CN1091427A - Has compound of antibiotic and mycoplasma activity resistance and its production and use - Google Patents

Abstract

(1-normon-2-base) oxazole derivative has the purposes in antibacterial therapy to new (furans-2-yl)-2-.

Description

Has compound of antibiotic and mycoplasma activity resistance and its production and use

The present invention relates to a class and have the antibiotic and active compound of mycoplasma, their preparation method and the purposes aspect people and veterinary medicine thereof, also relate to the intermediate that is used to prepare this compounds.

General formula (A) compound:

In the formula R ° represent one contain 1～4 be selected from oxygen, nitrogen and sulphur heteroatomic, can be optionally substituted 5 joint hetero-aromatic rings, general formula (A) compound before had been disclosed in EP-A-0087953(Beecham Group plc.) and EP-A-0123378(Beecham Group plc) and be acknowledged as its carboxylic acid group in the formula by the R ° of sour A(monic acid of the Buddhist nun A that rubs that is replaced) derivative.Such compound has demonstrated to have antibiotic and the mycoplasma activity.In the general formula described in the EP-A-0087953 (A) compound, its example be wherein R ° for being selected from the oxazolyl that group replaced in the group that comprises substituted-phenyl, substituted alkyl and thienyl.In addition, EP-A-0399645 and WO-A-91/09586(Beecham Group plc) disclosed general formula (A) compound be wherein R ° on the 5-position further by general formula (A) compound of oxazole-2-base that furyl, isoxazolyl or pyridyl replaced.Surprisingly, have now found that for the compound of 5-Fu Nan oxazole-2-base a kind of subclass with bioactive compound of increase is arranged.

Therefore, the invention provides logical formula I compound:

R wherein ¹Represent 2-nitro-furans-5-base group, it further can be replaced by nearly 2, the other substituting group that is preferably 1, and Z ₁, Z ₂And Z ₃Can be identical or different, they each is hydrogen or hydroxyl protecting group.Should be appreciated that R ¹Can be expressed from the next:

R in the formula ^aAnd R ^bEach represents substituting group arbitrarily.Suitable R ^aAnd R ^bExample comprise (C _1-5) alkyl and halogen.Preferred R ¹It is 5-nitro-furans-2-base.

Term used herein " halogen " is meant fluorine, chlorine, bromine and iodine.

The formula I compound can be by called after easily " (1-normon-2-base) oxazole ".The Normon base is 3-[(2S, 3R, and 4R, 5S)-and 5-[(2S, 4S, 5S)-2, and 3-bridging oxygen-5-hydroxy-4-methyl hexyl]-3,4-dihydroxyl tetrahydropyrans-2-yl]-the 2-methyl-prop-1(E)-thiazolinyl, shown in formula II:

Should be appreciated that in the formula I compound, the chiral centre of formula II base have with the Buddhist nun acid A that rubs in the identical absolute configuration of corresponding base.

Because The compounds of this invention is planned to be used in the medical compounds, thus should be understood that preferred formula I compound is pharmaceutically acceptable, promptly be formula (I is compound a):

R wherein ¹Regulation as mentioned.

(I a) compound is intended in the formula of medicine owing to formula of the present invention, therefore, certainly they each provides with purified form basically, for example purity is at least 50%, more suitably purity is at least 75%, and preferred purity is based on w/w for reaching 95%(% at least).(I a) the not pure preparation of compound can be used to prepare the more purified form that is used for formula of medicine to formula.Although the purity of midbody compound of the present invention is not too crucial, (I is preferably purified basically form with regard to the compound a) with regard to formula obviously.Preferably, whenever possible, compound of the present invention should be made into crystalline form.

When allowing some The compounds of this invention crystallization or from organic solvent, during recrystallize, in crystallized product, may contain recrystallisation solvent.Therefore the scope of the invention comprises such solvate.Equally, some compound of the present invention can be from water-containing solvent crystallization or recrystallize.When such situation, may form the water of hydration.The scope of the invention also comprise stoichiometric hydrate with can be by the compound that makes such as freeze-drying, contain different water gagings.

The example of The compounds of this invention comprises 5-(5-nitrofuran-2-yl)-2-(1-normon-2-base) oxazole, it has following formula:

And derivative, wherein some or all hydroxyls are protected by hydroxyl protecting group.

