KR100246946B1 - Novel carbapenem compounds - Google Patents

Abstract

The present invention relates to novel carbapenem derivatives of the following general formula (I), salts, esters, solvates and isomers thereof, useful as antibacterial agents.

Where

R ¹ represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl,

R ² represents hydrogen, a C _1-4 alkyl group, aminomethyl or 2-aminoethyl group,

R ³ represents hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group or an acyloxyalkyl group,

R ⁴ is C _1-4 alkyl group, aralkyl group or -NRR 'wherein R and R' are each independently hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group or acyloxyalkyl group ),

R ⁵ and R ⁶ each independently represent hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group, an acyloxyalkyl group or an amino group having at least one substituent, or to which they are attached Together with carbon atoms, it is possible to form saturated or unsaturated 3-6 membered rings which may contain one or more heteroatoms.

Description

Novel carbapenem antibiotics and preparation method thereof

The present invention provides novel carbapenem compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates and solvates and isomers thereof and methods for preparing the same, which are useful as antibiotics It is about the intermediates in the process and their preparation.

Where

R ¹ represents 1-hydroxyethyl, 1-aminoethyl, 1-fluoroethyl or hydroxymethyl,

R ² represents hydrogen, a C _1-4 alkyl group, aminomethyl or 2-aminoethyl group,

R ³ represents hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group or an acyloxyalkyl group,

R ⁴ is C _1-4 alkyl group, aralkyl group or -NRR 'wherein R and R' are each independently hydrogen, C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group or acyloxyalkyl group ),

R ⁵ and R ⁶ each independently represent hydrogen, a C _1-4 alkyl group, a C _3-6 alkenyl group, a C _3-7 cycloalkyl group, an acyloxyalkyl group or an amino group having at least one substituent, or to which they are attached Together with carbon atoms, it is possible to form saturated or unsaturated 3-6 membered rings which may contain one or more heteroatoms.

The present invention also encompasses epimeric, diastereoisomers and tautomeric isomers which may appear in general formula (I).

In 1976, Thienamycin, a beta-lactam ring with a structure completely different from that of conventional penicillin or cephalosporin antibiotics, was first isolated from the culture of Streptomyces cattleya (J. Am). Chem. Soc. 1978, 100, 6491). As it turns out that this new structure of compound has a broad spectrum of antimicrobial activity, the study of carbapenem antibiotics begins. Imipenem was then developed by Merck, which overcomes chemical instability due to the structural specificity of thienamycin (J. Med. Chem. 1979, 22, 1435). However, like thienamycin, imipenem has been found to be degraded by the dehydropeptidase (DHP-I, Dehy-dropeptidase-I) secreted by the kidney, and as a result, Cilastatin, a DHP-I inhibitor, To be used together (J. Antimicrob. Chemother. 1983, 12 (Suppl. D), 1). Carbapenem antibiotics are widely used to treat diseases caused by pathogenic bacteria, and are particularly useful for treating diseases caused by bacteria that are resistant to other antibiotics, such as penicillin compounds, and for treating penicillin-sensitive patients. However, the discovery of resistant strains due to too frequent use of imipenem has become a problem recently. Research on new carbapenem derivatives has been ongoing since then, and related patents and reports have been published. In particular, carbapenem derivatives have been reported that have excellent antibacterial activity against Gram-positive and negative bacteria, and are very stable against P-lactamase of bacteria as well as DHP-I secreted from the kidney. The representative compound is Meropenem, reported by Sumitomo (J. Antibiot. 1990, 519). On the other hand, the development of antibiotics with a broader and stronger antimicrobial force is required due to the constant expression of resistant bacteria.

Various derivatives have been studied in which the C-2 position of the carbapenem nucleus is linked to a substituted methyl group.

For example, Schmidt et al. (J. Antibiot. 1988, 780) describe carbapenem antibiotics of the following general formula (A).

Where

R ¹ is hydrogen, an acetyl group, a substituted or unsubstituted aminoacyl group,

R ² is hydrogen, potassium or an anion.

