CN101389597A - Carbonates of fenicol antibiotics - Google Patents

Abstract

The invention relates to carbonate derivatives of fenicol compounds of formulae I and II, wherein the variables are as defined in the claims, having useful properties as antibiotic prodrugs, together with methods of making and using these compounds.

Description

The carbonic ether of fenicol antibiotics

Invention field

The present invention relates to the carbonic ether prodrug of phenylpropyl alcohol (fenicol) compound, this prodrug has the solubleness of raising and the viscosity of minimizing in suitable solvent carrier.

Background of invention

Paraxin (Chloramphenical), thiamphenicol and florfenicol are the Broad spectrum antibioticss that is commonly referred to as " phenylpropyl alcohol alcohols ".Florfenicol is Broad spectrum antibiotics, and it has the activity of anti-multiple Gram-negative bacteria and gram-positive microorganism.Florfenicol can be for preventing and treat the bacterium that sensitive pathogens causes to infect in Mammals, bird, Reptilia, fish and Crustacean.One of its main application be treatment by mannheimia haemolytica (Mannhemia haemolytica), rocky Pasteurella (Pasteurella multocida) and (or) Histophilus (Histophilus somni) that sleeps the ox pneumonia and the relevant respiratory infection (being conventionally commonly referred to as ox respiratory disease or BRD) that cause.The infectivity cow hoof dermatitis being caused by actinomyces pseudonecrophorus (Fusobacterium necrophorum) and/or the fertile bacterium (Prevotella melaninogenicus) of product melanochrome Prey, by rocky Pasteurella (Pasteurella multocida), lobar pneumonia actinobacillus (Actinobacilluspleuropneumoniae), swine streptococcus (Streptococcus suis), Salmonella choleraesuis (Salmonella cholerasuis) and (or) the pig respiratory disease that causes of Mycoplasma (Mycoplasma spp.), the chicken colibacillosis being caused by bacillus coli (Escherichia coli), the catfish intestines septicemia being caused by Edwardsiella ictaluri and the salmon infantile malnutrition due to digestive disturbances or intestinalparasites disease being caused by aeromonas salmonicida (Aeromonas salmonicida) are also its treatment indications.Other bacterium florfenicol to the susceptibility of proof belongs to and comprises enterobacter (Enterobacter), Klebsiella (Klebsiella), Staphylococcus (Staphylococcus), enterococcus species (Enterococcus), rich for Bacillaceae (Bordetella), proteus (Proteus) and Shigella (Shigella).Especially, to the biological strain of paraxin resistance, for example bacillus canalis capsulatus (K.pneumoniae), enterobacter cloacae (E.cloacae), salmonella typhi (S.typhus) and bacillus coli (E.coli) are responsive to florfenicol.

As follows, florfenicol is the analog of thiamphenicol, and thiamphenicol is the derivative of paraxin, and the aromatic nitro that wherein relates to irreversible people's aplastic anemia paraxin induction, that dose is relevant is replaced by methylsulfonyl.

Paraxin thiamphenicol florfenicol

Florfenicol has the fluorine atom of the primary hydroxyl that replaces paraxin and thiamphenicol.Therefore cause florfenicol not very sensitive to the deactivation of the bacterium containing plasmid-encoded enzyme, E.C. 2.3.1.28 (CAT), Transacetylase makes the primary hydroxyl acetylize of paraxin and thiamphenicol.This acetylize stops these microbiotic to be combined with the ribosomal subunit of sensitive organism.The combination of this type of microbiotic and ribosomal subunit is the mechanism of action of paraxin and thiamphenicol inhibiting peptide based transferase main (but not being unique), and peptidyl transferase is responsible in bacterium amino acid transport, to growthing peptide chain, then forming protein.

The most conventionally by oral, subcutaneous or parenteral, give the patient's florfenicol that can be benefited by its advantage, parenteral is mainly intramuscular or intravenously.If need economic single-dose treatment in animal doctor's environment, still need new high density florfenicol preparation.

In addition, also need to maintain for a long time the florfenicol form of effective plasma level microbiotic level, to reach the administration reduction effect of improvement, for example, more easily provide single-dose treatment, especially in animal doctor's environment.

In the effort for expansion single injection florfenicol benefit, technology is considered as prodrug by florfenicol ester derivative.Florfenicol such as florfenicol acetic ester, florfenicol propionic ester, florfenicol butyric ester, florfenicol valerate, florfenicol capronate, florfenicol heptanoate, florfenicol octanoate, florfenicol pelargonate, florfenicol decylate, florfenicol undecane acid esters, florfenicol dodecylate and the florfenicol phthalic ester etc. of esterification such as Murthy etc., in the U.S. number of patent application 2005/0014828 of announcing, have been discussed.

In the U.S. of the announcement of owning together number of patent application 2005/0182031, also discussed the florfenicol of florfenicol phosphoric acid ester form, its water-soluble and prodrug with increase is active.

Yet in the art, be there are to long-term needs in deliquescent other phenylpropyl alcohol alcohols of economic single-dose treatment that provides in suitable carrier with increase.

Quoting of any reference in this article, should not be considered as admitting that " prior art " that this type of reference can be used as the application obtains.

Summary of the invention

Therefore, for solving above-mentioned needs, the invention provides the phenylpropyl alcohol alcohols carbonic acid ester derivative with useful prodrug character.In one embodiment of the invention, provide the phenylpropyl alcohol carbonate products corresponding to formula (I):

Formula I

R wherein ₁be selected from:

with

R ₂be selected from dichloromethyl, difluoromethyl, chlorine methyl fluoride, chloro methyl and methyl,

R ₃be selected from methylol, fluoro methyl, difluoromethyl, trifluoromethyl and CH ₂o-C (O) O-R ₅,

R ₄and R ₅independently be selected from replacement or unsubstituted C _1-10straight chain, side chain or cyclic alkyl; That replace or unsubstituted C _1-10alkoxyalkyl; C _1-10aryl; C _1-10arylalkyl; That replace or unsubstituted C _1-10straight chain, side chain or cycloalkenyl group.Preferably, R ₃for CH ₂f.In specific embodiment, R ₁for CH ₃sO ₂, R ₂for CHCl ₂, R ₃for CH ₂f.In addition, work as R ₁for NO ₂time, R ₃be not CH ₂o-C (O) O-R ₅.

In another embodiment, R ₄and R ₅independently being selected from following part replaces: methyl, methoxyl group, carboxyl, carbalkoxy and acyloxy.

In going back another embodiment, R ₄and R ₅independently be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, dodecyl, Octadecane base, 2-methyl-butyl, 1-ethyl-propyl group, 3-methyl-propyl-2-thiazolinyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxyl group-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyl-octa-6-thiazolinyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, methyl-2-furyl, 2-(methoxyl group-oxyethyl group)-ethyl, 2-(oxyethyl group-oxyethyl group)-ethyl, 2-[2-(methoxyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-[2-(oxyethyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-(hydroxyl-oxyethyl group)-ethyl, 2-[2-(hydroxyl-oxyethyl group)-oxyethyl group]-ethyl, 2-acetoxyl group-ethyl, 2-(acetoxyl group-oxyethyl group)-ethyl, 3-acetoxyl group-propyl group, 2-carboxyl-ethyl, 3-carboxyl-propyl group, 4-carboxyl-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl group, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxy carbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-methyl-phenyl, 4-methoxyl group-phenyl, 4-carboxyl-phenyl, 2-carboxyl-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylaminohydroxyphenylarsonic acid phenyl.

In a further embodiment, R ₁be selected from

with

R ₂for dichloromethyl or difluoromethyl, R ₃be selected from methylol, fluoro methyl and CH ₂o-C (O) O-R ₅, and optional,

R ₄be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, dodecyl, Octadecane base, 2-methyl-butyl, 1-ethyl-propyl group, 3-methyl-propyl-2-thiazolinyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxyl group-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyl-octa-6-thiazolinyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, methyl-2-furyl, 2-(methoxyl group-oxyethyl group)-ethyl, 2-(oxyethyl group-oxyethyl group)-ethyl, 2-[2-(methoxyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-[2-(oxyethyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-(hydroxyl-oxyethyl group)-ethyl, 2-[2-(hydroxyl-oxyethyl group)-oxyethyl group]-ethyl, 2-acetoxyl group-ethyl, 2-(acetoxyl group-oxyethyl group)-ethyl, 3-acetoxyl group-propyl group, 2-carboxyl-ethyl, 3-carboxyl-propyl group, 4-carboxyl-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl group, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxy carbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-methyl-phenyl, 4-methoxyl group-phenyl, 4-carboxyl-phenyl, 2-carboxyl-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylaminohydroxyphenylarsonic acid phenyl.

In going back another embodiment, R ₁for CH ₃sO ₂or NO ₂, R ₂for CHCl ₂, R ₃for OH, R ₄for ethyl, or, R ₁for CH ₃sO ₂or NO ₂, R ₂for CHCl ₂, R ₃for

R ₄for ethyl.

Preferably, phenylpropyl alcohol carbonic ether of the present invention is selected from following compound:

with

The present invention also especially comprises illustrational compound herein, and they comprise the phenylpropyl alcohol carbonic ether of listing in table 2 below.

In addition, also consider that the compounds of this invention comprises two phenylpropyl alcohol carbonic ethers.For example, this type of pair of phenylpropyl alcohol carbonic ether comprises containing the compound with Formula Il structure.

Formula II

R wherein ₁be selected from

with

Wherein a, c and e are the independent integers in 0-4 numerical range, and b and d are the independent integers in 0-2 numerical range, and condition is integer a, b, c, d and e's and in the numerical range of 2-8, and

R ₅₁and R ₅₂independently be selected from H, methyl, hydroxyl, methoxyl group and acetoxyl group.Preferably, a, b, c, d and e's and in the numerical range of 2-4.

More preferably, the present invention includes formula II compound, wherein R ₁for

R ₃for CH ₂f.

Even more preferably, the present invention includes formula II compound, this formula II compound has and is selected from following structure:

with

In a further embodiment, the present invention also comprises medicinal compositions, the formula I that said composition contains significant quantity or formula II phenylpropyl alcohol carbonate products or its solvate and pharmaceutically acceptable vehicle or solvent.Preferably, phenylpropyl alcohol carbonic ether accounts for the about 80%-of composition weight approximately 5%.

Preferably, pharmaceutically acceptable solvent comprises for example phenylcarbinol of at least one pharmaceutically acceptable alcohol.Conventionally, the alcohol content of medicinal compositions accounts for the about 5%-of composition weight approximately 98%.Preferably, the approximately 10%-approximately 90% that alcohol content range is composition weight.More preferably the approximately 20%-approximately 45% that, alcohol content range is composition weight.Phenylcarbinol concentration is especially best up to 45% (weight).

The present invention also comprises medicinal compositions, the formula I phenylpropyl alcohol carbonic ether that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent, wherein R ₁for CH ₃sO ₂, R ₂for CHCl ₂, R ₃for CH ₂f.

The present invention also further comprises medicinal compositions, the formula I that described composition contains significant quantity or formula II phenylpropyl alcohol carbonic ether and pharmaceutically acceptable vehicle or solvent, and containing corresponding phenylpropyl alcohol, wherein said corresponding phenylpropyl alcohol is the identical phenylpropyl alcohol of phenylpropyl alcohol discharging respectively in vivo with formula I or formula II phenylpropyl alcohol carbonic ether.

Also consider that medicinal compositions of the present invention also comprises at least one other medicine, can be before giving phenylpropyl alcohol carbonic ether of the present invention, afterwards and/or simultaneously, there is this other medicine of animal needing.

Other medicines are that for example florfenicol and/or be applicable to has any other kind medicine of the animal of needs.This other medicines for example comprise for example avermectin of microbiotic (endectocidal) compound.Only as an example, avermectin be selected from ivermectin, doramectin, abamectin, selamectin, because of the spit of fland of going out, Eprinomectin, Moxidectin, milbemycin and combination thereof.Preferably, the amount that avermectin compound exists is the about 20%w/v of about 0.03%w/v-.Other medicines also can comprise flukicide, optional and antibiotic medicine or hereinafter more the other medicines of detailed description combine.

Going back in another embodiment again, the present invention includes medicinal compositions, said composition is containing the formula III phenylpropyl alcohol compound of formula I phenylpropyl alcohol carbonic ether and applied in any combination.

Formula III

Its Chinese style I phenylpropyl alcohol carbonic ether and formula III phenylpropyl alcohol exist with the ratio of 50:1-1:50 (weight), wherein R ₁for CH ₃sO ₂, R ₂for CHCl ₂, R ₃for OH or F.The R of formula III ₁, R ₂and R ₃definition is same with above formula I.Also consider containing using the formula II of same or similar ratio and the analogous composition of formula III.Can on demand and/or put into practice requirement, give animal or fish prevention significant quantity and/or group's anti-(metaphylaxis) medicinal compositions of the present invention.

The present invention also provides on demand and/or puts into practice the correlation method that requires to prevent significant quantity and/or group anti-medicinal compositions of the present invention.The present invention also provides the method for in having the animal needing treatment or preventing disease or illness.These class methods can comprise formula I and/or the formula II phenylpropyl alcohol carbonic ether that gives pharmacy effective dose, and they comprise hereinafter described any compound of embodiment 1-30.Significant quantity scope is the about 150mg/kg treatment of for example about 1-the weight of animals.In a broad sense, treatment animal is any animal obtaining an advantage by giving the compounds of this invention.Conventionally, treatment animal is Mammals, bird, fish, Reptilia or invertebrates, is included in any animal hereinafter more itemizing.

The present invention also provides the method for synthetic compound of formula i, and the method is included in suitable solvent phenylpropyl alcohol compound is reacted with corresponding chloro-formic ester.Suitable solvent can comprise for example chlorinated solvent, ester solvent, polyethers solvent, formaldehyde acetal ether, cyclic ethers, ketone, mixing ether-ester solvent and glycol ether, preferably includes tetrahydrofuran (THF).

