JPH07503244A - Antibacterial 1-normon-2-ylthiazolyl ketones - 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] Antibacterial 1-norsen-2-ylthiazine ketones The present invention has antibacterial activity and Novel compounds with mycoplasmal activity, their preparation and human and veterinary medicine Its use in pharmaceutical medicine.

Mupirocin, a compound of H. influenzae, is a Durum-positive bacterium. H. influenzae), Legionella and Ma Shows good activity against Icoplasma. This is Beecham Group No. BuIJ. Tsuku・1) Mite Nodo Campa = (Beecham Group p lc) under the trademark BACTROBAN (X. , called butoidmonic acid), was rapidly hydrolyzed in vivo to form the formula ( B).

to inactive monic acid, a compound of

For example, C-1 heterocyclic derivatives (EP-A-0087953 and EP-A-0 123578), C-1 amide (EP-A-0001914) and heterocyclic C-1 esters, including C-1 ketones (EP-A-0029665) By modifying the functional groups, the metabolism of muviro/nine related to enzymatic hydrolysis can be improved. Various methods have been proposed to improve stability. Furthermore, Klein et al. lein et al.) (3rd North American Chemical Conference, Toronto (June 1988) The poster shown with reported the production of N-methylimidazol-2-ylketone. These are Hete A heteroaryl bonded to a ketone carbonyl group by the ring carbon atom adjacent to the ro atom It is characterized by having a ru group. From the limited data on these derivatives, These compounds are similar to butyl and methylbutymonate, which are less active. It can be seen that the activity is lower than that of phenylketone. The results of in vivo activity are Not reported, in vitro activity does not support in vivo studies not enough.

Recently, WO92102518 (published after the priority date of this application) Heterocontaining capto- and 2-methylsulfinylthiazol-5-ylketones Several examples of aryl ketones are disclosed.

However, surprisingly, it improved from a small group of other thiazol-5-ylketones. It was found that antibacterial properties can be obtained.

Therefore, the present invention relates to formula (I).

[Wherein, R1 is 2-(optionally substituted (self-1°)alcokyne)thiazole] 5-yl group, i.e. formula: (wherein R is an optionally substituted (CI-+)alcoquine) ] is provided.

Suitable optional substituents for the (C,~+o)alcoquino group include, for example, Halogen, cyano, azide, nitro, carboquine, (CI-s) alkoxylic Bonyl, carbamoyl, mono- and di(CI-s)alkylcarbamoyl, Sulfo, sulfamoyl, mono- or di(CI-6)alkyl sulfamoyl amino, mono- and di(C,-6)alkylamino, acylamino, Reid, (CI-s)alkoxycarbonylamino, 2.2.2-trichloroethane Toxycarbonylamino, trialkylthiomethyl, optionally substituted aryl , optionally substituted heterocyclyl, hydroxy, (CI-a)alkoxy, Acyloxy, oxo, acyl, 2-thenoyl, (CI-s)alkylthio, ( C3-6) Alkylsulfinyl, (01-.)alkylsulfonyl, hydroxy Ciimino, (CI-s)alkoxyimino, hydrazino, hydrazino, benzophyl Includes droximoyl, guanidino, amidino and iminoalkylamino. Ru.

Suitably R is optionally substituted (C,-6)alkoxy, preferably optionally Substituted methoxy, ethoxy or hexoxy, more preferably meth most preferably unsubstituted metquin. Preferably R1 is 2 -methoxythiazol-5-yl.

As used herein, the term "aryl" refers to the fluorophore, unless otherwise specified. phenyl or naphthyl. The aryl ring has up to 5, preferably 3 may be optionally substituted with up to 3 substituents. Suitable substituents include, for example , halogen, cyano, (01-6) alkyl, phenyl, (C1-6) alkoxy cy, halo(CI-s)alkyl, hydroxy, amino, mono- or di(CI-s) -6) Alkylamino, acylamino, nitro, carboxy, (C, ~6)al Koxycarbonyl, (CI-s) alkoxycarbonyl (CI-a) alkyl, (C,~6)alkylsulfonyloxy, (C1~6)alkylthio, (C5- 6) Alkylsulfinyl, (CI-s)alkylsulfonyl, sulfamoyl , mono- or di(C,~6)alkylsulfamoyl, carbamoyl, and and mono- or di(C,~6)alkylcarbamoyl.

As used herein, the term "heterocyclyl" refers to oxygen, nitrogen, or nitrogen in the ring. aromatic or aromatic containing up to 4 heteroatoms selected from sulfur and sulfur It includes single rings or fused rings that are not. Suitably there are 4 to 7 heterocycles, preferably contains 5-6 ring atoms. Fused heterocyclic ring systems include carbocycles and contain one heterocycle. It's fine as long as you are. The heterocyclyl ring is optionally substituted with up to 3 substituents. It's okay. Suitable substituents include, for example, halogen, (C,-6)alkyl, ( CI-6) alkoxy, halo (CI-6) alkyl, hydroxy, amino, mono - or di(CI-6) alkylamino, carboxy, (CI-e) alkoxy cycarbonyl, (C+~6) alkoxycarbonyl (CI-a) alkyl, ali and oxo.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine or means iodine.

The compound of formula (1) is named "(1-norsen-2-yl)-ketone" for convenience. do. Normonyl has the formula (TI): 3-[(2S, 3R, 4R, 5S)-5-[(2S, 3S, 4S, 5 S)-2,3-epoxy-5-hydroxy-4-methylbequinol]-3,4-di Hydroquine Tetrahydropyran-2-yl-2-methylprop-1(E)-e It is a common name for nyl group.

In the compound of formula (1), the substituent in the R1 group contains one or more asymmetric centers; It is considered good. The present invention does not include all such isomers obtained. be.

Since the compound of formula (1) of the present invention is for use in a pharmaceutical composition, , each in substantially pure form, e.g., at least 50% pure, more suitably at least 75% purity, preferably a minimum of 95% purity (% by weight). Formula (1) Impure preparations of compounds can be used to prepare more pure forms in pharmaceutical compositions. used to do. Although the purity of the intermediate compounds of the invention is not critical, the formula It is easy to understand that for the compound (1), a substantially pure form is preferable. Ru. Preferably, whenever possible, the compounds of the invention are obtained in crystalline form. Ru.

