JPS63310889A - 6-alkylthio-carbapenem derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> and R<2> are lower alkyl; R<3> is azetidinyl or pyrrolidinyl; (non)substituted alkyl]. EXAMPLE:A compound shown by formula II. USE:Providing a carbapenem compound having strongly antibacterial activity, inhibitory action on alpha-lactamase and excellent resistance to kidney dehydropeptidase. PREPARATION:A bicyclic keto-carboxylic acid compound shown by formula III (R<4> is carboxy protecting group) is treated with a reactive derivative and further with a mercapto reagent and then the protecting groups such as R<4>, etc., are removed.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field 1] The present invention relates to carbapenem antibiotics, and more specifically, an alkyl group in the β-configuration is introduced at the 1st position of the carbapenem skeleton, and an alkylthio group or an alkylthio group is further introduced at the 6th position. The present invention relates to a 6-furkylthio-carbapenem derivative into which an S-oxide group has been introduced.

[Prior Art and Problems] Many carbapenem antibiotics have been proposed for various antibacterial activities, which have Calper 2-benem-3-carboxylic acid as a basic skeleton represented by the following formula (): .

For example, early carbapenem antibiotics were developed from Streptomyces ca.
It is a natural white rice carpabenem compound such as chenamycin represented by the following formula (B) obtained by fermentation of A. ttleya). Chenamycin has an excellent antibacterial spectrum against a wide range of Gram-negative bacteria and Gram-negative bacteria, and was expected to be developed as a highly useful compound. This has not yet been achieved.

Therefore, many researchers have made efforts to develop a carbapenem compound represented by the above formula that retains the antibacterial activity of chenamycin and has ensured its chemical stability. Imipene (INN), represented by the following formula (), in which the 7-mino group of is formimidoylated, has appeared as a practical antibacterial agent.

However, although imibenem represented by the above formula (C) shows superior antibacterial activity to chenamycin and has a certain degree of chemical stability, it cannot be degraded and inactivated by renal dehydropeptidase (DHP) in vivo. It has the disadvantage that it occurs within a short period of time. Therefore, imibenem cannot be administered alone, and D H
It must be used in combination with a P inhibitor to suppress its decomposition and inactivation. Therefore, a practical formulation of this compound is cilastatin (c i
It is a combination prescription of imipenem/cilascutin used in combination with Iastatin (INN).

However, as a practical antibacterial agent used clinically, it is preferable that the antibacterial agent's original antibacterial activity be exhibited as is, and the DHP inhibitor used in combination may cause undesirable side effects in other tissues in the body. Needless to say, it is better to avoid combination prescriptions as much as possible, as there may be risks. Therefore, at the same time as antibacterial activity, D
There is a strong need for the development of carbapenem compounds that also possess resistance to HP.

Recently, various 1-methyl-rubapenem compounds, in which a methyl group is introduced into the 1-position of the carbapenem skeleton, have been proposed as ways to achieve the above-mentioned objectives. It has been reported that the resistance to decomposition and inactivation has been significantly improved and that it is highly useful.

The above-mentioned carbapenem compounds are all compounds in which a hydroxyethyl group is introduced at the 6-position of carper 2-penem-3-carboxylic acid represented by the above formula [A], and are basically carbapenem antibiotics derived from natural white rice. It belongs to the series of substances.

The present inventors investigated the search for new carbapenem compounds based on a concept completely different from those of the natural white rice series 6-(hydroxyethyl)-lupapenem compounds, and found that the 6-position substituent of the carbapenem skeleton The present inventors have newly discovered that a compound having an alkylthio group introduced therein and a β-configured alkyl group introduced into the 1-position has excellent antibacterial activity, and has completed the present invention.

Means for Solving Problem E 1 The present invention provides a carbapenem compound that has strong antibacterial activity, β-lactamase inhibitory action, etc., and has excellent resistance to renal dehydropeptidase. relates to a carbapenem compound in which the 1st position is substituted with lower alkyl in the β-configuration and a furkylthio group is introduced into the 6th position, which has not been studied in detail so far.

That is, the present invention provides the following formula (I): In the formula, R1 and R2 represent a lower alkyl group, and % R
3 represents an azetidinyl group, a pyrrolidinyl group, or a substituted or unsubstituted alkyl group, 6-furkylthio-carbapenem derivatives, their S-oxides, and pharmacologically acceptable salts thereof are provided.

