CN1260218C

CN1260218C - PDF enzyme inhibitor-hydroxamic acid serial compounds synthetic method and use thereof

Info

Publication number: CN1260218C
Application number: CN 200310106927
Authority: CN
Inventors: 王建武; 徐为人; 王平保; 贾炯; 任戎; 郑晓平; 郑洪艳; 刘登科; 冯勇; 李炎; 张士俊; 任晓文; 汤立达
Original assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Current assignee: Tianjin Institute of Pharmaceutical Research Co Ltd
Priority date: 2003-11-06
Filing date: 2003-11-06
Publication date: 2006-06-21
Anticipated expiration: 2023-11-06
Also published as: CN1613853A

Abstract

The present invention relates to a class of PDF enzyme inhibitors, namely hydroxamic acid series compounds, which are shown in the general formulas B, C, a synthesis method and the application thereof. The definition of each group in the formulas and the preparing method are detailed in the specification, the series compounds in the general formulas B, C indicate that the PDF enzyme inhibitors have the function for inhibiting bacteria, and therefore, the PDF enzyme inhibitors can be used for treating diseases caused by sensitive bacterial infection.

Description

Type of PDF enzyme inhibitors-hydroxamic acid series compound and synthetic method and purposes

Technical field

This product belongs to the antibiotic medicine field, specifically relates to structure, preparation method and the purposes of type of PDF enzyme inhibitors-hydroxamic acid compound.

Background technology

One of human the most serious problem that always faces is exactly and the long-term struggle that catches.Infection is to cause the first dead killer in the world wide.This makes anti-infectives become a clinical application the biggest similar drug.Because many regional sanitary conditions are relatively poor, and infection morbidity is higher, the infection medicine consumption ranks first in China.

In recent years, a more thorny situation is, once can have antibiotic resistance because of the bacterial micro-organism that causes infecting has had now to these with catching now all of usually treating of antibiosis and become uncontrollable.The generation of the resistance variation of a kind of modal infection pathogen---streptococcus aureus (Staphylococcus aureus) is exactly a good example.

Antibiotic being extensive use of, resistant organism rolls up and spreads, and makes new antibiotic market life shorter and shorter, presses for to strengthen antibiotic rational use of drug to reduce the generation of resistant organism, also should accelerate the antibiotic exploitation of novel texture simultaneously.This just needs us to seek target spot from the committed step of bacterial metabolism, and the design medicine farthest reduces the generation of resistance variation.It is found that in to eukaryote and bacterial metabolism research process eukaryote is different with protein of bacteria synthetic route and mammal.Do not influence host's metabolism if there is a kind of antibiotic preparation can cut off the metabolism of bacterium, this microbiotic gets a good chance of.

PDF, promptly peptide deformylase (Peptide deformylase) catalytic peptide piptonychia acidylate be essential process in intestinal bacteria and the most bacterial metabolism, and in the plastosome of Mammals and fungi, do not have this process.Therefore, with this process be target spot so-called PDF enzyme inhibitors class new antibiotic design and become a tempting target.

Marcher and Sanger 1964, Adams and Capecchim just found that the bacterioprotein synthetic starts will pass through the N-formylation after tRNA (tRNAfmet) connects methionine(Met) in 1966; Relate to a kind of PDF of being of catalytic process of two kinds of enzymes when sloughing the methionine(Met) that connects when starting in sophisticated protein chain, the N-formyl radical on the initial polypeptide is taken off, another kind is MAP (methionine aminopeptidase), further the methionine(Met) hydrolysis is fallen.

Formula 1

The PDF of bacterium is in the sixties in 20th century certified first from the primary extract of intestinal bacteria and Bacillus subtilus (Adams, nineteen sixty-eight), but owing to whole 25 years people of unstable of enzyme do not have and PDF can be separated.By 1993, Meinnel and Blanquet for the first time purifying have a protein structure that faint active homologous protein was reported the highly active PDF of purifying in 1997 first.

In screening to the PDF inhibitor, it is found that actinomycin (actinonin) is a strong PDF inhibitor, a series of subsequently compounds are synthesized out.Bibliographical information have PDF to suppress active compound following a few actinoidin class [Chen, D.Z.et al. (2000) Biochemistry.39,1256-1262 are arranged; Apfel, C.M.et al. (2001) Antimicrob Agents Chemother.45 (4) 1053-1057; Apfel, C.M.et al. (2001) Antimicrob Agents Chemother.45 (4) 1058-1064.]; Non-peptide class [Jayasekera, M.M.K.et al. (2000) Arch BiochemBiophys.381,313-316.]; Hydroxamic acid [Apfel, C.et al. (2000) J.Med.Chem.43,2324-2331.], [Apfel, C.et al, (2001), J.Med.Chem.44,1847-1852.]; Peptide aldehydes [Durand, D.J.et al. (1999) Arch Biochem Biophys.367 (2) 297-302.], other [Huntington, K.M.et al. (2000) Biochemistry.39 (15) 4543-4551.].What will have that PDF suppresses that the synthetic method of active compound and activity experiment method apply for a patent has WO 9957097 (VERSICOR, INT.US), WO 0110835 (BRITISH BIOPTECH PHARMACEUTICALS LIMITED.GB), WO0138561 (QUESTCOR (QUESTCOR PHARMACEUTICALS, INC.US), WO0144178 (VERSICDR, INC.US), WO0144179 (VERSICDR, INC.US), WO0185160 (SMITHKLINE BEECHAM CORPORATION.US), WO0185170 (SMITHKLINE BEECHAM CORPORATION.US), (QUES TCORPHARMACEUTICALS is INC.US) but a little less than the anti-microbial activity that has in the middle of them for WO0228829, though what have has stronger anti-microbial activity but bigger side effect is also arranged, and has been subjected to certain restriction in clinical use.

The present invention is the structure based on actinomycin; following hydroxamic acid series compound B and C have been designed and synthesized; it is characterized in that comprising in this molecular structure of compounds 2-R-3 (or 4)-hydroxamic acid base-third (or fourth) acyl group and 3 bit strips has phenyl or substituted-phenyl, and 4 bit strips have R ₁Substituently contain heteroatomic five-ring, its general formula is as follows:

Wherein

n＝1，2；Y＝O、N、S；Z＝N、C；

R, R ₁Be generally H, contain C ₁-C ₅Straight or branched alkyl, amino or substituted-amino such as methyl, ethyl, butyl, amyl group, sec.-propyl; Be preferably H, ethyl, amyl group, amino or kharophen; Preferred H, amyl group or kharophen;

R ₂Be generally unsubstituted, H or C ₁-C ₃Straight chained alkyl such as methyl, ethyl, propyl group; Preferred H, methyl;

X is generally H ,-R ' ,-OR ' ,-SR ' ,-halogen-CN ,-NH ₂,-NHR ' ,-NR ₂,-NO ₂, substituting groups such as-COOH (R ' for containing C ₁-C ₅The straight or branched alkyl); X can be single or multiple substituting groups and the contraposition that is in phenyl ring respectively or an ortho position or a position.Better X is H, methyl, methoxyl group ,-Cl ,-F;-NH ₂,-NHR ' ,-NO ₂, substituting groups such as-COOH; Preferred X is H, methyl, methoxyl group ,-Cl ,-F; Substituting groups such as-COOH, and X is single substituting group; And be in the contraposition or the ortho position of phenyl ring respectively;

Of the present inventionly contain heteroatomic five-ring and comprise following one group of chemical formula,

Combine preparation benzene dipole body with the phenyl of replacement by different five-membered ring, replace propargyl-2-R-succinyl (or glutaryl) imines or N-substituted allyl-2-R-succinyl with DL or optically active N-again, in the exsiccant methylene dichloride, react, reaction product is separated through silica gel column chromatography, with sherwood oil and ethyl acetate is eluent, carry out the hydroximic acid reaction with oxyammonia then, can make more than 30 DL or optically active B, C series compound.Wherein representational compound such as a:2-pentyl-3-hydroximic acid base-N-[3-(phenyl) isoxazolyl-5-] methyl-propionic acid amide; B:2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazolyl-5-] methyl-propionic acid amide; C:2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide; D:4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazoline-3-yl-5-] methyl-butyramide; E:2-pentyl-3-hydroximic acid base-N-[1-methyl-3-(to fluorophenyl) pyrazolyl-5-] methyl-propionic acid amide; F:2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) pyrazolyl-5-] methyl-propionic acid amide; G:2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) pyrazolinyl-5-] methyl-propionic acid amide; H:2-amyl group-3-hydroxamic acid base-N--[4-is to chlorophenyl-thiophene-2]-methyl-propionic acid amide; I:2-amyl group-3-hydroxamic acid base-N-[4-is to fluoro phenyl-furans-2]-methyl-propionic acid amide or the like.