When the compound of the invention is crystallized or recrystallized from an organic solvent, The solvent of crystallization is present in the crystalline product. The present invention also includes such solvates. do. Similarly, among the compounds of the present invention, crystallization from a water-containing solvent or recrystallization is possible. Some things are done. In such cases, water of hydration is formed. The scope of the invention is stoichiometric hydrates as well as indeterminate amounts produced by processes such as freeze-drying. This includes compounds containing water.

Preferred examples of compounds included in the present invention include 2-methquine-(thiazol-5-yl) )-1-(norsen-2-yl)ketone.

The compound of the present invention can be produced by a method known as a method for producing α,β-unsaturated ketones. will be built. Some of these processes are more appropriate than others.

Suitably, the compound of formula (1) is a compound of formula (II): (wherein Zl, Z2 and Z3 are the same or different and each is a hydrogen or hydroxyl protecting group ) or its activated derivatives with an organometallic reagent, followed by It can be prepared by a process consisting of removing the hydroxyl protecting group.

Suitable organometallic reagents include the following: (1) Formula: R'MgX (wherein R1 is the same as defined in formula (D), and X is chlorine, bromine or iodine. The reaction is carried out using copper(1) iodide as a catalyst. optionally in the presence of; (2) formula: R'Li (wherein R1 is the constant in formula (1)); The organolithium reagent (same as the meaning): (3) Formula: R'MnC1 (in the formula, R1 is the same as the definition in formula (1)) an organomanganese reagent; and (4) Formula: R'Li-CeX3 (wherein, R1 is the same as the definition in formula (I) and X is chlorine, bromine or iodine).

Reactions with organometallic reagents are conveniently carried out in ethereal or hydrocarbon solvents. , the selection of which depends on the specific requirements of the organometallic reagent. Preferably Grignard Reagents are prepared and used in diethyl ether or tetrahydrofuran.

The reaction is generally carried out at or below ambient temperature under an inert atmosphere such as argon or nitrogen. It will be done. The reaction time depends on the starting materials used. The progress of the reaction is slow Track by conventional methods such as layer chromatography to ensure that the optimal amount of product is present in the reaction mixture. The reaction is stopped when the

The compound of formula (III) in which Zl, 22 and Z3 are each hydrogen, The production method is G B 1587058 (Beechaa + Group (Beacham Group)).

Suitable activated derivatives of acids of formula (IrI) include formula <IV'): (wherein Zl, Z2 and Z3 are the same as defined above, and the groups in the formula include, in addition to the nitrogen atom, , one or two further heteroatoms selected from oxygen, nitrogen and sulfur. a 5- or 6-membered heterocycle that is substituted or itself substituted. represents a ring which may be fused with a benzene ring which may be Contains.

Preferred thioesters have the formula (JVa): (wherein Zl, 7.2 and Z3 are , the same as the above definition).

The compound of formula (IVa) can be obtained from Tetrahedron Letters. Letters), 1979.31.2875 by E.J. and D.A. Clark (E, J, Corey and D, A, By a method similar to that described by C1ark), the formula (III) can be converted to The compound was treated with 2.2°-dipyridyl disulfide in the presence of triphenylphosphine. Manufactured by processing.

Other suitable activated derivatives of acids of formula (II) are those of formula (V): (wherein Zl, Z2 and Z3 are the same as defined above, and R2 is (C+~6) alkyl. ), and the formula (Vl)・ (In the formula, Zl, Z2 and Z3 are the same as defined above, and R3 and R4 are identical or different, each optionally substituted aryl group, e.g. phenyl , or mixed anhydrides of (C+ to 11) alkoxy groups, e.g. including.

A compound of formula (V) can be prepared by combining a compound of formula (IIT) with a suitable compound of formula R20COC1, for example. Crimmin M, J, et al. l, ) (JC3Perkin I, 1989.2047) It can be obtained by processing using the following methods.

The compound of formula (Vl) is obtained by bactericidal reaction of the compound of formula (II) with CIPOR3R'. Baxter A, J, G, et al. ), Tetrahedron Letters ), 1980.21.5071. It is obtained by

Furthermore, suitable activated derivatives of acids of formula (Ill) include formula (Vll): (wherein , Zl, Z2 and Z3 are the same as defined above, and R5 and R6 are the same or or differently, each is (CI-6)alkyl, or the substituents R5 and and R6 form (Cz-t)alkylene), and the formula (Vlll): ( In the formula, Zl, Z2 and Z3 are the same as defined above, and R7 and R4 are Together with the associated nitrogen atoms, they form an imidazolyl or triazolyl ring ).

Preferred compounds of formula (\'II) are disclosed in WO91109855 (Beacham Group N-methkin- as described in Beecham Group) N-methylamide (i.e. R5 and R6 are each methyl) . Combination of N-methoxy-N-methylamide with organolithium or Grignard reagents Tetrahedron letters form a ketone through a reaction. edron Letters), 1981.3815. It is described by Nahra and Reinreb 7.

Preferred amides of formula (VIII) are imidazol-1-yl derivatives. α.

The reaction of a β-unsaturated acid or its imidazolyl derivative with a Grignard reagent Hew, Ber, 1965.95.1284.

Amides of formula (VII) and (Vlll) are suitably prepared by converting them from monic acid. isobutyl roroformate in tetrahydrofuran in the presence of triethylamine; The mixed anhydride intermediate (isobutyl monate carbonic anhydride). This intermediate is then converted into dichloro React with amine HN(OR')R' in methane at about 20°C for about 2 hours or or in the presence of triethylamine and 4-dimethylaminopyridine in THF , at about 20°C with the amine HNR'R'.HCI to form Zl, Z2 and Z3. are each hydrogen T (R1, R5, R6, R7 and R'' are the same as defined above ) to form a compound of formula (VII). The hydroxyl group is then converted into THF triethylamine and 4-dimethylaminopyridine as catalysts in solvents such as treatment with a suitable hydroxyl protecting agent, e.g. chlorotrimethylane, in the presence of Protect by

The thioester of formula (IV) is preferably an organic ester of formula R'MnC1 as defined above. Upon treatment with a manganese reagent, the amide of formula (Vll) or (Vlll) is preferably is treated with the organolithium reagent R'Li as defined above.

Preferably, the compound of formula (1) is a compound of formula (Vll) as defined above. It can be produced by treatment with the organolithium reagent R'Li.

