NO161000B - ANALOGUE PROCEDURE FOR PREPARING A THERAPEUTIC ACTIVE PENEMKARBOXYLIC ACID OR ESTER. - Google Patents

Abstract

Novel β-lactane-containing compounds of the formula. wherein R is hydrogen, lower alkyl, trichloroethyl, acetonyl, benzyl, substituted benzyl, phenyl, substituted phenyl, benzhydryl or a residue which will undergo metabolic activation "in vivo" and have favorable pharmacokinetic properties; Rs a hydrogen atom, lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl, wherein the alcoholic function of hydroxyalkyl is free or protected; Z is hydrogen, halogen, hydroxy, amino, carbamoyloxy, mercapto, pyridinium, OR, COOR, NHOOR or SRder each of 2 3. R and R are lower alkyl, aryl or a heterocyclic ring, each of which may be substituted or unsubstituted, and n is 0 or 1. The compounds have a wide range of antibacterial activity and β-lactamase inhibitory activity. Methods for preparing the β-lactam-containing compounds and various intermediates in the production of these compounds are also described.

Description

The present invention relates to the production of β-lactam-containing compounds.

More particularly, the present invention provides penemcarboxylic acid derivatives of the general formula (1):

wherein R"" means a hydrogen atom or an acetonyl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula

or CH2NHC0R2

where R 2 is an alkyl group having from 1 to 4 carbon atoms or a cycloalkyl or aryl group;

Z means an acetoxy or carbamoyloxy group or a group of the formula SR3 where R3 means a 5-methyl-1,3,4-tridiazol-2-yl-, 1-methyl-1H-tetrazol-5-yl-, 1,2 ,3-triazol-5-yl or pyrazinyl group or a pharmaceutically acceptable salt thereof.

The substituents in the 6-position have oc configuration and e configuration. The a configuration is preferred.

These compounds have broad spectrum antibacterial activity as well as β-lactamase inhibitory activity.

It should be pointed out that the stereochemistry at C5 of the title compounds as well as that of all the intermediates for their preparation is the same as in naturally occurring penicillins and cephalosporins.

Pharmaceutically acceptable salts of penemcarboxylic acids with the general formula (1), such as sodium, potassium, benzathine, procaine and similar salts which are usually formed with penicillins and cephalosporins, are, as mentioned, also within the scope of the invention.

The following diagram shows the preparation of compounds with the general formula (1) according to the invention

According to this, the invention is characterized by reacting a compound with formula (2):

in which R means an alkyl group and R<1>" means a 1-hydroxyethyl or 1-p-nitrobenzyloxycarbonyloxyethyl group, with an acetylenic derivative of the formula X'-C=C-Y in which X' is a group of the formula CH2Z', in which Z' is a hydroxy group or a group of the formula OCOCH3 and Y represents a hydrogen atom or a group of the formula CH2Z' in which Z' is as indicated above; isomerization of the resulting compound of formula (3):

wherein R 11', R, X' and Y are as defined above, in the presence of a base;

the resulting compound of formula (4):

wherein R"', R and Y are as defined above,

(i) reduced with PBr3 when X' is an acetoxymethyl group, or (ii) when X' is a hydroxymethyl group, the compound of formula (4) (a) is reduced with PBr3 and the resulting bromine derivative is treated with R3~S-Na where R3 is as indicated above, or (b) treated with chlorosulfonyl isocyanate and the resul tering compound is reduced with PBr3» ozonization of the resulting compound of formula (12): wherein X is CH 2 Z and R"', R, Z and Y are as defined above; solvolyzing the resulting compound of formula (13):

wherein R, R"<*> and X are as defined above,

condensation of the resulting compound of formula (14):

wherein X and R"' are as defined above with a compound of the formula CHOCOOR"", wherein R"" is as defined above, chlorination of the resulting compound of formula (15): wherein R"", R"' and X are as stated above; condensation of the resulting compound of formula (16): wherein X, R"" and R"' are as defined above, with triphenylphosphine to give a compound of formula (11):

wherein R"", R<1>" and X are as defined above,

cyclization of the compound of formula (11) by heating, any protective groups are removed and, if desired, an obtained free compound of formula (1) is converted into a pharmaceutically acceptable salt thereof.

In the starting materials of formula (2), the optionally protected hydroxyethyl group in the 6-position, R"', can be introduced according to the procedure according to Di Ninno et al., "Journal of Organic Chemistry", 42. 2960 (1977). Compounds of the formula (2) can also be prepared from a suitable ester of penicillanic acid S-oxide as shown in the following examples.

The substitution of the 6-position is stereospecifically directed towards the 6a derivatives.

