JPH07505379A - (Furan-2-yl)-2-(1-normon-2-yl)oxazole derivative with antibacterial activity - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] (Furan-2-yl)-2-(1-norsen-2-yl)oxane with antibacterial activity Sasol derivative The present invention relates to compounds having antibacterial and antimycoplasmal activity, methods for producing the same, and and its use in human and veterinary medicine, as well as for the production of chemical compounds. Regarding intermediates.

General formula (A)・ [wherein the group R0 is 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur] represents an optionally substituted 5-membered heteroaryl ring containing The compounds shown were previously published in EP-A-0087953 (Beacham Group Publink Limited Company (BeechalI Group plc) ) and EP-A-0123378 (Beacham Group Public Limited Ted Coppany), whose carboxylic acid group was replaced with a group R0. - It will be recognized as a derivative of monic acid A. mosquito The compound was found to have antibacterial and antimycoplasmal activity.

Among the compounds represented by formula (A) disclosed in EP-A-0087953 The RO group is substituted with a range of groups including substituted phenyl, ffi-substituted alkyl and chenyl. An example is given of oxasilyl which has been substituted. Furthermore, EP-A-03 No. 99645 and w〇2-91109586 (Beacham Group Pub Rick Limited Force/Bunny), R6 has frills, isoxazolyl or is an oxazol-2-yl group substituted in the 5-position by a pyridyl group A compound represented by (A) is disclosed. Surprisingly, 5-free hf kissa Subclass of compounds with enhanced biological activity of sol-2-yl compounds It turns out that there is.

Therefore, the present invention provides the formula (■): [wherein R1 is further substituted by up to two, preferably the same, further substituents represents a 2-nitro-furan-5-yl group which may be 3 may be the same or different, each being a hydrogen or hydroxyl protecting group. The compounds shown herein are provided. The group R1 has the sub-formula: [wherein Ro and and R5 each represent an arbitrary substituent. Ro and R” Preferred meanings include, for example, (CI-6) alkyl and halogen. It will be done. Preferably R1 is 5-nitro-furan-2-yl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine. Represents urin.

The compound represented by formula (1) is "(1-norsen-2-yl)oxazole" It is convenient to name it. Normonyl is 3-[(2S ,3R,4R,5S)-5-[(2S,4S,5S)-2,3-epoxy/-5- Hydroxy-4-methylbekyl]-3,4-dihydroxy-tetrahydropyra [en-2-yl]-2-methylproper-1(E)-enyl is a common name for the group . In the compound represented by formula (1), the xyl center of the group represented by formula (It) is , - is understood to have the same absolute configuration as the corresponding group in the basic acid A.

Since the compound of the present invention shows use as a pharmaceutical compound, it is preferable to use the compound represented by formula (1). Preferred compounds are pharmaceutically acceptable compounds, such as those of formula (Ia):C where R1 is This is the same compound as defined above.

Since the compound of formula (Ia) of the present invention shows use in pharmaceutical compositions, They are each in substantially pure form, e.g., at least 50% pure, more preferably at least 50% pure. Suitably at least 75% pure, preferably at least 95% pure (% vt /receipts). Non-containing compounds of formula (Ia) Contains pure substances: l! The product is prepared in a purer form than that used in the medical, [8] composition. used to. Although the purity of the intermediate compounds of the invention is not critical, As with the compound of formula (Ia), it is obvious that a substantially pure form is preferred. easily understood. Preferably, in all possible cases, the compounds of the invention Obtained in crystalline form.

When some of the compounds of the invention are crystallized or recrystallized from organic solvents, , the solvent of crystallization is present in the crystalline product. The present invention includes within its scope such Contains solvates. Similarly, some of the compounds of the invention can be removed from water-containing solvents. Crystallized or recrystallized. In such cases, water of hydration is formed. The present invention Within that scope, stoichiometric hydrates produced by methods such as freeze-tipping and Contains compounds containing variable amounts of water.

Examples of compounds within the scope of the invention include 5-(5-nitrofuran) of the formula: -2-yl)-2-(1-norsen-2-yl)oxazole and hydro Its derivatives in which some or all of the xyl groups are protected with hydroxyl protecting groups are Can be mentioned.

The compound represented by formula (1) is disclosed in EP-A-0399645 and WO-A-91 Disclosed to 109586 (Beecham Group) It can be prepared by a method similar to that described.