Type of PDF enzyme inhibitors of the present invention-hydroxamic acid series compound B and C comprises that any one requires the preparation method of the compound of mandate among the claim 1-4, it is characterized in that:

A) react in the exsiccant methylene dichloride by A1 or A2 and substituted benzene dipole body (I), product, with sherwood oil and ethyl acetate is that eluent separates through silica gel column chromatography, carries out the hydroximic acid reaction with oxyammonia then, preparation B1, B2 or C1, C2 series compound;

B1 Y＝O Z＝N C1 Y＝O Z＝N

B2 Y＝N Z＝N C2 Y＝N Z＝N

N=1 wherein, 2; R, R ₁Be H, ethyl, butyl, amyl group, sec.-propyl, amino or kharophen; R ₂Be, H or methyl; X is H, methyl, methoxyl group ,-Cl ,-F; X is single substituting group and is in contraposition or ortho position on the phenyl ring respectively; Or

B). optically active A1 ', A2 ', react in the exsiccant methylene dichloride with corresponding substituted benzene dipole body (I), product is an eluent with sherwood oil and ethyl acetate, separate through silica gel column chromatography, carry out the hydroximic acid reaction with oxyammonia then, can make optically active B3, C3 series compound;

OEt=mono ethyl ester wherein; N=1,2; Y=O, Z=N; R, R ₁, R ₂, X definition is described with preparation method a; Or

C). optically active A3 and compound III are reacted in the exsiccant methylene dichloride, and product separates through silica gel column chromatography, are eluent with sherwood oil and ethyl acetate, carry out the hydroximic acid reaction with oxyammonia then, can obtain optically active B4 or B5.

N=1,2; R, R ₁, X definition is described with a among the preparation method.

Type of PDF enzyme inhibitors of the present invention-hydroxamic acid series compound B and C's is synthetic, does not see any bibliographical information, belongs to novel cpd, and the inventor has designed synthetic route voluntarily.According to the reaction blending theory, adopted 1,3-dipole cycloaddition [3+2] reaction, the synthetic X+Y formula that is decomposed into target compound, the introducing that compound combines with acceptor positive charge position with coordinate bond, at design synthetic B, in the C series compound, with the conjugation that contains the Y-Z key, half conjugation five-ring links to each other with substituted benzene ring, replaced the valyl amine moiety in the actinomycin molecule, imagination is by the conjugation that contains the Y-Z key, Y in the half conjugation five-ring and the lone electron pair on the Z, form with coordinate bond combines with the positive charge position of acceptor, so that play the restraining effect to PDF.The synthetic route of the present invention's design is that open loop type or straight chain formula all are very economical, reasonable, utilization of resources degree height.Simple synthetic method, easy row are more suitable for large-scale industrial production.

PDF enzyme inhibitors of the present invention-hydroxamic acid series compound B and C has restraining effect to G+ bacterium and the microbial bacterial infection of G-.As bacillus pumilus, staphylococcus epidermidis, klebsiella pneumoniae certain bacteriostatic action is arranged.Therefore they can be used for treating the disease that above-mentioned various infectation of bacteria causes.

The pharmacological evaluation of hydroxamic acid compound anti-microbial activity is measured:

One. experiment material

(1) substratum: microorganism identification substratum PH7.9 ± 0.1 Beijing, three medicine scientific and technological development company lot numbers: 020425

(2) bacterial classification: bacillus pumilus CMCC 63202, staphylococcus epidermidis CMCC 26069, blue pus organism CMCC10211, klebsiella pneumoniae CMCC 46117, colon bacillus CMCC 44113, and above bacterial classification is all purchased in Nat'l Pharmaceutical ﹠ Biological Products Control Institute

Two. experimental technique

(1) sample and code:

A:2-pentyl-3-hydroximic acid base--N-[3-(phenyl) isoxazolyl-5-] methyl-propionic acid amide; B:2-pentyl-3-hydroximic acid base--N-[3-(p-methoxyphenyl) isoxazolyl-5-] methyl-propionic acid amide; C:2-pentyl-3-hydroximic acid base--N-[3-(p-methoxyphenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide; D:4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazoline-3-yl-5-] methyl-butyramide; E:2-pentyl-3-hydroximic acid base--N-[1-methyl-3-(to fluorophenyl) pyrazolyl-5-] methyl-propionic acid amide; F:2-pentyl-3-hydroximic acid base--N-[3-(p-methoxyphenyl) pyrazolyl-5-] methyl-propionic acid amide; G:2-pentyl-3-hydroximic acid base--N-[3-(to fluorophenyl) pyrazolinyl-5-] methyl-propionic acid amide; H:2-amyl group-3-hydroxamic acid base-N--[4-is to chlorophenyl-thiophene-2]-methyl-propionic acid amide; I:2-amyl group-3-hydroxamic acid base-N--[4-is to fluoro phenyl-furans-2]-methyl-propionic acid amide.

Take by weighing above-mentioned each sample of about 2mg respectively, in the 50ml volumetric flask, after a spot of DMF dissolving, add to scale with distilled water, concentration is 10 μ mol/L, and filtration sterilization is with the centrifuge tube packing of 2ml.

(2) preparation of culture dish:

Microorganism identification substratum I after a certain amount of sterilization (making substratum thickness is 3mm), be chilled to 48-50 ℃, add an amount of bacterium liquid (bacteria concentration is 0.1%) respectively, pour in the culture dish of the level of mixing up, carefully drive bubble away, after the culture medium solidifying, carry out mark in the graze cattle position of Tianjin cup of needs, standby.

(3) mensuration of sample

At interval 2.5-3cm places the Oxford cup on culture dish, notes correspondingly with mark position, gets each sample 50 μ l application of sample with micro sample adding appliance, do 2-3 multiple pipe, carry out the application of sample record, be placed in 37 ℃ of CO2 incubators cultivate 16-18h after, use the vernier caliper measurement antibacterial circle diameter.

Three. experimental result

The result shows that hydroxamic acid compound has certain bacteriostatic action to bacillus pumilus, staphylococcus epidermidis, klebsiella pneumoniae, and intestinal bacteria, Pseudomonas aeruginosa are not seen bacteriostatic action, points out this class formation to have the restraining effect of anti-G+ bacterium and G-bacterium.

	Staphylococcus aureus	Bacillus pumilus	Staphylococcus epidermidis	Kerekou pneumonia primary	Intestinal bacteria	Pseudomonas aeruginosa
	Staphylococcus aureus	Bacillus pumilus	Staphylococcus epidermidis	Kerekou pneumonia primary	Intestinal bacteria	Pseudomonas aeruginosa	a	+	+	+	+	-	-
b	+	+	+	+	-	-	a	+	+	+	+	-	-
b	+	+	+	+	-	-	c	-	-	-	-	-	-
d	-	-	-	-	-	-	c	-	-	-	-	-	-
d	-	-	-	-	-	-	e	+	+	+	+	-	-
f	+	+	+	+	-	-	e	+	+	+	+	-	-
f	+	+	+	+	-	-	g	-	-	-	-	-	-
h	-	+	+	-	-	-	g	-	-	-	-	-	-
h	-	+	+	-	-	-	i	-	+	+	-	-	-

+: have bacteriostatic action-: do not have bacteriostatic action

Embodiment

The present invention is described further below in conjunction with embodiment.

