HU190716B - Process for preparing antibiotics containing carbapenemic skeleton - Google Patents

Abstract

Disclosed are novel carbapenem derivatives characterized by a 2- substitutent of the formula <IMAGE> wherein A represents C2-C6 straight or branched chain alkylene group and R<10> and R<11> each independently represents optionally substituted aliphatic, cycloaliphatic, cycloaliphatic- aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroaraliphatic, or R<10> and R<11> taken together with the S<(+)> to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring. Such derivatives are useful as potent antibacterial agents. Also disclosed are processes for the preparation of such derivatives.

Description

The present invention relates to a novel carbapenem backbone antibiotic, wherein the carbapenem backbone at position 2 is a group of formula (a) wherein

A is an alkylene group having 2 to 4 carbon atoms,

R ¹⁰ and R ¹¹ together form a tetramethylene or pentamethylene group.

Numerous β-lactam derivatives containing carbapenem skeleton of formula (Ia) are known in the art. Such carbapenem derivatives have been reported to be useful as anti-bacterial agents and / or inhibitors of the β-lactamase enzyme.

The first known carbapenem derivatives were natural substances. For example, thienamycin (2) obtained by culturing Streptomyces cattleya (U.S. Pat. No. 3,950,357). Thienamacin is a particularly potent broad-spectrum antibiotic with remarkable activity against various species of Pseudomonas, which are resistant to most β-lactam backbone antibiotics.

Other compounds of natural origin containing carbapenem backbone include some derivatives of olivic acid, such as the antibiotic MM 13902 described in U.S. Patent 4,113,856; the antibiotic MM 17880 described in U.S. Patent 4,162,304; antibiotic formula MM 4550A described in U.S. Patent 4,172,129; and antibiotic formula 890A disclosed in U.S. Patent No. 4,264,735.

In addition to such compounds of natural origin, there is described a compound of formula (7), deacetyl-89QAi _O (U.S. Patent No. 4,264,734), prepared by enzymatic deacylation of the corresponding N-acetyl derivative. Various derivatives of naturally occurring olivic acid have also been prepared, such as those of Formula 8 where

CO ₂ R ₁ represents a free carboxyl group in the form of a salt or ester, n represents 0 or 1, and

R ₂ is hydrogen, acyl or

R3O3S group of the formula wherein R ₃ represents a counter ion, a methyl group or ethyl group, compounds, see European patent application No. 8885.

U.S. Pat. No. 4,235,922, supra

European Patent 2,058,058 discloses a carbapenem derivative of Formula 9 and British Patent Application No. 1,598,062 describes the isolation of a compound of Formula 10 from a culture medium used for the cultivation of a species of Streptomyces.

Unsubstituted carbapenem derivatives at the 6-position have also been prepared. Thus, U.S. Patent 4,210,661 discloses compounds of Formula 11 wherein R ₂ is phenyl or substituted phenyl; U.S. Patent 4,267,177 discloses compounds of Formula 12 wherein R 1 is optionally substituted pyridyl. , U.S. Patent 4,255,441, discloses the preparation of compounds of Formula 13 wherein

R ₂ and R ₃ is hydrogen or alkyl and

R 1 is NH-CO _n R ₆ where R ₆ is alkyl, phenyl or substituted phenyl and n is 1 or 2, and U.S. Patent 4,282,236 discloses the preparation of general formula (14). wherein R 1 is hydrogen or alkyl, and

R ₂ is cyano or CO ₂ R ₃ where R ₃ is hydrogen, alkyl, aryl or aralkyl for the preparation of compounds.

U.S. Patent 4,218,463 discloses the preparation of carbapenem derivatives of Formula 15 wherein

R ¹ is hydrogen or acyl, and

R ⁸ is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-substituted alkyl, alkyl-substituted cycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaryl, an alkyl group substituted by a heterocyclic or heterocyclic group.

This disclosure does not disclose compounds of Formula 15 wherein R ⁸ is a group of Formula (b) wherein A is an alkylene group in Formula (b).

Absolute configuration of naturally occurring thienamycin: 5R, 6S, 8R. This isomer, as well as the other seven thienamycin isomers, can be prepared by total synthesis as described in U.S. Patent No. 4,234,596. Methods for the total synthesis of thienamycin are described, for example, in U.S. Patent Nos. 4,287,123, 4,269,772, 4,282,148, 4,273,709, 4,293,947, and European Patent Application 7973. A key intermediate (intermediate) of the described synthetic routes is the compound of formula (16) wherein pNB is p-nitrobenzyl.

Because of the particularly potent biological activity of tienamycin, a large number of derivatives of this compound have been prepared and described in the literature. Examples of such compounds include:

1) N-formimidoylthienamycin (17), see European Patent Application 6639;

2) Nheterocyclic thienamycin derivatives of formula (18) and (19), wherein the ring of the two functional groups in formula (18) cs (19) may have an additional double bond, n is 1, 2, 3, 4 , 5 or 6;

p is 0, 1 or 2;

R ¹ is hydrogen, alkyl or aryl; and

Z is imino, oxo, hydrogen, amino or alkyl, see U.S. Patent 4,189,493;

3) substituted N-methylenethienamicin derivatives of formula (20) wherein:

X and Y are hydrogen, -R, -OR, -SR or -NR'R ² wherein R is substituted or unsubstituted

-2190 716 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-substituted alkyl, aryl, aralkyl, heteroaryl, heteroaryl-substituted alkyl, heterocyclic or heterocyclyl-substituted alkyl, and

R ¹ and R ² are hydrogen or R ', see U.S. Patent 4,194,047;

4) compounds of formula 21 wherein:

R ³ is aryl, alkyl, acyl or aralkyl, and

R 1 and R ² are independently hydrogen or acyl, including the acyl group of formula (c) wherein

R may also be an alkyl group substituted by a quaternary ammonium group, such as an acyl group represented by formula (d), see U.S. Patent No. 4,226,870;

5) compounds of formula 22 wherein:

