JPH09504512A - Derivatives of monic acids A and C having antibacterial, antimycoplasmal, antifungal and herbicidal activities - Google Patents

Abstract

(57) [Summary] Formula (I) [wherein A is an epoxy moiety or an E-double bond moiety; B is (a), (b), (c) (C (OH) = CHCO -B ³ is the same as), (d) (wherein, Q is selected from optionally a residue of aryl or heteroaryl ring which may be substituted); D is -CONR ¹ to B is a group of atoms, or, B-D for binding and represent the _{(E) -C (CH 3)} = CH, R 1 and R ² are the same or different and each is hydrogen or ( (C _1-6 ) alkyl, (C _3-7 ) cycloalkyl, (C _2-6 ) alkenyl, aryl, aryl (C _1-4 ) alkyl, heterocyclyl, (C _1-6 ) alkylcarbonyl, (C _{3-) 7)} cycloalkylcarbonyl, (C _2-6) alkenylcarbonyl, arylcarbonyl, aryl (C _1-4) alkylcarbonyl or heterocyclyl Cal Is selected from nil, each of which derivative Mont acids A and C indicated by 'may be optionally substituted have useful antibacterial activity, anti-mycoplasma activity, antifungal activity and herbicidal activity.

Description

Detailed Description of the Invention   Mon with antibacterial, antimycoplasmal, antifungal and herbicidal activity Derivatives of acids A and C   The present invention provides a novel antibacterial, antimycoplasmal and antifungal activity. The compounds, their method of manufacture and their use in human and veterinary medicine To intermediates for the production of such compounds. These compounds also have herbicidal activity And would be useful in agriculture.   The microorganism Pseudomonas fluorescens is Three of the pseudomonic acids known as pseudomonic acids A, B and C It produces a closely related tetrahydropyranyl compound. These compounds are It is of interest because of their antibacterial properties.   Pseudomonate A (now known as mupirocin) has the structure (A): Having. Formula (B): In the compound represented by, the ester-forming group is derived from 9-hydroxynonanoic acid. It is an ester of monic acid. Pseudomonic acid A is mainly Against sex bacteria, Haemophilus influenzae (Haemophilus influenzae) and Moraxella catarrhalis It also shows good antibacterial activity against some Gram-negative bacteria. Bacterial isoleucine Acting as a selective reversible inhibitor of t-TNA synthetase, which Inhibits bacterial protein synthesis. It has antimycoplasmal activity and antifungals Also active [Merck Index, 11th Edition, 1989, 9 93 and references therein and EP 0 251 434-A]. Conversion As a topical formulation, the compound is Beecham Group Public Limited Marketed under the trademark Bactroban by the company Beecham Group plc. ing. Systemic use is hindered by rapid metabolism to the inactive monic acid.   Pseudomonic acid C has the structure (C): Has [EP 003 069, Beecham Group Limited (B eecham Group Ltd)], due to the presence of the C10-C11 trans double bond. Distinguished from domodonic acid A.   The relative instability of pseudomonic acid A limits its therapeutic use to topical applications. Was. Therefore, it retains desirable antibacterial properties but allows for systemic use. Much effort has been devoted to the development of derivatives of pseudomonic acid A that are stable enough to Was. The α, β-unsaturated ester moiety is a species that is more resistant to enzymatic hydrolysis. Various other structural units, namely α-methyl-α, β-unsaturated esters (EP 0 090 603-A), α, β-unsaturated thiol esters (EP 0 002 37) 1-A), α, β-unsaturated amides (EP 001 914-A), α, β-unsaturated amides Tons (EP 0 029 665-A, WO 91/09855, WO 92/02 518, Journal of Medicinal Chemistry (J. Med. Chem.), 1 989, 32, 151), β-hydroxyketones (WO 93/06118), Cyclic ketones (WO 94/02478) and 5- and 6-membered heterocyclic rings (EP 0087 953-A, EP 0 123 378-A, EP 0 3529 09-A, EP 0 399 645-A and WO 91/09856). Attention was gathered to get it.   More recently, the marine closely related to pseudomonic acid has antibacterial activity. There have been reports of compounds produced by microorganisms. These compounds are “C” Leeds C10-C11 trans double bond and, in some cases, C-4 It has a Roxyl substituent. Further, the ester-forming group has a heterocyclic group at the carboxy terminus. 8-hydroxy present as an amide formed from an amine containing a cyclic moiety Derived from octanoic acid.   Formula (D): [Wherein R is hydrogen or hydroxyl] The compound shown by is an Alteromonas related to marine sponges. Produced by seed [Steelle DB and Stele DB Stierle A A, Two Hundreds National Mi 200th National Meetings of ACS, Washington DC, August 26-31, 1990, and Ixperien Experientia, 1992, 48, 1165]. C-4 hydroxyl stand The body chemistry was inferred to be β- based on spectroscopic experiments.   In addition, another compound named thiomarinol and thiomarinol C is Produced by the microorganism Alteromonas rava. this And the general formula (E): [Wherein R represents hydroxyl (thiomarinol) or hydrogen (thiomarinol C) Is)] Having. The stereochemistry is that in pseudomonic acid C at each of the common chiral centers They are the same. However, the stereochemistry of the 4-hydroxyl substituent is defined by Remain untouched [EP 0 512 824-A1, Sankyo Company Re Sankyo Co Ltd and Shiozawa et al., Journal Of Antibiotics, 1993 (12), 46, 18 34-1842 (Thiomarinol) and EP 0 595 458-A1, SA Nkyo Company Limited (Thiomarinol C)]. Thiomarinol is It has good antibacterial activity against both Gram-positive and Gram-negative bacteria. It is said to be active against plasma. The amine that forms the terminal amide is Pirotin, especially holotin. As its acetamide, it is known to have antibacterial properties. Compound Thiorutin [Merck Index, 11th Edition, 1989, 1471] and And horomycin [Merck Index, 11th Edition, 1989, 747]. Can be Thiorutin also has antifungal activity. For thiomarinol, α, The presence of the β-unsaturated ester moiety allows thiomarinol to undergo enzymatic hydrolysis. It is expected to mean that there is.   The inventors have surprisingly found that derivatives of monic acid with improved antibacterial properties. To incorporate the terminal 1,2-dithiolo [4,3-b] pyrrolonecarbamoyl moiety So I found what I could get.   Accordingly, the present invention provides a compound of formula (I): [Where,   A is an epoxy moiety or an E-double bond moiety: And   B is     (a)     (Where       B¹Is the group X¹, X², Y¹, NH or NHX¹And       X¹Is an optionally substituted aryl, preferably phenyl. Ren,       X²Is (C_1-10) Alkylene, (C_2-10) Alkenylene, (C_2-10) Arkini Ren, (C_3-7) Cycloalkylene or aryl (C_1-4) Is alkylene, which is Each of these may be optionally substituted,       Y¹Is an optionally substituted heterocyclyl, preferably Heteroaryl);     (b)     (Where       B²Is Y², Y²-X¹, Y²-X²Or Y²-Y^ThreeAnd       Y²Is 1 to 4 each selected from oxygen, sulfur or nitrogen, preferably , 1 to 3, most preferably 1 or 2 heteroatoms, optionally (C_1-10) Alkyl, (C_2-10) Alkenyl, (C_2-10) Alkynyl, (C_3-7) Cyclo Alkyl, aryl (C_1-4) By alkyl, aryl or heterocyclyl A 5- or 6-membered optionally substituted heteroaryl ring,       Y^ThreeIs an optionally substituted heterocyclic ring, preferably It ’s a lore,       X¹And X²Is the same as the above definition);     (c)     (In the formula, B^ThreeIs an optionally substituted hydrocarbyl or he A telocyclyl group, preferably the group B^Four-B^FiveAnd where B^FourIs (C_1-6) Archi Ren, (C_2-6) Alkenylene, (C_2-6) Alkynylene, B^FiveIs a direct bond, ( C_3-7) Cycloalkylene, (C_4-7) Cycloalkenylene, aryl or hetero Aryl, each of which is optionally substituted, or       B^FourIs a bond and B^FiveIs (C_3-7) Cycloalkylene, (C_4-7) Cycloa Is alkynylene, aryl or heteroaryl); or     (d)     Where Q is an optionally substituted aryl or heteroaryl Represents the residue of the ring) Selected from   D is B-CONR¹Is a group of atoms for attaching to, or   BD is (E) -C (CH_Three) = CH   R¹And R²Are the same or different and each represents hydrogen or (C_1-6) Alkyl, ( C_3-7) Cycloalkyl, (C_2-6) Alkenyl, aryl, aryl (C_1-4) Archi , Heterocyclyl, (C_1-6) Alkylcarbonyl, (C_3-7) Cycloalkyl calc Bonil, (C_2-6) Alkenylcarbonyl, arylcarbonyl, aryl (C_1-4) Selected from alkylcarbonyl or heterocyclylcarbonyl, each of these May optionally be substituted] And a compound represented by the formula:   The compounds of formula (I) are compared with the pseudomonic acids A and C in absolute Has improved antimicrobial properties with respect to potency and / or enhanced spectrum You.   For convenience and in comparison with the convention used for pseudomonic acid, A is Compounds of formula (I) that are poxy moieties are referred to as the "A" series, where A is E Compounds of formula (I) that are-double bond moieties are referred to as the "C" series.   The linking group of atom D comprises a carbon atom in a carbocyclic ring, ie an aryl ring. Containing one or more carbon atoms and / or heteroatoms in a heterocyclic ring It consists of heteroatoms, namely nitrogen, sulfur and oxygen.   Suitably D is a hydrocarbylene chain containing up to 20 carbon atoms, preferably Is a polymer having 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. It is a thylene chain, and this chain is   (a) If desired, for example, (C_1-6) May be substituted by an alkyl group ,   (b) If desired, it may be interrupted at one or more places by part M,   (c) direct bond, hetero atom selected from oxygen, sulfur or nitrogen, carbon Luoxy (COO), Oxycarbonyl (OCO), Carbonate (OCOO), Cal Vamoyl (CONH), NHCO, NHCONH, SO₂And SO₂NH, etc. B by proper connection¹, B², B^ThreeOr bound to Q,   (d) direct bond, optionally substituted (C_3-7) Cycloalkylene, Optionally substituted aryl, preferably phenylene, or Optionally substituted heterocyclyl, preferably heteroaryl By a suitable linkage such as -CONR¹Is connected to   Where M is a heteroatom selected from oxygen, sulfur or nitrogen, preferably an acid Elementary; (C_3-7) Cycloalkylene group; carbon-carbon double bond; carbon-carbon triple bond; CO; OC (O); C (O) O; NRCO; C (O) NR; NRCONR; NRC (O) O; OC (O) NR; SO₂NR; NRSO₂; CONRSO₂SO₂NRCO and And phenyloxy, where R is hydrogen or (C_1-6) Alkyl.   Y¹Suitable heteroaryl groups for are furan, thiophene, pyrro , Benzofuran, benzothiophene, indole, oxazole, isooki Sazole, thiazole, isothiazole, pyrazole, benzimidazole, o Xadiazole, thiadiazole, triazole, tetrazole, thiatriazo , Pyridine, quinoline, isoquinoline, pyrazine, pyrimidine, pyridazine And triazine, preferably thiophene, furan, pyrrole and thiazine. Includes azoles, isothiazoles, pyridines, pyrimidines and quinolines . Preferably, Y¹Is It is.   Y²Suitable heteroaryl groups for are furan, thiophene, pillow , Diazole, oxazole, thiazole, isoxazole, isothiazo , Triazole, oxadiazole, thiadiazole and tetrazole. Preferably; And   More preferably, Is mentioned.   Y^ThreeAnd a preferred heteroaryl for Is mentioned.   B^FiveSuitable heteroaryl groups for are pyrimidine, thiazole, Examples include xazole and pyridine. B^FiveAs a suitable aryl group for Is phenylene.   Suitable combination Y²-X¹as, Is mentioned.   Suitable combination Y²-Y^Threeas, Is mentioned.   Suitably, the aryl ring in which Q forms a residue is benzene or naphthalene. And preferably benzene, which in addition to D is unsubstituted or Up to 3, preferably up to 1 further substituent may be substituted.   Suitably, the heteroaryl ring in which Q forms a residue is both a single ring and a fused ring. And each ring is preferably up to four heptagons selected from oxygen, nitrogen and sulfur. The ring consists of a terror atom, and the ring is, in addition to D, unsubstituted or, for example, 2 Substituted by another substituent up to. Fused heteroaryl ring is aryl It must contain a ring and must contain only one heteroaryl ring. Suitable fused hetero ants Rings include bicyclic systems. Preferably, a heteroaryl ring in which Q forms a residue Is a monocyclic heteroaryl ring, for example pyridine or furan.   The part: A typical example of Is mentioned. Where each aryl or heteroaryl ring is optionally It may be substituted. In these cases, the aryl ring in which Q forms the residue is benze And the heteroaryl ring formed by Q is furan or pyridine.   Suitably, D is an oxyalkylene chain O (CH₂)_nOr alkylene chain (CH₂)_n Where n is an integer from 1 to 12.   Suitable definitions for BD include the following:   Suitable definitions for BD include the following:   Preferably, R¹Is hydrogen or (C_1-6) Alkyl. Preferably R¹Is Hydrogen.   Preferably, R²Is hydrogen or (C_1-6) Alkyl, for example methyl. Preferred Or R²Is hydrogen.   (C_1-6) Alkyl, (C_3-7) Cycloalkyl or (C_2-6) About the flucenyl group Suitable substituents for are, for example, halogen, cyano, nitro, carboxy, (C_1-6) Alkoxycarbonyl, carbamoyl, mono- or di- (C_1-6) Al Kircarbamoyl, sulfo, sulfamoyl, mono- or di- (C_1-6) Al Kirsulfamoyl, amino, mono- or di- (C_1-6) Alkylamino, a Silamino, ureido, (C_1-6) Alkoxycarbonylamino, 2,2,2-tri Chloroethoxycarbonylamino, aryl, heterocyclyl, hydroxy, ( C_1-6) Alkoxy, acyloxy, oxo, acyl, 2-thenoyl, (C_1-6A) Luquilthio, (C_1-6) Alkylsulfinyl, (C_1-6) Alkylsulfonyl, hydr Roxyimino, (C_1-6) Alkoxyimino, hydrazino, hydrazono, benzohi Include droximoyl, guanidino, amodino and iminoalkylamino You.   As used herein, the term "halogen" includes fluorine, chlorine, bromine and Means iodine.   The term "aryl", as used herein, unless otherwise defined. Includes phenyl or naphthyl. When substituted, the aryl group has a substituent It has up to 5, preferably up to 3. Suitable such substituents include, for example: Halogen, cyano, (C_1-6) Alkyl, phenyl, (C_1-6) Alkoxy, halo (C_{1 -6} ) Alkyl, hydroxy, amino, mono- or di- (C_1-6) Alkylamino , Acylamino, nitro, carboxy, (C_1-6) Alkoxycarbonyl, (C_1-6) Alkoxycarbonyl (C_1-6) Alkyl, (C_1-6) Alkylcarbonyloxy, ( C_1-6) Alkylthio, (C_1-6) Alkylsulfinyl, (C_1-6) Alkyl sulfoni Le, sulfamoyl, mono- or di- (C_1-6) Alkylsulfamoyl, mosquito Lubamoyl, and mono- or di- (C_1-6) Examples include alkylcarbamoyl It is.   As used herein, the term “heteroaryl” refers to single and fused rings. And each ring is preferably up to four, preferably selected from oxygen, nitrogen and sulfur. Preferably it contains up to 2 heteroatoms. Each ring has 4 to 7, preferably It has 5 or 6 ring atoms. Fused heteroaryl rings include carbocyclic rings, Only one heteroaryl ring needs to be included. With a suitable fused heteroaryl ring Include bicyclic systems.   As used herein, the term "heterocyclyl" includes oxygen, nitrogen in the ring. And containing up to 4 heteroatoms selected from sulfur and, if desired, up to 3 An aromatic and non-aromatic monocyclic or condensed ring which may be substituted with a substituent of Including. Suitably, the heterocyclic ring contains from 4 to 7 and this verse contains from 5 to 6 ring atoms. Have. Fused heterocyclic ring systems include carbocyclic rings and contain only one heteroaryl ring. Must be included.   When substituted, a heteroaryl or heterocyclyl group may have 3 substituents. Have up to Suitable such substituents include aryl and oxo The above-mentioned is mentioned.   As used herein, the term "hydrocarbylene" includes 20 carbon atoms. Up to, preferably up to 10 carbon atoms, conveniently up to 6 carbon atoms Including a group. Suitable groups include (C_1-6) Alkylene, (C_2-6) Alkenylene, (C_{2 -6} ) Alkynylene, (C_3-7) Cycloalkylene, (C_4-7) Cycloalkenylene and And aryl.   The compounds of formula (I) of the present invention are intended for use in pharmaceutical compositions. Where they are each in a substantially pure form, for example at least 50% pure, More suitably at least 75% pure, and preferably at least 95% pure It is understood that it is provided in the form (% is based on wt / wt). Formula (I) containing impurities Of the compounds to be prepared prepare more pure forms for use in pharmaceutical compositions Used for The purity of the intermediate compounds of the invention, although less critical, is substantially That the optically pure form is likewise preferred for the compounds of formula (I), It will be easily understood. Preferably, whenever possible, the compounds of the invention are , Obtained in crystalline form.   When some of the compounds of the invention are crystallized or recrystallised from organic solvents, The crystallization solvent is present in the crystalline product. The present invention is directed to such solvents within its scope Including Japanese. Similarly, some of the compounds of this invention are crystalline from a solvent containing water. Is crystallized or recrystallized In such cases, water of hydration is formed. The present invention Can be produced by processes such as stoichiometric hydrates and lyophilization. Includes compounds containing variable amounts of water.   The compound of formula (I) is a derivative of either monic acid A or monic acid C , It is easily accepted that it has the same absolute configuration at the corresponding chiral center as it is. Will be recognized. Monoacid A is a compound 4-{(2S, 3R, 4R, 5S) -5-[(2 S, 3S, 4S, 5S) -2,3-Epoxy-5-hydroxy-4-methylhexyl] -3,4-dihydroxytetrahydropyran-2-yl} -3-methylbuta-2 ( E) -is the name given to enoic acid. Monic acid C is a compound 4-{(2S, 3R, 4 R, 5S) -5-[(4S, 5S) -5-Hydroxy-4-methylhexa-2 (E) -E Nyl] -3,4-dihydroxytetrahydropyran-2-yl} -3-methylbutane It is the name given to -2 (E) -enoic acid. Therefore, the compound represented by formula (I) In particular, it is a derivative of monic acid A and has the formula (II): A first subset of compounds of formula I and derivatives of monic acid C, of formula (III) : There is a second subset of compounds represented by (wherein B, D, R¹And R² Is the same as the above definition).   The present invention provides a compound of formula (I) with a pharmaceutically or veterinary acceptable carrier or excipient. Pharmaceutical or veterinary medicine containing a compound represented by I) (hereinafter referred to as "drug") It also provides a specific composition. The composition can be administered by any route. May be formulated for and depends on the disease being treated. The composition is, for example, Tablets, capsules, powders, granules, suppositories, lozenges, as well as oral, topical It is in the form of a liquid or gel preparation containing the desired and sterile parenteral suspensions. Tablets and capsules for oral administration may be in unit dosage form, For example, syrup, gum arabic, gelatin, sorbitol, tragacanth, or Or polyvinyl-pyrrolidone; fillers such as lactose, sugar, corn Starch, calcium phosphate, sorbitol or glycine; lubricants for tablet formulations , For example, magnesium stearate, talc, polyethylene glycol or Silica; disintegrants such as potato starch or sodium laaryl sulphate What It may contain conventional excipients such as any acceptable wetting agent. The tablets are It may be coated according to methods well known in the pharmaceutical industry. Oral liquid preparation , For example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs May be in the form of a gel or with water or other suitable vehicle before use. It may be provided as a dry product for reconstitution. Such liquid preparations are Turbid agents such as sorbitol, syrup, methyl cellulose, glucose syrup , Gelatin, hydrogenated edible fats; emulsifiers such as lecithin, sorbitan-o Leic acid, or gum arabic; non-aqueous vehicles (including edible oils), eg Almond oil, fractionated coconut oil, oily ester, glycerin, propylene glycol Or ethyl alcohol; preservatives such as methyl and sichapropyl p- Conventional additives such as hydroxybenzoic acid or sorbic acid and, if desired, , May also contain conventional flavoring or coloring agents.   For topical application to the skin, the drug may be a cream, lotion or ointment. It may be formulated into an agent. Creams or ointments used for drugs are For example, Harry's Cosmeticology, 7th edition [U Wilkinson and Moore, 1982, George. George Godwin, Harlow, United Kingdom, and British Pharmacopoeia , As disclosed in the standard textbooks of medicine and cosmetics in the art It is a conventional formulation well known in.   Suppositories will contain conventional suppository bases, eg cocoa-butter or other glyceride. Will do.   For parenteral administration, fluid unit dosage forms include drug and sterile vehicle. Prepared. Depending on the vehicle and concentration used, the drug will It can be suspended in the curl. Conveniently local anesthesia, preservatives and buffers Adjuvants such as agents can be dissolved in the vehicle. To enhance stability For this purpose, the composition should be filled in a vial, the water should be removed under vacuum, and then frozen. Can be. The lyophilized powder is then sealed in the vial. The drug is sterile It can be sterilized by exposure to ethylene oxide before suspension in vehicle. You. Advantageously, the surfactant or wetting agent facilitates uniform distribution of the drug. For inclusion in the composition.   For topical administration to the ear, the drug may be water, glycerol, dilute ethanol, Suitable liquids such as propylene glycol, polyethylene glycol or fixed oils It may be formulated as a suspension in a carrier. For topical administration to the eye, the drug , As a suspension in a suitable sterile aqueous or non-aqueous vehicle. Buffering agents such as sodium metasulfite or disodium edetate Agents: Phenyl mercuric acetate or phenyl mercuric nitrate, benzalconi chloride Preservatives containing fungicides and fungicides such as um or chlorohexidine, Thickening agents such as hypromellose may also be included.   The dosage used for the topically administered compositions will, of course, be the region to be treated. It depends on the size of the area. For ears and eyes, the dose is typically Drug 1 It is in the range of 0 to 100 mg.   Veterinary compositions for the intramammary treatment of breast diseases in animals, in particular mastitis , Will generally contain a suspension of the drug in an oil vehicle.   The composition may, depending on the method of administration, be 0.1% to 99% by weight, preferably 10 to 60% by weight of the drug may be contained. The composition is in unit dosage form In that case, each dosage unit will preferably contain 50-500 mg of drug. Success The dose used for treatment of humans (average body weight of about 70 kg) depends on the route and time of administration. Depending on the number, preferably 100 mg to 3 g per day, eg drug per day Range from 250 mg to 2 g. Alternatively, the drug may be used in food intakes of non-human animals. It may be administered as part. In this case, the amount of drug used is 1 weight of the diet. %, And preferably 0.5% by weight or less. Animal foods are It may consist of normal foodstuffs added to it or it may be a May be included in the mix. A suitable method for administering the drug to animals is to use non-human animals. Is to add it to the drinking water of the thing. In this case, about 5-500 mg / ml, eg Thus, a concentration of drug in drinking water of 5 to 200 mg / ml is preferred.   