In particular, the present invention provides the formula (II+) [In the formula, R', Z, , Z2 and Z3 are the same as defined above] The compound is cyclized to form a compound of formula (1), and then optionally hydrogenated. Production of a compound represented by formula (1) characterized by removing the droxyl protecting group The present invention provides a method.

The compound represented by formula (I[[) is a carboxylic acid anhydride, mixed anhydride or acid salt. compounds, such as trifluoroacetic anhydride or trichloroacetic anhydride or trichloride. Cyclized using chloroacetyl. The latter consists of pyridine and 4-dimethylalcohol. Preferably it is used in the presence of minobirinone. In this reaction, 1-norcene- The hydroxyl group of the 2-yl group must be anorated and then deprotected . The trihaloacetyl group formed during the cyclization is free from water, alkanols or mixtures thereof. It is removed using potassium carbonate in a solvent such as a compound. Remove other acyl residues Suitable deprotection conditions will be readily apparent to those skilled in the art. alternatively is the hydroxyl group of the 1-norsen-2-yl group before cyclization with carboxylic anhydride. and deprotected by conventional methods as described below.

Cyclization of compounds of formula (I[I) can be performed using triethylamine or pyridine. Phosphorus oxychloride, phosgene, thionyl chloride or It is also suitably carried out using a chlorinating agent such as phosphorus chloride. The darning reaction starts from low temperature. The organic Conveniently carried out in a solvent such as dichloromethane or tetrahydrofuran . Preferably using phosgene or phosphorus oxychloride at temperatures between 0 and 20°C .

It is carried out using nylphosphine and carbon tetrachloride as the chlorinating agent. This type The method of H. Vorbruggen and Tetra by K. Krolikievicz Hedron Letters (Tetrahedron Lett), 1981.4 471 has had two races. It involves the formation of a compound of formula (I[+) and The cyclization from these to the compound represented by formula (I) is carried out in 5 situ. This is especially convenient.

The compound represented by formula (nl) as defined above is novel and can be used in the above method. It is useful as a chemical intermediate in Therefore, the present invention has the same definition as above. The present invention also provides a compound represented by the same formula (II+).

The compound represented by formula (m) was previously described in EP-A-0087953 (Beacham Reaction Nokens Disclosed to Group Publink Limited Company It is produced from a single base aA by a similar reaction Nokens. Preferably -base Acid A is first converted into an active derivative, e.g. in the presence of a suitable base such as triethylamine. converted to a mixed anhydride as formed by reaction with isobutyl chloroformate under This intermediate, in the presence of a suitable base such as triethylamine, is then converted to the formula (): %formula%() React with an amine/hydrochloride represented by [wherein R1 is the same as defined above] .

The compound of formula (IV) as defined above has a β-aminoketone side chain These are well-known or readily available, or conventional methods, e.g. organic preparations and brands. Rono Noyers 8 International (Organic Preparation) ns and Procedures Int.), 22(4), 399-484. ．． Starting materials produced by a method similar to that described in 199o can get.

The present invention also relates to formula (V).

[In the formula, zl, Z2 and Z are the same or different, and each represents hydrogen or is a hydroxyl protecting group] A compound represented by the formula (■): [wherein R1 is as defined above; M'' is a metal cation, preferably with an alkali metal cation, most preferably a lithium or sodium cation Yes: R2 is spontaneously removed at the β-hydroxyl group to produce an olefin Anionic stabilizing groups, preferably trialkylnoryl or dialkylphosphonates group, most preferably trimethylnoryl or diethylphosphonate. ]: Then, if desired, any hydroxyl Provided is a method for producing a compound represented by formula (1), which comprises also removing a protecting group. There are also things to do.

The reaction of the compound represented by formula (V) with the compound represented by formula (Vl) can be carried out from a low temperature. At high temperatures, e.g. -80° to +100°C, tetrahydrofuran, It is preferably carried out in an organic solvent such as ether or dimethyl sulfoxide. This is the case.

A compound represented by formula (v) in which each of Zl, Z, and Z3 is hydrogen, and its The manufacturing method is described in GB 1 587060. Zl, Z, and Zco is a hydroxyl protecting group, by conventional methods such as those described below. Therefore, it is manufactured. This compound has already been properly prepared using hydroxyl protecting groups. If produced, it may be used directly or even in 5 situ in the reaction. Alternatively, it may be deprotected and/or isolated, if desired.