Preferably, at catalyzer, for example under the existence of 4-dimethylamino-pyridine, 4-picoline, pyridine and combination thereof, carry out this synthetic method.

Preferably, at acid scavenger, for example under the existence of triethylamine, pyridine, sodium carbonate, sodium bicarbonate, salt of wormwood and combination thereof, carry out synthetic method.

Preferably carry out this synthetic method, wherein said chloro-formic ester is

R wherein ₄definition is same with above formula I.

Preferably carry out this synthetic method, wherein said phenylpropyl alcohol compound has following structure:

Or

During reaction, chloro-formic ester is pressed molar excess existence with respect to phenylpropyl alcohol compound.R ₁and R ₂definition is same with above formula I.

The method of synthesis type II compound is included in suitable solvent phenylpropyl alcohol compound is reacted with corresponding bischloroformates, and wherein phenylpropyl alcohol Compound Phase is for chloro-formic ester molar excess.

Preferably, in the method for preparation formula II compound, phenylpropyl alcohol is following compound,

Preferably this bischloroformates is

R ₁and R ₂definition is same with above formula I and or formula II.

accompanying drawing summary

Figure 1A illustrates the reaction process 1 with the benzyl carbonic ether prodrug of the synthetic florfenicol of chloro-formic ester and the similar thing of florfenicol.

Figure 1B illustrates the reaction process 2 by dihydroxy-benzene propyl alcohol (chloramphenicol-type) synthesize benzyl carbonic ether prodrug ester.

Fig. 2 A illustrates with the chloro-formic ester reagent that is less than 1 molar equivalent, by the reaction process 3 (dihydroxy fundamental mode phenylpropyl alcohol, method A) of dihydroxy-benzene propyl alcohol synthesize benzyl carbonic ether prodrug ester.

Fig. 2 B illustrates the reaction process 4 (dihydroxy fundamental mode phenylpropyl alcohol, method B) with the benzyl monocarbonate prodrug (chloramphenicol-type) of the synthetic dihydroxy-benzene propyl alcohol of protecting group strategy.

Fig. 3 A illustrates and uses selective hydrolysis strategy, the reaction process 5 (dihydroxy fundamental mode phenylpropyl alcohol, method C) of the benzyl monocarbonate prodrug (chloramphenicol-type) of synthetic dihydroxy-benzene propyl alcohol.

Fig. 3 B illustrates the C-O-R with X-(O) ₄reagent but not chloro-formic ester, the reaction process 6 of synthetic florfenicol and the similar thing benzyl of florfenicol carbonic ether prodrug.The value scope of ＂ X ＂ is provided by following table 1.

Fig. 4 illustrates the synthetic of phenylpropyl alcohol carbonate products D, and the method, by raw alcohol A is reacted with triethylamine, obtains chloro-formic ester B, and it is reacted with phenylpropyl alcohol C, obtains Compound D.

Fig. 5 illustrates the synthetic of phenylpropyl alcohol double manganese ester compound F 17-hydroxy-corticosterone, and the method, by bischloroformates E is reacted with substrate C, obtains phenylpropyl alcohol carbonate products F.

Fig. 6 illustrates the synthetic of phenylpropyl alcohol carbonate products H, and the method, by Vinyl chloroformate B is reacted with substrate G and triethylamine (not shown), obtains phenylpropyl alcohol benzyl double manganese ester compound H, benzyl carbonic ether I and primary alconol carbonic ether.

Fig. 7 a illustrates synthetic wherein R ₄with R ₅the reaction process 7a of different double manganese esters.

Fig. 7 b illustrates alternative synthetic wherein R ₄with R ₅the reaction process 7b of different double manganese esters.

发明详述

因此，本发明提供碳酸酯形式的苯丙醇例如氟苯尼考前药。一般 而言，此类苯丙醇碳酸酯难溶于水，但易溶于可用于注射给药的其它 合适的非刺性有机溶剂，此类酯可用于治疗和/或预防细菌感染。本 发明化合物可在体内容易地转化为游离的活性抗生素药物。

为更全面理解本发明，提供下定义。

在本说明书中，为了方便目的的数术语的使用决非如此限定。 因此，例如涉“一种微生物”包括涉一种或多种此类微生物。除另 有说明外，复数术语的使用也是非限制性的。例如，除另有说明外， 短语如“苯丙醇的碳酸酯衍生物”是指本文中鉴别的苯丙醇的任何碳酸 酯衍生物，包括独的个这种化合物或两种或多种此类化合物的组 合。

本文中使用的术语“近似”与术语“约”换使用，除另有说明外， 通常表示在所述值的20％内的值。

本文中使用的术语“前药”表示是药物前体的化合物，给予患者 后，通过代谢或化过程，该化合物经历化转化，产生活性药物， 例如苯丙醇抗生素的碳酸酯是在体内释放苯丙醇抗生素的前药。

本文中使用的术语苄基表示取代基或取代连接，其中取代基或取 代基连接在脂族和碳原子上，该碳原子直接与苯基或取代的苯环连 接。术语苄基碳酸酯表示与这种苄基位置连接的碳酸酯取代基 O-(O)C-OR。

本文中使用的“药用组合物”是指本发明化合物包括其溶剂合物 (例如氟苯尼考前药)和药上可接受的赋形剂和/或载体的制剂。存在 于载体中的本发明化合物的量为约1％-约80％(重量)。在特定的实施 方案中，载体是本发明化合物的溶剂，该溶剂相对不刺活组织且适 合注射，例如某些有机溶剂。

有机溶剂的粘度变化很大，作为苯丙醇和苯丙醇前药的制剂的组 分，它们为最终制剂提供粘性。因此，较低粘度的有机溶剂是苯丙醇 类和苯丙醇前药的高浓度制剂的优选的组分。例如，醇类例如乙醇、 异丙醇、苯甲醇、甘油缩甲醛(formal)(例如1，3-二氧六环-5-醇和1，3- 二氧戊环-4-基甲醇的平衡混合物)、低分子量乙二醇(ethylene glycerol) 醚代表注射剂可接受的低粘度溶剂的实例。相对低粘度的其它溶剂 例如酯(乙酸苄酯、乙二醇二乙酸酯、丙二醇二乙酸酯)、醚(低分子量 乙二醇或丙二醇的二醚)或酰胺(2-甲基吡咯烷酮、2-吡咯烷酮)也可用 作降低苯丙醇碳酸酯前药溶液总粘度的溶剂混合物的组分。但是，此 类溶剂或含此类溶剂的组合通常不会给母体苯丙醇药物提供足够的 溶解性。可通过使用苯丙醇苄基碳酸酯前药，在低粘度溶剂或含大比 例低粘度溶剂的溶剂混合物中，仍可得到需要的苯丙醇类高浓度。优 选的溶剂是与任选的赋形剂联合的苯甲醇。更优选的是含比例为2:1 (体积/体积)的三醋精/苯甲醇的载体。

“赋形剂”是指为进一步促进给予活性成分而加入到药理组合物 中的惰性物质。赋形剂的实例包括但不限于例如需要的各种糖和各种 淀粉、纤维素衍生物、明胶、植物油和聚乙二醇已知技术稳定剂、 着色剂等。

本文中使用的术语“治疗有效量”是指可足够快速水解并足量 提供活性苯丙醇浓度的本发明前药的量，该浓度可缓解患者中一种或 多种细菌感染症状至某种程度。在特定的实施方案中，治疗有效量是 指当给予患者后，活性抗生素例如苯丙醇足够血浆浓度递送给患者 便达到下效果的本发明化合物的量：(1)减少，优选消除患者体内 细菌细胞群体；(2)抑制(即延缓或优选终止)细菌细胞增殖；(3)抑制(即 延缓优选终止)细菌感染传播；和/或(4)缓解(优选消除)与感染有关的一 种或多种症状。

术语“预防有效量”是指给予动物或鱼后达到相应活性抗生素的 足够的血浆浓度，致于对该活性抗生素敏感的细菌的感染可能性和 /或程度显著减少的本发明前药的量。在给予较早的抗生素方案后，还 可用预防有效量的本发明化合物在动物或鱼中维持细菌细胞群体的 下降水平(或消除)。

“群防”是定时集中给予整个动物组药物，消除或使预期疾病爆 发最小化，例如在具有高感染风险的一种或多种动物中消除或使预期 疾病爆发最小化。在一个特定的实施方案中，高风险小牛是健康史未 知的重量轻的混合型远程运送的牛。

本文中使用的术语“最小抑制浓度”与＂MIC＂混用。＂MIC50＂是使 50％分离株生抑制的化合物(例如本发明前药)的浓度。同样，MIC90 是使90％分离株生抑制的化合物的浓度。

在本文中本发明化合物的合成部分上下文中使用的“合适的”溶 剂是指溶剂，其中反应物可溶解，且在反应中不会由自身与一种或多 种反应混合物成分反应或通过干扰成分之间相反应产生有害沉淀。 对于任何给出的反应，合适的溶剂选择完全在本领域技术人员的能力 范围内，且无需不适当的实验即可完成。

本发明化合物的合成

下反应流程举例说明如何制备本发明化合物。

流程1

用氯甲酸酯合成氟苯尼考和氟苯尼考类似物苄基碳酸酯前药

在一个实施方案中，适用于只有苄基羟基的苯丙醇类(例如氟苯 尼考其类似物)的制备苄基碳酸酯前药的便利方法通过图1A举例说 明。如所示，在适当的溶剂中，用或不用催化剂，使苯丙醇化合物(1) 与相应的氯甲酸酯反应，得到苄基碳酸酯(2)。所有图中的R ₁、R ₂和 R ₄定义同上给出的式I化合物。合适的溶剂包括例如氯化溶剂例如 二氯甲烷和1，2-二氯乙烷；酯溶剂例如乙酸乙酯、乙酸异丙酯、乙酸 异戊酯、乙二醇二乙酸酯、丙二醇二乙酸酯、甘油三乙酸酯；醚溶 剂例如乙醚、异丙醚、甲基叔丁基醚；聚醚溶剂例如乙二醇醚；二甲 基乙二醇醚、二甘醇醚；二甘醇二甲基醚、二甘醇二乙基醚；甲醛缩 醛醚例如二甲氧基甲烷、二乙氧基甲烷、二丁氧基甲烷；环醚例如四 氢呋喃、1，3-二氧戊环、1，4-二□烷；酮溶剂例如丙酮、甲乙酮、甲基 异丁基酮；由乙二醇和二甘醇的醚代表的混合醚/酯溶剂例如2-甲氧 基乙基乙酸酯、2-乙氧基乙基乙酸酯、2-(甲氧基-乙氧基)乙基乙酸酯、 2-(乙氧基-乙氧基)乙基乙酸酯。下提供的实例举例说明四氢呋喃作 为溶剂的用途。

在将苯丙醇转化为苄基前药的反应中，任选使用相对于苯丙醇摩 尔数过量(最高达3倍)的氯甲酸酯试剂、催化剂或催化剂组合、催化 剂和酸清除剂的组合、延的反应时间和升高的温度。优选的催化剂 包括例如4-二甲基氨基-吡、4-甲基吡和吡。优选的酸清除剂包 括例如三乙胺、吡、碳酸钠、碳酸氢钠和碳酸钾。优选在约0℃-约 50℃下，使反应进行约0.5-约10小时。

通常，在0℃下，通过将1.5-2.0当量氯甲酸酯的四氢呋喃溶液 加入含苯丙醇、1.0当量三乙胺和0.5当量4-N，N-二甲基氨基吡的四 氢呋喃溶液进行反应，让反应继续进行至完成。可通过本领域中的标 准方法，将未反应的苯丙醇(如果反应后仍存在)完全除，或任选让 其留在最后纯化的苄基碳酸酯前药物质中，便给药后立即提供初始 增加水平的氟苯尼考。

例如通过使相应的醇与光气或光气等同物(例如二光气、三光气) 反应，制备氯甲酸酯试剂。最好，得到的粗氯甲酸酯溶液可不经纯化 直接用于碳酸酯形成步骤。或者，如果有售，市售氯甲酸酯可用于碳 酸酯形成步骤。合适的氯甲酸酯的市售来源包括例如Aldrich和 Lancaster。

流程2

氯霉素型(二羟基苯丙醇)的苄基/伯醇双碳酸酯前药的合成

在再一个实施方案中，如图1B所示，也可通过将苄基羟基选择 性转化为相应的碳酸酯前药或将苄基和末端伯羟基均转化为前药部 分，形成苄基/伯醇双碳酸酯前药，由苯丙醇例如具有两个羟基的化合 物(3)(例如氯霉素、甲砜霉素、乙酰苯丙醇)制备苄基碳酸酯前药酯例 如化合物(4)。

可用类似于上述氟苯尼考类苯丙醇的条件，通过用两个或多个当 量的适当的氯甲酸酯处理相应的苯丙醇，将具有两个羟基的苯丙醇(氯 霉素型)转化为苄基/伯醇双碳酸酯前药。按照此类条件，可实现两个 羟基官能团同时转化，得到苄基/伯醇双碳酸酯前药(流程2)。

流程3

氯霉素型(二羟基苯丙醇)苄基碳酸酯前药的合成方法A

如图2A所示，可用小于1摩尔当量的氯甲酸酯试剂，通过用表 5中所示溶剂进行结晶或例如通过硅胶层析，将需要的苄基碳酸酯前 药从得到的碳酸酯和双碳酸酯的混合物中分离，制备氯霉素型(二羟 基，R ₁＝NO ₂)苄基碳酸酯前药(流程3)。

流程4

氯霉素型(二羟基苯丙醇)苄基碳酸酯前药的合成-方法B

如图2B所示，可用保基策略，通过在伯醇官能团上选择性引 入保基，然后使其与氯甲酸酯反应，在苄醇上选择性引入碳酸酯前 药部分，制备氯霉素型(二羟基，R ₁＝NO ₂)苄基碳酸酯前药(流程4)。