Suitable organometallic reagents are prepared by conventional methods. For example, the appropriate formula: R' The organomanganese reagent for MnC1 is the organolithium reagent R’Li mixed with manganese chloride and a solution of lithium chloride in dry THF or anhydrous manganese chloride in dry THF. Conveniently (prepared) by adding excess R'MnC1 to is preferred. Alternatively, Grignard reagents can be used instead of organolithium reagents. The organic manganese reagent R'MnC1 is obtained.

Other organomanganese reagents that can be used in place of R’MnC1 include: Examples include: (1) Synthetic Communications (R')sMn as described in Li or (R')sMnMgX (wherein, X is the same as defined above): (2) Synthetic Communications R' in ether as described in MnI; and (3) Tetrahedron Letters Letters), 1976.3155. In the case of 0R'MnC1, the organomanganese reagent can be used in 5 itu if necessary. Manufactured in

The organic cerium reagent is described by Imamoto et al. Null of Chemical Society, Chemical Communications OC hew Sac, ChewCommun),] 982.1042 By a method similar to that of Treat the organolithium compound of In this way, it can be obtained in 5 itu.

Another process for producing compounds of formula (1) is described in EP-A-0029665 (Bee Beecham Group) and has the formula (I Allyl of XI (wherein R1, Zl, Z2 and Z3 are the same as defined above) Treating alcohol with an oxidizing agent that converts allyl alcohol into α,β-unsaturated ketones and then removing the hydroxyl protecting group if necessary.

Suitable oxidizing agents include activated manganese dioxide, pyridinyl dichromate, etc. and pyridinium chlorochromate. For convenience, the oxidation reaction is For example, in a non-polar solvent such as benzene or toluene. .

Compounds of formula (IX) are novel intermediates useful in the process. Therefore , the present invention further provides compounds of formula (IX) as defined above.

The allyl alcohol of formula (IX) has the corresponding formula (X): (wherein Zl, Z2 and and Z3 are as defined above) are treated with an organometallic reagent as defined above, It can then be prepared by removing the hydroxyl protecting group if necessary.

The aldehyde of formula (X) can be treated as a Grignard reagent of formula R'MgX or, more preferably, as a Grignard reagent of formula R'MgX. Preferably, it is treated with the organic cerium reagent R'Li-CeX3 defined above.

The aldehyde of formula (X) is an amide of formula (Vll) defined above, - treatment with a suitable reducing agent such as aluminum hydride, followed by hydration if necessary. Produced by removing the roxyl protecting group. Other suitable alde of formula (X) The method for producing hydride is described in EP-A-0029665 (Beacham Group (Bee chamGroup)).

The compound of formula (1) is of formula (XI) (wherein Zl, Z2 and Z3 are as defined above) by formula (X11): HC:C-R’ (XI I) (wherein R1 is as defined above) with a terminal alkyne to form an intermediate; This is expressed in Helvetica, 1976.59.1233. Pauling, H., and Helvetica (H. elvetica), 1976.59.567 by C. El Orlan ( Tris-(triphenyl) as described by G., L. treatment with lunaryloxy)-vanadate and triphenylsilanol, then , can also be prepared by removing the hydroxyl protecting group if necessary.

The preparation of the compound of formula (XI) is described in GB1587060 (Beacham Group ( Beecha II Group)).

As used herein, the term "hydroxyl protecting group" refers to means any such group known in the art that can be removed without destroying the part. do. Suitable hydroxyl-protecting groups include ``Protecting Groups in Organic Synthesis'' ('P protective Groups in Organic 5ynthesi s’), T.W. Green (T.

1, Greene), Willie Interscience 7. (Wiley-In terscience), 2, - York, 1981. It will be done.

Hydroxyl groups of compounds of formulas (II) to (XI) can be isolated using conventional methods. , any stage of the process can be protected. Hydroxyl protecting groups can be obtained by enzymatic method. It can be removed by methods known in the art, including.

Particularly suitable hydroxyl protecting groups are those that are easily removed under mild conditions. Therefore, it is a noryl group. Such a group has the formula.

L, S i Y L 3S i OC = N S i L sL t S Y 2 L s S iN HCON HS z L 3L s S i N L　2　L　N　HCON　HS　i　L　3LsSiNH3iL3　’ tB uMe2Si OSO2CF3L x S i N HCOL (In the formula, Me represents methyl, tBu represents t-butyl, and Y represents halogen. represents, and each group independently represents hydrogen, (01~,)alkyl, (C1-6)alkyl. halo selected from koxy, aryl or aryl(C,-4)alkyl) It is introduced using conventional silylation reagents including silanes and silazane. preferred A suitable silylating reagent is trimethylsilyl chloride. A particularly suitable protecting group is Limethylsilyl, -butyldimethylsilyl and t-butylphenylsilyl groups It is. A preferred protecting group is a trimethylsilyl group because of its ease of removal. Ru.

The glycol group of the compounds of formulas (III) to (XI) is represented by formula (XIII): R' C(OR1°X0RI heavy X0RI (XIII) (wherein, R9 is hydrogen or is (C+~6)alkyl, and each of R" and R" is (C+~6)alkyl, R10% +-6) alkyl) by forming a cyclic derivative. therefore, in the cyclic derivative, Zl and Z2 together form R'C (○R12). R9 is hydrogen, methyl, ethyl, n- or iso-propyl Hydrogen is most suitable. RIG, Rl 1 and RI The two groups are methyl, ethyl, n- or 1so-propyl, or n-1iso -1sec- or t-butyl is suitable, methyl is most suitable . Similarly, the hydroxyl group of a compound of formula (I) can be added to another compound of formula (1) as defined above. may be protected before converting to . In each case, said hydroxyl protecting group is , for example, Clayton et al., JC3Perki Mild acid hydrolysis as described in Trans I, 1979.308 Following solution, it can be removed by alkaline hydrolysis.

The present invention also provides the formula ( A pharmaceutical or veterinary composition comprising the compound of I) (hereinafter referred to as "drug") is also provided. provide The compositions may be formulated for administration by any route, depending on the disease being treated. Exists. The composition may be in the form of tablets, capsules, powders, granules, troches, liquids or gels. formulations, such as oral, topical or sterile parenteral suspensions.

Tablets and capsules for oral administration are in unit dosage form, e.g. Kana, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone Which binders: e.g. lactose, sugar, corn starch, phosphoric acid Bulking agents such as rum, sorbitol or glycine; e.g. Tablet-forming lubricants such as silium, talc, polyethylene glycol or silica; For example, disintegrants such as potato starch, or sodium lauryl sulfate. It may also contain conventional excipients such as acceptable wetting agents. Tablets are regular pharmaceutical products In the examples, coating may be performed by a well-known method.

