried for filter cake and gets product.
NMRδH(DMSO,400MHz)δ9.6(1H,s),δ8.9(1H,s),δ8.4(1H,d),δ7.8(1H,d),δ7.6(1H,d),δ4.0(3H,s).
Embodiment 26:2-methyl-3-(3-(3-(trifluoromethyl) phenyl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide (YST-003-052, preparation as shown in Equation 34)
Formula 34
Get Pyrrolidine (1g, 15mmol, 1eq) and 100mL methylene dichloride and join in the eggplant-shape bottle of 250mL, ice bath is cooled to 0 ° of C.2-ethanoyl-3-Jia based quinoxaline 1; 4-dioxide (3.27g; 15mmol; 1eq) add wherein, keep simultaneously the temperature of solution at 0 ° of C, add 3-trifluoromethylated benzaldehyde (3.13g; 18mmol; 1.2eq) stirred 20 minutes under ice bath, TLC shows that raw material 2-ethanoyl-3-Jia based quinoxaline Isosorbide-5-Nitrae-dioxide reacts completely.Add approximately 100mL water; extracting and demixing; be spin-dried for organic phase; then add methyl alcohol to have solid to separate out; filter, filter cake obtains yellow solid with methyl alcohol (100mL*3) washing; be spin-dried for solvent and get product 2-methyl-3-(3-(3-(trifluoromethyl) phenyl) acryl) quinoxaline Isosorbide-5-Nitrae-dioxide.Suitable anti-split process: reference example 1.
δH(DMSO,400MHz)δ8.56(1H,d),δ8.4(1H,d),δ8.1(1H,d),δ8.0(4H,m),δ7.8(1H,d),δ7.6(1H,m),δ7.4(1H,d),δ2.5(3H,s).
Embodiment 27: quinoxaline-1s, the antibacterial activity in vitro test of 4-dioxide derivative
1, test materials:
(1) substratum:
I, LB liquid nutrient medium: be used for the cultivation of intestinal bacteria and Salmonellas, fill a prescription as follows:
Yeast extract 5 grams
Tryptones 10 grams
Sodium-chlor 10 grams
Add water to 1000ml
pH 7.0-7.2；
II, TSB liquid nutrient medium add volume percent 2% calf serum during use, be used for the cultivation of streptococcus aureus, fill a prescription as follows:
Tryptone 17g
Soy peptone 3g
Yeast Extract 6g
NaCl 5g
K
2HPO
4.3H
2O 2.5g
Glucose 2.5g
H
2O to 1L
pH 7.0-7.4；
III, thioglycollate medium (FT substratum): be used for the cultivation of clostridium perfringens, fill a prescription as follows:
Tryptones 15g
Yeast extract powder 5g
Glucose 5g
Sodium thioglycollate 0.5g
CYSTINE 0.5g
Sodium-chlor 2.5g
Resazurin 0.001g
Agar 0.75g
PH value 7.1 ± 0.2;
(2) strains tested: intestinal bacteria CAU0159, intestinal bacteria CAU0195, intestinal bacteria CAU0020, intestinal bacteria CAU0053, intestinal bacteria CAU0147, fowl typhoid Salmonellas CAU0206, fowl typhoid Salmonellas CAU0205, fowl typhoid Salmonellas QAU0399, Salmonella anatis CAU0118, Salmonella choleraesuls CEC19940146, streptococcus aureus CAU0871, streptococcus aureus CAU0868, streptococcus aureus CAU0869, streptococcus aureus CAU0866, streptococcus aureus CAU0804, clostridium perfringens CAU0859, clostridium perfringens CAU0855, clostridium perfringens CAU0795, clostridium perfringens CAU0591 and clostridium perfringens HNAU166: all preserve the center available from national veterinary microorganism bacterial classification.
(3) specimen
Quinocetone, olaquindox, carbadox and methlacetylquinoxalinediode: all available from SIGMA company.
Sample YST-003-001 etc.: prepared by embodiment 1-26.
