JPH0260678B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel N-alkyl-N-iminomethyl derivatives () of the antibiotic thienamycin (structure described below). Those compounds, including their O- and carboxyl derivatives and their pharmaceutically acceptable salts, are useful as antibiotics. The present invention also relates to these compounds, to processes for the preparation of pharmaceutical compositions comprising these compounds, and to methods of treatment consisting of administering these compounds and compositions when antibiotic efficacy is demonstrated. Compounds ^of the ^invention generally have ^the following structural formula: It is a pharmaceutically acceptable salt thereof. In addition, lower alkyl is 1 to
Means having 10 carbons. Preferably it has 1 to 6 carbon atoms. Further, the compound of the present invention can be attached with a protecting group as required, as is commonly practiced in the art. It is more convenient to represent the structure with the following symbol K0680, where "Th" is a symbol representing the bicyclo nucleus, which is the basic skeleton of thienamycin, that is, K0681, and the right side of "Th" indicates a substituent. There is. The upper row shows the substituent on carbon represented by 8, the middle row shows the substituent represented by 9, and the lower row means the substituent at the 2-position of the bicyclo nucleus. In addition, compounds of structural formula () include halides (chlorides, bromides, etc.), sulfates, phosphates,
Also included are pharmaceutically acceptable salts such as citrate, acetate, benzoate, and the like. It should also be noted that it can also be a zwitterion. Thienamycin, a new compound, is disclosed and claimed in US Pat. No. 3,950,357, issued April 13, 1976. This patent is incorporated herein by reference as thienamycin can be utilized as a starting material in the preparation of the compounds of the present invention. Thienamycin is known to have the following structure K0682. Starting materials (including all their isomers and isomer mixtures)
is described and claimed in U.S. Pat. No. 4,234,596 to Christensen, Johnston, and Schmitt (Merck & Co., Inc., Attorney's Office, No. 16029). It can also be obtained by total synthesis.
This patent application is incorporated herein to make available all the isomers (pure or as mixtures) that are suitable starting materials for the preparation of the compounds of the invention. . Other convenient starting materials for the preparation of compounds of the invention are N-
It is an alkylated thienamycin derivative ().
where K0683 R ⁵ is as defined above. N-alkylated thienamycins () are disclosed and claimed in US Pat. No. 4,235,920. This patent application is incorporated herein by reference for clarity regarding the preparation of N-alkylthienamycins as defined by above. There continues to be a need for new antibiotics. Unfortunately, continued widespread use of certain antibiotics can lead to the development of selectively resistant strains of pathogenic bacteria, so the effectiveness of the antibiotics is not stable. . Furthermore, known antibiotics have the disadvantage that they are only effective against certain types of microorganisms. The search for new antibiotics therefore continues. It has been unexpectedly found that the compounds of the present invention are broad spectrum antibiotics and are useful in the treatment of animals and humans and non-living systems. It is therefore an object of the present invention to provide a new antibiotic having the basic core structure of the antibiotic thienamycin and characterized as its N-alkyl-N-iminomethyl derivative. These antibiotics are
Gram-positive bacteria such as S. aureus, Strep pyogenes and B. subtilis and E. coli, Proteus morganii , Serratia, Pseudomonas and Klebsiella.A further object of the present invention is to treat such antibiotics and their a non-toxic pharmaceutically acceptable salt of such an antibiotic; a pharmaceutical composition comprising such an antibiotic; K0684 K0685 The starting materials are: No. 4,235,920, which is incorporated herein by reference for clarity regarding the preparation of N-monoalkylthienamycin derivatives (). Such N-monoalkyl derivatives are prepared by reacting thienamycin or a suitable derivative thereof or a suitably protected thienamycin with an N-alkylating agent. Any of a variety of well-known N-alkylation methods may be used, regardless of the nature of N-alkylation.The type of N-alkylating agent is selected within the range limited by the definition of ^R1 . -Alkylation can be carried out in a variety of solvent systems that are inert or substantially inert to the desired reaction route.Suitable solvents include water, lower alkanoyls such as ethanol, dioxane, Polar solvents such as tetrahydrofuran (THF), acetonitrile, hexamethylphosphoramide (HMPA), dimethylformamide (DMF) etc. and mixtures thereof (especially water-containing mixtures), halohydrocarbons such as benzene, methylene chloride, chloroform etc. Non-polar solvents are involved. Reactions typically run from -40°C.