The carbapenem compound represented by the formula (1) provided by the present invention can basically be produced by the method described below.

Reaction formula A: (n) (III) (■)
(1) (I-a) In the formula, R'%R2 and R3 are as defined above, R4 represents a carboxy protecting group, and Ra represents an acyl group.

That is, a reactive derivative of RaOH is reacted with a bicyclic ketocarposi acid compound represented by the formula (1) to form a compound represented by 2 (2), and then a mercapto reagent represented by the following formula (%) is added to the compound (2) (2). The compound represented by the formula (■) is obtained by reaction, and then, if a protecting group exists on the protecting group R4 or the substituent R', these protecting groups are also removed from the compound to obtain the compound represented by the formula (■) of the present invention. The carbapenem compound represented by Formula 1-a can be derived by converting this compound into an S-oxide compound.

Incidentally, the compound represented by the formula (2) which is the starting compound in this Reaction Formula A can be produced according to the method shown in Reaction Acid B below.

■Looking hawkishly (V) (■) (■)
(■) (IK) (il) In the formula, R1, R2 and R4 are as defined above, and R5 represents a protecting group for the amine 7 group.

That is, it has already been proposed by the present inventors (Japanese Unexamined Patent Publication No. 62
-53986), using as a starting material a compound represented by the formula (1), a flukylthio group is introduced into the 3-position of this azetidinone skeleton to form a compound represented by the formula (1), and then an amino Seven protecting groups R8 were removed to obtain a compound represented by formula (1), and then M g was added to this compound (2).
(00CCHzCOOR4)2 to form a compound represented by the formula (2). Next, the compound of formula (1) is reacted with an at compound in the presence of a base to form a diazo compound (2), and then a cyclization reaction is carried out in the presence of a metal catalyst to produce a compound of formula (2).

In this specification, the term "lower" means that the group or compound to which this term is attached has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.

The "lower alkyl group" may be linear or branched and preferably have 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, 5ee-butyl, tert-butyl, n-pentyl, isopentyl, n
-Hexyl, isohexyl groups, etc. are included.

Examples of the "carboxyl protecting group" include ester residues, such as methyl, ethyl, n-propyl, inpropyl, n 1
Lower alkyl ester residues such as jSO+See, tert-butyl, n-hexyl ester; pencil, p
- 7-aralkyl ester residues such as nitrobenzyl, 0-nitrobenol, p-methoxybenzyl; acetoxymethyl, propionyloxymethyl, n~? ;So w
Examples include lower aliphatic acyloxymethyl residues such as butyryloxymethyl and pivaloyloxymethyl.

In addition, "the acyl group J includes not only the atomic group remaining after removing OH from the carboxyl group of an organic carboxylic acid, but also includes, in a broad sense, an acyl group derived from an organic sulfonic acid or an organic phosphoric acid, for example. Lower alkanoyl groups such as acetyl, propionyl, butyryl; (halo)lower alkylsulfonyl groups such as methanesulfonyl and triple olomethanesulfonyl; benzenesulfonyl, p-nitrobenzenesulfonyl, p-7' lomobenzenesulfonyl, toluenesulfonyl, 2, Examples include substituted or unsubstituted 7-arylsulfonyl groups such as 4.6-dolyisobrobylbenzenesulfonyl; diphenylphosulfonyl groups, and the like.

Hereinafter, each step of producing the carbapenem compound represented by Formula I of the present invention represented by Reaction Formulas B and A will be explained in more detail.

Step (a) is to react the azetinone compound represented by the formula (■) with a flukylthiosulfonic acid ester in the presence of an alkyl metal catalyst to introduce a flukylthio group into the 4-position of the azetidinone skeleton, and to form the compound represented by the formula (■). In the 0 reaction, which is the process of obtaining, for example, ethers such as noethyl ether and tetrahydrofuran; hydrocarbons such as toluene, xylene, and cyclohexane; and halogenated hydrocarbons such as dichloromethane and chloroform, in a solvent inert to the reaction. etc., can be carried out particularly preferably in tetrahydro 7 run. Further, the reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, etc., but is generally about -100°C to about room temperature,
Preferably relatively low temperatures of about -78°C to about O'C are used.

This reaction is carried out in the presence of an alkyl metal catalyst, such as pritilithium, lithium diisopropylamide, etc., and these catalysts are generally used in an amount of about 2 to 3 molar equivalents per mole of compound .2~2
．． This results in a ratio of 5 equivalents being used. Further, as the alkylthiosulfonic acid ester used in the reaction, the substituent RIS of the carbapenem compound represented by formula I of the present invention is
- may be selected from various sources, and the following may be exemplified.

