JPH01211589A - (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H, alkali metal or carboxyl protecting group; R<2> is (substituted)alkyl or heterocyclic]. EXAMPLE:(5S)-3-Thio-8-oxo-1-azabicyclo[3.3.0]octa-2-ene-2-carb-oxylic acid. USE:An antimicrobial agent. PREPARATION:For example, pyrrolidine-2-ones expressed by formula II (L is acyl group, etc.) is reacted with N-acetyl-1,3-thiazoline-2-thiones in the presence of tintrifrate to give a compound expressed by formula III (R<4> is H or alkyl). Then the compound expressed by formula III is treated with Mg malonates to afford a compound expressed by formula IV (R<3> is protecting group), which is then diazotized and treated with copper powder, etc., and subjected to ring closure to give a bicyclo compound expressed by formula V, which is further enolized and the enolized bicyclo compound is reacted with a mercapto reagent to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel γ-lactam compound, more specifically, the following formula (I): In the formula, R1 represents a hydrogen atom, an alkali metal or a carboxyl protecting group, and R1 is unsubstituted or (5S)-3-substituted thio-8-oxo-1-, which represents a substituted alkyl group or a heterocyclic group;
The present invention relates to azabicyclo[3,3,01 oct-2-ene-2-carboxylic acid derivatives.

Up to now, various studies have been conducted to search for antibiotics with the aim of antibacterial activity, and many antibiotics such as penicillin compounds or cephem compounds having a penicillin skeleton or cephem skeleton have been provided, and some compounds have already been investigated. is used medically as a practical antibiotic. These penicillin compounds and cephem compounds basically have a β-lactam skeleton represented by the following formula:
It is classified as a lactam antibiotic.

By the way, research into the development of the above-mentioned β-lactam antibiotics has since shown remarkable progress, and recently Calper 2-, which is represented by the following formula:
Many carbapenem antibiotics having penem-3-carboxylic acid as the basic skeleton have been proposed, and among them, imipenem (imipenew: I N
N) has now appeared as a practical antibacterial agent.

In addition to the development studies of the above-mentioned β-lactam compounds, studies have also been carried out on antibiotics having a skeleton different from the β-lactam skeleton. For example, the following formula: where X represents 10N or -So, CH,
A bicyclopyrazolidione compound represented by the following has been proposed, and it has been reported that this compound also has a certain degree of antibacterial activity (27th ICAAC, September 1987, New York).

When considering the skeleton of this bicyclopyrazolidione compound, it can be determined that the compound is basically a derivative of a γ-lactam compound represented by the following formula: It has excellent antibacterial activity even in γ-lactam compounds. Although it is expected that this series of compounds exists, the reality is that this series of compounds has not been studied very vigorously to date.

Therefore, the present inventors investigated the synthesis of a compound having a γ-lactam skeleton, and as a result, the above formula! (5S
)-3-substituted thio8-oxo-1-azabicyclo[3
, 3, 0] It was confirmed that oct-2-ene-2-carboxylic acid derivatives have antibacterial activity, and the present invention was completed.

Therefore, the present invention provides a novel γ-lactam compound having antibacterial activity and having the above formula (1), which has not been described in the conventional literature.

In the compound represented by the formula (I) provided by the present invention, the "alkali metal" that can be represented by R1 includes sodium, potassium, etc., and the F carboxyl protecting group It can be any carboxyl protecting group known in the art, and examples thereof include ester residues. Such ester residues include, for example, methyl, ethyl, n-propyl, isopropyl, n-1iso-1sec- or ter
Lower alkyl ester residues such as t-butyl and n-hexyl esters; aral alkyl ester residues such as benzyl, p-nitrobenzyl, 0-nitrobenzyl, and p-methoxybenzyl: acetoxymethyl, propionyloxymethyl, n-1IsO - or tert-butyryloxymethyl, lower aliphatic acyloxymethyl residues such as pivaloyloxymethyl, and the like.

In addition, the "alkyl group" that can be represented by Rz may be linear or branched, and is preferably a lower alkyl group having 1 to 6 carbon atoms, such as methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 5ee-butyl, t
Included are ert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups, and the like.

"Substituted alkyl group" means an alkyl group in which any position of the above "alkyl group" is substituted with one or more various substituents; examples of such substituents include:
Amino, substituted amino, amidino, imino, guanidino,
Guanidinium, sulfamoyl, ureido, amide,
Examples include mercapto, alkylthio, and arylthio.