It is carried out for a few minutes to 5 hours at a temperature of 50°C. The reaction is usually carried out in the presence of an acid acceptor such as propylene oxide, magnesium oxide, potassium carbonate, etc. Preferred N-alkylating agents include active halides, sulfate esters and Michael addition reagents. The following reagents are representative of these alkylating agents: methyl iodide, dimethyl sulfate, methyl fluorosulfonate, and the like. Starting materials can be prepared in a variety of ways. One convenient starting material is tris-trimethylsilylthienamycin [Th(TMS) ₃ ] (see below). useful starting materials for the preparation of carboxyl-, O-; U.S. Pat.
No. 4208330, No. 4181733, and No. 4226870 are incorporated into the text as cited documents. As mentioned above, the N-alkylation reaction is carried out using a selected N-alkylating agent such as R ⁵ carried out in the presence of For example, when using Th(TMS) ₃ as described above, the desired product is obtained by an N-alkylation step followed by hydrolysis. The reaction scheme below summarizes the method (TMS is trimethylsilyl,
R ⁵ and X′ are as defined above. ) K0686 K0687 K0688 A second scheme for the preparation of monoalkylthienamycins ( ) includes the following substituents, substituted and unsubstituted: benzyl, benzylhydryl (-CH(C ₆ H ₅ ) ₂ ) and trityl ₍ -C( _C6H5 ) ₃ )
[Ring substituents on aralkyl include halogen, nitro,
Alkylation of N-substituted thienamycins that are easily eliminated bulky groups (R ⁰ ) such as aralkyl groups (lower alkyl, lower alkoxyl, etc.) are included. The reaction scheme below summarizes this scheme. All symbols in the formula are as defined above. With respect to the above scheme, starting materials 1~ prepared, for example, by reaction of thienamycin or a derivative thereof with an aralkyl halide, are as described above.
By reacting R ¹ X′ with a selected N-alkylating agent, N,
N-dialkyl intermediate 2 is provided. The aralkyl N-substituent R ⁰ is easily removed and hydrolysis gives 3~. Suitable conditions for this final cleavage step include hydrolysis of 2~ in hydrogen (1 to 4 atmospheres) in a solvent such as ethanol in the presence of a catalyst such as platinum, palladium or their oxides. is included. The final products of this reaction are primarily 3-,N-mono-lower alkyls. But N,
N-dilower alkylthienamycin is also produced as a by-product to some extent. Such contaminating by-products can be separated by chromatographic means and the degree of contamination can be reduced to 1.
It can be minimized by using an equal or lesser amount of alkylating agent R ⁵ X'. A third method for the preparation of N-monoalkyls, especially N-lower alkyls, is similar to the method described above, except that starting material 1a is N,N-dialkylthienamycin. . Such starting materials are prepared as follows. The reaction scheme below summarizes this process: All symbols in the formula are as described above. N
It should be noted that this scheme for the preparation of lower alkyl thienamycins is not complicated by the by-product of N,N-di-lower alkyl thienamycins. A fourth method particularly suitable for the preparation of N-lower alkylthienamycins () is by N-alkylation of the Schiff base of thienamycins. The scheme below summarizes this reaction. All symbols in the formula are as defined above,
Furthermore, φ may be phenyl, and H in -OH and -COOH may be a trimethylsilyl group (TMS). Preferred Schiff bases are those obtained by reacting thienamycin with benzaldehyde or nuclear-substituted benzaldehyde. There is no criticality to the method for preparing such Schiff bases, and their preparation is disclosed in US Pat. No. 4,172,144. This co-pending patent application describes the preparation of starting materials 4- and is incorporated herein by reference. 4~ and alkylating agent