The formula I compound can by with EP-A-0399645 and WO-A-91/09586(Beecham Group) described in the similarity method of method prepare.

Particularly, the invention provides a kind of method for preparing the formula I compound, this method comprises cyclisation formula III compound:

R wherein ¹, Z ₁, Z ₂And Z ₃Middle as mentioned defined to form the formula I compound, after this, if necessary, is removed any hydroxyl protecting group.

The cyclisation of formula III compound can be used carboxylic acid anhydride or mixed anhydride or chloride of acid, such as trifluoroacetic anhydride or Trichloroacetic anhydride or trichoroacetic chloride, and the preferred use latter in the presence of pyridine and 4-Dimethylamino pyridine.In this reaction, the hydroxyl of 1-normon-2-base group is by acidylate and must slough protection subsequently.The three halogen Acetyl Groups that form during the cyclisation can use the salt of wormwood in solvent such as water, alkanol or their mixture to remove.Removing the suitable condition of sloughing protection of other acyl residues will know concerning the person skilled in the art easily.On the other hand, with before the carboxylic acid anhydride cyclisation, can be earlier the hydroxyl protection of 1-normon-2-base group be got up, then by sloughing protection such as conventional process described below.

The cyclisation of formula III compound can also be used chlorizating agent such as phosphoryl chloride, phosgene, thionyl chloride or phosphorus pentachloride, in the presence of tertiary amine such as triethylamine or pyridine and carry out suitably.Such reaction can be easily at organic solvent, and for example methylene dichloride or tetrahydrofuran (THF), for example-80 ℃～100 ℃, carry out under several hours to several days condition in the time to high temperature at low temperature.Preferred phosgene or the phosphoryl chloride of using, temperature is 0～20 ℃.

On the other hand, can use triphenyl phosphine and tetracol phenixin,, in inert solvent such as acetonitrile or acetonitrile/pyridine, carry out cyclisation at tertiary amine triethylamine for example as chlorizating agent.These class methods by H.Vorbruggen and K.Krolikiewicz at Tetrahedron Lett., introduce in 1981,4471; Special advantage is the formation of formula III compound and it is cyclized into the formula I compound and can carry out on the spot.

Ding Yi formula III compound is new for useful as chemical intermediate in above-mentioned method as mentioned.Therefore, the present invention also provides the compound of formula III as hereinbefore defined.

The formula III compound can by rub Buddhist nun's acid by with before at EP-A-0087953(Beecham Group plc) described in the response procedures similar methods produce.Suitable is, the Buddhist nun's acid that rubs is converted to a kind of activatory derivative earlier, for example by with isobutyl chlorocarbonate suitable alkali such as triethylamine in the presence of reaction form a kind of mixed anhydride; Then make the hydrochloride of the amine of this intermediate and formula IV: R ¹COCH ₂NH ₃+ Cl ^-(IV) be R wherein ¹Regulation as mentioned; Suitable alkali such as triethylamine in the presence of the reaction.

Should be understood that, Ding Yi formula IV compound is the furans with beta-amino ketones side chain as mentioned, they both can be by known or by handy or pass through conventional process, for example by with at Organic Preparations and Procedures Int., 22(4), 399～484, the raw material that the method for the resemble process described in 1990 is produced makes.

The present invention also provides a kind of method for preparing the formula I compound, and this method comprises makes formula (V) compound:

Z wherein ₁, Z ₂And Z ₃For identical or inequality, and each is hydrogen or hydroxyl protecting group;

React with the formula VI compound:

R wherein ¹Be defined in as mentioned; M ⁺Be metallic cation, be preferably alkali metal cation, most preferably be lithium or sodium cation; And R ²Be anionic stabilizer, himself disappear and produce alkene with beta-hydroxy, preferably trialkylsilkl or di alkyl phosphonic acid ester group, most preferred is trimethyl silyl or diethyl phosphonate; After this and if necessary, remove any hydroxy-protective group.

The reaction of formula (V) compound and formula VI compound can be in organic solvent such as tetrahydrofuran (THF), diethyl ether or dimethyl sulfone, carries out easily under for example from-80 ° to 100 ℃ to high temperature at low temperature.