The compounds of the present invention are suitable for both Gram-negative and Gram-positive bacteria as listed below. Active against: Genus Bacteroides, eg Bacteroides B. fragilis BCl, Haemophilus genus , For example, H. influenzae Q1; Moraxella (Moraxella) genus, for example, M. catarrhalis 15 02; genus Streptococci, for example, Streptococcus ・ S. pyogenes CN10 and Streptococcus nimunier (S. pneumoniae) PU7; genus Staphylococci, for example, Stahirococcus aureus oxford; d Genus Escherichia, for example E. Coli DC 0, the genus Legionella, for example, Legionella pneumophila (L. Pneumophila); Pseudomonas genus, eg Pseudomonas ・ Erginosa Dalgleish and Entero Genus Enterobacter, for example, Enterobacter phaselis (En t.faecelis) I. Further, the compounds of the present invention are staphylococcus aureus Which Staphylococci microorganisms and other antibacterial agents, eg For example, β-lactam antibiotics such as methicillin; macrolides; aminoglycosides. And staphylococcus resistant to lincosamide (including multiple resistance) Staphylococcus (Staphyloc) such as S. epidermidis occi) active against coagulase-negative strains. Therefore, the present invention Compounds are useful in the treatment of MRSA, MRCNS and MRSE. Further In addition, the compound of the present invention is a staphylococcus (resistant to mupirocin ( It is useful in the treatment of microorganisms belonging to the genus Staphylococci. The bacterial infection being treated , Respiratory tract infections, otitis, meningitis, skin and soft tissue infections in humans, in cattle Mastitis and respiratory infections in animals such as pigs and cows. did Thus, in a further aspect, the invention provides a human or non-human animal in need of treatment. Comprising administering a therapeutically effective amount of a compound of formula (I) as defined above. The present invention provides a method for treating bacterial infections in human or non-human animals.   The compound of the present invention is effective for the mycoplasma-induced infection, especially in the pathogenesis of AIDS. Mycoplasma fermentans (Mycop) It is also active against infections caused by lasma fermentans. Therefore, In a further aspect, the invention provides a compound of formula (I) for treating a human in need thereof. Mycoplasma Fermen consisting of treating with an anti-mycoplasma effective dose Humans infected with M. fermentans, especially humans infected with HIV. The present invention provides a method for treating gut.   The compounds of the invention also have antifungal activity. They are, for example, other microorganisms Of the Trichophyton genus, Trichosporon Genus, Hendersonula genus, Microsporum genus , Epidermophyton genus, Candida genus, chestnut Cryptococcus genus, Saccharomyces genus, pe Species of the genus Paecilomyces and the genus Pityrosporum It is used to treat fungal infections in humans caused by. They are, for example, , Aspergillus, Coccidioides Genus, Paracoccidioides genus, Histoplasma Oplasma and Blastomyces species produced by various species It is also used in the treatment of other fungal infections. Therefore, in a further aspect The present invention provides a patient in need of antifungal treatment with an effective amount of a compound of formula (I) Providing a method of treating fungal infections in animals, including humans, comprising treating with Things.   No adverse toxicological effects are expected from the administration of the compound of formula (I). Yes.   The compounds of the present invention are also useful as herbicides and are useful for monocotyledonous species and dicots. It is active against a wide range of weed species, including cotyledonous plant species. Many compounds are cereals , Especially wheat, barley, corn, oilseed rape (oil seed rape) ), Sugar beet and rice show good selectivity. Application of the herbicidal composition of the present invention The mixture is preferably applied directly to the undesired plants (postemergence application), but Appropriate plants may be applied to the soil (pre-emergence application) before emergence. Therefore , In a further aspect, the invention provides a herbicidally effective amount of a compound of formula (I) as defined above. Severe damage to undesired plants consisting of spraying on the plant or plant growth medium. It provides a method of damaging or killing.   For herbicidal use, the compounds of the present invention are prepared from a carrier that is a liquid or solid diluent. It is preferably used in the form of a composition consisting of Suitable such compositions are ready for immediate use A diluted composition that is prepared for or concentrated with water, usually diluted before use It may be a composition. Suitable liquid compositions optionally include a surfactant. May consist of a solution or dispersion of the active ingredient in water, or in water A solution or dispersion of the active ingredient in a water immiscible organic solvent dispersed as droplets at May be different. A suitable solid composition may also be moistened to facilitate dispersion. Granules or powders or dispersible powders or grains containing wetting agents ) Form may be sufficient. Suitable herbicide conditioning agents are well known in the art. For example, WO 93/19599 [Zeneca Ltd. ].   Suitable rates of application for herbicides depend on the particular application, but are usually 0. 0001 to 20 kg / ha, preferably 0.001 to 10 kg / ha , And more preferably 0.001 to 2 kg / ha.   The compounds of the invention may be used alone or, preferably, in supplementary supplements in specific applications. It is used as a mixture with other herbicides having herbal activity. Suitable such supplemental herbicides Are disclosed in WO 93/19599 [Zeneca Ltd]. ing.   The compounds of formula (I) are of known utility by applying conventional synthetic methods. Easily obtained from sources.   The preferred general process is to leave the terminal heterocyclic moiety and the end of the synthetic sequence. Forming an amide bond with the rest of the compound present.   Accordingly, the present invention provides a compound of formula (IV): [Wherein, Z¹, Z²And Z^ThreeAre the same or different and each represents hydrogen or hydro. Is a xyl protecting group, A, B and D are as defined above] And an active derivative thereof, and a compound of formula (V): [Wherein, R¹And R²Is the same as the above definition] By reacting with an amine represented by and then removing the hydroxyl protecting group. The present invention provides a method for producing a compound represented by the formula (I).   Suitable amide formation conditions are well known to those of ordinary skill in the art and may be Combrehensive Organic Synthesis, Bae Disclosed in Pergamon Press 1991, 381-417. There are things.   Particularly suitable amide formation conditions are medium temperature, preferably in the range of -30 to + 30 ° C. And aproton such as chloroform, dichloromethane or tetrahydrofuran Suitable bases such as tertiary amines in organic solvents, eg pyridine, 2,6-lutidine Or an active derivative of an acid represented by the formula (IV) in the presence of 4-dimethylaminopyridine , For example, acyl halide or isobutyl carboxylic acid anhydride or meta Reaction of mixed acid anhydrides such as sulfonic acid anhydride with amines of formula (V) To Including that.   Suitable compounds of formula (IV) for the preparation of compounds of formula (I) are: Applicant's own prior patent specification for similar derivatives, namely EP 0 001 914-A, EP 0 029 665-A, WO 91/09855, W O 92/02518, WO 93/06118, EP 0 087 953-A, EP 0 123 378-A, EP 0 352 909-A, EP 0 399 6 45-A, WO 91/09856 and WO 94/02478 [Beachum. Beecham Group or SmithKline  Beecham)]. Shown by formula (IV) Is a suitable substituent -DCO₂H (where D is as defined above) Is considered to be a novel example of the initial derivative. Thus, for example, D Oxyalkylene chain O (CH₂)_nA useful starting point is a suitably protected Another hydroxy group (Z¹, Z²And Z^ThreeInitial monic acid induction with It is a hydroxy-substituted analog of the body. The isolated hydroxy group is then Reagent R_Three(CH₂)_nCOR^Four(Where R^ThreeIs a leaving group, R^FourIs a carboxy It is an alkyl group. Alternatively, the moiety -DCOOH (optionally , Suitably protected form) is present before the spacer group B is synthesized. It is incorporated at an early stage of the sequence by using For another definition of D, a derivative of monic acid with another functional group is used as a starting point. It will be easily recognized that it is used.   B is a moiety bonded to the tetrahydropyranylmethyl moiety -C (CH_Three) = CH- Suitable starting materials for the preparation of compounds of formula (IV) consisting of C, or an activated derivative thereof.   The compound of formula (IV) is a novel compound useful in the production of the compound of formula (I). It is a regulation intermediate. Therefore, in a further aspect, the invention relates to the previous application WO 94/02478 [SmithKline Beecham Public Limited Ka Intermediates disclosed in detail in Smith Kline Beechamplc] With the exception of the formula (IV) as defined above.   Monic Acid A is available at GB 1 587 058 [Beechem Group Limited (B eecham Group Ltd)]. It is easily obtained from pseudomonic acid A by hydrolysis of. Using a similar method To obtain monic acid C from pseudomonic acid C [Clayton J. P. (Clayton JP) et al., J Chem Soc Perkin Trans I, 1982, 2. 872]. Alternatively, monic acid C can be prepared by Clayton Jay Pee et al., J Chem S. oc Perkin Trans I, 1982, 2872 and EP 0 003 069-A [ Deoxidation from monic acid A, as disclosed by Beecham Group] Obtained by basing.   The amine represented by the formula (V) is represented by GB 2 170 498-A [Imperial Mical Industries Public Limited Company (Imperial Chemical Industries plc)] or thiol Manufactured by semi-synthetic methods starting from natural sources such as tin and horomycin You.   Derivatives of monic acid A and monic acid C, such as the compounds of the invention, are suitable for deoxygenation ( Interconversion can be easily achieved by the A → C) method and the epoxidation (C → A) method. Wear. In many cases, due to the availability of the initial starting materials, the formula in the "C" series When the compound represented by (I) is produced, the precursor in the "A" series is used. Starting, and then at some convenient points in the synthesis, a suitable deoxygenated prod It is more convenient to convert this into the corresponding "C" series compound by It is. The deoxidation conditions selected should be tailored to ensure that they match the rest of the molecule. It is understood.   As used herein, a "hydroxyl protecting group" splits the remainder of the molecule. Means any such group known in the art to be removed without . Suitable hydroxyl protecting groups are Protective Groups in Organic Procective Groups in Organic Synthesis, Green ( Greene) and Wuts, Willy-Inte rscience), New York, 2nd edition, 1991.   The hydroxyl groups of the monacids A and C and the compounds of formula (IV) are The method is used to protect at any stage of the process. Hydroxyl retention The protecting group is removed by methods known in the art including enzymatic methods. Special A suitable hydroxyl protecting group for is a silyl group. Because the silyl group is This is because it is easily removed under mild conditions. Such a group has the following formula: L_ThreeSiY; L₂SiY₂; L_ThreeSiNL₂; L_ThreeSiNHSiL_Three; L_ThreeSiNHCOL; L_Three SiO-C (L) = NSiL_Three; L_ThreeSiNHCONHSiL_ThreeLNHCONHSiL_Three ;^tBuMe₂Si-O-SO₂-CF_Three; [In the formula, Me represents methyl, t-Bu represents t-butyl, and Y represents halogen. And L is each independently hydrogen, (C_1-6) Alkyl, (C_1-6) Alkoxy, a Reel or aryl (C_1-4) Selected from alkyl] With conventional silylating agents including halosilanes and silazanes such as those shown in Will be introduced. The more silylating agent is trimethylsilyl chloride. Especially good Suitable hydroxyl protecting groups include trimethylsilyl, triethylsilyl and t-butyl. It is chill dimethyl silyl sushi. A preferred hydroxyl protecting group is trimethyl It is a rill group. This is because the trimethylsilyl group is easy to remove. .   The glycol function of the compounds of the formulas (IV) and the monoacids A and C is I):                 R^cC (OR^d) (OR^e) (OR^f) (VI) [Wherein, R^cIs hydrogen or (C_1-6) Alkyl and R^d, R^eAnd R^fIs (C_1-6 ) Is alkyl] In a cyclic derivative using a compound represented by²And Z^ThreeTogether Minute R^cC (OR^d) Is protected by forming a cyclic derivative. Good Suitably R^cIs hydrogen, methyl, ethyl, n- or iso-propyl, most Preferred is hydrogen. Group R^d, R^eAnd R^fIs methyl, ethyl, n-or Is iso-propyl or n-, iso-, sec- or t-butyl Preferred and most preferred is methyl. Hydroxy of compounds of formula (I) The sil group may also be protected before conversion to another compound of formula (I) above. . In such a case, the protecting group may be, for example, Clayt JP. on JP) et al. [JCS Perkin Trans I, 1979, 308]. Removed by mild acid hydrolysis, followed by alkaline hydrolysis as described .   The following examples illustrate the invention and limit the scope in any way. Not something.   Example 1   3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- (4-methyl -1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) calc Vamoylbut-1-yloxyphenyl} but-1-yl] -5S- (2S, 3S- Epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran   a) 4- (4-carbomethoxybut-1-yloxy) benzaldehyde   P-Hydroxybenzaldehyde (1.22 g, 10 (3 mmol) in dry dimethylformamide (30 ml) was added with sodium hydride ( 60% dispersion in oil; 400 mg, 10 mmol). 30 minutes later, 5-bro Methyl movalerate (1.43 ml, 10 mmol) was added. Then the mixture is Warm to 80 ° C. for 6 hours, then cool to room temperature (16 hours). Then the mixture The product was diluted with water and extracted with ethyl acetate. The organic phase is sodium carbonate solution, saline And then dried (MgSO 4_Four), Evaporated. Clean the residue over silica. Chromatographic elution with a dichloromethane / ethyl acetate mixture gave a solid. The title compound was obtained as δ_H(CDCl_Three) 1.81-1.95 (4H, m, 2'-H₂ , 3'-H₂) 2.38-2.48 (2H, t, J 6.9Hz, 4'-H)₂) 3.67 (3 H, s, CO₂Me), 4.08 (2H, t, J 5.9Hz, 1'-H₂), 6.99 (2H, d, J8.7Hz, 3,5-H₂), 7.53 (2H, d, J 8.7Hz, 2,6-H₂); (Measurement Value: M⁺, 236.1047. C₁₃H₁₃O_FourTheoretical value: M, 236.01049).   b) 3R, 4R-bistrimethylsilyloxy-2S- [4- (4-carbometo Xybut-1-yloxyphenyl) -4-hydroxy-2-oxobut-1- Ill] -5S- (2S, 3S-epoxy-5S-trimethylsilyloxy-4S- Methylhexyl) tetrahydropyran   Diisopropylamine (0.88 ml, 6 mmol) at -30 ° C under argon. ) In dry THF (40 ml) was added to a solution of n-butyllithium in hexane (1. It was treated dropwise with a solution of 5M, 4 ml, 6 mmol). After 15 minutes, the reaction mixture was cooled to -7 Cool to 0 ° C. and use tristrimethylsilyl monone^*(2.59 g, 5 mmol) T A solution in HF (12 ml) was added dropwise over 5 minutes. After 1 hour, the mixture was Treated with a solution of the product from (a) (1.18 g, 5 mmol) in THF (3 ml). . After another hour, saturated ammonium chloride was added. The mixture with ethyl acetate Extract, wash the organic phase with brine, dry (MgSO 4_Four), Then evaporated. Chromatography on silica, eluting with ethyl acetate / hexane mixtures. Gave the title compound (2.98 g, 79%); δ_H(CDCl_Three) Above all, 0. 89 (3H, d, J 7.0Hz, 17-H_Three), 1.22 (3H, d, J 6.3Hz, 14- H_Three) 3.68 (3H, S, CO₂Me), 5.07-5.16 (1H, m, 1-H), 6.8 4 (2H, D, J 8.6Hz, 3 ', 5'-H₂), 7.23-7.32 (2H, m, 2 ', 6'- H₂); M / z (NH_ThreeDCI⁺) 772 (MNH_Four ⁺, 10%), 115 (100%).   ^*By a method similar to the protection step described in Example 4 (a), in THF, Triethyl chloride in the presence of triethylamine and catalytic amount of 4-dimethylaminopyridine By treatment with methylsilyl, 2S-acetonyl-3R, 4R-dihydroxy Ci-5S- (2S, 3S-epoxy-5S-hydroxy-4S-methylhexyl) -2,3,5,6-tetrahydropyran [GB 1 587 058, Beecham Gu Beecham Group].   c) 3R, 4R-bistrismethylsilyloxy-2S- [4- (4-carbome Toxibut-1-yloxyphenyl) -2,4-dioxobut-1-yl] -5 S- (2S, 3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl Sil) tetrahydropyran   The product from (b) (2.9 g, 3.85 mmol) in benzene (140 ml) was added. Treated with manganese dioxide (4.35g), 2¹/₂Time, return under conditions of azeotropic removal of water Flow (Dean-Stark apparatus containing molecular sieve A4). Further man dioxide Gun (1.45 g) was added and heating continued for another 2 hours. Dioxane Diluted with water, filtered through Kieselguhr, and filtered with dioxane. The dwell was washed. The filtrate is evaporated and the residue is chromatographed on silica. And elute with ethyl acetate / hexane mixture to give the title compound (1.69 g, 5 8%) was obtained; δ_H(CDCl_Three) In particular, 0.88 (3H, d, J 7.1Hz, 17 -H_Three), 1.21 (3H, d, J 6.1Hz, 14-H_Three) 3.69 (3H, s, CO₂Me) , 6.20 (1H, s, 2-H), 6.92 (2H, d, J 8.9Hz, 3 ', 5'-H₂), 7 .87 (2H, d, J 8.8Hz, 2 ', 6'-H₂); M / z (NH_ThreeDCI) 753 (M H⁺, 5%), 90 (100%); (measured value: M⁺, 752.3862, C₃₇H₆₄O_TenS i_ThreeTheoretical value M 752.3807).¹The H spectrum shows that the title compound is substantially It was shown that it was a round shape.   d) 3R, 4R-dihydroxy-2S- [4- (4-carbomethoxybutan-1- Iloxyphenyl) -2,4-dioxobut-1-yl] -5S- (2S, 3S- Epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran   A solution of the product from (c) (1.6 g, 2.12 mmol) in THF (60 ml) was added. Treated with 0.4M HCl (12 ml). 2 minutes later, saturated aqueous sodium hydrogen carbonate solution (1 ml) was added. The mixture is then extracted with ethyl acetate and the organic phase is brine. Washed with water, dried (MgSO 4_Four), Then evaporated. Chromatography on silica Ruff and elute with a dichloromethane / methanol mixture to give the title compound ( 1.114 g, 98%) was obtained;_max(KBr) 3482, 1736, 1606, 1509, 1440 cm^-1; Λ_max(EtOH) 325 nm (ε_m22,970); δ_H (CDCl_Three) In particular, 0.92 (3H, d, J 7.1Hz, 17-H_Three), 1.21 (3 H, d, J 6.3Hz, 14-H_Three) 3.66 (3H, s, CO₂Me), 6.21 (1H, s , 2-H), 6.92 (2H, d, J 8.8Hz, 3 ', 5'-H₂), 7.88 (2H, d, J 8.9Hz, 2 ', 6'-H₂); Δ_c(CDCl_Three) 12.7 (C-17), 20.8 (C-1) 4) 2.16 (C-2 "), 28.5 (C-3"), 31.7 (C-9), 33.6 (C-4) "), 39.6 (C-8), 42.6 (C-4), 42.8 (C-12), 51.9 (C -6 "), 55.7 (C-10), 61.3 (C-11), 66.0 (C-16), 67.6 (C-1 "), 68.8 (C-6), 70.3 (C-7), 71.3 (C-13), 73.9 ( C-5), 96.5 (C-2), 114.5 (C-3 ', 5'), 126.7 (C-1 '), 1 29.3 (C-2 ', 6'), 162.7 (C-4 '), 173.6 (C-5 "), 182.9 ( C-1), 194.0 (C-3); m / z (NH_ThreeDCI) 537 (MH⁺, 60%), 2 51 (100%).¹H spectrum showed that the title compound was essentially in the enol form. That was shown.   e) 3R, 4R-dihydroxy-2S- [4- (4-carboxybut-1-yl) Oxyphenyl) -2,4-dioxobut-1-yl] -5S- (2S, 3S-epo Xy-5S-hydroxy-4S-methylhexyl) tetrahydropyran   Subtilisin Carlsberg (100 mg) in water It was dissolved in (50 ml) and the pH was adjusted to 6.5 with 0.01 M NaOH. Stir vigorously To the resulting mixture was added the product from (d) (196 mg, 0.36 mmol) in one portion. The pH was maintained at 6.5 by addition of 0.01M NaOH. 48 hours later, Toru The clear solution was ultrafiltered, the filtrate was evaporated to reduced volume and lyophilized. Profit The obtained amorphous solid was partitioned between ethyl acetate and water, and diluted with dilute H while stirring vigorously.₂SO_Four The pH was adjusted to 2.5 with (-0.01 M). The organic phase is separated, dried (MgS O_Four), The title compound (90 mg, 48%) was obtained;_max(KBr) 3414, 171 9, 1603, 1509, 1458 cm^-1; λ_max(EtOH) 326 nm (ε_m21,1 70), δ_H(D_Four-MeOH), especially 0.94 (3H, d, J 7.1Hz, 17-H_Three ), 1.21 (3H, d, J 6.4Hz, 14-H)_Three), 6.32 (~ 1H, s, 2-H), 6.98 (2H, d, J 8.9Hz, 3 ', 5'-H₂), 7.92 (2H, d, J 8.9Hz, 2 ', 5'-H₂); M / z (NH_ThreeDCI) 523 (MH⁺, 10%), 74 (100%) .¹1 H spectrum showed that the title compound was substantially in the enol form.   f) 3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- (4-me Cyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) carboxyl Lubamoylbut-1-yloxyphenyl} but-1-yl] -5S- (2S, 3 S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran   Of the product from (e) (60 mg, 0.115 mmol) at 0 ° C. under argon. The solution in THF (5 ml) was treated successively with triethylamine (17.6 μl, 0.12). 6 mmol) and i-butyl chloroformate (15 μl, 0.23 mmol). did. After 30 minutes, the mixture was treated with triethylamine (32 μl, 0.23 mmol), Then 6-amino-4-methyl-1,2-thiolo- [4,3-b] -pyrrole-5 (4H) -one hydrochloride [W. D. Celmer and Eye ・ A Solomons, Journal of American Chemica Le Society (J. Am. Chem. Soc.), 1955, 77, 2862] (33 mg , 0.138 mmol). After 3 hours, additional ants of triethylamine Cot (11 ml, 0.07 mmol) and amine hydrochloride (11 mg, 0.046 mi) Limol) was added. After an additional hour, the reaction mixture was diluted with ethyl acetate and diluted with 5 % Citric acid, washed with sodium bicarbonate solution, dried (MgSO_Four), Then steam I fired. The residue is chromatographed on silica in dichloromethane / medium. Elution with a mixture of tanols gave the title compound as a yellow solid (34mg, 45%). U; υ_max(KBr) 3410, 3034, 1658, 1600, 1532, 15 07,1438cm^-1; Λ_max(EtOH) 385.5 nm (ε_m10, 430), 324. 5 (22,930); δ_H(<10% CDCl_ThreeContaining d_Four-MeOH) 0.92 (3H, d, J 7.0Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14) -H_Three) 3.35 (3H, s, NMe), 6.28 (-1H, s, 2-H), 6.97 (2H, d, J 8.9Hz, 3 ', 5'-H₂), 7.16 (1H, s, 3 "'-H), 7.84 (2H, d , J 9.0Hz, 2 ', 6'-H₂); M / z (FAB: thioglycerol) 691 (M H⁺, 10%), 232 (100%).¹The H spectrum shows that the title compound is substantially It was shown that it was a round shape.   Example 2   N- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxopyrro Lo-6-yl) -monamide A   The title compound was prepared from monic acid A (172 mg) by the method described in Example 1 (f). Produced (7 mg, 3%);_max(KBr) 3403, 2923, 1653, 1 519, 1436 cm^-1Δ_H(D_Four-MeOH) 0.96 (3H, d, J 7.0Hz, 1 7-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three), 1.39 (1H, m, 12- H), 1.69 (2H, m, 9-H₂), 1.95 (1H, m, 8-H), 2.22 (3H, s, 15-H_Three) 2.18-2.83 (4H, m, 4-H₂, 10-H, 11-H), 3.35 (3H, s, N-Me), 3.38-4.05 (6H, m, 5-H, 6-H, 7-H, 13- H, 16-H₂), 5.97 (1H, s, 2H), 7.23 (1H, s, 3'-H); m / z ( EI⁺) 512 (M⁺).   