Instrument and reagent

BRUKER AV400 nuclear magnetic resonance analyser (CDCl3, TMS are interior mark)

Starting raw material 2-pentyl Succinic Acid of the present invention, N-acetylglutamat, (±) 2-amyl group-4-Succinic Acid mono etc. can be buied by the method preparation of relevant textbook instruction or from market.

A1, A2 preparation method's general reaction expression is as follows:

N-replaces the preparation of propargyl-2-R-succinyl (or glutaryl) imines (A1) and N-substituted allyl-2-R-succinyl (or glutaryl) imines (A2):

Concrete experiment is as follows:

The preparation of A1, A2-1

(1) 1,2, the preparation of 2-triethoxy carbonyl heptane

In the 250ml three-necked bottle, add the sodium that 100ml dehydrated alcohol and 1.5g (0.065mol) newly take by weighing.The sodium Metal 99.5 reaction finishes, and adds 16.1g (0.065mol) 1,1,2-triethoxy carbonyl ethane (FW:246.26 bp:99 ℃/0.5mmHg d:1.074 Beil:2,813).Drip 10.5g (0.065mol) bromo pentane, refluxing in the back, reacted 19 hours.Stopped reaction filters, evaporate to dryness ethanol, and washing extracts with ether (35ml * 4), combined ether layer, anhydrous magnesium sulfate drying.Filter, steam ether to the greatest extent, 176-180 ℃ of cut 15.2g, yield 73.5% are collected in underpressure distillation.(85℃/22.66Pa)

(2) preparation of 2-pentyl Succinic Acid

With 14.4g (0.046mol) 1,2,2-triethoxy carbonyl heptane and 170ml hydrochloric acid are poured heating reflux reaction in the 250ml three-necked bottle into.Reacting 44 hours. water layer is transferred pH value to 3 with concentrated hydrochloric acid, and the back merges organic layer, anhydrous magnesium sulfate drying with trichloromethane/THF (7: 3) (50ml * 4) extraction.Filter, steam solvent to the greatest extent, solidify product, totally 7 grams, yield 81.8%.(m.p.：72-74℃)

(3) preparation of 2-pentyl Succinic anhydried

11.8g (0.6mol) 2-pentyl Succinic Acid and 50ml Acetyl Chloride 98Min. were added in the single neck bottle of 100ml back flow reaction 2.5 hours, and air distillation boils off Acetyl Chloride 98Min., 176-180 ℃ of cut collected in decompression, the 8.7g colourless liquid directly carries out the next step, yield 81.5% altogether.

(4) preparation (A1) of 2-pentyl-N-propargyl-succimide

With 8.7g (0.05mol) 2-pentyl Succinic anhydried, (0.05mol0 propargylamine, 25ml methylene dichloride are added in the 50ml reaction flask 3.0g, and back flow reaction two hours behind the steaming vibrating dichloromethane, adds the 25ml Acetyl Chloride 98Min., and back flow reaction is stopped reaction after 3 hours.Eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=3: 1), get product 9.4g, yield 88.7%.1HNMR(CDCl ₃，TMS)，δ(ppm)：0.69(t)，3H；1.15(m)，6H；1.35(m)，1H；1.69(m)，1H；2.04(t)，1H；2.22(q)，1H；2.66(m)，2H；4.01(q)，2H.

The same method is reacted with allylamine, obtains 2-pentyl-N-allyl group-succimide.(A2) preparation of A1, A2-2

The preparation of 2-pentyl Pyroglutaric acid

(1). 4.57g 2-pentyl pentanedioic acid and 20ml Acetyl Chloride 98Min. were added in the 50ml round-bottomed flask back flow reaction 2.5 hours, and normal pressure boils off Acetyl Chloride 98Min., directly carries out the next step.

(2) preparation (A1) of 2-pentyl-N-propargyl-glutarimide

With (1) step gained 2-pentyl Pyroglutaric acid, 1.25g (0.023mol) propargylamine, the 25ml methylene dichloride is added in the 50ml reaction flask, and back flow reaction 3h behind the steaming vibrating dichloromethane, adds the 15ml Acetyl Chloride 98Min., and back flow reaction is stopped reaction after 3 hours.Washing, methylene dichloride (30ml * 3) extraction, column chromatography for separation, eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=5: 1), get pure products 2.87g.1HNMR (CDCl ₃, TMS), δ (ppm): 0.83 (t), 3H; 1.28 (m), 6H; 1.60-2.16 (m), 5H; 2.24-2.80 (m), 3H; 4.45 (d), 2H;

The same method is reacted with allylamine, obtains 2-pentyl-N-allyl group-glutarimide.(A2) preparation of A1, A2-3

(1) preparation of N-acetylglutamat acid anhydride

7.56g (0.04mol) N-acetylglutamat and 60ml diacetyl oxide were added in the 100ml round-bottomed flask back flow reaction 3 hours, and the pressure reducing and steaming diacetyl oxide directly carries out the next step.

(2) preparation (A1) of 2-acetamido-N-propargyl glutarimide

To go up step gained N-acetylglutamat acid anhydride, 2.75g (0.05mol) propargylamine, the 25ml methylene dichloride is added in the 50ml reaction flask, and back flow reaction 3h behind the steaming vibrating dichloromethane, adds the 18ml Acetyl Chloride 98Min., and back flow reaction is stopped reaction after 3 hours.Washing, methylene dichloride (30ml * 3) extraction, column chromatography for separation, eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=1: 1), get pure products 1.0g, total recovery 42.0%.

The same method is reacted with allylamine, makes preparation (A2) A1 of 2-acetamido-N-allyl group glutarimide, the preparation-4 of A2

(±) 2-amyl group-4-fourth oxygen acyl group-N-propargyl-butyramide (A1 ')

(±) 2-amyl group-4-Succinic Acid mono 0.01mol and 30ml thionyl chloride are returned slide reaction 1 hour, boil off unnecessary thionyl chloride, then add methylene dichloride and 0.01mol propargylamine to doing, and 0.015mol pyridine (0 ℃), reacted 1 hour, column chromatography for separation makes A1 ', yield 80%.

The same method is reacted with allylamine, makes (±) 2-amyl group-4-fourth oxygen acyl group-N-allyl group-butyramide (A2 ') the present invention and prepares the general general formula of B series compound

The open loop type building-up reactions formula of B series compound is:

Embodiment 1.

2-pentyl-3-hydroximic acid base-N-[3-(rubigan) isoxazolyl-5-] preparation method of methyl-propionic acid amide

(1) in the triangular flask of magnetic agitation is housed, 1.6g (10mmol) 4-chloro-benzaldehyde oxime is dissolved in the 40mL exsiccant methylene dichloride, add 1.7g (12mmol) N-chlorosuccinimide, stir, all after the dissolving, heat 10min a little, add 2.1g (10mmol) 2-pentyl-N-propargyl succimide, drip 1.2g (12mmol) triethylamine, have a large amount of white smoke to produce, reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=5: 1), get product (yellow solid) 2.3g, yield 62%.1HNMR(CDCl ₃，TMS)，δ(ppm)：0.85(t)，3H；1.30(m)，6H；1.50(m)，1H；1.90(m)，1H；2.43(m)，1H；2.87(m)，2H；4.80(s)，2H；6.49(s)，1H；7.38(q)，2H；7.67(q)，2H.

(2) oxammonium hydrochloride 0.7g (10mmol) is dissolved among the DMF, KOH.0.7g (12mmol) is dissolved in the water, after the aqueous solution of KOH is poured in the DMF solution of oxammonium hydrochloride, under ice-water bath reaction after 15 minutes with its suction filtration to 1.8g (5mmol) 2-pentyl-N-[3-(rubigan) isoxazolyl-5-] in the methyl succimide, stirring at room 24 hours gets final product, column chromatography, recrystallization, m.p.158.0-158.8 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.80(t)，3H；1.19(m)，6H；1.28-1.41(m)，2H；2.00-2.67(m)，3H；4.42(d)，2H；6.83(d)，1H；7.55(d)，2H；7.86(m)，2H；8.70-8.75(m)，2H；10.45(d)，1H.