Oral liquid preparations include, for example, aqueous or oily suspensions, solutions, emulsions, syrups or May be in the form of an elixir or mixed with water or other suitable vehicle before use. It may also be a dry product that is reconstituted by a process. Such liquid preparations contain sorbitol , syrup, methylcellulose, glucose syrup, gelatin, hydrogenated edible oil Suspending agents such as fats; for example, lecithin, sorbitan monooleate, or aca Emulsifiers such as shea; such as almond oil, fractionated coconut oil, glycerin non-aqueous vinyl such as oil-based esters, propylene glycol, or ethyl alcohol. vehicle (may contain edible oil); methyl p-hydroxybenzoate or protein Preservatives such as pill or sorbic acid and optionally conventional flavoring agents or may also contain conventional additives such as colorants.

For topical application to the skin, the drug may be made into a cream, lotion or ointment. stomach. Cream or ointment formulations for use with the drug are well known in the art. Usual formulations, e.g. Harry's Cosmeticology, 7th Edition, Wilkin Edited by Son J.B. and Moore R.J. (Harry’s Co. smeticology 7th Ed,, ed Yilkinson J, B , and Moore R.J., George Goodwin, Lon Mr. do A19 82) and the British Pharmacopoeia. It's like being there. For topical application to the ear, the drug may be carried in a suitable liquid carrier, For example, water, glycerol, dilute ethanol, propylene glycol, polyethylene suspension in glycol or fixed oil. For topical application to the eyes , the drug is formulated into a suspension in a suitable sterile aqueous or non-aqueous vehicle. additives, e.g. Buffers such as sodium metabisulfite or edetate disodium: Vinegar acids or phenylmercuric nitrate, benzalkonium chloride or chlorhexodine, etc. Preservatives, including bactericides and fungicides, and thickeners, such as hypromellose, etc. Can be mentioned. The dosage used for topically applied compositions will, of course, depend on the size of the area to be treated. Depends on the size. For ears and eyes, each dose typically contains 10 to 100 Contains drugs in the me range.

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

For parenteral administration, the drug and a sterile vehicle are used to form a fluid unit dosage form. Prepare. The drug, depending on the vehicle and concentration used, can be suspended in the vehicle. Ru. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are included in the vehicle. It can be dissolved in To improve stability, the composition may be frozen after filling into vials. The water can be removed under vacuum. Then seal the lyophilized powder in a vial . Sterilize the drug by contacting it with ethylene oxide before suspending it in a sterile vehicle be able to. Advantageously, surfactants or wetting agents are mixed into the composition to promotes uniform dispersion of

A veterinary composition for the mammary treatment of mammary diseases in animals, in particular bovine mastitis, is It generally contains a suspension of the drug in an oil vehicle.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60%, depending on the method of administration. % drug by weight. When the composition is in unit dosage form, each dosage unit Preferably, it contains 50 to 50,019 drugs. Adult human (typical weight approx. 7071 The dosage used for the treatment of 9) depends on the route and frequency of administration, preferably 100 mg/day. range of 1001 to 3 g of drug per day, for example 25019 to 29 of drug per day.

Alternatively, the drug may be administered to non-human animals as part of their diet. this In cases where the amount of drug used is less than 1%, preferably less than 0.5% by weight of the diet. be. The animal's diet consists of normal food, to which drugs are added or The agent is included in the premix of the mixture with the food product. Drug administration to non-human animals A suitable method of administration is to add it to the drinking water of non-human animals. this In this case, the concentration of the drug in the drinking water is about 5-500 μg/”s, e.g. 5-200 μg /ml is suitable.

The compounds of the invention are useful for bacterial and mycoplasma in non-human animals and humans. Treatment of infections caused by mosquitoes, such as respiratory tract infections, otitis, meningitis, and skin infections in humans. and soft tissue infections, mastitis in cattle, and nonhumans such as pigs and cattle. Useful in treating respiratory infections in outside animals. Therefore, in another aspect The present invention also provides a method for treating humans or non-human animals, comprising: administering a compound of formula (I) to a human or non-human animal in need of treatment. Provide a treatment consisting of: Alternatively, the pharmaceutical compositions described above may be used in therapy. It may also be used.

In one aspect of the treatment, a method for treating a bacterial infection in a human or non-human animal. , particularly for the treatment of respiratory infections in humans or non-human animals. . The compounds of the invention are suitable for use in the genus Haewophilus, e.g. Hoinfluenzae Q1: Branhamera genus Branhamella, e.g. B. catarrh alis) 1502; Streptococci, For example, Nis pyogenes (S, pyogenes) CN 10 and Varnish ・Pneumonia (S, pneumonia) P U 7: and Staphy o Staphylococci, such as Nis aureus o. aureus oxford (S, aureus oxford); ginella), such as L. pneumophila (L, pneumophila) It is active against both Gram-negative and Gram-positive microorganisms, including a). Furthermore , the compounds of the invention may be used with other antibacterial agents such as methicillin; macrolides; Resistant to β-lactam antibiotics such as Ricondo and Lincosamides (multi-resistant ) of Nis aureus and Nis epidermis (S, epidermis) It is active against Staphylococcus microorganisms such as.

The compounds of the present invention may also be used to treat the development of mycoplasma-induced infections, particularly AIDS. Mycoplasma fermentans (M. ycopl, asma fermentans). It is gender. Thus, in another aspect, the present invention provides M fermentans (M fermentans), particularly in humans also infected with HIV. The method provides a method of treatment for humans in need of such treatment. treatment with an anti-mycoplasma effective amount of a compound of formula (1).

In yet another aspect, the invention provides antibacterial and and/or of a compound of formula (I) in the manufacture of a medicament for anti-mycoplasma therapy. Provide usage.

No adverse toxicological effects are expected to occur from administration of compounds of formula (1).

The invention is illustrated in the following examples, which limit the scope of the invention. It's not a thing.