Example 3   2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxo Pyrrol-6-yl)] carbamoylhexoxy} -thiazol-5-yl-1- Normon-2-ylketone A series   a) 2- (7,7,7-Tris-methylthioheptoxy) -thiazole   3,4-Dihydro-2H-pyran (33.1 mmol) in 80 ml of diethyl ether 3.02 ml) was added to 6-bromohexanol (27.65 mmol, 5 g). Was. After 1.5 hours at room temperature, an additional 3,4-dihydro-2H-pyran (33.1 mm Mol, 3.02 ml) and stirred for 2.5 hours. Sodium bicarbonate saturated aqueous solution Solution (100 ml) was added, extracted with diethyl ether, dried (MgSO4)._Four), Reduced Evaporate to dryness under pressure, eluent dichloromethane / hexane (70-100% ) And column chromatography on silica using To give 2-6-bromohexyloxytetrahydropyran as a colorless oil. (6.459 g, 88%); δ_H(CDCl_Three) 1.5-1.75 (8H, m, 4 x C H₂) 3.4-3.6 (4H, m, CH₂Br and CH ₂O), 4.5 (1H, t, J 2. 8 Hz, OCHO).   Tris (methylthio) methane (in tetrahydrofuran (80 ml) at −78 ° C. 24.37 millimolar, 3.24 ml) to n-butyllithium (1.6M in hexane) (29.24 mmol, 19.5 ml) was added dropwise. After 1.5 hours, THF (20 ml ) Was added (24.37 mmol, 6.459 g) in Time It was stirred for a while. A saturated aqueous solution of ammonium chloride (30 ml) was added and diethyl ether was added. Extract and dry (MgSO 4_Four), Evaporated to dryness under reduced pressure, and used methanol as the eluent. Column chromatography on silica using methanol / dichloromethane (0-20%). Purified by feeding to give 7.7.7-Trismethyl as a colorless oil. Luthio-1-tetrahydropyran-2-yloxyheptane was obtained (7.112). 4g, 86%); δ_H(CDCl_Three) 2.1 (9H, s, 3 x SCH_Three) 3.35-3. 5 (2H, m, OCH₂) 3.7-3.9 (2H, m, cyclic OCH₂), 4.55 (1H, t, J 2.8Hz, O-CH-O).   To the above compound (20.98 mmol, 7.11 g) in methanol (150 ml) Amberlyst-15 (0.3g) was added. After 4 hours, filter Evaporate to dryness under reduced pressure and use diethyl ether / hexane (4%) as eluent. Purified by column chromatography on silica using 7,7,7-Trismethylthio-heptanol was obtained as a colored oil (3.73 g, 70%); 1.2-1.9 (10H, m, 5 x CH₂), 2.1 (9H, s, 3 x SCH_Three ) 3.6 (2H, t, J 6.5Hz, OCH₂).   The above compound (2 mmol, 0.508 g) was hydrogenated in THF (3 ml). (1.89 mmol, 0.057 g) was added. After 0.5 hours, 2-bromothia Zole (2.2 mmol, 0.2 ml) was added and the reaction heated at 40 ° C. for 4 hours. Cool, dilute with diethyl ether, filter, evaporate to dryness under reduced pressure and eluent. Column chromatography on silica using diethyl ether / hexane (0-10%). Purification by chromatography gave the title compound (0.232 g , 34%); δ_H(CDCl_Three) 1.3-1.9 (10H, m, 5 x CH₂) 2.1 (9 H, s, 3 x SCH_Three), 4.4 (2H, t, J 6.5Hz, OCH₂), 6.6 (1H, d, J 3.9 Hz, 5-H), 7.1 (1 H, d, J 3.8 Hz, 4-H).   b) [2- (7,7,7-Tris-methylthioheptoxy) -thiazol-5-i L] -1- (6,7,13-O-tristrimethylsilylnormon-2-yl) keto A series   2- (7,7,7-trismethylthioheptoxy) in THF (6 ml) at −78 ° C. Ci) thiazole (2 mmol, 0.67 g) in n-butyllithium (1. 6M) (2 mmol, 1.25 ml) was added dropwise. After 40 minutes in THF (10 ml) N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl) mona Mido [WO 93/06118, SmithKline Beecham Public Re Limited Company] (2 mmol, 1.206 g) was added dropwise. 2 hours later- Glacial acetic acid (4 mmol, 0.2 ml) was added while warming to 50 ° C., then water ( 10 ml) was added. Extract with diethyl ether, dry (MgSO 4)._Four), Under reduced pressure Evaporate to dryness and dry with ethyl acetate / hexane (0-20%) as eluent. Purification by column chromatography gave the title compound (0. 442 g, 25%); δ_H(CDCl_Three) 0.1-0.2 (27H, m, 9 x SiCH_Three) , 0.9 (3H, d, J 7.1Hz, 17-H_Three), 1.2 (3H, d, J 6.3Hz, 14- H_Three), 1.3-1.9 (10H, m, 5 x CH₂), 2.05 (9H, s, 3 x CH_Three) 2.2 (3H, s, 15-H_Three) 2.6 (2H, m, 10 and 11-H), 3.35 ( 1H, dd, J 2.9,8.9Hz, 6-H), 4.4 (2H, t, J 6.4Hz, OCH₂) , 6.5 (1H, s, 2-H), 7.7 (1H, s, Ar-H).   c) 2- (7,7,7-tris-methylthioheptoxy) -thiazol-5-yl -1-Normon-2-ylketone A series   The product from Example 3 (b) (0.5 mmol, 0.439) in THF (10 ml). g) and hydrochloric acid (0.4 M, 2.5 ml) were stirred at room temperature for 2 minutes. Sodium bicarbonate Saturated aqueous solution of llium was added, extracted with ethyl acetate, dried (MgSO_Four), Under reduced pressure , Evaporated to dryness, using methanol / dichloromethane (0-7%) as eluent Purified by column chromatography on silica to give a colorless The title compound was obtained as an oil (0.310 g, 93%);_max(KBr) 232 8, 1734, 1527, 1297, 838, 569cm^-1; Λ_max(EtOH) 3 02nm (ε_m17,227); δ_H(CD_ThreeOD) 0.9 (3H, d, J 7.1Hz, 1 7-H_Three), 1.2 (3H, d, J 6.6Hz, 14-H)_Three), 2.1 (9H, s, 3 x S CH_Three) 2.25-2.35 (2H, m, 4-H₂) 2.65-2.8 (2H, m, 10 o And 11-H), 3.4 (1H, dd, J 2.9, 9.0Hz, 6-H), 3.55 (1H, d, J 10.6 Hz, 16 "-H), 3.75-3.9 (4H, m, 5, 7, 13, 6-H), 4.45 (2H, t, J 6.4Hz, OCH₂), 6.7 (1H, s, 2-H), 7.9 (1H, s, Ar-H).   d) 2- (6-methoxycarbonylhexoxy) -thiazol-5-yl-1- Normon-2-ylketone A series   The product from Example 3 (c) (0.33) in methanol (6.3 ml) at -40 ° C. Mercury oxide II (3.38 mmol, 0.072 g) and 8 mmol, 0.224 g) Mercury chloride II (1.01 mmol, 0.27 g) was added. 55 minutes later, Celite Filtered through and washed with saturated aqueous ammonium chloride solution (10 ml), Extract with tan (12 ml), dry (MgSO 4_Four), And evaporate under reduced pressure to obtain an eluent. Column chromatography on silica using methanol / diethyl ether (0-4%). Purify by subjecting to chromatography to give the title compound (0.113 g, 60% ) Got; υ_max(KBr) 1646, 1479, 1258, 1187, 1055 cm^-1; Λ_max(EtOH) 302 (ε_m20,224); δ_H(CD_ThreeOD) 0.95 ( 3H, d, J 7.1Hz, 17-H_Three), 1.2 (3H, d, J 6_.3Hz, 14-H_Three), 2 .2 (3H, s, 15-H_Three) 2.25-2.4 (3H, m, CH₂CO₂And 4-H), 2.7-2.85 (3H, m, 4, 10 and 11-H), 3.4 (1H, dd, J 2.7, 10.5Hz, 6-H), 3.55 (1H, d, J 10.5Hz, 16 "-H), 3.6 (3H , s, CO₂CH_Three) 3.75-3.9 (4H, m, 5, 7, 13 and 16-H), 4.4 5 (2H, t, J 6.5Hz, OCH₂), 6.7 (1H, s, 2-H), 7.9 (1H, s, A r-H); m / z (EI) 569 (M⁺, 50%), 83 (100%); (measured value: M⁺ 569.2667, C₂₈H₄₃NO₉Theoretical value of S M 569.2659).   e) 2- (6-Carboxyhexoxy) -thiazol-5-yl-1-normon -2-Ilketone A series   The product from Example 3 (d) (0.5 mmol, 300 ml) in acetone (30 ml) ) Solution of Protease Subricin Carlsberg (125 mg) to The mixture was treated with sodium hydrogen phosphate (27 mmol, 0.1 m, 270 ml, pH 7). Buffered with and maintained at a constant pH of 6.5. After stirring for 16.5 hours, reduce the volume. Small The reaction was washed with ether and the layers were separated with ethyl acetate. Phosphonic acid ( The pH is adjusted to 3.5 with 1.5M) and the aqueous layer is extracted with ethyl acetate The layers were washed with brine, dried (MgSO 4_Four), Evaporated to dryness under reduced pressure to give a colorless gum. This gave the title compound in the form of a solid (0.247 g, 89%). δ_H(d_Four-MeOD), 0.96 (3 H, d, J 7.1Hz, 17-H_Three), 1.21 (3H, d, J 6.3Hz, 14-H)_Three), 1. 24-2.08 (12H, m, 2 "-H₂, 3 "-H₂, 4 "-H₂, 5 "-H₂, 8-H, 9-H₂ , 12-H), 2.23 (3H, s, 15-H_Three) 2.25-2.35 (3H, m, 4-H , 6 "-H₂), 2.72 (1H, dd, J 2.2, 7.5Hz, 11-H), 2.76 (1H, s, 4-H), 2.81 (1H, dt, J 2.3, 5.7Hz, 10-H), 3.38 (1- H, dd, J 3.0, 9.0 Hz, 6-H), 3.55-3.60 (1 H, m, 16-H), 3.70-3.90 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.46 (2H, t, J 6.4Hz, 1 "-H₂), 6.72 (1H, s, 2-H), 7.93 (1H, s, 4'- H).   f) 2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -o Xoxopyrrol-6-yl) carbamoylhexoxy} -thiazol-5-yl-1 -Normon-2-ylketone A series   Example 3 (d) in dry tetrahydrofuran (20 ml) at 0 ° C. under argon. These products (0.21 mmol, 120 mg) were treated successively with triethylamine ( 0.23 mmol, 0.032 ml) and isobutyl chloroformate (0.23 millimolar) , 0.027 ml). After 30 minutes, the mixture was charged with silethylamine (0.2 9 mmol, 0.041 ml), then 6-amino-4-methyl-1,2-dithio. Rho- [4,3-b] -pyrrole-5 (4H) -one hydrochloride (0.27 mmol, 0.2 061 g). After an additional 24 hours, the reaction was diluted with ethyl acetate and washed with heavy charcoal. Wash with an aqueous solution of sodium acid and brine, dry (MgSO 4_Four), Evaporate to dryness under reduced pressure I let it. The brown residue was subjected to column chromatography in dichloromethane. Purified by eluting with 4% methanol to give a solid as a bright orange solid. The above compound was obtained (77 mg, 51%); λ_max(EtOH) 303 nm (ε_m2098 6); δ_H(d₆-Acetone), 0.92 (3H, d, J 7.1Hz, 17-H_Three) 1.1 7 (3H, d, J 6.3Hz, 14-H_Three), 1.23-2.05 (12-H, m, 2 "-H)₂ , 3 "-H₂, 4 "-H₂, 5 "-H₂, 8-H, 9-H₂, 12-H), 2.23 (3H, d, J  0.9Hz, 15-H_Three) 2.31-2.36 (1H, dd, J 9.3,14.2Hz, 4) -H), 2.46 (2H, t, J 7.3Hz, 6 "-H), 2.70 (1H, dd, J 2.2, 7.4 Hz, 11-H), 2.73 (1H, s, 4-H), 2.81 (1H, dt, J 2.2, 5.7 Hz, 10-H), 3.24 (3H, s, N-CH_Three) 3.40-3.45 (1H, m , 6-H), 3.55-3.60 (1H, m, 16-H), 3.64 (1H, s, -OH), 3.75-3.95 (4H, m, 5-H, 7-H, 13-H, 16-H, -OH), 4.5 0 (2H, t, J 6.7Hz, 1 "-H), 6.76 (1H, s, 2-H), 7.09 (1H, s, 3 "'-H), 7.93 (1H, s, 4'-H), 8.86 (1H, s, N-H); m / z (EI⁺) 723 (M⁺, 1%), 267 (5), 186 (100), and 128 (70 ).   Example 4   2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxo Pyrrol-6-yl) carbamoylhexoxy} -thiazol-5-yl-1-no Lumon-2-ylketone C series   a) N-methoxy-N-methyl-6,7,13-O-tris (trimethylsilyl) Monamide C   At 0 ° C., monic acid C [JP Clayton et al., J.C. S. Perkin I, 1982, 2827] (4.10 g, 12 mmol) in THF ( 30 ml) in succession, triethylamine (1.83 ml, 13.2 mmol) ) And i-butyl chloroformate (1.42 ml, 12 mmol). 40 After minutes, the mixture was diluted with ether, filtered and then evaporated. Remove the residue It was dissolved in chloromethane (30 ml) and N, O-dimethylhydroxylamine (2. 4 mmol) in dichloromethane (10 ml). 1¹/₂After hours, the The mixture was washed with sodium bicarbonate solution, brine, then dried (MgSO4)._Four) And evaporated.   The residue was dissolved in THF (30 ml) at 0 ° C. and, successively, triethylamine ( 7.68 ml, 55 mmol), trimethylsilyl chloride (6.70 ml, 53 millimolar) ) And DMAP (~ 2 mg). After 20 hours at room temperature, the mixture is filtered The solid was washed with hexane and the filtrate was evaporated. Dissolve the residue in hexane Washed with brine, dried and evaporated. Chromatograph the residue on silica. Elute with a mixture of ethyl acetate / hexane to give the title compound as an oil. Was obtained (2.3 g, 32%); δ_H(d_Four-MeOH), 0.97 (3H, d, J 7.1) Hz, 17-H_Three), 1.06 (3H, d, J 6.3Hz, 14-H_Three) 2.16 (3H, s, 15-H_Three) 3.20 (3H, s, NMe), 3.68 (3H, s, OMe), 5.30-5. 50 (2H, m, 10-H, 11-H), 6.19 (1H, s, 2-H).   b) 2- (7,7,7-tris-methylthioheptoxy) -thiazol-5-yl -1-Normon-2-ylketone C series   2- (7,7,7-trismethylthioheptoxy) in THF (6 ml) at −78 ° C. Ci) thiazole (2.42 mmol, 0.815 g) in n-butyryllithium (hex 1.1M in Sun) (2.42 mmol, 2.2 ml) was added. 40 minutes later, THF N-methoxy-N-methyl-6,7,13-O-tris (trimethylol) in (10 ml) Rusilyl) monamide C (2.2 mmol, 1.3 g) was added dropwise. Two hours later, -50 While warming to ℃, add glacial acetic acid (4 mmol, 0.2 ml) and then water (10 ml). Added. The mixture was extracted with ethyl acetate, dried (MgSO_Four), Evaporate to dryness under reduced pressure Hardened. The residue was dissolved in THF (66 ml) and hydrochloric acid (0.4M, 13.2 ml). Was added and the mixture was stirred at room temperature for 2 minutes. Saturated aqueous solution of sodium hydrogen carbonate Was added, extracted with ethyl acetate, dried (MgSO 4_Four), Evaporated to dryness under reduced pressure, Color on silica using methanol / dichloromethane (0-7%) as eluent. It was purified by column chromatography to give the title compound as an amorphous solid. Was obtained (0.545 g, 38%); δ_H(CDCl_Three) 0.99 (3H, d, J 7.1H z, 17-H_Three), 1.15 (3H, d, J 6.3Hz, 14-H)_Three), 2.10 (9H, s, ( (SMe)_Three), 2.26 (3H, s, 15-H_Three) 5.35-5.55 (2H, m, 10-H, 11-H), 4.38-4.48 (2H, m, 1 "-H₂), 6.60 (1H, s, 2-H), 7.75 (1H, s, 4'-H).   c) 2- (6-methoxycarbonylhexoxy) -thiazol-5-yl-1- Normon-2-ylketone C series   The product from Example 4 (b) (0.8 mi) in methanol (20 ml) at -40 ° C. Limol, 0.545 g) to mercury oxide II (0.8 mmol, 0.173 g) and chloride Mercury II (2.4 mmol, 0.652 g) was added. 55 minutes later, through Celite Filtered, washed with saturated aqueous ammonium chloride solution (10 ml) and washed with dichloromethane ( 35 ml), dried (MgSO 4_Four), Evaporated under reduced pressure and metathesized as eluent. Column chromatography on silica with a nol / dichloromethane mixture The title compound was obtained as an amorphous solid (0.353 g). , 80%); δ_H(CDCl_Three) 0.98 (3H, d, J 7.1Hz, 17-H)_Three) 1.1 5 (3H, d, J 6.3Hz, 4H_Three), 2.26 (3H, s, 15-H_Three) 3.67 (3H, s, CO₂Me), 4.40-4.45 (2H, m, 1 "-H₂), 5.35-5.55 (2H, m, 10-H, 11-H), 6.60 (1H, s, 2-H), 7.75 (1H, s, 4'-H) .   d) 2- (6-carboxylatohexoxy) -thiazol-5-yl-1-nor Mon-2-ylketone C series   The product from Example 4 (c) (320 mg, 0.6 mmol) in THF (4 ml). The solution was treated with 2.5M sodium hydroxide (7.2ml). After 4 hours, mix with stirring The mixture was further treated with sodium hydroxide (3.6 ml). After 1 hour, the mixture was Evaporate to reduce volume and add THF (4 ml) and water (50 ml). 1 After 0 minutes, the mixture was washed with ethyl acetate and the aqueous phase was acidified to pH 2 with 5N HCl. It was saturated with brine and extracted with ethyl acetate. The organic phase is dried (MgSO 4_Four), Evaporated. The residue was chromatographed on silica with dichloromethane. Elution with a mixture of methanol / methanol gave the title compound as a gum (81 mg, 25%). Δ_H(D_Four-MeOH) 0.97 (3H, d, J 7.1Hz, 17-H_Three), 1.08 (3 H, d, J 6.3Hz, 14-H_Three), 2.26 (3H, s, 15-H_Three) 4.45-4.5 0 (2H, m, 1 "-H₂) 5.40-5.45 (2H, m, 10-H, 11-H), 6.7 3 (1H, s, 2H), 7.93 (1H, s, 4'-H).   e) 2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-6-yl) carbamoylhexoxy} -thiazol-5-yl-1- Normon-2-ylketone C series   Using the method described in Example 3 (f), the product from Example 4 (d) (76 mg , 0.14 mmol) was converted to the title compound (38 mg, 38%);_max(KB r) 3437, 2922, 1644, 1600 and 1229 cm^-1; Λ_max(Et OH) 304nm, (ε_m19,518); δ_H(d_Four-MeOH), 0.98 (3H, d, J 7.1Hz, 17-H_Three), 1.09 (3H, d, J 6.3Hz, 14-H)_Three) 1.20 -2.20 (12H, m, 2 "-H₂, 3 "-H_2,4 "-H₂, 5 "-H₂, 8-H, 9-H₂, 12-H), 2.24 (3H, s, 15-H₂) 2.30-2.38 (1H, m, 4-H), 2.39-2.43 (1H, t, J 7.3Hz, 6 "-H₂) 2.75-2.78 (1H, m , 4-H), 3.34 (3H, s, N- (CH_Three)) 3.39-3.42 (1H, dd, J 3 0.0, 9.2 Hz, 6-H), 3.42-3.63 (1 H, m, 16-H), 3.75-3.9 0 (4H, m, 5-H, 7-H, 13-H, 16-H), 4.46 (2H, t, J 6.4Hz , 1 "-H₂), 5.40-5.45 (2H, m, 10-H, 11-H), 6.69 (1H, s) , 2-H), 7.17 (1H, s, 3 "'-H), and 7.86 (1H, s, 4'-H) ;?_c (d_Four-MeOH), 16.2 (C-17), 19.9 (C-15), 20.1 (C-14) , 26.0 (C-4 ", C-5"), 27.8 (N-CH_Three), 29.1 (C-2 ", C-3") , 33.3 (C-9), 35.0 (C-6 "), 43.3 (C-8), 44.2 (C-4), 44.8 (C-12), 65.5 (C-16), 69.5 (C-6), 171.1 (C-7) , 71.7 (C-13), 73.6 (C-1 "), 75.8 (C-5), 112.4 (C-3) "'), 115.0 (C-6a" "), 121.5 (C-2), 129.2 (C-11), 13 5.4 (C-10), 135.5 (C-5 '), 136.2 (C-3a "'), 137.2 (C- 6 "'), 143.5 (C-4'), 159.4 (C-3), 166.3 (C-5), 173. 6 (C-7 "), 180.3 (C-2 '), and 184.2 (C-1), m / z (EI⁺) 7 07, (M⁺, 1.25%), 446 (40), 186 (100) and 128 (75).   Example 5   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] octane-1-yl} monamide A   a) Triethylammonium N-7- (carboxyheptyl) monamide A   Under argon at -10 ° C, monic acid A (688 mg, 2 mmol) in THF (10 solution) in succession, triethylamine (0.6 ml, 4.4 mmol) and hexane. Treated with isobutyl rologate (0.26 ml, 2 mmol). 30 minutes for the mixture Stir for 30 min, triethylamine (0.3 ml, 2.2 mmol) and 8-aminocap Treat the clear solution with phosphoric acid (318 mg, 2 mmol), followed by sufficient water. Obtained. The mixture was stirred at room temperature overnight and evaporated. The residue is flushed over silica. Chromatography, eluting with a dichloromethane / methanol mixture , The title compound as a mixture with triethylammonium monate A (710 mg, 61%) was obtained; δ_H(250MHz, CD_ThreeOD, Me_FourSi) Above all, 0.95 (3 H, d, J 7Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three), 1.3 3 (9H, t, J 6.4Hz, 3 x CH_Three), 1.35-1.72 (13H, m, 5 x C) H₂, 9-H₂, 12-H), 1.95 (1H, m, 8-H), 2.13 (3H, s, 15-H)_Three ), 2.10-2.68 (4H, m, CH₂CO, 4-H₂) 2.68-2.86 (2H, m, 10-H, 11-H), 3.20 (6H, q, J 6.4Hz, 3 x NCH₂) 3.1 5-3.92 (8H, m, N-CH₂, 5-H, 6-H, 7-H, 13-H, 16-H₂), 5.73 (1H, s, 2-H).   b) N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoyl] octane-1-yl} monamide A   THF (10 mg) of the product from Example 5 (a) (370 mg) at -10 ° C under argon. 10 ml) in succession, triethylamine (0.12 ml) and chloroformic acid Treated with isobutyl (0.1 ml). After 20 minutes, the mixture was triethylamine ( 0.12 ml) and 6-amino-4-methyl-1,2-dithiolo- [4,3-b]- Treat with pyrrole-5- (4H) -one hydrochloride (165 mg), then enough water. A clear solution was obtained. The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate, Wash with water and brine, dry (MgSO 4_Four), Evaporated. Residue on silica Subject to flash chromatography and dissolve with dichloromethane / methanol mixture Separated to give the title compound (102 mg, 25%);_max(KBr) 3415 (br), 2928, 1653, 1531cm^-1; Λ_max(EtOH) 390 (ε_m10 , 489), 312.5 (ε_m4,216); δ_H(250MHz, CD_ThreeOD, Me_FourSi), 0.94 (3H, d, J 7Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14- H_Three), 1.28-1.72 (13H, m, 5 x CH₂, 9-H₂, 12-H), 1.96 ( 1H, m, 8-H), 2.12 (3H, s, 15-H_Three), 2.10-2.61 (2H, 2 x  m, 4-H₂) 2.38 (2H, t, J 7.3Hz, 2'-H)₂) 2.68-2.82 (2 H, m, 10-H, 11-H), 3.18 (2H, t, J 6.8Hz, 8'-H)₂) 3.35 (3H, s, NMe), 3.33-3.94 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂), 5.73 (1H, s, 2-H), 7.25 (1H, s.3 ″ -H); δ_c(CD_Three OD); 17.25 (C-17), 18.80 (C-15), 20.31 (C-14), 26.58, 27.63, 29.99, 30.06, 30.36 (C-3 ', C-4', C -5 ', C-6', C-7 '), 28.02 (C-NCH_Three), 32.99 (C-9), 36. 52 (C-2 '), 40.03 (C-8'), 41.63 (C-8), 43.64 (C-4) , 43.71 (C-12), 56.69 (C-10), 61.25 (C-11), 66.3. 0 (C-16), 70.06 (C-6), 70.70 (C-13), 71.60 (C-7) , 76.22 (C-5), 112.87 (C-3 "), 115.38 (C-6a"), 12 1.28 (C-2), 135.94 (3a "), 137.56 (C-6"), 151.64 ( C-3), 168.60 (C-5 "), 169.66 (C-1), 174.21 (C-1 ') M / z (EI) (measured value M⁺653.2814, C₃₁H₄₇N_ThreeO₈S₂Theoretical value of M6 53.2805).   Example 6   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] octane-1-1yl} monamide C   a) Triethylammonium N- (7-carboxyheptyl) monamide C   As described in Example 5 (a) from the mixed anhydride of monic acid C and 8-aminocaprylic acid. Prepared in a similar manner to the method with a yield of 30%; δ_H(250MHz, CD_ThreeOD, Me_FourSi) and Reason, 0.99 (3H, d, J 7Hz, 17-H_Three), 1.09 (3H, d, J 6.4Hz , 14-H_Three), 1.31 (9H, t, J 7.3Hz, 3 x CH)_Three) 1.25-1.70 (13H, m, 5 x CH₂, 9-H₂, 12-H), 1.76 (1H, m, 8-H), 2.1 0-2.70 (7H, m, 2'-H₂, 4-H₂, 15-H_Three), 3.20 (6H, q, J 7. 3Hz, 3 x CH₂) 3.20-3.87 (8H, m, 5-H, 6-H, 7-H, 13- H, 16-H₂, 8'-H₂), 5.43 (2H, m, 10-H, 11-H), 5.74 (1H , s, 2-H).   b) N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoyl] octane-1-yl} monamide C   The mixed anhydride of Example 6 (a) and 6-amino-4-methyl-1,2-dithiolo The method described in Example 5 (b) from-[4,3-b] -pyrrole-5 (4H) one.hydrochloride. Was prepared in 17% yield similar to_max(KBr) 3412 br, 2925, 1 657, 1532 cm^-1; Λ_max(EtOH) 389.5 (ε_m9,546), 310 ( ε_m3,836): δ_H(250MHz, CD_ThreeOD, Me_FourSi), 0.99 (3H, d, J 6.9Hz, 17-H_Three), 1.09 (3H, d, J 6.3Hz, 14-H)_Three) 1.27-1 .83 (14H, m, 5 x CH₂, 8-H, 9-H₂, 12-H), 2.13 (3H, s, 1 5-H_Three) 2.15 and 2.61 (2H, 2 x m, 4-H)₂) 2.38 (2H, t, J 7.3Hz, 2'-H₂), 3.18 (2H, t, J 7Hz, 8'-H)₂) 3.36 (3H, s, NCH_Three) 3.43-3.87 (6H, m, 5-H, 6-H, 7-H, 13-H, 16 -H₂), 5.44 (2H, m, 10-H, 11-H), 5.74 (1H, s, 2-H), 7. 26 (1H, s, 3 "-H); m / z (EI) (measured value M⁺637.2851, C₃₁H₁₄ N_ThreeO₇S₂Theoretical value of 637.2855).   Example 7   5- (4- (3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoylprop-1-oxy) phenyl) -2- (1 -Normon-2-yl) oxazole A   a) Aminomethyl 4-hydroxyphenyl ketone / hydrochloride   4'-Hydroxyacetophenone (13.62 g, 100 mmol) was dried over Dissolve in loromethane (200 ml), triethylamine (16 ml) 115 millimolar ) Was added and the mixture was cooled in an ice bath before dichlorotrimethylsilane (1 3.3 ml, 105 mmol) was added. Then¹/₂After stirring for an hour, Luamine (16.7 ml, 120 mmol) was added, followed by trimethylsilyl. Triflate (21.3 ml, 110 mmol) was added. Then¹/₂Stirring for hours After that, N-bromosuccinimide (18.69 g, 105 mmol) was added. . After stirring for 1 hour, water (160 ml) and 5N hydrochloric acid (40 ml) were added and the mixture was mixed. Compound¹/_FourStir vigorously for hours. The phases are separated and the organic phase is aqueous sodium metasulfite. Washed with solution and brine, dried and evaporated. Chromatograph the crude product Partially purified by feeding to an off-white solid (15.69g) I got Nmr is the starting material and the desired bromomethyl 4-hydroxyphenyl group. It was shown to be a mixture with phenyl ketone.   Dissolve this material in acetone (100 ml), dilute with water (30 ml) and azide. Sodium (4.73 g, 73 mmol) was added. 4 of the mixture¹/₂Stirring for hours Then reduced in vacuo, diluted with water and extracted with ethyl acetate (x2). Combination The combined organic extracts were washed with brine, dried and evaporated to a light brown solid (1 4.29g) was obtained and chromatographed to give 20-40% vinegar in hexane. Partially purified by eluting with ethyl acid to give an off-white solid (12. 99g) was obtained;_max(KBr) 3304, 2104, 1661, 1573 and 1165 cm^-1;¹H nmr indicates that the product is the desired azide and 4'-hydroxy. It was shown to be a mixture with cyacetophenone; m / z 178 (MH⁺, 5%) 177 (M⁺, 4%), 170 (5), 136 (M⁺, 40), 122 (81), 121 ( 100), and 93 (99).   This material was taken up in ethanol (130 ml), water (40 ml) and 5N hydrochloric acid (25 ml). Dissolve and hydrogenate the mixture with 10% palladium on charcoal catalyst (1.0 g). Was. From time to time more catalyst was added. After hydrogenation for 3 hours, the catalyst was filtered off and washed with water. Washed and the solution was evaporated to dryness. The residual powder obtained was mixed with diethyl ether. Stir vigorously, filter off the desired product, dry under vacuum and buff powder (6.5 83g, 35%) was obtained;_max(KBr) 3424, 3055, 1673, 16 02 and 1488 cm^-1: Δ_H((CD_Three)₂SO) 4.45 (2H, s, CH₂), 6. 95 (2H, d, J 8.7Hz, 2 x Ar-H), 7.89 (2H, d, J 8.7Hz, 2 x Ar-H), 8.38 (3H, br.s, -N)⁺H_Three), And 10.86 (1H, s, O H); δ_H(D₂O) 4.60 (2H, s, CH₂), 6.96 (2H, d, J 8.7Hz, 2) x Ar-H), and 7.90 (2H, d, J 8.7Hz, 2 x Ar-H); m / z1 52 (M-Cl, 12%), 151M⁺-HCl, 73), 121 (100), and 93 (92); (Measurement value: M⁺151.0639, C₈H₉NO₂Theoretical value of M151.063 4); measured value C, 49.89; H, 5.43; N, 7.38%. C₈H_TenClNO₂Reason Theoretical value C, 51.21; H, 5.37; N, 7.47%.   