2, test method (test tube doubling dilution)
Test method adopts the test tube doubling dilution, take p-Thymol, the anti-microbial activity of streptococcus aureus is tested as example (testing different compounds identical to the method for different bacterium anti-microbial activity).If specimen is during to the anti-microbial activity of intestinal bacteria and Salmonellas, substratum LB liquid nutrient medium.And test during clostridium perfringens with fresh FT substratum, surface coverage one deck paraffin oil during cultivation is to keep anaerobic environment.Concrete test method is as follows:
A, select 12 sterile test tube numbering 1～12;
B, aseptic adding in 9.5 milliliters of TSB liquid nutrient medium to the 1 pipes, aseptic adding in 5.0 milliliters of TSB liquid nutrient mediums to the, 2 to 11 pipes;
C, add 0.5 milliliter of testing sample solution in the 1st pipe, get 5.0 milliliters after then the 1st pipe being mixed to the 2nd pipe, successively to the 10 pipe, then get 5.0 milliliters from the 10th pipe and lose, the 11st pipe is made positive control for not adding specimen;
D, separately prepare 5.0 milliliters of TSB liquid culture parent tubes (the 12nd pipe) and do not add specimen, bacterium, as negative control;
E, the 1st～11 pipe add respectively bacterium to be tested, and (bacterial concentration is about 10
8Cfu/ml) bacterium liquid 50.0 microlitres (the bacterium cell age is 16-18h);
F, 37 ℃ of static cultivation 16h.
G, result are judged: visual inspection has or not bacterial growth, positive visible haze growth, negative visible clarification (negative and positive control must be correct).Press the test tube numbering, last pipe Chinese traditional medicine concentration that bacterial growth do not occur is that testing sample is to the minimal inhibitory concentration (μ g/mL) of streptococcus aureus.
3, test-results
Derivative that embodiment 1-26 synthesized and the antibacterial activity in vitro of present clinical use De quinoxaline antiseptic-germicide have been tested, test result shows YST-003-002, YST-003-042, YST-003-045 and the stronger resisting gram-positive bacterium of YST-003-052 tool, and antibacterial effect is better than carbadox, methlacetylquinoxalinediode, olaquindox and quinoline sigh the ketone that approval is at present used.And YST-003-021 has the anti-gram prolapse of uterus active (table 1-4) that effect is better than carbadox, methlacetylquinoxalinediode, olaquindox and quinoline sigh ketone etc.In addition, compared simultaneously the cis-trans-isomer of sample YST-003-002 and YST-003-042 and the biological effect of mixed form, the anti-microbial activity of cis-trans structure is close as a result.
Table 1: quinoxaline-1, the external minimal inhibitory concentration (MIC, μ g/mL) of 4-dioxide derivative to streptococcus aureus
Annotate: the specimen of not indicating especially in table is all mixtures of cis-trans structure, and is lower same.
Table 2: quinoxaline-1, the external minimal inhibitory concentration (MIC, μ g/mL) of 4-dioxide derivative to clostridium perfringens
Table 3: quinoxaline-1, the 4-dioxide derivative is to colibacillary external minimal inhibitory concentration (MIC, μ g/mL)
Table 4: quinoxaline-1, the external minimal inhibitory concentration (MIC, μ g/mL) of 4-dioxide derivative to Salmonellas
Experimental example 28: quinoxaline-1s, the 4-dioxide derivative is to acute toxicity test in mice
1. material
1.1 tested material
Quinocetone, olaquindox, YST-003-002, YST-003-021, YST-003-042 and YST-003-052 etc.
1.2 laboratory animal
The Kunming kind SPF level healthy mice that Guangdong Medical Lab Animal Center provides, body weight 18～22g.
2. method
Select the healthy Kunming kind small white mouse of body weight 18-22g, 10 of each dosage groups, male and female half and half, fasting be can't help water after 16 hours, and maximum dose level gives tested material by 20000mg/kg BW dosage, gavage amount 0.4ml/10g BW, 1 time can the person of pouring into, and gavage is once; Once can not the person of pouring into, gavage twice more than every minor tick 4h, is observed a week, records mouse poisoning manifestations and death condition.
3. result
The acute toxicity tests show YST-003-002, YST-003-021, YST-003-042 and YST-003-052 to the LD50 of acute toxicity test in mice all greater than the 20000mg/kg body weight, belong to non-toxic substance, its toxicity is lower than olaquindox and Quinocetone (table 5).