Example 12-Methoxy-(thiazol-5-yl)-1-(norsen-2-yl) ketones 2-Methoxythiazole (silane and vinyl) under argon atmosphere at -78°C. -Bridges (G, Lein and B, Pr1js), Helveti Force Si HelvChim Acta, 195.4.37.2057) A solution of (7,279) in dry THF (100s+1) was prepared using n-butyl in hexane. Treated by dropwise addition of lithium (1.5 M, 42 Wl). 0.75 at -70℃ After hours, N-methoxy N-methyl-6,7,13 in dry THF (160d) -0-tris-(trimethylsilyl)monamide (15,49,1,00 mmol ) (W092102518, Beecham Group Public Limited ・Campa = - (Beecham Group plc)), temperature -65℃ Added dropwise while keeping the temperature lower (addition time 1 hour). After 1.25 hours at -70℃ , acetic acid (7°71N) was added. Extracted with diethyl ether and dried (sulfuric acid After evaporation, the residue was dissolved in THF (842 ml) and the salt Acid (0.4M, 21011) was treated all at once. After stirring at high speed for 2 minutes, saturated charcoal Sodium oxyhydrogen solution (250,1) was added quickly. The reaction mixture was diluted with ethyl acetate. organic phase is separated, washed with brine and dried (sulfuric acid mag evaporation to give the crude title compound (219).

The material obtained in the above process (e.g. 36 g) was subjected to flash chromatography. - attached. The substance was dissolved in dichloromethane/toluene and added under suction to dry silica ( I J19) and the column was flushed with ether followed by a methanol/ether mixture ( 2% to 6%) to give the title compound as an amorphous solid (249); Question (CD30D) 0.94 (3H, d, J 7.I Hz, 17-Hs) , 1.20 (3H.

d, J 6.5Hz, 14 Hs), 1.32-1.46 (IH, m, 12-H), 1°65-1.73 (2H, m, 9H2), 1.91-2. 01 (IH, m, 8-H), 2.23 (3H,, s, 15 Hs), 2. 33 (IH, dd, J14.3 and 9.5Hz, 4-H), 2.68-2 ．． 85 (3H, m, 4.10 and 1l-H), 3.39 (LH, dd , J9.0 and 3, OHz, 6-H), 3.60 (IH, d, Jll, 3H z, 16-H), 3.74-3.93 (4H, m, 5. 7. 13 and 16-H), 4.13 (3H, s, 0CHs), 6.73 (LH, s, 2-H), 7.95 (IH, s, 4'H); δc (CDsOD) 12.2 (C17), 20.2 (C-15), 20.3 (C-14), 33.0 ( C-9), 41.8 (C-8), 43,7 (C-12), 44.3 (C-4 ), 56.9 (C-10), 59.8 (C-11), 61.2 (OCH3 ), 66.4 (C-16), 70.0 (C-6), 70.7 (C-7), 71.6 (C-13), 76.4 (C-5), 121.8 (C-2), 1 37.1 (C-5°), 143.9 (C-4°), 159.8 (C-3), 181.1 (C-2'), 184.6 (C-1).

Dissolve the amorphous title compound (489) in ethyl acetate (2oo*I) and The solution was first cooled to 10°C for 5 hours and then to -10°C for a further 16 hours. Obtained The resulting solid was collected by filtration and dried to yield the crystalline title compound (409).

Melting point: 115°C. [δ]D (20℃) knee 6℃ (cll, MeOH): v,,, (KBr)3452.3301.1639.1592.1484C@-';λ N, , (EtOH) 3010 m (ε., 20.710).

Example 2 2-(2-methoxyethoxy)thiazol-5-yl-1-(norcene -2-yl)ketone (a) 2-(2-methyneethoxy)thiazole sodium hydride (12,75 mmol, 0.3849) in tetrahydrofuran (1.0 ml) Ethanol (13.5 mm/L, 1.0239) +: Added. 0. After 5 hours, 2-bromothiazole (15 mmol, 2.4579) was added and the The reaction was heated at 40°C for 1.5 hours. Cool the suspension and dilute with diethyl ether. diluted, filtered and evaporated to dryness under reduced pressure using diethyl ether/hexane as eluent. Purification by column chromatography on silica using 20% An oily 2-(2-methoxyethoxy)thiazole was obtained (1.171 g, 58% ); δn (CDCIg) 3.4 (3H,s, -OMe), 3.75 (2 H, m.

CH, -OMe), 4.5 (2H, m, Ar0CHt), 6.7 (IH, d , J3.7Hz.

4-H), 17.1 (LH, d, J3.7Hz, 5-H).

(b) [2-(2-methoxyethoxy)thiazol-5-yl]-1-(6,7, 13-0-tristrimethylnlylnormon-2-yl)ketone - at 78°C, n -Butyllithium (1.6M in hexane) (2.25 mmol, 1.5 m/) 2-(2-methoxyethoxy)thiazole in tetrahydrofuran (5 ml) dripped into. After 20 min at -78°C, N-methoxy-N- in THF (5 m/) Methyl-6,7,13-0-tris(trimethylsilyl)monamide (1,5 mi 0.9059) was added dropwise keeping the temperature below -65°C. − After a further hour at 78°C, acetic acid (0,239) was added followed by water C20d>. Added. Extracted with diethyl ether, dried (MgSO4) and evaporated under reduced pressure. The silica was dried and purified using ethyl acetate/hexane (0-20%) as eluent. Purification by upper blade ram chromatography gave the title compound as a yellow oil (0 ．． 2639.25%); δ11 (CDCIs) 0.01-0.2 (27H, m , 9xSiCHs), 0.7-0.8. (3H, d, J7.OHz, 17H 3), 1.0-1.1 (3H, d, J6゜3Hz, 14 H3), 2.1 ( 3H, s, 15 H3), 3.2-3.3 (3H, s.

OMe), 4.4-4.5 (2H, m, J9, OHz, Ar0CH2), 6 ．． 35 (LH.

s, 2-H), 7.55 (LH, s, ArH).

(c) 2-(2-methoxyethoxy)thiazol-5-yl-1-(norcene-2 −il) ketone Said ketone (0.25 mmol, 0.173 g) and salt in THF (5 mJ) The acid (0.4M, 1.2ml) was stirred at room temperature for 2 minutes. Saturated sodium bicarbonate solution, extracted with diethyl ether, dried (MgSO4) and dried under reduced pressure. Evaporate to dryness using methanol (0-8%) in dichloromethane as eluent. The title compound was purified by silica blade chromatography to give the title compound as a pale yellow foam. Obtained (93.2 mg, 78%); v,... (KBr) 2883.2 359.2330.1729.1528cm-';λ,,, (EtOH)30 2nm (ε, 16.580); δH (CD30D) 0.9 (3H, d, J7. IHz, 17 Hz), 1.2 (3H, d.