b) N- [2- (4-hydroxyphenyl) -2-oxoethyl] monamide A   Monoacid A (3.44 g, 10 mmol) in dry tetrahydrofuran (100 ml) And triethylamine (1.53 ml, 11 mmol) and cooled in an ice bath. It was then treated with isobutyl chloroformate (1.30 ml, 10 mmol). The mixture To¹/₂Stir for hours, then aminomethyl 4 in THF: water (1: 2, 15 ml). -Hydroxyphenyl ketone hydrochloride (2.064 g, 11 mmol) was added, Triethylamine (3.48 ml, 25 mmol) was then added. The mixture Becomes dark purple and after stirring for 1 hour while cooling it, the volume is reduced under vacuum. Reduced. This caused most of the crude product to precipitate as a purple oil. . The rest of the product is extracted with ethyl acetate and then extracted with methyl isobutyl ketone. Issued. The combined product was evaporated then redissolved in methanol and silica Pre-absorbed and then subjected to column chromatography to 0 to 0 in dirolomethane. Purified by eluting with 12% methanol and labeled as an orange foam. Compound (2.680 g, about 56%) was obtained;_max(KBr) 3405, 1678, 1 659, 1627, 1603 and 1230 cm^-1; Λ_max(EtOH) 220 (ε_m 25,041) and 279 nm (16,898): δ_H(CD_ThreeOD) (especially ) 0.92 (3H, d, J 7.1Hz, 17-H)_Three), 1.18 (3H, d, J 6.4Hz, 1) 4-H_Three), 2.14 (3H, s, 15-H3), 4.63 (2H, s, 1'-H)₂) 5.8 8 (1H, s, 2-H), 6.80-6.87 (2H, m, 2 x Ar-H), and 7.8. 4-7.91 (2H, m, 2 x Ar-H) (nmr is also a trace amount of CH_ThreeOh oh And Triethylamine hydrochloride); m / z (NH_Three, DCI) 478 (MH⁺, 5 8%), 91 (100), and 74 (100).   c) 5- (4-hydroxylphenyl) -2- (1-normon-2-yl) oxa Zol A   N- [2- (4-hydroxyphenyl) -2-oxoethyl] monamide A (2.6 0 g, 5.4 mmol) was suspended in dry dichloromethane (100 ml) and in an ice bath. Cooled and treated successively with pyridine (5.3 ml, 65 mmol), trichloroacetate chloride. Treated with chill (6.8 ml, 54 mmol) and 4-dimethylaminopyridine (catalyst) I understood. 1¹/₂After stirring for an hour, reduce the volume of the mixture and dilute with ethyl acetate. Water, 5% aqueous citric acid solution, aqueous sodium hydrogen carbonate solution (x2) and saline Washed with, dried and evaporated to give an orange foam.   This material was dissolved in methanol (60 ml), cooled and potassium carbonate (3.3 8 g, 24.5 mmol) was added. 1¹/₂After stirring for an hour, the volume of the mixture It was reduced, washed with water and extracted with ethyl acetate (x3). The combined organic extracts Dried and pre-absorbed on silica. Chromatography for dichloromethane Elute with 0-6% methanol in to give the title compound as an off-white powder. Ta (2.363g, 94%); υ_max(KBr) 3386, 3260, 2971, 1 651, 1616, 1252 and 836 cm^-1, λ_max(EtOH) 204 (ε_m1 4,870,238 (7,144), and 309 nm (20,693); δ_H(CD_ThreeO D) (among others) 0.95 (3H, d, J 7.0Hz, 17-H)_Three), 1.20 (3H, d, J 6.4Hz, 14-H_Three), 2.29 (3H, s, 15-H_Three), 6.22 (1H, s, 2- H), 6.80-6.90 (2H, m, 2 x ArH), 7.28 (1H, s, 4'-H), And 7.48-7.58 (2H, m, 2 x ArH);_c(CD_ThreeOD) 12.2 (C- 17), 19.6 (C-15), 20.2 (C-14), 32.9 (C-9), 41.5 (C -8), 43.6 (C-12), 43.7 (C-4), 56.8 (C-10), 61.2 (C -11), 66.3 (C-16), 69.9 (C-6), 70.6 (C-7), 71.5 (C -13), 76.4 (C-5), 113.6 (C-2), 116.8 (C-3 ", C-5") , 120.6 (C-4 '), 120.8 (C-1 "), 126.7 (C-2", C-6 "), 1 48.0 (C-5 '), 152.0 (C-3), 159.1 (C-4 "), and 161.7 (C-2) '); M / z 459 (M⁺, 6%), 244 (8), and 215 (100). (measured value: M⁺459.2264, C_{twenty five}H₃₃NO₇Theoretical value M459.2258).   d) 5- [4- (3-carboxycyprop-1-oxy) phenyl] -2- (1- Normon-2-yl) oxazole A   Argoned sodium hydride (60% in oil, 0.040 g, 1 mmol) Suspended in dry dimethylformamide (5 ml) then 5 times in DMF (7 ml). -(4-hydroxyphenyl) -2- (1-normon-2-yl) oxazole A ( 0.460 g, 1 mmol) was added. The mixture¹/₂Stir for hours, then D 4-Bromobutanoic acid (3,4,5,6-tetrahydropyran-2- in MF (3 ml) Yl) (0.251 g, 1 mmol) was added. After stirring for 24 hours, the mixture Was reduced in volume with a vacuum and diluted with aqueous sodium hydrogen carbonate solution, ethyl acetate Extracted with (x2). The combined organic extracts were washed with brine, dried and evaporated. I let you. The crude product is subjected to column chromatography 0-8 in dichloromethane (A) Tetrahydropyrani as white foam separated by eluting with Ruester (0.190 g, 30%), (b) starting material (0.175 g, 38%) Was recovered. Tetrahydropyranyl ester (0.185 g, 0.29 mmol) Was dissolved in methanol (5 ml) and water (4 ml) and glacial acetic acid (1 drop) was added. . 3 of the mixture^Three/_FourStir for hours, then dilute with aqueous sodium bicarbonate, Washed with diethyl ether. The aqueous phase was then layered with ethyl acetate, 1.5M The pH was adjusted to 3.5 with phosphonic acid. The phases were separated and the aqueous phase was diluted with ethyl acetate (x2). Extracted. The combined ethyl acetate layers were washed with brine, dried, evaporated and white Colored foam (0.155g, 28% overall); υ_max(KBr) 3435, 2924, 1 719, 1500 and 1251 cm^-1; Λ_max(EtOH) 240 (ε_m8,461 ) And 308 nm (25,210); δ_H(CD_ThreeOD) (especially) 0.95 (3 H, d, 17-H_Three), 1.2 (3H, d, 14-H_Three), 2.3 (3H, s, 15-H_Three), 2 .5 (2H, t, 3'-H₂), 4.08 (2H, t, 1'-H₂), 6.25 (1H, s, 2-H ), 7.0-7.1 (2H, m, 2 x ArH), 7.35 (1H, s, 4'-H) and 7. 6-7. 7 (2H, m, 2 x ArH); m / z 545 (M⁺, 15%), 527 (5), 301 (6) , 215 (70), 121 (85), and 43 (100). (Measurement value: M⁺ 545.2 627, C₂₉H₃₉NO₉Theoretical value M 545.2625).   e) 5- (4- (3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -Oxopyrrol-6-yl) carbamoylprop-1-oxy) phenyl) -2 -(1-Normon-2-yl) oxazole A   5- [4- (3-carboxyprop-1-oxy) phenyl] -2- (1-normo N-2-yl) oxazole A (0.140 g, 0.26 mmol) was added to dry tetrahydo. To Drofra (10 ml) and triethylamine (0.04 ml, 0.29 mmol). Dissolve and cool in an ice bath, isobutyl chloroformate (0.034 ml, 0.26 mm). Mol). The mixture¹/₂Stir for hours, then triethylamine (0. 047 ml, 0.34 mmol), then 6-amino-4-methyl-1,2-dithio Oro- [4,3-b] -pyrrole-5 (4H) -one hydrochloride (0.070 g, 0.31) Mmol). The mixture at room temperature 22¹/₂Stir for hours, during which time a precipitate occured. The reaction was diluted with methanol and dichloromethane and preabsorbed on silica. Column chromatography followed by 0-8% methanol in dichloromethane. Eluting with This gives a slightly impure product (0.150 g) Was. Therefore, triturate with dichloromethane to give the title compound as a yellow powder. (0.106 g, 57%) was obtained. Melting point 163-164 ° C; υ_max(KBr) 342 0, 3262, 1681, 1660, 1652 and 1527 cm^-1; Λ_max(Et OH) 238 (ε_m11,628), 309 (25,018), and 392 nm (8,4) 57); δ_H(CD_ThreeOD / CDCl_Three) 0.95 (3H, d, J 7.0Hz, 17-H)_Three) 1.22 (3H, d, J 6.4Hz, 14-H_Three), 1.38-1.48 (1H, m, 12 -H), 1.62-1.81 (2H, m, 9-H₂), 1.92-2.02 (1H, m, 8- H), 2.10-2.22 (2H, m, 2 "-H₂), 2.30 (3H, s, 15-H_Three), 2. 35 (1H, dd, J 14.8, 9.5Hz, 4-H), 2.62 (2H, t, J 7.3Hz, 3 "-H₂) 2.7-2.9 (3H, m, 4-H, 10-H, 11-H), 3.37 (3H, s, NCH_Three), 3.43 (1H, dd, J 3.0, 8.9Hz, 6-H), 3.60 (1H, br. d, J 10.4Hz, 16-H), 3.75-3.93 (4H, m, 5, 7, 13, 16-H) 4.11 (2H, t, J 6.0Hz, 1 "-H₂), 6.25 (1H, s, 2-H), 6.98 (2H, d, J 9.9Hz, 2xArH), 7.10 (1H, s, 4'-H), 7.24 (1 H, s, 3 "'-H), and 7.57 (2H, d, J 9.9Hz, 2xArH); m / z (NH_Three, DCI) 714 (MH⁺, 7%), 91 (54) and 74 (100); m / z (Electro Spray) 736 (MNa⁺, 5%), 714 (MH⁺, 18), and 1 69 (100).   Example 8   5- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylmethyloxy-phenyl] -2- (1-normon -2-yl) oxazole A   a) 5- (4-methoxycarbonylmethyloxyphenyl) -2- (1-normo N-2-yl) oxazole A   5- (4-hydroxyphenyl) -2- (1-normon-2-yl) oxazole (1.011 g, 2.2 mmol) (Example 7c) was treated with dry dimethylformamide ( 12 ml) and dissolved in 1,1,3,3-tetramethylguanidine (0.30 ml, 2. 4 mmol) was added. The mixture was stirred for 5 minutes, then methyl bromoacetate (0.23 ml, 2.4 mmol) was added. After stirring for 16 hours some starting material Quality remains and therefore, additional 1,1,3,3-tetramethylguanidine (0.083 ml, 0.66 mmol) and methyl bromoacetate (0.062 ml, 0.06 ml). 66 mmol) was added twice. Stir for a further 1 hour, then add sodium bicarbonate. It was diluted with an aqueous solution of sodium and extracted with ethyl acetate (x2). Eat the combined organic extracts Washed with brine, dried and evaporated. Subject the product to column chromatography Elute with 0-8% methanol in dichloromethane and title as a white foam. Compound obtained (0.751 g, 64%);_max(KBr) 3420, 2923, 17 59, 1499 and 1213 cm^-1; Λ_max(EtOH) 236 (ε_m8,900) And 306 nm (28,297); δ_H(CD_ThreeOD) (among others) 0.96 (3H, d, J 7.1Hz, 17-H_Three), 1.21 (3H, d, J 6.5Hz, 14-H)_Three), 2.31 ( Three H, s, 15-H_Three) 3.81 (3H, s, CO₂CH_Three), 4.78 (2H, s, 1 "-H₂) , 6.25 (1H, s, 2-H), 6.98-7.1 (2H, m, 2 x ArH), 7.38 ( 1H, s, 4'-H), and 7.61-7.71 (2H, m, 2 x ArH); m / z5 31 (M⁺, 10%) and 287 (100). (Measurement value: M⁺531.2469, C₂₈ H₃₇NO₉Theoretical value M531.2468).   b) 5- (4-carboxymethyloxyphenyl) -2- (1-normon-2- Yl) Oxazole A   5- (4-methoxycarbonylmethyloxyphenyl) -2- (1-normon- 2-yl) oxazole A (0.250 g, 0.47 mmol) in acetone (25 ml) ), Disodium hydrogen phosphate buffer (0.1 M, pH 7, 225 ml), then Subtilisin Carlsberg enzyme (0.1 25 g) was added. The clear solution is stirred for 6 hours and then reduced in volume in vacuo. Dilute, wash with ether (75 ml), layer with ethyl acetate and p with 1.5 M phosphoric acid. Adjusted to H3.5. The mixture is filtered through Celite, the phases are separated and the aqueous phase is separated. Was further filtered and extracted with ethyl acetate (x2). Combine the combined organic extracts with salt Wash with water, dry and evaporate to a colorless gum (0.255g,> 100%). Got: δ_H(CD_ThreeOD) (among others) 0.96 (3H, d, J 7.1Hz, 17-H)_Three ), 1.21 (3H, d, J 6.4Hz, 14-H)_Three), 2.31 (3H, s, 15-H_Three), 4.72 (2H, s, 1 "-H₂), 6.25 (1H, s, 2-H), 7.04 (2H, d, J 8.9 Hz, 2 x ArH), 7.38 (1 H, s, 4'-H), and 7.65 (2 H, d, J 8.9Hz, 2 x ArH); m / z 517 (M⁺, 2%), 273 (28), 91 (8 7), and 69 (100). (Measurement value: M⁺517.2308. C₂₇H₃₅NO₉Reason Argument M 517.2311).   c) 5- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-6-yl) carbamoylmethyl-oxyphenyl] -2- (1-nor Mon-2-yl) oxazole A   The title compound was prepared using the method described in Example 7e. The product is orange Solid (0.24 g, 78%);_max(KBr) 3372, 2922, 1 653, 1616 and 1497 cm^-1; Λ_max(EtOH) 307 (ε_m31,50 3) and 393 nm (11,405); δ_H(CD_ThreeOD / CDCl_Three) 0.93 (3H, d, J 7.1Hz, 17-H_Three), 1.19 (3H, d, J 6.5Hz, 14-H)_Three), 1.3 4-1.46 (1H, m, 12-H), 1.67-1.79 (2H, m, 9-H)₂), 1.9 -2.05 (1H, m, 8-H), 2.28 (3H, s, 15-H_Three) 2.27-2.39 ( 1H, m, 4-H), 2.67-2.84 (3H, m, 4-H, 10-H, 11-H), 3. 37 (3H, s, NCH_Three), 3.35-3.45 (1H, m, 6-H), 3.57 (1H, b rd, J 11.6 Hz, 16-H), 3.71-3.97 (4 H, m, 5, 7.13, 16) -H), 4.69 (2H, s, 1 "-H₂), 6.22 (1H, s, 2-H), 7.05-7. 15- (2H, m, 2 x ArH), 7.21 (1H, s, 4'-H), 7.28 (1H, s, 3 "'-H), and 7.59-7.69 (2H, m, 2xArH); m / z (NH_Three, D CI), 686 (MH⁺, 7%) and 74 (100).   Example 9   3R, 4R-dihydroxy-2-S- [2,4-dioxo-4- {4- [3- (4- Methyl-1,2-thiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) Carbamoylprop-1-yloxy] phenyl} but-1-yl] -5S- (2S , 3S-Epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyra N   a) 4- (3-carbomethoxyprop-1-yloxy) benzaldehyde   Using the method described in Example 1a, p-hydroxybenzaldehyde (1.2 2 g, 10 mmol) with methyl 4-bromobutyrate (1.81 g, 10 mmol). To give the title compound (1.37 g, 61%) as a pale yellow solid; δ_H(C DCl_Three) 2.16 (2H, m, 2'-H), 2.58 (2H, t, J 7.1Hz, 3'-H)₂) 3.72 (3H, s, CO₂Me), 4.11 (2H, t, J 6.0Hz, 1'-H₂), 6. 95 (2H, d, J 8.7Hz, 3,5-H₂), 7.88 (2H, d, J 8.7Hz, 2.6) -H₂). (Measurement value: M⁺222.0888, C₁₂H₁₄O₂Theoretical value of M 222.089 2).   b) 3R, 4R-bistrimethylsilyloxy-2S- [4- {4- (3-carbohydrate Methoxyprop-1-yloxy) phenyl} -4-hydroxy-2-oxobuta -1-yl] -5S- (2S, 3S-epoxy-5S-trimethylsilyloxy- 4S-methylhexyl) -tetrahydropyran   Using the method described in Example 1b, the product from Example 9a (1.11 g, 5 mi Limol) with tristrimethylsylmonone (2.59 g, 5 mmol) , The title compound (0.9 g) was obtained; δ_H(CDCl_Three) Especially 0.88 (3H, d, J 7.0Hz, 17-H_Three), 1.21 (3H, d, J 6.3Hz, 14-H)_Three) 3.69 (3 H, s, CO₂Me), 5.05-5.17 (1H, m, 1-H), 6.85 (2H, d, J 8) .6 Hz, 3 ', 5'-H₂), 7.21-7.28 (2H, m, 2 ', 6'-H₂).   c) 3R, 4R-bistrimethylsilyloxy-2S- [4- {4- (3-carbo Methoxyprop-1-yloxy) phenyl} -2,4-dioxobut-1-yl] -5S- (2S, 3S-epoxy-5S-trimethylsilyloxy-4S-methyl Hexyl) -tetrahydropyran   The product from Example 9b (3.6 g, 4.8 g) was prepared using the method described in Example 1c. 6 mmol) was oxidized with manganese dioxide (5.4 g, 1.8 g) to give the title compound (1 .77 g, 47%) was obtained;_H(CDCl_Three) Especially 0.88 (3H, d, J 7.1 Hz, 17-H_Three), 1.22 (3H, d, J 6.1Hz, 14-H)_Three) 3.70 (3H, s, CO₂Me), 6.21 (1H, s, 2-H), 6.93 (2H, d, J 8.7Hz, 3 ', 5' -H₂), 7.85 (2H, d, J 8.7Hz, 2 ', 6'-H₂); M / z (EI) 739 ( MH⁺, 75%), 90 (100%).¹The H spectrum shows that the title compound is substantially It was shown that it was a round shape.   d) 3R, 4R-dihydroxy-2S- [4- {4- (3-carbomethoxypropa -1-yloxy) phenyl} -2,4-dioxobut-1-yl] -5S- (2S, 3S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyra N   Using the method described in Example 1d, the product from Example 9c (1.0 g) was title. Compound (780 mg); δ_H(CDCl_Three) Especially 0.92 (3H, d, J 7 0.0 Hz, 17-H_Three), 1.22 (3H, d, J 6.2Hz, 14-H)_Three) 3.71 (3H, s, CO₂Me), 6.21 (1H, s, 2-H), 6.93 (2H, d, J 9.0Hz, 3 ', 5'-H₂), 7.86 (2H, d, J 8.9Hz, 2 ', 6'-H₂).¹H spectrum is It was shown that the title compound was substantially in the enol form.   e) 3R, 4R-dihydroxy-2S- [4- {4- (3-carboxypropa-2 -Yloxy) phenyl} -2,4-dioxobut-1-yl] -5S- (2S, 3S -Epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyran   The product from Example 9d (300 mg) was supported using the method described in Example 1e. Treated with Subtilisin Carlsberg (150mg) Gave the title compound (133 mg, 91%); λ_max(EtOH) 323 nm (ε_m2 0,110); δ_H(D_Four-MeOH) especially 0.92 (3H, d, J 7.1Hz, 17 -H_Three), 1.20 (3H, d, J 6.3Hz, 14-H)_Three), 6.34 (to H, s, 2-H) , 6.99 (2H, d, J 8.9Hz, 3 ', 5'-H₂), 7.92 (2H, d, J 8.9Hz , 2 ', 6'-H₂); M / z (electro spray) 509 (MH⁺, 100%).¹H The spectrum showed that the title compound was substantially in the enol form.   f) 3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- [3- (4 -Methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6-ii ) Carbamoylprop-1-yloxy] phenyl} but-1-yl] -5S- ( 2S, 3S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydro Piran   The product from Example 9e (130 mg) was labeled using the method described in Example 1f. Converted to the title compound (60 mg, 34%); ν_max(KBr) 3420, 3261, 1676, 1645, 1589 cm^-1; Λ_max(EtOH) 387.5 nm (ε_m10, 2 50), 324.5 (23,920); δ_H(CDCl_Three+ D_Four-MeOH), especially 0. 90 (3H, d, J 7.1Hz, 17-H_Three), 1.22 (3H, d, J 6.2Hz, 14- H_Three) 3.32 (3H, s, NMe), 6.18 (1H, s, 2-H), 6.73 (1H, s, 3 "'-H), 6.88 (2H, d, J 8.9Hz, 3', 5'-H)₂), 7.81 (2H, d, J 8.8Hz, 2 ', 6'-H₂); M / z (electro spray) 677 (NH⁺, 100 %).¹H spectrum shows that the title compound was substantially in the enol form. Was.   Example 10   3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- [4- (1,2 -Dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) carbamoyl Buta-1-yloxy) phenyl} but-1-yl] -5S- (2S, 3S-epoxy Ci-5S-hydroxy-4S-methylhexyl) tetrahydropyran   The product from Example 1e (180 mg, 0.3) was prepared using the method described in Example 1f. 45 mmol) to holothin hydrochloride (99 mg, 0.474 mmol) To give the title compound (41 mg, 17%);_max(KBr) 3404 , 1636, 1599, 1506 cm^-1; Λ_max(EtOH) 387.5 nm (ε_m10, 154), 323.5 (22,970); δ_H(CDCl_Three/ D_Four-MeOH) especially 0 .92 (3H, d, J 7.1Hz, 17-H_Three), 1.21 (3H, d, J 6.3Hz, 14- H_Three), 6.90 (1H, s, 3 "'-H), 6.95 (2H, d, J 8.9Hz, 3', 5'-H)₂) , 7.84 (2H, d, J 8.9Hz, 2 ', 6'-H₂); M / z (electro spray ) 677 (MH⁺, 100%).¹H spectrum shows that the title compound is substantially enol It was shown to be in shape.   Example 11   3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- (3-1,2- Dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) carbamoylp Ropa-1-yloxy] phenyl} but-1-yl] -5S- (2S, 3S-epoxy Ci-5S-hydroxy-4S-methylhexyl) tetrahydropyran   The product from Example 9e (577 mg, 1. 13 mmol) was reacted with forosin hydrochloride (353 mg, 1.69 mmol) Gave the title compound (206 mg, 27%); ν_max(KBr) 3414, 165 3,1607 cm^-1; Λ_max(EtOH) 324.5 nm (ε_m22, 566), 385.5 (10,486); δ_H(CDCl_Three/ D_Four-MeOH) especially 0.93 (3H, d, J 7.0Hz, 17-H_Three), 1.21 (3H, d, J 6.3Hz, 14-H)_Three), 6.19 (~ 1H, s, 2-H), 6.85 (1H, s, 3 "'-H), 6.94 (2H, d, J 8.8Hz, 3 ', 5'-H₂), 7.84 (2H, d, J 8.8Hz, 2 ', 6'-H₂); M / z (electric Trospray) 663 (MH⁺, 100%).   Example 12   2- {4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylbutoxy} thiazol-5-yl 1-normon- 2-ylketone A   a) 2- {5,5,5-tris (methylthio) pent-1-oxy} thiazole   Diethyl 3,4-dihydro-2H-pyran (9.3 ml, 101.9 mmol) was added. 4-Bromobutanol (12.94 g, 84.6 millimolar) in ether (160 ml). Added). After 2 hours at room temperature, an additional 3,4-dihydro-2H-bilane (5. 0 ml, 59.9 mmol) was added and the mixture was stirred for 1 hour. Sodium bicarbonate Saturated aqueous solution of lithium (100 ml) was added and the mixture was extracted with diethyl ether. , Dried (MgSO_Four). Evaporate to dryness under reduced pressure and use 50% dihexane in hexane as the eluent. For column chromatography on silica gel with chloromethane It was thus purified to give 2- (4-bromobutoxy) tetra-hydro as a colorless oil. Pyran was obtained (16.9 g, 84%); δ_H(CDCl_Three) 1.50-2.10 (10 H, m, 5 x H₂) 3.40-3.92 (6H, m, 4'-H₂, 1'-H₂, 6-H₂) And 4.60 (1H, t, J 3.7Hz, 2-H).   n-Butyllithium (2.3M in hexane, 34.6 ml, 79.7 mmol) Tris (methylthio) meta in dry tetrahydrofuran (120 ml) at -78 ° C. Solution (8.83 ml, 66.3 mmol). After 1.5 hours, the temperature is -60 ° C. While maintaining the following, the compound (16. 8 g, 66.3 mmol) was added dropwise. The mixture was stirred at -60 ° C for 20 minutes,- It was heated to 45 ° C. and stirred for another 2 hours. Saturated ammonium chloride aqueous solution (120 ml), extracted with diethyl ether, dried (MgSO 4_Four), Under reduced pressure, evaporation After drying to dryness, 5,5,5-tris (methylthio) -1- (tetrahydropyran-2- Yl) oxypentane (22.6 g, 102% crude); δ_H(CDCl_Three) 1.50 -2.00 (12H, m, 6 x H₂) 2.10 (9H, s, 3 x SCH_Three) 3.38 -3. 94 (4H, m, 1-H₂, 6'-H₂), And 4.58 (1H, t, J 3.9Hz, 2'- H).   4-Toluenesulfonic acid (0.8 g, 42 mmol) was added to methanol (200 ml). ) Was added to the above compound (13.1 g, 42.2 mmol) and stirred at room temperature for 1 hour. did. Sodium hydrogen carbonate solution (100 ml, saturated) was added and the mixture was diluted with diethyl ether. Extracted with ether. Dried (MgSO_Four), Evaporated to dryness under reduced pressure, and used as an eluent. And chromatography on silica using 10-40% ethyl acetate in hexane. The product was purified by applying it to 5,5,5-tris (methyl) as colorless oil. Thio) pentanol was obtained (8.49 g, 89%); δ_H(CDCl_Three) 1.50-1. 69 (7H, m, OH, 3 x H₂) 2.10 (9H, s, 3 x SCH_Three), And 3. 53 (2H, t, J 6.4Hz, 1-H₂).   Sodium hydride (60% dispersion in oil, 0 mL) in dry tetrahydrofuran (5 mL) 1.9 g, 37.5 mmol) was suspended and, with stirring, dry tetrahydrofuran (4 The above compound (8.49 g, 37.5 mmol) in 5 ml) was added dropwise. After addition, The mixture was stirred for 2 hours. 2-Bromothiazole (6.76 g, 41.2 mmol) ) Was added and the mixture was heated to 40 ° C. and stirred for 4 hours. The reaction mixture was washed with water ( 100 ml), extracted with diethyl ether and dried (MgSO 4)._Four). Decompression Evaporate to dryness under reduced pressure and wash with 5-15% ethyl acetate in hexane as the eluent. Chromatography gave the title compound (7.4 g, 63%); δ_H( CDCl_Three) 1.72-2.00 (6H, m, 3 x H)₂), 2.10 (9H, s, 3 x S CH_Three), 4.33 (2H, t, J 6.1Hz, 1'-H)₂), 6.67 (1H, d, J 3.9) Hz, 5-H), and 7.10 (1H, d, J 3.8 Hz, 4-H).   b) 2- (5,5,5-tris (methylthio) pent-1-oxy) thiazole-5 -Yl 1- (6,7,13-O-tristrimethylsilylnormon-2-yl) keto A   At -78 ° C, 2- (5,5,5-tris (meth) in dry tetrahydrofuran (7 ml). To tylthio) pent-1-oxy) thiazole (0.84 g, 2.72 mmol), While stirring, n-butyllithium (1.5 M in hexane, 1.81 ml, 2.72 ml Lmol) was added dropwise. The mixture was stirred for 1.5 hours, then dried with tetrahydrochloride. N-methoxy-N-methyl-6,7,13-O-tris (tri) in furan (4 ml) Mersilyl) Monamide A (WO93 / 06118, SmithKline Beecham ・ Public Limited Company (SmithKline Beechamp.l.c.) ( 1.643 g, 2.72 mmol) was added dropwise. Stir at -78 ° C for 1.5 hours, then 1 hour Warm to −30 ° C. over time and then glacial acetic acid (0 ml) in diethyl ether (1 ml). Quench with .345 g, 4 mmol). The mixture was warmed to 0 ° C. and diluted with water , Extracted with diethyl ether. Dried (MgSO_Four), Evaporated to dryness under reduced pressure, Column chromatography on silica using 10% ethyl acetate in hexane as eluent. Purify by topography to give the title compound (1.17g, 50%) Got; ν_max(KBr) 3370, 2963, 2916, 1648, 1480, 1 455, 1253 and 1054 cm^-1; Λ_max(EtOH) 303 nm (ε_m21, 2 21); δ_H(CDCl_Three) (Among others) 0.10-0.24 (27H, m, 9 x SiC) H_Three), 1.19 (3H, d, J 7.4Hz, 14-H)_Three), 2.01-2.20 (10H, m , 3 x SCH_Three, 4-H), 2.58-2.72 (3H, m, 10, 11 and 4-H) 3.40 (1H, dd, J 2.4,7.0Hz, 6-H), 3.56 (1H, d, J 11. 4Hz, 16-H), 3.68-3.98 (4H, m, 5, 7, 13 and 16-H), 4. 40-4.50 (2H, m, 1 "-H₂), 6.55 (1H, s, 2-H), and 7.75 ( 1H, s, 4'-H).   c) 2- (5,5,5-tris (methylthio) pent-1-oxy) thiazole-5 -Yl 1-normon-2-yl ketone A   The above product (1.06 g, 1.24 mmol) was added to tetrahydrofuran (25 ml). Was dissolved. Hydrochloric acid (6.2 ml, 0.4M) was added and the solution was stirred for 2 minutes. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added and the mixture was extracted with ethyl acetate. Issued. Dried (MgSO_Four), And evaporated to dryness under reduced pressure. Column chromatography on silica gel with 0-5% methanol in tan. To give the title compound (0.71 g, 90%);_max( KBr) 2963, 1648, 1480, 1455, 1349 and 1258. cm^-1; Λ_max(EtOH) 303 nm (ε_m21,221); δ_H(CDCl_Three) (Toriwa K) 0.95 (3H, d, J 7.0Hz, 17-H_Three), 1.22 (3H, d, J 6.1Hz, 14-H_Three), 1.70-2.04 (9H, m, 3 x H2,9-H)₂And 8-H), 2 .15 (9H, s, 3 x SCH_Three), 2.24 (3H, s, 15-H_Three), 4.45 (2H, t, 1 "-H₂), 6.58 (1H, s, 2-H), and 7.75 (1H, s, 4'-H).   d) 2- (4-methoxycarbonylbutoxy) thiazol-5-yl 1-normo N-2-ylketone A   The product of Example 12c (0.619 g, 0.10 g) was prepared by the method described in Example 2d. The title compound was prepared from 97 mmol). The product was a white foam. (0.301g, 57%); ν_max(KBr) 2921, 1736, 1456, 12 58, 1186 and 1059 cm^-1; Λ_max(EtOH) 301.5 nm (ε_m20,0 78); δ_H(CD_ThreeOD) (among others) 0.95 (3H, d, J 7.0Hz, 17-H)_Three ), 1.20 (3H, d, J 6.4Hz, 14-H)_Three), 1.70-2.08 (9H, m, 3 x H₂, 9-H₂And 8-H), 2.25 (3H, s, 15-H_Three) 3.70 (3H, s , CO₂CH_Three), 4.50 (2H, t, J 5.9Hz, 1 "-H)₂), 6.23 (1H, s, 2 -H), and 7.95 (1H, s, 4'-H); m / z 541 (M⁺, 14%) and 1 15 (100). (Measurement value: M⁺541.2359, C₂₆H₃₉HO₉Theoretical value of S M 5 41.2346).   