Table 5: quinoxaline-1,4-dioxide derivative acute toxicity test in mice result
Embodiment 29: quinoxaline-1s, the acute toxicity test of 4-dioxide derivative to broiler chicken
1. material
1.1 tested material
Quinocetone, olaquindox, YST-003-002, YST-003-021 and YST-003-042 etc.
1.2 laboratory animal
The fast large-scale broiler chicken of yellow plumage, 14 ages in days, Guangdong Ke Ze poultry company.
2. method
Select the fast large broiler chicken of the healthy yellow plumage of 14 suitable ages in days of body weight, 10 of each dosage groups, male and female half and half, fasting be can't help water after 16 hours, and maximum dose level gives tested material by 20000mg/kg BW dosage, gavage amount 0.4ml/10g BW, observe a week, record poisoning manifestations and the death condition of test chicken.
3. result
The acute toxicity tests show YST-003-002, YST-003-021, YST-003-042 to the LD50 of the fast large-scale broiler chicken acute toxicity test of yellow plumage all greater than the 20000mg/kg body weight, belong to non-toxic substance, its toxicity is lower than olaquindox and Quinocetone (table 6).
Table 6: quinoxaline-1, the acute toxicity tests of 4-dioxide derivative to broiler chicken
Embodiment 30: quinoxaline-1s, the acute toxicity test of 4-dioxide derivative to the meat duck
1. material
1.1 tested material
Quinocetone, olaquindox, YST-003-002, YST-003-021 and YST-003-042 etc.
1.2 laboratory animal
Cherry Village Ducks, 14 ages in days, poultry company of Guangdong Jiangmen agricultural university provides.
2. method
Select the healthy Cherry Village Ducks of 14 suitable ages in days of body weight, 10 of each dosage groups, male and female half and half, fasting be can't help water after 16 hours, and maximum dose level gives tested material by 20000mg/kg BW dosage, gavage amount 0.4ml/10g BW, observe a week, poisoning manifestations and the death condition of record test duck.
3. result
The acute toxicity tests show YST-003-002, YST-003-021, YST-003-042 to the LD50 of Cherry Village Ducks acute toxicity test all greater than the 20000mg/kg body weight, belong to non-toxic substance, its toxicity is lower than olaquindox and Quinocetone (table 7).
Table 7: quinoxaline-1, the acute toxicity tests of 4-dioxide derivative to the meat duck
Embodiment 31: quinoxaline-1s, 30 days feeding studys (broiler chicken) of 4-dioxide derivative
1. material
1.1 tested material:
Quinocetone, olaquindox, YST-003-002, YST-003-021, YST-003-042
1.2 dosage design:
Tested material Quinocetone, YST-003-002, YST-003-021 and YST-003-042 establish three dosage groups, and high dosage is the 5000mg/Kg feed, and middle dosage is the 2500mg/Kg feed, and low dosage is the 1250mg/Kg feed; Olaquindox is established three dosage groups, and high dosage is the 200mg/Kg feed, and middle dosage is the 100mg/Kg feed, and low dosage is the 50mg/Kg feed.
1.3 sample preparation:
Tested material is ground into powder, admixes feed, freely ingests for laboratory animal.
1.4 laboratory animal:
Fast rheum officinale broiler chicken 7 ages in days.
2 methods
2.1 test method:
Fast large yellow-feathered broiler, 7 ages in days, totally 240,15 every group, random packet.5 tested materials share a control group.Experiment begins and experiment periods claims weekly body weight and food ration.Carry out gross examination of skeletal muscle every day, records generally performance of animal, behavior, poisoning manifestations and death condition.
2.2 observation index
2.2.1 the average weight gain of statistical test chicken and average the food utilization amounts of 100 gram foods that body weight consumes (weightening finish) weekly.
2.2.2 final blood biochemical is learned index: gpt in serum (ALT), glutamic-oxal(o)acetic transaminase (AST), total bilirubin (TBIL), serum lactic dehydrogenase (LDH), creatine kinase (CK), total protein (TP), albumin (ALB), creatinine (CREA), blood sugar (GLU), sodium (Na), potassium (K), chlorine (Cl), calcium (Ca), triglyceride level (TG), total cholesterol (CHOL) concentration.