Methyl methanethiosulfonate or ethyl ester ethyl ethyl ester Methyl or ethyl ester n-propylthiosulfonate Methyl or ethyl ester n-propylthiosulfonate Methyl or ethyl ester lso-propylthiosulfonate Methyl or ethyl ethyl ethyl thiosulfonate lso-butylthiosulfone Methyl or ethyl acid ester QeC-Butylthiosulfone ester methyl or ethyl tert-butylthiosulfonate Step (b) involves converting the protecting group R5 of the 7-mino group of the compound represented by the formula (■) obtained in step (a) with an acid. This step is to obtain a compound represented by formula (1).

In this case, the protecting group R5 of the amine 7 group in the compound of formula (1)
tert-butyldimethylsilyl group is preferably commonly used, and such removal of R5 can be carried out using methanol, ethanol, acetonitrile, tetrahydro7
Hydrochloric acid, sulfuric acid, etc.
0 to 100° in the presence of an acid such as hydroturic acid or acetic acid.
0 at a temperature of C.

It can be subjected to acidic hydrolysis for 5 to 18 hours.

Through the darning step, the desired compound represented by formula (2) can be quantitatively obtained.

Step (c) is to react the azetino-7 compound represented by the formula (1) produced in the step (b) with a magnesium malonate compound represented by the formula (R'00CCHzCOz)2Mg in the presence of imidazole, to form a compound of the formula This is a step to obtain the compound represented by (2).

The reaction is preferably carried out in an inert organic solvent, such as ether solvents such as ether, tetrahydro7rane, and dioxane; hydrocarbon solvents such as toluene, xylene, and cyclohexane; and halogenated hydrocarbon solvents such as nochloromethane and chloroform. ; Although acetonitrile and the like can be mentioned, tetrahydrofuran is particularly preferably used.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but is generally about 0°C to about 100°C, preferably 50 to 70°C.
Temperatures in °C are used.

The amount of magnesium malonate compound to be used is approximately equimolar to the compound of formula (1), and the reaction is completed in about 50 hours, preferably about 20 hours.

The magnesium malonate compound to be used is, for example, paranitrobennormagnesi! Among them, valanitropennormagnesium malonate is preferably used.

In step (d), the compound represented by the formula (■) obtained in step (c) is treated with an azide compound in the same inert organic solvent as described in step (b) in the presence of a base to achieve the desired A noazo compound of formula (2) is obtained.

Examples of the azide compounds used include p-carboxybenzenesulfonyl azide, toluenesulfonyl azide, methanesulfonyl azide, dodecylbenzenesulfonyl azide, and bases such as triethylamine, pyrinone, and diethylamine. can be exemplified.

The reaction is preferably carried out in 7setonitrile in the presence of triethylamine by adding 9-)luenesulfonyl azide and
This can be carried out by treating at ~100° C., preferably at room temperature, for 1 to 50 hours, thereby making it possible to obtain the desired noazo compound of formula (2) in high yield.

Step (e) is a step in which the noazo compound of formula (1) obtained in step (d) is cyclized to form a compound represented by formula X. The process suitably comprises, for example, preparing a compound of formula (1) in an inert solvent such as benzene, toluene, tetrahydro7rane, cyclohexane, dithyl acetate, nochloromethane, etc., preferably in toluene, at a temperature of 25 to 110°C. In 1
~5 hours, bis(acetylacetonato)Cu(■), C
It is carried out by treatment in the presence of a metal catalyst such as a metal carboxylate compound such as U5O, copper powder, Rh2(OCOCH3), rhodium octanoate or Pb(OCOCH,). On the other hand, as another method,
The above cyclization step also involves passing the compound of formula (1) through a Pyrex filter (wavelength is 300n-up) in a solvent such as benzene, noethyl ether, etc. at a temperature of 0-250°C for 0.5-2 hours. It can also be carried out by irradiating light.

In this way, a bicyclic compound represented by the formula (■) shown in Reaction Formula B can be obtained. Next, the compound (2) is induced into a compound represented by the formula I, which is a carbapenem compound of the present invention, according to the production process shown in Reaction Formula A. be done. To explain the details of these steps, step (f) involves reacting the compound of formula (1) produced according to reaction formula B with a reactive derivative of the acid represented by RaOH (e.g., acid anhydride, halide, etc.). gives a compound of formula I[r.