Each Z wherein ₁, Z ₂And Z ₃For formula (V) compound and the production method thereof of hydrogen are described in GB1587060.Z wherein ₁, Z ₂And Z ₃For the derivative of formula (V) compound of hydroxy-protective group can be produced by for example conventional process cited below.When this compound is formed in the appropriate location and has had hydroxy-protective group, it can be directly used in or even be used for above-mentioned reaction on the spot, perhaps it at random can be removed protection and/or segregation.

The formula VI compound can pass through conventional process, by as with EP-A-0123378(Beecham Group plc.) described in the method similar methods prepare.For example, according to W.S.Wadsworth Jr, Organic Reactions, 1977,25,73 method; With by E.J.Corey and D.L.Boger, Tetrahedron, 1978,5; T.H.Chan,, Acc.Chem.Res.1977,10,442, can be hydrogen or halogen and R with W wherein ¹Ding Yi formula (VII) compound as mentioned:

Being transformed into wherein, M is lithium and R ²Formula VI compound for trimethyl silyl.On the other hand, by with B.H.Lipshutz and K.W.Hungate, J.Org.Chem., method similar methods in 1981,46,1410, formula (VII) compound can be converted into wherein that M is basic metal and R ²Formula VI compound for diethyl phosphonate.

Formula (VII) compound that should be understood that as mentioned regulation be 2-substituted-5-(furans-2-base) oxazole, and they be known and be easy to buy or can produce by conventional process.At Comprehensive Heterocyclic Chemistry, ed.Katritzky and Rees, 6, Chapter 4.18 Zhong Dui oxazoles are synthetic comments.Method according to explanation, a kind of synthetic method is easily used the furyl derivative, for example above the formula IV compound of regulation is a raw material, then by with at J.L.LaMattina, J.Org.Chem., 1980,45, the similar methods of method described in 2261 is translated into formula (VII) compound.

The present invention further provides a kind of method for preparing the formula I compound, it comprises with highly basic handles formula (VIII) compound:

R in the formula ¹, Z ₁, Z ₂And Z ₃Regulation as mentioned, and Y is a leavings group, after this and if necessary, by with EP-A-0399645(Beecham Group plc.) described in the method similar methods remove any hydroxy-protective group.The Y that is suitable for comprises that for example, aryl sulfonyl is p-toluenesulfonyl, alkyl sulphonyl for example; The alkyl or aryl sulfinyl; Quaternary ammonium is trialkyl ammonium for example; With the dialkoxy phosphine oxide.The highly basic that is suitable for comprises, for example, 1,8-diaza-bicyclo [5.4.0] undecane-7-alkene (DBU) and 1,5-diaza-bicyclo [4.3.0] nonane-5-alkene (DBN).Suitable is make be reflected at solvent for example the acetonitrile neutral temperature under-20～80 ℃, carry out.

Formula (VIII) compound of regulation is new for useful as intermediate in aforesaid method as mentioned.Therefore, formula (VIII) compound of definition during the present invention also provides as mentioned.

Formula (VIII) compound can be by preparing with formula (X) compound treatment formula (IX) compound.

Formula (IX) is:

Z in the formula ₁, Z ₂And Z ₃Can be identical or inequality, each is hydrogen or hydroxy-protective group, and Y stipulates in as mentioned.

R in the formula ¹Stipulate in as mentioned, or be its respective analogs that the aldehyde functionality of its Chinese style (X) compound is masked under dehydration conditions.Suitable dehydration conditions described dehydration conditions when obtaining the formula I compound with regard to cyclisation formula III compound hereinbefore is similar.Specially suitable condition is included in triethylamine and has use triphenylphosphine cooperation tetracol phenixin or hexachloroethane down.

The preparation of formula (IX) compound has been presented in EP-A-0399645(Beecham Group plc.) in.

Formula (X) compound is acknowledged as the aldehyde derivatives of furans, they or can buy from market or known or make by the ready-made raw material that gets by the standard method that adapts.

Be understood that, when some situation, be production (VIII) compound (through type as noted before (IX) compound and formula (X) compound reaction) on the spot more easily, as noted before then, with " one jar " method it is brought in the compound of formula I and the midbody compound of need not emanating.

The present invention also provides a kind of method for preparing the formula I compound, and this method comprises method by known isomerization carbon-to-carbon double bond with the carbon-to-carbon double bond isomerization of formula (XI) compound, and formula (XI) is:

R in the formula ¹, Z ₁, Z ₂And Z ₃Regulation as mentioned.Suitable isomerization method, was done in 1980,36557 to introduce at Tetrahedron by Sonnet, and these methods comprise photochemical method and addition-elimination method.Formula (XI) compound can be by obtaining with formula VI compound treatment formula (V) compound, and is as noted before.This reaction lack stereoselectivity also can cause forming formula I and (XI) compound, and these two kinds of compounds can be by conventional process chromatography and being separated for example then.