R ³ is hydrogen, acyl, or a monovalent, optionally substituted hydrocarbon group;

^R1 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl-alkyl, cycloalkyl-substituted alkyl, aryl, aralkyl, heteroaryl, or substituted heteroaryl alkyl, and

R ² represents an acyl group, including the (C) acyl groups of the formula where R ¹¹ is alkyl substituted by a quaternary ammonium group, such an acyl group may be for example a group of formula (d), lásdazl 604 276számú U.K. Patent and EP 4235917 US patent specification;

6) compounds of formula 23 wherein

^{R5, R6} and ^R7 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl, substituted cycloalkyl known substituted alkyl, aryl, aralkyl, heteroaryl, or alkyl substituted with heteroaryl, see U.S. Patent 4,235,920;

7) compounds of formula 24 wherein:

R 'and R ² are independently selected from the group consisting of R, defined below, and hydrogen, nitro, hydroxy, C 1-6 -alkoxy, amino, C 1-6 -alkylamino, di (C 1-6 -alkyl) an amino group or a tri (C 1 -C 6 alkyl) ammonium group, the latter group having an equilibrium with an additional anion; or

R ¹ and R ² together form, together with the nitrogen to which they are attached, a substituted or unsubstituted, monocyclic or bicyclic 4 to 10-membered, optionally containing a further heteroatom selected from O, S, or heteroaryl, or a heterocyclic group containing a nitrogen atom .

R is cyano, substituted or unsubstituted carbamoyl, carboxyl, (C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 10 cycloalkyl Alkyl containing 4 to 12 carbon atoms, cycloalkenyl substituted with 4 to 12 carbon atoms, alkenyl substituted with 5 to 12 carbon atoms, cycloalkenyl substituted with 3 to 10 carbon atoms, alkenyl substituted with 5 to 12 carbon atoms, cycloalkenyl substituted with 4 to 12 carbon atoms, Aralkyl containing from 7 to 16 carbon atoms, alkenyl substituted by 8 to 16 carbon atoms, alkynyl substituted by 8 to 16 carbon atoms, or mono- or bicyclic heteroaryl t, heteroaryl-substituted alkyl, heterocyclic, or heterocyclic-substituted alkyl, wherein the heterocycle is 4- to 10-membered and contains one or more heteroatoms, such as oxygen, sulfur, and / or nitrogen, and wherein the heteroaryl or heterocyclyl is substituted its aliphatic moiety contains from 1 to 6 carbon atoms; the substituent (s) present in the R, R ¹ and R ² groups and in the -NR ³ R ² group may be:

chlorine, bromine, iodine or fluorine, azido,

Acyl, mercapto, sulfo, phosphono, thiocyanato, nitro, cyano, amino, hydrazino containing up to three carbon atoms, up to three,

Amino or hydrazino substituted with C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylmercapto, carboxyl, OXO, C 1-6 alkoxy carbonyl, 2 Acyloxy, carbamoyl, C 1-4 alkylcarbamoyl or di (C 1-4 alkyl) carbamoyl containing -10 carbon atoms;

R ₃ is hydrogen, acyl or one of R ⁴ as defined below;

R 1 is C 1 -C 10 alkyl; substituted carbonylmethyl; C 1-6 alkyl substituted with C 1-6 alkoxy; Substituted with a cycloalkoxy group containing from 3 to 6 carbon atoms

C 1-6 alkyl;

Alkanoyloxyalkyl having from 2 to 12 carbon atoms; partially or completely halo3

190,716 genes for alkylation containing from 1 to 6 carbon atoms, wherein the halogen atom (s) may be chlorine, bromine or fluorine; an aminoalkyl group; Alkenyl containing from 2 to 10 carbon atoms; Alkynyl containing from 2 to 10 carbon atoms; acyl; Alkoxycarbonylalkyl having 3 to 14 carbon atoms; A dialkylaminoacetoxyalkyl group containing from 4 to 21 carbon atoms; Alkanoylaminoalkyl containing from 2 to 13 carbon atoms; aryl substituted C 1-3 alkyl wherein the aryl may have from 6 to 10 carbon atoms; mono- or bicyclic alkyl having from 1 to 3 carbon atoms substituted with 1 to 4 heteroatoms such as oxygen, sulfur and / or nitrogen or with a heterocyclic group containing from 4 to 10 members; aralkyl or heteroalkyl-substituted alkyl substituted with chloro, fluoro, bromo, iodo or C 1-6 alkyl; aryl or ring-substituted aryl wherein the aryl ring may contain from 6 to 10 carbon atoms and the ring substituent may be hydroxy, C 1-6 alkyl or chloro, fluoro or bromo; aralkoxyalkyl group; Alkyl-mercaptoalkyl containing from 2 to 12 carbon atoms; A cycloalkylmercaptoalkyl group containing from 4 to 12 carbon atoms; C2-C10 alkyl substituted with an acyl mercapto group; or C 2 -C 6 alkenyl substituted with phenyl;

^R5 is a substituted or unsubstituted

Alkyl having 1 to 10 carbon atoms;

Alkenyl or alkynyl containing from 2 to 10 carbon atoms; ring-substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkenyl-substituted alkyl or cycloalkyl-substituted alkyl, wherein the cycloalkyl groups contain from 3 to 6 carbon atoms and the aliphatic moiety optionally present may contain up to 6 carbon atoms; Aryl having 6 to 10 carbon atoms; C 1-6 alkyl substituted with 6 to 10 carbon atoms aryl; mono- or bicyclic heteroaryl or heteroaryl-substituted alkyl, wherein the heteroaryl is