2.3 statistical treatment:
Data are carried out variance analysis with the SPSS13.0 software package.
3. result
Comprehensive death, weightening finish, food utilization, internal organs weigh, internal organs/weight ratio changes of biochemical indexes can be found out, the toxicity of YST-003-042 and YST-003-021 minimum (seeing table 8-12 for details).
Watch 8: the fast large chicken death situation (only) of each group
Table 9: each is organized the laboratory animal mean body weight and changes (g)
Table 10: each organizes the average efficiency of feed utilization of laboratory animal
Table 11: each organizes the organ weights (g) of laboratory animal
* has compared utmost point significant difference (P＜0.01) with control group; * compared significant difference (P＜0.05) with control group
Table 12: each organizes laboratory animal dirty/body ratio
* has compared utmost point significant difference (P＜0.01) with control group; * compared significant difference (P＜0.05) with control group
Embodiment 32: quinoxaline-1s, the genetoxic of 4-dioxide derivative (mouse sperm deformity test)
1. material
1.1 tested material
Quinocetone, olaquindox, carbadox, YST-003-002, YST-003-021, YST-003-042
1.2 laboratory animal
The Kunming kind SPF level healthy mice that Guangdong Medical Lab Animal Center provides.
2 methods
2.1 dosage design
Tested material is established dosage group of 2500mg/kg BW, and wherein olaquindox and carbadox caused experimental animal dead because toxicity is too high in 5 days with the continuous gavage of this dosage, respectively dosage were reduced to 625mg/kg BW and 200mg/kg BW.Separately establish negative control group and positive controls.Negative control group gives 0.5% carboxymethyl cellulose of equivalent, and positive controls is selected and is subjected to amount of reagent is the endoxan of 40mg/kg BW.
2.2 test method
Select Male Kunming strain mice, body weight 25-35g, numbering random packet, 5 every group.Every day gavage once, gavage is 5 days continuously, the gavage amount is 0.2ml/10g BW, after the contamination, the 35th day execution animal got the film-making routinely of bilateral epididymis, dyeing first, under high power lens, every mouse is observed 1000 complete sperms, counting contains quantity and the type of teratospermia, calculates and respectively organizes Sperm malformation rate (‰), takes statistics to learn by the rank test method and processes.
3 results
From the statistics of mouse sperm deformity rate, YST-003-002, YST-003-021, rate of teratosperm and the negative control group of YST-003-042 and Quinocetone test group are close, and the rate of teratosperm of carbadox and olaquindox higher (table 13).
Table 13: mouse sperm deformity test-results
* has compared utmost point significant difference (P＜0.01) with negative control group
Embodiment 33: quinoxaline-1s, the genetoxic of 4-dioxide derivative (mouse marrow cell micro nuclear test)
1. material
1.1 tested material
Quinocetone, olaquindox, carbadox, YST-003-002, YST-003-021, YST-003-042
1.2 laboratory animal
The Kunming kind SPF level healthy mice that Guangdong Medical Lab Animal Center provides.
2 methods
2.1 dosage design
Tested material is established dosage group of 2500mg/kg BW.Separately establish negative control group and positive controls.Negative control group gives 0.5% carboxymethyl cellulose of equivalent, and positive controls is selected and is subjected to amount of reagent is the endoxan of 40mg/kg BW.
2.2 test method
Adopt and tested to the tested material method in 30 hours.Select Kunming mouse, body weight 25-30g, numbering random packet, 6 every group, male and female half and half.The gavage amount is 0.2ml/10g BW, contaminate for the second time with same dosage after 24 hours, after 6 hours, put to death mouse and get every mouse observation 1000 polychromatic erythrocytes (PCE) under the film-making of bone marrow of sternum material, dyeing, oily mirror, counting contains the polychromatic erythrocyte number of micronucleus, calculate and respectively organize microkernel incidence (‰), that observes when counting simultaneously 200 PCE just incarnadines cell (NCE), obtain polychromatic erythrocyte number and mature erythrocyte ratio (PCE/RBC), take statistics to learn by the rank test method and process.