Reaction of R ⁵ X' gives intermediates 5~, which upon hydrolysis or catalytic hydrolysis gives the desired N-lower alkylthienamycins 6~. A fifth method for the preparation of N-lower alkylthienamycins () is to desulfurize N-thioacylthienamycins in the presence of a hydrogenation catalyst such as Raney nickel. where _R8 is hydrogen or a lower alkyl moiety having 1-5 carbon atoms. The N-thioacyl thienamycin starting material is fully disclosed in Japanese Patent No. 1335541, and the patent application discloses the preparation of such starting material, so references cited in the text are included. It has been adopted as. The desulfurization described above is typically carried out in a polar protic solvent such as water, a lower alkanol such as ethanol, or a mixture thereof at a temperature of 0-50°C for a period of 2 minutes to 5 hours. The preparation of compounds of the invention is conveniently described by the definition of ^R6 . There are two cases of these: (1) amidines (R ⁶ = H, or R (lower alkyl); (2) guanidines (R ⁶ = NH ₂ ); (1) amidines In general, compounds of class (1) are can be conveniently prepared by reacting the desired N-alkylthienamycin () with the imidoester (a). K0701 where R ₁ and R are as defined above, −
OR″ (R″ is lower alkyl such as methyl, ethyl, etc.) is a leaving group. Depending on the type of thienamycin substrate and reaction reagents, solvents for the preparation of Class 1 compounds based on the above reaction scheme may include water, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, acetone, acetonitrile or Includes mixtures thereof. Reaction at 0℃
and about 25° C. for 1 to 6 hours. There is no criticality as to the exact type of reaction solvent, reaction variables within the limits set forth above, so long as the reaction solvent is inert or substantially inert to the intended reaction route. Representative suitable reaction reagents include: (a) Imidoesters: K0702 X ⁰ =O or S Methylformimidate, Ethylformimidate, Methylacetimidate, Ethylacetimidate , ethyl N-methylformimidate,
Methyl N-methylformimidate, methyl N-
Isopropylformimidate etc. Such imidoester reagents (a) are conveniently prepared by any of a variety of known methods, such as: (1) Reaction of nitrile, RCN, and lower alkanol in the presence of HCl using the well-known pinner synthesis. (2) Reaction of nitriles, RCN, and lower alkanols in the presence of a base. Typically, the reaction is carried out at 0-40°C in the presence of excess alcohol with a catalytic amount of alkali metal alkoxide for 15 minutes to 4 hours. (3) Amide at 25℃-45℃ for 1-4 hours.

The reaction between [Formula] and an alkyl chloroformate such as methyl chloroformate. (4) N- in an inert solvent such as ether or chloroform at 0-23℃ for about 10 minutes to 2 hours.
substituted amide,

Reaction of the formula with an equivalent amount of an alkylating agent such as triethyloxonium fluoroborate. (5) In a mixture of water and an immiscible solvent (ether, chloroform, etc.), 0-
23°C, 5 minutes to 1 hour, a readily available imidoester,

[Formula] (R′ may be hydrogen) and an alkylamine,
the desired imidoester of said imidoester by reaction of R′NH ₂ ,

Conversion to [formula]. Reactions using reaction reagent (a) are typically represented by the following scheme: where OR'' is the leaving group of the imidoester reagent. (2) Guanidine Generally, compounds of class (2) are and (a)-OR'' (e.g. O-alkyl, O-aryl) pseudourea or S-alkyl or It can be conveniently prepared by reaction with S-aryl pseudothiourea. Water as a suitable solvent for such reactions, and
Examples include a mixture of buffered water with a pH of 7-9 and a polar organic solvent, or an anhydrous polar organic solvent such as dimethylformamide or hexamethylphosphoramide. At this time, the reaction temperature is from 0℃ to 40℃
The reaction time is 1 to 24 hours. Suitable reagents (a) and (b) include: (a) -OR pseudourea and -SR pseudourea O-methyl pseudourea, S-methyl pseudothiourea, O-N,N-trimethyl pseudourea, etc. Reactions using reagent (a) are typically shown in the following scheme: K0707 K0708 where R ¹ is as defined above, X″ is O or S, R″ is as defined but , lower alkyl or aryl. The products of the invention () form a wide range of pharmaceutically acceptable salts, such as acid addition salts such as hydrochloric, bromic, sulfuric, nitric, toluene-p-sulfonic and methanesulfonic acids. The salts of the present invention are pharmaceutically acceptable non-toxic derivatives and can be used as active ingredients in suitable unit dosage pharmaceutical forms. They can also be combined with other agents to provide compositions with a broad spectrum of activity. The new compounds are valuable antibiotics effective against a variety of Gram-positive and Gram-negative bacteria and therefore have utility as human and veterinary medicines. The compounds of the invention can therefore be used, for example, in Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia.
bacteria such as Pneumonia pneumonia, Serratia, Salmonella thypose, Pseudomonas and Bacterium proteus.