4- to 10-membered and may contain one or more oxygen, nitrogen and / or sulfur atoms and 1-6 carbon atoms in the alkyl chain; and the optional substituent (s) present may be the following; amino-di (C 1-6 -alkyl) amino or tri (C 1-6 -alkyl) substituted with chloro, bromo, iodo or fluoro, azido, cyano, amino, C 1-6 alkyl - an ammonium group, which in the latter group is equilibrated with a separate anion and is hydroxyl, C 1-6 alkoxy, C 1-6 alkylmercaptoalkyl, carboxyl, oxo, (C 1-6) alkoxy) carbonyl, C2-C10 acyloxy, carbamoyl, (C1-C4 alkyl) carbamoyl, di (C1-C4 alkyl) carbamoyl, thiocyanate or nitro;

R ⁶ is hydrogen, hydroxy, mercapto, and -R, -OR, -SR or -NR'R ² where R, R 'and R ² are as defined above;

X is hydroxy, mercapto, amino or acyloxy, and -OR ⁴ , -SR ⁴ ,

-NHR ⁴ , -N (R ⁴ ) ₂ , -OM, -OQ, or when the compound is in zwitterionic form, X is -O, in which case the molecule does not have the anion A ';

A, when the compound is in non-zwitterionic form, is an ion;

M is a pharmaceutically acceptable cation; and

Q is a protecting group, see U. S. Patent No. 1,604,275; and

8) compounds of formula (25), wherein the group (e) attached to the nitrogen atom of the thienamycin amino group is a monocyclic or polycyclic heterocyclic group, and

R is hydrogen or substituted or unsubstituted alkyl, aryl, alkenyl, heterocyclic-substituted alkenyl, aralkenyl, heterocyclyl-substituted alkyl or aralkyl, and -NR ₂ , -COOR, -CONR ₂ , -OR or a cyano group, see European Patent Application 21 082.

The compounds disclosed in U.S. Patent 4,235,920 include the compound of Formula 26, wherein

A is a pharmaceutically acceptable anion.

This quaternary amine derivative of general formula (26) is described in Recent Advances in Chemistry of β-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, 240-254. The method of this compound is described as having an average antibacterial activity of between about half and two thirds of that of thienamycin.

To the best of the applicants' knowledge, the literature does not disclose carbapenem derivatives of the present invention containing the 2-position groups of formula (a), but there are a number of recent patents which are broadly encompassed by the present invention. Such compounds are present. Examples of such patents include:

1) European Patent Application 40 408 discloses compounds of formula 27 wherein R 1 is hydrogen, methyl or hydroxy;

190,716

R _S1 is a monovalent organic group such as, for example, substituted alkyl or -CH ₂ R ₇ wherein R 1 is an optionally substituted 5- or 6-membered heterocycle;

2) the number of European Patent Application 38869 discloses compounds of the formula (28) wherein R ^1, R ⁷ and R ^s are independently hydrogen, substituted or unsubstituted alkyl, alkenyl or alkynyl group having 1 to 10 carbon atoms; cycloalkyl, cycloalkyl-substituted alkyl or alkyl-substituted cycloalkyl, the latter of which may have from 3 to 6 carbon atoms in the cycloalkyl group and the aliphatic moiety may contain from 1 to 6 carbon atoms; an aryl group such as phenyl; aralkyl, aralkenyl or aralkinyl wherein the aryl is phenyl and the aliphatic moiety may contain from 1 to 6 carbon atoms; heteroaryl, heteroaryl-substituted alkyl, heterocyclyl or heterocyclyl-substituted alkyl; wherein the substituent (s) in the above groups may be halogen (chlorine, bromine or fluorine), hydroxy, -OR ¹ alkoxy or aryloxy, -O-CO-NR'-R ² carbamoyloxy group represented by the formula -CO-NR ² carbamoyl, -C NRJ ^ -NR'R ² amidino group of the formula -NR ² amino group, R ^1, nitro, -N ⁺ (R ') 3 a tri-substituted ammonium group of the formula wherein R 'is independently -O (oxo) -C (R') = N-OR ² , -alkyl or aryl-mercapto -SR ¹ , -SjNR'R ² - sulfonamido, - Ureido group NH-CO-NR'R ² , amido group R'-CO-NR ² , carboxyl group, ester group -CO 2 R ', acyl group -CO-R ¹ , -O-CO-R ^{1 group} acyloxy group, mercaptoc group, a alkylsulphinyl group -SO-R ¹ of the formula or aryl-sulfinyl group, alkylsulfonyl group -SO ₂ -R ² Formula I, or arylsulfonyl group, and a cyano or azido; wherein the R ^6, R ⁷ and R R ¹ and R ^{2 in the} substituents ⁸ are independently hydrogen, C 1-10 alkyl, alkenyl or alkynyl; cycloalkyl, cycloalkyl-substituted alkyl or alkyl-substituted cycloalkyl, wherein the cycloalkyl ring may contain from 3 to 6 carbon atoms and the alkyl moiety

1-6 carbon atoms; an aryl group such as phenyl; aralkyl, aralkenyl or aralkynyl wherein the aryl is phenyl and the aliphatic moiety may contain from 1 to 6 carbon atoms; heteroaryl, heteroaryl-substituted alkyl, heterocyclyl, and heterocyclyl-alkyl, wherein said heterocyclic group may contain from 1 to 4 heteroatoms selected from oxygen, nitrogen and / or sulfur, and the alkyl groups attached to said heterocyclic groups may have from 1 to 6 carbon atoms; European Patent Applications 1627, 1628, 10,317, 17,992, 37,080, 37,081 and 37,082;

3) European Patent Application 24,832 discloses compounds of formula 29 wherein R ¹ is hydrogen, hydroxy,

A sulfuric acid ester group of the formula -OSOjH, or a salt thereof, or an alkyl ester thereof containing from 1 to 4 carbon atoms, and -OR ² , -SR ³ , -OCOR ² , -OCO ₂ R ³ or -OCONHR ³ , wherein R ² is 1 -C 6 alkyl or optionally substituted benzyl, and R ⁶ is C 1 -C 6 alkyl, or optionally substituted benzyl or phenyl, and

R ¹² is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 alkynyl where the triple bond is on a carbon atom other than sulfur, aralkyl, C 1 -C 6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl. wherein any of the R ¹² groups may optionally be substituted as antibacterial agents.