Term used herein " hydroxy-protective group " is meant any being removed in the prior art and can not makes such group of the remaining partial rupture of molecule.The hydroxy-protective group that is suitable for is in that ' New York is described in 1980 for Protective Group in Organic Synthesis'T.W.Greene, Wiley-Interscience.

The hydroxyl of sour A of the Buddhist nun that rubs and formula III, (V), (VIII), (IX) and (XI) compound can use conventional process and be protected in arbitrary step of aforesaid method.Hydroxy-protective group can be removed by the whole bag of tricks in the prior art, and these methods comprise enzyme catalysis method etc.Specially suitable hydroxy-protective group is a silyl, because they easily are removed under mild conditions.Such group is to use habitual silylating agent to import, and said silylating agent comprises various halogenated silanes and silazane, for example by those represented materials of following formula:

L ₃SiY;L ₂SiY ₂;L ₃SiNL ₂;L ₃SiNHSiL ₃;L ₃SiNHCOL;

L ₃SiO-C（L）＝NSiL ₃;L ₃SiNHCONHSiL ₃;LNHCONHSiL ₃;

^tBuMe ₂Si-O-SO ₂-CF ₃;

Me represent methylidene in the formula, ^tBu represents the tertiary butyl, and X is a halogen and each L base is independently selected from hydrogen, (C _1-5) alkyl, (C _1-5) alkoxyl group, aryl or aryl (C _1-4) alkyl.A kind of preferred silylating agent is a trimethylsilyl chloride.Particularly preferred hydroxy-protective group is trimethyl silyl, triethyl silyl and tertiary butyl dimethylsilyl.Preferably select for use trimethyl silyl as hydroxy-protective group, because it is removed easily.

The functionalized with glycols of sour A of the Buddhist nun that rubs and formula III, (V), (VIII), (IX) and (XI) compound can be protected by use formula (XII) compound formation cyclic derivatives.

Formula (XII) is R ³C(OR ⁴) (OR ⁵) (OR ⁶), R in the formula ³Be hydrogen or (C _1-5) alkyl, and the R of each ⁴, R ⁵And R ⁶Be (C _1-5) alkyl so that in cyclic derivatives Z ¹And Z ²Become R together ³C(OR ⁴) part.Suitable R ³For hydrogen, methyl, ethyl, just-or different-propyl group; Only is hydrogen.Radicals R ⁴, R ⁵And R ⁶Suitable is methyl, ethyl, just or sec.-propyl, or just, different, second month in a season or the tertiary butyl; Only is methyl.The oh group of formula I compound also can be protected before being transformed into alternative formula I compound, as previously discussed.When every kind of situation, above-mentioned blocking group also can then be removed by alkaline hydrolysis by the weak acid hydrolysis, and for example, as Clayton et al, J.C.S.Perkin Trans.I is described in 1979,308.

The present invention also provides a kind of medicine or veterinary drug prescription, and this prescription comprises the formula I compound (being referred to as " medicament " hereinafter) of on medicine or veterinary drug acceptable carrier or vehicle.Prescription can be prepared by any drug delivery route with according to the disease of being treated.Prescription can have various forms, and for example tablet, capsule, pulvis, particle, suppository, ingot and liquid or gel preparation comprise oral, local and aseptic parenteral suspensoid.

The tablet and the capsule that are used for oral dispenser can be taked with dosage unit existence form, and they can contain habitual vehicle such as caking agent, for example syrup, kordofan gum, gelatin, sorbyl alcohol, tragacanth gum or polyvinylpyrrolidone; Filler, for example lactose, sugar, W-Gum, calcium phosphate, sorbyl alcohol or glycine; Compressing tablet lubricant, for example Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide; Decomposition agent, yam starch for example, or acceptable wetting agent is such as sodium lauryl sulphate.Tablet can coat according to the method for knowing in the common medicinal practice.Oral liquid preparation can be taked, and for example, forms such as moisture or oily suspensoid, solution, emulsion, syrup or elixir perhaps exist with dry products and are made into liquid preparation with water or other suitable carriers more before use.Such liquid preparation can contain various habitual additives such as suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, glucose syrup, gelatin, hydrogenation edible-fat; Emulsifying agent, for example lecithin, sorbitan-oleic acid ester or gum arabic; Non-aqueous carrier (it can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, oily ester, glycerine, propylene glycol, ethanol; Sanitas, for example methyl of P-hydroxybenzoic acid or propyl diester or Sorbic Acid; And also contain habitual fragrance or tinting material if necessary.