Embodiment 2

With reference to embodiment 1 preparation 2-pentyl-3-hydroximic acid base-N-[3-(phenyl) isoxazolyl-5-] methyl-propionic acid amide m.p.146.0-148 ℃.1HNMR(DMSO，TMS)，δ(ppm)；0.79(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；4.41(d)，2H；6.79(d)，1H；7.75(d)，3H；7.83(m)，2H；8.55-8.71(m)，2H；10.40(d)，1H.

Embodiment 3

With reference to embodiment 1 preparation 2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-propionic acid amide, m.p.165.0-166.5 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.80(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；4.42(d)，2H；6.81(d)，1H；7.33(d)，2H；7.90(m)，2H；

8.76(m)，2H；10.40(d)，1H.

Embodiment 4

With reference to embodiment 1 preparation 2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazolyl-5-] methyl-propionic acid amide: m.p.141.0-143 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.78(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；3.84(s)，3H；4.40(d)，2H；6.81(d)，1H；7.25(d)，2H；7.73(d)，2H；8.0-8.73(m)，2H；10.45(d)，1H.

The present invention prepares the general general formula of C series compound

The open loop type building-up reactions formula of C series compound is as follows

Embodiment 5

With reference to embodiment 1 preparation 2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide, m.p.134.0-135 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.80(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；3.0-3.60(m)，2H；3.84(s)，3H；4.20-4.70(m)，2H；4.96(m)，1H；7.27(d)，2H；7.75(d)，2H；8.0-8.75(m)，2H；10.46(board)，1H.

Embodiment 6

With reference to embodiment 1 preparation 2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide, m.p.145.0-146.5 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；3.0-3.60(m)，2H；4.20-4.70(m)，2H；4.96(m)，1H；7.35(d)，2H；7.92(m)，2H；8.78(m)，2H；10.45(d)，1H.

Embodiment 7

3-hydroximic acid base-N-[3-(rubigan) isoxazolyl-5-] preparation method of methyl-propionic acid amide

(1) .N-[3-(rubigan) isoxazolyl-5-] preparation of methyl succimide

In the triangular flask of magnetic agitation is housed, 1.6g (10mmol) 4-chloro-benzaldehyde oxime is dissolved in the 40mL exsiccant methylene dichloride, add 1.7g (12mmol) N-chlorosuccinimide, stir, all after the dissolving, heat 10min a little, add 1.4g (10mmol) N-propargyl succimide (making), drip 1.2g (12mmol) triethylamine, have a large amount of white smoke to produce by Succinic anhydried and propargylamine reaction, reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=5: 1), get product (yellow solid) 1.50g, yield 60%.

(2). oxammonium hydrochloride 0.7g (10mmol) is dissolved among the DMF, KOH.0.7g (12mmol) is dissolved in the water, after the aqueous solution of KOH is poured in the DMF solution of oxammonium hydrochloride, under ice-water bath reaction after 15 minutes with its suction filtration to 1.45g (5mmol) N-[3-(rubigan) isoxazolyl-5-] in the methyl succimide, stirring at room 24 hours gets final product, column chromatography, recrystallization, m.p.170.0-172. ℃.1HNMR(DMSO，TMS)，δ(ppm)：2.22(t)，2H；2.40(t)，2H；4.41(d)，2H；6.90(s)，1H；7.56(d)，2H；7.87(d)，2H；8.59-8.71(m)，2H；10.40(s)，1H.

Embodiment 8

With reference to embodiment 7 preparation 3-hydroximic acid base-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-propionic acid amide m.p.172.0-173.6. ℃.1HNMR(DMSO，TMS)，δ(ppm)：2.38-2.49(m)，4H；4.42(d)，2H；6.84(s)，1H；7.35(m)，2H；7.90(m)，2H；8.59(m)，1H；12.06(s)，1H.

Embodiment 9

With reference to embodiment 7 preparation 3-hydroximic acid base-N-[3-(phenyl) isoxazolyl-5-] methyl-propionic acid amide m.p.165.0-167 ℃.1HNMR(DMSO，TMS)，δ(ppm)：2.38-2.49(m)，4H；4.43(d)，2H；6.92(s)，1H；7.50(m)，3H；7.82(m)，2H；8.57(m)，1H；12.04(s)，1H.

Embodiment 10

With reference to embodiment 7 preparation 3-hydroximic acid base-N-[3-(p-methylphenyl) isoxazolyl-5-] methyl-propionic acid amide m.p.162.0-163.6. ℃.1HNMR(DMSO，TMS)，δ(ppm)：2.35(s)，3H；2.37-2.50(m)，4H；4.41(d)，2H；6.78(s)，1H；7.30(d)，2H；7.71(d)，2H；8.56(m)，1H；12.03(board)，1H.

Embodiment 11

With reference to embodiment 7 preparation 3-hydroximic acid base-N-[3-(phenyl)-4-methyl-isoxazolyls-5-] methyl-propionic acid amide m.p.165.0-167 ℃.1HNMR(DMSO，TMS)，δ(ppm)：2.38-2.49(m)，7H；4.43(d)，2H；6.92(s)，1H；7.50(m)，3H；7.82(m)，2H；8.57(m)，1H；12.04(s)，1

Embodiment 12

2-pentyl-N-[3-(p-methylphenyl) isoxazolyl-5-] preparation of methyl-glutarimide

(1). in the triangular flask of magnetic agitation is housed, 0.27g (2mmol) p-tolyl aldehyde oxime is dissolved in the 10mL exsiccant methylene dichloride, add 0.32g (2.4mmol) N-chlorosuccinimide, stir, all after the dissolving, heat 30min a little, add 0.44g (2mmol) 2-pentyl-N-propargyl-glutarimide, drip 0.20g (2mmol) triethylamine, have a large amount of white smoke to produce, reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=5: 1), get product (white solid) 0.53g, yield 75.0%.1HNMR(CDCl ₃，TMS)，δ(ppm)：0.82(t)，3H；1.26(m)，6H；1.45-2.20(m)，4H；2.30(s)，3H；2.35-2.82(m)，3H；5.04(s)，2H；6.36(s)，1H；7.15(d)，2H；7.56(d)，2H.

Embodiment 13

With reference to embodiment 12 preparation 2-pentyl-N-[3-(p-methoxyphenyl) isoxazolyl-5-] polydimethyl glutarimide gets product (white solid) 20g, yield 45%.1HNMR (CDCl ₃, TMS), δ (ppm): 0.81 (t), 3H; 1.26 (m), 6H; 1.45-2.20 (m), 4H; 2.35-2.82 (m), 3H; 3.75 (s), 3H; 5.02 (s), 2H; 6.34 (s), 1H; 6.85 (d), 2H; 7.60 (d), 2H.

Embodiment 14

With reference to embodiment 12 preparation 2-pentyl-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-glutarimide (yellow solid), yield 42%; 1HNMR (CDCl ₃, TMS), δ (ppm): 0.81 (t), 3H; 1.27 (m), 6H; 1.45-2.20 (m), 4H; 2.35-2.82 (m), 3H; 5.04 (s), 2H; 6.34 (s), 1H; 6.98 (m), 2H; 7.66 (m), 2H.

Embodiment 15

With reference to embodiment 12 preparation 2-pentyl-N-[3-(rubigan) isoxazolyl-5-] methylpent diimine yellow solid, yield 50%.1HNMR(CDCl ₃，TMS)，δ(ppm)：0.81(t)，3H；1.26(m)，6H；1.45-2.20(m)，4H；2.35-2.85(m)，3H；5.04(s)，2H；6.37(s)，1H；7.26(m)，2H；7.65(m)，2H.