Reactive derivatives of such acids include, for example, acetic anhydride,
acetyl chloride, probionyl chloride)', p-) luenesulfonic anhydride'kJ, p-nitrobenzenesulfonic anhydride, 2,4.6-) lyisopropylbenzenesulfonic anhydride, methanesulfonic anhydride, trifluoro Examples include lomethanesulfonic anhydride, nophenylphosphoryl chloride, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, and diphenylphosphoryl chloride (Ra = minidiphenylphosphoryl) is particularly preferred.

The reaction of a compound of formula (U) with a reactive derivative of the above acid is
It can be carried out in the same manner as the usual acylation method, for example, using a base such as diisopropylethylamine, triethylamine, 4-tumethylaminopyridine, etc. in an inert solvent such as methylene chloride, 7-cetotril, dimethylformamide, etc. in the presence of about 3
This can be done by treating for 0 minutes to about 24 hours.

In step (g), the compound represented by formula (2) obtained in step (f) above is reacted with a mercapto reagent represented by formula: R'-8H to obtain a compound represented by formula (2). In this case, the reaction with the mercapto reagent is, for example, a compound represented by the formula (■),
In a suitable solvent such as tetrahydro7rane, dichloromethane, dioxane, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., an approximately equimolar amount to about 1.5 times molar excess of the formula: R' -8H and preferably in the presence of sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine base.
This can be carried out by reacting at a temperature in the range of about 25° C. for about 30 minutes to about 24 hours.

The above reaction yields a carbapenem compound represented by formula (1), but this compound (2) may have a protecting group for the amino group in the side chain substituent at the 2-position, and also has a carboxylic acid at the 3-position. is protected with carboxy protecting group R4. Removal of these protecting groups can be carried out by deprotecting group reactions known per se, such as solvolysis or hydrogenolysis. Typically, the compound represented by 2) is prepared using tetrahydro-7 containing, for example, morpholinopropanesulfonic acid-hydroxylated at pH 7, phosphate buffer at pH 7, dipotassium phosphate, sodium bicarbonate, etc. Using 1 to 4 atmospheres of hydrogen in a mixed solvent such as Ran-water, tetrahydro-7 Ranan-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, etc., platinum oxide, palladium-activated carbon , in the presence of a hydrogenation catalyst such as palladium hydroxide-activated carbon, from about O to about 5
This can be done by treating at a temperature in the range of 0°C for about 0.25 to about 4 hours.

(The carbapenem compound represented by formula I of the present invention can be obtained by doing this, but in the carbapenem compound represented by formula 1, the substituent at the 6-position is a furkylthio group,
This can be converted into the S-oxide compound Q&I (1-a) by treatment with a peroxide compound.

The carbapenem compound of the present invention produced as described above may be prepared according to methods known per se, if necessary, into pharmacologically acceptable salts, such as alkali metal salts such as sodium salts and potassium salts; arginine salts, ornithine salts; , basic amino acid salts such as lysine salts, and amine salts such as diethanolamine salts and triethanolamine salts. Particularly preferred salts are the sodium and potassium salts.

As already mentioned, the carbapenem compound represented by the formula I of the present invention or a pharmacologically acceptable salt thereof is a novel compound that has not been specifically disclosed in the conventional literature, and is a dehydrobeptine compound. It has been found that it is extremely stable against attack by a renal enzyme known as DHP and has excellent antibacterial activity. The excellent action of the compound represented by formula (1) or its salt provided by the present invention can be demonstrated by the biological activity test shown below.

I: Select AjU1 Wipe JLIL: Japanese Society of Chemotherapy Standard Method [Chemotherapy
The agar plate dilution method was carried out according to J. T. Vol. 129, 76-79 (1981)]. That is, M of the test bacteria
uel Ier-Hinton (Ml) agar liquid medium 3
7℃, -night culture 1! Add Buffered saline gelatin to approximately 10'cells/d.
(BSG) solution, and seeded about 5 μ2#c on MH agar medium containing test compound using a microplanter, and added 37
After 18 hours of incubation at
concentration (MIC).

In addition, a standard strain was used as the strain used.

1-1: It is shown in Table 1 below.

Note that compounds (17), (19), and (21) described in Examples below were used as test compounds of the present invention.