It can be used as an antibacterial agent to treat infections caused by positive and gram-negative bacteria. The antibacterial agent of the present invention can further be used as a feed additive for preserving animal feed and as a disinfectant. For example, these antibacterial agents can be used as agents to inhibit the growth and disinfection of harmful bacteria on medical and dental instruments, and in industrial products such as water-based paints and in white water in paper mills. It can be used in aqueous compositions at concentrations of 0.1 to 100 ppm per solution as agents to inhibit the growth of bacteria. A comparison of the antibacterial activity of representative compounds of the present invention and thienamycin against various bacteria is shown below. The activity of thienamycin was set as 1 for comparison.

[Table] As is clear from the table, the compound of the present invention had superior antibacterial activity compared to thienamycin. The products of the invention can be used alone or as one active ingredient in a variety of pharmaceutical compositions. These antibiotics and their corresponding salts can be used in capsules, or as tablets, powders or liquid solutions, or as suspensions or panaceas. They can be administered orally, intravenously or intramuscularly. Preferably, the composition is provided in a form adapted to be absorbed by the gastrointestinal tract. Tablets and capsules for oral administration may be in unit dosage form and may contain a binder such as syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, such as lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine. It contains the usual excipients such as fillers such as magnesium stearate, talc, polyethylene glycol, lubricants such as silica, dispersants such as potato starch, acceptable wetting agents such as sodium lauryl sulfate, etc. You can leave it there. The tablets may be coated by methods well known in the art. Oral liquid preparations may take the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be reconstituted with water or other suitable carrier before use. It may also be provided as a dry product for constitution.
Such liquid preparations include, for example, sorbitol,
syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible oils (e.g. almond oil, fractionated coconut oil), oily esters, propylene glycol, or ethyl alcohol. It is possible to contain customary additives such as suspending agents, preservatives such as methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories will contain conventional suppository bases such as cocoa butter or other glycerides. Compositions for injection can be presented in unit dosage form in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous carriers, and may contain formulation agents such as suspending, stabilizing, and/or dispersing agents. It may contain a drug. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, immediately before use. The composition may be prepared in a suitable form that can be absorbed through the throat and nasal mucosa or bronchial tissues, such as as a powder or liquid spray, or as an inhaler, tablet, throat paint, etc. It's convenient. For eye or ear treatment, the composition may be provided as separate individual capsules, liquid or semi-solid, or used as drops.
For parenteral administration, they are formulated into hydrophobic or hydrophilic bases such as ointments, creams, lotions, paints, powders, and the like. In addition to carriers, the compositions can also contain other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, adhesives, flavoring agents, and the like.
Furthermore, the composition may contain other active ingredients to broaden the spectrum of antibiotic activity. As a veterinary drug, the composition can be formulated, for example, as a long-acting or immediate-acting intramammary composition. The amount to be administered is determined mainly by the condition of the subject to be treated, the host's weight, the route of administration, and the number of administrations; however, the parenteral route is preferred for general infections, and the oral route is preferred for intestinal infections. preferable. Generally, the daily oral dose is 1 kg of subject's body weight.
Each drug contains about 2 to 600 mg of active ingredient, and is administered once or several times a day. The preferred daily dosage for adult humans is in the range of about 15 to 150 mg of active ingredient per kg of body weight. The composition can be administered in several unit dosage forms, such as, for example, solid or liquid orally ingestible dosage forms. The composition per unit dose, whether in liquid or solid form, contains from 0.1% to 99% of active substance;
A preferred range is about 10-60%. Compositions generally contain from about 15 mg to about 1500 mg of active ingredient, although it is generally preferred to employ dosages within the range of about 100 mg to 1000 mg. For parenteral administration, the unit dosage is usually presented as the pure compound in slightly acidified sterile aqueous solution or in the form of a soluble powder intended for solution. The following specific examples are illustrative of the products, methods, compositions, or methods of treatment of the present invention, but are not intended to be limiting. Example 1 Preparation of N-methyl-N-formimidoyl thienamycin K0714 N-methyl thienamycin (14 mg) at pH 7.0,
Dissolve 1N in 0.1N phosphate buffer (2.5ml)
PH using an automatic brewet adding NaOH
Adjust to 8. Add methylformimidate hydrochloride (25 mg) to this solution while maintaining the pH at 8.5 and stirring with a magnetic stirrer. After 20 minutes, add more methylformimidate (25 mg). The reaction was allowed to continue for another 25 minutes and the pH was adjusted with 2.5N NCl.