The number of European Patent Application 38,869 mentioned above discloses carbapenem derivatives of the formula (30) wherein R ⁶ and R ⁷ are as defined above, and

^R2 is a readily removable carboxyl protecting group, for the preparation of intermediates. This application also describes intermediates of general formula (31) wherein X is a leaving group.

However, as mentioned above, carbapenem derivatives containing the substituents at the 2-position in formula (f) and carbapenem derivatives at the 2-position in the general formula (g) have been described in the literature, wherein in formula (g)

R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-substituted alkyl, alkyl-substituted cycloalkyl, phenyl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaryl-substituted alkyl, heterocyclyl-substituted

No. 190,716, to the applicant's knowledge, have not disclosed carbapenem derivatives in which the alkylene group A in the 2-position substituent is directly attached to a sulfonium group. 5

Despite the fact that a large number of carbapenem derivatives have been described in the literature, there is still a need for new carbapenem derivatives, which would be more advantageous than those known to have a broader spectrum of activity, higher activity, more stable and / or less toxic side effects.

The present invention relates to a series of novel carbapenem derivative which substituents at the 2-position a, is represented by the following formula (a) wherein the specified 15, R ¹⁰ and R ¹¹ in the introduction of (a) wherein .

More particularly, the present invention relates to a process of formula (I) wherein:

R ¹ is hydroxy (C 1 -C 4) alkyl; 20

A is an alkylene group having 2 to 4 carbon atoms;

R ² is hydrogen, an anionic charge, or p-nitrobenzyl, provided that when R ² is hydrogen or p-nitrobenzyl, a counterion is present in the molecule;

R ¹⁰ and R ¹¹ taken together are tetramethylene or pentamethylene to form carbapenem derivatives. 30

The compounds of formula (I) exhibit potent antibacterial activity or may be used as intermediates for the preparation of such agents.

The novel compounds of formula (I) above contain the carbapenem backbone of formula (Ia) and may thus be referred to as 1-carba-2-penem-3-carboxylic acid derivatives. This backbone may also be numbered in other ways as shown in Formula 1b, and such compounds may be referred to as 7-oxo-1-azabicyclo [3.2.0] -hept-2-ene-2-carboxylic acid derivatives. Although the present invention encompasses all compounds in which the protons at the 5 and 6 positions are cis relative to each other and those in which the protons occupy the trans position, the preferred compounds of the present invention The configuration of the carbon atoms at positions 5 and 45 is similar to that of thienamycin: 5R, 6S (trans).

The term "conventional, easy-to-cleave carboxyl protecting group" refers to known ester groups that have been used previously to protect the carboxyl group during the chemical reactions described below and which may be cleaved, if desired, by methods known in the art. such as chemical or enzymatic hydrolysis, treatment with mild conditions, chemical reducing agents, irradiation with ultraviolet light, and catalytic hydrogenation. Such ester-type protecting groups include, for example, benzhydryl, ρ-nitrobenzyl, 2-naphthylmethyl, benzyl, trichloroethyl, θθ-silyl, such as trimethylsilyl, and phenacyl, ρ-methoxy. benzyl, acetonyl, ο-nitrobenzyl, 4-pyridylmethyl and C 1-6 alkyl groups such as methyl, ethyl or tert-butyl. Also included are protecting groups which are hydrolyzed in the body, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly preferred carboxyl protecting group is the p-nitrobenzyl group, which is readily cleaved by catalytic hydrogenolysis.

The compounds of formula (I) are useful as antimicrobial agents and are valuable intermediates which can be converted to the aforementioned biologically active compounds.

Preferred are compounds of formula I according to the present invention wherein

R 'is 1-hydroxyethyl or 2-hydroxy-2-propyl.

The absolute configuration of the most preferred compounds is 5R, 6S, 8R.

The alkylene group A in the compounds of formula (I) may be straight or branched and may contain from 2 to 4 carbon atoms. Preferred compounds are those compounds of formula I wherein A is - (CH ₂ ) _n - wherein n is 2, 3 or 4, and particularly preferred are compounds wherein A is ethylene.

Particularly preferred are compounds of formula I wherein R ¹ is 1-hydroxyethyl, the absolute configuration of the preferred compounds being 5R, 6S, 8R.

Most preferred are the compounds of formula I according to the present invention wherein A is ethylene and wherein

R ¹ is 2-hydroxy-2-propyl or 1-hydroxyethyl.

Most preferred compounds of the present invention are those compounds of formula (Ic) wherein R ² is hydrogen, an anionic charge or p-nitrobenzyl, with the proviso that when R ² is hydrogen or a protecting group, the molecule also has an anion. .

All such optical isomers and epimers are within the scope of the present invention. Similarly, in some cases, a substituent at the 6-position, such as a hydroxyethyl group, may have the R or S configuration and the resulting isomers and epimeric mixtures are also within the scope of the present invention.

The carbapenem derivatives of formula (I) according to the present invention are represented by formula (ΠΙ) wherein R 'is as defined above, and

R ² 'is a conventional, easily cleaved carboxyl protecting group, prepared from starting materials. Compounds of formula (III) are described, for example, in European Patent Application No. 38,869 (compound of formula 7), and can be prepared by the general methods described in that application.

Compounds of formula (I) are prepared from compounds of formula (III) according to Scheme A.