Furthermore, the above-mentioned substituted alkyl group also includes an alkyl group substituted with a "heterocyclic group" described below.

A "heterocyclic group" is a preferably 4- to 8-membered aromatic or aliphatic cyclic group containing at least one of oxygen, nitrogen, or sulfur atoms as a heteroatom, such as azetidinyl, furyl, etc. , furfurinothienyl, pyridyl, pyrimidyl, pyrrolidinyl, piperidyl, oxazolidinyl, thiazolidinyl, thiazolyl, oxasilyl, thiadiazolyl, triazolyl, tetrazolyl, etc., and these may be bonded via a methylene chain as described above. good. Additionally, ring carbon atoms may be substituted with the substituents described above for substituted alkyl groups.

Preferred specific examples of R2 include aminoethyl group and 3-azetidin-3-yl group.

The compound represented by the formula (I) of the present invention can be basically produced according to the steps shown in Reaction Formula A below.

Reaction circle A (II) (DI) (V) (Vl) (■
) (■) ([) (X) In the above reaction formula,
L represents a leaving group such as an acyl group, R3 represents a carboxyl protecting group, R' represents a hydrogen atom or an alkyl group, and Ra represents an acyl group. Each step is shown in parentheses.

In addition, the "acyl group" represented by and R1 in the above formula
includes not only the atomic group remaining after removing OH from the carboxyl group of an organic carboxylic acid, but also, in a broad sense, acyl groups derived from organic sulfonic acids and organic phosphoric acids.
For example, lower alkanoyl groups such as acetyl, propionyl, butyryl; (halo)lower alkylsulfonyl groups such as methanesulfonyl and trifluoromethanesulfonyl groups:
Benzenesulfonyl, p-nitrobenzenesulfonyl,
p-bromobenzenesulfonyl, toluenesulfonyl,
2.4. Substituted or unsubstituted arylsulfonyl groups such as 6-triisopropylbenzenesulfonyl; diphenylphosphoryl groups, and the like.

Each step of the above reaction will be explained in more detail below.

In step (a), the N-acetyl-1,3-thiazolidine-2-thione derivative of formula (1) is reacted with tin (
■) React with triflate to produce a di-root, which is then reacted with a compound of formula (I[) to form a compound of formula (IV
) of pyrrolidin-2-one derivatives.

The enolization reaction of the N-acetyl-1,3-thiazolidine-2-thione derivative of the above formula ([[) with tin (■) triflate is usually carried out in a solvent inert to the reaction, such as diethyl ether, Ethers such as 7ran; hydrocarbons such as toluene, xylene, and cyclohexane; halogenated hydrocarbons such as dichloromethane and chloroform; and particularly, the reaction can be suitably carried out in tetrahydrofuran.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but is generally about -100°C to about room temperature, preferably about -7°C.
Relatively low temperatures of 8°C to about 0°C are used.

Although the amount of tin (■) triflate used relative to the compound of formula (I[I) is not critical, it is usually
The tin (■) triflate can be used in a ratio of about 1 to about 2 mol, preferably 1 to 1.5 mol, per mol of the compound ().

The above enolization reaction is carried out under basic conditions, and examples of bases that can be used include triethylamine, diisopropylethylamine azabicyclo[2.2.2]octane, N-methylmorpholine, N-ethylpiperidine, and pyridine. Examples include tertiary amines, among which N-ethylpiperidine is advantageously used. These bases are generally used in amounts of about . o to about 3 equivalents, preferably 1.0 to 2
．． It can be used in a proportion of 0 equivalents.

The enolization reaction can generally be completed in about 5 minutes to about 4 hours, thereby yielding erulate.

Following this enolization reaction, the resulting erulate can be directly reacted with the compound of formula (II).

The alkylation reaction between the erulate and the compound of formula (...) can generally be carried out at a temperature of about -100<0>C to about room temperature, preferably about -78<0>C to about lo<0>C. The amount of the compound of formula (III) used in this case is not critical and can be changed as appropriate, but is usually about 0.5 to about 5 It is appropriate to use it in a molar ratio, preferably 0.5 to 2 molar.