However, the manufacturing process has a disadvantage that it is multi-stage and antibacterial activity is not extensive.

Immuta et al. Describe the carbapenem antibiotics of the following general formula (B) in Chem. Pharm. Bull. 1991, 39, 663 and 672.

Where

R ¹ is hydrogen, potassium or an anion,

Het is substituted pyridine, pyrimidinium, pyrimidinium derivatives.

However, the disadvantage that the antibacterial activity, including Pseudomonas aeruginosa, is not extensive.

I have it.

Arnold et al. (Tetrahedron Lett. 1992, 7133) have the following general formula (C)

Carbapenem antibiotics are described.

Where

R ¹ and R ² are each hydrogen or a protecting group,

R ³ is an aryl or acyl group,

A is an element such as oxygen, nitrogen, or sulfur.

However, there is no mention of their antimicrobial activity.

Sendo et al. Describe examples of carbapenem antibiotics of the general formula (D) in Chem pharm. Bull. 1992, 40, 2410.

Where

Het is a heterocyclic ring such as thiadiazole,

X is fluorine, nitrile group, hydroxy or acetyloxy.

However, their production method has the disadvantage of being multi-stage and the intermediate is not easily separated easily, and is inferior to Pseudomonas aeruginosa in terms of antibacterial activity.

On the other hand, US Patent No. 5,064,954 describes a process for preparing 2-halomethyl-carbapenem of the following general formula (e).

Where

R ¹ is hydrogen, substituted or unsubstituted alkyl,

R ² is hydrogen, substituted or unsubstituted alkyl.

R ⁵ is hydrogen or a carboxyl protecting group,

Hal is halogen.

This formulation patent suggests a useful formulation for introducing various substituted methyl derivatives at the C-2 position of the carbapenem parent nucleus.

Thus, the present inventors have conducted research to introduce various derivatives at the C-2 position of carbapenem, and as a result, the core phosphorus (1,5,6-substituted-4-aminopyrimidin-2-yl) thiomethyl group of the present invention The discovery of a carbapenem compound having a strong activity against a wide range of pathogens has led to the completion of the present invention for the compound represented by the general formula (I). Compounds according to the invention include geometric isomers or mixtures of isomers. In addition, solvates (including hydrates) of the compound of formula (I) are also included in the scope of the present invention. Furthermore, since the compound of general formula (I) may have the same resonance structure as general formula (I ′), such a resonance structure is also within the scope of the present invention.

Pharmaceutically acceptable non-toxic salts of the compounds of formula (I) are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid or acetic acid, trifluoro acetic acid, citric acid, formic acid, maleic acid, hydroxyl, succinic acid, benzoic acid Salts with organic carboxylic acids such as tartaric acid, fumaric acid, manderic acid, ascorbic acid, dried acid or sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and other acids known and used in the art of penicillin and cephalosporin; Contains salts. These acid addition salts are prepared by conventional techniques. The compounds of formula (I) may also form nontoxic salts. Bases used herein include alkali metal hydroxides (e.g. caustic soda, caustic), alkaline earth metal hydroxides (e.g. calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or calcium carbonate). Inorganic bases and organic bases such as amino acids. Examples of esters capable of physiological hydrolysis of the compound of general formula (I) include indanyl, phthalidyl, methoxymethyl, pivaloyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, 5-methyl-2 Oxo-1,3-dioxoren-4-yl methyl and other physiologically hydrolysable esters known and used in the art of penicillin and cephalosporin. Such esters can be prepared by known methods.

Formula (I) compound has high antimicrobial activity against various Gram-negative bacteria and is used for prevention and treatment of bacterial infection in animals including humans. Formula (I) compounds are formulated by known methods using known pharmaceutical carriers and excipients and are in unit dosage forms or in multidose containers. The compositions are in the form of solutions, suspensions or emulsions in oil or aqueous media and may contain conventional dispersing agents, suspending agents or stabilizers. In addition, the composition may be in the form of a dry powder which is dissolved, for example, before use as sterile, exothermic material removed. The compounds of formula (I) may also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. If desired, the compounds of the present invention may be administered in combination with other antibacterial agents such as penicillin or cephalosporin. When forming the composition in unit dosage form, it is preferable to contain about 50 to 1,500 mg of the active ingredient of the compound of formula (I). The dosage of the compound of general formula (I) depends on the doctor's prescription depending on factors such as the patient's weight and age and the specific nature and severity of the disease.