The results show that the carbapenem compound of the present invention has excellent antibacterial activity.

The carbapenem compound of the present invention exhibits a broad antibacterial spectrum, has excellent resistance to DI (P), and has excellent antibacterial effects against clinically active pathogens, as well as effective protection against infection in mice. In tests, it was observed that it showed good effects against various test bacteria.

Therefore, the carbapenem compound represented by formula I of the present invention and its pharmacologically acceptable salts can be used in clinical treatment as a practical antibacterial agent only when the conventional imibenem is combined with cilastatin, a DHP inhibitor. In contrast, it has become possible to use it alone, and there is no concern about side effects when used in combination with DHP inhibitors. It is extremely useful as a

When used as an antibacterial agent, the carbapenem compound of formula I and its pharmacologically acceptable salts can be used in humans, including humans, in the form of a pharmaceutical composition containing an antibacterially effective amount thereof. can be administered to feeder animals.

The dosage can vary over a wide range depending on the age, weight, symptoms of the patient to be treated, the form of administration of the drug, the doctor's diagnosis, etc., but in general, for adults it is about 200 to about Doses within the range of 3w000+mg are standard and can be administered orally, parenterally or topically, usually in single or divided doses per day.

The above pharmaceutical compositions may thus be prepared using inorganic or organic solid or liquid pharmaceutical carriers or diluents customary in the formulation of pharmaceuticals, especially antibiotics, such as starch, lactose, sucrose, crystalline sugar, etc. Excipients such as cellulose and calcium hydrogen phosphate; binders such as acacia, hydroxypropylcellulose, alginic acid, gelatin, and polyvinylpyrrolidone; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc, and hydrogenated vegetable oil; Disintegrants such as modified starch, calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; and solubilizing agents such as nonionic surfactants and anionic surfactants, as well as oral, parenteral, or local administration. It can be formulated into a dosage form suitable for. Dosage forms suitable for oral administration include solid preparations such as tablets, coatings, capsules, troches, powders, fine granules, granules, and dry syrups, and liquid preparations such as syrups. Dosage forms suitable for administration include, for example, injections, drips, suppositories, and the like.

Dosage forms suitable for topical administration also include ointments, tinctures, creams, gels, and the like. These formulations can be prepared by methods well known per se in the field of pharmaceutical sciences.

The carbapenem compounds and salts thereof of the present invention are preferably administered parenterally, particularly in the form of injections.

[Example] Next, the production of the carbapenem compound of the present invention will be explained in more detail with reference to Examples.

Note that the symbols in each example have the following meanings.

ph: phenyl group PNB: paranitrobenol group PNZ: paranitrobenzyloxycarbonyl group -
si: t-butyldimethylsilyl group to c-niacetyl group Et: ethyl group Example 1 S[Tri7late 84.1. was dissolved in anhydrous tetrahydro 7ran 260 Yen 1 and cooled to -40 to -50°C,
N-ethylpiperidine 29.3il and 1 compound (2)
A solution of 31.9 g of anhydrous tetrahydro 7 run in 130 ml was added, and the mixture was stirred at the same temperature for 4 hours.

Next, 18.06 g of compound (1) anhydrous tetrahydro 7
Add Lan 751 solution and stir at O'C for 1 hour. After the reaction is complete, add 1 ml of 0.1 MIJ acid buffer with pH 7.0 to the reaction solution. was added, diluted with 2 g of ethyl acetate, and filtered through Celite. The furnace solution was washed successively with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, and dried over tetralim sulfate. The solvent was distilled off, and the residue was purified by silica sol chromatography (eluted with nochloromethane:ethyl acetate = 6:1).
34.2 g (90%) of compound (3) was obtained.

Yellow needle crystals IR(CHCL) cm-': 1 7 6 0 with a melting point of 121-122°C
, 168 ONMR (CDCh) δ: 1.01 (3H,
L), 1.24 (38%d), 1466-2.10 (2
H, Kasu), 2.73-3.2 0 (3H, Import), 3
, 44-3 , 6 5 (1) Kashi, -), 3.90-
4.05 (I H, Is), 4.85-5°30 (2H
Sm), 6.20 (I H, bs) Example 2: Compound (3) obtained in Example 1 4.05. A solution of 4.47% of monobutyldimethylsilyl chloride was cooled with water to a solution of 1511% of anhydrous dimethylformamide. and triethylamine 8.3 theory 1 were added and stirred at the same temperature for 0.5 hour. After the reaction was completed, extraction was carried out with ethyl acetate, the solvent was washed, dried and distilled off, and the residue was applied to silica sol 20 (eluted with hexane:ethyl acetate = 7:3) to obtain compound (4) with a melting point of 94-9.
5.75 as a yellow prism product at 5°C. Obtained.