Under such conditions, the reaction can generally be completed in about 5 minutes to about 5 hours, more generally about 5 minutes to about 2 hours.

The enolization reaction and the alkylation reaction described above are preferably, but not necessarily, carried out under an inert atmosphere, such as a nitrogen gas or argon gas atmosphere.

Finally, the reaction product is washed with water. For example, after the reaction is completed, a phosphate buffer solution with a pH around 7 is added and stirred, insoluble matter is filtered off, and then the compound of formula (IV) is separated and purified by conventional methods such as extraction, recrystallization, chromatography, etc. Can be done.

Step (b) is the formula (IV) produced in step (a).
A pyrrolidin-2-one derivative represented by the above formula is reacted with a magnesium malonate compound represented by the formula (R300CCH, Go2Mg) in the presence of imidazol to form the formula (
This is a step of obtaining a compound represented by V).

The reaction is preferably carried out in an inert organic solvent, such as ether solvents such as ether, tetrahydrofuran and dioxane; hydrocarbon solvents such as toluene, xylene and cyclohexane; halogenated hydrocarbon solvents such as dichloromethane and chloroform; niacetonitrile; Among them, acetonitrile is particularly preferably used.

The reaction temperature is not strictly limited and can be varied widely depending on the starting materials used, but generally a relatively low temperature of about 0°C to about 100°C, preferably around room temperature, is used. Ru.

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

In addition, examples of the magnesium malonate compound to be used include paranitrobenzylmagnesium malonate, benzylmagnesium malonate, methylmagnesium malonate, etc. Among them, it is preferable to use paranitrobenzylmagnesium malonate. .

In step (C), the compound represented by formula (V) obtained in step (b) is treated with an azide compound in the same inert organic solvent as described in step (b) in the presence of a base. ,
The desired diazo compound of formula (Vl) is obtained.

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

The reaction is preferably carried out in acetonitrile in the presence of triethylamine by adding p-toluenesulfonyl azide and
This can be carried out by heating at ~100°C, preferably at room temperature, for 1 to 50 hours, and thereby the desired diazo compound of formula (Vl) can be obtained in high yield.

Step (d) is a step in which the diazo compound of formula (Vl) obtained in step (C) is cyclized to form a compound represented by formula (■). This step suitably comprises, for example, preparing a compound of formula (Vl) in an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane, etc., preferably in toluene, at 25 to 110%
Bis(acetylacetonato)Cu(II), CuOa, copper powder, Rh2(O
COCHs) rhodium octanoate or Pb(O
It is carried out in the presence of a metal catalyst such as a metal carboxylate compound such as COCH, ). - As a universal method, the above cyclization step also includes formula (Vl)
of the compound in a solvent such as benzene, diethyl ether, etc. at a temperature of 0 to 250°C for 0.5 to 2 hours using a Virex filter (wavelength greater than 300 nm).
It can also be carried out by irradiating light through.

Then, in step (e), the compound of formula (■) obtained in step (d) is reacted with a reactive derivative of the acid represented by R@OH (e.g., acid anhydride, halide, etc.) to obtain the compound of formula (■). A compound indicated by (■) is obtained.

Reactive derivatives of such acids include, for example, acetic anhydride,
Acetyl chloride, propionyl chloride, p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4.6-1-lyisoprobylbenzenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride Diphenylphosphoryl chloride, diphenylphosphoryl chloride, toluenesulfonyl azide F, p-7' lomobenzenesulfonyl chloride and the like are particularly preferred, with diphenylphosphoryl chloride (R1=diphenylphosphoryl group) being particularly preferred.

The reaction between the compound of formula (■) and the reactive derivative of the above acid is
It can be carried out in the same manner as the usual acylation method, for example, in an inert solvent such as methylene chloride, acetonitrile, dimethylformamide, etc., in the presence of an appropriate base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc. This can be carried out by treating at a temperature of -20 to 40°C for about 30 minutes to about 24 hours.

Next, step (f) is a step of reacting the compound I represented by formula (■) obtained in step (e) with a mercapto reagent: H3-R'' to obtain a compound represented by formula (II).