However, dosages required for adult treatment typically range from about 500 to 5,000 mg per day, depending on the frequency and route of administration. A total daily dosage of about 150 to 3,000 mg per day will be sufficient, separated into single doses for intramuscular or intravenous administration to adults, but higher daily dosages are preferred for some strains of infection.

The compounds according to the invention exhibit a wide range of antimicrobial activities, which are generally highly active against Gram-positive bacteria, and this activity also applies to many Gram-negative bacteria producing β-lactamases. In particular, the penicillin-resistant strain MRSA (Methicillin-resistant Staphylococcus aureus) has a significantly higher antimicrobial activity than the control drug Meropenem (Meropenem). MRSA bacteria are very resistant to antibiotics, and considering that their treatment is not easy for infectious diseases, the usefulness of the compounds according to the present invention is very high.

Compounds of formula (I), pharmaceutically acceptable non-toxic salts thereof, physiologically hydrolysable esters, hydrates or solvates thereof according to the present invention may be prepared by the following compounds of formula (II) It is prepared by reacting with a compound of formula (III) and removing the hydroxy protecting group or acid protecting group before or after the reaction if necessary.

Where

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as described above,

R ⁷ is hydrogen, a C _1-4 alkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group, acyloxyalkyl group or carboxyl protecting group, and an alkyl (C _1-12 ) group (e.g. isopropyl, t- Butyl, etc.), lower alkoxy lower alkyl group (e.g., methoxymethyl.ethoxymethyl, isobutoxymethyl, etc.) lower aliphatic alkoxy lower alkyl group (e.g., acetoxy methyl, propionyl oxymethyl, butyryloxymethyl, pivaloyloxy Methyl, etc.), lower alkoxycarbonyloxy lower alkyl groups (e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxymethyl, etc.), aryl lower alkyl groups (e.g. p-methoxybenzyl, o-nitrobenzyl, p Nitrobenzyl, zuhydryl, phthalidyl, and the like), tri (lower alkyl) silyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, etc.), diaryl (lower alkyl) silyl (e.g. t-butyldiphenyl Silyl, etc.), tri (lower alkyl) silyl lower alkyl groups (e.g. trimethylsilylethyl, etc.), alkenyl (C _2-6 ) groups (e.g. allyl, vinylethyl, etc.),

R ⁸ is a 1-fluoroethyl or —CH (R ^a ) —OR ^b group, R ^a represents hydrogen or a C _1-4 alkyl group, R ^b is a hydrogen or hydroxy protecting group, and a lower alkenyl group (e.g., Allyl, etc.), lower alkanoyl (e.g., acetyl, etc.), lower alkoxycarbonyl groups (e.g., t-butoxycarbonyl, etc.), lower alkenyl oxycarbonyl groups (e.g., allyl oxycarbonyl, etc.), aryl lower alkoxy carbonyl groups (e.g., : Benzoyloxycarbonyl, p-methoxybenzoyloxycarbonyl, etc.), a trilower alkylsilyl group (e.g. trimethylsilin, t-butyldimethylsilyl, etc.) or an aryl lower alkyl group (e.g. benzyl, etc.), L is As leaving group, halogen. Alkanoyloxy groups, alkanesulfonyloxy, arylsulfonyloxy, alkoxycarbonyloxy or phosphoric esters.

Suitable solvents for the reaction of compounds (II) and (III) are organic solvents of the same kind, such as dimethyl formamide, acetonitrile. It proceeds well in the presence of inorganic salts such as alkali metals (eg potassium halides), and the reaction temperature is appropriately between -25 ° C and 35 ° C.