With regard to topical application, medicament can be made frost, lotion or ointment to skin.The prescription that can be used as the frost of medicine or ointment be as at the standard textbook of medicine and makeup such as " Harry's Cosmeticology " published by George Godwin, the habitual prescription of the prior art of being introduced in London and the British Pharmacopoeia.

Suppository contains habitual suppository host, for example theobroma oil or other glyceryl ester.

With regard to non-enteron aisle dispenser, use medicine and sterile carrier to be prepared into various liquid unit dosage forms.Different according to the used carrier and the degree of depth can be with pharmaceutical suspension in carrier.Various auxiliarys such as local anesthetic, sanitas and buffer reagent can be dissolved in the carrier easily.In order to increase stability, can be injected into bottle and under vacuum, carry out freezing to prescription after the dehydration.Then the lyophilize powder of doing is sealed up for safekeeping in bottle.Can be before it is suspended in sterile carrier and medicine is sterilized by being exposed in the oxyethane.Advantageously, tensio-active agent or wetting agent are included in the prescription to promote the uniform distribution of medicine.

With regard to local dispenser to ear, medicine can be formed in the suspensoid in the suitable liquid vehicle, said liquid vehicle is such as water, glycerine, Diluted Alcohol, propylene glycol, polyoxyethylene glycol or mixing oil.With regard to the local dispenser to eyes, medicine is formulated at suitable sterile aqueous or the suspensoid in the non-aqueous carrier.Various additives, for example, buffer reagent is such as inclined to one side nitrous acid hydrogen sodium or disodium ethylene diamine tetraacetate; The sanitas that comprises sterilant and fungicides is such as phenylmercury acetate or Phenylmercurinitrate, chlorobenzene alkane ammonium or chlohexidine; Thickening material such as Vltra tears also can be included in wherein.

Certainly, the consumption of topical application prescription depends on the size of being disposed area.With regard to ear and eyes, each dosage is generally 10～100mg medicine.

Be used for the animal mamma as raw material disease, particularly the veterinary drug prescription of the breast internal therapy of bovid mammary gland class generally contains the suspensoid in the oily carrier.

According to the difference of medication, prescription can contain 0.1% to 99% weight, preferred 10-60%(weight) medicament.When prescription was taked unit dosage form, each dose unit preferably contained the medicine of 50～500mg.The using dosage that is used for adult treatment (mean body weight is about 70 kilograms) is preferably every day 100mg to 3g, for example every day be 250mg to 2g, this depends on the approach and the frequency of administration.On the other hand, can be with medicine as the part of non-human animal's total foodstuff intake and bestow.When this situation, employed pharmaceutical quantities can be less than 1% weight of abundance of food, and preferably be not more than 0.5% weight.Animal foodstuff can be made up of the normal foodstuff that wherein is added with medicament, or can be made up of pre-composition that is mixed with medicament and foodstuff.The appropriate method of medicament being bestowed animal is that it is added in non-human animal's the tap water.When this situation, the concentration of medicament in tap water is about 5～500 μ g/ml, and for example 5～200 μ g/ml are suitable.

Compound of the present invention is applicable to that treatment comprises in the human animal because the infection that bacterium and bioblast cause, such as people's respiratory tract infection, otitis, meningitis, skin and soft tissue infection, and bovine mastitis, and the respiratory tract infection of animal such as pig and ox.Therefore, on the other hand, (I is compound a) to the invention provides a kind of confession treatment formula usefulness, middle definition as mentioned.The present invention provides a kind of mankind of treatment or non-human animal's bacterium and/or the method that bioblast infects in addition, and this method comprises that the formula I compound of middle definition as mentioned of significant quantity is applied to people or the non-human animal that needs are treated like this with treating upward.The present invention further provides will be as mentioned in defined formula I compound be used to make the method for antibiotic and/or anti-bioblast medicine.