用于保伯醇的保基可是酯基例如甲酸酯、乙酸酯、苯甲酸 酯、新戊酸酯(pivaloate)；碳酸酯基例如叔丁氧基碳酸酯；甲硅烷基保 基例如三甲基甲硅烷基、叔丁基二甲基甲硅烷基。在苯丙醇分子的 苄醇位置上引入需要的碳酸酯前药部分后，可用适合除特定基团的 条件，通过化法除保基(Protective Groups in Organic Synthesis； Theodora W.Greene，Peter G.M.Wuts；第3版，June1999，John Wiley & Sons Inc)，或通过选择性酶水解将保基除而不影响苄基碳酸酯前 药部分(流程4)。

流程5

氯霉素型(二羟基)苄基碳酸酯前药的合成-方法C

如图3A所示，也可通过先制备苄基/伯醇双碳酸酯前药，然后通 过化或酶法将伯醇碳酸酯官能团选择性水解，制备氯霉素型(二羟基 苯丙醇，R ₁＝NO ₂)苄基碳酸酯前药(流程5)。

流程6

用X-(O)C-O-R ₄试剂而非氯甲酸酯合成氟苯尼考和氟苯尼考类 似物苄基碳酸酯前药

如图3B所示，也可用非氯甲酸酯试剂制备苯丙醇的苄基碳酸酯 前药。可使用具有非氯离基团的试剂，便按类似于与氯甲酸酯反 应的方式，加或不加入催化剂，引入碳酸酯部分。可用于这种转化的 此类试剂的无数实例存在于文献中，下提供一些。

参见图3B流程6，X的值可包括下表1中列举的任一部分。各 个这种部分引用代表性参考文献，各自通过引用结合到本文中。

表1

流程7a和7b

在苄醇和伯醇官能团上含不同碳酸酯部分的氯霉素型(二羟基苯 丙醇)的苄基/伯醇双碳酸酯前药的合成

如图7A所示，可按流程7a所示，用通过上述方法A-C得到的 苄基碳酸酯(化合物6)，制备在苄醇和伯醇官能团上含不同碳酸酯部 分的氯霉素型(二羟基苯丙醇)苄基/伯醇双碳酸酯前药，再使它们与氯 甲酸酯Cl-(O)C-O-R ₅(R ₄≠R ₅)或与流程6有关的上述类型 X-(O)C-O-R ₅(R ₄≠R ₅)试剂反应。

或者，可先将需要的碳酸酯前药官能团引入到伯醇官能团上，可 再使得到的伯醇碳酸酯中间体(化合物5)与氯甲酸酯Cl-(O)C-O-R ₄(R ₄ ≠R ₅)反应，或通过与流程6有关的上述类型X-(O)C-O-R ₄(R ₄≠R ₅)试 剂反应，得到需要的苄基/伯醇双碳酸酯前药(按图7B制备流程7b所 示)。该特定合成流程可方便的利用预计的伯醇官能团的较高反应性。

本发明化合物的使用方法

本发明还提供通过本发明化合物在体内释放的一种或多种抗生 素药物，给予预防有效量的方法，用于按需要和/或实践要求防止即预 防和/或群防和/或治疗感染，例如可预防和/或治疗的细菌感染等。优 选如此保或治疗的动物，但不排除脊椎动物，更优选哺乳动物、鸟 或鱼。可给予动物患者任何本发明化合物或此类化合物的合适组合。 合适的动物患者包括那些野生动物、家畜(例如为肉、奶、奶油、蛋、 毛、革、羽毛和/或羊毛目的饲养的)、驮畜、研究动物、伴侣动 物和为/在动物园、野外栖息地和/或马戏团中饲养的那些动物。

在特定的实施方案中，动物患者是哺乳动物。可治疗的哺乳动物 包括灵目动物，例如猴、大猩猩和任选人。其它哺乳动物患者是牛 (例如牛或奶牛)、猪(例如公猪或猪)、羊(例如山羊或绵羊)、马(例如马)、 犬(例如狗)、猫(例如家猫)、骆驼、鹿、羚羊、兔、豚鼠和啮齿类动物 (例如松鼠、大鼠、小鼠、沙鼠和仓鼠)、鲸类动物(鲸、海豚、小鲸)、 鳍足动物(pinnipeds)(海豹、海象)。鸟包括鸭科(例如天鹅、鸭和鹅)、 鸠鸽科(例如小野鸽和家鸽)、雉科(例如鹧鸪、松鸡和火鸡)、Thesienidae (例如家鸡)、鹦鹉目(例如尾小鹦鹉、金刚鹦鹉和鹦鹉)、猎禽和平胸 类鸟(例如鸵鸟)。

由本发明化合物治疗或保的鸟可与商业或非商业鸟类饲养有 关。这些包括例如鸭科例如天鹅、鹅和鸭；鸠鸽科例如小野鸽和家鸽 例如家鸽；雉科例如鹧鸪、松鸡和火鸡；Thesienidae例如家鸡；鹦鹉 目例如其中作为宠物饲养或为收藏家市场饲养的尾小鹦鹉、金刚鹦 鹉和鹦鹉。

按照本发明目的，术语“鱼”应理解为包括但不限于分在Teleosti 组的鱼即硬骨鱼。鲑目(它包括鲑科)和鲈形目(它包括棘臀鱼科)包括在 Teleosti组中。其中潜在鱼接受者的实例包括鲑科、鲻科、鲷科、丽鱼 科、太阳鱼科、三线矶鲈(Parapristipoma trilineatum)和蓝眼琵琶鱼 (Plecostomusspp)。

另外，潜在鱼接受者的实例包括鲑科、鲻科、鲷科、丽鱼科、太 阳鱼科、三线矶鲈(Parapristipoma trilineatum)和蓝眼琵琶鱼 (Plecostomusspp)。仅用于举例说明目的，下表中列出用本发明化合物 治疗的其它鱼。

鲑科

鲻科的某些成员

Sparidae科的某些成员

some member of Cichlidae section

some member of Centrarchidae

The example of going back other of medicable fish includes but not limited to catfish, Ju Sushi, tuna, halibut, arctic Jiayu, sturgeon, halibut, flatfish, sole, carp, tilapia, Tiao Wen Shi Sushi, yellow eel, sea bream, long back of the body Yellowtail, amberjack, grouper and bango.

Also consider that other animal also can benefit from the inventive method, they comprise marsupial (for example kangaroo), Reptilia (for example raising tortoise), crustacean (for example lobster, crab, shrimp and prawn) mollusk (for example octopus and shellfish), and the inventive method can be safely and/or effectively treat and/or prevent the large animal of other economic worth of its infection.

In another embodiment, patient is companion animals.According to the object of the invention, term " companion " animal is understood to include domestic cat (feline), dog (Canis animals), Lagomorpha, horse (equine species), cavy; Rodent (for example squirrel, rat, mouse, gerbil jird and hamster); Primate (such as monkey) and bird such as pigeon, little rock dove, parrot, parakeet, macaw, canary bird etc.

Medicinal compositions

The animal the compounds of this invention that can be same have needs or the physiologically acceptable solvate of this compound, maybe can give the medicinal compositions of aforementioned substances wherein and suitable mixed with excipients.Preparation and medicine-feeding technology can be at Remington ' s Pharmacological Sciences, Mack Publishing Co., and Easton, PA, finds in latest edition.The preparation of discussing in Remington is main relevant with the use of human patients with technology; But the technology that can know by veterinary technician easily changes them into non-human patients and uses.

When described the compounds of this invention herein gives as animal feed ingredient, or when being dissolved in or being suspended in tap water, provide composition, wherein active medicine is dispersed in inert support or thinner fully.Inert support is the carrier that does not react and can give safely animal with the compounds of this invention.Preferably, the carrier giving for feed is can be maybe the composition of the quantitative feed of animal (animalration).

Suitable composition contains feed pre-composition or supplement, and wherein the amount of activeconstituents is relatively large, and they are applicable to directly giving animal or directly or add feed after intermediate dilute or mixing step.The typical carrier or the thinner that are applicable to such composition comprise such as distiller's dried grain, Semen Maydis powder, citrus pulp, fermentation residue, oyster shell powder, Wheat bran powder, the residual juice of molasses, corn cob meal, edible bean powder feed, soyabeen grists, lime powder etc.By method for example pulverize, stir, grinding or overturning, the compounds of this invention is dispersed in whole carrier fully.Composition containing about 0.05%-approximately 5.0% or about 0.005%-approximately 2.0% (weight) the compounds of this invention is especially suitable as feed pre-composition.Directly give the compounds of this invention of the feed additive of animal containing about 0.0002%-0.3% (weight).

By giving, finished product feedstuff is treated and the amount of the activity compound concentration that control sensitive microbial needs, and these type of supplement are added to animal-feed.Although the expectation concentration of the compounds of this invention changes the concrete derivative according to above-mentioned factor and use, but conventionally in feed, by about 0.0001%-0.02% or about 0.00001%-approximately 0.002% concentration, give described compound, to reach the anti-microbial effect needing.

Route of administration

" giving " used herein or " administration " refer to as treatment or prophylaxis of microbial infect, and be delivered to organism by the compounds of this invention or solvate or containing the medicinal compositions of the compounds of this invention.

Suitable route of administration can include but not limited to per os, rectum, part, thoroughly in mucous membrane, intramuscular, subcutaneous, marrow, in sheath, directly in indoor, intravenously, vitreum in (intravitreal), intraperitoneal, nose, ear or intraocular.Preferred route of administration is per os and parenteral.

Or, can be by part but not systemic fashion for example by being directly coated in the ointment preparation of infected zone or topical application preparation or by compound is injected directly in infected tissue, giving described compound.In arbitrary situation, all can use sustained release preparation.

Therefore, can be by any generally acknowledged mode of administration or for the material of similar effectiveness, by pure form or suitable medicinal compositions form, give the compounds of this invention or its pharmaceutically acceptable solvate.Route of administration can be any approach that those of ordinary skill is known.Can be solid, semisolid, lyophilized powder or liquid dosage form such as tablet, suppository, pill, soft elastic glue wafer and hard-gelatin capsules, powder, solution, suspensoid or aerosol etc. by any generally acknowledged technology type, by the unit or a plurality of dosage form that are applicable to simply giving accurate dosage, there are those animal the compounds of this invention that need.Composition comprises conventional medicine carrier or vehicle and as the compounds of this invention of active medicine, also can comprise other medicament, medicine, carrier, auxiliary agent etc. in addition.

Composition/preparation

Can, by method well known in the art for example with the multiple mixing of knowing, dissolving, granulation, dragee preparation, grinding, emulsification, encapsulate, embedding or freeze drying process, prepare medicinal compositions of the present invention.Can with one or more physiologically acceptable carrier combinations compositions formulated, carrier comprises vehicle and the auxiliary agent that can promote active compound to be processed into pharmaceutically useful preparation.Suitable preparation depends on selected route of administration.

For including but not limited to that intravenously, intramuscular and subcutaneous injection are in interior injection, available polar solvent preparation the compounds of this invention, this kind solvent includes but not limited to propylene glycol; Alcohols is phenylcarbinol or ethanol, polyoxyethylene glycol for example; With METHYLPYRROLIDONE, 2-Pyrrolidone, other pyrrolidone; N,N-dimethylacetamide, DMF, methyl-sulphoxide, acetone, glycerol acetate, Sericosol N, optional concentration are up to 10% water; Combination with any aforementioned excipients or known other material of those of ordinary skill.For across mucosa delivery, in preparation, use the permeate agent that is applicable to seeing through barrier.This type of permeate agent is conventionally known in the art.

Dosage

Treatment significant quantity refers to effective prevention and/or infected by microbes is minimized and/or treat, alleviate and/or alleviate the amount of the compound of the symptom that infected by microbes causes.The mensuration for the treatment of significant quantity in those skilled in the art's limit of power, especially can be measured according to summary of the invention herein completely.

For any compound for the inventive method, the known properties of the antibiotic medicine that first can be discharged by drug compound before the present invention is estimated treatment significant quantity.Then, preparation is for the dosage of animal model, to reach the circulation composition scope that is equal to or greater than minimum inhibition concentration as known in the art (＂ MIC ＂).Then available this information is determined the dosage that can be used for patient more accurately.

Can pass through standard medicament method, in cell culture or laboratory animal, measure toxicity and the curative effect of compound described herein.For example, can, by method well known in the art, measure the minimum inhibition concentration (＂ MIC ＂) of specific compound and 50% lethal dose (the ＂ LD for the treatment of group ₅₀＂).For example,, according to the clinical and governing principle mensuration MIC that (CLSI) ＂ proposes of laboratory standard institute (Clinical and Laboratory StandardsInstitiute).

The available data that obtain are formulated the dosage range that can be used for patient.This dosage can change naturally, and it depends on dosage form and route of administration.Relevant clinical teacher can be according to patient's illness, select definite preparation, route of administration and dosage (referring to for example Fingl, et al., 1975 at ＂ ThePharmacological Basis of Therapeutics ＂, Ch.1 p.1 described in).In a broad sense, concentration by the microbiotic that effectively reaches and/or make to discharge in blood plasma and bodily tissue maintains effective treatment and eliminates responsive infectious microorganism or prevent the dosage in the level of new infection, and keep the sufficiently long time to reach the target of needs, need the animal the compounds of this invention of this treatment.Those of skill in the art will appreciate that, according to clinical response, the dosage range of below estimating is adjustable, and explain the relative quantity of fenicol antibiotics and the phenylpropyl alcohol mol ratio of every prodrug (Dan Yushuan) carbonate products being discharged by each corresponding front drug compound.For example, for subcutaneous administration, conventionally by the about 150mg/kg body weight of about 1mg-dosage, give the compounds of this invention.Administration frequency scope can be also single dosage/day-a plurality of dosage/days.For oral administration, preferably by giving once a day dosage.