Compounds (II) are well known in the literature for other carbapenems, such as US Pat. No. 5,064,954. The compound of general formula (II) can remove the hydroxy protecting group or carboxyl protecting group by conventional methods if necessary. That is, these protecting groups are removed by a suitable and easy method such as acid, base, metal or enzyme catalyst hydrolysis or reduction while minimizing the degree of destruction of the basic structure. From the reaction product of the reaction, the desired compound of formula (I) can be separated or purified by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

Representative compounds according to the present invention are as follows.

Ia: (1S, 5R, 6S) -2-[[(4-amino-1-methyl) pyrimidinium-2-yl] thiomethyl] -6-[(1'R) -hydroxyethyl-1- Methylcarbaphen-2-m-3-carboxylate

Ib: (1S, 5R, 6S) -2-[(1,4-diaminopyrimidin-2-yl) thiomethyl-6-[(1'R) -hydroxyethyl] -1-methylcarbafen -2-m-3-carboxylate

Ic: (1S, 5R, 6S) -2-[(1,4-diamino-6,7-dihydro-5H-cyclopentapyrimidin-2-yl) thiomethyl] -6-[(1 ' R) -hydroxyethyl-1-methylcarbafen-2-m-3-carboxylate

Id: (1S, 5R, 6S) -2-[(1,4-diamino-5,6,7.8-tetrahydroquinazolinium-2-yl) thiomethyl] -6-[(1'R) -hydrate Roxyethyl-1-methylcarbafen-2-m-3-carboxylate

Ie: (1S, 5R, 6S) -2-[(4-amino-1-methyl-lH-pyrido [2.3-d] pyrimidin-2-yl) thiomethyl-6-[(1'R) -Hydroxyethyl-1-methylcarbaphen-2-m-3-carboxylate

General formula (I) compounds and their nontoxic salts (preferably alkali metal salts, alkaline metal salts, organic salts, salts with inorganic and organic acid salts or amino acids) according to the present invention are a wide variety of pathogenic bacteria, including various Gram-positive and negative bacteria. It has a high antimicrobial activity against and is useful for the treatment of bacterial infections in animals including humans. The usefulness was evaluated by obtaining the minimum inhibitor concentration (Minimum Inhibitoru Concentration) for the standard strain using the known compound Meropenem as a control drug. The minimum inhibitory concentration was obtained by diluting the test compound by a 2-fold dilution method, dispersing it in Muller Hinton Agar medium, and then inoculating 2 m1 of the test strain having 10 ⁷ CFU per m1, and then inoculating 20 at 37 ° C. Obtained by time incubation, the results are shown in Table 1.

As shown in Table 1, the compounds of (I-a) to (I-e) show excellent antimicrobial activity against the MRSA strains that are recently in question.

Table 1. Minimum Inhibitory Concentrations of Test and Control Compounds.

In the following Examples, the method for preparing Compound (I) of the present invention will be described in detail.

Example-1

(A) Allyl (1S, 5R, 6S) -2-[[(4-amino-1-methyl) pyrimidinium-2-yl] thiomethyl] -6-[(1'R)-

(Allyloxycarbonyloxy) ethyl-1-methylcarbafen-2-m-3-carboxylate

Allyl (1S, 5R, 6S) -2-[(diphenyloxyphosphoryloxy) methyl] -6-[(1'R)-(allyloxycarbonyloxy) ethyl] -1-methylcarbafen-2- M-3-carboxylate (480 mg, 0.8 mmol) is dissolved in anhydrous dimethylformamide (3 ml), followed by addition of sodium iodide (1.3 equiv). To this was slowly added dropwise 4-amino-1-methyl-2 (1H) -pyrimidinethiol (2 equiv) dissolved in dimethylformamide (4 ml). After stirring at 25 ° C. for 2 hours, distillation under reduced pressure and purification by column chromatography yielded the title compound (335 mg, 0.54 mmol) (yield: 68%).