3 results
Show YST-003-002 from the statistic analysis result of Micronuclei In The Mouse Bone Marrow test micronuclear rates, YST-003-021, the genetoxic of YST-003-042 and Quinocetone is low, and the genetoxic of carbadox and olaquindox high (table 14).
Table 14: mouse marrow cell micro nuclear test result
* has compared utmost point significant difference (P＜0.01) with negative control group
Embodiment 34: part quinoxaline-1, the growth-promoting effect test of 4-dioxide derivative to broiler chicken
1. test materials and method
1.1 experimental animal and raising
Choose that 612 plumage 1 ages in days are healthy, growth conditions is identical and the fast rheum officinale plumage hen seedling of body weight close (in 10g) as subjects, be purchased from Jiangmen city Xinhui District Da Ze town pool poultry Development Co., Ltd of section.Test chicken such as table 15 divide into groups and give different medicated premixs, and duration of test is raised on the net, free choice feeding.
1.2 feed:
Select the fast large chicken mixed feed of Jiangmen city Xinhui District Da Ze town University of Science and Technology feed corporation,Ltd as basal diet, do not add microbiotic.
1.3 test sample:
Quinocetone, YST-003-002, YST-003-021
Table 15: experimental animal grouping and additive usage, consumption
2. test-results
Statistical result showed, the Quinocetone, YST-003-002 or the YST-003-021 that add respectively 30ppm in beverage all can significantly improve weightening finish and the price of deed (table 16).
The test-results on the meat chicken production performance impact such as table 16:YST-003-002
Annotate: the female difference fully of same column shoulder marking-up is significant difference (P＜0.05)
Embodiment 35: quinoxaline-1s, the growth-promoting effect test of 4-dioxide derivative to pig
The Du Dachang ternary of 180 body weight close (in 62-66kg) the lean meat species store pig of mixing is divided into 6 test group, every group of three repetitions, each heavy 10 pig at random.Add respectively different medicated premixs in feed.The duration of test free choice feeding, one month trial period, the weightening finish during statistical test and the price of deed.Result shows that YST-003-002, YST-003-021 and YST-003-042 all can improve the weightening finish of test pig, and improves the price of deed (table 17).
The test-results on the impact of store pig production performance such as table 17:YST-003-042
| Group | Medicine | Dosage (ppm) | Average daily gain (kg/ .d) | Feedstuff-meat ratio |
| 1 | Blank | - | 0.78±0.06 a | 3.21±0.33 a |
| 2 | YST-003-042 | 50 | 0.88±0.02 b | 3.01±0.40 b |
| 3 | YST-003-046 | 50 | 0.77±0.05 a | 3.19±0.31 a |
| 4 | YST-003-021 | 50 | 0.91±0.08 a | 2.96±0.32 a |
| 5 | YST-003-002 | 50 | 0.89±0.07 b | 3.03±0.39 a |
| 6 | Quinocetone | 50 | 0.86±0.05 b | 3.04±0.38 a |
Annotate: the female difference fully of same column shoulder marking-up is significant difference (P＜0.05)
Embodiment 36: quinoxaline-1s, the growth-promoting effect test of 4-dioxide derivative to duck
1, test materials
1 age in days Cherry Village Ducks, rich kind of Guangzhou agriculture duck field.
807 type full price meat duck material: do not contain any antibiotics growth stimulant, good fortune feed company in the good fortune of Shuande.
Testing ground: animal experiment field, English Saite Jiangmen
2, test method
500 1 age in days Cherry Village Duckss are divided into 4 groups at random, 100 every group.Each group is added different growth stimulants (table 18) in feed, survival rate, weightening finish and the price of deed of each group of statistics 1-46 age in days.Process of the test is for raising in cages on the net.
The test grouping on the impact of meat duck production performance such as table 18:YST-003-021
3, test-results
The raising experiment result shows, adds respectively YST-003-002 in feed, and YST-003-021 after YST-003-042, and does not add medicine control group and Quinocetone group and compares obvious growth promoting function (table 19) is all arranged.
The test-results on the impact of meat duck production performance such as table 19:YST-003-021
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, within being included in protection scope of the present invention.