The ester of penicillanic acid S-oxide (2) where R is an alkyl group and R"' is as indicated above can be heated in an inert solvent such as benzene or toluene, usually at a temperature of from 70 to 140°C, with a suitable acetylenic derivative of the general formula X'C=CY, where X' is a group of the formula CH2Z', where Z' is a hydroxy group or a group of the formula OCOCH3 and Y is a hydrogen atom or a group of the formula d^Z' where Z' has the meaning given above.

In the compounds of formula (4), if desired, the X' group can be converted into an X group where X is a group of formula CEtøZ in which Z has the meaning given above by means of known substitution reactions, an example of which is given in the following examples. The captured compound of formula (3) can be isomerized using a base to the compound of formula (4) which can be converted to the final compound of formula (I) in the following manner.

The compound of formula (4) can be reduced under ordinary conditions to give the compound of formula (12) which is ozonized on both double bonds to give the compound of formula (13), and after hydrolysis the compound of formula (14). Glyoxylation of the compound of formula (14) gives the compound of formula (15) which can then be transformed to the chlorine derivative of formula (16) and then to the phosphorane of formula (II) which is cyclized to the compounds of formula (1), simply by heating in an inert solvent such as toluene at a temperature from 50 to 140°C.

The reaction sequence is preferably carried out with the alcoholic function in the 6-position protected.

Compounds of formula (1) where R"" is a hydrogen atom can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds and the hydroxyethyl group in the 6-position can have its protection removed by means of hydrogenolysis.

Compounds of formula (1) where R"" is a hydrogen atom can be converted into acceptable salts thereof by salt formation.

Much work has previously been done in connection with the total chemical synthesis of g<->lactam compounds. The most representative literature publication in connection with the class of penems is DE-OS 2 819 655 which describes 2-penem compounds of the formula:

wherein R 1 is a hydrogen atom, an organic residue or an etherified mercapto group and R 2 is hydrogen or a carboxy protecting group. The C5 has both R and S configuration.

The described compounds are stated to be antibacterial agents and ε-lactamase inhibitors.

The present invention provides new 6-substituted penem compounds with special substituents on a methyl group in the 2-position and 5R configuration at C5.

The narrow subclass of penem compounds according to the present invention shows, compared to the above-described known compounds, an improved broad-spectrum antibacterial activity, high potency and efficiency. Thus, the penem compounds according to the invention represent a significant advance in antibacterial therapy.

A series of tests was carried out in vitro to compare the effect of

(1) (5R, 6S )-2-acetoxymethyl-6-[1(R)hydroxyethyl]-2-penem-3-carboxylic acid, (2) (5R,6S)-2-[(1-methyl-1H- tetrazol-5-yl)-thiomethyl-6-[1(R)hydroxyethyl]-2-penem-3-carboxylic acid, (3) (5R,6S)-2-[(5-methyl-1,3,4- thiadlazol-2-yl)-thiomethyl]-6-[1(R)hydroxyethyl)-2-penem-3-carboxylic acid and

(4) (5R,6S)-2-(pyrazinyl)thiomethyl-6-[1(R)hydroxyethyl]-2-penem-3-carboxylic acid

with a reference compound [(5R,S)-2-methyl-2-penem-3-carboxylic acid], shown as preferred in the above-mentioned DE-OS 2 819 655.

Table 1 below reports the results of the above samples as MIC, minimal inhibitory concentration.

Example 1: (5R)-acetoxymethyl-6-(1-hydroxyethyl)-2-acetoxymethyl-2-penem-3-carboxylate 0.060 g 5R-acetoxymethyl-6-(1-p-nitrobenzyloxycarbonyl-oxyethyl)-2-acetoxymethyl- 2-penem-3-carboxylate was poured over 1 a mixture of water, ethanol and K2HPO4 and hydrogenolyzed with 105É Pd/C. A quick purification by column chromatography on silica gel gave 0.015 g of the title compound. Subexample a: (5R)-2-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-2-penem-3-carboxylic acid

The title compound was produced as described in the base document. (5R)-p-nitrobenzyl-2-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-2-penem-3-carboxylate was prepared according to a similar method, also as described in the preceding examples.

IR (CHCl3): 1800 (e-lactam), 1750 and 1720.