The procedure illustrated in Scheme A is described in detail below:

The starting compound (ΠΙ) in an inert organic solvent such as dichloromethane, acetonitrile or dimethylformamide in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine or the like, is about equivalent

-61,190 diphenyl chlorophosphate to give intermediate IV. The diphenylphosphoryloxy group is introduced into the 2-position of the starting compound (III) as a leaving group such that the above reaction is preferably carried out at a temperature of about -20 ° C to about 40 ° C, and preferably about 0 ° C. let's do it. If desired, the intermediate of formula (IV) may be isolated but conveniently used in the next step without isolation or purification. n

Intermediate (IV) is then converted to intermediate (V) by a conventional substitution reaction. For this purpose, the intermediate of formula (IV) is in a base organic solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile, a base such as diisopropylethylamine, triethylamine. in the presence of sodium bicarbonate, potassium carbonate or 4-dimethylaminopyridine, about one equivalent of the mercaptan-2 derivative of the formula HS-A-OH. The temperature of this substitution reaction is not critical, but is preferably from about -40 ° C to + 25 ° C. Most conveniently, the reaction is carried out under cooling, for example at about 0 ° C. 2

The intermediate (V) is then acylated in an inert organic solvent, in the presence of a base, with methanesulfonyl chloride or an equivalent reagent such as methanesulfonic anhydride to form the cleavage group on the methane sulfoxide of intermediate (VI). . This acylation is carried out in an inert solvent such as tetrahydrofuran, dichloromethane, acetonitrile or dimethylformamide in the presence of a suitable base such as diisopropylethyl-3-amine, triethylamine, 4-dimethylaminopyridine and the like. The reaction may be carried out over a wide range of temperatures, for example at temperatures between -40 ° C and +40 ° C, but most preferably with cooling, for example between about -30 ° C and -40 ° C.

Intermediate (VI) is then subjected to a substitution reaction to provide intermediate (II) containing the iodo atom as the leaving group. It has been found that this cleavage group 4 particularly facilitates the preparation of final products containing the carbapenem base of formula (I). Therefore, the use of intermediates of formula (II) is a preferred embodiment of the process of the invention.

Substitution of the methanesulfonyloxy group as a protecting group is accomplished by reacting a compound of Formula VI with an iodide ion reactant in an inert organic solvent such as acetone, dimethylformamide or dimethylsulfoxide. Reagents which may be used are any compound which, when dissociated in a solvent, produces iodide ions such as alkali metal iodides such as sodium iodide and potassium iodide. The temperature of the substitution reaction is not critical, but it is most preferable to operate at room temperature or above to ensure that the reaction does not proceed for too long. The iodide ion-supplying reagent is used in an amount such that

716 ^{2 to provide} about one equivalent or more of iodide ion.

The desired carbapenem derivatives of formula (I) are prepared by carrying out a nucleophilic substitution reaction wherein the cleavage group of intermediate (II), iodine, is replaced by the desired group (h). To this end, the intermediate of formula (II) in an inert organic solvent in the presence of silver ions) k sulfide with at least one equivalent and preferably an excess amount of ^r Vant. Suitable inert organic solvents include tetrahydrofuran, dioxane, dichloromethane, diglyme, dimethoxane-ethane and the like. As silver ion delivery reagent, any silver compound which substantially dissociates in the solvent can be used to provide silver ions and an inert anion such as silver perchlorate. Generally, silver ions are used in an equivalent amount to intermediate 3 to facilitate the substitution reaction. The reaction may be carried out over a wide range of temperatures, for example from about -25 ° C to about + 25 ° C, but preferably about 0 ° C. Intermediate (Γ) is in equilibrium with an anion (derived from the silver salt employed) which may be substituted at this stage of the synthesis by another anion, such as a pharmaceutically acceptable anion, by methods known per se. Alternatively, this anion is as follows. the deprotection step is also removed.

The R ² 'carboxyl protecting group of intermediates of formula (Γ) may be cleaved by methods known per se such as solvolysis, chemical reduction, or hydrogenolysis. The p-nitrobenzyl group containing intermediate (Γ) in a suitable solvent such as dioxane, water and ethanol, tetrahydrofuran / aqueous dipotassium hydrogen phosphate solution and isopropanol or the like is a hydrogenation catalyst such as palladium on carbon. , palladium hydroxide, platinum oxide or the like at temperatures between 0 ° C and 50 ° C for about 0.24 hours to 4 hours, 1 · 10 ⁵

It can be hydrogenated at a pressure of from 4 to 10 · 5 ⁵ Pa.

The novel carbapenem derivatives of formula (I), wherein R ² is hydrogen, an anionic charge or p-nitrobenzyl group exhibit potent antibiotic activity with various Gram-positive and Gram-negative bacteria and can thus be used as growth-promoting additives in animal feed as preservatives, as bactericides in industrial processes, such as in paper mills, in water-soluble paints or in washing water, in which the growth of harmful bacteria is inhibited by these compounds, and as disinfectants in medical and dental instruments to inhibit the growth of harmful bacteria. These compounds are particularly useful in the treatment of infectious diseases caused by Gram-positive or Gram-negative bacteria in humans and animals.

The pharmacologically active compounds of the present invention may be used alone or in the form of pharmaceutical compositions which are carbapenem

They contain, in addition to the active ingredient 190 716, a pharmaceutically acceptable carrier or diluent. These compounds can be administered by a variety of routes, with the most important routes being oral (oral), topical and parenteral (bypassing the gastrointestinal tract), i.e., intravenous (via the vein) and intramuscular (into the muscle). dosage. The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, and the like, or in liquid form such as solutions, suspensions, and emulsions. These compounds are preferably administered by injection, the injection compositions can be used in ampoules as unit dosage forms, and in multi-dose formulations, and may contain formulations, stabilizers and dispersants necessary for the formulation of the dosage forms.

These formulations may be in a ready-to-use form or in powder form for reconstitution with a suitable vehicle, such as sterile water, prior to administration. 20

The dosage employed will depend to a large extent on the particular active ingredient, the formulation, the mode of administration, the nature and condition of the patient, and which part of the body is being attacked by the particular microorganism. The dose and route of administration should be determined by the treating physician. Generally, however, these compounds are administered parenterally or orally to mammals at daily doses of about 5 mg to about 200 mg / kg body weight. The compounds are generally administered in divided doses, for example three to four times daily.