Can regulate individually dosage amount and interval time, so that the blood plasma level of the compound of the concentration that is enough to maintain the level that is more than or equal to MIC or any other needs to be provided.This type of blood plasma level is commonly referred to minimum effective concentration (MECs).The MEC of each compound is different, but can for example reach the essential concentration that 80% above microbial population suppresses by vitro data, estimates.Available described mensuration is herein determined MEC.The essential dosage that reaches MEC should depend on concrete property and/or animal and/or the route of administration of compound.Plasma concentration and/or its corresponding active result of available HPLC mensuration or biological assay deterministic compound.

Also available MEC value is determined the dosage timed interval.Be applied in 10-90% is kept above the blood plasma level of MEC scheme in the time and give compound.

The in the situation that of topical or selectivity picked-up, effectively local drug concentration can be irrelevant with plasma concentration, and available other method as known in the art is measured correct dosage amount and the timed interval.

Can be by once a day or be divided into a plurality of dosage and give composition.Conventionally only a dosage is just enough to treatment infection.In some cases, for treatment animal, need to first give a dosage, after 48 hours, give again second dosage.As recognized in those of ordinary skills, the individual character of the organism that definite dosage should depend on stage of infection and seriousness, infection to the susceptibility of composition and the animal kind for the treatment of.

The amount nature of the composition giving should depend on treated patient; Cause pathogenic agent or the bacterium of infection; The seriousness infecting; Administering mode is per os, intravenously, part etc.; Prescribe doctor, animal doctor's etc. judgement.

Conventionally, when making subcutaneouly, by the about 150mg/kg domestic animal of about 1mg-(catle) body weight dosage, give the compounds of this invention.Preferably, the about 70mg/kg body weight of about 20mg-dosage.More preferably, dosage is about 60mg/kg.But when giving the compounds of this invention by intramuscular (IM) approach, preferably twice gives dosage, giving the about 24-of first dosage after approximately 48 hours, gives second dosage.

In pig, conventionally by the about 150mg/kg body weight of about 10mg-dosage, give the compounds of this invention.Preferably, about 20mg-70mg/kg body weight dosage.Conventionally, the about 24-of intramuscularly first, after approximately 48 hours, injects for the second time.

In poultry, conventionally by about 10mg-150mg/kg body weight dosage, give the compounds of this invention.Every daily tap water per os gives prodrug, as long as press clinical requirement, for example about 3-continues medication for approximately 7 days.

Give hydrocoles

The present invention also provides in fish and optional aquatic invertebrate and eliminates, reduces or prevent the method that bacterium infects.These class methods comprise the compounds of this invention that has the hydrocoles of needs significant quantity.Conventionally by feed, give the compounds of this invention of animal effective dose or animal or animal population are immersed in the solution containing the active compounds solution of significant quantity, completing administration.Also can understand, can by by medicament administration to holding in the pond or other water storage region of animal, allow animal pass through its cheek and suck compound or absorb the compounds of this invention dosage, give the compounds of this invention.For the concrete animal of individualized treatment some fish in animal doctor or fishpond environment for example, direct injection or to inject by the infiltration releasing device containing the compounds of this invention independent or that combine with other medicines be the optional method that gives the compounds of this invention.

Animal doctor can be as usual, be used in parameter and method described in above other kind animal, be determined at the dosage that effectively reduces, eliminates or prevent the compounds of this invention that bacterium infects in fish or other water biological species, although it may change, depend on the kind of treated fish, related concrete microorganism and gradient of infection.For aquatic organism indication, conventionally by the about 70mg/kg of about 1mg/kg-, preferably 10mg/kg-30mg/kg dosage gives the compounds of this invention.Suitable route of administration comprises: intravenously, subcutaneous, intramuscular and/or on demand to water biological species spraying or aquatic organism is soaked, and/or compound is directly added in the water of receiving volume.

For oral administration, preferably by above-mentioned dosage, give the about 10-of the compounds of this invention approximately 15 days.

Although can give respectively activeconstituents and food, consider, aspect preferred, active substance is mixed to fish meal.Can reach the administration level needing by the compounds of this invention of appropriate amount being mixed to commercially available fish meal product, preparation dosing fish meal.The amount of mixing the compounds of this invention of fish meal depends on the speed of feeding fish.For by about 0.2%-4% biomass/sky speed feeding fish, preferably medicated feed contains about 50-10,000mg/kg feed, 100-2 more preferably from about, 000mg/kg feed.

Although before making pellets feed, but the compounds of this invention is added to fodder mixtures, but preferably by with the compounds of this invention by feed piller dressing, form medicated feed.

The compounds of this invention treatment that available treatment or pre-bacteriological protection infect comprises any fish of fresh water and salt water class, and the invertebrates water biological species of enumerating above.

With combining of other medicines and form of therapy

Also consider, before the present invention, drug compound and other effective known technology are medication combined, simultaneously or sequential giving (for example, in same composition or the composition that separates).This type of known technology medicine comprises such as other microbicide such as microbiotic, anti-mycotic agent, antiviral drug, wormer etc.; With nutritious supplementary, fodder additives etc.For example, consider to combine to give the compounds of this invention and any known technology standard (non-prodrug) phenylpropyl alcohol.This type of phenylpropyl alcohol alcohols comprises and is called the florfenicol of D-(threo form)-1-(4-methyl sulphonyl phenyl)-fluoro-1-propyl alcohol of 2-dichloro acetamino-3-.Another kind of preferred Antibiotique composition is D-(threo form)-1-(4-methyl sulphonyl phenyl)-fluoro-1-propyl alcohol of 2-difluoro acetylaminohydroxyphenylarsonic acid 3-.Another kind of effectively microbiotic is thiamphenicol.The preparation method of these Antibiotique compositions and the intermediate that can be used for these class methods are in the U.S. patent No. 4,311,857; 4,582,918; 4,973,750; 4,876,352; 5,227,494; 4,743,700; 5,567,844; 5,105,009; 5,382,673; In 5,352,832 and 5,663,361, set forth, they are incorporated herein by reference.The similar thing of other florfenicol and/or prodrug are open, and this type of analogue can be used for the present composition and method [referring to for example U.S. public announcement of a patent application number; 2004/0082553 and U.S. public announcement of a patent application number 2005/0182031, all integral body is attached to herein by reference].When Antibiotique composition is florfenicol, the concentration of florfenicol is generally the about 50%w/v of about 10%-, and preferred level is the about 40%w/v of about 20%-, and even preferred level is at least about 30%w/v.

Can be tilmicosin with the another kind of effective antibiotics compound of the compounds of this invention coupling.Tilmicosin is macrolide antibiotic, and its chemistry is defined as 20-dihydro-20-deoxidation-20-(cis-3,5-lupetidine-1-yl)-decarburization sugar tylosin, it is in the U.S. patent No. 4, open report in 820,695, it is incorporated herein by reference.Disclosed in the U.S. patent No. 4,820,695 is again injection, and it is the aqueous solution preparation containing 50% (volume) propylene glycol, 4% (volume) phenylcarbinol and 50-500mg/ml activeconstituents.Tilmicosin can alkali or the form of phosphoric acid ester exist.After by drug administration by injection treatment in 4 days, find that tilmicosin can be used for treating respiratory infection, especially ox pasteurella haemolytica (Pasteurella haemolytica) infects.Therefore, tilmicosin can be used for treating for example new calves pneumonia and ox respiratory disease.When there is tilmicosin, its amount is about 1%-approximately 50%, and preferably 10%-approximately 50%, in specific embodiment, is 30%.

Can be that mycin (tulathromycin) is drawn in holder with the another kind of effective antibiotics of the compounds of this invention coupling.Can draw mycin according to the method preparation holder proposing in U.S. patent publication No. 2003/0064939 A1, its by reference integral body be attached to herein.Can, by the injected dose form of about 5.0%-approximately 70% (weight) concentration level, provide holder to draw mycin.Holder draws mycin to expect most by the 200mg/kg/ per daily dose of about 0.2mg/kg body weight/day (mg/kg/ day)-Yue, by single dose or divided dose (being 1-4 dosage/day), give, more preferably 1.25,2.5 or 5mg/kg, weekly or twice, although must change, it depends on treated species, body weight and patient's illness.Can, by the injected dose form of about 5.0%-approximately 70% (weight) concentration level, provide holder to draw mycin.

Can be fluoroquinolone antibiotics with the another kind of effective antibiotics of the compounds of this invention coupling, for example Enrofloxacin, danofloxacin, difloxacin, orbifloxacin and Marbofloxacin.In the situation of Enrofloxacin, can give by about 100mg/ml concentration, can provide danofloxacin by about 180mg/ml concentration.

Can comprise ketolide compound with other effective macrolide antibiotic of the compounds of this invention coupling, or azalides more specifically.In for example U.S. patent No. 6,514,945,6,472,371,6,270,768,6,437,151 and 6,271,255 and the U.S. patent No. 6,239,112,5,958,888 and the U.S. patent No. 6,339,063 and 6, in 054,434, have the discussion of this compounds, they all by reference integral body be attached to herein.

Can comprise tsiklomitsin with other effective antibiotics of the compounds of this invention coupling, especially duomycin and terramycin.

Other microbiotic can comprise for example a kind of in penicillins of beta-lactam, for example combination of penicillin G, penicillin K, penbritin, amoxycilline Trihydrate bp or amoxycilline Trihydrate bp and clavulanic acid or other beta-lactamase inhibitor.Other concrete beta-lactam comprises cephalosporins such as ceftiofur, cefquinome etc.In preparation of the present invention, the concentration of cynnematin optionally changes between about 1mg/ml-500mg/ml.

In addition, the present invention is also optionally included in the composition for the treatment of microorganism and parasitic infection in animal, and said composition comprises and one or more the compounds of this invention and optional carrier and/or one or more above-listed microbiotic of mixed with excipients and/or combination.

For all described method and the compounds of this invention herein, the compound of also consider differentiating easily with kill or control various types of parasites and for example comprise one or more known technology drug combinations of described all vermins and endoparasite herein.Therefore, although compare with the method for use previously known medicine with previously known medicine, preferred the compounds of this invention and method, but in some optional embodiment, consider by they with for killing or control other known technology medicine of various insects or the combination medicine of this type of known technology medicine is combined, while or sequential use (for example, at same composition or the composition that separates).

Comprise for example wormer of known technology with these other medicines of the compounds of this invention coupling, for example, for example, for example, for example, for example, for example, as phenols (nitroxinil (nitroxynil)), miazines (pyrantel), Imidazothiazole class (LEVAMISOLE HCL) and the praziquantel of avermectin (ivermectin, Moxidectin, milbemycin), benzoglyoxaline (albendazole, triclabendazole), Salicylanilide (closantel, oxyclozanide), replacement.

Kill with other of the compounds of this invention coupling or the known technology medicine of Control pests comprises organic phosphate insecticide.This insecticides has utmost point activity biocidal activity for example widely, and has in some cases anthelmintic activity.Organic phosphate insecticide for example comprises hundred controls spirit, terbufos, Rogor, diazinon, thiodemeton, Trichlorphon, azinphos-methyl, Chlorpyrifos 94, Malathion, acephate, acephatemet, acephate (acephate), ethyl parathion, parathion-methyl, acephatemet (mevinphos), phorate, carbophenothion, Phosalone, only enumerates several these compounds.Also consider to comprise the combination of the inventive method and compound and carbamate insecticides, carbamate insecticides comprises such as sevin, Furadan, aldicarb, molinate, methomyl etc., and with the combination of organochlorine insecticides.Also consider to comprise the combination with biotic pesticide, biotic pesticide for example comprise wormer, pyrethrin (and synthetic variant for example esbiothrin, chrysron, permethrin, bromine chrysanthemum ester) and are typically used as acaricidal nicotine.The combination of other consideration is and the combination of various sterilants that they comprise Bacillus thuringiensis (Bacillus thuringiensis), Ovotran, carbonamidine (for example amtitaz); Copper compound is copper hydroxide, sulfuric acid cupric oxychloride for example; Cyfloxylate, Cypermethrin, kelthane, 5a,6,9,9a-hexahydro-6,9-methano-2,4, come good fortune spirit, fenvalerate, Senior Three cyfluthrin ester, methoxy-DDT and sulphur.

In addition, for all described method and new compounds herein, the compound of also consider differentiating can be easily and synergist for example piperonyl alcohol (PBO) and triphenylphosphate (TPP); And/or insect growth regulator(IGR) (IGRs) and juvenile hormone analogue (JHAs) such as diflubenzuron, encircle the couplings such as the third chlorine piperazine, methoprene, thereby in animal patient and in the environment of animal patient, provide parasitic initial and Sustainable Control (all stages in insect growth comprise worm's ovum).

With cyclodiene, Lan Niting, KT-199 and/or older known technology wormer be avermectin class (ivermectin for example for example, Moxidectin, milbemycin), benzimidazoles (albendazole for example, triclabendazole), Salicylanilide class (closantel for example, oxyclozanide), the phenols (for example nitroxinil) replacing, miazines (for example pyrantel), Imidazothiazole class (for example LEVAMISOLE HCL), praziquantel and some organophosphate for example combination of naftalofos and pyraclofos are also considered for this type of combination medicine.

Especially, other parasiticide compound can be used in the scope of the invention is preferably comprised of avermectin compounds.As mentioned above, avermectin family compound is in known effective wide spectrum resisting mammal body and the very strong serial anti-parasite medicine of verminal activity.

Can be preferably ivermectin with the compound of the compounds of this invention coupling within the scope of the present invention.Ivermectin is the semi-synthetic derivative of avermectin, and that conventionally obtain is at least 80%22,23-dihydro avermectin B1 _abe less than 20% 22,23-dihydro avermectin B1 _bmixture.Ivermectin is open in the U.S. patent No. 4,199,569, and it is incorporated herein by reference.Since 1980 mid-nineties 90s, ivermectin is just used for the treatment of various zooparasites and parasitic disease as antiparasitic.