Compound of the present invention is to comprising Haemophilus, for example H.influenzae Q1; Branhamella, for example B.catarrhalis 1502; Streptococci, for example S.pyogenes CN10 and S.pneumoniae PU7; Staphylococci, for example S.aureus Oxford; And Legionella, for example negative organism of the Glan of L.pneumophila [dyeing] and the positive organism of Glan [dyeing] all have activity.In addition, compound of the present invention has the activity of the coagulase-negative bacterial strain of anti-Staphylococci organism such as S.aureus and Staphylocci such as S.epidermidc.These organisms are anti-(comprising multiple anti-) other antiseptic-germicides, for example, beta-Lactam antibiotics such as methicillinum, Macrolide, aminoglycosides and lincomycin class (lincosamides), that is, compound of the present invention is effective when treatment MRSA, MRCNS and MRSE.In addition, compound of the present invention is effective when the Staphy-lococci organism of the anti-mupirocin of treatment.

Compound of the present invention also has the anti-infection activity that is caused by mycoplasma, the particularly anti-infection activity that causes by Mycoplasma fermentans, and these infect has been thought the pathogenetic cofactor of AIDS in the dark.Therefore, on the other hand, the invention provides a kind of treatment and have the patient that M.fermentans infects, particularly also have the patient's that HIV infects method, this method comprises that (I a) compounds for treating need be done the patient of this treatment with the formula of mycoplasma significant quantity.

Expection imposes formula, and (I a) compound can not produce bad toxic reaction.

Following embodiment is for the present invention is described, and must not be considered to scope of the present invention is limited:

Embodiment 1

5-(5-nitrofuran-2-yl)-2-(1-normon-2-base) oxazole

A) 5-(5-nitrofuran-2-yl)-and 2-(6,7,13-O-three-trimethyl silyl-1-normon-2-base) oxazole

With three (trimethyl silyl) tolylsulfonyl ylmethyl-acid amides (60.0g, 82.4mmol) [EP-A-0399645; Embodiment 12(C), Beecham Group plc.] be dissolved in the acetonitrile (175ml).Add 5-nitro-2-furfural (14.1g, 100mmol), then add triphenylphosphine (30.5g, 116mmol) and triethylamine (54ml, 387mmol).Added hexachloroethane then in 20 minutes (27.5g 116mmol), cools off simultaneously temperature is remained between 18～26 ℃ in batches.At room temperature the vigorous stirring reaction mixture is 3 hours, then other triphenyl phosphine, triethylamine and hexachloroethane (as above) is added it.At room temperature add 1 after 15 minutes, and 8-diazabicyclo [5.4.0] undecane-7-alkene (DBU) (49ml, 330mmol), to mixture restir 15 minutes.(5 * 600ml) extract mixture, and total organic extracting solution is washed with 2% sodium bicarbonate aqueous solution (400ml), and (dried over mgso is used in 2 * 80ml) washings, filters and vaporising under vacuum to use salt solution then with hexane.Black viscous oil is purified with silica gel (1kg) by the vacuum flash chromatography, to contain the hexane wash-out of 0～14% ethyl acetate, obtains the title compound (43.0g, 75%) of orange oily foams: δ H(CDCl ₃) 0.91(3H wherein, d, J7.1.Hz, 17-H ₃), 1.20(3H, d, J 6.3Hz, 14-H ₃), 2.32(3H, S, 15-H ₃), 6.28(1H, S, 2-H), 6.74(1H, d, J 3.9Hz, 3 " H), 7.42(1H, d, J 3.9Hz, 4 " H) and 7.62(1H, S, 4 '-H); M/z:694(M ⁺, 1%), 605(1), 117(100), 73(90).(measured value: M ⁺, 694.3144.C ₃₂H ₅₄N ₂O ₉Si ₃Require M, 694.3137).