A. To illustrate the potent broad-spectrum antibacterial activity and low toxicity of the carbapenem derivatives of the present invention, both under in vitro and in vivo conditions, the preferred carbapenem derivative of the present invention is described below as described in Example 1. Prepared from 3- [2- (1-Tetrahydrothiophenium) ethylmercapto] -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene carboxylate [Formula (Ia]] 40 biological data.

STATEMENT OF IN VITRO EFFECT

A sample of the above carbapenem derivative is dissolved in water, diluted in culture medium, and cultured in the presence of this solution at 37 ° C overnight in the presence of this solution. The minimum inhibitory concentration (MIC) values determined by the dilution method are given in the table below. N-formimidoyl-thienamycin was used as reference compound.

Demonstration of in vivo effects

The in vivo therapeutic efficacy of the compound prepared as described in Example 1 and 55 N-formimidoyl-thienamycin was determined by experimentally infecting mice with various microorganisms listed in the table below and then administering the two compounds intramuscularly to the animals. The loading table 60 is shown in the PD values are _S0 (the PD _50, in mg / kg dose which protects 50% of the infected mice).

Mice were treated intramuscularly with the microorganisms A21559, A15167-2, A9900, A9843a, A20481, and 20599 at 65 and 2 hours after infection, and with the other microorganisms at 1 and 3.5 hours after infection, respectively; five mice were used in each group.

The in vitro antibacterial activity of the carbapenem derivative prepared as described in Example 1

MIC Otg / ml) (Ia) N-formimidoyl-thienamycih

Micro-organism

S. pneumoniae A-9585 0,002 0,004 S. pyogenes A-9604 0,004 0,001 S. aureus A-9537 0,008 0,004 S. aureus + 50% serum A-9537 0.03 0,016 S. aureus (Pen. Res.) A-9606 0,016 0,008 S. aureus (Meth. Res.) A15097 2 0.5 S. faecalis A20688 0.5 0.5 E. coli (10 ⁴ ) dilution A15119 0.03 0,016 Dilution of E. coli (10 ^-3 ) A15119 0.06 0.03 E. coli (10 ^'1) dilution A15119 0.06 0.06 E. coli (10 ⁴ ) dilution A20341-1 0.03 0.03 Dilution of E. coli (10 ^-3 ) A20341-1 0.03 0.03 E. coli (10 ~ ² ) dilution A20341-1 0.06 0.13 K. pneumoniae A-9664 0.06 0.13 K. pneumoniae A-20468 0.13 0.06 P. mirabilis A-9900 0.13 0.06 P. vulgaris A21559 0.03 0.03 P. morganii A15153 0.06 0.13 P. rcttgeri A22424 0.25 0.25 S. marcescens A20019 0.06 0.03 E. cloacae A-9659 0.13 0.06 E. cloacae A-9656 0.13 0.06 P. aeruginosa A-9843 1 1 P. aeruginosa A21213 0.25 0.25 H. influenza A-9833 8 16 H. influenza A20178 8 32 H. influenza A21518 8 32 H. influenza A21522 8 32 B. fragilis A22862 0.06 0,016 B. fragilis A22053 0.06 0.06 B. fragilis A22696 0.25 0.13 B. fragilis A22863 0.06 1

Demonstration of protective activity of intramuscularly administered drugs in infected mice

Micro-organism

Infection (number of microorganism cells introduced)

PD _sl) / treatment (mg / kg) N-formimidoyl'-thienamicin

S. aureus A-9606 1 x 10 ' 0.19 0.07 * E. coli A15119 6 x 10 ⁶ 1.6 2.2 * K. pneumoniae A-9664 7 X 10 ⁶ 5 2.4 * E. cloacae A-9659 4 x 10 ⁶ 1.3 - P. mirabilis A-9900 4 x 10 ⁶ 7.7 * 3/15 * P. vulgaris A21559 4 X 10 ⁵ 3.3 - P. rettgeri A15167-2 3 X 10 ⁷ 8.7 6.9 M. morganii A15149 7 x 10 ⁵ 3.3 - S. marcescens A20335 9 x 10 ⁶ 5 __ P. aeruginosa A-9843 3 X 10 ⁴ 0.6 0.5 * P. aeruginosa A20481 3 x 10 ⁴ 0.8 0.4 P. aureginosa A20599 9 X 10 ⁴ 1.3 -

• Literature data.

190,716

TOXICITY

Toxicity of the compound prepared as described in Example 1 was determined in mice by intracranial (intracranial) administration. The results are shown in the table below.

Intracranial toxicity in mice

Compound LD _S0 * (mg / kg) It is the highest, not yet causing clinical toxic symptoms dose (mg / kg) la > 40 -5 N-formimidoyl thienamycin 32 5 ~

• Average of 25-25 mice per compound.

DETERMINATION OF BLOOD LEVELS AFTER INTRAMUSCULAR DOSAGE IN MOUSE

Mice are dosed intramuscularly with 20 mg / kg of the compound prepared as described in Copy 1 and N-formimidoylthienamycin, and blood levels and half-lives are determined. The compounds were administered at pH 7, dissolved in 0.1 M phosphate buffer. The values in the table below are from a single assay using four mice per compound.

Vérsziní (/ ug / ml) Half-life _v ... postdose time GAT * ^egyUCt 10 20 30 45 60 90 t _{I / 2,} gg-hr / ml, min 14.7 13.5 8.7 3 minutes Ia, 2 0.9 <0.6 9 7.4

N-formimidoiI- _{6 η 3 2 6 ö? <0 3 9 6}

-thienamycin * GAT = Area under the curve.

QUANTITY OF ACTIVE SUBSTANCE FOR URINE The compound prepared as described in Example 1 and

Urinary excretion of N-formimidoyl-thienamycin in mice was determined by intramuscular administration of the active compounds at a dose of 20 mg / kg. The active compounds were administered at pH 7, dissolved in 0.1 M phosphate buffer. The values in the table below are the results of a single experiment using four mice per compound.