The compound of formula (■) can be prepared by conventional methods using EP-A-0123378. (Beacham Group Public Limited Company) Manufactured by a method similar to that of For example, double niss watsuzuwa Wadsworth Jr. (W, S, Wadsworth Jr), Organic Re Akun Yongs (Organic Reactions), 1977.25.73 ．． and E.J.Corey and D.E. Le Poger (D, L, Boger), Tetrahedr on), 1978.5. T H C+:/ (T, H, Chan), Account on Chemical Research (Ace, Chew, Res,) , 1977.10.442, formula (■) In the formula E, W is hydrogen or halogen, and R1 is the same as defined above] The compound shown is a compound in which M is lithium and R2 is trimethylsilyl. It is converted into a compound represented by formula (Vl). Alternatively, B H Lip / Yanotsu (B, H, Lipshutz) and K.W. Hankate ( K, W, Hungate), Journal on Organic Chemistry - (J, Org, Chem,), 1981.46.1410 method similar to the method , M is an alkali metal, and R2 is converted into a compound represented by formula (Vl), in which is diethylphosphonate.

The compound represented by the formula (■) defined above is a 2-substituted-5-(furan-2-yl) )oxazole, which is well known and readily available; Alternatively, it is understood that they may be produced by conventional methods. The synthesis of oxazole is , “Comprehennobu Heterocyclink Chemistry J henseHeterocyclic CheIIstry), Catholic Katritzky and Rees Akebono, 6th, 4.18th grade Disclosed. By way of illustration, a convenient synthetic stratenow is Noei L. Mattina (J, L, La Mattina), Journal on Auger 1-Tsuku Chemistry (J, Org, Chew,), 19 80.45.2261 by a method similar to that described by As a point, a furanyl derivative, for example a compound of formula (rV) as defined above is then converted into a compound represented by formula (■).

Furthermore, the present invention is based on EP-A-0399645 (Beacham Group Publications) The formula ( ■) [In the formula, R1, Zl, Z2 and Z are the same as defined above, and Y is a leaving group. ] is treated with a strong base, and then optionally treated with any hydrogen. A method for producing a compound represented by formula (I), characterized in that the roxyl protecting group is also removed. It provides law. )', for example, aryl Sulfonyl, e.g. p-toluenesulfonyl, alkylsulfonyl, alkyl or arylsulfinyl, quaternary ammonium, e.g. ammonium, and noalcoquine phosphine oxides. with a suitable strong base For example, 1,8-noacypinoclo[5,4,0]undec-7-ene (D B U) and 1,5-ene azopinchloro[4,3,0]non-5-ene ( D B N).

Suitably, the reaction is carried out in acetonitrile at a temperature ranging from -20 to +80°C. It is carried out in a solvent such as

The compound represented by the formula (■) defined above is novel, and is an intermediate compound in the above method. It is useful for the body. Therefore, the present invention is represented by the formula (■) defined above. It also provides compounds that

The compound represented by the formula (■) is prepared under dehydration conditions by formula (■): [wherein Zl, 22 and and Z3 are the same or different and each is a hydrogen or hydroxyl protecting group. and Y is the same as defined above] is represented by the formula (X): RICHO(X) A compound represented by [wherein R1 is the same as defined above] or represented by formula (X) The aldehyde functionality of the compound to be treated with its corresponding analogue is masked. Manufactured by. Suitable dehydration conditions include cyclization of the compound represented by formula (III). The conditions are the same as those described above for obtaining the compound represented by formula (1).

Particularly suitable conditions include carbon tetrachloride or hexachloride in the presence of triethylamine. Mention may be made of the use of triphenylphosphine in combination with chloroethane.

The preparation of compounds of formula (IX) is described in EP-A-0399645 (Beacham ・Group Public Limited Company).

The compound of formula (X) is recognized as an aldehyde derivative of furan and is commercially available. known or standard method. Produced from readily available starting materials depending on the application.