e) 2- (4-Carboxybutoxy) thiazol-5-yl 1-normon-2- Irketone A   Using the method described in Example 8b, the product of Example 12d (0.230 g, 0.2 The title product was prepared from 43 mmol). The product was a white gum. (0.187g, 83%); δ_H(CD_ThreeOD) (especially) 0.96 (3H, d, J  7.0Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H)_Three) 2.25 (3 H, s, 15-H_Three) 2.39 (2H, t, J 7.1Hz, 4 "-H)₂), 4.51 (2H, t, J6.1Hz, 1 "-H₂), 6.74 (1H, s, 2-H), and 7.94 (1H, s) , 4'-H); m / z 527 (M⁺, 0.5%), 128 (48), 100 (100), and 56 (94); m / z (NH_Three, DCI) 528 (MH⁺, 4%), 147 (100), Yo 91 (100).   f) 2- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-6-yl) carbamoylbutoxy] -thiazol-5-yl 1-nor Mon-2-yl ketone A   Using the method described in Example 7e, the product of Example 12e (0.170 g, 0.10 g. The title compound was prepared from 32 mmol). The product was an orange foam. (0.151g, 68%); ν_max(KBr) 3415, 1669, 1648, 16 00, 1480 and 1454 cm^-1; Λ_max(EtOH) 250 (ε_m9,390), 304 (19,226) and 391 nm (8,600); δ_H(CDCl_Three/ CD_ThreeOD) 0.94 (3H, d, J 7.1Hz, 17-H_Three), 1.22 (3H, d, J 6.3Hz, 14) -H_Three), 1.34-1.44 (1H, m, 12-H), 1.65-2.06 (7H, m, 8) -H, 9-H₂, 2 "-H₂, 3 "-H₂), 2.24 (3H, s, 15-H_Three) 2.33 (1 H, dd, J 9.3,14.7Hz, 4-H), 2.46 (2H, t, J 7.0Hz, 4 "-H₂) 2.68-2.85 (3H, m, 4,10,11-H), 3.35 (3H, s, NCH_Three), 3.41 (1H, dd, J 3.1, 9.1Hz, 6-H), 3.58 (1H, br.d, J 1) 1.3 Hz, 16-H), 3.69-3.96 (4 H, m, 5, 7, 13, 16-H), 4.4 7 (2H, t, J 5.9Hz, 1 "-H₂), 6.60 (1H, s, 2-H), 6.81 (1H, s, 3 "'-H), and 7.77 (1H, s, 4'-H) ;?_c(CDCl_Three/ CD_ThreeOD) 12.4 (C-17), 20.2 (C-15), 20.4 (C-14), 21.8 (C-3 " ), 27.9 (NCH_Three), 28.3 (C-2 "), 31.9 (C-9), 35.4 (C-4") , 39.9 (C-8), 42.3 (C-12), 43.5 (C-4), 55.8 (C-10). , 61.0 (C-11), 65.7 (C-16), 68.7 (C-6), 70.3 (C-7) , 70.7 (C-13), 72.3 (C-1 "), 75.1 (C-5), 110.6 (C-3" '), 114.5 (C-6a "'), 120.9 (C-2), 134.0, 135.7 and 136.7 (C-5 ', 3a "', 6" '), 142.5 (C-4'), 158.2 (C-3), 167.4 (C-5 "'), 171.6 (C-5"'), 179.3 (C-2 '), and 18 3.4 (C-1); m / z (electrospray) 696.3 (MH⁺, 100%).   Example 13   2- {1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl} Carbamoylmethyloxythiazol-5-yl 1-normon-2-yl ketone A   a) 2,2,2-tris (methylthio) ethanol   n-Butyllithium (2.5M in hexane, 6.38 ml, 16.0 mmol) , Tris (methylthio) meta in dry tetrahydrofuran (40 ml) at -78 ° C. Solution (2.05 g, 13.28 mmol). Stir for 1.5 hours. flask Inside, paraformaldehyde (3g) was heated and the resulting formaldehyde was The surface of the reaction mixture, which was vigorously stirred with a gon stream, was covered with brown. Further at -50 ° C Stir for 1.5 h, then add saturated aqueous ammonium chloride solution (50 ml). Was. The mixture was extracted with diethyl ether, dried (MgSO 4)._Four), Under reduced pressure, evaporation Dry to dryness and chromatograph on silica using 33% ethyl acetate in hexane as the eluent. Purify by chromatography to give the title compound as a colorless oil. Obtained (1.7 g, 72%); δ_H(CDCl_Three) 2.13 (9H, s, 3 x SCH_Three), 2.52 (1H, t, J 6.6Hz, OH), and 3.72 (2H, d, J 6.6Hz, C) H₂). D₂2.13 (9H, s, 3 x SCH by addition of O_Three) And 3.72 (2 H, s, CH₂).   b) 2- (2,2,2-tris (methylthio) ethoxy) thiazole   Sodium hydride (60% dispersion in oil, in dry tetrahydrofuran (5 ml), 0.382 g, 9.55 mmol) was stirred and the compound (1.76 g, 9.55 mmol) was stirred. Mol) in dry tetrahydrofuran (10 ml) was added over 15 minutes. The reaction was stirred for an additional 1.5 hours. Then bromothiazole (0.947 ml 10.5 mmol) was added over 15 minutes and the mixture was warmed to 40 ° C. Stir for hours and then at room temperature overnight. Water (50 ml) was added. Diethyl Extract with ether, dry (MgSO 4)._Four), Evaporated and 6 in hexane as eluent Chromatography on silica with 6% dichloromethane to give the title A compound was obtained (containing 25% bromothiazole, as indicated by nmr. Had) (2.0 g, 78%) δ_H(CDCl_Three) 2.22 (9H, s, 3 x SCH_Three), 4.81 (2H, s, 1'-H)₂), 6.71 (1H, d, J 3.9Hz, 5-H) , And 7.11 (1H, d, J 3.9Hz, 4-H).   c) 2- {2,2,2-tris (methylthio) ethoxy} thiazol-5-yl 1- (6,7,13-O-Tristrimethylsilylnormon-2-yl) ketone A   At -70 ° C the compound (crude containing 25% bromothiazole, 2.0 g , 7.5 mmol) in a solution of dry tetrahydrofuran (7 ml) in n-butyllithium. Um (2.4 M in hexane, 4.4 ml, 10.6 mmol) was added dropwise with stirring. Was. The mixture was stirred at -70 ° C for 1.5 hours. N-methoxy-N-methyl-6, 7,13-O-tris (trimethylsilyl) monamide A (WO93 / 06118, SmithKline Beecham Public Limited Company (SmithK line Beecham plc)) (5/0 g, 8.28 mmol) of dry tetrahydrofuran Solution (10 ml) was added dropwise over 10 minutes and the mixture was stirred at -70 ° C for 1.5 hours. Stirred. The mixture was warmed to -30 ° C over 30 minutes and stirred at this temperature for 1 hour. did. Then using glacial acetic acid (0.746 mg in diethyl ether (2 ml)) The reaction was quenched, warmed to 0 ° C, diluted with water (20ml) and with diethyl ether. Extracted. Dried (MgSO_Four), Freeze-dried under reduced pressure, and eluent hexane. Chromatography on silica using 8-16% ethyl acetate in The title compound was obtained as a colored oil (1.49 g, 29%); δ_H(CDCl_Three) ( Inter alia) 0.11-0.29 (27H, m, 9 x SiCH_Three), 0.95 (3H, d, J  7.0Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three) 2.21 (9 H, s, 3 x SCH_Three), 3.41 (1 H, dd, J 2.4, 8.9 Hz, 6-H), 3.5 6 (1H, d, J 11.3Hz, 16-H), 3.80-4.00 (4H, m, 5, 7, 13 And 16-H), 4.35 (2H, s, 1 "-H₂), 6.55 (1H, s, 2-H), And 7.72 (1H, s, 4'-H).   d) 2- {2,2,2-tris (methylthio) ethoxy} thiazol-5-yl 1- Normon-2-yl ketone A   The above product (1.35 g, 1.67 mmol) was added to tetrahydrofuran (33 ml). Was dissolved. Hydrochloric acid (8.34 ml, 0.4M) was added and the mixture was stirred for 2 minutes. Was. A saturated aqueous solution of sodium hydrogen carbonate (17 ml) was added and the mixture was diluted with ethyl acetate. Extracted. Dried (MgSO_Four), And evaporated to dryness under reduced pressure. Chromatography on silica using 5% methanol in dichloromethane Thus purified to give the title compound as a yellow foam (0.62 g, 62%); δ_H (CDCl_Three) (Among others) 0.95 (3H, d, J 7.0Hz, 17-H)_Three) 1.12 (3H, d, J 6.3Hz, 14-H_Three), 2.22 (9H, s, 3 x SCH_Three) 2.29 (3H, s, 15-H_Three), 3.61 (1H, d, J 10.0Hz, 16-H), 4.35 (2 H, s, 1 "-H₂), 6.60 (1H, s, 2-H), and 7.75 (1H, s, 4'-H) .   e) 2- (4-methoxycarbonylmethyloxy) thiazol-5-yl 1-no Lumon-2-ylketone A   The above compound (0.88 g, 1.48 mmol) was dissolved in methanol (60 ml). And cooled to -40 ° C. Mercury oxide (yellow, 0.321 g, 1.48 mmol ) And mercuric chloride (1.20 g, 4.42 mmol) were added and the mixture was added to 5 Stirred for 0 minutes. Cold chlorination of the mixture via kieselguhr Filter into saturated aqueous ammonium solution (150 ml) and wash with methanol (20 ml) did. The mixture was extracted with dichloromethane. Dried (MgSO_Four), Under reduced pressure, steam Dry to dryness on silica using 10% methanol in ethyl acetate as eluent. Chromatography shows a mixture of the desired product and the orthoester (about 1 1 ratio) (0.104 g, 13%). Add this to methanol (28 ml) and It was dissolved in water (28 ml) and 0.4 M HCl (1.9 ml) was added. 2 minutes later, charcoal A saturated aqueous solution of sodium hydrogen carbonate (4 ml) was added. This gives the orthoester Was converted to the desired product. The mixture was extracted with dichloromethane and the extract was brined. Washed with water, dried and evaporated. 0-6% in diethyl ether as eluent Chromatography on silica gel with methanol gives a white foam The desired product was obtained as (0.062 g, 8.4%);_max(KBr) 2923, 1762, 1646, 1422, 1184, and 1049 cm^-1; Λ_max(EtO T) 299 (ε_m19,323); δ_H(CD_ThreeOD) (especially) 0.95 (3 H, d, J 7.1Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three), 2. 22 (3H, s, 15-H_Three), 3.40 (1H, dd, J 2.1,9.0Hz, 6-H), 3 .80 (3H, s, CO₂CH_Three), 5.10 (2H, s, 1 "-H)₂), 6.71 (1H, s, 2 -H), and 7.90 (1H, s, 4'-H).   f) 2- (Carboxymethyloxy) thiazol-5-yl 1-normon-2- Irketone A   The product (290 mg, 0.58 mmol) in acetone (30 ml) and phosphorus Protease in solution in disodium hydrogen citrate buffer (0.1 M, 270 ml, pH 7) -Subtilisin-Carlsberg (157 mg) was added and the mixture was added for 2.5 hours. Stirred. The solution was reduced under reduced pressure to a volume of 100 ml and washed with ethyl acetate (30 ml). The solution was then layered with ethyl acetate (40 ml) and chlorinated. Saturated with sodium solids and adjusted to pH 3.5 with phosphonic acid (1.5M) did. The mixture was separated and the aqueous phase was pre-extracted with ethyl acetate (2x40ml). Existence The organic phase is washed with brine, dried (MgSO 4_Four), Evaporated to dryness to give a colorless oil. To give the title compound (185 mg, 65%); δ_H(CD_ThreeOD) (among others) 0. 96 (3H, d, J 7.0Hz, 17-H_Three), 1.21 (3H, d, J 6.3Hz, 14- H_Three), 2.25 (3H, s, 15-H_Three), 2.71 (1H, dd, J 2.3,7.4Hz, 1 1-H), 3.41 (1H, dd, J 3.0,9.0Hz, 6-H), 3.61 (1H, d, J  11.2Hz, 16-H), 3.82-3.98 (4H, m, 5, 7, 13 and 16-H ), 5.05 (2H, s, 1 "-H₂), 6.72 (1H, s, 2-H), and 7.92 (1 H, s, 4'-H).   g) 2- {1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Ill} carbamoylmethyloxythiazol-5-yl 1-normon-2-yl Ketone A   From Example 13f in dry tetrahydrofuran (3 ml) at 0 ° C. under argon. The product of (162 mg, 0.335 mmol) was sequentially treated with triethylamine ( 49.9 μl, 0.359 mmol) and isobutyl chloroformate (46.6 μl, It was treated with 0.359 mmol). After stirring for 30 minutes, the mixture was triethyl Amine (66 μl, 0.478 mmol), then 6-amino-1,2-dithiolo -[4,3-b] -Pyrrole-5 (4H) -one hydrochloride (90 mg, 0.43 mmol) ) And the mixture was stirred for 18 hours after reaching room temperature. Dig the mixture Dilute with loromethane, wash with water and brine, dry (MgSO 4_Four), Under reduced pressure, Evaporated to dryness. The product was used with 1% methanol in methyl acetate as the eluent. And purified by column chromatography on silica gel, A bright orange solid was obtained (46 mg, 21%); v_max(KBr) 2942, 16 82, 1651, 1640, 1464 and 1261 cm^-1; Λ_max(EtOH) 2 99 (ε_m13,405) and 391 nm (7,312); δ_H(CD_ThreeOD) (Toriwa K) 0.95 (3H, d, J 6.9Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H_Three), 2.25 (3H, s, 15-H_Three), 2.35 (1H, dd, J 9.4,14. 3Hz, 4-H), 2.70-2.78 (2H, m, 4-H and 11-H), 3.41 ( 1H, dd, J 3.1,9.0Hz, 6-H), 3.60 (1H, d, J 11.5Hz, 16 -H), 3.75-3.84 (2H, m, 13-H and 5-H), 3.86-3.92 ( 2H, m, 16-H and 7-H), 5.15 (2H, s, 1 "-H₂), 6.74 (1H, s, 2-H), 7.13 (1H, s, 3 "'-H), and 7.94 (1H, s, 4'-H); m / z (ESI) 640 (M⁺, 1%), 527 (85), and 258 (100).   Example 14   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] -2-oxooct-1-yl} nonamide A   a) Methyl 9-bromo-8-oxononanoate   Suberic acid monomethyl ester (2.50 g, 13.3 mmol) was added to dichloromethane. Dissolve in tan (30 ml) and dimethylformamide (0.1 ml) and dichloroform. Treatment with oxalyl chloride (1.28 ml, 14.6 mmol) in methane (5 ml) dropwise. did. The reaction was stirred under argon for 30 minutes, then evaporated to dryness and again From toluene. Then the method of Lmbardi [Chem. & Ind., 21, 108 (1990)], slowly diazomethane (about 30 mmol) And aerated into the cooled solution of the acid chloride in diethyl ether (150 ml). I let it. The mixture was stirred for a further 30 minutes, then concentrated hydrobromic acid (10 ml) was added. Added slowly. After stirring vigorously for 30 minutes, the phases are separated and the acidic phase is etherified. Extract with (2 x 50 ml). The combined ethereal phases are washed with saturated sodium hydrogen carbonate solution. Wash with solution (x2) and brine, dry and evaporate to give a white oily solid. (1.60 g, 45%), which was used without further purification; v_max(CH₂Cl₂) 2945, 1730 and 1175 cm^-1Δ_H(CDCl_Three) 1.24-1.49 (4 H, m, 2 x H₂), 1.51-1.79 (4H, m, 2 x H)₂), 2.31 (2H, t, J 7.4Hz, 2-H₂) 2.66 (2H, t, J 7.3Hz, 7-H)₂) 3.67 (3H , s, CO₂CH_Three), And 3.88 (2H, s, 9-H)₂); M / z 265/267 (M H⁺, 1%), 233/235 (M-OMe, 20), 171 (94), 139 (91) And 129 (100); m / z (NH_Three, DCI) 282/284 (MNH_Four ⁺, 90%) , 204 (100) and 187 (99). (Measurement value: M⁺-OMe 233.0180 , C₉H₁₄BrO₂Theoretical value M-OMe 233.0177).   b) Methyl 9-azido-8-oxononanoate   Methyl 9-bromo-8-oxononanoate (1.57 g, 5.92 mmol) was added. Dissolve in cetone (30 ml) and water (10 ml), then add sodium azide ( 0.423 g, 6.5 millimoles) was added and the mixture was stirred for 18 hours. The solution Was reduced in volume under vacuum and extracted with ethyl acetate (x2). Combined organic extraction The product was washed with brine, dried and evaporated to give a colorless oil (1.28g). This was subjected to column chromatography on silica (36g) in hexane. Purified by eluting with 10-15% ethyl acetate to give a solid as a colorless oil. The title compound was obtained (1.10 g, 82%), which was refrigerated to solidify;_max(C H₂Cl₂) 2940, 2109 and 1730 cm^-1Δ_H(CDCl_Three) 1.23- 1.48 (4H, m, 2 x H₂), 1.52-1.78 (4H, m, 2 x H)₂) 2.30 (2H, t, J 7.4Hz, 2-H₂) 2.44 (2H, t, J 7.3Hz, 7-H₂), 3. 66 (3H, s, CO₂CH_Three), And 3.93 (2H, s, 9-H)₂); M / z (NH_Three, DCI) 245 (MNH_Four ⁺, 100%), 228 (MH⁺, 17), 204 (64), 1 88 (71), and 187 (83).   c) Aminomethyl 6-methoxycarbonylhex-1-ylketone / hydrochloride   Methyl 9-azido-8-oxononanoate (1.08 g, 4.75 mmol) was added. Dissolve in tanol (15 ml), water (5 ml) and 5N hydrochloric acid (2.5 ml) and mix the mixture. The mixture was hydrogenated with 10% palladium-charcoal (0.1 g) for 1 hour. Key the mixture Filter through kieselguhr, wash with water, evaporate to dryness and turn off. A white solid was obtained. It was then crushed with diethyl wooter and Air dried to give a white powder (0.983 g, 87%);_max(KBr) 342 8, 2938, 1721 and 1694 cm^-1: Δ_H(D₆-DMSO) is 2.1 The product is methyl, as indicated by the two triplets at 9 and 2.29. It was shown to be a mixture of ester and the corresponding acid (about 1: 1).   d) N- (8-methoxycarbonyl-2-oxooct-1-yl) monamide A   Monoacid A (1.376 g, 4.0 mmol) was added to dry tetrahydrofuran (40 ml). ) And trimethylamine (0.61 ml, 4.4 mmol) and dissolved in an ice bath. Cooled and treated with isobutyl chloroformate (0.52 ml, 4.0 mmol). The mixture Compound¹/₂Stir for hours, then triethylamine (1.22 ml, 8.8 mmol) ) Was added, and then the product of Example 14c (0.96 g, ca. A solution in lahydrofuran: water (1: 1, 10 ml) was added. The reaction was warmed to room temperature. While warming 2¹/₂Stir for hours, then dilute with ethyl acetate and sodium bicarbonate Wash with solution and brine, dry and evaporate to dryness to give a pale yellow oil (1. 27 g) was obtained. The aqueous phase is saturated with sodium chloride and layered with ethyl acetate, 1. The pH was adjusted to 3.2 with 5M phosphonic acid. Separate the layers and extract the aqueous layer with ethyl acetate. did. The combined organic extracts (from pH 3.2) are washed with brine, dried and evaporated. A second product (0.80 g, ca 39%) was obtained.   The second product is, according to nmr, N- (8-carboxy-2-oxooctane. It was found to be a mixture of ta-1-yl) monamide A and monic acid A.   The first product was subjected to column chromatography on silica (35g) to give Purified by eluting with 0-5% methanol in chloromethane to give a colorless gas. The title compound was obtained as a gum (0.715 g, 34%); δ_H(CD_ThreeOD) (and R Reason) 0.95 (3H, d, J 7.1Hz, 17-H_Three), 1.20 (3H, d, J 6.4H z, 14-H_Three), 2.14 (3H, s, 15-H_Three), 2.31 (2H, t, J 7.4Hz, 8) '-H₂) 2.48 (2H, t, J 7.3Hz, 3'-H)₂), 3.64 (3H, s, CO₂C H_Three), 4.02 (2H, s, 1'-H₂), And 5.82 (1H, s, 2-H); m / z 5 27 (M⁺, 1%), 509 (1), 283 (34), 111 (78), and 55 (10) 0). (Measurement value: M⁺527.3081, C₂₇H₄₅NO₉Theoretical value of M 527.309 4).   e) N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoyl] -2-oxooct-2-yl} monami De A   N- (8-carboxy-2-oxooct-1-yl) nonamide A containing impurities (0.39 g, about 0.88 mmol) was dried with tetrahydrofuran (40 ml) and Dissolve in triethylamine (0.14 ml, 0.97 mmol) and cool in an ice / salt bath. It was treated with isobutyl chloroformate (0.12 ml, 0.88 mmol). The anti The reaction was stirred for 1 hour and then triethylamine (0.16 ml, 1.15 mmol). ) And 6-amino-4-methyl-1,2-dithiolo- [4,3-b] -pyrrole- 5 (4H) -one hydrochloride (0.236 g, 1.06 mmol) was added and another 2 Stirring was continued for 1 hour. The mixture was diluted with ethyl acetate and saturated with sodium hydrogen carbonate Washed with aqueous solution and brine, dried and evaporated. The residue is silica (22 g ) 0-6% methanol in dichloromethane by column chromatography on Eluting with toluene to give the title compound as an orange foam (0.206g, 60%); ν_max(KBr) 3419, 2926, 1733, 1668, 1637 and 15 26 cm^-1; Λ_max(EtOH) 214 (ε_m24,029), 315 (2,986), And 389 nm (8,379); δ_H(CD_ThreeOD) 0.94 (3H, d, J 7.1Hz, 1 7-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three), 1.30-1.48 (5H, m, 12-H, 5'-H₂, 6'-H₂), 1.52-1.77 (6H, m, 9-H₂, 4'-H₂ , 7'-H₂) 1.90-2.02 (1H, m, 8-H), 2.13 (3H, s, J 0.7) Hz, 15-H_Three), 2.10-2.25 (1H, m, 4-H), 2.38 (2H, t, J 7.4Hz, 8'-H₂), 2.49 (2H, t, J 7.3Hz, 3'-H)₂) 2.61 (1H, br.d, J 14.2Hz, 4-H), 2.70 (1H, dd, J 2.2,7.6Hz, 11 -H), 2.80 (1H, dt, J 2.2, 5.7Hz, 10-H), 3.35 (3H, s, N) CH_Three), 3.31-3.39 (1H, m, 6-H), 3.55 (1H, br.d, J 11. 6Hz, 16-H), 3.68-3.92 (4H, m, 5, 7, 13, 16-H), 4.02 ( 2H, s, 1'-H₂), 5.83 (1H, s, 2-H), and 7.25 (1H, s, 3 "-) H); δ_c(CD_ThreeOD) 12.1 (C-17), 19.0 (C-15), 20.3 (C-1) 4), 24.4 (C-7 '), 26.5 (C-5'), 28.1 (NCH_Three), 29.8 (C- 6 '), 29.9 (C-4'), 33.0 (C-9), 36.5 (C-8 '), 40.4 (C- 3 '), 41.7 (C-8), 43.8 (C-4 and C-12), 49.7 (C-1'), 56.9 (C-10), 61.3 (C-11), 66.3 (C-16), 70.1 (C-6) , 70.7 (C-7), 71.6 (C-13), 76.3 (C-5), 112.8 (C-3 " ), 115.4 (C-6a "), 120.6 (C-2), 135.9 (C-3a"), 137 .6 (C-6 "), 153.2 (C-3), 168.6 (C-1), 169.7 (C-5"), 174.2 (C-9 '), and 208.4 (C-2'); m / z (electrospray ) 704 (MNa⁺, 1%), 699 (MNH_Four ⁺, 2), 682 (MH⁺, 2.5), 437 ( 2) and 147 (100).   Example 15   5- [6- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylhexyl] -2- (1-normon-2-yl) oxy Sazol A   N- {8-[(4-thymer-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] -2-oxooct-1-yl} monamide A (0.160 g, 0.235 mmol) (Example 14) was added to dry dichloromethane (2 0 ml) and pyridine (0.23 ml, 2.82 mmol) and cooled in an ice bath. And, successively, trichloroacetyl chloride (0.23 ml, 1.88 mmol) and And 4-dimethylaminopyridine (only a few crystals). 1 of the mixture¹ /₂Stir for time, reduce volume under vacuum and dilute with ethyl acetate. This solution water, Washed with 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and brine, Dry and evaporate.   The residue was dissolved in methanol (5 ml) and potassium carbonate (0.138 g, 1.0) was added. Mmol). The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate (x Extracted in 3). The combined organic extracts were washed with brine, dried and evaporated . The crude product was chromatographed on silica (8 g) to give dichlorometa. 0 to 5¹/₂Purified by eluting with% methanol to give an orange foam. Gave the title compound (0.040 g, 26%); λ_max266 and 390 nm; δ_H(CD_ThreeOD) 0.96 (3H, d, J 7.1Hz, 17H_Three), 1.21 (3H, t, J  6.5Hz, 14-H_Three), 1.31-1.54 (5H, m, 12-H, 3 "-H₂, 4 "-H₂ ), 1.59-1.79 (6H, m, 9-H)₂, 2 "-H₂, 5 "-H₂) 1.91-2.03 (1H, m, 8H), 2.19 (3H, s, 15-H_Three) 2.28 (1H, dd, J 9.6, 14.4Hz, 4-H), 2.40 (2H, t, J 7.3Hz, 6 "-H₂) 2.66-2. 87 (5H, m, 4,10,11-H, 1 "-H₂) 3.37 (3H, s, NCH_Three) 3.3 8-3.46 (1H, m, 6-H), 3.56 (1H, br.d, J 11.5Hz, 16-H ) 3.73-3.95 (4H, m, 5, 7, 13, 16-H), 6.14 (1H, s, 2H) , 6.80 (1H, s, 4'-H), and 7.23 (1H, s, 3 "'-H); m / z (d Rectoplay) 686 (MNa⁺, 5%), 664 (MH⁺, 41), and 164 ( 100).   Example 16   5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Il) carbamoylhexyl] -2- (1-normon-2-yl) oxazole A   a) 5- (6-methoxycarbonylhexyl) -2- (1-normon-2-yl) Oxazole A   Using the method described in Example 15, N- (8-methoxycarbonyl-2-oxy) Sooct-1-yl) nonamide A (from Example 14d, 0.695 g, 1.32 mm Of the title compound as a colorless gum (0.106 g, 16%); δ_H(CD_ThreeOD) (among others) 0.96 (3H, d, J 7.1Hz, 17- H_Three), 1.21 (3H, d, J 6.4Hz, 14-H)_Three), 2.20 (3H, s, 15-H_Three) 2.34 (2H, t, J 7.3Hz, 6 "-H₂) 2.62-2.89 (5H, m, 4, 1 0,11-H, 1 "-H₂) 3.66 (3H, s, CO₂CH_Three), 6.14 (1H, s, 2- H), and 6.80 (1H, s, 4'-H); m / z (DCI, NH_Three) 510 (MH⁺, 1 00%) and 265 (68).   b) 5- (6-carboxyhexyl) -2- (1-normon-2-yl) oxazo A   The product of the above reaction (0.097 g, 0.19 g) was prepared using the method described in Example 8b. To give the title compound (0.079 g, 84) as a colorless gum. %) Was obtained; δ_H(CD_ThreeOD) (among others) 0.94 (3H, d, J 7.1Hz, 17 -H_Three), 1.20 (3H, d, J 6.5Hz, 15-H)_Three), 2.18 (3H, s, 15-H_Three ) 2.23-2.35 (3H, m, 4-H, 6 "-H₂) 2.64-2.85 (5H, m, 4,10,11-H, 1 "-H₂), 6.13 (1H, s, 2-H), and 6.79 (1H, s, 4'-H).   c) 5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole- 6-yl) carbamoylhexyl] -2- (1-normon-2-yl) oxazole A   Using the method described in Example 10, the product of the above reaction (0.075 g, 0.15 g 1 mmol) was reacted to give the title compound as an orange foam (0.046 g, 47). %) Was obtained; ν_max(KBr) 3416, 2925, 1640, 1597 and 1 533 cm^-1, λ_max(EtOH) 265 (ε_m20,899) and 388 nm (10,9) 15); δ_H(CD_ThreeOD) 0.94 (3H, d, J 7.2Hz, 17-H_Three), 1.19 ( 3H, d, J 6.5Hz, 14-H_Three) 1.32-1.49 (5H, m, 12-H, 3 "- H₂, 3 "-H₂, 4 "-H₂), 1.58-1.78 (6H, m, 9-H₂, 2 "-H₂, 5 "- H₂), 1.89-2.01 (1H, m, 8-H), 2.17 (3H, s, 15-H)_Three), 2. 27 (1H, dd, J 9.7,14.5Hz, 4-H), 2.39 (2H, t, J 7.4Hz, 6 "-H₂) 2.63-2.84 (5H, m, 4,10,11-H, 1 "-H₂) 3.38 ( 1H, dd, J 3.1, 8.8Hz, 6-H), 3.56 (1H, br.d, J 11.5Hz, 16-H), 3.71-3.92 (4H, m, 5,7,13,16-H), 6.12 (1H, s, 2-H), 6.78 (1H, s, 4'-H), and 7.07 (1H, s, 3 "'-H); m / z (electro spray) 673 (MNa⁺, 10%) and 650 (MH⁺, 10 0).   Example 17   5- [4- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Il) carbamoylmethyloxyphenyl] -2- (1-normon-2-yl) oxy Sazol A   Using the method described in Example 10, the product of Example 8b (0.212 g, 0.4 1 mmol) was reacted to give the title compound as an orange foam (0.104 g, 38 %) Was obtained; ν_max(KBr) 3385, 1666, 1537, 1498 and 1 245 cm^-1; Λ_max(EtOH) 306 (ε_m29,743) and 388 nm (12,3) 64); δ_H((CD_Three)₂SO) 0.83 (3H, d, J 7.0Hz, 17-H_Three) 1.0 6 (3H, d, J 6.4Hz, 14-H_Three) 1.25-1.41 (1H, m, 12-H), 1.54-1.69 (2H, m, 9-H₂), 1.77-1.89 (1H, m, 8-H), 2. 