Abamectin is the disclosed avermectin that is called avermectin B1a/B1b in the U.S. patent No. 4,310,519, and this patent by reference integral body is attached to herein.Abamectin is containing at least 80% avermectin B1 _awith the avermectin B1 that is no more than 20% _b.

Another kind of preferred avermectin is and is called 25-cyclohexyl-avermectin B ₁doramectin.The structure of doramectin and preparation are open in the U.S. patent No. 5,089,480, and this patent by reference integral body is attached to herein.

Another kind of preferred avermectin is Moxidectin.The Moxidectin that is called again LL-F28249 α can be learnt by the U.S. patent No. 4,916,154, and this patent by reference integral body is attached to herein.

Another kind of preferred avermectin is selamectin.Selamectin is de-(de) (1-methyl-propyl)-5-deoxidation-22 of 25-cyclohexyl-25-, 23-dihydro-5-(oxyimino)-avermectin B ₁monose.

Milbemycin or B41 are separated materials from the fermenting broth of streptomyces (Streptomyces) strain of production milbemycin.In the U.S. patent No. 3,950,360 and the U.S. patent No. 3,984,564, microorganism, fermentation condition and separation method have more fully been discussed.

Can be by the U.S. patent No. 5,288,710 or 5,399, preparation because of the spit of fland of going out (4 ＂-deoxidation-4 ＂-Biao-methylamino avermectin B described in 717 ₁) be the mixture of 4 ＂-deoxidation-4 ＂-Biao-methylamino avermectin B1a and two homologues of 4 ＂-deoxidation-4 ＂-Biao-methylamino avermectin B1b.Preferably, use the salt because of the spit of fland of going out.The limiting examples that can be used for the salt because of the spit of fland of going out of half invention comprises the U.S. patent No. 5,288, salt described in 710, derivative salt such as the phenylformic acid by phenylformic acid, replacement, Phenylsulfonic acid, citric acid, phosphoric acid, tartrate, toxilic acid.Most preferably, for of the present invention because of the spit of fland salt that goes out be because of the spit of fland benzoate that goes out.

The chemical name of Eprinomectin is 4 ＂-Biao-acetylaminohydroxyphenylarsonic acid, 4 ＂-deoxidation-avermectin B ₁.Especially develop for the domestic animal of all kinds and the Eprinomectin of all age groups.It is first show in antibody and vermin broad spectrum activity and in meat and milk residual minimum avermectin.When medicine is passed in part, its another advantage is that effect is high.

The present composition optionally comprises the combination of one or more following parasiticide compounds.

U.S. public announcement of a patent application number: described parasiticide compound imidazo [1,2-b] pyridazine in 2005/0182059, the document is incorporated herein by reference.U.S. public announcement of a patent application number: the compound of parasiticide described in 2005/0182139 1-(4-mono-and dihalo-methylsulfonyl phenyl)-2-acyl amino-3-fluorine propyl alcohol, the document is incorporated herein by reference.U.S. public announcement of a patent application number: the parasiticide compound of the trifluoro-methylsulfonyl aniline of N-described in 2006/0063841 oxime ether derivatives, the document is incorporated herein by reference.U.S. public announcement of a patent application number: the compound of parasiticide described in 2006/0128779 phenyl-3-(1H-pyrroles-2-yl) vinyl cyanide, the document is incorporated herein by reference.The U.S. patent application serial number 11/448 that on June 7th, 2006 submits to, the compound N of parasiticide described in 421-[(phenoxy group) phenyl]-1,1,1-fluoroform sulphonamide and N-[(phenyl sulfanyl) phenyl]-1,1,1-fluoroform sulfone amide derivative, the document is incorporated herein by reference.Parasiticide compound N-phenyl-1 described in the U.S. patent provisional application sequence number 60/790,893 of submitting on April 10th, 2006,1,1-fluoroform sulphonamide hydrazone, the document is incorporated herein by reference.

The compounds of this invention also can with flukicide coupling.Suitable flukicide comprises for example triclabendazole, fenbendazole, albendazole, clorsulon and oxibendazole.Can recognize, above combination also can comprise the combination of microbiotic, parasiticide and anti-fluke active compound.

Except above combination, also consider to provide described the inventive method and compound and other animal health-care product herein for example trace element, antiphlogistic drug, anti-infective, hormone, comprise the skin preparation of sanitas and sterilizing agent and for for example combination of vaccine and antitoxic serum of prophylactic immunity biological agent.

For example, this type of anti-infectives comprises one or more microbiotic, optionally gives together, for example, by compound and/or the dosage form that separates during with the treatment of the compounds of this invention or method.The known technology microbiotic that is applicable to this object comprises those microbiotic of for example above enumerating.

In addition, also consider that the inventive method and compound are preferably in same composition or different compositions, combine with such as trace element, VITAMIN, antiphlogistic drug, anti-infective etc. of known technology animal health-care product, simultaneously or sequential use.

Suitable antiphlogistic drug comprises for example steroidal and non-steroid antiinflammatory drug.Comprise that its wherein applicable racemic mixture or the non-steroid antiinflammatory drug of single enantiomer can comprise Ibuprofen BP/EP, flurbiprofen, Ketoprofen, aclofenac, diclofenac, aloxiprin, celecoxib, acetylsalicylic acid, diflunisal, fenoprofen, indomethacin, mefenamic acid, Naproxen Base, Phenylbutazone, piroxicam, salicylic amide, Whitfield's ointment, sulindac, deoxidation sulindac (desoxysulindac), tenoxicam, U-26225A, ketorolac, flufenisal, salsalate, triethanolamine salicylate, pyramidon, quinizine, Tacote, Azapropazone, Scha 306, Flufenamic Acid, clonixeril, Sch-10304, meclofenamic acid, fluorine Buddhist nun willow, colchicine, NSC-3096, other purine, oxypurine, benzydamine hydrochloride, dimefadane, Indoxole, intrazole, hydrochloric acid rice nurse wood, hydrochloric acid Renytoline (paranylene), Trometamol, hydrochloric acid benzyl indoles woods, R.D. 17345, ibufenac, Naproxol, fenbufen, Viophan, diflumidone sodium, fenamole, flutiazin, Metazimid, letimde hydrochloride, Nexeridine Hydrochloride, octazamide, molinazole, Tolysin, nimazole, citric acid Pu Luosha azoles, tesicam, tesimide, tolmetin and triflumidate.

In specific embodiment, the compounds of this invention and the coupling of fluorine Buddhist nun willow, [referring to for example U.S. patent No. 6,790,867B2, this patent by reference integral body is attached to herein].In relevant embodiment, the invention provides the medicinal compositions containing the compounds of this invention and fluorine Buddhist nun willow.

Steroidal antiphlogistic drug for example comprises for example dexamethasone of glucocorticoid medicine, cortisone, hydrocortisone, prednisone, beclometasone (beclomethasone), Betamethasone Valerate, flunisolide, meprednisone, paramethasone, prednisolone, bent An Songlong (triamcinolome), Modrasone, amcinonide, clobetasol, fluohydrocortisone, diflurosone diacetate, fluocinolone acetonide, FML, flurrenolone, halcinonide, Zpoflogin, Mometasone and pharmacy acceptable salt thereof and mixture.

Packing

If needed, can provide composition by packing or the dispenser device kit that for example FDA ratifies, this kit can contain one or more unit dosage forms, and this unit dosage form is containing activeconstituents.This packing can contain for example metal or for example Blister Package of plastic foil.Packing or dispenser device can attach administration specification sheets.Packing or divider can attach the notice relevant with container of government organs' true-to-shape of management pharmaceutical production, use or sale, the composition forms that this notice Shi Gai mechanism ratifies or give human or animal's reaction.This notice can be for example the prescription drugs label of U.S. food and drugs administration approved or the product inset of approval.Also can prepare containing the composition that is formulated in the compounds of this invention in compatibe drug carrier, be placed in suitable container, stick the label of treated indication.In optional embodiment, packing pack contains glass or Plastic Bottle or contains other container of a plurality of dosage.

Embodiment

Provide following examples to illustrate certain embodiments of the present invention, they should not be considered as them to limit the scope of the invention unintentionally by any way yet.

Embodiment 1-25

the preparation of florfenicol carbonic ether prodrug

Synthesizing of florfenicol carbonic ether prodrug and analogue thereof

Referring to Fig. 4, at 0 ℃, under nitrogen atmosphere, by raw alcohol A (0.68M, 1.78 molar equivalents) and the anhydrous tetrahydrofuran solution of triethylamine (0.68M, 1.78 molar equivalents) be added drop-wise in the anhydrous tetrahydrofuran solution of triphosgene (0.48M, 0.64 molar equivalent).The mixture obtaining is stirred 30 minutes at 0 ℃, then, by filter paper fast filtering, ammonium salt is removed.The filtrate of this chloro-formic ester solution B is for following carboxylation (carbonation) reaction, without being further purified.

By new system chloro-formic ester B solution or commercially available chloro-formic ester B (0.34M, 1.78 molar equivalents) anhydrous tetrahydrofuran solution is transferred in dropping funnel, at 0 ℃, under nitrogen atmosphere, 2/3 solution is added drop-wise to containing corresponding phenylpropyl alcohol C (0.64M, 1 molar equivalent, in the anhydrous tetrahydrofuran solution of 4-N.N-dimethyl aminopyridine (0.5 molar equivalent) and triethylamine (1.5 molar equivalent).Mixture is stirred 30 minutes at 0 ℃, by thin-layer chromatography, monitor reaction process.When showing to react incomplete by thin-layer chromatography, then add chloro-formic ester solution, reaction is proceeded until raw material disappears.Make the solution obtaining fast by filter paper filtering, ammonium salt is removed.Filtrate is concentrated, add ethyl acetate, crude product is dissolved.The solution obtaining is used to 1MHCl (aqueous solution), saturated NaHCO successively ₃(aqueous solution) and saturated NaCl (aqueous solution) washing, then by silica gel and Na ₂sO ₄pad fast filtering.Filtrate is concentrated, and the crude product obtaining dodges column chromatography or recrystallization (solvent of listing with table 5) purifying through silica gel, obtains pure carbonic ether prodrug D.By above method, obtain the compound of following examples numbering:

Table 2

Embodiment 1

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl methyl

Making crude product recrystallization in methanol/water, obtain title product, is white solid, yield 93%;

H ¹-NMR(DMSO-d6)，δ＝3.2ppm(s，3H)，3.70ppm(s，3H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 438.0 (M+Na).

Embodiment 2

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester ethyl ester

By florfenicol (250g, 0.7mol), the 1.2L tetrahydrofuran solution of 4-dimethylaminopyridine (42g, 0.35mol), triethylamine (130ml, 0.91mol) stirs at 0-5 ℃, with feed hopper, drip pure Vinyl chloroformate (80mL, 0.83mol) simultaneously.By triethylamine hydrochloride, precipitating proved response carries out.Mixture is at room temperature stirred 30 minutes, by filtering, salt is removed from mixture.Filtrate is concentrated, add 600mL ethyl acetate, solution is used to 1MHCl (2 * 200mL), saturated NaCl (200mL) washing successively, pass through Na ₂sO ₄/ layer of silica gel is filtered.Filtrate is concentrated, make the crystallization in 450mL Virahol of thick oily matter, obtain pure title product (286g).

m.p.110-112℃；H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(t，3H)，3.2ppm(s，3H)，4.1ppm(q，2H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.2ppm(d，1H)；

Mass spectrum 452.0 (M+Na).

Embodiment 3

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester propyl ester

Making crude product crystallization in Virahol, obtain title product, is white solid, yield 91%.

H ¹-NMR(DMSO-d ₆)，δ＝0.85ppm(t，3H)，1.58ppm(hex，2H)，3.2ppm(s，3H)，4.1ppm(t，2H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.2ppm(d，1H)；

Mass spectrum 466.0 (M+Na).

Embodiment 4

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester isopropyl ester

Making crude product crystallization in Virahol, obtain title product, is white solid, yield 92%.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(2d，6H)，3.2ppm(s，3H)，4.3-4.7ppm(m，3H)，4.75ppm(hep，1H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.0ppm(d，1H)；

Mass spectrum 466.0 (M+Na).

Embodiment 5

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester isobutyl ester

Making crude product crystallization in Virahol/ethanol, obtain title product, is white solid, yield 92%.

H ¹-NMR(DMSO-d ₆)，δ＝0.85ppm(d，6H)，1.85ppm(hep，1H)，3.2ppm(s，3H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 480.0 (M+Na).

Embodiment 6

The fluoro-1-of plutonium carbonate propyl group methyl esters (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester

Crude product is by purification by silica gel column chromatography, and then crystallization in ethyl acetate/hexane, obtains title product, is white solid, yield 72%.

H ¹-NMR(DMSO-d ₆)，δ＝0.25ppm(dd，2H)，0.55ppm(dd，2H)，1.05(m，1H)，3.2ppm(s，3H)，3.9ppm(d，2H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 477.9 (M+Na).

Embodiment 7

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 3-methyl but-2-ene ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white foam shape thing, yield 80%.

H ¹-NMR(DMSO-d ₆)，δ＝1.65ppm(s，3H)，1.70ppm(s，3H)，3.2ppm(s，3H)，4.25-4.7ppm(m，5H)，5.25ppm(t，1H)，5.9ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 491.8 (M+Na).

Embodiment 8

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester isopentyl ester

Making crude product recrystallization in ethyl acetate/hexane, obtain title product, is white solid, yield 85%.

H ¹-NMR(DMSO-d ₆)，δ＝0.85ppm(d，6H)，1.45ppm(m，2H)，1.60ppm(hep，1H)，3.2ppm(s，3H)，4.10ppm(m，2H)，4.3-4.7ppm(m，3H)，5.9ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 494.1 (M+Na).

Embodiment 9

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester penta-3-base ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white solid, yield 73%.

H ¹-NMR(DMSO-d ₆)，δ＝0.8ppm(dt，6H)，1.5ppm(m，4H)，3.2ppm(s，3H)，4.3-4.7ppm(m，4H)，5.95ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 493.9 (M+Na).