IR(CHC1=)am-':1735.1705N
M R (COC13) δ: 0.20 (3HSs), 0
．． 26 (3HSs), 0.95 (9HSs), 1.02
(3H, t), 1.25 (3HSt) Example 3: 37.3 g of compound (4) obtained in Example 2 and 26.4 B of imidazole were dissolved in 40 Owl of anhydrous tetrahydro-7 run, and stirred at room temperature for 5 hours. do. Next, 12 ml of a 10% aqueous citric acid solution was added, and after vigorous stirring, 200 g of common salt was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the sodium sulfate, the solvent was distilled off, and the residue was chromatographed on silica gel (eluted with a solution of nochloromethane and acetone) to obtain a melting point of 12.
19. Compound (5) as colorless needle crystals at 8-129°C.
058 (76%) was obtained.

IR(CHCI3)cll-':173 ONMR
(CDCI,) δ: 0.22 (3H, s), 0.27
(3H,s), 0.97 (9g%s), 1.18 (3H
, d) Example 4: 28.5 ml of a hexane solution of 1.55 M n-butyllithium was added to a solution of 6.21 noisoprobylamine in 1001 anhydrous tetrahydro7ran under cooling with water, and the mixture was heated at the same temperature for 15 min.
Agitate for minutes. Then, it was cooled to -78°C, and 5.14 g of the compound (5) obtained in Example 3 was added to
001 solution was added over a period of 2 hours and stirred for 1 hour. Next, 3.1 ml of methyl methanesulfone) was added and stirred at the same temperature for 0.5 hours and at 0°C for 2 hours. After the completion of the reaction, 10% citric acid aqueous solution was added, extracted with ethyl acetate, washed with water, After drying the Glauber's salt, the solvent is distilled off. The residue was subjected to silica sol chromatography (eluted with a mixture of 7 tons of nochloromethane and dichloromethane) to obtain 5.93 g (98%) of compound (6) as colorless crystals with a temperature of 71 to 72°C.

IR(CHCI,) cm-': 1740. 175
ONMR (CDCI3) δ: 0.20 (3H, s), 0
．． 28 (3H, s), 0.93 (9H, s), 1.25
(3H, d), 2.17 (3H, s), 2.98 (I
H), 3.54 (IH), 4.34 (IH).

Elemental analysis: C13H2SN O3S iS calculated value: C:
51.46; H: 8.31; N: 4.62 Experimental value:
C: 51.60; H: 8,31: N: 4,68 Example 5
: 5.59 g of the compound (6) obtained in Example 4 was mixed with 50% of a 40% aqueous solution of hydrofluoric acid and acetonitrile (7:96).
ial mixture and stirred at room temperature for 2 hours.

After the reaction was completed, the reaction solution was extracted with ethyl acetate, washed with water, dried with sodium sulfate, and then the solvent was distilled off. The residue was recrystallized from chloroform-hexane to obtain compound (7) with a melting point of 125-126°C.
2.91 g (84%) of foliar crystals were obtained.

IR(CHCl,)cm-': 1740.1705
NMR(CDCIs)δ: 1.24(3H,
d), 2.12 (3H,S) Example 6: 2.91 g of the compound (7) obtained in Example 5 and N.

A solution of 3.0 g of N'-carbonylciimiguzole in 155 mol of anhydrous tetrahydro7rane was stirred at room temperature for 7 hours. Mg(02CCH2CO-P'N B )2 in the reaction solution
11.68 was added and stirred at 55-60°C for 22 hours. After the reaction is completed, the reaction solution is filtered through Celite, and the furnace solution is reduced to 10%.
Citric acid aqueous solution, saturated hydrogen carbonate) +7um aqueous solution,
Wash sequentially with brine, dry with Glauber's salt, and evaporate the solvent. The residue was subjected to silica gel chromatography (elution with chloromethane:ethyl acetate = 7:3) to obtain 3.42 g (61%) of compound (8) as a colorless oil.