J6.4Hz, 14 Hs), 2.72-2.82 (2H, m, 10 and 1 l-H), 3.4 (3H, s, OMe), 4.45-4.6 (2H, m, A r0CH2), 6.72 (IH, s, 2-H), 7.9 (2H, s, ArH) ; m/z (E, L) 485 (M", 20%), 59 (100%): (measured value +M”485.2090, Czs) The theoretical value of IxsNO,S is M2B5.20 83).

Example 3 2-(2-isopropoquinoethoxy)thiazol-5-yl-1-(no lucen-2-yl)ketone (a) 2-(2-isopropoxyethoxy)thiazole At 40°C, sodium hydride (12,75 mmol, 0.3849) in tetrahydrofuran (2,0,1 ) in 2-isopropoxyethanol (13.5 mmol, 1.6++/) added. After 0.5 hours, 2-bromothiazole (15 mmol, 1°35/) was added. and the reaction was heated at 40°C for 3 hours, followed by 80°C for 1 hour. suspension The solution was cooled, diluted with diethyl ether, filtered, evaporated to dryness under reduced pressure, and eluted. Column chromatography on silica using diethyl ether/hexane (10%) as liquid. Purified by chromatography to form an oily 2-(2-isopropoxyethquin)thiamine. The azole was obtained (0.6449.27%). δH (CDC13) 1.2 (6 H.

d, 2xCHs), 3.65 (IH, m, CH0CH2), 3.8 (2H, m, CH-OCH2), 4.5 (2H, m, Ar0CHz), 6.6 (IH , d, J3°88Hz.

5-H), 7.1 (IH, d, J3.88Hz, 4-H).

(b) [2-(2-isopropoquinethoxy)thiazol-5-yl]-1-( 6゜7,13-0-) listtrimethylsilylnormon-1-yl) ketone-7 At 8°C, n-butyllithium (1.6M in hexane) (3 mmol, 188 ml ) in tetrahydrofuran (7 ml) of 2-(2-isopropoxyethoxy) Dropped into azole. After 35 min at -78°C, N- in THF (10s+4') Metquin-N-methyl-6,7,13-0-tris(trimethylnoryl)mona (2 mmol, 1.205 g) dropwise while maintaining the temperature below -65°C. I put it down. After a further 1.5 hours at -78°C, glacial acetic acid (5 mmol, 0.3 ml) was added. followed by the addition of water (15 liters). Extract with diethyl ether and dry (MgSOJ, evaporated to dryness under reduced pressure, ethyl acetate/hexane ( 0-20%) and purified by column chromatography on silica to give a yellow The title compound was obtained as a colored oil (0.3122q, 21%): 6M (CDsOD) 0 ．． 1-0.2 (27H, m.

9XSiCHs), 0.9 (3H, d, 17-Hs), 1.15 (6H, d , 2xCHs), 1.2 (3H, d, 14-H3), 2.2 (3H, s, 1 5 Hs), 3.8 (2H, m.

CH! 0CH), 4.55 (2H, m, Ar0CHz), 6.7 (IH, s, 2-H), 7.9 (IH, s, ArH).

(c) 2-(2-isopropoxyethoxy)thiazol-5-yl-1-(Norce (2-yl)ketone The ketone (0.425 mmol, 0.310 g) and THF (8.5 mmol) Medium hydrochloric acid (0.4M, 2.13ml) was stirred at room temperature for 2 minutes. saturated sodium bicarbonate solution, extracted with diethyl ether, dried (MgSO4) and reduced. Evaporate to dryness under pressure and methanol in dichloromethane (0-7%) as eluent. The foamy title compound was purified by column chromatography on silica. Obtained (177 feet 9.81%) 3. ．． 2926.2324.1776.137 9.806cm'; λ, , (EtOH)301n+*(ε, 19.539) : δH (CDsOD) 0.95 (3H.

d, J 7.12Hz, 17-Hs), 1.15 (6H, d, J6.44Hz , 2xCHs), 2.75-2.85 (2H, m, 10 and 1l-H), 4 ．． 55 (2H, m.

Ar0CHz), 6.7 (IH, s, 2-H), 17.95 (IH, s, A rH); m/z (E, 1.) 513 (M”, 45%), 45 (100%) :(Measurement value: M”513.2391, theoretical value of C2s Hs e N Om S is M513.2395).

Example 4 2-(7,7,7-dolys(methylthio)heptoxy)-thiazole -5-yl-1-norsen-2-ylketone (a) 2-(7,7,7-doris methylthiohebtoquine) thiazole 3,4-hydro 2H-pyran (33,1 mmol, 3.0214) of 6-bromohexano in 80 Il of diethyl ether. (27.65 mmol, 59). After 1.5 hours at room temperature, another 3 ．． 4-dihydro-2H-bilane (33.1 mmol, 3.02 m/) was added, Stirred for 2.5 hours. Add saturated sodium bicarbonate solution (100 x 1) and dilute Extracted with ethyl ether, dried (MgSO4) and evaporated to dryness under reduced pressure. silica using dichloromethane/hexane (70-100%) as synergist. Purification by ram chromatography yielded 2-6-bromohexylol as a colorless oil. Xytetrahydrobilane was obtained (6.4599.88%).

δH (CDCIs) 1.5-1.75 (8H, m, 4XCH, 3.4-3. 6 (4H.

m, CH2Br and CH20), 4.5 (IH, t, ocHo). -78℃ and n-butyllithium (1.6M in hexane) (29.24 mmol, 19 ．． 5++I) in tetrahydrofuran (801/) to tris(methylthio)meta (24.37 mmol, 3.24 ml') was added dropwise. After 1.5 hours, TH F (20ml) Add the above compound (24°37 mmol, 6.4599) and stirred at -65°C for 1 hour. Add saturated ammonium chloride solution (30m/) extracted with diethyl ether, dried (MgSO4) and evaporated to dryness under reduced pressure. and silica using methanol/dichloromethane (0-20%) as eluent. Purified by Kakamiba ram chromatography to produce a colorless oily 7.7.7-tri Smethylthio-1-tetrahydrobilan-2-yloxyhebutane was obtained (7. 1124g, 86%); 6H (CDCIs) 2.1 (9H.