Embodiment 16

With reference to embodiment 12 preparation 2-pentyl-N-[3-(o-methoxyphenyl) isoxazolyl-5-] polydimethyl glutarimide, yellow oily liquid, yield 54%.1HNMR(CDCl ₃，TMS)，δ(ppm)：0.81(t)，3H；1.26(m)，6H；1.45-2.10(m)，4H；2.35-2.82(m)，3H；3.78(s)，3H；5.04(s)，2H；6.56(s)，1H；6.91(dd)，2H；7.30(m)，1H；7.75(dd)，1H.

Embodiment 17

With reference to embodiment 12 preparation 2-pentyl-N-[3-(rubigan) isoxazoline-3-yl-5-] the methylpent diimine.

Embodiment 18

4-hydroximic acid base 2-amyl group-N-[3-(p-methylphenyl) isoxazolyl-5-] methyl-butyramide

Oxammonium hydrochloride 0.7g (10mmol) is dissolved among the DMF, KOH.0.7g (12mmol) is dissolved in the water, after the aqueous solution of KOH is poured in the DMF solution of oxammonium hydrochloride, reaction replaced its suction filtration to the above gained of 1.8g (5mmol) in the glutarimide compound after 15 minutes under ice-water bath, stirring at room 24 hours, get final product, column chromatography, recrystallization.m.p.162.0-163.6.℃。1HNMR(DMSO，TMS)，δ(ppm)：0.75(t)，3H；1.14(m)，6H；1.29-2.20(m)，7H；2.29(s)，3H；4.36(d)，2H；6.66(s)，1H；7.24(d)，2H；7.65(d)，2H；8.20-8.63(m)，1H；10.25(board)，1H.

Embodiment 19

With reference to embodiment 18 preparation 4-hydroximic acid base 2-amyl group-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-butyramide m.p.165.0-166.7 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.82(t)，3H；1.18(m)，6H；1.28-1.51(m)，4H；1.80-2.50(m)，3H；4.40(d)，2H；6.81(d)，1H；7.35(d)，2H；7.90(m)，2H；8.77(m)，2H；10.40(d)，1H.

Embodiment 20

With reference to embodiment 18 preparation 4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazolyl-5-] methyl-butyramide m.p.158.0-158.8 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.17(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；4.41(d)，2H；6.82(d)，1H；7.55(d)，2H；7.88(m)，2H；8.70-8.75(m)，1H；10.50(d)，1H.

Embodiment 21

With reference to embodiment 18 preparation 4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazoline-3-yl-5-] methyl-butyramide m.p.138.0-140.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.18(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；3.10-3.20(m)，2H；4.20-4.60(m)，2H；5.05(m)，1H；7.55(d)，2H；7.85(m)，2H；8.70-8.77(m)，1H；10.51(d)，1H.

Embodiment 22

2-acetamido-N-[3-(p-methoxyphenyl) isoxazolyl-5-] polydimethyl glutarimide-as the preparation

In the triangular flask of magnetic agitation is housed, 0.14g (1.0mmol) aubepine oxime is dissolved in the 10mL exsiccant methylene dichloride, add 0.16g (1.2mmol) N-chlorosuccinimide, stir, all after the dissolving, heat 30min a little, add 0.21g (1.0mmol) 2-acetamido-N-propargyl-glutarimide, drip 0.10g (1mmol) triethylamine, have a large amount of white smoke to produce, reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=1: 1), get product (white solid), yield 27.3-60.5%.

Embodiment 23

With reference to embodiment 22 preparation 2-acetamido-N-[3-(p-methylphenyl) isoxazolyl-5-] polydimethyl glutarimide.(white solid) 0.28g, yield 55.7%.1HNMR(CDCl ₃，TMS)，δ(ppm)：2.0-2.23(m)，2H；2.33(s)，3H；2.48(s)，3H；2.49-2.90(m)，2H；4.50-4.69(m)，3H；6.42(s)，1H；6.60(board)，1H；7.19(d)，2H；7.60(d)，2H

Embodiment 24

With reference to embodiment 22 preparation 2-acetamido-N-[3-(p-methoxyphenyl) isoxazolyl-5-] methyl-glutaramide (white solid) 0.30g, yield 56.1%.1HNMR(CDCl ₃，TMS)，δ(ppm)：2.0-2.23(m)，2H；2.44(s)，3H；2.49-2.90(m)，2H；3.76(s)，3H；4.40-4.70(m)，3H；6.38(s)，1H；6.85(d)，2H；7.10(board)，1H；7.60(d)，2H.

Embodiment 25

With reference to embodiment 22 preparation 2-acetamido-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-glutarimide (white solid) 0.32g, yield 60%.1HNMR (CDCl ₃, TMS), δ (ppm): 2.0-2.23 (m), 2H; 2.46 (s), 3H; 2.49-2.90 (m), 2H; 4.40-4.70 (m), 3H; 6.40 (s), 1H; 7.10 (m), 2H; 6.90 (board), 1H; 7.65 (d), 2H.

Embodiment 26

With reference to embodiment 22 preparation 2-acetamido-N-[3-(rubigan) isoxazolyl-5-] methyl-glutarimide (white solid) 0.20g, yield 37.03%.1HNMR(CDCl ₃，TMS)，δ(ppm)：2.0-2.23(m)，2H；2.47(s)，3H；2.49-2.90(m)，2H；4.43-4.70(m)，3H；6.42(s)，1H；6.80(board)，1H；7.30(d)，2H；7.62(d)，2H.

Embodiment 27

With reference to embodiment 22 preparation 2-acetamido-N-[3-(o-methoxyphenyl) isoxazolyl-5-] methyl-glutarimide, (white solid) 0.18g, yield 33.6%.1HNMR(CDCl ₃，TMS)，δ(ppm)：1.85-2.23(m)，2H；2.43(s)，3H；2.45-2.90(m)，2H；3.80(s)，3H；4.40-4.70(m)，3H；6.61(s)，1H；6.85-7.00(dd)，2H；7.10(board)，1H；7.30(m)，1H；7.70(m)，1H.

Embodiment 28

4-hydroximic acid base 2-amino-N-[3-(to fluorophenyl) isoxazoline-3-yl-5-] preparation method of methyl-butyramide

Oxammonium hydrochloride 0.07g (1.0mmol) is dissolved in the 4ml water, KOH 0.07g (1.0mmol) is dissolved in the 4ml water, after the aqueous solution of KOH is poured in the aqueous solution of oxammonium hydrochloride, react at normal temperatures after 15 minutes with its suction filtration to the above gained 2-of 0.12g (0.33mmol) acetamido-N-[3-(to fluorophenyl) isoxazolyl-5-] in methyl-glutarimide compound, stirring at room 24 hours, separate out white solid, recrystallizing methanol gets the finished product.m.p.182.0-183.6.℃。1HNMR(DMSO，TMS)，δ(ppm)：1.91(m)，1H；2.20(m)，2H；2.15(m)，1H；4.05(q)，1H；4.46(d)，2H；6.86(s)，1H；7.34(t)，2H；7.83(s)，1H；7.90(q)，2H；8.72(t)，1H.

Embodiment 29

With reference to embodiment 28 preparation 4-hydroximic acid base 2-amino-N-[3-(rubigan) isoxazoline-3-yl-5-] methyl-butyramide, white solid, m.p.178.0-180.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：1.91(m)，1H；2.15(m)，2H；2.29(m)，1H；4.05(q)，1H；4.47(d)，2H；6.88(s)，1H；7.57(t)，2H；7.85(s)，1H；7.86(q)，2H；8.73(t)，1H.

Embodiment 30

With reference to embodiment 28 preparation 4-hydroximic acid base 2-amino-N-[3-(p-methylphenyl) isoxazoline-3-yl-5-] methyl-butyramide, white solid, m.p.169.0-170.5 ℃.1HNMR(DMSO，TMS)，δ(ppm)：1.90(m)，1H；2.13(m)，2H；2.27(m)，1H；2.34(s)，3H；4.04(q)，1H；4.44(d)，2H；6.81(s)，1H；7.30(d)，2H；7.72(d)，2H；7.86(s)，1H；8.73(t)，1H.