B) 5-(5-nitrofuran-2-yl)-2-(1-mormon-2-base) oxazole

With 5-(5-nitrofuran-2-yl)-2-(6,7,13-0-three-trimethyl silyl-(43.0g 61.9mmol) is dissolved in the tetrahydrofuran (THF) (680ml) 1-normon-2-base) oxazole, adds the solution of concentrated hydrochloric acid (1.75ml) in water (140ml).Mixture was stirred 16 minutes, add saturated sodium bicarbonate aqueous solution (26ml) then, (2 * 250ml) extract mixture with ethyl acetate.(dried over mgso is used in 2 * 80ml) washings to total organic extracting solution, filters, and make volume-diminished under vacuum with salt solution.The oily vigorous stirring of this kind is added diisopropyl ether (1l) on one side lentamente.In the dark with room temperature under with the mixture stirred overnight.Filter out the solid of generation, with diisopropyl ether washing and dry and obtain yellow powder (28.3g) under vacuum.Be dissolved in this material in the warm acetone (115ml) and stirred and add hexane (80ml) simultaneously at leisure.Product is gone out by crystallization and is slowly adding more hexane (220ml) restir hour before.After half an hour, mixture placed the ice bath cooling and stir half an hour.Product is leached, and (ratio is 1: 4, and 50ml) hexane wash is used in washing then, and the dry fusing point that obtains is 119～120 ℃ a yellow crystalline solid (26.50g, 90%) under vacuum with the acetone/hexane mixture; Measured value: C, 57.64; H, 6.18; C, 57.64; H, 6.18; N, 5.86%; And C ₂₃H ₃₀N ₂O ₉In

C, 57.73; H, 6.32; N, 5.85%; ν maximum (KBr)

3412,1507,1451,1352,1275, and 1049cm ^-1; λ maximum (EtOH) 384nm( ^εM 18,819); δ H(CD ₃OD) 0.95(3H wherein, d, J 7.0Hz, 17-H ₃), 1.20(3H, d, J 6.4Hz, 14-H ₃), 2.31(3H, s, 15-H ₃), 6.28(1H, s, 2-H), 6.99(1H, d, J3.9Hz, 3 " H), 7.59(1H, d, J3.9Hz, 4 " H), and 7.69(1H, s, 4 '-H); δ C(CD ₃OD) 12.3(C-17), 20.0(C-15), 20.3(C-14), 33.0(C-9), 41.7(C-8), 43.7(C-12), 44.0(C-4), 56.9(C-10), 61.3(C-11), 66.4(C-16), 70.0(C-6), 70.7(C-13), 71.6(C-7), 76.4(C-5), 110.5,112.9,114.9(C-2, C-3 ", C-4 "), " 128.2(C-4), 141.1,146.9(C-5 ', C-2 "), 152.4,153.2(C-3, C-5 "), and 164.1(C-2 '); M/z478(M ⁺: 15%), 234(100), 121(74), and 75(75) .(measured value: M ⁺, 478.1948.C ₂₃H ₃₀N ₂O ₉Theoretical value M, 478.1951).

Biological data

(a) anti-various bacteriums (the H.influenzae Q1 of embodiment 1 compound; B.catarrhalis 1502; Strep pyogenes CN10; Strep.pneumoniae PU7; With Staph.aureus Oxford) activity in the treatment of human diseases, be important, this activity is to use in a series of dilution nutrition agar that contain 5% dark brown horse blood to measure in test tube.After 37 ℃ are cultivated 18 hours down, measure the MIC value and find that the MIC value is in the scope of 0.03～0.06 μ g/ml.

(b) in addition, the anti-Legionella organism of embodiment 1 compound, L.Pneumophila 1624, the anti-microbial activity of serogroup l be to use by from melt freeze the skimming milk piece and (BCYEa Oxoid) forms that the bacterium colony of growing in the substratum of striped measures at the buffers active charcoal yeast extract agar that replenishes.These bacterium colonies are suspended in that the barium sulfate opacity standard to MacFarland is 0.5 in the tissue culture medium (TCM) (TCM=Eagle ' minimum must medium+be supplemented with the Earles salt of 10% tire ox slurry, 2mML-glutamine and 1% non-essential amino acid) then.This suspensoid further is diluted to 1: 100 and obtains 4.83 * 10 in TCM ⁶The final cultivation liquid of cfu/ml.

By in 6-ware plate, growing into 80% junction rate, remove medium, the PBS washing monolayer secondary with Dulbecco prepares human fetal lung fibroblast (MRC-5) then.With these cell inoculations, removed medium after 16 hours then, the monolayer secondary of washing inoculation is to remove the organism in any adherent, acellular.