(B) (1S, 5R, 6S) -2-[[(4-amino-1-methyl) pyrimidinium-2-yl] thiomethyl] -6-[(1'R) -hydroxyethyl]- 1-methylcarbaphen-2-m-3-carboxylate (Ia)

Example 1 (A) Compound (500mg, 0.81mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 4.4 equivalents) synthesized in dimethylformamide (2ml) under nitrogen Dissolve in dichloromethane (2 ml), and then slowly add dropwise tetrakis (triphenylphosphine) paladum (0) (0.2 equiv) dissolved in dichloromethane (3 ml). The light was blocked in the reactor and stirred for 3 hours, after which ethyl acetate was added to form a precipitate. The precipitate is filtered and washed with dichloromethane and ether to give the title compound (237 mg, 0.65 mmol) as an off-white solid (yield: 80%).

Example 2

(A) Allyl (1S, 5R, 6S) -2-[(1,4-diaminopyrimidin-2-yl) thiomethyl] -6-[(1'R)-(allyloxy carbonyloxy) Ethyl] -1-methylcarbaphen-2-m-3-carboxylate

Example 1 In the same manner as in (A), allyl (1S, 5R, 6S) -2-[(diphenyloxyphosphoryloxy) methyl] -6-[(1'R)-(allyloxycarbonyloxy) The desired title compound is obtained from ethyl] -1-methylcarbafen-2-m-3-carboxylate and 1,4-diamino-2 (1H) -pyrimidinethione.

(B) (1S, 5R, 6S) -2-[(l, 4-diaminopyrimidin-2-yl) thiomethyl] -6-[(1, R) -hydroxyethyl] -1-methyl Carbafen-2-m-3-carboxylate (Ib)

From the compound synthesized in Example 2 (a) in a similar manner to Example 1 (b)

Get the desired title compound,

Example 3

(A) Allyl (1S, 5R, 6S) -2-[(1,4-diamino-6,7-dihydro-5H-cyclopentapyrimidin-2-yl) thiomethyl] -6-[( I'R)-(allyloxycarbonyloxy) ethyl-1-methylcarbafen-2-m-3-carboxylate

Example 1 In the same manner as in (A), allyl (1S, 5R, 6S) -2-[(diphenyloxyphospho

Ryloxy) methyl-6-[(IR ')-(allyloxycarbonyloxy) ethyl-1-methylcarbaphen-2-m-3-carboxyl

From the rate and 1,4-diamino-1,5,6,7-tetrahydrocyclopentapyrimidin-2-thione the desired title compound is obtained.

(B) (1S, 5R, 6S) -2-[(1,4-diamino-6,7-dihydro-5H-cyclopentapyrimidinin-2-yl) thiomethyl] -6-[(1 'R) -hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate (Ic)

In a similar manner to Example 1 (b). Example 3 The desired title compound is obtained from the compound synthesized in (a).

Example 4

(A) Allyl (1S, 5R, 6S) -2-[(1,4-diamino-5,6,7,8-tetrahydroquinazolinium-2-yl) thiomethyl] -6-[(1 ' R)-(allyloxycarbonyloxy) ethyl] -1-methylcarbafen-2-m-3-carboxylate

Example 1 In the same manner as in (A), allyl (1S, 5R, 6S) -2-[(diphenyloxyphospho

Ryloxy) methyl] -6-[(1'R)-(allyloxycarbonyloxy) ethyl-1-methyl carbafen-2-m-3-carboxylate and 1,4-diamino-5,6 From 7,8-tetrahydro-1H-quinazolin-2-thione the desired title compound is obtained.

(B) (1S, 5R, 6S) -2-[(1,4-diamino-5,6,7,8-tetrahydroquinazolin-2-yl) thiomethyl] -6-[(1'R ) -Hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate (Id)

From the compound synthesized in Example 4 (a) in a similar manner to Example 1 (b)

Obtain the desired title compound.

Example 5

(A) allyl (1S, 5R, 6S) -2-[(4-amino-1-methyl-1H-pyrido [2.3-d] pyrimidin-2-yl)

Thiomethyl] -6-[(1'R)-(allyloxycarbonyloxy) ethyl] -1-methylcarbafen-2-m-3-carboxylate

Example 1 Allyl (1S, 5R, 6S) -2-[(diphenyloxyphosphoryloxy) methyl] -6-[(1'R)-(allyloxycarbonyloxy) ethyl ] -1-methylcarbaphen-2-m-3-carboxyl

From the rate and 4-amino-1-methyl-lH-pyrido [2.3-d-pyrimidine-2-thione the desired title compound is obtained.