Embodiment 31

With reference to embodiment 28 preparation 4-hydroximic acid base 2-amino-N-[3-(p-methoxyphenyl) isoxazoline-3-yl-5-] methyl-butyramide, white solid, m.p.165.0-167.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：1.90(m)，1H；2.12(m)，2H；2.27(m)，1H；3.80(s)，3H；4.04(q)，1H；4.44(d)，2H；6.78(s)，1H；7.04(d)，2H；7.75(d)，2H；7.85(s)，1H；8.72(t)，1H.

The present invention prepares the general general formula of optically active B, C series compound

The straight chain formula synthetic route of optically active compd B and C is as follows:

Embodiment 32

Racemization or optically-active 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl group-N-[3-(substituted-phenyl) isoxazolyl-5-] methyl-third (or fourth) acid amides and racemization or optically-active 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl group-N-[3-(substituted-phenyl) isoxazoline-3-yl-5-] preparation of methyl-propionic acid amide

(1) in the triangular flask of magnetic agitation is housed; 3mmol 4-chloro-benzaldehyde oxime is dissolved in the 10mL exsiccant methylene dichloride; add 1.8mmol N-chlorosuccinimide; stir; all after the dissolving; heat 30min a little; add 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl groups-N-propargyl-third (or fourth) acid amides (A1 ') of 3mmol racemization or optically-active and 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl groups-N-allyl group-third (or fourth) acid amides of racemization or optically-active (A2 '); drip the 4mmol triethylamine; there are a large amount of white smoke to produce; reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v1: 1), get product, yield 30-50%.

(2) preparation of corresponding hydroximic acid

Oxammonium hydrochloride 1.0mmol is dissolved in the 4ml water; KOH 1.0mmol is dissolved in the 4ml water; after the aqueous solution of KOH is poured in the aqueous solution of oxammonium hydrochloride; react after 15 minutes its suction filtration at normal temperatures and add as 0.33mmol embodiment 32 gained racemizations or optically-active 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl group-N-[3-(substituted-phenyl) isoxazolyl-5-] methyl-third (or fourth) acid amides and racemization or optically-active 2-fourth (or penta) base-3 (or 4)-Ding oxygen acyl group-N-[3-(substituted-phenyl) isoxazoline-3-yl-5-] in methyl-propanamide compounds; stirring at room 24 hours; separate out white solid; recrystallizing methanol gets the finished product.

Embodiment 33

With reference to the preparation method of embodiment 32 prepare 2-pentyl-3-hydroximic acid base-N-[3-(phenyl) isoxazolyl-5-] methyl-propionic acid amide: m.p.146.0-148 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.79(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；4.41(d)，2H；6.79(d)，1H；7.75(d)，3H；7.83(m)，2H；8.55-8.71(m)，2H；10.40(d)，1H.

Embodiment 34

With reference to the preparation method of embodiment 32 preparation (2R) 2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) isoxazolyl-5-] methyl-propionic acid amide, m.p.165.0-166.5 ℃.[α](25℃，2％，MeOH)，+23o。1HNMR(DMSO，TMS)，(ppm)：0.80(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；4.42(d)，2H；6.81(d)，1H；7.33(d)，2H；7.90(m)，2H；8.76(m)，2H；10.40(d)，1H.

Embodiment 35

With reference to the preparation method of embodiment 32 make 2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazolyl-5-] methyl-propionic acid amide: m.p.141.0-143 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.78(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；3.84(s)，3H；4.40(d)，2H；6.81(d)，1H；7.25(d)，2H；7.73(d)，2H；8.0-8.73(m)，2H；10.45(d)，1H.

Embodiment 36

With reference to the preparation method of embodiment 32 make 2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide, m.p.134.0-135 ℃, 1HNMR (DMSO, TMS), δ (ppm): 0.80 (t), 3H; 1.18 (m), 6H; 1.29-1.42 (m), 2H; 2.00-2.80 (m), 3H; 3.0-3.60 (m), 2H; 3.84 (s), 3H; 4.20-4.70 (m), 2H; 4.96 (m), 1H; 7.27 (d), 2H; 7.75 (d), 2H; 8.0-8.75 (m), 2H; 10.46 (board), 1H.

Embodiment 37

With reference to the preparation method of embodiment 32 make 2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) isoxazoline-3-yl-5-] methyl-propionic acid amide, m.p.145.0-146.5 ℃.1HNMR(DMSO，TMS)，δ(ppm)；0.81(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；3.0-3.60(m)，2H；4.20-4.70(m)，2H；4.96(m)，1H；7.35(d)，2H；7.92(m)，2H；8.78(m)，2H；10.45(d)，1H.

Embodiment 38

With reference to the preparation method of embodiment 32 make 4-hydroximic acid base 2-amyl group-N-[3-(aminomethyl phenyl) isoxazolyl-5-] methyl-butyramide m.p.162.0-163.6 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.75(t)，3H；1.14(m)，6H；1.29-2.20(m)，7H；2.29(s)，3H；4.36(d)，2H；6.66(s)，1H；7.24(d)，2H；7.65(d)，2H；8.20-8.63(m)，1H；10.25(board)，1H.

Embodiment 39

With reference to preparation method's system (2R) 4-hydroximic acid base-2-amyl group-N-[3-of embodiment 32 (to fluorophenyl) isoxazolyl-5-] methyl-butyramide m.p.165.0-166.7 ℃.[α](25℃，2％，MeOH)，+19o。

1HNMR(DMSO，TMS)，δ(ppm)：0.82(t)，3H；1.18(m)，6H；1.28-1.51(m)，4H；1.80-2.50(m)，3H；4.40(d)，2H；6.81(d)，1H；7.35(d)，2H；7.90(m)，2H；8.77(m)，2H；10.40(d)，1H.

Embodiment 40

With reference to the preparation method of embodiment 32 make 4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazolyl-5-] methyl-butyramide m.p.158.0-158.8 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.17(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；4.41(d)，2H；6.82(d)，1H；7.55(d)，2H；7.88(m)，2H；8.70-8.75(m)，1H；10.50(d)，1H.

Embodiment 41

With reference to the preparation method of embodiment 32 make 4-hydroximic acid base 2-amyl group-N-[3-(rubigan) isoxazoline-3-yl-5-] methyl-butyramide m.p.138.0-140.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.18(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；3.10-3.20(m)，2H；4.20-4.60(m)，2H；5.05(m)，1H；7.55(d)，2H；7.85(m)，2H；8.70-8.77(m)，1H；10.51(d)，1H.

Synthesizing of pyrazoles, pyrazoline hydroxamic acid compound

Embodiment 42

4-hydroximic acid base-2-pentyl-N-[1-replacement-3-(substituted-phenyl) pyrazolyl-5-] preparation method of methyl-third (or fourth) acid amides

(1). in the triangular flask of magnetic agitation is housed, 2mmol N1-replacement-substituted benzene methyl hydrazone muriate is dissolved in the 10mL exsiccant methylene dichloride, stir, all after the dissolving, add 2mmol 2-pentyl-N-and replace propargyl-glutarimide, drip 0.20g (2mmol) triethylamine, have a large amount of white smoke to produce, reflux condensing tube is installed, reflux 2h.Silica gel column chromatography separates, and eluent is sherwood oil (b.p.60-90 ℃)-ethyl acetate (v: v=5: 1), get product (white solid), yield 55.0%

(2). oxammonium hydrochloride 0.07g (1.0mmol) is dissolved in the 4ml water, KOH 0.07g (1.0mmol) is dissolved in the 4ml water, after the aqueous solution of KOH is poured in the aqueous solution of oxammonium hydrochloride, react at normal temperatures after 15 minutes its suction filtration to the above gained 2-pentyl of 0.12g (0.33mmol)-N-[1-replacement-3-(substituted-phenyl)-4-replacement-pyrazolyl-5-] in methyl-Ding (or penta) imide compound, stirring at room 24 hours, separate out white solid, recrystallizing methanol gets the finished product.