17-2.31 (4H, m + s, 4-H, 15-H_Three) 2.61-2.78 (3H, m, 4 , 10,11-H), 3.18-3.29 (1H, m, 6-H), 3.44 (1H, br.d, J 10.5Hz, 16-H), 3.59-3.78 (4H, m, 5, 7, 13, 16-H), 4.50 (1H, d, J 4.7Hz, OH), 4.65 (1H, d, J 7.3Hz, OH), 4 .76 (1H, s, J 3.5Hz, OH), 4.83 (2H, s, 1 "-H₂), 6.18 (1H , s, 2-H), 7.04 (2H, d, J 9.2Hz, 2 x Ar-H), 7.14 (1H, s , 4'-H), 7.57 (1H, s, 3 "'-H), 7.66 (2H, d, J 8.8Hz, 2x Ar-H), 10.04 (1H, s, NH), and 10.83 (1H, s, NH); m / z (Electro Spray) 672 (MH⁺, 6%) and 296 (100).   Example 18   N- {4- [3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-ylaminocarbonyl) -propyloxy] phenyl} monami De A   a) N- (4-hydroxyphenyl) monamide   Similar to the method described in Example 5a, a mixture of monic acid A anhydride (688 mg, 2 Limol) was treated with 4-hydroxyaniline to give the title compound (641 mg, 74% ) Was obtained; ν_max(KBr) 3400 (br), 1663, 1637 and 1513 cm^-1Δ_H(250MHz, CD_ThreeOD, Me_FourSi) 0.95 (3H, d, J 7Hz, 17 -H_Three), 1.20 (3H, d, J 6.5Hz, 14-H)_Three) 1.40 (1H, m, 12-H) 1.69 (2H, m.9-H₂), 1.97 (1H, m, 8-H), 2.20 (4H, m, 1) 5-H_Three, 4-H), 2.62-2.88 (3H, m, 10-H, 11-H, 4-H), 3. 33-3.95 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H), 5.89 ( 1H, s, 2-H), 6.73 and 7.35 (4H, ABq, J 6.8Hz, Ph); m / z (EI⁺) 435 (M⁺, 12%).   b) N- [4- (3-carboxypropyloxy) phenyl] monamide A   The product from Example 18a (218 mg, 0.5 mmol) at room temperature under argon. ) And tetramethyl-guanidine (0.13 ml, 1 mmol) in dry DMF ( 5 ml) in 4-bromobutanoic acid (3,4,5,6-tetrahydropyran-2- Ill) (251 g, 1 mmol). Stir overnight, dilute with ethyl acetate, Wash with saturated aqueous sodium hydrogen carbonate solution, brine, dry (MgSO_Four), Evaporated I let you. The crude product was subjected to flash chromatography on silica and subjected to dichloromethane. Separated by eluting with a mixture of methanol in dichloromethane (130 mg, 43%). Released. Tetrahydropyran in methanol (10 ml) and water (10 ml) at room temperature The ranyl ester (382 mg) was treated with glacial acetic acid (2 drops). After 3 hours, the mixture Evaporated and flash chromatographed on silica to dichloromethane Elution with a mixture of medium methanol gave the title compound (291 mg, 88%);_max (KBr) 3416 (br), 2924, 1715, 1665, 1636 and 1510 cm^-1Δ_H(250MHz, CD_ThreeOD, Me_FourSi) 0.96 (3H, d, J 7 Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H)_Three), 1.41 (1H, m, 12-H), 1.71 (2H, m, 9-H₂), 1.98 (1H, m, 8-H), 2.06 (2 H, m, CH₂), 2.22 (4H, m, 4-H, 15-H_Three) 2.45 (2H, t, J 7.3Hz, CH₂CO), 2.60-2.80 (3H, m, 4-H, 10-H, 11-H) 3.35-4.00 (6H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂), 4. 00 (2H, t, J 6.7Hz, OCH₂), 5.92 (1H, s, 2H), 6.88 and 7.46 (4H, ABq, J 9Hz, Ph); m / z (NH_ThreeDCI⁺) 522 (MH⁺, 2 9%).   c) N- {4- [3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -Oxopyrrole-6-ylaminocarbonyl) propyloxy] phenyl} mona Mid A   The product from Example 18b (261 mg) was prepared by the method described in Example 5b. Converted to the title compound (106 mg, 31%). ν_max(KBr) 3418 (br) , 2924, 1648, 1509 and 1230 cm^-1; Λ_max(EtOH) 393 (ε_m10,298), 280.5 (ε_m17,164); δ (250 MHz, CD_ThreeOD, M e_FourSi) 0.96 (3H, d, J 7Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H_Three), 1.41 (1H, m, 12-H), 1.70 (2H, m, 9-H)₂) 1.98 (1H, m, 8-H), 2.05-2.30 (6H, m, 4-H, 15-H_Three, CH₂), 2. 60 (2H, t, J 7.3Hz, CH₂CO), 2.61-2.89 (3H, m, 4-H, 1 0-H, 11-H), 3.35 (3H, s, NMe), 3.35-3.95 (6H, m, 5-) H, 6-H, 7-H, 13-H, 16-H₂), 4.03 (2H, t, J 6Hz, OCH₂), 5.91 (1H, s, 2-H), 6.88 and 7.44 (4H, ABq, J 9Hz, Ph) , 7.25 (1H, s, 3 "-H); δ_c(CD_ThreeOD) 13.55 (C-17), 17.1 5 (C-15), 18.49 (C-14), 24.51 (C-3 '), 26.17 (C-N) CH_Three), 31.16, 31.42 (C-9, C-2 ′), 39.86 (C-8), 41.7. 0 (C-12), 42.13 (C-4), 55.06 (C-10), 59.43 (C-11) ), 64.50 (C-16), 66.58 (C-4 '), 68.26 (C-7), 68.89 (C-6), 69.61 (C-13), 74.41 (C-5), 110.96 (C-3 "), 113.61 (C-6a "), 113.63 and 121.06 (C-Ph), 119. 64 (C-2), 131.33 (C-3a "), 135.26 (C-6"), 151.96 ( C-5 "), 165.66, 166.24 (C-1, C-3), 171.67 (C-1 ') M / z (NH_ThreeDCI⁺) 690 (MH⁺, 8%).   Example 19   N- {4- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrole-6-ylaminocarbonyl) -butyloxy] benzyl} monamide A   a) Methyl 5- (4-methylphenoxy) pentanoate   4-methylphenol (2.66 g), tetramethylguanidine (3.4 ml) and And a mixture of methyl 5-bromopentanoate in dry DMF (20 ml) for 7 days at room temperature. Stirred. Dilute with ethyl acetate, wash with water and brine, dry (MgSO 4_Four) And evaporated. Flash chromatography of ethyl acetate in hexane The title compound (1.6g, 29%) was isolated by eluting with the mixture. δ_H (250MHz, CDCl_Three, Me_FourSi), 1.82 (4H, m, 2 x CH₂) 2.30 ( 3H, s, CH_Three) 2.42 (2H, m, CH₂CO), 3.75 (3H, s, OCH_Three) 3 .98 (2H, m, OCH₂), 6.79 and 7.08 (4H, ABq, J 8.4Hz, Ar ).   b) methyl 5- (4-azidomethylphenoxy) pentanoate   The product from Example 19a (1.6 g) and N-bromosuccinimide (1.6 g). 28 g) of a mixture of carbon tetrachloride (20 ml) is refluxed for 30 minutes under strong light, Cooled in an ice bath, filtered and evaporated. This crude bromide was added to DMF (5 Redissolved in 0 ml) and treated with sodium azide (0.47 g). 45 minutes later, the The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO_Four), Evaporated. The residue was subjected to flash chromatography on silica to give acetic acid. Elution with a mixture of ethyl and hexane gave the title compound (1.5g, 79%). Was. ν_max(CH₂Cl₂) 2952, 2089, 1732 and 1248 cm^-1Δ_H (250MHz, CDCl_Three, Me_FourSi) 1.85 (4H, m, 2 x CH₂) 2.43 ( 2H, m, CH₂CO), 3.68 (3H, s, OCH_Three) 3.97 (2H, m, OCH₂), 4.26 (2H, s, CH₂N_Three), 6.90-7.24 (4H, m, Ar); m / z (EI⁺ ) 263 (M⁺, 13%).   c) Methyl 5- (4-aminomethylphenoxy) pentanoate   The product from Example 9b (526 mg) in ethanol (30 ml) was stirred at room temperature. And hydrogenated at 5% Pd / C (100 mg) for 30 minutes at atmospheric pressure. The mixture is filtered And evaporated to give the title compound (476 mg, 100%);_max(CH₂Cl₂ ) 2952, 1733 and 1511 cm^-1Δ_H[250 MHz, (CD_Three)₂CO, Me_Four Si] 1.79 and 1.95 (4H, 2 x m, 2 x CH₂) 2.41 (2H, m, CH₂CO), 3.63 (3H, s, OMe), 4.01 (2H, m, OCH)₂) 4.36 (2 H, s, NCH₂), 6.85-7.31 (4H, m, Ar); m / z (EI⁺) 237 (M⁺ , 55%).   d) N- [4- (4-methoxycarbonylbutyloxy) benzyl] monamide A   Mixed anhydride of monic acid A (688 mg, 2 mmol) as described in Example 5a. Was treated with the product from Example 19c (474 mg, 2 mmol) and chromatographed. After ruffing, the title compound (425 mg, 38%) was obtained; v_max(CH₂Cl₂ ) 3436 (br), 2929, 1732, 1666 and 1511 cm^-1Δ_H(2 50MHz, CD_ThreeOD, Me_FourSi) 0.96 (3H, d, J 7Hz, 17-H_Three) 1.2 1 (3H, d, J 6.5Hz, 14-H_Three), 1.41 (2H, m, 12-H), 1.61- 1.85 (6H, m, 9-H₂, 2 x CH₂), 1.96 (1H, m, 8-H), 2.10- 2.25 (4H, m, 15-H_Three, 4-H), 2.42 (2H, m, CH₂CO), 2.52- 2.85 (3H, m, 4-H, 10-H, 11-H), 3.35-3.93 (6H, m, 5- H, 6-H, 7-H, 13-H, 16-H₂) 3.66 (3H, s, OCH_Three) 3.98 ( 2H, m, OCH₂), 4.32 (2H, s, NCH₂), 5.79 (1H, s, 2-H), 6. 87 and 7.21 (4H, ABq, J 8.6Hz, Ar); m / z (NH_ThreeDCI⁺) 5 64 (MH⁺, 6%).   e) N- [4- (4-carboxybutyloxy) benzyl] monamide A   The product from Example 19d (410 mg) was prepared by the method described in Example 1e. Converted to the title compound (353 mg, 88%); ν_max(KBr) 3425 (br), 2927, 1715, 1659, 1624 and 1246 cm^-1Δ_H(250M Hz, CD_ThreeOD, Me_FourSi) 0.95 (3H, d, J 7Hz, 17-H_Three), 1.21 (3H , d, J 6.5Hz, 14-H_Three), 1.41 (2H, m, 12-H), 1.63-1.88 ( 6H, m, 9-H₂, 2 x CH₂), 1.97 (1H, m, 8-H), 2.10-2.26 ( 4H, m, 4-H, 15-H_Three) 2.38 (2H, m, CH₂CO), 2.55-3.87 ( 3H, m, 4-H, 10-H, 11-H), 3.36-3.93 (6H, m, 5-H, 6- H, 7-H, 13-H, 6-H₂), 4.00 (2H, m, OCH₂), 4.33 (2H, s, NCH₂), 5.79 (1H, s, 2-H), 6.88 and 7.21 (4H, ABq, J8) .6 Hz, Ar); m / z (NH_ThreeDCI⁺) 550 (MH⁺, 8%).   f) N- {4- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H ) -Oxopyrrole-6-ylaminocarbonyl) butyloxy] benzyl} monami De A   The product from Example 19e (275 mg) was obtained by the method described in Example 5b. Converted to the title compound (80 mg, 22%); ν_max(KBr) 3410 (br), 2 928 (br), 1661, 1640, 1511 and 1245 cm^-1; Λ_max(Et OH) 389.5 (ε_m6,709), 309 (ε_m2867), 222.5 (ε_m32, 283); δ_H[250 MHz, (CD_Three)₂SO, Me_FourSi] 0.82 (3H, d, J 7.4 Hz, 17-H_Three), 1.06 (3H, s, J 6.4Hz, 14-H_Three), 1.31 (1H, m, 12-H), 1.57 (2H, m, 9-H₂), 1.61-1.88 (5H, m, 3'-H2, 4'-H₂, 8-H), 1.98 (1H, m, 4-H), 2.10 (3H, s, 15-H)_Three), 2.35-2.78 (5H, m, 4-H, 10-H, 11-H, 2'-H₂) 3.12-4 .33 (13H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂, 5'-H₂NCH₂, NCH_Three), 4.50 (1H, d, J 4.6Hz, OH), 4.59 (1H, d, J 7.2Hz) , OH), 4.73 (1H, d, J 3.1Hz), 5.70 (1H, s, 2-H), 6.87 And 7.15 (4H, ABq, J 8.6Hz, Ar), 7.35 (1H, s, 3 "-H), 8. 22 (1H, t, J 5.6Hz, N'-H), 10.0 (1H, s, N "-H); m / z ( Electro Spray) 718 (MH⁺, 100%).   Example 20   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] -octyl} monamide A   a) N- (7-carboxyoctyl) monamide A   A solution of monic acid A (820 g) in THF (10 ml) at −10 ° C. under argon. , Successively, triethylamine (0.36 ml) and isobutyl chloroformate (0.3. 31 ml). The mixture was stirred for 30 minutes and triethylamine (0.72 m l) and 9-aminononanoic acid (0.5 g), then treated with plenty of water to give a clear A different solution was obtained. The mixture was stirred at room temperature overnight, then pH was adjusted with 5% citric acid solution. Acidified to 3.5. Extracted with ethyl acetate (x2). Combined extracts with saline Washed with water, dried (MgSO 4_Four), Evaporated. Flush residue on silica Chromatographic elution with a methanol / dichloromethane mixture, The title compound (520 mg) was obtained as a mixture with acid A. δ_H(250MHz, CD_Three OD, MeSi) Especially 0.98 (3H, d, J 7Hz, 17-H_Three), 1.22 (3H, d, J 6.4Hz, 14-H_Three), 1.25-1.77 (15H, m, 9-H₂, 12-H, 6 x CH₂), 1.96 (1H, m, 8-H), 2.06-2.34 (6H, m, 4-H, 15-H_Three, CH₂CO), 2.53-2.89 (3H, m, 4-H, 10-H, 11-H) 3.19 (2H, m, NCH₂) 3.26-3.95 (6H, m, 5-H, 6-H, 7- H, 16-H), 5.51 (1H, s, 2-H).   b) N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) o) Xoxopyrrol-6-yl) -carbamoyl] octyl} monamide A   The mixture from Example 20a (520 mg) was prepared by the method described in Example 5b. Converted to the title compound (190 mg, 12% overall);_max(KBr) 3402 (br ), 2925, 1653 and 1528 cm^-1; Λ_max(EtOH) 389.5 (ε_m1 0,067), 311.5 (ε_m3,990), 214.5 (ε_m23,634); δ_H(2 50MHz, CD_ThreeOD, Me_FourSi) 0.96 (3H, d, J 7Hz, 17-H_Three) 1.2 2 (3H, d, J 6.4Hz, 14-H_Three), 0.97 (12H, m, 6 x CH₂) 1.5 2 (1H, m, 12-H), 1.69 (2H, m, 9-H)₂) 1.96 (1H, m, 8-H) 2.16 (4H, m, 4-H, 15-H_Three) 2.40 (2H, t, J 7.4Hz, CH₂C O), 2.51-2.87 (3H, m, 4-H, 10-H, 11-H), 3.19 (2H, t , J 6.8 Hz), 3.23 (9H, m, 5-H, 6-H, 7-H, 13-H, 16-H, H Me), 5.75 (1H, s, 2-H), 7.27 (1H, s, 3 "-H); δ_c(CD_ThreeOD); 1 2.28 (C-17), 18.84 (C-15), 20.35 (C-14), 27.97 ( NCH_Three), 2667, 28.07, 30.12, 30.21, 30.26, 30.4. 3 (C-3 ', C-4', C-5 ', C-6', C-7 ', C-8'), 27.97 (C-NC H_Three), 33.01 (C-9), 38.60 (C-2 '), 40.10 (C-9'), 41.6. 4 (C-8), 43.67 (C-4), 43.73 (C-12), 56.90 (C-10) , 61.27 (C-11), 66.31 (C-16), 70.09 (C-6), 70.72 (C-13), 71.62 (C-7), 76.25 (C-5), 112.89 (C-3 "), 115.42 (C-6a "), 121.31 (C-2), 135.88 (C-3a"), 1 37.58 (C-6 "), 151.66 (C-3), 188.59 (C-5"), 189.6 5 (C-1), 174.23 (C-1 '); m / z (EI⁺) (Measurement value M⁺667.29 69, C₃₂H₄₉N_ThreeO₈S₂Theoretical value M 667.2961).   Example 21   N- {9-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] -nonyl} monamide A   a) Triethylammonium N- (9-carboxynonyl) monamide A   Similar to the method described in Example 5a, 10% of mixed anhydride of monic acid A (550 mg) was added. -Reacted with aminodecanoic acid (360 mg) to give triethylammonium monate The title compound (80 mg) was obtained as a mixture with A; δ_H(250MHz, CD_ThreeOD , Me_FourSi) Especially 0.96 (3H, d, J 7Hz, 17-H_Three), 1.22 (3H, d, J 6.5Hz, 14-H_Three), 1.25-1.75 (26H, m, 3 x CH_Three, 7 x C H₂, 9-H₂, 12-H), 1.96 (1H, m, 8-H), 2.10-2.33 (6H, m , 4-H, 15-H, CH₂CO), 2.55-2.88 (3H, m, 4-H, 10-H, 1 1-H), 3.13-3.93 (5-H, 6-H, 7-H, 13-H, 16-H₂, NCH₂ , 3 x NCH₂), 5.75 (1H, s, 2-H); m / z (NH_ThreeDCI⁺), 514 ( MH⁺, 5%).   b) N- {9-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoyl] nonyl} monamide A   The product from Example 21a (739 mg) was obtained by the method described in Example 5b. Converted to the title compound (190 mg, 17% overall);_max(KBr) 3373 (br ), 2926, 1659, 1531 and 1435 cm^-1; Λ_max(EtOH) 39 2.5 (ε_m9,285), 315 (ε_m3,399), 214.5 (ε_m24, 303); δ_H (250MHz, CD_ThreeOD, Me_FourSi) 0.96 (3H, d, J 7.1Hz, 17-H_Three) 1.21 (3H, d, J 6.5Hz, 14-H_Three) 1.27-1.75 (17H, m, 9) -H₂, 12-H, 7 x CH₂), 1.98 (1H, m, 8-H), 2.13-2.25 ( 4H, m, 4-H, 15-H_Three) 2.38 (2H, t, J 7.3Hz, CH₂CO), 2.5 5-2.87 (3H, m, 4-H, 10-H, 11-H), 3.16-3.93 (11H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂, NCH₂, NCH_Three), 5.75 (1 H, s, 2-H), 7.27 (1H, s, 3 "-H); δ_c(CD_ThreeOD) 12.26 (C- 17), 18.82 (C-15), 20.33 (C-14), 26.68, 27.99, 30.14, 30.23, 30.27, 30.39, 30.44 (C-3 ', C-4', C -5 ', C-6', C-7 ', C-8', C-9 '), 28.04 (C-NCH_Three), 32.9 9 (C-9), 36.59 (C-2 '), 40.10 (C-10'), 41.26 (C-8) , 43.64 (C-4), 43.71 (C-12), 56.89 (C-10), 61.26. (C-11), 66.30 (C-16), 70.07 (C-6), 70.70 (C-13) , 71.60 (C-7), 76.23 (C-5), 112.90 (C-3 "), 115.3 9 (C-6a "), 121.30 (C-2), 135.90 (C-3a"), 137.56 ( C-6 '), 151.62 (C-3), 166.59, 169.84 (C-1, C-5 "), 174.24 (C-1 '); m / z (electrospray) 682 (MH⁺, 100%) .   Example 22   N- {10-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-6-yl) carbamoyl] -decyl} monamide A   a) N- (10-carboxydecyl) monamide A   As described in Example 20a, mixed anhydride of monic acid A (688 mg, 2 mmol). Was reacted with 11-aminoundecanoic acid (474 mg, 2 mmol) to give the title compound. A compound was obtained (200 mg, 19%); δ_H(250MHz, CD_ThreeOD, MeSi) 0.9 6 (3H, d, J 7Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H)_Three), 1 .26-1.75 (19H, m, 9-H₂, 12-H, 8 x CH₂), 1.95 (1H, m, 8-H), 2.10-2.33 (6H, m, 4-H, 15-H, CH₂CO), 2.53- 2.87 (3H, m, 4-H, 10-H, 11-H), 3.12-3.93 (8H, m, 5- H, 6-H, 7-H, 13-H, 16-H₂, NCH₂), 5.75 (1H, S, 2-H); m / z (NH_ThreeDCI⁺) 528 (MH⁺, 28%).   b) N- {10-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H)- Oxopyrrol-6-yl) carbamoyl] -decyl} monamide A   The product from Example 22a (200 mg) was prepared by the method described in Example 5b. Converted to the title compound (139 mg, 53%); ν_max(KBr) 3411 (br) , 2924, 1653 and 1531 cm^-1, λ_max(EtOH) 391 (ε_m10,5 47), 312 (ε_m4,035), 212.5 (ε_m24,511); δ_H(250 MHz , CD_ThreeOD, Me_FourSi) 0.96 (3H, d, J 7.1Hz, 17-H_Three), 1.21 (3H , d, J 6.5Hz, 14-H_Three), 1.26-1.74 (19H, m, 9-H)₂, 12-H, 8 x CH₂), 1.96 (1H, m, 8-H), 2.08-2.23 (4H, m, 4-H, 15-H_Three), 2.54-3.85 (3H, m, 4-H, 10-H, 11-H), 3.18 ( 2H, t, J 6.8Hz, CH₂N), 3.28-3.91 (9H, m, 5-H, 6-H, 7 -H, 13-H, 16-H₂, NCH_Three), 5.74 (1H, s, 2-H), 7.27 (1H, s, 3 "-H); δ_c(CD_ThreeOD) 12.48 (C-17), 19.05 (C-15), 20.56 (C-14), 26.91, 28.26, 30.39, 30.52, 30.5 6, 30.64, 30.69, 30.74 (C-3 ', C-4', C-5 ', C-6', C- 7 ', C-8', C-9 ', C-10'), 28.26 (C-NCH_Three), 32.28 (C-9) , 36.62 (C-2 '), 40.33 (C-11'), 41.68 (C-8), 48.69 (C-4), 43.95 (C-12), 57.11 (C-10), 61.47 (C-11) , 66.53 (C-16), 70.31 (C-6), 70.93 (C-13), 71.65 (C-7), 76.47 (C-5), 113.07 (C-3 "), 115.65 (C-6a") , 121.53 (C-2), 136.12 (C-3a "), 137.61 (C-6"), 1 51.86 (C-3), 168.82 (C-5 "), 169.67 (C-1), 174.4 7 (C-1 '); m / z (FAB) (measured value: MH⁺696.2814, C₃₄H₅₄N_ThreeO₈ S₂Theoretical value of 696.3353).   Example 23   N- {11-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-5-yl) carbamoyl] -undecyl} monamide A   a) N- (11-carboxyundecyl) monamide A   Mixture of monic acid A anhydride (688 mg, 2 millimolar) as described in Example 20a. Reaction with 12-aminododecanoic acid (504 mg, 2 mmol) to give the title compound Compound (135 mg, 12%) was obtained; δ_H(250MHz, CD_ThreeOD, Me_FourSi) 0. 96 (3H, d, J 7.1Hz, 17-H_Three), 1.22 (3H, d, J 6.4Hz, 14- H_Three), 1.26-1.76 (21H, m, 9-H₂, 12-H, 9 x CH₂) 1.96 ( 1H, m, 8-H), 2.06-2.85 (6H, m, 4-H, 15-H_Three, CH₂CO), 2.62-2.86 (3H, m, 4-H, 10-H, 11-H), 3.12-3.95 (8 H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂, NCH₂), 5.75 (1H, s, 2-H); m / z (NH_ThreeDCI⁺) 542 (MH⁺, 100%).   b) N- {11-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H)- Oxopyrrol-5-yl) carbamoyl] undecyl} monamide A   The product from Example 23a is converted to the title compound by the method described in Example 5b. Converted (97 mg, 60%);_max(KBr) 3404 (br), 2924, 1 653 and 1538 cm^-1; Λ_max(EtOH) 391.5 (ε_m9,918), 31 5.5 (4,172), 212.5 (26,196); δ_H(250MHz, CD_ThreeOD, Me_Four Si) 0.96 (3H, d, J 7Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H_Three), 1.24-1.75 (2H, m, 9-H)₂, 12-H, 9 x CH₂), 1. 96 (1H, m, 8-H), 2.08-2.23 (4H, m, 4-H, 15-H_Three) 2.4 0 (2H, t, J 6.9Hz, CH₂CO), 2.53-2.86 (3H, m, 4-H, 10 -H, 11-H), 3.18 (2H, t, J 6.9Hz, NCH₂) 3.26-3.92 ( 9H, m, 5-H, 6-H, 7-H, 13-H, 16-H₂, NCH_Three), 5.75 (1H, s, 2-H), 7.27 (1H, s, 3 "-H); δ_c(CD_ThreeOD) 12.28 (C-17 ), 18.85 (C-15), 20.35 (C-14), 26.71, 28.05, 30.1 9, 30.33, 30.40, 30.50, 30.55, 30.58 (C-3 ', C-4' , C-5 ', C-6', C-7 ', C-8', C-9 ', C-10', C-11 '), 28.05. (C-NCH_Three), 33.03 (C-9), 36.62 (C-2 '), 40.13 (C-12') ), 41.67 (C-8), 43.68 (C-4), 43.75 (C-12), 56.91 ( C-10), 61.26 (C-11), 66.33 (C-16), 70.10 (C-6), 70.73 (C-13), 71.64 (C-7), 76.27 (C-5), 112.87 ( C-3 "), 115.44 (C-6a"), 121.32 (C-2), 135.93 (C- 3a "), 137.60 (C-6"), 151.64 (C-3), 168.82 (C-5 ") 169.88 (C-1), 174.23 (C-1 '); m / z (FAB) (measured value: M H⁺710.3517, C₃₅H₅₆N_ThreeO₈S₂Theoretical value of 710.3510).   Example 24   N- {9-[(1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6 -Yl) carbamoyl] nonyl} monamide A   The product from Example 21a (710 mg) was prepared by the method described in Example 10. , Converted to the product containing the title compound; ν_max(KBr) Especially 3393 ( br), 2970, 1653 and 1537 cm^-1Δ_H(250MHz, CD_ThreeOD, Me_FourSi) Especially 0.96 (3H, d, J 7Hz, 17-H_Three), 1.21 (3H, d, J  6.4Hz, 14-H_Three), 1.25-1.75 (17H, m, 9-H)₂, 12-H, 7 x CH₂), 1.96 (1H, m, 8-H), 2.06-2.30 (4H, m, 4-H, 15- H_Three) 2.40 (2H, t, J 7.3Hz, CH₂CO), 2.55-2.88 (3H, m, 4-H, 10-H, 11-H), 3.13-3.95 (8H, m, 5-H, 6-H, 7-H , 13-H, 16-H₂, NCH₂), 5.75 (1H, s, 2-H), 7.08 (1H, s, 3 "-H); m / z (electro spray⁺ve) 668.6 (MH⁺, 100%).   Example 25   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5 [5- (4-methyl-1,2-dithiolo [4,3-b] -5 -(4H) -Oxopyrrol-6-yl) carbamoylpent-1-yloxy] ii Hand-On-1-On   a) 2-Bromo-5-t-butyldimethylsilyloxybenzyl bromide   4-Bromo-3-methylpheno in N, N-dimethylformamide (30 ml) (4.49 g, 24.0 mmol), t-butyldimethylsilyl chloride (5.43 g) , 36.0 mmol) and imidazole (4.90 g, 22.0 mmol) at room temperature. It was stirred for 16 hours. Water (100 ml) was added and the product was extracted with ethyl acetate. . Dried (MgSO_Four), Evaporated to dryness under reduced pressure and using hexane as the eluent. Purified by flash chromatography to yield the crude silylated foam. An enol (4.16 g, 57%) was obtained. This crude product (4.16 g, 13.77 N-bromosuccinimide (2.70 g, 15.15 mmol) and And carbon tetrachloride (100 ml) were added. The mixture on a 150W incandescent lamp at 2 o'clock Heated to reflux for a while. Cool to 5 ° C, filter and evaporate the filtrate to dryness under reduced pressure and elute Purification by flash chromatography using hexane as the liquid. Prepared to give the title compound as a colorless oil; δ_H(CDCl_Three) 0.20 [6H, s, Si (CH_Three)₂], 0.97 (9H, s,^tBu), 4.50 (2H, s, CH₂Br), 6.6 3 (1H, dd, J 2.9 and 8.5Hz, 4-H), 6.91 (1H, d, J 2.9Hz , 5-H), 7.37 (1H, d, J 8.5Hz, 3-H); m / z (EI) 382 (M⁺ , 5%), 380 (M⁺, 10%), 378 (M⁺, 5%); (Measured value: M⁺377.964 2, C₁₃H₂₀Br₂OS theoretical value M 377.9652).   b) E-2- {2- [3R, 4R-bis-trimethylsilyloxy-5S- (2S , 3S-Epoxy-5S-trimethylsilyloxy-4S-methylhexyl) teto Lahydropyran-3S-yl]-(1-methylethylidene)}-5-t-butyldime Cylsilyloxyindan-1-one   N-methoxy-N-meth in THF (30 ml) was maintained while maintaining the temperature below -65 ° C. Chill-6,7,13-O-tris (trimethylsilyl) monamide A (3.60 g, 6. (00 mmol) to diisopropylamine (0.16 ml, 1.16 mmol) and And t-butyllithium (1.7 M in hexane, 3.88 ml, 6.60 mmol). It dripped continuously. After 1 hour at −70 ° C., 2-bromo-5-t-butylmethylsilane Ryloxy-benzyl bromide (3.01 g, 7.90 mmol) and iodide Tium (0.20 g, 1.31 mmol) was added and the mixture was heated at reflux for 60 hours. did. The product was poured into water, extracted with ethyl acetate, dried (Na₂SO_Four), Reduced Evaporated to dryness under pressure. Hexane / ethyl acetate (6: 1) was used as an eluent. Excessive benzyl bromide present by flash chromatography Was removed to give a complex mixture (2.30 g). This mixture was subjected to TH at -70 ° C. T-Butyllithium (1.7M in hexane) in F (20ml) (3.30ml, 5. 61 mmol) for 2 hours. Add water, extract with ethyl acetate and dry. (Na₂SO_Four), Evaporated to dryness under reduced pressure, and hexane / ethyl acetate (7 Purified by flash chromatography using: A complex mixture (1.03 g) containing the desired deconjugated ketone was obtained. This mixture The mixture was treated with potassium t-butoxide (0.20 g, in THF (10 ml) at -70 ° C). (1.60 mmol) for 2 hours. Acetic acid (0.16 ml, 2.8 mmol), then Then water was added. Extract with ethyl acetate, dry (Na₂SO_Four), Under reduced pressure, illness First dry to dryness and flush with hexane / ethyl acetate (8: 1) as eluent Purify by chromatography and title compound as a white foam. Was obtained (0.63 g, 14%); δ_H(CD_ThreeOD) 0.10-0.27 (33H, m , 11 x SiCH_Three), 0.92 (3H, d, J 7.0Hz, 17-H)_Three), 1.01 (9H , s,^tBu), 1.20 (3H, d, J 6.3Hz, 14-H_Three) 1.28-1.42 (1H , m, 12-H), 1.67-1.83 (3H, m, 9-H₂And 8-H), 2.36 (1 H, dd, J 13.4 and 10.5Hz, 4-H), 2.40 (3H, s, 15-H_Three), 2.58 (1H, d, J 13.4Hz, 4-H), 2.72-2.82 (2H, m, 10 and 11-H), 3.50-3.95 (8H, m, 5,7,13,16-H, 16-H₂And And CH₂Ph), 6.87 (1, dd, J 8.3 and 2.0 Hz, phenyl), 6.93 ( 1H, d, J 2.0Hz, phenyl), 7.63 (1H, d, J 8.3Hz, phenyl); m / Z762 (M⁺, 13%), 173 (100%); (measured value: M⁺762.4209, C₃₉H₇₀O₇Si_FourTheoretical value M 762.4199).   c) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) -tetrahydropyran-2S-I ]-(1-Methylethylidene)}-5-hydroxyindan-1-one   The ketone from Example 25b (0.62 g, 0.81 mmol) in THF at 5 ° C. Treatment with tetra-n-butylammonium fluoride in (15 ml) for 10 minutes. pH7 buffer (20 ml) was added, extracted with ethyl acetate and evaporated to dryness under reduced pressure ( Na₂SO_Four), Using 10% methanol in dichloromethane as the eluent Purify by chromatography on the column and combine with the title compound as a white foam. Obtained (0.34 g, 97%); υ_max(KBr) 3423, 2966, 2927 , 1669, 1623, 1585, 1304, 1266, 1093cm^-1; Λ_max (EtOH) 213 nm (ε_m16,596) and 293.5 nm (sh) (ε_m14,07 2); δ_H(CD_ThreeOD) 0.94 (3H, d, J 7.1Hz, 17-H_Three), 1.19 (3 H, d, J 6.4Hz, 14-H_Three), 1.33-1.44 (1H, m, 12-H), 1.6 1-1.83 (2H, m, 9-H₂), 1.87-1.97 (1H, m, 8-H), 2.40 ( 2H, s, 15-H_Three) 2.45 (1 H, dd, J 13.6 and 9.6 Hz, 4-H), 2.72-2.84 (3H, m, 4, 10 and 11-H), 3.40 (1H, dd, J 9 .3 and 3.0 Hz, 6-H), 3.53 (1 H, d, J 11 Hz, 16-H), 3.50 -3.94 (6H, m, 5,7,13,16-H and CH₂Ph), 6.77 (1H, dd, J 2.1, 8.3 Hz, phenyl), 6.80 (1 H, d, J 2.1 Hz, phenyl), (1 H, d, J 8.3Hz, phenyl); δ_c(CD_ThreeOD) 12.2 (C-17), 18.7 ( C-14), 20.3 (C-15), 32.9 (CH₂Ph), 33.0 (C-9), 41. 