s, 3xSCHs), 3.35~3.5 (2H, m, 0CHz), 3.7~ 3.9 (2H.

m, cyclic OCH, ), 4.55 (IH, t, ○-CH-0). amber list -15(0,39) in methanol (150,1) Limol, 7°11g). After 4 hours, filter and evaporate to dryness under reduced pressure. Column filter on silica using diethyl ether/hexane (4%) as eluent. Purified by chromatography to give 7,7,7-dorismethylthio as a colorless oil. Hebutanol was obtained (3,739.70%); 1.2-1.9 (IOH, m , 5xCHz), 2.1 (9H.

s, 3XSCH3), 3.6 (2H, t, 0CH2). Sodium hydride ( 1,89 mmol, 0.0579) in THF (3 ml). rimole, 0.5089). After 0.5 hours, 2-bromothiazole (2 , 2 mmol, 0.2 special table 1,7-503244 (B) g/) was added and the reaction was heated at 40° C. for 4 hours. Then, cool and diethyl Diluted with ether, filtered and evaporated to dryness under reduced pressure, diluted with diethyl ether/hexane. (0-10%) as eluent for silica blade ram chromatography. Further purification gave the title compound f = (0,2329,34%); 6M (C DCIS) 1.3-1.9 (10H, m, 5XCH, 2.1 (9H, s , 3xSCHs), 4.4 (2H, t, 0CR1), 6.6 (IH, d, 5- H), 7.1 (IH, d, 4-H).

(b) [2-(7,7,7-tris-(methylthio)heptoxy)-thiazole 5-yl]-1-(6,7,13-0-tristrimethylsilylnormon-2- il) ketone n-butyllithium (1.6M in hexane) (2 mmol, 1.2 2-(7,7,7-1-rismethylthiohept) in THF (6 ml) xy)thiazole (2 mmol, 0.674 p) l: added dropwise. 40 minutes later, Ding H N-methoxy-N-methyl-6,7,13-0-tris( Trimethylsilyl)monamide (2 mmol, 1.2069) was added dropwise. 2 o'clock After a period of time, after warming to -50°C, glacial acetic acid (4 mmol, 0.2 mf) was added, followed by and added water (10 g).

Extracted with diethyl ether, dried (MgSO4) and evaporated to dryness under reduced pressure. After that, chromatography was performed on silica using ethyl acetate/hexane (0-20%) as eluent. Purification by mucochromatography gave the title compound (0.4429.25 %); δl1 (CDCIs) 0.1-0.2 (27H, m, 9xSiCH , ), 0.9 (3H, d.

17-H3), 1.2 (3H, d, 14-Hs), 1.3-1.9 (IOH , m, 5xCH2), 2.05 (9H, s, 3xCHs), 2.2 (3H, s, 15 Hz), 2°6 (2H, m, 10 and 1l-H), 3.35 ( IH, dd, 6-H), 4.4 (2H, t+0CHz), 6.5 (IH, s , 2-H), 7.7 (LH,s, Ar-H).

(c) 2-(7,7,7-tris-(methylthio)heptoxy)thiazole-5 -yl-1-(norsen-2-yl)ketone R Keto> (0.5 mi!J mole, 0.439g) OyoUTHF (10m Medium block acid (0.4M, 2.5ml) was stirred at room temperature for 2 minutes. Saturated bicarbonate Add thorium solution, extract with ethyl acetate, dry (MgS　O4) and reduce Evaporate to dryness under pressure and use methanol/dichloromethane (0-7%) as eluent. The product was purified by column chromatography on silica to form a colorless oil. A compound was obtained (0.310 g, 93%): v, (KBr) 2328. 1734.1527.1297.838.569cm-';λ,, (EtO H) 302 nm (ε, 17,227); δ, l (CDIOD) 0, 9 (3 H, d, J 7. IHz, 17-Hs), 1.2 (3H, d, J6.6Hz .

14 Ha), 2.1 (9H, s, 3xCHs), 2.25-2.35 (2 H, m, 4-H2), 2.65-2.8 (2H, m, 10 and 1l-H), 3.4 CIH, dd.

6-H), 3.55 (LH, d, 16''-H), 3.75-3.9 (4H , m, 5°7.13.6-H), 4.45 (2H, t, 0CH2), 6.7 (IH, s, 2-H), 7.9 (LH, s, Ar-H).

Example 5 2-(6-Medquincarbonylhexoxy)-thiazol-5-yl- 1-norsen-2-ylketone - Mercury(II) oxide (3.38 mmol, 0.0729) and salt at 40°C Mercury(II) oxide (1,01 mmol, 0.279) was dissolved in methanol (6,311 ) to the ketone of Example 5C (0.338 mmol, 0.2249).

After 55 minutes, filter through Celite and add saturated ammonium chloride solution (10 ml aliquots). Washed, extracted with dichloromethane (12m=/), dried CMg5O<), vacuum Evaporate to dryness under The title compound was purified by column chromatography on silica using 0.113y, 60%);v,,, (KBr) 1646.1479.125 8.1187.1055c11-';λ,,, (EtOH)302nm (ε , 20.224): δ, (CD30D) 0.95 (3H.

d, 17-Ha), 1.2 (3H, d, 14-Hs), 2.2 (3H, s, 15-Hs), 2.25-2.4 (3H, m, CH3CO2 and 4-H), 2.7-2.85 (3H.

m, 4. 10 and 1l-H), 3.4 (IH, dd, 6-H), 3.5 5 (IH.

d, 16”-H), 3.6 (3H, s, C02CH3), 3.75-3.9 (4H, m.

5, 7.13 and 16-H), 4.45 (2H, t, 0CH2), 6.7 (LH,s.

2-H), 7.9 (IH, s, Ar-H); m/z (E, 1.) 56 9 (M", 50%), 83 (100%): (Measurement value: M'569.2667 , Cz*H43NOsS, theoretical value M569.2659).

Example 6 2-(6-carpoxylatehexoxy)-thiazol-5-yl-1 -norsen-2-ylketone sodium protease subtilisin Carlsbar (Protease 5ubtilisin Carlsberg) (20u ) by slow addition of sodium hydroxide solution (0, OIM). The ketone of the above example (0°0 69 mmol, 39 ml). The reaction mixture was lyophilized and dissolved in ethanol. Dissolved, filtered through celite and evaporated under reduced pressure to give the title compound (4 219, 100%): v, , (KBr) 2925, 1644, 1455, 1261.1053C1-1, λ, , (EtOH)303 (ε, 13,51 2); δ, 0.85 (3H, d, 17 Hz), 1.1 (3H, d, 14-H z), 1.2-1.6 (9H.

rll, 4xCH2 and 12-H), 1.7 (2H, m, 9 Hz), 1. 9 (IH, m.