Embodiment 10

The fluoro-1-of plutonium carbonate polyhexamethylene (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester

Crude product, through purification by silica gel column chromatography, obtains title product, is white solid, yield 75%.

H ¹-NMR(DMSO-d ₆)，δ＝1.1-1.9ppm(m，10H)，3.2ppm(s，3H)，4.3-4.65ppm(m，4H)，5.95ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 505.0 (M+Na).

Embodiment 11

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 2-methoxyl group ethyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 78%.

H ¹-NMR(DMSO-d ₆)，δ＝3.15ppm(s，3H)，3.25ppm(s，3H)，3.5ppm(m，2H)，4.2ppm(m，2H)，4.3-4.7ppm(m，3H)，5.95ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 481.9 (M+Na).

Embodiment 12

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 2-ethoxy ethyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 33%.

H ¹-NMR(DMSO-d ₆)，δ＝1.05ppm(t，3H)，3.15ppm(s，3H)，3.4ppm(q，2H)，3.55ppm(m，2H)，4.2ppm(m，2H)，4.3-4.7ppm(m，3H)，5.95ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 496.0 (M+Na).

Embodiment 13

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 2-butoxyethyl

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 93%.

H ¹-NMR(DMSO-d ₆)，δ＝0.85ppm(t，3H)，1.25ppm(m，2H)，1.45ppm(m，2H)，3.15ppm(s，3H)，3.35ppm(t，2H)，3.55ppm(m，2H)，4.2ppm(m，2H)，4.3-4.7ppm(m，3H)，5.95ppm(d，1H)，6.45ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 524.0 (M+Na).

Embodiment 14

The fluoro-1-of carbon acid benzyl ester (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester

Making crude product crystallization in Virahol/ethanol, obtain title product, is white solid, yield 88%.

H ¹-NMR(DMSO-d ₆)，δ＝3.2ppm(s，3H)，4.3-4.7ppm(m，3H)，5.15ppm(s，2H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.38ppm(s，5H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 514.0 (M+Na).

Embodiment 15

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 4-methyl benzyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white foam shape thing, yield 73%.

H ¹-NMR(DMSO-d ₆)，δ＝2.3ppm(s，3H)，3.2ppm(s，3H)，4.3-4.7ppm(m，3H)，5.07ppm(s，2H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.15ppm(d，2H)，7.25ppm(d，2H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 528.0 (M+Na).

Embodiment 16

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 4-methoxy benzyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 41%.

H ¹-NMR(DMSO-d ₆)，δ＝3.2ppm(s，3H)，3.75ppm(s，3H)，4.3-4.7ppm(m，3H)，5.05ppm(s，2H)，5.9ppm(d，1H)，6.4ppm(s，1H)，6.9ppm(d，2H)，7.25ppm(d，2H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 543.9 (M+Na).

Embodiment 17

(S) the fluoro-1-of-2-(1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propoxy-) ketonic oxygen base) ethyl propionate

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 71%.

H ¹-NMR(DMSO-d ₆)，δ＝1.15ppm(t，3H)，1.4ppm(d，3H)，3.2ppm(s，3H)，4.15ppm(q，2H)，4.3-4.7ppm(m，3H)，4.95ppm(q，1H)，5.98ppm(d，1H)，6.42ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，9.05ppm(d，1H)；

Mass spectrum 523.9 (M+Na).

Embodiment 18

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester dodecyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 35%.

H ¹-NMR(CDCl ₃)，δ＝0.9ppm(t，3H)，1.2-1.4ppm(m，18H)，1.65-1.75(m，2H)，3.1ppm(s，3H)，4.1-4.6ppm(m，5H)，5.95ppm(s，1H)，6.05ppm(d，1H)，6.95ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 19

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester stearyl

Crude product, by purification by silica gel column chromatography, obtains title product, is white solid, yield 42%.

H ¹-NMR(CDCl ₃)，δ＝0.9ppm(t，3H)，1.2-1.4ppm(m，30H)，1.65-1.75(m，2H)，3.05ppm(s，3H)，4.1-4.6ppm(m，5H)，5.9ppm(s，1H)，6.02ppm(d，1H)，6.98ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 20

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester-(3R, S)-3,7-dimethyl oct-6-ene ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white solid, yield 30%.Shown in structure illustrate that this material is isomer mixture.

H ¹-NMR(CDCl ₃)，δ＝0.9ppm(d，3H)，1.1-2.0ppm(m，13H)，3.05ppm(s，3H)，4.1-4.6ppm(m，5H)，5.05ppm(t，1H)，5.9ppm(s，1H)，6.0ppm(d，1H)，7.0ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 21

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 2-(2-methoxy ethoxy) ethyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white solid.

H ¹-NMR(CDCl ₃)，δ＝3.05ppm(s，3H)，3.38ppm(s，3H)，3.55-3.65ppm(m，6H)，4.25-4.6ppm(m，5H)，5.9ppm(s，1H)，6.0ppm(d，1H)，7.05ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 22

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester monooctyl ester

Crude product, by purification by silica gel column chromatography, obtains the product of needs, obtains title product, is white solid, yield 44%.

H ¹-NMR(CDCl ₃)，δ＝0.9ppm(t，3H)，1.2-1.4ppm(m，12H)，1.65-1.75(m，2H)，3.05ppm(s，3H)，4.1-4.6ppm(m，5H)，5.9ppm(s，1H)，6.0ppm(d，1H)，6.9ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 23

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl ester 2-(2-(2-methoxy ethoxy) oxyethyl group) ethyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white semi-solid material, yield 31%.

H ¹-NMR(CDCl ₃)，δ＝3.05ppm(s，3H)，3.38ppm(s，3H)，3.55-3.7ppm(m，10H)，4.2-4.6ppm(m，5H)，5.95ppm(m，2H)，7.25ppm(d，1H)，7.6ppm(d，2H)，7.95ppm(d，2H).

Embodiment 24

Carbonic acid (1R, 2S)-1-(4-(6-cyanopyridine-3-yl) phenyl)-2-(2,2-dichloro acetamino)-3-fluorine propyl ester ethyl ester

Crude product, by purification by silica gel column chromatography, obtains title product, is white foam shape thing, yield 97%.

H ¹-NMR(DMSO-d ₆)，δ＝1.19ppm(t，3H)，4.1ppm(q，2H)，4.25-4.6ppm(m，3H)，5.05ppm(s，2H)，5.9ppm(d，1H)，6.2ppm(t，1H)，7.5ppm(d，2H)，7.85ppm(d，2H)，8.1ppm(d，1H)，8.35ppm(d，1H)，9.1ppm(s，1H)，9.3ppm(d，1H).

Embodiment 25

The fluoro-1-of carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-methyl fluoride alkylsulfonyl) phenyl) propyl ester ethyl ester

Crude product, by purification by silica gel column chromatography, obtains the title product of quantitative yield, is white foam shape thing.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(t，3H)，4.1ppm(q，2H)，4.3-4.7ppm(m，3H)，5.7ppm(d，2H)，5.95ppm(d，1H)，6.4ppm(s，1H)，7.85ppm(d，2H)，7.95ppm(d，2H)，9.05ppm(d，1H).

Embodiment 26

by react synthetic florfenicol prodrug and analogue thereof with the bischloroformates of glycol

Referring to Fig. 5, by bischloroformates E (1 molar equivalent, anhydrous tetrahydrofuran solution 0.34M) is put into dropping funnel, at 0 ℃, under nitrogen atmosphere, be added drop-wise to containing substrate C (2.2 molar equivalents, 0.64M), in the anhydrous tetrahydrofuran solution of DMAP (0.5 molar equivalent) and triethylamine (2.2 molar equivalent).Mixture is stirred 30 minutes at 0 ℃, then at room temperature spend the night.The solution obtaining, by filter paper fast filtering, is removed ammonium salt.Filtrate is concentrated, add ethyl acetate, crude product is dissolved.The solution obtaining is used to 1MHCl (aqueous solution), saturated NaHCO successively ₃(aqueous solution) and saturated NaCl (aqueous solution) washing, then by silica gel and Na ₂sO ₄pad fast filtering.Filtrate is concentrated, and the crude product obtaining dodges column chromatography purification by silica gel, obtains pure carbonic ether prodrug F.

By above method, obtain following compound:

Embodiment 26

Two carbonic acid two (the fluoro-1-of (1R, 2S)-2-(2,2-dichloro acetamino)-3-(4-(methyl sulphonyl) phenyl) propyl group) second-1,2-bis-base esters

Crude product, by purification by silica gel column chromatography, obtains title product, is white semisolid, yield 62%.

H ¹-NMR (DMSO-d ₆), δ=3.2ppm (s, 6H), 4.3-4.7ppm (m, 10H), 5.95ppm (d, 2H), 6.42ppm (s, 2H), 7.6ppm (d, 4H), 7.9ppm (d, 4H), 9.05ppm (d, 2H); Mass spectrum 852.9 (M+Na).

Embodiment 27-30

synthesizing of the benzyl carbonic ether prodrug (H and I) of chloramphenicol-type phenylpropyl alcohol

Referring to Fig. 6, use following methods.

Method I

By Vinyl chloroformate B (2.2 molar equivalents, anhydrous tetrahydrofuran solution 0.34M) is put into dropping funnel, at 0 ℃, under nitrogen atmosphere, be added drop-wise to containing substrate G (1 molar equivalent, 0.64M), in the anhydrous tetrahydrofuran solution of DMAP (0.5 molar equivalent) and triethylamine (2.4 molar equivalent).Mixture is stirred 30 minutes at 0 ℃, then at room temperature spend the night.The solution obtaining, by filter paper fast filtering, is removed ammonium salt.Filtrate is concentrated, add ethyl acetate, crude product is dissolved.The solution obtaining is used to 1M HCl (aqueous solution), saturated NaHCO successively ₃(aqueous solution) and saturated NaCl (aqueous solution) washing, then by silica gel and Na ₂sO ₄pad fast filtering.Filtrate is concentrated, by the product drying under reduced pressure obtaining, obtain pure carbonic ether prodrug H.

Method II

By Vinyl chloroformate B (1 molar equivalent, anhydrous tetrahydrofuran solution 0.34M) is put into dropping funnel, at 0 ℃, under nitrogen atmosphere, be added drop-wise to containing substrate G (1 molar equivalent, 0.64M), in the anhydrous tetrahydrofuran solution of DMAP (0.5 molar equivalent) and triethylamine (2.4 molar equivalent).Mixture is stirred 30 minutes at 0 ℃, then at room temperature spend the night.The solution obtaining, by filter paper fast filtering, is removed ammonium salt.Filtrate is concentrated, add ethyl acetate, crude product is dissolved.The solution obtaining is used to 1M HCl (aqueous solution), saturated NaHCO successively ₃(aqueous solution) and saturated NaCl (aqueous solution) washing, then by silica gel and Na ₂sO ₄pad fast filtering.Filtrate is concentrated, and the crude product obtaining dodges column chromatography purification by silica gel, obtains pure carbonic ether prodrug H and I.

By above method, obtain following examples compound:

Embodiment numbers compound name

27 2 carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-1-(4-nitrophenyl) the third-1,3-bis-base ester diethyl esters

28 carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-3-hydroxyl-1-(4-nitrophenyl) propyl ester ethyl ester

29 2 carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-1-(4-(methyl sulphonyl) phenyl) the third-1,3-bis-base ester diethyl esters

30 carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-3-hydroxyl-1-(4-(methyl sulphonyl) phenyl) propyl ester ethyl ester

Embodiment 27

Two carbonic acid (1R, 2S)-2-(2,2-dichloro acetamino)-1-(4-nitrophenyl) the third-1,3-bis-base ester diethyl esters

By above method I, obtaining product, obtain title product, is white foam shape thing, yield 88%.Also can obtain product by method II, obtain title product, be white foam shape thing, yield 25%.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(m，6H)，4.05-4.25ppm(m，6H)，4.5ppm(m，1H)，5.95ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，8.2ppm(d，2H)，8.95ppm(d，1H).

Embodiment 28

Carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-3-hydroxyl-1-(4-nitrophenyl) propyl ester ethyl ester

By above method II, obtaining product, obtain title product, is white foam shape thing, yield 19%.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(t，3H)，3.35ppm(m，1H)，3.45ppm(m，1H)，4.0-4.2ppm(m，3H)，5.19ppm(t，1H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，8.2ppm(d，2H)，8.75ppm(d，1H).

Embodiment 29

Two carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-1-(4-(methyl sulphonyl) phenyl) the third-1,3-bis-base ester diethyl esters

By above method II, obtaining crude product, obtain title product, is white foam shape thing, yield 19%.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(m，6H)，3.19ppm(s，3H)，4.05-4.25ppm(m，6H)，4.45ppm(m，1H)，5.9ppm(d，1H)，6.4ppm(s，1H)，7.6ppm(d，2H)，7.9ppm(d，2H)，8.95ppm(d，1H).

Embodiment 30

Carbonic acid (1R, 2R)-2-(2,2-dichloro acetamino)-3-hydroxyl-1-(4-(methyl sulphonyl) phenyl) propyl ester ethyl ester

By above method II, obtaining crude product, obtain title product, is white foam shape thing, yield 20%.

H ¹-NMR(DMSO-d ₆)，δ＝1.2ppm(t，3H)，3.2ppm(s，3H)，3.35ppm(m，1H)，3.45ppm(m，1H)，4.0-4.2ppm(m，3H)，5.19ppm(t，1H)，5.85ppm(d，1H)，6.42ppm(s，1H)，7.58ppm(d，2H)，7.9ppm(d，2H)，8.75ppm(d，1H).

Embodiment 31-35

The practical assessment of florfenicol benzyl carbonic ether prodrug

Embodiment 31

the viscosity of composition

Following table 4 provides the evaluation of the florfenicol benzyl carbonic ether prodrug of the selection that concentration is equivalent to 300mg/ml florfenicol (30% weight/volume) to the shot capacity of drug solns.