Urinary excretion of 20 mg / kg intramuscularly in mice

The amount of active substance excreted in urine is the amount administered

% Of compound dose is first

0-3 3-6 6-24 0-24 hours la 15.6 2.1 <0.2 17.7 ± 2.9

N-formimidoyl-thienamycin 12.1 0.1 <0.1 12.2 ± 3.6

The invention is further illustrated by the following non-limiting Examples.

Example 1

3- [2- (tetrahydro-I-dibenzothiophenium) ethylthio] -6a [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2- Preparation of Carboxylate (Formula Ia) (Scheme B) Step a /

3- (2-Hydroxyethylmercapto) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p-nitro) benzyl) ester

1.69 g (4.85 mmol) of 6a- [1- (R) -hydroxyethyl] -3,7-dioxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p A solution of the nitrobenzyl ester (IIIa) in acetonitrile (20 mL) was cooled to 0 ° C under nitrogen. A solution of diisopropylethylamine (726 mg, 7.18 mmol) in acetonitrile (2 mL) was added dropwise over a period of 3 min. The reaction mixture was stirred for 20 minutes at 0 ° C to give 3- (diphenylphosphoryloxy) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2- There is thus obtained en-2-carboxylic acid (p-nitrobenzyl) ester. To this solution was added a solution of diisopropylethylamine (726 mg, 7.18 mmol) in acetonitrile (2 mL) followed by a solution of 2-mercaptoethanol (439 mg, 5.63 mmol) in acetonitrile (2 mL). After stirring for 3 hours at 0 ° C, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (200 mL), then with 20% aqueous phosphoric acid (100 mL), and brine. The solution dried over magnesium sulfate gave the solvent by distillation to a semi-solid residue which was triturated with dichloromethane and filtered to give a solid. This gave 1.2 g (61%) of the title compound (Va) as a white amorphous solid.

Nuclear Magnetic Resonance Spectrum (DMSO-d6 ₎ δ 1.20 (3H, d,

J = 6.0 Hz), 2.9-3.2 (9H, m), 5.22 (1H, d, J = 8.5 Hz), and 8.23 (2H, d, J = 8), 5 Hz).

IR (KBr) _vmax: 3500, 1770 and 1700 cm ^1st

Calculated for C ₈ H ₂ oN ₂ 0 ₇ S Formula:

Found: C, 52.93; H, 4.94; N, 6.86; S, 7.85;

Found: C, 52.83; H, 4.90; N, 6.42

S, 8.31%.

b / Step

3- (2-Methanesulfonyloxyethylmercapto) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p) -nitrobenzyl) ester (Scheme C)

To a solution of Va (4.2 g, 10.3 mmol) in tetrahydrofuran (200 mL) was added methanesulfonyl chloride (1.3 g, 11.3 mmol) at -40 ° C and 1.26 g (12 g) were added dropwise. (4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The reaction mixture was then stirred at -40 ° C for 5 hours and then at -30 ° C for a further 2 hours under nitrogen. It is then poured into a biphasic mixture of 700 ml of ethyl acetate and 1000 ml of 6% aqueous phosphoric acid solution, the ethyl acetate portion is separated,

It was washed with 190,716 brine, dried over magnesium sulfate and the solvent was distilled off. The syrup-like residue was purified by silica gel column chromatography (eluent: dichloromethane: ethyl acetate = 3: 1). This gave 3.95 g (75%) of the title compound as a white amorphous solid.

NMR (CDC1 _3, delta): 1.25 (3H, d, J = 6.0 Hz), 3.05 (3H, s), 3.06-3.40 (5H, m), 4 05-4.40 (4H, m), 5.25 (1H, d, J = 14Hz), 5.50 (1H, d, J = 14Hz), 7.70 (2H, d, J = 8) , 5 Hz), and 8.23 (2H, d, J = 8.5 Hz). IR KBr lambda max: 3400, 1770 and 1600 ^first Analysis for C39H22N2O9S2:

Found: C, 46.90; H, 4.56; N, 5.76.

Found: C, 46.52; H, 4.32; N, 5.91.

c / Step

3- (2-Iodoethylmercapto) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p-nitro) benzyl) ester (Scheme D)

A solution of intermediate (Via) (350 mg, 0.72 mmol) and sodium iodide (216 mg, 1.4 mmol) in acetorinal (20 mL) was heated to reflux for 4 hours. The acetone was then distilled off and the resulting white amorphous solid was filtered off and dried under reduced pressure. This gave 300 mg (80%) of the title compound (Ha) as a white amorphous powder.

NMR _(DMSO-d6) delta: 1.18 (3H, d, J = 6.0 Hz), 3.20-3.60 (7H, m), 3.80 to 4.25 (2H , m), 5.10 (1H, d, J = 5.5 Hz), 5.25 (1H, d, J = 12.0 Hz), 5.45 (1H, d, J = 12.0 Hz) ), 7.70 (2H, d J = 8.5 Hz) and 8.27 (2H, d, J = 8.5 Hz).

IR (KBr) _p: 3500, 1768 and 1700 cm ^1st

Analysis using the formula C ^ Hig ^ CM:

Calculated: C, 41.71; H, 3.70; N, 5.41; 24.48;

Found: C, 42.10; H, 3.75; N, 5.97.

I: 23.20%.

d / step

3- [2- (l-Tetrahydro-dibenzothiophenium) ethylthio] -6a [l- (R) -hydroxyethyl] -7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2- carboxylate (Scheme E) (Scheme E)

104 mg (0.2 mmol) of 3- (2-iodoethylmercapto) -6a- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-en-2 To a solution of the carboxylic acid (p-nitrobenzyl) ester in 5 ml of tetrahydrofuran was added 0.3 ml (0.35 mmol) of tetrahydrothiophene, followed by 60 mg (0.3 mmol) of silver perchlorate in 0.5 ml tetrahydrofuran. After stirring for 1 hour at room temperature, the solvent was distilled off under reduced pressure. This gives a yellow sticky substance (formula). Trituration of this intermediate with 100 mL of Celite gave an amorphous solid.