The reaction between the compound of formula (■) and a mercapto reagent can be carried out, for example, by reacting the compound of formula (■) with tetrahydro7rane,
dichloromethane, dioxane, dimethylformamide,
In a suitable solvent such as dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, etc., an approximately equimolar to about 1.5 times molar excess of the mercapto reagent and preferably sodium bicarbonate, potassium carbonate, triethylamine, etc. in the presence of a base such as diisopropylethylamine at a temperature within the range of about -40 to about 25°C for about 30 minutes to
This can be carried out by reacting for about 24 hours.

A compound represented by formula (ff) can be obtained by the above reaction, and in this compound, the carboxylic acid at the 2-position is protected with a carboxyl protecting group Hs. Removal of this protecting group R3 (step g) can be carried out by deprotecting group reactions known per se, such as solvolysis or hydrogenolysis. Typically, a compound of formula Platinum oxide, palladium-activated carbon, hydroxide using hydrogen at 1 to 4 atmospheres in a mixed solvent such as , tetrahydro7rane-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-, etc. In the presence of a hydrogenation catalyst such as palladium on activated carbon, from about O to about 50
This can be done by treatment at a temperature within the range of 0.25 to about 4 hours.

In this way, a compound of formula (X) in which R1 in the target compound of formula I of the present invention is represented by a hydrogen atom can be obtained.

Incidentally, the compound can be converted into salts such as sodium salts and potassium salts according to methods known per se.

The compound of formula (2) produced as described above has excellent antibacterial activity and is expected to be used as an antibacterial agent.

The present invention will be further explained below with reference to Examples.

697 mg (1,67 m, u) of tin triflate was suspended in 2.5 m12 of anhydrous tetrahydrofuran under a nitrogen stream, and after cooling to -40 to -50°C, 0.26 m12 of N-ethylpiperidine and 243 mg of compound (2) were suspended. Add 1.5 mQ of anhydrous tetrahydrofuran solution and stir at the same temperature for 3
．． Stirred for 5 hours. Then, a solution of 239 mg of compound (1) in 1.5 mQ of anhydrous tetrahydrofuran was added, and the mixture was heated to 0°C.
The mixture was stirred for 2 hours. A 10% aqueous citric acid solution and chloroform were added to the reaction solution, which was then filtered through Celite. The filtrate was washed with saturated brine and dried over Na25O. The solvent was distilled off, the residue was purified by silica gel column chromatography, and 302 mg (86%) of compound (3) was obtained as a yellow oil.
) I got it.

NMR(δ, CDC(2s): l
, 02 (3H, t-y=7Hz), 1.6-2.6 (
6HS m), 2.9-3.3 (2H1m),
3.4-3.9 (2HS m), 3,95-4
．． 25 (LH, m), 5.0-5.3 (IHSm)
, 6°33 (IH, bs).

Product 4) To a solution of 326 mg of the compound (3) obtained in Example 1 in 12 mff of anhydrous acetonitrile was added 20 ml of imidazole under a nitrogen stream.
After adding 4 mg and stirring at room temperature for 5.5 hours, M g (0
2CCH! 2899 mg of COOP N B ) was added thereto, and the mixture was further stirred at 60°C for 18 hours under a nitrogen stream. After the reaction was completed, ethyl acetate was added to the reaction solution, and 1N hydrochloric acid, 5%
Wash sequentially with sodium bicarbonate aqueous solution and saturated saline,
It was dried with Na25Oa. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 214 mg (56%) of compound (4) as a white solid.

NMR (δ, CD CQs): 2.2-2.5 (4H
, m), 2.8-3.0 (2H, m), 3.60 (2H
, S), 3.9-4.2 (LH, m), 5.3 (2H,
s), 6.53 (IH, bs), 7.53 (2H, d,
J = 8.8Hz), 8.22 (2H, d, J = 8
．． 8Hz).

Example 3: (5S)-5-(3-diazo-3-p
-nitrobenzyloxycarbonyl-2-compound (4)
214 mg of anhydrous acetonitrile in 3゜5ml solution,
170 mg of paraturcosulfonyl azide and 0.121 mff of tricotylamine were added, and the mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 230 mg (quantitative) of Compound (5) as a pale yellow substance.

NMR (δ, CD CQ3): 2.2-2.5(
4H1m), 3.0-3.2 (2H,m), 4.0-4
．． 3 (IH, m), 5.38 (2H1s), 6.50 (
IH, bs), 7.56 (2H, d, J=8.8Hz
), 8.26 (2H.

d, J=8.8Hz).