Table 4

^aconcentration corresponding to the benzyl carbonic ether prodrug of the florfenicol of 35% (weight/volume) concentration

^bthe solution of preparing with the solution of every milliliter of 300mg florfenicol, 250mg METHYLPYRROLIDONE, 150mg propylene glycol and appropriate Liquid Macrogol

^cby following drop syringe method evaluation.

Discuss

Give for convenience the microbiotic of the requirement of necessary amounts, phenylpropyl alcohol or be included in the concentration of the phenylpropyl alcohol medicine in phenylpropyl alcohol prodrug conventionally must be high.Because phenylpropyl alcohol alcohols is limited in the solubleness of the acceptable many organic solvents of injection formulations or solvent mixture, therefore be restricted for preparing the selectable solvent of florfenicol solution of high density.Therefore, the high density phenylpropyl alcohol drug solution that is dissolved in organic solvent or the solvent mixture very thickness that can become, is difficult to by syringe administration.Therefore, phenylpropyl alcohol benzyl carbonic ether prodrug is the more acceptable organic solvent of injection or the dissolving power in solvent mixture of wide region provide potentiality for preparing the highly concentrated solution of low viscosity injection liquid.Table 4 shows the contrast of shot capacity of the florfenicol benzyl carbonic ether prodrug strong solution of the mixture examples be dissolved in organic solvent, and these solvent mixtures are normally subcutaneous or intramuscularly administration is acceptable.Preparation is containing being equivalent to

the florfenicol benzyl carbonic ether test soln of the florfenicol concentration (mg/mL) of formulation concentrations.By the shot capacity of " making syringe drop " method evaluation solution, wherein, under free gravity flow condition, at 15 ℃, measure the drop time (second) of isopyknic this type of solution being flowed out by the syringe of vertically placing.Extract out after the expansion link of 5ml polyethylene disposable syringe (5ml Luer, N om-Ject Zentrish/Henke Saas WolfGMBH), to syringe install disposable aspiration needle (

16G1 PrecisionGlide/BentonDickinson & CO), from top, by testing liquid inhalation syringe, by triplicate, record 2mL (scale between 3ml and 1ml) the essential time of solution unrestricted flow.That by use, measures is commercially available

the drop time of formulation samples (input number 13) is except the drop time of testing liquid (input 1-12), calculating with respect to shot capacity.As result in table 4 proves, the relative shot capacity <1.00 having containing the shot capacity of the testing liquid of phenylcarbinol viscosity thinner, is therefore better than (propylene glycol/Liquid Macrogol of 30% weight/volume florfenicol/2-methyl-2-pyrrolidone solution).Due to they good shot capacities, these solution represent the more favourable preparation of injected delivery florfenicol.Triactin/2-Pyrrolidone-1/1 solution that does not contain phenylcarbinol viscosity thinner of embodiment 2 florfenicol benzyl carbonic ethers is unique shot capacity ratios

the solution of the difference of (input number 5).Containing concentration higher than (input numbers 2; 35%w/v is to 30%w/v) the embodiment 2 florfenicol benzyl carbonate solutions of florfenicol also show more excellent shot capacity.Meaningfully, containing the solution that is equivalent to the free florfenicol of 30%w/v mixed form and the florfenicol solution of florfenicol benzyl carbonic ether prodrug (input 11-12), also show and be better than

the shot capacity of preparation.

Embodiment 32

fusing point and water solubility contrast

The physicochemical property of the improvement that can be obtained by the benzyl carbonic ether prodrug (phenylpropyl alcohol analogue) of phenylpropyl alcohol alcohols carbonic ether prodrug or phenylpropyl alcohol alcohols are very important for the ability of the organic solvent based formulation that gives animal that obtains needing.With respect to parent phenylpropyl alcohol alcohols, the high-dissolvability of phenylpropyl alcohol benzyl carbonic ether prodrug in some organic solvent or ORGANIC SOLVENT MIXTURES is in part because the fusing point of this type of carbonic ether prodrug is low with respect to parent drug.The lattice energy of the carbonic ether prodrug that these low melting point reflections reduce, this energy is the reason of the solubleness of increase.In each embodiment of florfenicol prodrug, the contrast of the florfenicol fusing point of available crystalline form sees the following form 5.

In some treatment application, with the subcutaneous florfenicol that gives of dense organic solution, wherein form that to cause the medicament slow release of needs be known to the location drug depot in circulating.In this type of situation, the solubleness representative of florfenicol in aqueous medium determines one of important factor of slow release speed.Impact is to the concentration of drug solns and the solvent compositions of preparation by another important factor of subcutaneous reservoir position slowly-releasing florfenicol.Except can be used for the more wide region solvent of acceptable florfenicol benzyl carbonic ether prodrug formulation, these prodrugs also allow the water-soluble of wide region.The water solubility of the multiple florfenicol benzyl carbonic ether prodrug of measuring is in Table 5.The solubility range of these prodrugs is slightly lower than the extremely remarkable solubleness lower than florfenicol.The water solubility of the minimizing of this type of prodrug is used in subcutaneous reservoir position and controls the dissolution rate of prodrug and can make parent drug realize best slowly-releasing.

Table 5

^a-non-crystallizable; By after the solvent evaporation in column chromatography flow point, if obtain solid matter, measure fusing point.

Embodiment 33

the contrast of solubleness in organic solvent (triactin/phenylcarbinol 2:1 mixture)

The solubleness of following table 6 explanation florfenicol equivalents, this solubleness is with the benzyl carbonic ether florfenicol prodrug of selection, to obtain in as embodiment solvent mixture triactin/phenylcarbinol 2:1 (volume/volume) of low viscosity composition with phenylcarbinol.With benzyl carbonic ether florfenicol prodrug, obtain the concentration that is equal to or greater than 30% (weight/volume) needing.Florfenicol parent drug is insoluble to triactin/phenylcarbinol 2:1 (volume/volume), and concentration is even low to moderate 10% (weight/volume).Meaningfully, when the benzyl carbonic ether prodrug of florfenicol also exists, florfenicol becomes more easily molten in triactin/phenylcarbinol 2:1 (volume/volume).The combination of embodiment 14 prodrugs of 275mg/ml and the florfenicol of 100mg/ml is dissolved in triactin/phenylcarbinol 2:1 (volume/volume), and the content that obtains florfenicol is the stabilizing solution of 30% (weight/volume) (upper table 4, input number 12).

Table 6

Embodiment 34

benzyl carbonic ether prodrug in vitro enzymatic discharges parent florfenicol

As the prodrug derivant of the parent drug molecule in free parent drug source in vivo the ability of useful effect determine the treatment effectiveness of specific prodrug.Can be by giving to measure after animal prodrug the whole body level of parent drug, determine that under the existence of endogenous enzyme prodrug discharges the ability of parent drug in vivo.Can discharge by measuring parent drug after mixing with animal's whole blood, blood plasma or serum, evaluate this vitro release.After mixing with bovine serum in vitro, the florfenicol that detects the benzyl carbonic ether prodrug of the florfenicol of selecting discharges.As shown in table 7 below, test compound demonstrates favourable parent drug release characteristics.It is maximum that embodiment 8 and 14 compounds demonstrate the release rate of florfenicol in serum.The stronger common trend of close ester that occurs the florfenicol carbonic ether of higher degraded and release rate seems all to exist in the compound of participating in test.Find that a significant exception is embodiment 26 (two-florfenicol carbonic ether).

Table 7

^abQL-is lower than quantitative limit

50 microlitre carbonic ether prodrug stock solutions (the DMSO solution of 10mg/mL) are added to 5mL donor bovine serum, mix.By 400 microliter aliquot, the solution obtaining is transferred in 1.5mL plastic centrifuge tube.Each plastics tubing is put into 37 ℃ of water-baths, incubation.At 0,1,2,4,8 and 24 hour, take out sample, add after 400 microlitre acetonitriles reaction terminating, rapid stirring 30 seconds.By pressing 14000rpm centrifugal 5 minutes on Eppendorf5415G, precipitation is removed.From clarified supernatant, sample, carry out HPLC analysis.Transformation efficiency with the calculated by peak area prodrug of florfenicol.

HPLC condition is as follows:

System: Agilent 1100 series

Post: Varian Microsorb-5 μ, C18,150mm * 2.1mm

Column temperature: 30 ℃

Flow velocity: 0.5mL/min

Sampling volume: 40 μ l

Organic solution: acetonitrile

The aqueous solution: 0.1% first aqueous acid

Working time: 20min

Gradient is as follows:

time (mm)organic solution %

0 5

15 40

17 40

18 5

After processing with seroenzyme in vitro, the benzyl carbonic ether of the experiment results proved florfenicol of the stability of the prodrug of the selection providing in table 7 in bovine serum discharges parent drug.It is the evidence that is present in the substrate of the lytic enzyme in bovine serum that these results provide the benzyl carbonic ether of florfenicol.

Embodiment 35

benzyl carbonic ether prodrug discharges parent florfenicol in vivo

Give after prodrug, measure as follows the interior pharmacokinetic properties of body of living antibiotics:

1. with two kinds of different animals, confirm interior release of body of living antibiotics:

By intravenously (＂ IV ＂) approach, give rat and ox patient embodiment 18 front drug compounds, then measure the florfenicol concentration in the blood plasma gathering in time.

Following table 8 data declaration IV give after rat and the front drug compound of ox embodiment 18, the florfenicol blood plasma level obtaining.

Table 8

The embodiment numbering of compound	Animal kind	Dosage (mg/kg)	Approach	AUC (hr·mg/L)	Cmax (mg/L)
						18	Rat (n=3)	20	IV	26.4±16.8	6.2±3.8
18	Ox (n=3)	10	IV	20.2±2.8	0.6±0.1

2. by different approaches, give after prodrug the living antibiotics being discharged by prodrug:

Following table 9 data declarations are the blood plasma level that IV and subcutaneous (＂ SC ＂) give the florfenicol that obtains after the front drug compound of embodiment 2 by two kinds of different approaches.

Table 9

The embodiment numbering of compound	Animal kind	Dosage (mg/kg)	Approach	AUC (hr·mg/L)	Cmax (mg/L)
						2	Ox (n=3)	9	IV	18±1.7	3.6±0.8
2	Ox (n=3)	18	SC	42.6±13.7	1.6±0.8

3. the dose-dependently that active part discharges increases

Following table 10 digital proofs give after the front drug compound of embodiment 2 of ascending-dose, and the blood plasma level of living antibiotics (florfenicol) according to dosage dependency increases.

Table 10

The embodiment numbering of compound	Animal kind	Dosage (mg/kg)	Approach	AUC (hr·mg/L)	Cmax (mg/L)
						2	Ox (n=3)	18	SC	42.6±13.7	1.6±0.8
2	Ox (n=5)	42	SC	152.6±77	2.7±1.3

4. time of releasing of active part:

A. following table 11 and 12 digital proof give after the front drug compound of different animal species embodiment 2, the living antibiotics discharging within less than half an hour (florfenicol).

Table 11

By IV approach, by 20mg/kg, give rat

Table 12

By IV approach, by 9mg/kg, give ox

B. following table 13 and 14 digital proof are when giving after ox by IV and SC approach, and the front drug compound of embodiment 2 discharges rapidly living antibiotics.

Table 13

By SC approach, by 48mg/kg, give ox

Table 14

By IV approach, by 9mg/kg, give ox

5. the effect of preparation:

The advantage of triactin/phenylcarbinol preparation of phenylpropyl alcohol carbonic ether prodrug

By giving triactin/phenylcarbinol (2:1 weight/volume ratio) preparation and giving triactin/2-Pyrrolidone (2:1 weight/volume ratio) preparation, the release dynamics of comparing embodiment 2 compounds.With ox (n=3), study.

Press 20mg/kg dosage, with triactin/2-Pyrrolidone, the average A UC value that SC gives after embodiment 2 compounds is 42.6hrmg/L.

Press 40mg/kg dosage, with triactin/phenylcarbinol, the average A UC value that SC gives after embodiment 2 compounds is 152.1hrmg/L.

Because the dosage for two researchs is different, so calculate the normalized value of dosage, the value of triactin/2-Pyrrolidone and triactin/phenylcarbinol is respectively 2.13hr/L (42.6/20) and 3.8hr/L (152.1/40).

6. subcutaneous giving after embodiment 2 benzyl carbonic ether prodrugs, the bioavailability of florfenicol in ox

Calculate the pharmacokinetic data of embodiment 2 compounds:

The overall average AUC=152.11hrmg/L of active part (florfenicol)

The overall average AUC=38.04 of embodiment 2 compounds, it equals again 30.43hrmg/L florfenicol equivalent

Once absorb from SC position, 83.5%MC-9148 is converted into florfenicol.

the effect research of embodiment 2 compounds

SC suffers from after the ox of abiogenous ox respiratory disease (BRD), by single dose (Schering-Plough Animal Health) contrasts with the curative effect of the embodiment 2 front drug compounds of single dose.Result is as follows:

Table 15

^*300mg/ml florfenicol

^*be equivalent to 40mg/kg florfenicol

^{* *}brine treatment zooscopy interrupted at the 3rd day, because disease symptoms is without improvement.

In a word, observe the florfenicol that embodiment 2 prodrugs discharge effect can with the florfenicol of market brand

) compare.

Conclusion

Therefore can recognize, the invention provides the using method that new fenicol antibiotics prodrug is treated in animal or human with them or pre-bacteriological protection infects.

Although set forth the present invention by some embodiment and embodiment, do not departing under the prerequisite of the scope of the invention, can to shown in embodiment and embodiment change and will be apparent to those skilled in the art.