In some cases, (as above, the compound represented by formula (IX) is replaced by the compound represented by formula (X)) by reacting with a compound represented by the formula (■) in 5 itu compound and then, without isolation of the intermediate compound, by the one-pot J method. , it is more convenient to complete the compound of formula (I) as defined above. It is understood that

The present invention utilizes the formula (Xi ): [wherein R1, Zl, Z, and Z are the same as defined above] A compound represented by formula (I) characterized by isomerizing the carbon-carbon double bond of the compound It also provides a method for producing the compound. A preferred isomerization method is Sonet (S onnet) by Tetrahedron (TetrahedrOn), 1980 ．． 36.557, including photochemical and addition-removal methods. . Similarly to the above, the compound represented by formula (XI) is a compound represented by formula (V). It can be obtained by treatment with a compound represented by formula (Vl). This reaction lacking body selectivity and forming compounds represented by formulas (I) and (X[), It is then separated by conventional methods such as chromatography.

As used herein, the term "hydroxyl protecting group" refers to Represents any group known in the art that is removed without cleavage. suitable Hydroxyl protecting groups are recommended by Protective Groups in Organics. 0 sense J (Protective Groups in Or, gan ic 5ynthesis), Te4' Double Green (T, W, G reene), Wiley-I intersc. ), New York, 1981.

- Basic acid A and formulas (I[I), (V), (■), (■) and (X[) The hydroxyl group of the compound represented by protection at all stages. Hydroxyl protecting groups are known in the art, including enzymatic methods. removed by a method known in the art. Silyl groups are easily removed under mild conditions A particularly preferred hydroxyl protecting group is a silyl group. Such a group is Conventional lylating agents, including halosilanes and norasanes, such as the formula % formula % : In formula E, Me represents methyl, t-Bu represents t-butyl, and X represents halogen. and each L group independently represents hydrogen, (C+-a)alkyl, (C+-a)a selected from lucoquine, aryl or aryl(C+-+)alkyl] It is introduced using the following. Preferred/lylating agent is trimethyl chloride It is le. Particularly preferred hydroxyl protecting groups are trimethylsilyl, triethylsilyl, lyl and t-butylnomethylrinryl groups. Preferred hydroxyl protecting groups are , because of its ease of removal, is the trimethylsilyl group.

- Basic acid A and formulas (I[[), (V), (■), (IX) and (X[) The glycol functional group of the compound represented by formula (■).

R3C(OR'X0R3XOR') (Xl[) [wherein R3 is hydrogen or (C 1-s) alkyl, R4, R5 and R6 are each in the cyclized derivative , Zl and Z2 together are R”C(OR’) group It is a kill] is protected by forming a cyclized derivative using a compound of the form:

Suitably R3 is hydrogen, methyl, ethyl, n- or iso-propyl; Most preferred is hydrogen. The R4, R5 and R6 groups are preferably methyl, ethyl n- or iso-propyl, or n-, iso-1Sec- or t- Butyl, most preferably methyl. Hydro of the compound represented by formula (1) The xyl group may be protected prior to conversion to further compounds of the above formula good. In each case, said protecting group is, for example, as described by Clayton et al. Journal on Chemical Society Perkin Transactions (J, C, S.

Perkin Trans, ) I, 1979.308. It is removed by acid hydrolysis followed by alkaline hydrolysis.

The present invention provides compounds of the formula ( A drug characterized by comprising the compound represented by I) (hereinafter referred to as "drug") Pharmaceutical or veterinary compositions are provided. The composition is suitable for any It may also be formulated for administration by any route, depending on the disease being treated. Current The composition may be, for example, a tablet, capsule, powder, granule, suppository, lozenge, and liquid or gel preparations, including oral, topical and sterile parenteral suspensions. It is in the form of a product.

Tablets and capsules for oral administration may be in unit dosage preparation form and include a binder. , such as syrup, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone: fillers such as lactose, sugar, tow Morocono starch, calcium phosphate, sorbitol or glycine; tabletting Lubricants, such as magnesium stearate, talc, polyethylene glycol or disintegrants, such as potato starch, or sodium lauryl sulfate. Contains conventional excipients such as acceptable wetting agents such as thorium. The tablets are They may be coated according to methods well known in routine pharmaceutical practice. oral liquid tA V products include, for example, aqueous or oily suspensions, solutions, emulsions, drops, or May be in the form of an elixir or mixed with water or other suitable It may also be present as a dry product for reconstitution with excipients. Such liquid preparation The product contains suspending agents such as sorbitol, Noronobu, methylcellulose, gluco 70 knobs, gelatin, hydrogenated edible fat 1 emulsifier, e.g. lenotin, mono sorbitan oleate or gum arabic 1 non-aqueous excipient (including edible oil), For example, almond oil, fractionated coconut oil, oil esters, glycerin, propylene lenoglycol or ethyl alcohol; preservatives such as p-hydroxyl alcohol; @, aroma resistant methyl or propyl or sorbic acid, and optionally conventional aroma It may contain conventional additives such as flavoring agents or coloring agents.