The test compound that makes the concentration that requires in TCM is added in the cell.With 0.5,2 and the concentration of 8mg/ml embodiment 1 compound is tested, and be 0.5 and the erythromycin of 2mg/ml thing in contrast with concentration.After administration 0,3,12,24, in the time of 36,48 and 72 hours, after medicament, medium were removed from a ware/processing, monolayer was washed secondary.Add aseptic distilled water and place 30 minutes with dissolved cell.After firmly smashing to pieces, dilute one by one and be coated on BYCEa and the 5% horse blood agar with Miu Le-Xin Dunshi liquid nutrient medium (Mueller Hinton broth).The L.peumophila bacterial strain is calculated after 72 hours 37 ℃ of cultivations.Observe positive anti-microbial activity to L.pneumophlia.

Confirmed the stability of compound in TCM through 72 hours.Every kind of compound concentrations of preparation is 2mg/ml solution and cultivates at 37 ℃ or 4 ℃ in TCM, and the timed interval is in accordance with regulations taken out aliquots containig.The sample that use makes in TCM is measured the anti-Bacillus subtilis ATCC 6633 and Sarcina lutea NCTC 8340 activity of embodiment 1 compound and erythromycin respectively.

Claims (12)

1, formula I compound:

R wherein ¹Represent 2-nitro-furans-5-base, it further can be replaced by two extra substituting group nearly, and Z ₁, Z ₂And Z ₃Can be identical or different and each be hydrogen or hydroxy-protective group.

2, the desired compound of claim 1, wherein Z ₁, Z ₂And Z ₃Each be hydrogen.

3, desired compound, wherein R in the claim 1 or 2 ¹The substituting group of furyl be selected from (C _1～6) alkyl and halogen.

4, the compound of each claim, wherein R in the claim 1～3 ¹It is 5-nitro-furans-2-base.

5, as the formula I compound of regulation in the claim 1, it is 5-(5-nitrofuran-2-yl)-2-(1-normon-2-base) oxazole; Or its derivative, wherein some is protected with the severe blocking group of hydroxyl with hydroxyl with whole hydroxyls.

6, the method for preparation as formula I compound claimed in claim 1, this method comprises:

(a) cyclisation formula III compound:

R in the formula ¹, Z ₁, Z ₂And Z ₃As defined in the claim 1, to form the formula I compound;

(b) make formula (V) compound:

Z in the formula ₁, Z ₂And Z ₃As regulation in the claim 1, react with the formula VI compound:

R in the formula ¹As regulation in the claim 1; M ⁺Be metallic cation; R ²For negatively charged ion is stablized group, it is spontaneously eliminated with beta-hydroxy and produces alkene;

(C) handle formula (VIII) compound with highly basic:

R in the formula ¹, Z ₁And Z ₃As defined in the claim 1, and Y is a leavings group;

(d) with formula (X) compound: R ¹The CHO(X) processing formula (IX) compound;

Z in the formula (IX) ₁, Z ₂And Z ₃Can be identical or inequality and each be hydrogen or hydroxyl protecting group, and Y as mentioned in regulation, R in the formula (X) ¹Regulation as mentioned, or be its respective analogs, the aldehyde official of its Chinese style (X) compound can be covered spacious under dehydration conditions, the midbody compound of the formula (VIII) of regulation in producing as mentioned on the spot, then, the midbody compound that need not emanate and form thus, handling said with highly basic is mesosome; Or

(e) the two keys of carbon one carbon in isomerization formula (XI) compound:

R in the formula ¹, Z ₁, Z ₂And Z ₃Regulation as mentioned;

With if necessary, remove hydroxy-protective group later on.

7, a kind of comprise as defined in claim 2 the formula I compound and medicine on or the medicine or the veterinary drug prescription of qualified vehicle on the veterinary drug.

8, be used for the treatment of as the defined formula I compound of claim 2.

9, utilize the medicine that the anti-manufacturing of formula I compound as claimed in claim 2 is antibiotic or mycoplasma is treated.

10, the formula III compound as defining in the claim 6.

11, formula (VIII) compound as defining in the claim 6.

12, the method for a kind of preparation formula (VIII) compound, it comprises with formula (X) compound treatment formula (IX) compound:

Z in the formula (IX) ₁, Z ₂And Z ₃As regulation in the claim 1, and Y is a leavings group,

R wherein ¹As regulation in the claim 1, or be its respective analogs, the aldehyde official of its Chinese style (X) compound can be covered spacious under dehydration conditions.