IR (KBr), p _MAA: 3400, 1772, 1700 and 1100 cm ^1st

This compound of formula (a) is then hydrogenated without further purification as follows:

To a suspension of the above compound (I'a) in a mixture of diethyl ether (20 mL) and tetrahydrofuran (20 mL) was added potassium bicarbonate (40 mg, 0.4 mmol) and dipotassium hydrogen (35 mg, 0.2 mmol). phosphate in 20 ml of water was added 120 mg of palladium on carbon and the mixture hydrogenated at 10% for 1 hour, 2.76 XlO ⁵ psi in a Parr shaker. The catalyst is then filtered off and washed twice with 5 ml of water. The combined filtrate and washings were washed with diethyl ether (2 x 50 mL) and freeze-dried. The residue, a yellow powder which was purified by a 7g Cit spent Bondapak reverse phase silica gel (Waters Associates) column 5,52xlO high pressure using a ⁴ psi pressure liquid chromatography, eluting with water and 15 ml fractions collected. Fractions showing ultraviolet absorption at 300 nm were combined and freeze-dried. This gave 12 mg (18% yield of Ha) of the title compound as a white solid.

Nuclear Magnetic Resonance Spectrum (D ₂ O), δ 1.23 (3H, d, J = 6.0)

Hz), 2.25-2.45 (4H, m), 3.0-3.70 (11H, m), 3.95-4.30 (2H, ni).

IR (potassium bromide) max 3400, 1760 and 1590 cm @ -1.

UV spectrum, λ _max (ethanol) 289 m (ε = 6200).

Claims (7)

A process of the formula I wherein R ¹ is hydroxy (C 1 -C 4) alkyl, A is an alkylene group having 2 to 4 carbon atoms, R ² is hydrogen, an anionic charge, or p-nitrobenzyl, provided that when R ² is hydrogen or p-nitrobenzyl, a counterion is present in the molecule, and R ¹⁰ and R ¹¹ together are tetramethylene or penfamethylene group for the preparation of compounds wherein a,) (1) is a compound of formula III wherein R * is as defined above and R ² 'is a conventional, easily cleaved carboxyl protecting group, preferably p-nitrobenzyl, in an inert organic solvent, in the presence of a base, reacted with diphenyl chlorophosphate, (2) where R' and R ² 'is reacted with mercaptan of formula HS-A-OH in the presence of a base, in the presence of a base, in an inert organic solvent, followed by (3) the resulting intermediate of formula (V) wherein R ¹ , A and R ² 'in the above inert solvent, in the presence of a base, are reacted with methanesulfonyl chloride or an equivalent acylating agent, (4) the resulting intermediate of formula (VI) wherein R ¹ , A and R ² 'are reacted with iodide ion reactant in the above inert organic solvent and finally (5) the resulting intermediate of formula (Π), wherein R *, A and R ² 'in the above nucleophilic substitution reaction are either neutral -101 In an organic solvent in the presence of silver ions, 190 716, R '-S-R, wherein R' and R are as defined above, is reacted with a sultide, if desired. Of the general formula (T) wherein 5 X is an anion, and R '. A. R '. R and R ² 'are as defined above. R ² 'is removed from the compound of formula (2) or a_) is a compound of formula II. where K ^! es If ifese is below, and R 'is a conventional, easily removable, carhoxyl protecting group. preferably p-nitrobenzyl. 15 cosylenes in a nucleophilic substitution reaction in an inert organic solvent in the presence of silver ions. R'-SR. wherein R ¹ and R are as defined above. React with Valid. and nvert is a compound of formula (Γ). Wherein is an anion, and R '. A. R '. R and R ² 'are as defined above. If desired, the R ² 'carboxyl protective esoprol is removed if desired. 25 A process according to claim I for the preparation of compounds of general formula (I) wherein: R 'is 2-hydroxy-2-propyl or 1-hydroxyethyl, and R '. R. A and R ^{2 are} as defined in claim 1. characterized by being (Π), '(III). We start from compounds of the formulas HS-A-OH and R'-SR. aho! ₃₅ R 'a down. and R '. R. A and R ^{2 are} as defined in claim I., .1. The process of claim I for the preparation of compounds of general formula ti). where R 'is 1-hydroxyethyl. and R R ¹⁰ , R, A and R ^{2 are} as defined in claim 1, characterized by. so fllj. (III), starting from the HS-A-OH and R ^l0 from compounds of formula -SR ^11, wherein R ^{1 is} as defined above and R ^lu. R ¹¹ . A and R ^{2 are} as defined in claim 1. A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is 1-hydroxyethyl. and the absolute configuration of the compound is 5R, 6S, 8R, and R ¹⁰ . R. A and R ^{2 are} as defined in claim 1. that is (II). '(III). We start from compounds of the formulas HS-A-OH and R ¹⁰ -SR. wherein R ^{1 is} as defined above and R ¹⁰ . R ¹¹ . A and R ^{2 are} as defined in claim 1. 5. A process according to any one of claims 1 to 6 for the preparation of compounds of formula I wherein A is ethylene and R ¹ . R ² . R ¹⁰ and ^{11 are} as defined in claim 1. such that (11) / (111). We start from compounds of the formulas HS-A-OH and R ¹⁰ -SR ⁿ . where A is as defined above and R is ¹ . R ² . R ¹⁰ and R ^{11 are} as defined in claim 1. 6. The process of claim 1 is a general image (Ic). where R ^; represents a hydrogen atom, an anionic charge, or pnitrobenzyl group. with the proviso that when R ² is hydrogen or p-nitrobenzyl. then there is an anion attached to the molecule. chemical compounds and their pharmaceutically acceptable salts. characterized in that it is based on appropriately substituted materials. A process for the preparation of compounds of formula (Ic) according to claim 6, wherein R ² is a p-nitrobenzyl group, characterized in that. starting from properly substituted materials. The process for the preparation of compounds of formula (Ic) according to claim 6, wherein R ² is an anionic charge, characterized in that it is based on appropriately substituted materials.