For topical administration to the skin, the drug may be used in creams, rosylan or ointments. It may be formulated into Creams and ointments used for the drug: 1 : Ma, for example, Noyoji Godwin (Georg Godwin) (Ron) Published by Harry's Cosmeticology (Harry' s　Cosmeticology) J and British Pharmacopoeia, etc. Pharmaceuticals and cosmetics LS is well known in the art, as disclosed in the standard texts of It is a conventional formulation.

Suppositories contain conventional suppository bases such as cocoa butter or other glycerides.

For parenteral administration, liquid unit dosage forms contain the drug and sterile excipient II. Prepared for I. Depending on the excipient used and the degree of It is possible to make one or two slurps. Conveniently, local anesthetic, preservative 11f11 and Auxiliary agents such as buffers (hi11) can also be dissolved in the excipient to enhance stability. 1. The composition is frozen after filling into a vial, and then the water is removed under vacuum. It is possible to remove the power.

The dried lyophilized powder is then sealed in a vial. The drug concerned (false, sterile In form? Stable oxidation by exposure to ethylene oxide before ffi I can do it forcefully.

Conveniently promotes homogeneous distribution of the drug! 2nd biparticular grouped acid ↓ 2 surfactant II or contains a wetting agent.

For topical administration to the ear, the drug may be mixed with water, glycerol, dilute ethanol-J or , propylene glycol, polyethylene glycol, fixed oil, etc. It can be formulated into a suspension in a suitable liquid carrier. Topical administration to the eye t2 = 11, the drug The product is formulated as a suspension in a suitable sterile aqueous or non-aqueous vehicle. Addition II, for example (i, sodium metabisulfate or edetate disodium) <・Sofa - Phenylmercuric acetate or phenylmercuric nitrate, benzalkonium chloride Mumatoko 1 is a preservative containing bactericides and fungicides such as chlorohequinodine, and Even if it contains thickeners such as hypromellose and (1°) The dosage used for topically administered compositions will, of course, depend on the treatment. It depends on the size of the area where it is placed. For ears and eyes, each dose is typical The drug ranges from 10 to 1001w.

Breast treatment for animal udder diseases, especially orchid mastitis! Veterinary compositions for use in , containing a suspension of the drug in an oily vehicle.

The composition preferably contains from 0.1 to 99% by weight of the drug, depending on the method of administration. contains 10 to 60% by weight. If the composition is in unit dosage form, each administration Preferably, the unit contains 50 to 500 mp of the drug. Adult (average weight approx. 7f) kg) The dosage when used for treatment depends on the route and frequency of administration: Preferably, the amount is in the range of 100 to 3 g/day, for example, the drug 25019 ~2g/day. Alternatively, the Drugs may also be administered. In this case, the amount of drug used is less than 1% by weight of the diet. , preferably 0.5% by weight or less. The animal food is added with the drug. may consist of ordinary food or the drug may be a pre-mix for mixing with food. may be included in the box. A preferred method of administering the drug to animals is to administer it to non-human animals. It is added to the drinking water of animals. In this case, the drug 1 degree in drinking water is about 5 to 500μ9/m1. For example, it is suitable that it is 5 to 200 μg/ml.

The compounds of the invention are useful for respiratory tract infections, otitis, meningitis, human skin and soft tissue infections, for humans, such as mastitis, and the treatment of respiratory infections in animals such as pigs and orchids. It is useful in the treatment of bacterial and mycoplasma-induced infections in animals including. Therefore In a further aspect, the present invention provides a compound of formula (1a) as defined above for treatment. It provides a compound. Furthermore, the present invention provides A human or non-human animal in need of treatment for a Zuma infection represented by formula (I) as defined above. human or non-human animal species, characterized in that the administration of an effective therapeutic amount of a compound A method of treating bacterial and/or mycoplasmal infections is provided. moreover, The present invention relates to the above-mentioned methods for producing antibacterial and/or antimycoplasma therapeutic drugs. The present invention provides the use of compounds of formula (1) as defined below.