Claims (61)

1. a formula I phenylpropyl alcohol carbonic ether or its solvate:

Formula I

R wherein ₁be selected from:

with

R ₂be selected from dichloromethyl, difluoromethyl, chlorine methyl fluoride, chloro methyl and methyl,

R ₃be selected from methylol, fluoro methyl, difluoromethyl, trifluoromethyl and CH ₂o-C (O) O-R ₅,

R ₄and R ₅independently be selected from replacement or unsubstituted C _1-10straight chain, side chain or cyclic alkyl; That replace or unsubstituted C _1-10alkoxyalkyl; C _1-10aryl; C _1-10arylalkyl; That replace or unsubstituted C _1-10straight chain, side chain or cycloalkenyl group.

2. the phenylpropyl alcohol carbonic ether of claim 1, wherein works as R ₁for NO ₂time, R ₃be not CH ₂o-C (O) O-R ₅.

3. the phenylpropyl alcohol carbonic ether of claim 1, wherein R ₄and R ₅independently be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, dodecyl, Octadecane base, 2-methyl-butyl, 1-ethyl-propyl group, 3-methyl-propyl-2-thiazolinyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxyl group-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyl-octa-6-thiazolinyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, methyl-2-furyl, 2-(methoxyl group-oxyethyl group)-ethyl, 2-(oxyethyl group-oxyethyl group)-ethyl, 2-[2-(methoxyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-[2-(oxyethyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-(hydroxyl-oxyethyl group)-ethyl, 2-[2-(hydroxyl-oxyethyl group)-oxyethyl group]-ethyl, 2-acetoxyl group-ethyl, 2-(acetoxyl group-oxyethyl group)-ethyl, 3-acetoxyl group-propyl group, 2-carboxyl-ethyl, 3-carboxyl-propyl group, 4-carboxyl-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl group, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxy carbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-methyl-phenyl, 4-methoxyl group-phenyl, 4-carboxyl-phenyl, 2-carboxyl-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylaminohydroxyphenylarsonic acid phenyl.

4. the phenylpropyl alcohol carbonic ether of claim 3, wherein R ₄and R ₅independently being selected from following part replaces: methyl, methoxyl group, carboxyl, carbalkoxy and acyloxy.

5. the phenylpropyl alcohol carbonic ether of claim 3, wherein R ₁be selected from

with

R ₂for dichloromethyl or difluoromethyl, and R ₃be selected from methylol, fluoro methyl and CH ₂o-C (O) O-R ₅.

6. the phenylpropyl alcohol carbonic ether of claim 1, wherein R ₁for CH ₃sO ₂, R ₂for CHCl ₂, and R ₃for CH ₂f.

7. the florfenicol carbonic ether of claim 6, wherein R ₄be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, dodecyl, Octadecane base, 2-methyl-butyl, 1-ethyl-propyl group, 3-methyl-propyl-2-thiazolinyl, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxyl group-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyl-octa-6-thiazolinyl, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, methyl-2-furyl, 2-(methoxyl group-oxyethyl group)-ethyl, 2-(oxyethyl group-oxyethyl group)-ethyl, 2-[2-(methoxyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-[2-(oxyethyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-(hydroxyl-oxyethyl group)-ethyl, 2-[2-(hydroxyl-oxyethyl group)-oxyethyl group]-ethyl, 2-acetoxyl group-ethyl, 2-(acetoxyl group-oxyethyl group)-ethyl, 3-acetoxyl group-propyl group, 2-carboxyl-ethyl, 3-carboxyl-propyl group, 4-carboxyl-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl group, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxy carbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-methyl-phenyl, 4-methoxyl group-phenyl, 4-carboxyl-phenyl, 2-carboxyl-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylaminohydroxyphenylarsonic acid phenyl.

8. the phenylpropyl alcohol carbonic ether of claim 1, wherein R ₃for CH ₂f.

9. the phenylpropyl alcohol carbonic ether of claim 1, wherein R ₁for CH ₃sO ₂or NO ₂, R ₂for CHCl ₂, R ₃for OH, and R ₄for ethyl.

10. the phenylpropyl alcohol carbonic ether of claim 1, wherein R ₁for CH ₃sO ₂or NO ₂, R ₂for CHCl ₂, R ₃for

And R ₄for ethyl.

The phenylpropyl alcohol carbonic ether of 11. claims 1, described carbonic ether is selected from

with

The phenylpropyl alcohol carbonic ether of 12. claims 1, described carbonic ether is selected from the compound of enumerating in table 2.

13. 1 kinds of phenylpropyl alcohol carbonic ethers, described carbonic ether comprises formula II compound

Formula II

R wherein ₁be selected from

with

Wherein a, c and e are the independent integers in 0-4 numerical range,

B and d are the independent integers in 0-2 numerical range,

Condition is integer a, b, c, d and e's and in the numerical range of 2-8,

R ₅₁and R ₅₂independently be selected from H, methyl, hydroxyl, methoxyl group and acetoxyl group.

The compound of 14. claims 13, wherein a, b, c, d and e's and numerical range be 2-4.

The compound of 15. claims 13, wherein R ₁for

The compound of 16. claims 13, described compound has and is selected from following structure:

with

17. 1 kinds of medicinal compositionss, the phenylpropyl alcohol carbonic ether of the claim 1 that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent.

18. 1 kinds of medicinal compositionss, the phenylpropyl alcohol carbonic ether of the claim 13 that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent.

19. 1 kinds of medicinal compositionss, the phenylpropyl alcohol carbonic ether of the claim 6 that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent.

The medicinal compositions of 20. claims 17, described composition also comprises flunixin.

The medicinal compositions of 21. claims 20, described composition also comprises corresponding phenylpropyl alcohol, and wherein said corresponding phenylpropyl alcohol is the identical phenylpropyl alcohol of phenylpropyl alcohol discharging in vivo with described phenylpropyl alcohol carbonic ether.

The medicinal compositions of 22. claims 19, described composition also comprises flunixin.

The medicinal compositions of 23. claims 18, described composition also comprises flunixin.

The medicinal compositions of 24. claims 23, described composition also comprises corresponding phenylpropyl alcohol, and wherein said corresponding phenylpropyl alcohol is the identical phenylpropyl alcohol of phenylpropyl alcohol discharging in vivo with described phenylpropyl alcohol carbonic ether.

25. 1 kinds of medicinal compositionss, the phenylpropyl alcohol carbonic ether of the claim 1 that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent, and containing corresponding phenylpropyl alcohol, wherein said corresponding phenylpropyl alcohol is the identical phenylpropyl alcohol of phenylpropyl alcohol discharging in vivo with described phenylpropyl alcohol carbonic ether.

26. 1 kinds of medicinal compositionss, the phenylpropyl alcohol carbonic ether of the claim 13 that described composition contains significant quantity and pharmaceutically acceptable vehicle or solvent, and containing corresponding phenylpropyl alcohol, wherein said corresponding phenylpropyl alcohol is the identical phenylpropyl alcohol of phenylpropyl alcohol discharging in vivo with described phenylpropyl alcohol carbonic ether.

The medicinal compositions of 27. claims 17, described composition also comprises at least one other medicine.

The medicinal compositions of 28. claims 18, described composition also comprises at least one other medicine.

The medicinal compositions of 29. claims 17, described composition also comprises florfenicol.

The medicinal compositions of 30. claims 18, described composition also comprises florfenicol.

The medicinal compositions of 31. claims 27, wherein said other medicine is Antibiotique composition.

The medicinal compositions of 32. claims 28, wherein said other medicine is Antibiotique composition.

The medicinal compositions of 33. claims 31, wherein said Antibiotique composition is avermectin, and described avermectin is selected from ivermectin, doramectin, abamectin, selamectin, because of the spit of fland of going out, Eprinomectin, Moxidectin, milbemycin and combination thereof.

34. 1 kinds of medicinal compositionss, the formula III phenylpropyl alcohol compound of the phenylpropyl alcohol carbonic ether that described composition comprises claim 1 and applied in any combination

Formula III

Its Chinese style I phenylpropyl alcohol carbonic ether and formula III phenylpropyl alcohol exist in the ratio of 50:1-1:50 weight, wherein R ₁for CH ₃sO ₂, R ₂for CHCl ₂, and R ₃for OH or F.

The medicinal compositions of 35. claims 17, the about 80%-of weight approximately 5% that wherein said phenylpropyl alcohol carbonic ether accounts for described composition.

The medicinal compositions of 36. claims 33, the amount that wherein said avermectin compound exists is the about 20%w/v of about 0.03%w/v-.

The medicinal compositions of 37. claims 33, described composition also comprises flukicide.

The medicinal compositions of 38. claims 17, wherein said solvent comprises at least one pharmaceutically acceptable alcohol.

The medicinal compositions of 39. claims 38, wherein said alcohol is phenylcarbinol.

The medicinal compositions of 40. claims 38, the approximately 5%-approximately 98% that the described alcohol content of wherein said composition is described composition weight.

The medicinal compositions of 41. claims 38, the described alcohol content of wherein said composition is about 20%-approximately 45% weight.

The method of 42. 1 kinds for the treatment of or preventing disease or illnesss in having the animal needing, described method comprises the phenylpropyl alcohol carbonic ether of the claim 1 that gives medicine effective quantity.

The method of 43. 1 kinds for the treatment of or preventing disease or illnesss in having the animal needing, described method comprises the phenylpropyl alcohol carbonic ether of the claim 13 that gives medicine effective quantity.

The method of 44. claims 42, the amount that wherein said phenylpropyl alcohol carbonic ether gives is the about 150mg/kg of about 1-by animal weighing scale.

The method of 45. claims 42, wherein said animal is Mammals, birds, fish, Reptilia or invertebrates.

The method of 46. claims 42, wherein before giving described phenylpropyl alcohol carbonic ether, afterwards or simultaneously, have at least one other medicine of animal needing.

The method of 47. claims 42, wherein said other medicines are Antibiotique compositions.

The method of 48. claims 47, wherein said Antibiotique composition is avermectin, described avermectin is selected from ivermectin, doramectin, abamectin, selamectin, because of the spit of fland of going out, Eprinomectin, Moxidectin and milbemycin.

The method of 49. 1 kinds for the treatment of or preventing disease or illnesss in having the animal needing, described method comprises the compound that gives medicine effective quantity, described compound is selected from compound and the combination thereof of embodiment 1-30.

The method of the compound of 50. 1 kinds of synthetic claims 1, described method is included in suitable solvent phenylpropyl alcohol compound is reacted with corresponding chloro-formic ester.

The method of 51. claims 50, wherein said solvent is selected from chlorinated solvent, ester solvent, polyethers solvent, formaldehyde acetal ether, cyclic ethers, ketone, mixing ether-ester solvent and diethylene glycol ethers.

The method of 52. claims 50, wherein said solvent comprises tetrahydrofuran (THF).

The method of 53. claims 50 is wherein carried out described reaction under the existence of catalyzer.

The method of 54. claims 53, wherein said catalyzer is selected from 4-dimethylamino-pyridine, 4-picoline, pyridine and combination thereof.

The method of 55. claims 50 is wherein carried out described reaction under the existence of acid scavenger.

The method of 56. claims 55, wherein said acid scavenger is selected from triethylamine, pyridine, sodium carbonate, sodium bicarbonate, salt of wormwood and combination thereof.

The method of 57. claims 50, wherein said chloro-formic ester is

R wherein ₄be selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, dodecyl, Octadecane base, 2-methyl-butyl, 1-ethyl-propyl group, 3-methyl-propylene-2-base, 2-methoxyl group-ethyl, 2-oxyethyl group-ethyl, 2-propoxy--ethyl, 2-butoxy-ethyl, 1-methyl-2-methoxyl group-ethyl, cyclopropyl-methyl, cyclopentyl-methyl, cyclohexyl-methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3,7-dimethyl-octa-6-base, benzyl, 2-methyl-benzyl, 3-methyl-benzyl, 4-methyl-benzyl, 2-methoxyl group-benzyl, 3-methoxyl group-benzyl, 4-methoxyl group-benzyl, methyl-2-furyl, 2-(methoxyl group-oxyethyl group)-ethyl, 2-(oxyethyl group-oxyethyl group)-ethyl, 2-[2-(methoxyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-[2-(oxyethyl group-oxyethyl group)-oxyethyl group]-ethyl, 2-(hydroxyl-oxyethyl group)-ethyl, 2-[2-(hydroxyl-oxyethyl group)-oxyethyl group]-ethyl, 2-acetoxyl group-ethyl, 2-(acetoxyl group-oxyethyl group)-ethyl, 3-acetoxyl group-propyl group, 2-carboxyl-ethyl, 3-carboxyl-propyl group, 4-carboxyl-butyl, 2-methoxycarbonyl-ethyl, 3-methoxycarbonyl-propyl group, 4-methoxycarbonyl-butyl, 2-methoxycarbonyl-benzyl, 3-methoxycarbonyl-benzyl, 4-methoxycarbonyl-benzyl, 1-ethoxy carbonyl-ethyl, 1-methoxycarbonyl-ethyl, phenyl, 4-methyl-phenyl, 4-methoxyl group-phenyl, 4-carboxyl-phenyl, 2-carboxyl-phenyl, 4-methoxycarbonyl-phenyl, 2-methoxycarbonyl-phenyl and 4-acetylaminohydroxyphenylarsonic acid phenyl.

The method of 58. claims 50, wherein said phenylpropyl alcohol compound has following structure:

R wherein ₁be selected from

with

R wherein ₂be selected from dichloromethyl, difluoromethyl, chlorine methyl fluoride, chloro methyl and methyl.

The method of 59. claims 50, wherein during reaction, exists with respect to chloro-formic ester molar excess described in described phenylpropyl alcohol compound.

The method of the compound of 60. 1 kinds of synthetic claims 13, described method is included in suitable solvent phenylpropyl alcohol compound is reacted with corresponding bischloroformates, and wherein with respect to described chloro-formic ester, described phenylpropyl alcohol compound molar excess exists.

The method of 61. claims 60, wherein said phenylpropyl alcohol is

And described bischloroformates is

R wherein ₁be selected from

with

And R ₂be selected from dichloromethyl, difluoromethyl, chlorine methyl fluoride, chloro methyl and methyl.

Images