I R (Nujol) cm-': 1 7 6 5
, 1740, 171N M R (CD CIs)
δ: 1.25 (3H, d), 2.17 (3H, s), 3
．． 04 (I H), 3.67 (2'H,s), 3.7
4 (I H), 5.29 (2H, d), 7.54.8
゜24 (4H1 aromatic ring proton) M ass (M / Z ) 366 (M '') Example 7: N2 3.42 g of the compound (8) obtained in Example 6 and 2.70 g of p-)rienesulfonyl azide Acetonitrile 28
ml, water-cooled water triethylamine 1°30-1 was added thereto, and the mixture was stirred at the same temperature for 1.5 hours. After the reaction was completed, the solvent was distilled off, and the residue was subjected to silica sol chromatography (elution with benzene:ethyl acetate = 2:1) to give 3.55 g (97 g) of compound (9) as colorless needle crystals with a melting point of 101°C. %)Obtained.

IR(CHCl5)can-': 2150.17
75.17NMR (CDCI3) δ: 1.21 (3H
, d), 2.18 (3HSs), 5.36 (2HSs)
, 7.54.8.25 (4H, aromatic ring proton) Example 8: Compound (9) 39+ag obtained in Example 7 was dissolved in one part of anhydrous benzene and placed in an oil bath at 100°C under an argon gas stream. Next, a solution of 1 mg of rhodium octanoate in 0.1 ml of chloroform is added to this solution, and the mixture is stirred at the same temperature for 1 hour. The reaction solution was concentrated, and the residue was subjected to silica gel chromatography (eluting with benzene ethyl acetate = 3:1) to obtain compound (10) as a colorless oil.
1 (71%).

IR(CHCIs)Cs-':1775.175ON
MR (CDCI,) δ: 1.32 (3H, cl), 2.
27 (3H, s) Mass (M/Z) 364 (M”) Example 9
: 36 mg of the compound (10) obtained in Example 8 above was dissolved in 0.5 mol of anhydrous acetonitrile, and while cooling with water, 25 μm of di-7-dylphosphoric acid chloride and 19 μm of diisopropylethylamine were added, and the mixture was heated to 1°5 at the same temperature. The reaction mixture was stirred for an hour, then diluted with ethyl acetate, and the organic layer was washed with 0.1 MIJ acid buffer (pH 7.0) and saline, and dried with mirabilite. The solvent was distilled off, and the residue was subjected to silica sol chromatography (eluted with benzene-ethyl acetate = 9:1) to obtain the compound (
55 mg (93%) of 11) was obtained as a colorless oil.

I R(CHCl+)am″″’: 1 7 8 5
, 1725HMR (CDCI3) δ: 1.24 (3H,
d), 2.22 (3H, s), 4.16 (I H), 4
．． 20 (IH), 5°21.5.35 (2H), 7.0
0-7.40 (IOH.

l), 7,52.8.11 (4H, aromatic ring proton) Elemental analysis value: CzaH25N 20 IS P calculation value: C
: 56.37; H: 4.23; N, 4.70 experimental value: C
,56,60;H,4,14;N,4.89 Example 10
: Compound o1) 10+1s-Q-pNz → (a) 8 mg of the compound ('11)IS obtained in Example 9 was dissolved in 1.31 g of anhydrous acetonitrile, and the solution was heated to -35°C.
While cooling, a solution of 98 mg of compound (12) in 1.3 to 1 solution of anhydrous acetonitrile and 60 mg of diisopropylethylamine was added.
Drop the μm. Next, gradually increase the reaction temperature to -10℃ with ν1 Jf4-i! -13 parts of ethyl acetate were added, and the organic layer was washed successively with pH 7.0 phosphate buffer and saline, and dried with Glauber's salt. The solvent was distilled off, and the residue was chromatographed on silica sol (eluted with benzene-ethyl butyrate = 2:1).
135mH (81%) of compound (13) was obtained as crystals with a melting point of 62-63°C.

IR(CHCL)cm-': 1780.1720
．． 17N M R (CD CI3) δ: 1,34 (3H
Sd), 1.80-2.20 (2H, m), 2.26 (
38Ss) (b) Then the compound obtained in (a) above (
13) Dissolve 425 μg in a mixture of Tetrahydro 7ran 27 pseudo 1 and 2'7++ l of water, add platinum oxide 1421, and catalytically reduce the solution under a hydrogen pressure of 3.0 kg/cva2 for 2 hours. The catalyst was separated in the furnace, the furnace liquid was washed with ether, and the aqueous layer was cooled and dried to obtain the 11-isocarboxylic acid of compound (14).