8-H), 2.05 (2H, t, CH2C0h), 2.15 (3H, s, 1 5 Hs), 2.2 (IH, dd, 4-H), 2.6 (3H, m, 4", 10 and 1l-H), 3.25 (LH, dd, 6-H), 3.45 (IH , m, 16”-H), 3.65-3°85 (4H, m, 5.7.13 and 16-H), 4.3 (2H, t, 0CHx), 6.6 (LH, s, 2-H ), 17.8 (IH, s, Ar-H); m/z (FAB) 578 (MH″″ , 13%).

biological data H. influenzae Q1, B. catarrhalis 1502, Nis. pyogenes C. Nl0. Nis pneumoniae PU17 and Nis aureus oxford The activity of the exemplified compounds against the In vitro evaluation was performed using medium serial dilutions. After culturing at 37°C for 18 hours , MIC was measured and values in the range of 0.06 to 4 my/l-1 were observed. Change The compound of Example 1 was used as a microorganism belonging to the genus Legionella, L. pneumophila 1624, Antibacterial activity against serogroup 1 was evaluated by the following method.

Thaw cultures from frozen skim milk stock and transfer to supplemented buffered charcoal yeast extract agar (BC '1' Eα, 0xoid). After 3 days, colonies were transferred to tissue culture medium ( TCM = Eagle's Minimum Basic Medium + 10% Fetal Bovine Serum, 2mM L-Glutamine and 1% non-essential amino acids and suspended in Niall's salt). -Rand's barium sulfate opacity standard was set to 15. The suspension was further diluted with 1+ in TCM. Diluted by 100t to obtain a final inoculum of 4.83 x 106 cfu/ll. . Next, human fetal lung fibroblast (MRC-5) cells were inoculated. This cell is Once grown to 80% confluency in a 6-well plate, remove the medium and remove the monolayer. Washed twice with Darbe and Noko's PBS. 16 hours after inoculation (time 0), remove the medium. The inoculated bilayer was washed twice to remove adherent non-intracellular microorganisms. T Test compounds were added to the cells at the desired concentration in CM. Compound of Example 1 were tested at 0.5.2 and 8 μg/- and as controls, 0.5 and 2 μg/- 1 of erythromycin was used. 0,3.12.24.36.48 and After 72 hours, the medium was removed from the well (1 well/treatment volume) and the monolayer was washed twice.

Sterile distilled water was added and left for 30 minutes to lyse the cells. After vigorous grinding , the lysate was serially diluted in Mueller-Hinton Brother and BYCEα and 5% horse blood agar plated.

After culturing at 37°C for 72 hours, L. pneumophila colonies were counted.

Positive antibacterial activity was observed against L. pneumophila.

Furthermore, for confirmation, the stability of the compound in TCM was thoroughly tested for 72 hours. Ta. Solutions of 2 μg/me of each compound were prepared in TCM and incubated at 37°C or (or 4°C). Incubate and remove aliquots at regular intervals. Compound of Example 1 and Process 1 Nothromain was prepared in TCM using a standard of C. subtilis blood! Ratings for Nos ATCC6633 and Sartina Lutea NCTC8340 It's worth it.

Continuation of front page (81) Specified times 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, SN, TD.

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

CZ, DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, N.

, NZ, PL, RO, RU, SD, SE, SK, US (72) Mister Bonds, Jean Nister, UK, Lee R.H. 3rd and 7th Age A, Bettisworth, Brodscombe Park (no street address displayed) SmithKline ・Beacham Pharmaceuticals (72) Inventor O'Hanlon, Peter John Lee R.A., UK 3/7 Agey, Betschworth, Brodscombe Park (no address displayed) SmithKline Beecham Pharmaceuticals

Claims (1)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 is 2-(optionally substituted (C1-10)alkoxy)-thiazol-5-yl group]. 2. (C1-10) alkoxy group in R1 is methoxy, ethoxy or hexyl 2. The compound according to claim 1, which is soxy. 3.2-Methoxy-(thiazol-5-yl)-1-(normon-2-yl)keto 2-(2-methoxyethoxy)thiazol-5-yl-1-(normon-2- il) ketones, 2-(2-isopropoxyethoxy)thiazol-5-yl-1-(normon-2 −il) ketone, 2-(7,7,7-tris-(methylthio)heptoxy)-thiazol-5-yl -1-normon-2-ylketone, 2-(6-methoxycarbonylhexoxy)-thiazol-5-yl-1-normo N-2-iluketone, 2-(6-carboxyhexoxy)-thiazol-5-yl-1-normon-2- Irketone 2. The compound according to claim 1, which is a sodium salt thereof. 4. Examples 1 to 3 together with a pharmaceutically or veterinarily acceptable carrier or excipient. A pharmaceutical or veterinary composition comprising a compound of formula (I) according to any one of the claims. 6. 4. A compound of formula (I) according to any one of claims 1 to 3 for use in therapy. 6. Claims 1 to 3 for the manufacture of a medicament for use in antibacterial therapy. Uses of compounds of formula (I). 7. Claims 1 to 3 for the manufacture of a medicament for use in anti-mycoplasma therapy Use of a compound of formula (I) as described above. 8. (i) Formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, Z1, Z2 and Z3 are the same or different, each being a hydrogen or hydroxyl protecting group] or or an activated derivative thereof with an organometallic reagent, (ii) formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) [In the formula, R1 is Z1, Z2 and Z3 are the same as defined above] Treating the alcohol with an oxidizing agent that converts allyl alcohol into an α,β-unsaturated ketone. understand, (iii) Formula (XI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI) [In the formula, Z1, Z2 and Z3 are Same as above definition] is a ketone of formula (XII): HC≡C-R1(XII) [wherein R1 is as defined above] with a terminal alkyne to form the intermediate which is combined with tris-(triphenylsilyloxy)-vanadate and tris-(triphenylsilyloxy)-vanadate. treated with liphenylsilanol, Claims 1 to 3, characterized in that the hydroxyl protecting group is then removed if necessary. 3. A method for producing a compound of formula (I) according to any one of 3.