The compounds of the present invention are suitable for use in Haemophilus, e.g. Lus influenzae (H, 1nfluenzae) Q1: Branhamera (B ranhamella), for example Branhamella catarrhalis (B, c atarrhalis) 1502; Streptofuccus (5treptoc occus), for example, Streptococcus pyogenes (S. pyogenes) es) CNIQ and Streptococcus pneumo j-(S, pneumo niae) PU 7; Staphylococcus (S taphylococcus) s), for example, Staphylococcus aureus (S, aereus) xford; and legionell a), for example, L. pneumophila It is active against Gram-negative and Durham-positive bacteria, including. Furthermore, the compound of the present invention The product may contain other antibacterial agents such as methicillin, macrolides, aminoglyconds and resistant to β-lactam antibiotics such as lincosamides (including multidrug resistance). ) Staphylococcus such as Staphylococcus aureus (S, aureus) Loco socus and Staphylococcus eidermizois (S, epid Active against coagulase-negative bacteria such as Staphylococcus ermidis) It is. That is, the compound of the present invention has \4RSA, MRCNS and MR3E. The page is for treatment. Furthermore, the compound of the present invention has mupiroc It is useful in the treatment of Staphylococcus bacteria that are resistant to In.

The compounds of the present invention are believed to be cofactors in the pathogenesis of mycoplasma-induced infections, particularly AIDS. Mycoplasma fermentans (Mycoplasma It is also active against infections caused by P. ermentans. Shit In a further aspect, the present invention provides a method for treating a human in need of treatment with a compound of formula (Ia). mycoplasma, characterized in that it is treated with an anti-mycoplasma effective amount of a compound represented by Humans infected with Plasma fermentans (M, fermentans) In particular, the present invention provides a method for treating humans infected with HIV.

No toxicological side effects are expected from administration of the compound of formula (1a). stomach.

The following examples illustrate the invention but are not intended to limit its scope in any way. isn't it.

Example 1 5-(5-nitrofuran-2-yl)-2-(1-norsen-2-yl ) Oxazole a) 5-(5-nitrofuran-2-yl)-2-(6,7,13-〇-tris Trimethylnoryl-1-norsen-2-yl)oxazole tris-trimethyl Silyl tosylmethyl monoamide (60,09,82,4111 mol) (E P-A-0399645; Example 12(c), Beecham Group Publications Ltd.) was dissolved in acetonitrile (175 ml). 5 - Add nitro-2-furfuraldehyde (14, 19, 100 mmol) and then Then, triphenylphosphine (30,59,116111101) and triphenylphosphine (30,59,116111101) Ethylamine (54ml, 38711+nol) was added. Then cool down Hexachloroethane (27,59,1 161Ql101) was added dropwise over 20 minutes. The reaction mixture was heated at room temperature for 3 hours. , stir vigorously and then add triphenylphosphine, triethylamine and and hexachloroethane (same as above) were added dropwise. After 15 minutes at room temperature, 1.8- N'Azabinkuro [5,4, OF Uncar-7-en (DBU) (49mj, 33 0++ mol) was added and the mixture was stirred for a further 15 minutes. Pour the mixture into Extracted with San (5X 600+1).The combined organic extracts were extracted with 2% sodium bicarbonate Wash with aqueous solution (40 (bl)), then with saline (2X8011) dried over magnesium sulphate, filtered and evaporated in vacuo.

The black viscous oil was subjected to vacuum flash chromatography on glue (1 kg). and purified by eluting with 0-14% ethyl acetate in hexane. The title compound was obtained as an orange oily foam (43.09.75%): δ++(C DCI's) especially 0.91 (3H, d, J 7. IHz, 17-H s), 1.20 (3H, d, J 6°3Hz, 14-83), 2.32 (3 H, s, 15-Hs), 6.28 (L H, s, 2-H), 6゜74 ( IH, d, J 3.9Hz, 3”-H), 7.42 (LH, d, J 3.9H z, 4”-H), and 7.62 (IH, s, 4-H); m/z 694 (M', 1%), 605(1), 117(100), and 73(90). ( Measured value: M”, 694.3144° C32HuNxO*Si2 theory N: M, 6 94.3137).

b) 5-(5-nitrofuran-2-yl)-2-(1-norsen-2-yl)o Xazole 5-(5-nitrofuran-2-yl)-2-(6,7,13-0-tris-tri Methylnoryl-1-norsen-2-yl)oxazole (43, Og, 61.9 -■ol) was dissolved in tetrahydrofuran (680,1), and then concentrated hydrochloric acid (1 A medium temperature solution of water (14011) was added. Stir the mixture for 16 minutes Then, a saturated aqueous sodium hydrohydrogen solution (26,1) was added and the mixture was Extracted with ethyl acetate (2X250Hl). The combined organic extracts were dissolved in saline (2X 80 ml), dried with magnesium sulfate, 11! then under vacuum , reduced to a small amount. Di-iso-propyl ether (11) was slowly added. The oil was stirred vigorously. The mixture was stirred in the dark at room temperature overnight. . The resulting solid was filtered, washed with di-iso-propyl ether, and dried under vacuum. , yellow powder (28, 39) was obtained.