Claims (9)
1. quinoxaline-1, the derivative of 4-dioxide or its salt is characterized in that the ， quinoxaline-1, the structural formula of the derivative of 4-dioxide suc as formula 1 or formula 2 shown in:
Formula 1
Formula 2
R in formula 1 and formula 2
1-R
5Be selected from-OH ,-CH
3, C
1To C
6Alkane, phenyl ring, hydrogen, benzyl, halogen ,-O-CH
3Or-NO
2, R
6, R
7Group be selected from hydrogen, halogen or-O-CH
3
2. quinoxaline-1 according to claim 1, the derivative of 4-dioxide or its salt is characterized in that, described halogen is F or Cl.
3. quinoxaline-1 according to claim 1, the derivative of 4-dioxide or its salt is characterized in that, the R in formula 1 and formula 2
6, R
7Be-H R
1Be-H R
2Be-F or-CH
3, R
3, R
4, R
5Be-H.
4. quinoxaline-1, the derivative of 4-dioxide or its salt is characterized in that the ， quinoxaline-1, the structural formula of the derivative of 4-dioxide is suc as formula 3, shown in formula 4, formula 5 or formula 6:
Formula 3
Formula 5
Formula 6
R in formula 3, formula 4, formula 5 and formula 6
1To R
4Group is selected from-OH ,-CH
3, C
1To C
6Alkane, hydrogen, halogen or-O-CH
3
5. quinoxaline-1 according to claim 4, the derivative of 4-dioxide or its salt is characterized in that, described halogen is F or Cl.
6. quinoxaline-1 according to claim 4, the derivative of 4-dioxide or its salt is characterized in that, the R in formula 3, formula 4, formula 5 and formula 6
1, R
2, R
3, R
4Be-H; Or R
1, R
3Be-F R
2, R
4Be-H.
Suc as formula 1, De quinoxaline-1 shown in formula 2, formula 3, formula 4, formula 5 or formula 6, the derivative of 4-dioxide or its salt are in preparation Animal diseases prevention or medicine or the application in the preparation animal feed additive for promoting growth.
8. application according to claim 7, is characterized in that, described animal is pig, chicken, duck, goose, beef cattle, milk cow, sheep, fish, shrimp, fox, ermine or the racoon dog of each growth phase.
9. application according to claim 7, it is characterized in that, described promoting animal growth feed is perfect compound feed, interpolation is the De quinoxaline-1 suc as formula 1, shown in formula 2, formula 3, formula 4, formula 5 or formula 6, and the derivative of 4-dioxide or its salt consumption during as feed additive for promoting growth is 5～500ppm of perfect compound feed quality.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103342683A (en) * | 2013-07-30 | 2013-10-09 | 中国农业大学 | Quinocetone hapten as well as preparation method and application thereof |
| CN103360328A (en) * | 2013-07-30 | 2013-10-23 | 中国农业大学 | Desoxyquinocetone hapten, and preparation method and application thereof |
| CN103664807A (en) * | 2013-12-02 | 2014-03-26 | 河北美荷药业有限公司 | 3-methyl-2-(methoxy styrene keto)-quinoxaline-1,4-dioxide, and preparation method and application thereof |
| CN103724284A (en) * | 2013-12-13 | 2014-04-16 | 河北美荷药业有限公司 | 3-methyl-2-(amino styrene ketone)-quinoxaline-1, 4-dioxide as well as preparation method and application thereof |
| CN106727576A (en) * | 2015-12-29 | 2017-05-31 | 广州英赛特生物技术有限公司 | Quinoxaline -1,4- dioxide derivatives as colistine sulfate synergist application |
| CN110269859A (en) * | 2019-05-07 | 2019-09-24 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | Quinoxaline-Isosorbide-5-Nitrae-application of the dioxy class compound on Infection Toxoplasma gondii |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4373101A (en) * | 1980-06-03 | 1983-02-08 | Egyt Gyogyszervegyeszeti Gyar | Quinoxaline-2-yl ethenyl ketones |