Embodiment 43

Preparation method with reference to embodiment 42 prepares 2-pentyl-3-hydroximic acid base-N-[1-methyl-3-(to fluorophenyl) pyrazolyl-5-] methyl-propionic acid amide, m.p.160.0-166.1 ℃.HNMR(DMSO，TMS)，δ(ppm)：0.80(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；3.7(s)，3H；4.42(d)，2H；6.81(d)，1H；7.33(d)，2H；7.90(m)，2H；8.3(s)，1H；8.76(m)，2H；10.40(d)，1H.

Embodiment 44

Preparation method with reference to embodiment 42 prepares 2-pentyl-3-hydroximic acid base-N-[3-(p-methoxyphenyl) pyrazolyl-5-] methyl-propionic acid amide: m.p.141.0-143 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.78(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；3.84(s)，3H；4.40(d)，2H；6.81(d)，1H；7.25(d)，2H；7.73(d)，2H；8.0-8.73(m)，2H；10.45(d)，1H.13.1(broad)，1H.

Embodiment 45

Preparation method with reference to embodiment 42 prepares 2-pentyl-3-hydroximic acid base-N-[1-methyl-3-(p-methoxyphenyl) pyrazolinyl-5-] methyl-propionic acid amide, m.p.134.0-135 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.80(t)，3H；1.18(m)，6H；1.29-1.42(m)，2H；2.00-2.80(m)，3H；3.0-3.60(m)，2H；3.84(s)，3H；4.20-4.70(m)，5H；4.96(m)，1H；7.27(d)，2H；7.75(d)，2H；8.0-8.75(m)，2H；10.46(board)，1H.

Embodiment 46

Preparation method with reference to embodiment 42 prepares 2-pentyl-3-hydroximic acid base-N-[3-(to fluorophenyl) pyrazolinyl-5-] methyl-propionic acid amide, m.p.142.0-143.5 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.18(m)，6H；1.28-1.51(m)，2H；1.80-2.50(m)，3H；3.0-3.60(m)，2H；4.20-4.70(m)，3H；4.96(m)，1H；7.35(d)，2H；7.92(m)，2H；8.78(m)，2H；10.45(d)，1H.

Embodiment 47

Preparation method with reference to embodiment 42 prepares 4-hydroximic acid base-2-amyl group-N-[1-methyl-3-(rubigan) pyrazolyl-5-] methyl-butyramide m.p.158.0-158.8 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.17(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；3.81(s)，3H；4.41(d)，2H；6.82(d)，1H；7.55(d)，2H；7.88(m)，2H；8.20(s)，1H；8.70-8.75(m)，1H；10.50(d)，1H.13.20(broad)，1H.

Embodiment 48

Preparation method with reference to embodiment 42 prepares 4-hydroximic acid base-2-amyl group-N-[3-(rubigan) pyrazolinyl-5-] methyl-butyramide m.p.148.0-150.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.18(m)，6H；1.28-1.41(m)，4H；2.00-2.67(m)，3H；3.10-3.20(m)，2H；4.20-4.60(m)，2H；5.05(m)，1H；7.55(d)，2H；7.85(m)，2H；8.70-8.77(m)，2H；10.51(d)，1H.13.1(s)，1H；

It is as follows that the present invention prepares the general general formula of B4, B5 series compound:

Embodiment 49

2-fourth (or penta) base-4-Succinic Acid (or pentanedioic acid) mono ethyl ester makes by literature method.2-fourth (or penta) base-4-Succinic Acid (or pentanedioic acid) mono ethyl ester 0.01mol and 30ml thionyl chloride are returned slide reaction 1 hour; boil off unnecessary thionyl chloride to doing; then add methylene dichloride and 0.01mol N-[3-replacement-4-substituted-phenyl-thiophene (or furans)-2]-methylamine and 0.015mol pyridine (0 ℃); reacted 1 hour; generate 2-fourth (or penta) base-3 (or 4)-ethoxy acyl groups-N--[3-replacement-4-substituted-phenyl-thiophene (or furans)-2]-methyl-third (or fourth) acid amides, yield 70%.2-fourth (or penta) base-3 (or 4)-ethoxy acyl groups-N--[3-replacements-4-substituted-phenyl-thiophene (or furans)-2]-methyl-third (or fourth) acid amides in methyl alcohol with oxyammonia reaction, generation B3 or B4, yield 80%

Embodiment 50

Prepare 2-amyl group-3-hydroxamic acid base-N--[4-to chlorophenyl-thiophene-2 with reference to embodiment 49 methods]-methyl-propionic acid amide: m.p.134.0-136.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.82(t)，3H；1.18(m)，6H；1.28-1.41(m)，2H；2.00-2.67(m)，3H；4.20-4.60(m)，2H；6.80(s)，1H；6.91(s)，1H；7.55(d)，2H；7.85(m)，2H；8.70-8.77(m)，2H；10.51(d)，1H.

Embodiment 51

Prepare 2-amyl group-3-hydroxamic acid base-N--[4-to fluoro phenyl-furans-2 with reference to embodiment 49 methods]-methyl-propionic acid amide: m.p.134.0-136.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.21(m)，6H；1.28-1.43(m)，2H；2.00-2.69(m)，3H；4.20-4.60(m)，2H；7.10(s)，1H；7.21(s)，1H；7.55(d)，2H；7.85(m)，2H；8.70-8.77(m)，2H；10.41(d)，1H.

Embodiment 52

Prepare 2-amyl group-4-hydroxamic acid base-N--[4-to chlorophenyl-thiophene-2 with reference to embodiment 49 methods]-methyl-butyramide: m.p.134.0-136.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.82(t)，3H；1.19(m)，6H；1.28-1.41(m)，2H；2.00-2.67(m)，5H；4.30-4.60(m)，2H；6.82(s)，1H；6.94(s)，1H；7.50(d)，2H；7.80(m)，2H；8.70-8.77(m)，2H；10.61(d)，1H.

Embodiment 53

Prepare 2-amyl group-4-hydroxamic acid base-N--[4-to fluoro phenyl-furans-2 with reference to embodiment 49 methods]-methyl-butyramide: m.p.134.0-136.0 ℃.1HNMR(DMSO，TMS)，δ(ppm)：0.81(t)，3H；1.21(m)，6H；1.28-1.45(m)，2H；2.00-2.69(m)，5H；4.20-4.63(m)，2H；7.13(s)，1H；7.24(s)，1H；7.51(d)，2H；7.82(m)，2H；8.70-8.77(m)，2H；10.35(d)，1H.

The pharmaceutical composition that type of PDF enzyme inhibitors-hydroxamic acid series compound B and C form, it comprises the medicine of the described treatment significant quantity of claim 1-4, and pharmaceutically acceptable carrier, thinner or vehicle.

Hydroxamic acid series compound B of the present invention and C can itself oral or non-oral administrations, perhaps oral the or non-oral administration of composition (as tablet, granule, sustained release preparation, capsule, injection, solution etc.) that forms with itself and pharmaceutically acceptable carrier, vehicle and other additive.

During oral administration, composition can be made into tablet, granule, capsule or oral solution.The preparation oral compositions can adopt lactose, crystallite, starch, N.F,USP MANNITOL etc. to do weighting agent, and gelatin, carboxymethyl cellulose, methylcellulose gum, polyvinylpyrrolidone, hypromellose etc. are as suitable binder or thickening material.Suitable disintegrants can be selected carboxymethylstach sodium, starch, polyvinylpolypyrrolidone or Microcrystalline Cellulose etc. for use, and with talcum powder, micropowder silica gel, stearin, calcium stearate or Magnesium Stearate etc. are as suitable antisticking agent and lubricant.Its preparation process be activeconstituents and carrier and optionally with the disintegrating agent composition mixture, this mixture with contain the aqueous solution of tackiness agent or the alcoholic solution of different concns carries out granulating in suitable device.Behind the dried particles, direct packaging is granule; Or in particle, add examples of suitable lubricants and antisticking agent, this mixture is carried out compressing tablet; Or in particle, add examples of suitable lubricants and antisticking agent, incapsulate and make capsule.