Adjust to 7.0. Then dowex the whole solution for 50 minutes.
Chromatography is performed on -x4 resin (25 c.c., Na ⁺ cycles, 200-400 meshes) and eluted with water. The N-methyl-N-formimidoyl derivative is eluted at a volume of 3-4 times the column volume and is lyophilized to give a white solid (3 mg). UV (PH7, 0.1N phosphate buffer), λ _nax 298n
m, IR (nujyormuru) 1760, 1710cm ^-1 NMR
(100MHz, D ₂ O) δ1.32 (d, J=6Hz, CH ₃ −
CH), 3.12 (S, NCH ₃ ), 7.86 (S,

Example 2 N-formimidoyl-N-ethyl thienamycin A solution of N-ethyl thienamycin (5.6 mg) in 2.8 ml of 0.2N, PH 7 phosphate buffer was adjusted to PH 8.5 and diluted with ethyl form. Imidate Hydrochloride (50mg)
Add. The pH of this solution is maintained at 8.5 by adding 1N sodium hydroxide solution under the control of a PH stat. This mixture was heated to 25° at 23°.
Stir for min and then add another portion of formimidate (50
mg). After 25 minutes, the reaction mixture is neutralized with dilute hydrochloric acid and chromatographed on a 1.5x15 cm column of Dowex 50-x4 resin (Na ⁺ cycle, 200-400 mesh). Elute the column with water at a flow rate of 0.5 cc/min and transfer the eluate to HPLC.
(1/4″×1′C ¹⁸ Porasil; Solvent 0.01N, NaHPO ₄
Solution, flow rate - 2 c.c./min; retention time for N-ethyl thienamycin = 5 minutes, N-formimidoyl,
N-ethyl thienamycin RT = 9.5 min). Product fraction (UV42 ODU, λ _nax 298n
(in step m) was combined, concentrated to 5 ml, and lyophilized. Reference example (Synthesis example of raw materials) Silylation of N-methyl thienamycin Hexamethyldisilazane (0.1 ml) and trimethyl were added to a suspension of N-methyl thienamycin (8 mg) in 1 ml of tetrahydrofuran under a nitrogen stream. Add chlorosilane (20μ). The mixture is stirred vigorously for 20 minutes at 25° and then the ammonium chloride is removed by centrifugation. The supernatant is concentrated to an oil under a stream of nitrogen, and this oil is used directly in the next reaction. Example 3 Preparation of K0716 N-methyl-N-guanyl thienamycin N-methylthienamycin (8.9 mg) was dissolved at pH 7.0.
Dissolve in 0.1N phosphate buffer (0.7ml) and N,N-dimethylformamide (0.3ml) and bring the solution to pH 9.5 by adding 2.5N sodium hydroxide solution. Addition of O-methylisourea hydrogen sulfate (43 mg) to the magnetically stirred solution slightly lowers the PH. Furthermore, add sodium hydroxide solution to return the pH to 9.5, and store this solution at 23℃.