Next, this product was dissolved in an aqueous solution containing 56.8 tg of sodium hydrogen carbonate, applied to an Amberly XAD-2 column, and eluted with a 10% ethanol/water mixture to give a melting point of 24.
Compound (14) as a solid at 0°C (decomposed) at 52 m
g<23%) was obtained.

IR(KBr)am-':1760.166ONM
R (D20) δ: 1,24 (3H1d), 2.19 (3
H, s), 2.20-2.70 (2H, m), 3.10
-3.80 (4H, m), 3.80~4.1 0 (2
H, m), 4.10-4.30 (I HSm), 4.4
0 <2 H, d) Mass: 315.336 Elemental analysis value: CI) H, 7N 20 s S 2 N
a-H20 calculated value: C, 44,06; H, 5,40;
N, 7.90 Experimental value: C, 44,38; H, 5,23;
N, 7.97 Example 11: Compound no+1Is-3-pNz -> 875 mg of compound (11) obtained in Example 19 and compound (15) 51
1+*g and treated in the same manner as described in Example 10 (a) and (b) to obtain compounds (16) and (17).
I got it.

Compound (16): Solid I with melting point 58-60'C
R(CHC13)cm-': 1760,
1720, 17NMR (CDC13) δ: 1.28
(3H, d), 2.26 (3HSs), 3.04-3
．． 36 (I Hlm), 3.88-4.12 (4H,■
), 4.16-4.26 (2H.

Is), 4.38-4.54 (IH,m), 5.19
(2H.

S), 5.30 & 5.48 (2H, Q), 7.49.7
゜66.8.22 (8H, aromatic ring proton) compound (1
7): Solid I R (K B
r)c+++″″’: 1760.160ONMR(D2
0) δ:1.1? (3H, d, J=7.3)2.14
(3H1s), 3.03-3.40 (IH, m), 3.
83-4.1 3 (3H1 theory), 4.17-4.45
(4H, m) Elemental analysis value: C, 2H,, N20. S2- H,0 Calculated value: C145,28; H,5,66; N, 8.81 Experimental value: C,45,57; H,5,82; N, 9.04 Example 12: Example 9 Compound (11) obtained in 59mg of N-PN
Example 10 using 32 mg of Z-glycyl-cystamine
Compounds (18) and (
19) was obtained.

Kashu Shokuchi' Uni Oil IR (CHCL) cm-': 1775.1720.
168O NMR(CD CI=)δ:1,29(3HS d
), 2.24 (3HX s), 2.72-3.28 (2
H, m), 3.28-3.79 (3H11), 3.88
(2H, cl), 4°17 (IH, s), 4.23
(I H, q), 5.20 (2HS s), 5
．． 2 7 (I H, d), 5.5 0 (I
H, d) Container C" Unisolid I R (KBr) cm-': 1745.1670.16
oON M R (D, 0) δ: 1.14 (3HSd
), 2.18 (3H, s), 2.95-3.80 (5H
, m), 3.82 (2HScl), 4.05-4.33
(2HSm) Example 13: 83 ng of the compound (13H) obtained in Example 10 (,) was dissolved in 3 volumes of ethyl acetate and cooled to -78°C.

To this, add 62% of di-4-perbenzoic acid one by one, stir at the same temperature for 11 hours, and then remove the organic layer with hydrogen carbonate.
Wash sequentially with aqueous sodium chloride solution and saline, and dry with mirabilite. The solvent was distilled off, and the residue was chromatographed on silica sol (eluted with benzene-ethyl acetate = 2:1) to obtain 127 mg (66%
)Obtained.

IR(CHCL)cu-': 1780.1705 Example 14: Added to a mixture of 314aag of compound (20) obtained in Example 13 and 105+ag of platinum oxide and 20o1 of tetrahydrofuran and 27ml of water, hydrogen pressure 3, Okg/ca
+2"C Hydrogenation was carried out for 2 hours. The catalyst was separated into a furnace, and the furnace liquid was washed with ether and freeze-dried.
The compound (
21) was obtained in an amount of 94-g (61%).

Claims (1)

[Claims] 1. The following formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 and R^2 represent a lower alkyl group,
R^3 represents an azetidinyl group, a pyrrolidinyl group, or a substituted or unsubstituted alkyl group, 6-alkylthio-carbabenem derivatives, their S-oxides, and pharmacologically acceptable salts thereof.