(B) (1S, 5R, 6S) -2-[(4-amino-1-methyl-1H-pyrido [2.3-d] pyrimidin-2-yl) thiomethyl] -6-[(1 ' R) -hydroxyethyl-1-methylcarbafen-2-m-3-carboxylate (Ie)

In a similar manner to Example 1 (b), the desired title compound is obtained from the compound synthesized in Example 5 (a).

[Production example]

Allyl (1S, 5R, 6S) -2-[(diphenyloxyphosphoryloxy) methyl] -6-[(1'R)-(allyloxycarbonyloxy) as starting materials from Examples 1-5 Ethyl] -1-methylcarbafen-2-m-3-carboxylate is obtained by the following method. Allyl (1S, 5R, 6S) -2-hydroxymethyl-6-[(1'R)-(allyloxycarbonyloxy) ethyl] -1-methylcarbafen-2-m-3-carboxylate ( 284 mg) was dissolved in anhydrous dichloromethane (4 ml), followed by the dropwise addition of dimethylaminopyridine (1.2 equiv) at -78 ° C, followed by the slow addition of diphenylchlorophosphate (1.1 equiv). Stir for 30 min at −78 ° C., dilute with ethyl acetate (30 ml) and wash twice with ammonium chloride solution. The organic layer was dried over magnesium sulfate, filtered and distilled under reduced pressure, and then allyl (1S, 5R.6S) -2-[(diphenyloxyphosphoryloxy) methyl-6-[(1 / R)-(allyloxycarboxe) Bonyloxy) ethyl-1-methylcarbaphen-2-m-3-carboxylate (435 mg) is obtained.

Claims (4)

The carbapenem compound represented by the following general formula (I), a pharmaceutically acceptable nontoxic salt thereof, or an isomer thereof. Where R ¹ represents a 1-hydroxy lower alkyl group, R ² represents hydrogen or a lower alkyl group, R ⁴ represents hydrogen, lower alkyl group or amino group, R ⁵ and R ⁶ each independently represent hydrogen or a C _3-7 cycloalkyl group, or together with the carbon atoms to which they are attached may form a saturated or unsaturated 5-6 membered ring containing one or two nitrogen atoms; have. The compound of claim 1, wherein R ¹ is 1-hydroxyethyl. The compound of claim 1, wherein R ² is hydrogen or methyl. The compound according to claim 1, wherein the compound of formula (I) is selected from the following (I-a) to (I-e), or a pharmaceutically acceptable non-toxic salt thereof or an isomer thereof. Ia: (1S, 5R, 6S) -2-[[(4-amino-1-methyl)] pyrimidinium-2-yl] thiomethyl] -6-[(1'R) -hydroxyethyl]- 1-methylcarbaphen-2-m-3-carboxylate Ib: (1S, 5R, 6S) -2-[(1,4-diaminopyrimidin-2-yl) thiomethyl] -6-[(1'R) -hydroxyethyl] -1-methylcarba Phen-2-m-3-carboxylate Ic: (1S, 5R, 6S) -2-[(1,4-diamino-6,7-dihydro-5H-cyclopentapyrimidinium-2-yl] thiomethyl] -6-[(1 'R) -hydroxyethyl] -1-methylcarbafen-2-m-3-carboxylate Id: (1S, 5R, 6S) -2-[(1,4-diamino-5,6,7,8tetrahydroquinazolinium-2-yl) thiomethyl] -6-[(1'R)- Hydroxyethyl] -1-methylcarbaphen-2-m-3-carboxylate Ie: (1S, 5R, 6S) -2-[(4-amino-1-methyl-1H-pyrido [2.3-d] pyrimidin-2-yl) thiomethyl] -6- [(1'R ) -Hydroxyethyl] -1-methylcarbaphen-2-m-3-carboxylate