Dissolve this material in hot acetone (115 m/) and slowly add hexane (80,1). while stirring. After crystallizing the product and stirring for each hour, further Hexane<220R1) was added slowly. After a further A hour, the mixture was diluted with water. Cooled in bath and stirred for 1 hour. The product was filtered and diluted with acetone:hexane (1: 4.50 mA), then washed with hexane and dried under vacuum to give a yellow crystalline solid (2 6,509,90%) was obtained. Melting point 119-1208C; Elemental analysis (C*5H xoN10. ): Measurement 1 mC, 57, 64: H, 6, 18; N, 5.86%, Theoretical value C, 57,73; H, 6,32; N, 5.85%: v,, (KBr ) 3412.1507.1451.1352.1275, and 1049cm- ’;λ, , (EtOH)384n+*(ε, 18.819), δ, (CD3 0D) especially region 95 (3H, d, J 7.OHz, 17-H*), 1.20 (3H, d, J 5.4Hz, 14-Hs), 2.31 (3H, s, 15 -Hs), 6.28 (IH, s, 2-H), 6.99 (LH, d, J 3.9 Hz, 3”-H), 7.59 (IH, d.

J 3.9Hz, 4”-H), and 7°69 (LH, s, 4°-H), δc (CD, 0D) 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-1 3), 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゜ctsl (s・N, O・theoretical value M, 47 8.1951).

biological data (a) Serial dilution in nutrient agar containing 5% chocolate-colored horse blood. A variety of bacteria important in human disease (Haemophilus influenzae) X (H, 1NFLUE ++ ZAE) Q L; Blanc Hamera Catalari B. catarrhalis 1502; Streptococcus pyogenes (S trep, pyogenes) CN 10; Streptococcus Pneumoniae (S trep, pneuaoniae) P U 7: and Staphylococcus aureus (Staph, aereus) Ox The activity of the compound of Example 1 against (Oxford) was determined in vitro. o assayed. After incubating at 37°C for 18 hours, the MIC value was determined. , was found to be in the range of 0.03-0.06 μg/ml.

(b) Additionally, thawed from frozen skim milk stock and then supplemented with 11 Streaked culture on charcoal powdered yeast extract agar medium (BCYEa, Oxoid) Colonies grown from the culture were used to isolate Legionella Bacteria, Rejunella pneumophila (L, pneumophila) 1624 , antibacterial activity of the compound of Example 1 against serogroup 1 The sex was assayed. These colonies were then cultured in tissue culture medium (TCM = Eagle Medium). Eagle supplemented with a small minimum essential medium + 1 diluted glutamine and 1% dispensable amino acids salt) and suspended in a McFarland barium sulfate turbidity standard of 0.5. moreover, The suspension was diluted 1:100 with TCM to make the final inoculum 4. 8 3 X 1 I got 0@cfu/l.

Human fetal lung fibroblasts (MRC-5) were grown in confluenza cells in 6-well plates. The medium was removed and the monolayers were grown in Dulbecco's PBS. Prepared by washing twice. These cells were then seeded and incubated for 16 hours. Afterwards, remove the medium and wash the inoculated monolayer twice to remove any attached non-intracellular microorganisms. Organisms were also removed.

Test compounds prepared at predetermined concentrations in TCM were added to the cells. 0.5 and Using 2s9/me of erythromynon as a control, the compound of Example 1 was Tested at 5, 2 and 8 mg/mt. Administration O13, 12, 24, 36, 48 And after 72 hours, the medium was removed from one well/treatment and the monolayers were washed twice.

Sterile distilled water was added and allowed to stand for 30 minutes to lyse the cells. After crushing strongly, melt Lysates were serially diluted in Mueller-Hinton Broth medium, BYCEa and 5% horse. Plated on blood agar. After 72 hours of incubation at 37°C, Count the number of colonies of L. pneumophila Ta. Positive against L. pneumophila Antibacterial activity was observed.