Stir for 30 minutes. This solution is then neutralized to pH 7.0. A solution containing a mixture of N-methyl thienamycin and N-methyl-N-guanyl thienamycin was added to 20 c.c. of Dowex 50×4 resin (Na ⁺
Chromatography is performed on a 200-400 mesh cycle and the product is recovered by lyophilization. Example 4 N,N'-dimethyl-N-formimidoyl
Preparation of thienamycin K0717 N-methyl thienamycin (140mg) at PH7.0
Dissolved in 0.1N phosphate buffer (10ml) of 1N
The pH of this solution is adjusted to 8.5 using an automatic brewet that injects NaOH. The pH of this solution is 8.5
Add methyl-N-methylformimidate hydrochloride (20μ) while maintaining the temperature. After 40 minutes PH is 2.5N
Adjusted to 7.0 with HCl, this solution was added to Dowex 50-×4 resin (72 c.c., Na ⁺ cycles, 200-400
Chromatography is carried out on a mesh plate and eluted with deionized water. The N,N'-dimethyl-N-formimidoyl derivative is eluted in two column volumes and gives a white solid upon lyophilization. Example 5 Preparation of N-ethyl-N'-isopropyl-N-formimidoyl thienamycin K0718 N-ethyl thienamycin (110 mg) was
Dissolve in 0.1N phosphate buffer (7ml) and add 1N
PH using an automatic brewet to inject NaOH
Adjust to 8.5. A solution of methyl N-isopropyl formimidate hydrochloride (300 mg) in p-dioxane (1 ml) is added to the magnetically stirred buffer while maintaining the pH at 8.5. After 25 minutes, the pH of the solution was adjusted to 7.0 using 2.5N NaOH and added to Dowex 50-×4 resin (53 c.c., Na ⁺ cycle,
Chromatography is performed on a 200-400 mesh (200-400 mesh) and eluted with deionized water. Chromatography is carried out at 3°C using a column with a water jacket. The N-ethyl-N'-isopropyl-N-formimide derivative is eluted in two portions of the column and upon lyophilization a white solid is obtained. Example 6 Following the methods specified in the text and examples above, the following compounds of the invention are obtained. K0719 Example of Preparation of Pharmaceutical Composition One unit dosage form contains 120 mg of N-methyl, N-
Formimidoylthienamycin 20mg lactose,
Mixed with 5 mg of magnesium stearate, 145
mg of this mixture into a No. 3 gelatin capsule. Similarly, other dosage forms can be placed in No. 3 gelatin capsules using more active ingredients and less lactose. It is also possible to prepare larger capsules, such as compressed tablets and pills, if it is necessary to mix together 145 mg or more of the ingredients. The following specific examples illustrate the preparation of pharmaceutical formula compositions. Tablets N-methyl, N-formimidoylthienamycin 125 mg Corn starch, USP 6 mg Dicalcium phosphate 192 mg Lactose USP 190 mg per tablet The active ingredients are mixed with the dicalcium phosphate , lactose and half the amount of corn starch. This mixture is then granulated with 15% corn starch paste (6 mg) and passed through a coarse sieve. Dry at 45℃ and pass through a No. 16 sieve again. The remaining corn starch and magnesium stearate are added and the mixture is compressed into tablets approximately 0.5 inches in diameter and weighing 800 mg each. Parenteral solution ampoule N-methyl, N-formimidoylthienamycin 500 mg Ophthalmic solution N-methyl, N-formimidoyl thienamycin 100 mg Hydroxypropylmethyl 5 mg Sterile water 1 ml Auris solution N-methyl, N-formimide Ilthienamycin 100mg Benzalkonium chloride 0.1mg Sterile water 1ml Topical ointment N-Methyl, N-formimidoylthienamycin 100mg Polyethylene glycol 4000U.SP 400mg Polyethylene glycol 400U.SP 1.0g Active ingredients in the official compositions mentioned above is alone,
or together with other biologically active ingredients such as other antibacterial agents such as lincomycin, penicillin, streptomycin, novobiocin, gentamicin, neomycin, colistin and kanamycin, or other therapeutic agents such as probenecid. It is possible to administer.

Claims (1)

[Claims] 1 Formula K0671 [wherein R ¹ is hydrogen or lower alkyl, R ⁵ is lower alkyl and R ⁶ is hydrogen, lower alkyl or amino]. ] and its pharmaceutically acceptable salts. 2. The compound according to claim 1, which is represented by the formula K0672. 3. The compound according to claim 1, which is represented by the formula K0673. 4. The compound according to claim 1, which is represented by the formula K0674. 5. The compound according to claim 1, which is represented by the formula K0675. 6 Formula K0676 [wherein R ¹ is hydrogen or lower alkyl, R ⁵ is lower alkyl and R ⁶ is hydrogen, lower alkyl or amino]. ] In the method for producing a compound represented by formula K0677 [wherein R ⁵ is as defined above]
or its O- and/or carboxyl derivatives to a compound of formula K0678 [wherein -X ⁰ R'' is a leaving group, X ⁰ is -O- or -S-, and R ¹ and R ⁶ are as defined above].