6 (C-4), 41.7 (C-8), 43.6 (C-12), 56.8 (C-10), 61. 3 (C-11), 66.4 (C-16), 70.3 (C-6), 70.7 (C-7), 71. 6 (C-13), 76.9 (C-5), 112.3, 116.8, 126.6, 133. 5 (q), 133.6 (q), 151.2 (q), 153.3 (q), 164.9 (q), 19 5.1 (C-1); m / z 432 (M⁺, 4%); (Measured value: M⁺432.2158, C_{twenty four} H₃₂O₇Theoretical value M432.2148).   d) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) -tetrahydropyran-2S-I ] -1-Methylethylidene} -5- (methoxycarbonylpent-1-yloxy Shi) Indan-1-on   The product from Example 25c (0.5 g, 1.15 mmol) in THF (5 ml). Dissolved and sodium hydride (43 mg, 1.04 mmol) in THF (3 ml) Added to the suspension. The mixture was stirred for 10 minutes under an argon atmosphere. THF Methyl 6-iodohexanoate (0.3 g, 1.15 mmol) in (3 ml), then And DMF (5 ml) and 15-crown-5 (0.1 g, 0.58 mmol) were added. Was added. The resulting solution was stirred for 48 hours. The mixture is poured into water and ethyl acetate is added. Extracted. The combined organic extracts were washed with water, dried (MgSO_Four), Evaporated I let you. The crude product was subjected to flash chromatography 5 in dichloromethane Purify by eluting with% methanol to give the title compound (2 50 mg, 39%) was obtained;_max(KBr) 3422, 2924, 1735, 16 81, 1623 cm^-1: Λ_max(EtOH) 309.5 nm (ε_m22, 954), 239. 5 nm (ε_m7,265); δ_H(CD_ThreeOD) 0.96 (3H, d, J 7.1Hz, 17-H_Three ), 1.2 (3H, d, J 6.5Hz, 14-H)_Three) 1.29-2.0 (10H, m, 9H₂ , 8,12-H and 3xCH₂) 2.37 (2H, t, J 7.3Hz, CH₂) 2.4 2 (3H, s, 15-H_Three) 2.5 (1H, d, J 9.7Hz, 4-H), 2.6-2.8 5 (3H, m, 10, 4 and 11-H), 3.41 (1H, dd, J 3.2 and 9.2) Hz, 6-H), 3.55 (1H, d, J 11.6Hz, 16-H), 3.63 (3H, s, OC H_Three) 3.69-3.92 (6H, m, 7,5,13,16 and CH₂-Ph), 4.08 (2H, t, J 6.3Hz, CH₂), 6.91 (1 H, dd, J 2.2 and 8.6 Hz, A r-H), 6.99 (1H, d, J 2.2Hz, Ar-H), 7.61 (1H, d, J 8.6H z, Ar-H); m / z (FAB, thiochrycerol) (MH⁺) 561.   e) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- (5-carboxypent-1-yloxy) in Dan-1-on   The methyl ester from Example 25d (10 mg, 0.018 mmol) was added to pH 7 buffer. Opposition Na₂HPO_Four(9 ml) and acetone (1 ml). Subtilisin Carlsberg (6 mg) was added and the resulting suspension was stirred for 48 hours. Solvent Removed by lyophilization. The residue was treated with ethanol (25 ml) and filtered. The filtrate was evaporated, the resulting solid was dissolved in water and acidified to pH3. The product Are extracted with ethyl acetate, the combined organic extracts are washed with water and dried over anhydrous magnesium sulfate. And the solvent was removed to give the desired product as a white solid (7.3 mg). , 75%); δ_H(CD_ThreeOD) 0.95 (3H, d, J 7.1Hz, 17-H_Three), 1. 21 (3H, d, J 6.5Hz, 14-H_Three), 1.29-2.0 (10H, m, 9-H₂, 8 And 12-H and 3xCH₂), 2.31 (2H, t, J 7.3Hz, CH₂), 2. 42 (3H, s, 15-H_Three), 2.48 (1H, d, J 9.7Hz, 4-H), 2.69- 2.88 (3H, m, 4,10 and 11-H), 3.41 (1H, dd, J 3.0Hz) And 9.2 Hz, 6-H), 3.53 (1 H, d, J 11.5 Hz, 16-H), 3.69- 3.93 (6H, m, 5,7,13,16 and CH₂Ph), 4.08 (2H, t, J 6.4) Hz, CH₂), 6.92 (1 H, dd, J 2.2 and 8.5 Hz, Ar-H), 7.0 (1 H, d, J 2.2 Hz, Ar-H), 7.63 (1 H, d, J 8.5 Hz, Ar-H).   f) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- [5- (4-methyl-1,2-dithiolo [4,3-b ] -5 (4H) -Oxopyrrol-6-yl) carbamoylpent-1-yloxy ] Indan-1-on   The acid from Example 25e (58 mg) in dry THF (10 ml) under an atmosphere of argon. 1.06x10^-FourMol) while maintaining the external temperature at -20 ° C. Min (0.016ml, 1.16x10)^-FourMol, 1.1 equivalents), then chloroformic acid Sobutyl (0.014 ml, 1.06x10)^-FourMol) was added.¹/₂After hours, Triethylamine (0.03 ml, 2.12x10)^-Four2 equivalents), then 6-a Mino-4-methyl-1,2-dithiolo [4,3-b] pyrrole-5 (4H) -one.salt Acid salt (W. D. Celmer) and I.A. Solomo Lens (IA Solomons), Journal of American Chemical Society ( J. Am. Chem. Soc.), 1955, 77, 2861) (30 mg, 1.27 x 10).^-Four Mol, 1.2 eq) was added and the resulting solution was warmed to room temperature. 22 hours later The reaction product was diluted with ethyl acetate, water and NaHCO._ThreeAnd wash with brine, It was dried over gnesium and the solvent was removed. The crude product was flashed over silica gel. Subject to chromatography and elute with 3% methanol in dichloromethane. Gave the title compound (25 mg, 33%) as a yellow solid; λ_max(Et OH) 391.5 (ε_m9041), 309.0 (ε_m22,989), 271 (ε_m13, 877), 233.0 (ε_m13, 107); δH [(CD_Three)₂SO] 0.82 (3H, d, J 7.1Hz, 17-H_Three), 1.08 (3H, d, J 6.4Hz, 14-H_Three) 1.2- 1.9 (10H, m, 3 x CH₂, 9Hz, 8,12-H), 2.3 (1H, dd, J 13. 4 and 9.4 Hz, 4-H), 2.36 (3 H, s, 15-H_Three) 2.39 (2H, t, J  7.2Hz, CH₂) 2.6-2.75 (3H, m, 4, 10, 11-H), 3.25 (3H , s, NCH_Three) 3.38-3.79 (6H, m, 6,7,5,13-H, 16-H₂), 4. 05 (2H, t, J 6.4Hz, CH₂), 4.45 (1H, d, J 2.7Hz, OH), 4. 62 (1H, d, J 7.6Hz, OH), 4.75 (1H, d, J 3.4Hz, OH), 6.9 5 (1H, dd, J 2.1 and 8.5Hz, Ar-H), 7.05 (1H, d, J 1.7H z, Ar-H), 7.32 (1H, s, 3 "-H), 7.55 (1H, d, J 8.5Hz, Ar- H), 9.92 (1H, s, NH), m / z (NH_ThreeDCI) (MH⁺) 715.   Example 26   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) -tetrahydropyran-2S-yl]- 1-Methylethylidene} -5- [3- (4-methyl-1,2-dithiolo [4,3-b] -5- (4H) -Oxopyrrol-6-yl) carbamoylprop-1-yl] yne Dan-1-on   a) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- (3-methoxycarbonylprop-1-yloxy Shi) -Indan-1-on   The product from Example 25c (0.53 g, 1.22 x 10)^-3Mol) dried DMF (5 ml), then sodium hydride (44 mg, 1.09x10)^-3Mo (0.9 eq.) Of a suspension in dry DMF (3 ml) was added. 20 minutes later, 4-yo Methyl dobutanoate (0.27g, 1.22x10)^-3Mol) to dry DMF (1 ml) Was added. After 1 hour, additional methyl 4-iodobutanoate (0.06 g, 2.7x1) was added. 0^-FourMol, 0.2 eq) was added and the resulting solution was stirred for 22 hours. Add water And the product was extracted into ethyl acetate. Combine the organic extracts with water and brine. It was washed, dried over anhydrous magnesium sulfate and evaporated to dryness. Syringe the crude product Flash chromatography on kagel 5% meta in dichloromethane Purify by eluting with Nol to give the title compound as a white solid (0.32 g , 52%)_max(KBr) 3421, 2959, 1735, 1680, 1623 cm^-1; Λ_max(EtOH) 308.0 nm (εm23,033), 239.0 nm ( ε_m6,998): δ_H(CD_ThreeOD) especially 0.93 (3H, d, J 7.1Hz, 17-H_Three ), 1.2 (3H, d, J 6.4Hz, 14-H)_Three) 2.41-2.50 (4H, m, 15 -H_Three, 4-H), 2.53 (2H, t, J 7.3Hz, CH₂) 2.7-2.88 (3H, m, 4,10,11-H), 3.41 (1H, d, J 9.2Hz and 3.1Hz, 6-H) 3.55 (1H, d, J 11.5Hz, 16-H), 3.69 (3H, s, OCH_Three), 3. 7-3.92 (6H, m, 7,5,13,16-H, CH₂), 4.1 (2H, t, J = 6.2Hz , CH₂), 6.9 (1H, dd, J 2.1 and 8.5Hz, Ar-H), 7.01 (1H, d, J 2.1 Hz, Ar-H), 7.63 (1 H, d, J 8.5 Hz, Ar-H); m / z ( EI) (measured value: M⁺532.2679; C₂₉H₄₀O₉Theoretical value of M 532.2672 ).   b) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- (3-carboxyprop-1-yloxy) in Dan-1-on   Methyl ester from Example 26a (310 mg, 5.8x10)^-FourMol) to pH 7 Buffer Na₂HPO_FourIt was stirred in (279 ml) and acetone (31 ml). Subchi Lysine-Carlsberg (50 mg) was added and the resulting suspension was stirred for 48 hours. Was. The volume was reduced to ~ 150 ml under vacuum and ethyl acetate was added. 1.5 MH_Three PO_FourPH was adjusted to 3.5. The product was extracted with ethyl acetate, water and sodium chloride. Wash with water, dry over anhydrous magnesium sulfate and evaporate to dryness to a white solid. Gave the title compound (0.24 g, 80%);_max(KBr) 3429, 2892 , 1680, 1621, 1607 cm^-1; Λ_max(EtOH) 310.0 (ε_m22,7 15) 239.0 (ε_m7,171); δ_H(CD_ThreeOD) Especially 0.95 (3H, d, J 7.1Hz, 17-H_Three), 1.2- (3H, d, J 6.2Hz, 14-H_Three) 2.4- 2.55 (6H, m, 15-H_Three, CH₂, 4-H), 2.7-2.85 (3H, m, 10,1 1,4-H), 3.45 (1H, dd, J 3.1 and 9.2Hz, 6-H), 3.55 (1 H, d, J 11.5Hz, 16-H), 3.7-3.92 (6H, m, 6,5,7,13-H, CH₂), 4.15 (2H, t, J 6.3Hz, CH₂), 6.95 (1H, dd, J 2.1 And 8.5 Hz, Ar-H), 7.05 (1 H, d, J 2.1 Hz, Ar-H), 7.65 (1 H, d, J 8.5 Hz, Ar-H); m / z (NH_ThreeDCI) (MH⁺) 519.   c) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- [3- (4-methyl-1,2-dithiolo [4,3-b ] -5 (4H) -Oxopyrrol-6-yl) carbamoylprop-1-yloxy ] Indan-1-on   The acid from Example 26b (0.2 ml) in dry THF (25 ml) under an argon atmosphere. 1 g, 4.05 mmol) while maintaining the external temperature at -20 ° C. (0.065ml, 4.45x10^-FourMol, 1.1 equivalents), and then chloroformate Sobutyl (0.055ml, 4.0x10^-FourMol) was added.¹/₂After hours, Triethylamine (0.1 ml, 9.1x10)^-FourMol, 2 equivalents), then , 6-amino-4-methyl-1,2-dithiolo [4,3-b] pyrrole-5 (4H)- On hydrochloride (0.1g, 4.5x10)^-FourMol, 1.2 eq) was added. The reactant Was warmed to room temperature and after 22 hours diluted with ethyl acetate and washed with NaHCO 3._Three, Water and salt It was washed with water and dried over anhydrous magnesium sulfate. Evaporate solvent to produce crude product Get things, This was flash chromatographed on silica gel with dichloromethane. Purified by eluting with 2% → 5% methanol in and labeled as a yellow solid. The compound was obtained (0.09 g, 33%); υ_max(KBr) 3415, 3252, 30 44, 1673, 1644, 1597, 1532 cm^-1; Λ_max(EtOH) 391 0.0 (ε_m9,952), 308.5 (ε_m25,582), 232.0 (ε_m12,756) Δ_H[(CD_Three)₂SO] Especially 0.81 (3H, d, J 7.0, 17-H_Three) 1.0 8 (3H, d, J 6.4Hz, 14-H_Three) 2.25-2.4 (4H, m, 4-H, 15-H_Three ) 2.5-2.8 (5H, m, CH₂, 4,10,11-H), 3.25 (3H, s, NCH_Three ) 4.1 (2H, t, J 6.9Hz, CH₂) 4.5 (1H, d, J 4.6Hz, OH), 4.67 (1H, d, J 7.6Hz, OH), 4.78 (1H, d, J 3.3Hz, OH), 6 .9 (1H, d, J 8.5Hz, Ar-H), 7.05 (1H, s, Ar-H), 7.32 (1H , s, 3 "-H), 7.6 (1H, d, J 8.5Hz, Ar-H), 10.0 (1H, s, N-H) ); M / z (electro spray) (MH⁺687.   Example 27   E-2- {2- [3R, 4R-Civitroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5- [1- (4-methyl-1,2-dithiolo [4,3-b]- 5- (4H) -oxopyrrol-6-yl) carbamoylmethoxy] ind-1-o N   a) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropin-2S-yl]- 1-Methylethylidene} -5- (methoxycarbonylmethoxy) indan-1-o N   Sodium hydride (45mg, 1.2x10^-3Mol, 0.9 equivalent) of dry DMF ( The product from Example 25c (0.56 g) in dry DMF (5 ml) to a suspension in 1 ml). 1.29x10^-3Mol) was added slowly. 20 minutes later, methyl bumolate (0.23g, 1.58x10^-3Mol, 1.2 eq.) And the resulting solution The mixture was stirred for 5 hours in a Rugong atmosphere. Add water and extract the product into ethyl acetate did. The combined organic extracts were washed with water and brine and dried over anhydrous magnesium sulfate. Dry and evaporate to dryness. Flash chromatography of the crude product on silica gel Purify by chromatography and eluting with 2% methanol in dichloromethane. Prepared to give the title compound as a white solid (0.18 g, 28%);_max(KBr ) 3455, 1750, 1680, 1606 cm^-1, λ_max(EtOH) 301.0nm (ε_m21,523), 232.5 nm (ε_m6,842); δ_H(CD_ThreeOD) 0.98 (3 H, d, J 7.1Hz, 17-H_Three), 1.2 (3H, d, J 6.4Hz, 14-H)_Three), 1. 35-1.50 (1H, m, 12-H), 1.63-1.88 (2H, m, 9H₂), 1.9 -2.02 (1H, m, 8-H), 2.4-2.52 (4H, m, 15-H3, 4-H), 2 .7-2.9 (3H, m, 4,10,11-H), 3.44 (1H, dd, J 3.1Hz and 9.2Hz, 6-H), 3.56 (1H, d, J 11.5Hz, 16-H), 3.7-4. 0 (9H, m, 13,5,16,7-H, CH₂& OCH_Three), 4.71 (2H, s, CH₂), 6.95-7.05 (2H, m, Ar-H₂), 7.69 (1H, d, J 8.4Hz, Ar-H) M / z (EI) (measured value: M⁺504.2365; C₂₇H₃₆O₉Theoretical value of M 50 4.2361).   b) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- (1-carboxymethoxy) indan-1-one   Methyl ester from Example 27a (310 mg, 6.15x10^-FourMol) to pH 7 buffer Na₂HSO_Four(279 ml) and acetone (31 ml). Subchi Lysine-Carlsberg (50 mg) was added and the resulting suspension was stirred for 16 hours. Was. The volume was reduced to ~ 150 ml under vacuum and ethyl acetate was added. 1.5 MH_Three PO_FourPH was adjusted to 3.5. The product was extracted into ethyl acetate and washed with water and sodium chloride. Wash with water, dry over anhydrous magnesium sulfate and evaporate to dryness to a white solid. Gave the title compound (0.22 g, 70%);_max(KBr) 3421, 2855 , 1735, 1679, 1622, 1600 cm^-1; Λ_max(EtOH) 311.5n m (ε_m9,560), 273.0 (ε_m5,129), 241.0 nm (ε_m3,205); δ_H (CD_ThreeOD) especially 0.97 (3H, d, J 7.1Hz, 17-H_Three) 1.2 (3H, d, J 6.4Hz, 14-H_Three) 2.40-2.55 (4H, m, 15-H_Three, 4- H), 2.7-2.9 (3H, m, 4,10,11-H), 3.45 (1H, dd, J 3.1) Hz and 9.2 Hz, 6-H), 3.55 (1 H, d, J 11.6 Hz, 16-H), 3. 7-4.0 (6H, m, 6,5,7,13-H, CH₂), 4.79 (2H, s, CH₂), 6. 98-7.10 (2H, m, Ar-H₂), 7.0 (1H, d, Ar-H), 7.7 (1H, d, J 8.3Hz, Ar-H); m / z (NH_ThreeDCI / MH⁺) 491.   c) E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy -5S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-Methylethylidene} -5- {1- (4-methyl-1,2-dithiolo [4,3-b ] -5- (4H) -Oxopyrrol-6-yl) carbamoylmethoxy] indan- 1-on   The acid from Example 27b (0.2 g) in dry THF (10 ml) under an atmosphere of argon. 4.08x10^-FourMol) while maintaining the external temperature at -20 ° C. Min (0.056ml, 4.08x10)^-FourMol), then isobutyl chloroformate (0 0.05 ml, 4.08 x 10^-FourMol) was added.¹/₂After an additional hour, Min (0.1ml, 8.16x10)^-FourMol, 2 equivalents) and then 6-amino -4-Methyl-1,2-dithiolo [4,3-b] pyrrole-5 (4H) -one hydrochloride (0.1g, 4.4x10^-FourMol, 1.1 eq.) Was added. Warm the reaction to room temperature After 22 hours, it was evaporated to dryness. Flash the crude product over silica gel. Chromatography eluting with 2% methanol in dichloromethane Purified by and filtered to give the title compound (70 mg, 27%) as a yellow solid. U; υ_max(KBr) 3384, 1670, 1599, 1528 cm^-1; Λ_max(Et OH) 394.5 nm (ε_m11,083), 302.0 nm (ε_m25, 132), 266. 5 nm (ε_m12,818); δ_H[(CD_Three)₂) SO] especially 0.85 (3H, d, J 7. 0Hz, 17-H_Three), 1.05 (3H, d, J 6.4Hz, 14-H)_Three) 1.30-1.4 0 (1H, m, 12-H), 1.48-1.70 (2H, m, 9-H)₂) 1.75-1.8 5 (1H, m, 8-H), 2.28-2.38 (4H, m, 15-H3, 4-H), 2.55 -2.8 (3H, m, 4, 10, 11-H), 3.4 (1H, d, J 11.0Hz, 1 6-H), 3.6-3.8 (6H, m, 5,6,7,13, CH₂), 4.45 (1H, d, J 4.6 Hz (OH), 4.6 (1 H, d, J 7.5 Hz, OH), 4.7 (1 H, d, J 3.3) Hz, OH), 4.9 (2H, s, CH₂), 6.95 (1H, dd, J 8.4Hz and 1. 8Hz, Ar-H), 7.05 (1H, d, J 1.8Hz, Ar-H), 7.4 (1H, s, CH) , 7.6 (1H, d, J 8.5Hz, Ar-H), 10.15 (1H, s, NH).   Example 28   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) -tetrahydropyran-2S-yl]- 1-methylethylidene} 5- [1- (1,2-dithiolo [4,3-b] -5 (4H) -o Quinpyrrole-6-yl) carbamoylmethoxy] indan-1-one   The acid from Example 27b (160 mg) in dry THF (10 ml) under an argon atmosphere. mg, 3.38x10^-FourMmol) while maintaining the external temperature at -20 ° C. Cylamine (0.052 ml, 3.7x10^-FourMol), then isobuty chloroformate Le (0.044ml, 3.38x10)^-FourMol) was added.¹/₂After hours, triethyl Amine (0.095 ml, 6.7x10)^-FourMol), then 6-amino-1,2-di Thiolo [4,3-b] pyrrole-5 (4H) -one hydrochloride (85 mg, 3.72 x 10)^-Four Mol) was added. The reaction was warmed to room temperature. After 2 hours, add ethyl acetate The product was washed with water and brine, dried over anhydrous magnesium sulfate and steamed. It was allowed to dry. The crude product was subjected to flash chromatography on silica gel. Purified by eluting with 2% methanol in dichloromethane, The title compound was obtained as a solid (20 mg, 10%);_max(KBr) 3422, 3 052, 1660, 1598 cm^-1; Λ_max(EtOH) 382 nm (ε_m6,543), 294.5 nm (ε_m12,951); δ_H[(CD_Three)₂SO] 0.85 (3H, d, J 7.0 2Hz, 17-H_Three), 1.05 (3H, d, J 6.4Hz, 14-H)_Three) 1.2-1.9 ( 4H, m, 8,12-H, 9H₂) 2.4 (4H, m, 15-H)_Three, 4H), 2.6-2.8 ( 3H, m, 4,10,11-H), 3.6-3.8 (6H, m, 16,5,7,13-H, CH₂ ), 4.50 (1H, d, J 4.6Hz, OH), 4.65 (1H, d, J 7.5Hz, OH) 4.75 (1H, d, J 3.2Hz, OH), 4.95 (2H, s, CH₂), 6.95-7 .10 (2H, m, J 8.2Hz, Ar-H₂), 7.15 (1H, s, CH), 7.6 (1H, d, J) 8.5 Hz, Ar-H), 10.1 (1 H, br s, NH), 10.8 (1 H, br s, NH) M / z (electro spray) (MH⁺) 645.3.   Example 29   E-2- {2 [5 (5S-hydroxy-4R-methylhex-2-enyl) -3R , 4R-Dihydroxytetrahydropyran-2S-yl] -1-methylethylidene } 5- [1- (1,2-dithiolo [4,3-b] -5 (4H) -oxopyrrole-6-y ) Carbamoyl-methoxy] indan-1-one   a) 2-Bromo-5-t-butyldimethylsilyloxybenzyl iodide   2-Bromo-5-t-butyl dimethyl from Example 25a in acetone (40 ml) Cylsilyloxybenzyl bromide (2 g, 5.2 mmol) in sodium iodide (7.9 g, 52 mmol) was added. The resulting solution was stirred for 24 hours. Next , Filtered and evaporated to dryness. The crude product was dissolved in dichloromethane (40 ml) And washed with 10% aqueous sodium thiosulfate solution, water and saline. Then nothing Dry over magnesium sulfate, filter and evaporate to dryness to give a colorless oil. The above compound was obtained (2.12 g, 95%); δ_H(CDCl_Three) 0.19 (6H, s, Si ( CH_Three)₂), 0.98 (9H, s, t-Bu), 4.43 (2H, s, CH)₂), 6.62 (1H , dd, J 2.9 Hz, and 8.7 Hz, Ar-H), 6.91 (1 H, d, J 2.9 Hz, Ar-H), 7.4 (1H, d, J 2.8Hz, Ar-H), 7.35 (1H, d, J 8.7H) z, Ar-H).   b) E-2- {2 [5 (5S-trimethylsilyloxy-4R-methylhexa- 2E-enyl) -3R, 4R-bistrimethylsilyloxytetrahydropyran- 2S-yl] -1-methylethylidene} 5-t-butyldimethylsilyloxyin Dan-1-on   N-Methoxy- in dry THF (20 ml) keeping the temperature below -65 ° C. N-methyl-6,7,13-O-tris (trimethylsilyl) monamide C (1.87 g 3.17 mmol) (Example 4a) to diisopropylamine (0.08 ml, 0.04 ml). 63 mmol) and t-butyllithium (1.7 M in pentane) (2.2 ml, 3 .8 Mi Limol) was added continuously. After 1 hour at -70 ° C, the 2-buth from Example 29a Lomo-5-t-butyldimethylsilyloxybenzyl iodide (2 g, 4.7 mm Mol) was added and the mixture was stirred at -70 ° C for 1 hour. Temperature slowly at 2 o'clock The temperature was raised to room temperature over a period of time. A saturated aqueous solution of ammonium chloride (10 ml) was added. The product was extracted into ethyl acetate, washed with water and brine and dried over anhydrous magnesium sulfate. Dried with um and evaporated to dryness. The crude product was flashed over silica gel. By chromatography, eluting with hexane / ethyl acetate (6: 1). It refine | purified and the complex mixture (1.75g) was obtained. The mixture is dried at -70 ° C. T-Butyllithium (1.7M in pentane) in THF (15ml) (2.6ml, 4ml) 0.4 mmol) for 2 hours. Add saturated ammonium chloride solution (10 ml) The product was extracted into ethyl acetate, washed with water and brine, and anhydrous magnesium sulfate was added. Dried over nesium and evaporated to dryness to give a complex mixture (1.4g). This mixture The product was dried at -70 ° C with potassium t-butoxide (1M) (2M) in dry THF (15ml). 0.5 ml, 2.5 mmol) for 2 hours. Acetic acid (0.16 ml), then water Was added. The product was extracted with ethyl acetate, washed with water and brine and dried over anhydrous sodium sulfate. It was dried over gnesium and evaporated to dryness. The crude product was flashed over silica gel. Subject to chromatography and elute with hexane / ethyl acetate (96: 4). Purification by evaporation afforded the title compound as a white foam (0.8g, 34%). Δ_H(CDCl_Three) Especially 0.1-0.3 (33H, m, Si-CH_Three), 1.05 (3H , d, J 6.1Hz, 14-H_Three) 2.45 (3H, s, 15H_Three) 2.55 (1H, d, 4 H), 5.35-5.42 (2H, m, 10,11-H), 6.78-6.88 (1H, dd , Ar-H), 7.69 (1H, d, J 8.2Hz, Ar-H).   c) E-2- {2 [5 (5S-hydroxy-4R-methylhexa-2E-enyl) -3R, 4R-Dihydroxy-tetrahydropyran-2S-yl] -1-methyle Tylidene} -5-hydroxyindan-1-one   To the product from Example 29b (0.75 g, 1 mmol) in THF (10 ml). Tetrabutylammonium fluoride (5 ml, 5 mmol) was added and obtained The solution was stirred for 30 minutes. pH7 buffer was added and the product was extracted into ethyl acetate. Out, wash with water and brine, dry over anhydrous magnesium sulfate and evaporate to dryness. I let you. The crude product was subjected to flash chromatography on silica gel to give Elution with 5% methanol in chloromethane gave the title compound as a white foam (0. 34g, 82%) was obtained;_max(KBr) 3424, 1673, 1622, 15 98 cm^-1; Λ_max(EtOH) 310.0 nm (ε_m14,150), 293 (ε_m11,8 68), 271 (ε_m7_,760); δ_H(CD_ThreeOD) Especially 1.0 (3H, d, J 6 .9 Hz, 17-H_Three), 1.09 (3H, d, J 6.4Hz, 14-H)_Three) 1.78 (1H, m, 8H), 2.35-2.48 (4H, m, 4-H, 15-H_Three) 3.49-3.9 (8 H, m, 16-H₂, 6,5,7,13-H, CH₂), 5.45 (2H, s, CH₂) 5.4 2-5.50 (2H, m, 10,11-H), 6.75-6.85 (2H, m, Ar-H)₂), 7.49 (1H, d, J 8.3Hz, Ar-H); m / z (EI) (M⁺) 416.   d) E-2- {2 [5 (5S-hydroxy-4R-methylhexa-2E-enyl) -3R, 4R-Dihydroxy-tetrahydropyran-2S-yl] -1-methyle Tylidene} 5- (1-methoxycarbonylmethoxy) indan-1-one   The product from Example 29c (320 mg, 0.77 mi) in dry DMF (10 ml). Limol) to tetramethylguanidine (0.14 ml, 1.15 mmol), and then Methyl lomoacetate (0.1 ml, 1.15 mmol) was added. The obtained solution is Stir for 45 minutes under a rogon. Water was added and the product was extracted into ethyl acetate, It was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The crude product was subjected to flash chromatography on silica gel for dichloro Purified by eluting with 3% methanol in methane to give a white foam. The above compound was obtained (290 mg, 78%);_max(KBr) 3426, 1760, 1 674, 1624, 1601 cm^-1. λ_max(EtOH) 301.0 nm (ε_m21,30 4) 231.0 nm (ε_m6_,633); δ_H(CD_ThreeOD) 1.0 (3H, d, J 6.9H z, 17-H_Three), 1.09 (3H, d, J 6.4Hz, 14-H)_Three) 1.76 (1H, m, 8 -H), 2.1-2.3 (3H, m, 9H₂, 12-H), 2.4-2.52 (4H, m, 15 -H_Three, 4H), 2.75 (1H, d, J 12.2Hz, 4-H), 3.4-3.9 (11H, m, 16-H₂, 6,5,7,13-H, OCH_Three, CH₂), 4.85 (2H, s, CH₂), 5.42-5.50 (2H, m, 10,11-H), 6.98-7.06 (2H, m, Ar- H₂), 7.65 (1H, d, J 8.4Hz, Ar-H); m / z (EI) (M⁺) 488.   e) E-2- {2 [5 (5S-hydroxy-4R-methylhexa-2E-enyl) -3R, 4R-Dihydroxytetrahydropyran-2S-yl] -1-methylethyl Ridene} -5- (1-carboxymethoxy) indan-1-one   Acetone (27 ml) and pH7 buffered Na₂HPO_FourExample 29 in (243 ml) Subtilisin curl to the methyl ester from d (270 mg, 5.5 mmol) Sberg (50 mg) was added and the resulting suspension was stirred for 24 hours. Body under vacuum The volume was reduced to ~ 150 ml and ethyl acetate was added. 1.5MH_ThreePO_FourBy p The H was adjusted to 3.5. The product was extracted into ethyl acetate and washed with water and brine. Purified, dried over anhydrous magnesium sulfate, evaporated to dryness and labeled as a white solid. The compound was obtained (240 mg, 91%); ν_max(KBr) 3434, 2924, 17 36, 1674, 1622, 1600 cm^-1; Λ_max(EtOH) 311.5 nm (ε_m 22,755), 241.0 nm (8,448); δ_H(CD_ThreeOD) 1.0 (3H, d, J 6.9Hz, 17-H_Three), 1.09 (3H, d, J 6.3Hz, 14-H)_Three) 1.78 (1 H, m, 8H), 2.25 (3H, m, 9H2,12-H), 2.45 (4H, m, 15-H)_Three , 4-H), 2.79 (1H, d, J 13.5Hz, 4-H), 3.4-3.9 (8H, m, 1) 6-H₂, 5,6,7,13-H CH₂), 4.75 (2H, s, CH₂) 5.42-5.5 2 (2H, m, 10,11-H), 6.95-7.05 (2H, m, Ar-H₂), 7.69 ( 1H, d, J 8.4Hz, Ar-H); m / z (NH_ThreeDCI) (MH⁺) 475.   f) E-2- {2 [5 (5S-hydroxy-4R-methylhexa-2E-enyl) -3R, 4R-Dihydroxytetrahydropyran-2S-yl] -1-methylethyl Ridene} 5- [1- (1,2-dithiolo [4,3-b] -5 (4H) -oxopyrrole- 6-yl) carbamoylmethoxy] indan-1-one   Acid from Example 29e (210 mg, 0.45 mmol) in dry THF (12 ml). ), While maintaining the external temperature at -10 ° C, triethylamine (0.07 ml, 0.4 5 mmol), then isobutyl chloroformate (0.058 ml, 0.45 mmol) ) Was added.