Example b: Methyl 6a-(1'-hydroxyethyl)-penicillanate-S-oxide

A solution of 2.3 g of methylpenicillinate S-oxide in 50 ml of anhydrous <1>tetrahydrofuran was cooled to -78°C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1.6M BuLi-hexane solution), dissolved in anhydrous tetrahydrofuran was added and the mixture was left for 10 minutes at -78°C. 5 ml of acetaldehyde was added little by little and the mixture stirred for 15 minutes. Then, the reaction mixture was added to a saturated aqueous NH4CI-0PPI0S-ning, extracted with ethyl acetate, washed twice with water and dried over Na2SC-4. After evaporation of the solvent, the residue was purified by short column chromatography on silica gel and eluted with dichloromethane-ethyl acetate (1:1). Yield 1.5 grams. The title compound which consisted of a 2:3 mixture of the epimer of the hydroxyl group on the carbon atom according to NMR, where the new C^-Cg bond due to the stereo of the reaction -specific character under the applied conditions is only in ot position.

NMR (CDCl3): 1.27S (s, 3H, oc-CH3), 1.40S (d, 3H, J - 5.7 Hz, CH 3-CHOH) major isomer, 148S (d, 3H, J-5 .7 Hz, CH3-CHOH)-minor isomer, 1.70 S (s, 3H, e-CH3), 3.4 - 3.8 & (m, 1H, H-6), 3.80S (s, 3H , COOCH3), 4.1 - 4.7S (m, 1H, CHOH), 4.50 S (s, 1H, H-3), 4.98 S (d, J - 1.9 Hz, 1H, H -5) minor isomer, 5.05 S (d, J - 1.9 Hz, 1H, H) major isomer.

Example C: Methyl 6-(1-hydroxyethyl)-3-penicillanate

A slight excess of lithium diisopropylamide was added to a solution of 2.2 g of methylpenicillanate in 30 ml of anhydrous tetrahydrofuran at -78°C under nitrogen. An excess of acetaldehyde was added dropwise, the mixture was stirred for 5 minutes and quenched with acetic acid, poured into water and extracted with methylene chloride. The organic layer which was dried over Na 2 SO 4 and evaporated in vacuo gave 0.8 g of the title compound.

Example d: Methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-penicillanate

1.2 g of methyl 6-(1-hydroxyethyl)-3-penicillanate was dissolved in 40 ml of tetrahydrofuran, cooled to -78°C and treated with 1 equivalent of butyllithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to the resulting mixture. After 30 minutes at -78°C, the reaction mixture was left for 60 minutes at room temperature, poured into water and extracted with methylene chloride. The mixture was evaporated after drying over Na 2 SC- 4 and contained 1.4 g of the title compound. Example e: Methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-penicillanate-S-oxide 1.8 g of methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-penicillanate was dissolved in 50 ml of methylene chloride and treated at 0° C with 1.5 equivalents of m-chloroperbenzoic acid. The organic phase was shaken with saturated NaHCO3 solution, extracted, dried over Na2SO4 and evaporated. 1.4 g of the expected sulfoxide was obtained. Example f: 4P-vinylthio-(1,2-diacetoxymethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-methoxycarbonyl-2-methyl-2-propenyl)-azetidin-2-one-S-oxide

A solution of 2.0 g of methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-phenylalanine-S-oxide and 2.4 g of butynediol dlacetate in 50 ml of toluene was refluxed for 124 hours. The inclusion compound was then purified by column chromatography and eluted with 9:1 dichloromethane-ethyl acetate. 1.1 g of the title compound was obtained.

Example g: 4P-vinylthio-(1,2-diacetoxymethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one-S-oxide

1.3 g of 4ε-vinylthio-(1,2-diacetoxymethyl)-3-(1-p-nitrobenzyl-oxycarbonyloxyethyl)-1-(methoxycarbonyl-2-methyl-2-propenyl)-azetidin-2-one-S-oxide was dissolved in 80 ml of dichloromethane. 0.3 g of triethylamine was added and the mixture was left for 2 hours at room temperature. The pure title compound was obtained in quantitative yield after evaporation of the solvent. Example h: 4e-vinylthio-(1,2-diacetoxymethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one 1.5 g of vinylthio- (1,2-Diacetoxymethyl)-3-(1-p-nitrobenzyl-oxycarbonyloxyethyl)-1-(methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one-S-oxide was dissolved in 10 ml of anhydrous dimethyl -mamide and cooled to -20°C, 0.8 ml of phosphorus tribromide was added, the mixture was stirred for 10 minutes, diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. Organic layers which were dried over Na2SO4 and evaporated gave 1.1 g of the title compound. Example i: 4g<->acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-methoxyoxalyl-azetidin-2-one

1.4 g of 4g<->vinylthio-(1,2-diacetoxymethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one in 120 ml of dichloromethane was cooled to -78° C. Ozone in oxygen was blown through until it turns blue. The solution was shaken with aqueous ^283O5 solution and dried over Na 2 SO 4 . After evaporation, 0.8 g of the title compound was obtained.