Hydroxamic acid series compound of the present invention is soluble in water, can the injection form administration, though dosage changes according to treatment target, administering mode, symptom and other factor, but common dosage is the 0.1mg/kg-100mg/kg body weight when the non-oral administration of adult that sensitive bacterial is infected, preferred about 1mg/kg-80mg/kg body weight, preferred 5mg/kg-50mg/kg body weight, medication every day once, administration in continuous 5 days is useful.During non-oral administration, compound of the present invention can be made into injection liquid, transfusion, injectable sterile powder, injection lyophilized powder, aerosol etc.During the preparation injection liquid, activeconstituents can be dissolved in water for injection or the various medicinal organic solvent, add suitable solubility promoter such as polyoxyethylenated castor oil, polysorbate, polyvidone and buffer reagent etc., selectively add stablizer again.The back adds gac, whip attachment, carbon removal, smart filter, embedding, sterilization.During the preparation transfusion, activeconstituents can be dissolved in water for injection or the various medicinal organic solvent, add suitable solubility promoter such as polyoxyethylenated castor oil, polysorbate, polyvidone and salt buffer etc., selectively add stablizer, isotonic regulator again.Add gac, whip attachment, carbon removal, smart filter, embedding, sterilization.During the preparation injectable sterile powder, activeconstituents is dissolved in water for injection, spraying drying, packing, sterilization.During preparation injection lyophilized powder, get activeconstituents and add water for injection, regulate pH value with medicinal basic and make its dissolving to 4-8.Add vehicle again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals promptly.During the preparation aerosol, activeconstituents, latent solvent, oxidation inhibitor and spices are dissolved in distilled water or various medicinal organic solvent, are sub-packed in container, the dress valve is tightened, and is pressed into propellent, shakes up, and promptly gets solution aerosol.

In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.Preparation can adopt any one compound among the present invention as activeconstituents.

Embodiment 1

Every tablet preparation that contains the 100mg activeconstituents:

The mg/ sheet

A-laboratory sample 100

Lactose 50

Microcrystalline Cellulose 150

Pregelatinized Starch 150

Hypromellose 40

Carboxymethylstach sodium 45

Magnesium Stearate 5

Talcum powder 10

With activeconstituents, lactose, pregelatinized Starch, Microcrystalline Cellulose are crossed 100 mesh sieves, and abundant mixing, the 2% hypromellose aqueous solution joined in the above-mentioned mixed powder mix, cross 20 mesh sieve system softwoods, make wet granular in 45-55 ℃ of drying, carboxymethylstach sodium, Magnesium Stearate and talcum powder are joined compressing tablet in the above-mentioned dried particles.

Embodiment 2

Every capsule preparation that contains the 100mg activeconstituents:

F-laboratory sample 100mg

Lactose 150mg

Starch 50mg

Polyvinylpolypyrrolidone 10mg

Polyvinylpyrrolidone 20mg

Magnesium Stearate 5mg

Lactose, starch, polyvinylpolypyrrolidone are crossed 100 mesh sieves respectively, and abundant mixing.Above-mentioned mixed powder and activeconstituents are mixed.The 10% polyvinylpyrrolidone aqueous solution is joined in the mixed powder that contains activeconstituents, cross 20 mesh sieve system softwoods, make wet granular in 45-55 ℃ of drying, add Magnesium Stearate, whole grain is surveyed intermediate, and is encapsulated.

Embodiment 3

The preparation of injection liquid

E-laboratory sample 200mg

Propylene glycol 100mg

Polysorbate 80 is an amount of

Distilled water 300ml

Get activeconstituents and join in the water for injection that dissolves sorbyl alcohol and propylene glycol, add medicinal basic and regulate pH value and make its dissolving to 4-8.Add gac, whip attachment 30 minutes, carbon removal, smart filter, embedding, sterilization.

Embodiment 4

The preparation of injection lyophilized powder

B-laboratory sample 100mg

Medicinal basic 0.1-7%

N.F,USP MANNITOL 55-85%

Get activeconstituents and add water for injection, regulate pH value with medicinal basic and make its dissolving to 4-8.Add N.F,USP MANNITOL again, carry out autoclaving by the requirement of injection, add gac, adopt filtering with microporous membrane, filtrate is carried out packing, adopts freeze-drying, makes loose block, seals promptly.

Embodiment 5

The preparation of aerosol

H-laboratory sample 1g

Distilled water 2ml

Lemon flavour is an amount of

Ethanol 15ml

Methyl chlorofluoride is an amount of

Activeconstituents is dissolved in distilled water, and lemon flavour is dissolved in ethanol, with the two mixing, is sub-packed in container again, and the dress valve is tightened, and is pressed into propellent, shakes up, and promptly gets solution aerosol.

Claims

1, type of PDF enzyme inhibitors-hydroxamic acid series compound B and C, it is characterized in that comprising in this molecular structure of compounds 2-R-3 (or 4)-hydroxamic acid base-third (or fourth) acyl group and 3 bit strips has phenyl or substituted-phenyl, and 4 bit strips have R ₁Substituently contain heteroatomic five-ring;

Its structural formula is as follows:

N=1 wherein, 2;

Y＝O、N、S；Z＝N、C；

R, R ₁For H, contain C ₁-C ₅Straight or branched alkyl, amino or C ₁-C ₃Substituted-amino;

R ₂Can not replace, can be H or C yet ₁-C ₃Straight chained alkyl;

X is H ,-R ' ,-OR ' ,-SR ' ,-halogen-CN ,-NH ₂,-NHR ' ,-NR ' ₂,-NO ₂,-COOH substituting group (R ' for containing C ₁-C ₅The straight or branched alkyl);

X is single substituting group; And be in contraposition or ortho position on the phenyl ring respectively.

2, compound according to claim 1 is characterized in that describedly containing heteroatomic five-ring and comprising following one group of chemical formula:

3, compound according to claim 1 is characterized in that described R, R ₁Be H, ethyl, amyl group, amino or kharophen; R ₂Be, H or methyl; X is H, methyl, methoxyl group ,-Cl ,-F; X is single substituting group; And be in contraposition or ortho position on the phenyl ring respectively.

4, the preparation method of type of PDF enzyme inhibitors-hydroxamic acid series compound B and C is characterized in that:

A). react in the exsiccant methylene dichloride by A1 or A2 and substituted benzene dipole body (I), product separates through silica gel column chromatography, with sherwood oil and ethyl acetate is eluent, carries out the hydroximic acid reaction with oxyammonia then, preparation B1, B2 or C1, C2 series compound;

N=1 wherein, 2;

R, R ₁Be H, ethyl, amyl group, amino or kharophen; R ₂Be, H or methyl; X is H, methyl, methoxyl group ,-Cl ,-F; X is single substituting group; And be in contraposition or ortho position on the phenyl ring respectively;

Or

B). optically active A1 ', A2 ', react in the exsiccant methylene dichloride with corresponding substituted benzene dipole body (I), product separates through silica gel column chromatography, with sherwood oil and ethyl acetate is eluent, carry out the hydroximic acid reaction with oxyammonia then, can obtain optically active B3, C3 series compound;

OBu=mono wherein; N=1,2; Y=O, Z=N; R, R ₁, R ₂, X definition is described with a;

Or

C). optically active A3 and compound III prepared in reaction B4 or B5.

N=1,2; R, R ₁, X definition is described with a.

5, the pharmaceutical composition of type of PDF enzyme inhibitors-hydroxamic acid series compound B and C formation, it comprises the medicine of the described treatment significant quantity of claim 1-5, and pharmaceutically acceptable carrier, thinner or vehicle.

6, type of PDF enzyme inhibitors-hydroxamic acid series compound B and the C application in preparation treatment sensitive bacterial infection medicine.