¹/₂After hours, triethylamine (0.09 ml, 0.67 mmol), Next Then, 6-amino-1,2-dithiolo [4,3-b] pyrrole-5 (4H) one ・ hydrochloric acid Salt (0.11 g, 0.54 mmol) was added. Three¹/₂After hours, the reaction was Dilute with chill and dichloromethane / methanol, add silica and mix the mixture. Evaporated to dryness. Flash chromatography of the crude product on silica gel Purified by elution with 3% methanol in dichloromethane and A colored solid was obtained. The solid was triturated in dichloromethane, filtered and triethylamine The hydrochloride salt was removed and evaporated to give the title compound as a yellow solid (80mg, 30%); ν_max(KBr) 3412, 1667, 1598 cm^-1; Λ_max(EtOH ) 388.0 nm (ε_m11,079), 297.5 nm (ε_m24,499); δ_H[(CD_Three)₂ SO] 0.9 (6H, m, 17-H_Three, 14-H_Three), 1.6 (1H, m, 8H), 2.05 ( 3H, m, 12-H, 9-H₂), 2.31 (4H, m, 15-H_Three, 4-H), 2.65 (1 H, d, J 12.3Hz, 4-H), 2.8-3.7 (8H, m, CH₂, 6-H₂, 5,7,1 3,16-H), 4.31 (1H, d, J 4.6Hz, OH), 4.69 (2H, m, 2x) OH), 4.88 (2H, s, CH₂), 5.4 (2H, m, 10, 11-H), 6.98-7 .05 (2H, m, Ar-H₂), 7.1 (1H, s, CH), 7.6 (1H, d, J 8.5Hz, Ar-H), 10.1 (1H, s, NH), 10.85 (1H, s, NH); m / z (electric Trospray) [MH] 627.   Example 30   E-2- {2 (3R, 4R-dihydroxy-5S [2S, 3S-epoxy-5S- Hydroxy-4S-methylhexyl) tetrahydro-pyran-2S-yl] -1- Methylidene} 5- [3- (1,2-dithiolo [4,3-b] -5 (4H) -oxo pillow Lu-6-yl) carbamoylpropyloxy] indan-1-one   The acid from Example 26b (187 mg, 0 in dry THF (10 ml) at -20 ° C. .36 mmol) to triethylamine (0.05 ml, 0.36 mmol), then Isobutyl chloroformate (0.064 ml, 0.36 mmol) was added.¹/₂time After that, more triethylamine (0.1 ml, 0.72 mmol) was added, followed by 6-amino. -1,2-dithiolo [4,3-b] pyrrole-5 (4H) one.hydrochloride (85 mg, 0. 37 mmol) was added. The reaction was warmed to room temperature. 24 hours later, dichloro Me Tan was added and the product washed with water and brine. Make them anhydrous magnesium sulfate Dried over sium, filtered and evaporated. Flash chromatography on silica gel Purify by chromatography and eluting with 3% methanol in dichloromethane. Prepared to give the title compound as a yellow solid (60 mg, 25%);_max(KBr) 3415, 1672, 1647, 1597 cm^-1; Λ_max(EtOH) 391.0 nm ( ε_m8,097), 307.5 nm (ε_m17,790); δ_H[(CD_Three)₂SO] 0.81 ( 3H, d, J 7.0Hz, 17-H_Three), 1.03 (3H, d, J 6.4Hz, 14-H_Three), 1.31 (1H, m, 12-H), 1.5-1.7 (2H, m, 9-H)₂), 1.79 (1H, m, 8-H), 2.0 (2H, t, J 6.6Hz, CH₂), 2.32 (4H, m, 15H_Three, 4 -H), 2.5-2.8 (5H, m, CH₂, 10,11,4-H), 3.4 (2H, m, 6,1) 6-H), 3.6-3.7 (6H, m, CH₂), 5,7,13,6-H), 4.1 (2H, t, J 6.2Hz, CH₂), 4.49 (1H, d, J 4.6Hz, OH), 4.61 (1H, d, J 5.7 Hz, OH), 4.7 (1 H, d, J 3.4 Hz, OH), 6.90-7.10 (3 H, m, CH and Ar-H₂), 7.55 (1H, d, J 8.5Hz, Ar-H), 9.9 ( 1H, s, NH), 10.65 (1H, s, NH); m / z (NH_ThreeDCI) (MH⁺) 67 3.   Example 31   5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Il) carbamoylhexyl] -2- (1-normon-2-yl) -1,3,4-oxy Thaziazole A   a) N '-(6-carbomethoxyhexoyl) monohydrazide   Under argon at 0 ° C., suberic acid monomethyl ester (3.73 ml) in THF The solution in (60 ml) was treated successively with triethylamine (2.90 ml) and chloroform. Treated with isobutyl acidate (2.7 ml). After 45 minutes, at 0 ° C. under argon, the solution was dissolved. The solution was mixed with monohydrazide (6.75 g) and pyridine (3.03 ml) as acetonite. Add to solution in ril (100 ml). After an additional 45 minutes, the reaction was washed with sodium bicarbonate. Quenched with aqueous arium and evaporated the mixture to a reduced volume. The residue Was extracted with ethyl acetate, the organic phase was dried and evaporated. Chromatography on silica Chromatographically eluting with a dichloromethane / methanol mixture to give the title compound (4.02 g, 40%) was obtained; δ_H(CD_ThreeOD) (among others) 0.95 (3H, d, J 7.1Hz, 17-H_Three), 1.21 (3H, d, J 6.4Hz, 14-H)_Three) 1.31 -1.49 (5H, m, 12-H, 3'-H₂, 4'-H₂), 1.91-2.01 (1H, m, 8-H), 2.19 (3H, s, 15-H_Three), 2.20 (3H, m, 4-H, 6'-H₂), 2.61 (1H, d, J 14.2Hz, 4-H), 3.58 (1H, d, J 14.2Hz, 1) 6-H), 3.67 (3H, s, OCH_Three), And 5.80 (1H, s, 2-H).   b) 5- (6-carbomethoxyhex-1-yl) -2- (6,7,13-O-to Lis (trimethylsilyl) -1-normon-2-yl] -1,3,4-oxadiazo The   The product from Example 31a (2.112 g, 4 mmol) in THF (10 ml). Triethylamine (2.8 ml, 20 mmol), chlorotrithymersilane (2.5 4 ml, 20 mmol) and a catalytic amount of DMAP. After 2 hours at room temperature The mixture was filtered and evaporated. The residue was extracted with ethyl acetate and the extract was filtered , Evaporated to dryness. The residue obtained is acetonitrile (20 ml) and pyridine. It was dissolved in a mixture of (20 ml) and then successively with triethylamine (1.68). ml, 12 mmol), carbon tetrachloride (2.4 ml, 2.4 mmol) and tripheny It was treated with ruphosphine (3.12 g, 12 mmol). After 1.5 hours, Add triethylamine (1.68 ml) and triphenylphosphine (3.12 g) Added. After an additional 1.5 hours, pour the mixture into saturated aqueous sodium bicarbonate solution. , Extracted with ethyl acetate. The extract was washed with brine then evaporated to dryness . The residue was treated with toluene and re-evaporated. Chromatography on silica Elution with ethyl acetate / hexane mixture to give the material containing the title compound. Obtained (1.53 g); δ_H(CD_ThreeOD) (especially) 2.20 (3H, s, 15-H_Three) 2.65 (1H, d, J 14.2Hz, 4-H), 3.50-3.60 (2H, m, 16- H, 6-H), 3.65 (3H, s, OCH_Three) 3.81-3.96 (4H, m, 13-H, 16-H, 5-H and 7-H), and 6.21 (1H, s, 2-H).   c) 5- (6-carbomethoxyhex-1-yl) -2- (1-normon-2- Yl) -1,3,4-oxadiazole A   The product from Example 31b (1.5g) in THF (40ml) was treated with 0.4M HCl. (10 ml). After 2 minutes, add saturated aqueous sodium bicarbonate solution (20 ml) And the mixture was extracted with ethyl acetate. The organic phase was dried and evaporated. silica Chromatography on eluting with a dichloromethane / methanol mixture. Gave the title compound (1.02 g, 100%); ν_max(KBr) 1734, 16 56, 1576, 1253, 1107 and 1052 cm^-1; Λ_max(EtOH) 2 46 nm (ε_m18,587); δ_H(CD_ThreeOD) (especially) 0.93 (3H, d, J 7.1Hz, 17-H_Three), 1.20 (3H, d, J 6.4Hz, 14-H)_Three) 1.32-1 .46 (5H, m, 3'-H₂, 4'-H₂And 12-H), 1.94 (1H, m, 8-H) 2.25 (3H, s, 15-H_Three) 3.40 (1H, dd, J 3.1,9.0Hz, 6-H) ), 3.58 (1H, d, J 11.4Hz, 16-H), and 6.25 (1H, s, 2-H). ); M / z 510 (M⁺, 2%), 266 (100), and 73 (100).   d) 5- (6-carboxyhex-1-yl) -2- (1-normon-2-yl) -1,3,4-oxadiazole A   The product from Example 31e (500 mg) was prepared using the method described in Example 8b. Converted to the title compound (436 mg, 90%); δ_H(CD_ThreeOD) (among others) 0.96 (3H, d, J 7.0Hz, 17-H_Three), 1.36-1.51 (5H, m, 12H, 3'-H₂And 4'-H₂), 2.25 (3H, s, 15-H_Three) 3.42 (1H, dd, J 3.0, 9.0 Hz, 6-H), 3.61 (1 H, d, J 11.3 Hz, 16-H), and And 6.22 (1H, s, 2-H), m / z 496 (M⁺, 18%), 178 (100), and 73 (50).   e) 5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxapyrrole- 6-yl) carbamoylhexyl] -2- [1-normon-2-yl] -1,3,4- Oxadiazole A   Using the method described in Example 10, the product of Example 31d (294 mg) is titled. Converted to compound (242 mg, 62%); u_max(KBr) 3403, 3246, 2924, 2855, 1650, 1539 and 1051 cm^-1; L_max(EtOH ) 387 (e_m10,800), 303 (3,275), and 245nm (23,891); δ_H(CD_ThreeOD) (among others) 0.95 (3H, d, J 7.3Hz, 17-H_Three), 1. 20 (3H, d, J 6.4Hz, 14-H_Three), 1.35-1.50 (5H, m, 12-H, 3'-H₂And 4'-H₂), 2.21 (3H, s, 15-H_Three) 3.39 (1H, dd, J 3.1, 9.0 Hz, 6-H), 3.58 (1 H, d, J 10.9 Hz, 16-H), 6. 21 (1H, s, 2-H), and 7.07 (1H, s, 3 "-H); d_c(CD_ThreeOD) 1 2.23 (C-17), 20.07, 20.30 (C-14, 15), 25.76, 26. 40, 27.16, 29.56, 29.58, 36.41 (C-1 ", 2", 3 ", 4", 5 " , 6 "), 32.98 (C-9), 41.70 (C-8), 43.71 (C-12), 43. 78 (C-4), 56.68 (C-10), 61.26 (C-11), 66.37 (C-1) 6), 69.98 (C-6), 70.30 (C-13), 70.70 (C-7), 76.5. 2 (C-5), 109.76 (C-2), 113.52, 120.36, 135.07, 137.89, 170.36 (C-3 "', 3a"', 5 "', 6"', and 6a "'), 153 .01 (C-3), 165.51 (C-5 '), 167.45 (C-1), and 174. 15 (C-7 ").

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI C07D 407/06 303 9159-4C C07D 407/06 303 (31) Priority claim number 9401139.2 (32) Priority date January 21, 1994 (33) Priority claiming country United Kingdom (GB) (81) Designated country EP (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU, MC , NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, MW, SD), AM, AT, AU, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, ES, FI, GB, GE, HU, JP, KE, KG, KP, KR, Z, LK, LT, LU, LV, MD, MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, SI, SK, TJ, TT, UA, US, UZ , VN (72) Inventor Bloom, Niger John Perryman Sally Earl 3.7 UK, Betchworth, Blockham Park (no address) SmithKline Beecham Pharmaceuticals (72) Inventor O'Hanlon, Peter John Sally Earl H. 3.7AJ, Betchworth, Blockham Park (no address) Smith Lane Beecham Pharmaceuticals (72) Inventor Osbourne, Neil Frederick Sally Earl 3.7 UK, Betchworth, Blockham Park (No street address) Smith Crane Beecham Pharmaceuticals (72) Inventor Pengery, Donna Sally Earl 3.7 UK, Betchworth, Blockham Park (Not shown) Smith Crane Beecham Pharmaceuticals

Claims (1)

[Claims]   1. Formula (I): [Where,   A is an epoxy moiety or an E-double bond moiety: And   B is     (a)     (Where       B¹Is the group X¹, X², Y¹, NH or NHX¹And       X¹Is an optionally substituted aryl,       X²Is (C_1-10) Alkylene, (C_2-10) Alkenylene, (C_2-10) Arkini Ren, (C_3-7) Cycloalkylene or aryl (C_1-4) Is alkylene, which is Each of these may be optionally substituted,       Y¹Is an optionally substituted heterocyclyl);     (b)     (Where       B²Is Y², Y²-X¹, Y²-X²Or Y²-Y^ThreeAnd       Y²Is 1 to 4 heteroatoms each selected from oxygen, sulfur or nitrogen If desired, (C_1-10) Alkyl, (C_2-10) Alkenyl, (C_2-10) Archi Nil, (C_3-7) Cycloalkyl, aryl (C_1-4) Alkyl, aryl or het A 5 or 6 membered heteroaryl ring optionally substituted by rocyclyl And       Y^ThreeIs an optionally substituted heterocyclic ring,       X¹And X²Is the same as the above definition);     (c)     (In the formula, B^ThreeIs an optionally substituted hydrocarbyl or he A telocyclyl group); or     (d)     Where Q is an optionally substituted aryl or heteroaryl Represents the residue of the ring) Selected from   D is B-CONR¹Is a group of atoms for attaching to, or   BD is (E) -C (CH_Three) = CH   R¹And R²Are the same or different and each represents hydrogen or (C_1-6) Alkyl, ( C_3-7) Cycloalkyl, (C_2-6) Alkenyl, aryl, aryl (C_1-4) Archi , Heterocyclyl, (C_1-6) Alkylcarbonyl, (C_3-7) Cycloalkyl calc Bonil, (C_2-6) Alkenylcarbonyl, arylcarbonyl, aryl (C_1-4) Selected from alkylcarbonyl or heterocyclylcarbonyl, each of these May optionally be substituted] A compound represented by the formula:   2. The atom linking group D is one or more carbon atoms, including carbon atoms in a carbocyclic ring. And / or consisting of heteroatoms including heteroatoms in a heterocyclic ring. A compound represented by formula (I):   3. D is a hydrocarbylene chain containing up to 20 carbon atoms, which chain is ,   (a) optionally substituted,   (b) If desired, it may be interrupted at one or more places by part M,   (c) B by a suitable linking group¹, B², B^ThreeOr bound to Q,   (d) —CONR by a suitable linking group¹Is connected to   Wherein M is a heteroatom selected from oxygen, sulfur or nitrogen; (C_3-7) Chloroalkylene group; carbon-carbon double bond; carbon-carbon triple bond; CO; OC (O) C (O) O; NRCO; C (O) NR; NRCONR; NRC (O) O; OC (O) N R; SO₂NR; NRSO₂; CONRSO₂SO₂NRCO and Phenyloxy Represents R, where R is hydrogen or (C_1-6) Alkyl 3. A compound of formula (I) as described above.   4. In (c) the linking group is selected from a direct bond, oxygen, sulfur or nitrogen. Heteroatom, carbonyloxy (COO), oxycarbonyl (OCO), carbo Nato (OCOO), carbamoyl (CONH), NHCO, NHCONH, SO₂ And SO₂A compound of formula (I) according to claim 3 which is NH.   5. In (d), the linking group may be a direct bond or optionally substituted ( C_3-7) Cycloalkylene, optionally substituted aryl or optionally More optionally substituted heterocyclyl of formula (I) according to claim 3 Compound.   6. The heterocarbylene chain is a polymethylene chain having 1 to 20 carbon atoms A compound of formula (I) according to claim 3.   7. A polymethylene chain of formula (I) according to claim 6 having 1 to 12 carbon atoms. Compound.   8. D is an oxyalkylene chain O (CH₂)_nOr alkylene chain (CH₂)_nIs ( Here, n is an integer of 1 to 12) The formula (1) according to any one of claims 1 to 7. A compound represented by I).   9. Y¹But furan, thiophene, pyrrole, benzofuran, benzothiophe , Indole, oxazole, isoxazole, thiazole, isothiazo Le, pyrazole, benzimidazole, oxadiazole, thiadiazole, tho Riazole, tetrazole, thiatriazole, pyridine, quinoline, isoquino Claim selected from phosphorus, pyrazine, pyrimidine, pyridazine and triazine Item 9. A compound represented by formula (I) according to any one of items 1 to 8.   10. Y¹But The compound of formula (I) according to claim 9.   11. Y²Is furan, thiophene, pyrrole, diazole, oxazole, thi Azole, isoxazole, isothiazole, triazole, oxadiazo It is le, thiadiazole or tetrazole. A compound represented by formula (I):   12. Y²But, The compound of formula (I) according to claim 11, wherein   13. Y²But The compound of formula (I) according to claim 12.   14． Y^ThreeBut The compound of formula (I) according to any one of claims 1 to 13.   15. B^ThreeIs based on B^Four-B^FiveAnd where B^FourIs (C_1-6) Alkylene, (C_2-6) Alkenylene, (C_2-6) Alkynylene, B^FiveIs a direct bond, (C_3-7) Cyclo Alkylene, (C_4-7) Is cycloalkenylene, aryl or heteroaryl And each of these may be optionally substituted; or B^FourIs the result And B^FiveIs (C_3-7) Cycloalkylene, (C_4-7) Cycloalkenylene, a Formula (I) according to any one of claims 1 to 14, which is reel or heteroaryl. A compound represented by the formula:   16. B^FourIs a direct bond, and B^FiveIs pyrimidine, thiazole, oxazole, A compound of formula (I) according to claim 15 which is pyridine or phenyl.   17． Y²-X¹But The compound of formula (I) according to any one of claims 1 to 16.   18. Y²-Y^ThreeBut The compound of formula (I) according to any one of claims 1 to 17, wherein   19. Q is unsubstituted or, in addition to D, up to 3 further substituents 19. A benzene ring residue which may be substituted with A compound represented by formula (I) according to item 1.   20. Q is unsubstituted or, in addition to D, up to 2 further substituents Forming a residue of a pyridine or furan ring which may be substituted with 9. A compound represented by formula (I) according to any one of 8 above.   21. BD The compound of formula (I) according to any one of claims 1 to 20.   22. R¹Is hydrogen and is of the formula (I) according to any one of claims 1 to 21. Compound.   23. R²Is a hydrogen of formula (I) according to any one of claims 1 to 22; Compound.   24.3R, 4R-Dihydroxy-2S- [2,4-dioxo-4- {4- (4- Methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl ) Carbamoylbut-1-yloxyphenyl} but-1-yl] -5S- (2S, 3S-epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyra N;   N- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxopyrro Lo-6-yl) -monamide A;   2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxo Pyrrol-6-yl)] carbamoylhexoxy} -thiazol-5-yl-1- Normon-2-yl ketone Example 3-2- {6- (4-methyl-1,2-dithiolo) -[4,3-b] -5- (4H) -oxopyrrol-6-yl)] carbamoylhexo Xy} -thiazol-5-yl-1-normon-2-ylketone-A series;   2- {6- (4-methyl-1,2-dithiolo- [4,3-b] -5- (4H) -oxo Pyrrol-6-yl) carbamoylhexoxy} -thiazol-5-yl-1-no Lumon-2-ylketone-C series;   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] octan-1-yl} monamide A;   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] octane-1-yl} monamide C;   5- (4- (3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrol-6-yl) carbamoylprop-1-oxy) phenyl) -2- (1 -Normon-2-yl) oxazole A;   5- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylmethyloxyphenyl] -2- (1-normon- 2-yl) oxazole A;   3R, 4R-dihydroxy-2-S- [2,4-dioxo-4- {4- [3- (4- Methyl-1,2-thiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) Carbamoylprop-1-yloxy] phenyl} but-1-yl] -5S- (2S , 3S-Epoxy-5S-hydroxy-4S-methylhexyl) tetrahydropyra N;   3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- [4- (1,2 -Dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) carbamoyl But-1-yloxy) phenyl} but-1-yl] -5S- (2S, 3S-epoxy Ci-5S-hydroxy-4S-methylhexyl) tetrahydropyran;   3R, 4R-dihydroxy-2S- [2,4-dioxo-4- {4- (3-1,2- Dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl) carbamoylp Ropa-1-yloxy] phenyl} but-1-yl] -5S- (2S, 3S-epoxy Ci-5S-hydroxy-4S-methylhexyl) tetrahydropyran;   2- {4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylbutoxy} thiazol-5-yl 1-normon- 2-ylketone A;   2- {1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrol-6-yl} Carbamoylmethyloxythiazol-5-yl 1-normon-2-yl ketone A;   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] -2-oxooct-1-yl} monamide A;   5- [6- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxopi Roll-6-yl) carbamoylhexyl] -2- (1-normon-2-yl) oxy Sazole A;   5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Il) carbamoylhexyl] -2- (1-normon-2-yl) oxazole A;   5- [4- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopeel-6-y ) Carbamoylmethyloxyphenyl] -2- (1-normon-2-yl) oxa Zol A;   N- {4- [3- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xopyrrole-6-ylaminocarbonyl) propyloxy] phenyl} monamide A;   N- {4- [4- (4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -o Xoxopyrrole-6-ylaminocarbonyl) butyloxy] benzyl} monamide A;   N- {8-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] octyl} monamide A;   N- {9-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoyl] nonyl} monamide A;   N- {10-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-6-yl) carbamoyl] decyl} monamide A;   N- {11-[(4-methyl-1,2-dithiolo- [4,3-b] -5 (4H) -oxy Sopyrrol-5-yl) carbamoyl] undecyl} monamide A;   N- {9-[(1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6 -Yl) carbamoyl] nonyl} monamide A;   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5 [5- (4-methyl-1,2-dithiolo [4,3-b] -5 ( 4H) -oxopyrrol-6-yl) carbamoylpent-1-yloxy] in Dan-1-on;   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5- [3- (4-methyl-1,2-dithiolo [4,3-b]- 5- (4H) -oxopyrrol-6-yl) carbamoylprop-1-yl] inda N-1-on;   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5- [1- (4-methyl-1,2-dithiolo [4,3-b]- 5 (4H) -oxopyrrol-6-yl) carbamoylmethoxy] indan-1-e N;   E-2- {2- [3R, 4R-dihydroxy-5S (2S, 3S-epoxy-5S -Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1- Methylethylidene} 5- [1- (1,2-dithiolo [4,3-b] -5 (4H) -oxo Pyrrol-6-yl) carbamoylmethoxy] indan-1-one;   E-2- {2 [5 (5S-hydroxy-4R-methylhex-2-enyl) -3R , 4R-Dihydroxytetrahydropyran-2S-yl] -1-methylethylidene } 5- [1- (1,2-dithiolo [4,3-b] -5 (4H) -oxopyrrole-6-y Ru) carbamoylmethoxy] indan-1-one;   E-2- {2 (3R, 4R-dihydroxy-5S [2S, 3S-epoxy-5S- Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1-me Tylidene} 5- [3- (1,2-dithiolo [4,3-b] -5 (4H) -oxopyrrole -6-yl) carbamoylpropyloxy] indan-1-one; and   5- [6- (1,2-dithiolo- [4,3-b] -5 (4H) -oxopyrrole-6- Il) carbamoylhexyl] -2- (1-normon-2-yl) -1,3,4-oxy A compound of formula (I) according to claim 1 selected from Sadiazole A.   25. A compound of formula (I) according to any one of claims 1 to 24 and a pharmaceutical agent. Pharmaceutical or veterinary medicine consisting of a pharmaceutically or veterinary acceptable carrier or excipient Composition.   26. A compound of formula (I) according to any one of claims 1 to 24 for therapeutic use. .   27. Claims in the manufacture of a therapeutic agent for bacterial infections in humans and non-human animals Use of a compound of formula (I) as described in 1.   28. For the manufacture of therapeutic agents for mycoplasma infections in humans and non-human animals Use of a compound of formula (I) according to claim 1.   29. Claims in the manufacture of a therapeutic agent for fungal infections in humans and non-human animals Use of a compound represented by formula (I) according to item 1.   30. The compound of formula (I) according to claim 1 can be administered to patients in need of treatment. Treatment of bacterial infections in humans and non-human animals consisting of administering a bacterially effective amount Method.   31. The compound of formula (I) according to claim 1 can be administered to patients in need of treatment. In humans and non-human animals consisting of administering an effective amount of mycoplasma How to treat Icoplasma infection.   32. The compound of formula (I) according to claim 1 can be administered to patients in need of treatment. Fungal infections in humans and non-human animals consisting of administering an effective amount of fungi Treatment method.   33. A herbicidally effective amount of the compound of formula (I) according to claim 1 Severely damage unnecessary plants consisting of applying to How to wither.   34. A compound of formula (I) according to any one of claims 1 to 24 and a compound A herbicidal composition comprising a herbicidally acceptable carrier.   35. Formula (IV) under amide formation conditions: [Wherein, Z¹, Z²And Z^ThreeAre the same or different and each represents hydrogen or hydro. Is a xyl protecting group and A, B and D are as defined in claim 1.] An acid represented by the formula (V): [Wherein, R¹And R²Is the same as the definition in claim 1] Is reacted with an amine represented by   Removing the hydroxyl protecting group A process for producing a compound of formula (I) according to claim 1.   36. Amide forming conditions are moderate temperature in the presence of a suitable base in an aprotic solvent, The acyl halide or mixed anhydride derivative of the acid of formula (IV) is represented by formula (V) 36. The method according to claim 35, which comprises reacting with an amine.   37. E-2- {2- [3R, 4R-bis-trimethylsilyloxy-5S- (2 S, 3S-epoxy-5S-trimethylsilyloxy-4S-methylhexyl) te Trahydropyran-3S-yl]-(1-methylethylidene)}-5-t-butyldi Methylsilyloxyindan-1-one;   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl]-( 1-methylethylidene)}-5-hydroxyindan-1-one;   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5- (methoxycarbonylpent-1-yloxy) in Dan-1-on; and   E-2- {2- [3R, 4R-dihydroxy-5S- (2S, 3S-epoxy-5 S-Hydroxy-4S-methylhexyl) tetrahydropyran-2S-yl] -1 -Methylethylidene} -5- (5-carboxypent-1-yloxy) indane -1- on The compound of formula (IV) according to claim 33, wherein   38. Claim 1 substantially as defined in any one of the Examples. Listed compounds.   39. 37. A definition substantially as defined in any one of the Examples. The manufacturing method described.