| CN1224717A (en) * | 1998-01-24 | 1999-08-04 | 中国农业科学院兰州畜牧与兽药研究所 | Quinoxaline-1,4-dioxide derivative and its synthesis |
| CN101074214A (en) * | 2007-06-21 | 2007-11-21 | 广东新南都饲料科技有限公司 | Synthesis of antibiotics N,N-oxazoline dioxide-2-methanal hydrazone compound |
| CN101081836A (en) * | 2007-07-03 | 2007-12-05 | 中国农业科学院兰州畜牧与兽药研究所 | Quinoxaline acquired by heavy ion beam irradiation effect |
| CN101182313A (en) * | 2007-07-03 | 2008-05-21 | 中国农业科学院兰州畜牧与兽药研究所 | Chemical synthesis technique of quinoxaline |
| WO2010138686A1 (en) * | 2009-05-29 | 2010-12-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mdri-inverse agents |
| CN101914071A (en) * | 2010-07-16 | 2010-12-15 | 中国农业大学 | Preparation method of 2-methyquinoxaline-1,4-dioxide |
-
2013
- 2013-03-18 CN CN201310087021.7A patent/CN103145631B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4373101A (en) * | 1980-06-03 | 1983-02-08 | Egyt Gyogyszervegyeszeti Gyar | Quinoxaline-2-yl ethenyl ketones |
| CN1224717A (en) * | 1998-01-24 | 1999-08-04 | 中国农业科学院兰州畜牧与兽药研究所 | Quinoxaline-1,4-dioxide derivative and its synthesis |
| CN101074214A (en) * | 2007-06-21 | 2007-11-21 | 广东新南都饲料科技有限公司 | Synthesis of antibiotics N,N-oxazoline dioxide-2-methanal hydrazone compound |
| CN101081836A (en) * | 2007-07-03 | 2007-12-05 | 中国农业科学院兰州畜牧与兽药研究所 | Quinoxaline acquired by heavy ion beam irradiation effect |
| CN101182313A (en) * | 2007-07-03 | 2008-05-21 | 中国农业科学院兰州畜牧与兽药研究所 | Chemical synthesis technique of quinoxaline |
| WO2010138686A1 (en) * | 2009-05-29 | 2010-12-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Mdri-inverse agents |
| CN101914071A (en) * | 2010-07-16 | 2010-12-15 | 中国农业大学 | Preparation method of 2-methyquinoxaline-1,4-dioxide |
Non-Patent Citations (6)
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103342683A (en) * | 2013-07-30 | 2013-10-09 | 中国农业大学 | Quinocetone hapten as well as preparation method and application thereof |
| CN103360328A (en) * | 2013-07-30 | 2013-10-23 | 中国农业大学 | Desoxyquinocetone hapten, and preparation method and application thereof |
| CN103360328B (en) * | 2013-07-30 | 2015-12-02 | 中国农业大学 | A kind of desoxyquinocetone haptens and preparation method thereof and its application |
| CN103664807A (en) * | 2013-12-02 | 2014-03-26 | 河北美荷药业有限公司 | 3-methyl-2-(methoxy styrene keto)-quinoxaline-1,4-dioxide, and preparation method and application thereof |
| CN103724284A (en) * | 2013-12-13 | 2014-04-16 | 河北美荷药业有限公司 | 3-methyl-2-(amino styrene ketone)-quinoxaline-1, 4-dioxide as well as preparation method and application thereof |
| CN106727576A (en) * | 2015-12-29 | 2017-05-31 | 广州英赛特生物技术有限公司 | Quinoxaline -1,4- dioxide derivatives as colistine sulfate synergist application |
| WO2017113526A1 (en) * | 2015-12-29 | 2017-07-06 | 广州英赛特生物技术有限公司 | Applications of quinoxaline-1,4-dioxide derivative as colistin sulfate synergist |
| CN106727576B (en) * | 2015-12-29 | 2020-08-04 | 广州英赛特生物技术有限公司 | Use of quinoxaline-1, 4-dioxide derivatives as potentiators of colistin sulphate |
| CN110269859A (en) * | 2019-05-07 | 2019-09-24 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | Quinoxaline-Isosorbide-5-Nitrae-application of the dioxy class compound on Infection Toxoplasma gondii |
| CN110269859B (en) * | 2019-05-07 | 2022-05-17 | 中国农业科学院上海兽医研究所(中国动物卫生与流行病学中心上海分中心) | Application of quinoxaline-1, 4-dioxide compound in resisting toxoplasma gondii infection |
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