Example j: 4β<->acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one

0.800 g of 4e-acetylglycolthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-methoxyoxalyl-azetidin-2-one was dissolved in 150 ml of methanol and a few grams of silica gel were added. The mixture was allowed to stand for 160 minutes at room temperature, the insoluble material was filtered off and the filtrate gave, after evaporation, 0.300 g of the title compound. Example k: 4P-acetylglycolthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-acetoxymethyloxycarbonyl-1-hydroxymethyl)-azetidin-2-one

0.5 g of 4P-acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-azetidin-2-one and 0.5 g of acetoxymethylglyoxylate in 30 ml of benzene were retained at reflux until the reaction was complete (2 hours ). The obtained title compound could be used in the next step without further purification.

Example 1: 4β<->acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-acetoxycarbonyl-1-(1-acetoxymethyloxycarbonyl-1-chloromethyl)-azetidine-2- Wed

0.35 g of 4e-acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-acetoxymethyloxycarbonyl-1-hydroxyniethyl)-azetidin-2-one was dissolved in 110 ml of anhydrous tetrahydrofuran at 0°C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added. The mixture was stirred for 10 min. The precipitate was filtered off, and the filtrate, after evaporation, gave the title compound in quantitative yield. The impure product was used as such in the next step. Example m: 4e-acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-acetoxymethyloxycarbonyl-1-triphenyl-phosphoranylidenemethyl)-azetidin-2-one

0.400 g of 4B-acetylglycolylthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-acetoxymethyloxycarbonyl-1-chloromethyl)-azetidin-2-one was dissolved in 20 ml of a 1:1 mixture of tetrahydrofuran and dioxane . 2 equivalents of triphenylphosphines and 1.1 equivalents of pyridine were added and the mixture was stirred overnight at 50°C. The title compound was purified by column chromatography on silica gel eluting with 70:30 dichloromethane-ethyl acetate. 0.280 g of the precursor was obtained.

Example n: (5R)-acetoxymethyl-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-2-acetoxymethyl-2-penem-3-carboxylate

0.210 g of 4p-acetylglycolylthio-3-(l-p-nitrobenzyloxycarbonyloxyethyl)-l-(1-acetoxymethyloxycarbonyl-l-triphenylphosphoranylidenemethyl)-azetldin-2-one was dissolved in 17 ml of toluene and the solution was kept for 2 hours under reflux . Purification by short column chromatography eluting with 95:5 dichloromethane-ethyl acetate gave 0.050 g of the title compound.

Example 2: (5R)-acetonyl-2-1"(5-methyl-1.3.4-thiadlazol-2-v1)-thiomethyl-6a-(1-hydroxyethyl1-2-penem-3-carboxvlate (Reaction 1 ) 0. 450 g of the starting compound was dissolved in 25 ml of acetonitrile containing a few drops of ethanol and hydrogenated over 10# palladium on carbon in an amount of 400 mg. The catalyst was removed by filtration and the filtrate was chromatographed on silica gel eluting with dichloromethane:ethyl acetate 7: 3, giving 0.18 g of title compound 1. R: 3605, 1795, 1745, 1720.

Example 3:

( 5R )- acetonyl- 2- r( 1. 2. 3- triazol- 5- yl )- thionerethyli - 6a-( 1-hydroxyethyl)- 2- penem- 3- carboxyvlate. (Reaction 1)

By starting from 0.380 g of starting compound and/or working as in example 2 above, 0.12 g of the title mixture was obtained. I.R: 3610, 1795, 1750, 1720. Example 4 ( 5R )- 2 f ( 5- methyl- 1 . 3 . 4 - 11 ad i azo 1 - 2- y 1 l- thiometvll- 6a-( 1-hydroxymetvl )- 2- penem- 3- carboxylic acid (Reaction i):

A solution of 0.200 g of the compound as prepared in Example 82 in 30 ml of acetonitrile containing a few drops of water was cooled to 0°C; 5 ml of a 0.1 N NaOH solution was added under nitrogen and the solution was stirred for 110 minutes. The alkaline mixture was extracted twice with methylene chloride, acidified with a 105É aqueous citric acid solution and extracted again twice with methylene chloride. The combined organic phases were dried over Na 2 SO 4 and evaporated to give 0.110 g of the title compound. I.R: 3500, 1795, 1665.