Example 4: (5S)-1-aza-2,7-thioxo 8
-p-nitrobenzyloxycarbonyl-bicyclo[3,3,0]off compound (5)
1 mg of rhodium (n) acetate was added to a solution of 88 mg of ethyl acetate, and the mixture was stirred at 80°C for 15 minutes under a nitrogen stream. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain compound (6). 70m as pale yellow oil
g (87%) was obtained.

NMR (δ, CD CQs): 2.1"'3.0 (6
H, m), 4.2-4-6 (LH, m), 4.85 (I
H, bs), 5.23 and 5.50 (2H, ABq,
J=13Hz), 7.55(2H,,d, J=
8.8Hz), 8.28(2H,d, J-8,8Hz
).

(Compound 7) To a solution of 80 mg of the compound (6) obtained in Example 4 in 1 m+2 of anhydrous acetonitrile, 0.06 m+2 of diphenylphosphoric acid salt and diisopropylethylamine Q,
Q5m12 was added and stirred for 1 hour under a nitrogen stream. After the reaction was completed, the reaction solution was distilled off under reduced pressure, and the residue was purified using silica gel chromatography to obtain compound (7) as a yellow oil.
6 mg (80%) was obtained.

NMR (δ, CD CQ3): 2.3-3.1 (6H
, m), 4.3-4.7 (IHSm), 5.15 and 5.39 (2H, ABq, J-10Hz), 7.1-
7.4 (IOH, m), 7.53 (2H, d, J-8
, 8Hz), 8.12 (2H, d, J=8.8Hz)
.

Example 6: To a solution of 304 mg of compound (7) in anhydrous acetonitrile,
169 mg of 4-ol compound (8) and 1 mQ of diisopropylethylamine were added under ice cooling, and the mixture was stirred for 1 hour under a nitrogen stream. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 290 mg (97%) of compound (9) as a yellow substance.

NMR (δ, CD CQs): 2.2-3.0 (6
H, m), 3.8-4.7 (6H, m), 5.19 (2
8%s), 5.25 and 5.52 (2H.

ABQ, J=13H2), 7.4~8.3(8H, m
).

Example 7: (1) To a solution of 320 mg of compound (7) in anhydrous acetonitrile were added 170 mg of mercapto compound (10) and 0.12 ml of diisopropylethylamine under water cooling, and the mixture was stirred for 2 hours under a nitrogen stream. The reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to obtain 309 mg (quantitative) of compound (11) as a yellow substance.

NMR (δ, CD CQs”): 1.6 to 2-1 (
2H, m), 2.3~3.6 (8B, m), 4.4~
4.8 (IH, m), 5.2 (2H, s), 5°52 and 5.25 (2H1ABq, J = 13Hz),
7.4-8.3 (8H.

m).

Example 8: (5S)-3-(3-azetidinyl)thio-8-oxo-■-azabicyclo A mixture of 232 mg of the compound (9) obtained in Example 6 in tetrahydro7rane and water (121) was oxidized. 40 mg of platinum was added, and hydrogenation was carried out at room temperature under a hydrogen stream (3 atm) for 1 hour. After the reaction was completed, the reaction solution was filtered through Celite, and after washing the Celite with ether, the organic layer was distilled off under reduced pressure and then freeze-dried to give 84 mg (84 mg) of Compound (12) as a white powder.
0%) obtained.

NMR (δ, Dgo): 1.8-2.8 (lOH
-m), 3.9 to 4-5 (2H, m) Carboxylic acid (compound 13) Using 205 mg of compound (11) obtained in Example 7, hydrogenation using 40 mg of platinum oxide was carried out in the same manner as in Example 8. The compound (13) was prepared as a white powder and lyophilized to give 53 m
g (59%) was obtained.

NMR (δ, CD C12s): L, 8-3.0 (
IIH, m).

Claims (1)

[Claims] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) In the formula, R^1 represents a hydrogen atom, an alkali metal, or a carboxyl protecting group, and R^2 is (5S)-3-substituted thio-8-oxo-1-, which represents an unsubstituted or substituted alkyl group or a heterocyclic group formula;
Azabicyclo[3.3.0]oct-2-ene-2-carboxylic acid derivative. 2. The compound according to claim 1, wherein R^2 is an aminoethyl group or an azetidin-3-yl group.