The stability of the compound in TCM was confirmed over 72 hours. Various types in TCM A solution of compound 2 g/xi was prepared and incubated at 37°C or 4°C. I took out the kotsuto from time to time. Using standards prepared in TCM, Vanolas Bacillus 5ubtilis ATCC 6 6 3 3 and Sarcina lutea (Sarcina 1utea) NCTC 8 3 The compound of Example 1 and erythromynon were assayed against 4.0.

Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML , MR, NE, SN.

TD, TG), AT, AU, BB, BG, BR, CA.

CH, CZ, DE, DK, ES, FI, GB, HU, JP, KP, KR, KZ, LK, LU, MG, MN, MW, NL, No, NZ, PL, PT, R○, RU, SD.

SE, SK, UA, US (72) Inventor: Elder John Stephen Lee R.E. 13.7 Agey, Betschworth, Brodscombe Park (no street address displayed) SmithKline Beecham Pharmaceuticals

Claims (13)

[Claims] 1. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [wherein R1 represents up to two further 2-nitro-furan-5-yl group which may be further substituted with a substituent Z1, Z2 and Z3 may be the same or different and each represents hydrogen or is a hydroxyl protecting group]. 2. 2. A compound according to claim 1, wherein Z1, Z2 and Z3 are each hydrogen. 3. The substituent of the furanyl group in R1 is selected from (C1-6) alkyl and halogen 3. The compound according to claim 1 or 2. 4. Any one of claims 1 to 3, wherein R1 is a 5-nitro-furan-2-yl group. Compounds described. 5.5-(5-nitrofuran-2-yl)-2-(1-normon-2-yl)o xazole; or some or all of the hydroxyl groups are hydroxyl protected The compound of formula (I) according to claim 1, which is a derivative thereof protected with a group . 6. (a) Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R1, ZI, Z2 and Z3 is the same as defined in claim 1] by cyclizing the compound represented by the formula ( I) or (b) form a compound of formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, Z1, Z2 and Z3 are The compound represented by the formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) [In the formula, R1 is Same as the definition, M■ is a metal cation, R2 is a β-hydroxyl group is an anionic stabilizing group that is naturally removed to produce an olefin] React with the compound shown in; (c) Formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) [In the formula, R1, Z1, Z2 and and Z3 are the same as defined in claim 1, and Y is a leaving group] (d) under dehydration conditions, the compound represented by formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) [In the formula, Z1, Z2 and Z3 are are the same or different, each is a hydrogen or hydroxyl protecting group, and Y is The compound represented by the formula (X): R1CHO(X) A compound represented by [wherein R1 is the same as defined above], or a compound represented by formula (X) The aldehyde functionality of the indicated compound was treated with its corresponding analogue where it was masked. , producing in situ an intermediate compound represented by the same formula (VII) as defined above, then, without isolating the intermediate compound formed, the intermediate is treated with a strong base; or (e) Formula (XI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI) [In the formula, R1, Z1, Z2 and Z 3 is the same as the above definition] isomerize the carbon-carbon double bond of the compound and optionally then removing the hydroxyl protecting group. Item 1. A method for producing a compound represented by formula (I) according to item 1. 7. A compound represented by formula (I) according to claim 2 and a pharmaceutically or veterinarily acceptable compound. A pharmaceutical or veterinary composition, characterized in that it consists of an excipient that can be contained therein. 8. 3. A compound of formula (I) according to claim 2 for therapeutic use. 9. The formula ( Use of the compounds shown in I). 10. A human or non-human animal in need of treatment is given the formula (I) according to claim 2. to a human or non-human animal, characterized in that administering a therapeutically effective amount of a compound How to treat bacterial or mycoplasmal infections in. 11. A compound represented by formula (III) according to claim 6. 12. A compound represented by formula (VIII) according to claim 6. 13. Under dehydration conditions, formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) [In the formula, Z1, Z2 and Z3 are Same as the definition in claim 1, Y is a leaving group] A compound represented by formula (X): R1CHO(X) A compound represented by [wherein R1 is the same as defined in claim 1], or Corresponding analogues of compounds of formula (X) in which the aldehyde functionality is masked A method for producing a compound represented by formula (VIII), which comprises treating the compound with formula (VIII).