Example 5:

( 5R )- 2- T( 1 . 2 . 3- triazol- 5- yl- thiomethyl- 6o-( 1- hydroxyethyl)- 2-penem- 3- carboxylic acid (Reaction 1):

Starting from 0.25 g of the compound as prepared in Example 3 above and working as shown in Example 4 above, 0.135 g of the title compound was obtained. IR: 3490, 1795, 1660.

Example 6: Natrlum( 5R. 6S )- 6~ n( R ) hvdroxwetvll - 2- f( 1- metvl- l. 2. 3. 4-tetrazole- 5- vl)- thiomethyl1- penem- 3- carboxylate

From 2.5 g of 4p-(1-bromomethyl)-vinylthio-3c-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-(1-methoxycarbonyl-2-methyl-1-propenyl)-azetidin-2-one and by work as described in example 2 above but by using 1-methyl-1,2,3,4-tetrazole-5-thiol sodium salt instead of 5-methyl-1,3,4-thiadiazole-2-thiol sodium salt, and by treating the resulting compound by twice extraction with cold ethyl acetate and subsequent C 2 g reverse phase chromatography eluting with water gave 0.13 g of the title compound.

UV (H20) X max 315 nm

NMR (D 2 O) 5 ppm 1.28 (3H, d, J=6.3 Hz)

3.87 (1H, dd, J-1.4 and 6.3 Hz)

4.10 (3H, s)

4.19 (1H, m)

4.40 (2H, ABq, J=16.0 Hz, separation

of internal lines • = 13 Hz)

5.59 (1H, d, J-1.4 Hz)

Example 7: Sodium f 5R. 6S)- 6- f 1 ( R ) hydroxymethyl 1 - 2-( pyrazinylthiomethyl )-penem- 3- carboxylate

By working as in example 6 but using pyrazine-2-thiol sodium salt instead of 1-methyl-1,2,3,4-tetrazol-5-thiol sodium salt, the title compound was obtained.

UV (H20) X max 250 (c=10,344)

c-8,682)

NMR (D 2 O) 8 ppm 3.74 (1H, dd, J=1.5 and 5 Hz)

4.58 (2H, s)

5.41 (1H, d)

8.37, 8.51 and 8.62 (each 1H) IR (KBr) v max (cm-<1>) 1760, 1600, 1570

Claims (1)

1. Analogous process for the preparation of a therapeutically active penemcarboxylic acid or an ester of formula (1) with 5R configuration: wherein R"" means a hydrogen atom or an acetonyl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group with the formula or CH 2 NHCOR 2 where R 2 is an alkyl group having from 1 to 4 carbon atoms or a cycloalkyl or aryl group; Z means an acetoxy or carbamoyloxy group or a group of the formula SR3 where R3 means a 5-methyl-1,3,4-thiadiazol-2-yl-, 1-methyl-1H-tetrazol-5-yl-, 1,2 ,3-triazol-5-yl or pyrazinyl group or a pharmaceutically acceptable salt thereof, characterized by reaction of a compound with formula (2): in which R means an alkyl group and R"' means a 1-hydroxyethyl or 1-p-nitrobenzyloxycarbonyloxyethyl group, with an acetylenic derivative of the formula X'-C=C-Y in which X<*> is a group of; the formula CH2Z', in which Z <*> is a hydroxy group or a group of the formula 0C0CH3 and Y means a hydrogen atom or a group of the formula CH2Z" wherein Z<*> is as indicated above; isomerization of the resulting compound of formula (3): wherein R"', R, X' and Y are as defined above, in the presence of a base; the resulting compound of formula (4): wherein R"', R and Y are as defined above, (i) reduced with PBr3 when X' is an acetoxymethyl group, or (ii) when X' is a hydroxymethyl group, the compound of formula (4) (a) is reduced with PBr3 and the resulting bromine derivative is treated with R3~S-Na where R3 is as indicated above, or (b) treated with chlorosulfonyl isocyanate and the resul terating compound is reduced with PBr3, ozonization of the resulting compound of formula (12): wherein X is CH 2 Z and R"', R, Z and Y are as defined above; solvolyzing the resulting compound of formula (13): wherein R, R"' and X are as defined above, condensation of the resulting compound of formula (14): wherein X. and R<1>" are as indicated above with a compound of the formula CHOCOOR"", where R"" is as indicated above, chlorination of the resulting compound of formula (15): wherein R"", R<1>" and X are as defined above; condensation of the resulting compound of formula (16): wherein X, R"" and R"<*> are as indicated above, with triphenylphosphine to give a compound of formula (li): wherein R"", R"' and X are as defined above, cyclization of the compound of formula (11) by heating, any protective groups are removed and, if desired, an obtained free compound of formula (1) is converted into a pharmaceutically acceptable salt thereof.