HU197904B - Process for producing carbapenem antibiotics - Google Patents

Abstract

Disclosed is a new and more efficient process for producing carbapenem antibiotic derivatives having a 2substituent of the general formula <IMG> in which A represents a C1-C6 straight or branched chain alkylene group; R5 represents an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heteroaryl, heteroaraliphatic, heterocyclyl or heterocyclyl-aliphatic radical; and <IMG> represents a nitrogen-containing aromatic heterocycle attached to the alkylene group A at a ring carbon atom and quaternized by substituent R5.

Description

The present invention relates to a novel carbapenem derivative of formula IA; in this formula

A is a C 1-4 alkylene group,

R ¹ is C 1-4 alkyl substituted by hydroxy,

R ⁵ and R ⁶ are independently C 1 -C 6 alkyl,

R ¹⁵ is C 1-4 alkyl or hydrogen.

Such a carbapenem derivative having a chemical structure having antibacterial activity is disclosed in German Patent Application Publication No. 3334937. They are in the general formula (I)

R ⁸ * is hydrogen;

R 'is hydrogen; optionally substituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl (C 3 -C 6) -cycloalkyl (C 1 -C 6) -alkyl, phenyl, in the aliphatic moiety of 1 to 6, respectively Phenyl-alkyl, phenylalkenyl or phenylalkynyl containing from 2 to 6 carbon atoms, having 1 to 4 nitrogen and / or oxygen or sulfur atoms as heteroatoms and optionally having from 1 to 6 carbon atoms in the alkyl moiety, five or six membered heterocyclic or heterocyclylalkyl, wherein the groups listed herein may optionally have one or more of the following substituents: phenyl; aralkyl, aralkenyl or aralkynyl wherein aryl is phenyl and the aliphatic moiety is C 1-6; heteroaryl, heteroaralkyl, heterocyclic and heterocyclylalkyl, wherein the above heterocyclic groups contain from 1 to 4 oxygen and / or nitrogen and / or sulfur atoms as heteroatoms and the alkyl groups to which the heterocyclic groups are attached have from 1 to 6 carbon atoms; and the groups listed above contain one or more of the following substituents:

C 1-6 alkyl optionally substituted with amino, halogen, hydroxy or carboxyl; halogen; -OR ³ ; -OC (O) -NR ³ R ⁴ ; -C (O) -NR ³ R ⁴ ; -NR ³ R ⁴ radical; -C (= NR ³ ) -NR ³ R ⁴ ; -S (O) 2 -NR ³ R ⁴ ; -NHC (O) -NR ³ R ⁴ ; R ³ C (O) -NR ⁴ - or a group of formula -CO2R ^3; = 0; -OC (O) R ³ ; -SR ³ ; -S (O) R ⁹ ; -S (O) 2 R ⁹ ; -CN; -N3; -OSO ₃ R ³ ; -OS (O) ₂ R ⁹ ; -NR ³ S (O) R ⁹ &gt; -OP (O) (OR ³ ) (OR ⁴ ) 2; -NR ³ C (R ³ ) = NR ⁴ ; -NR CO2R ^{3 4} radical; -NO2; wherein, for the substituents listed above, R ³ and R ⁴ are independently hydrogen; C 1 -C 10 alkyl, alkenyl or alkynyl; cycloalkyl, cycloalkylalkyl or alkylcycloalkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms and the alkyl group contains from 1 to 6 carbon atoms; phenyl; aralkyl, aralkenyl or aralkynyl wherein aryl is phenyl and the aliphatic moiety is C 1-6; heteroaryl, heteroaralkyl, heterocyclic or heterocyclylalkyl, wherein the heterocyclic groups listed above contain from 1 to 4 oxygen and / or nitrogen and / or sulfur atoms as heteroatoms, and the alkyl groups to which the heterocyclic groups are attached are from 1 to 6 carbon atoms; obsession

R ³ and R ^{4 taken} together with the nitrogen atom to which at least one of them is attached form a 5- or 6-membered nitrogen containing heterocyclic ring;

R ⁹ has the same meaning as R ³ except that it cannot be hydrogen; obsession

R ¹ and R ⁸ together may form a C 2 -C 10 alkylidene group substituted with a hydroxy group;

R ^? is C 1 -C 10 alkyl, alkenyl or alkynyl; cycloalkyl or cycloalkylalkyl wherein the cycloalkyl ring contains from 3 to 6 carbon atoms and the alkyl group contains from 1 to 6 carbon atoms; phenyl; aralkyl, aralkenyl or aralkynyl wherein aryl is phenyl and the aliphatic moiety is 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclic or heterocyclylalkyl, wherein the heterocyclic groups listed above contain from 1 to 4 oxygen and / or nitrogen and / or sulfur atoms and the alkyl groups to which the heterocyclic groups are attached are from 1 to 6 carbon atoms; and the groups listed in R ⁵ are optionally substituted with 1 to 3 substituents:

C 1-6 alkyl optionally substituted with amino, fluoro, chloro, carboxyl, hydroxy or carbamoyl; fluorine, chlorine or bromine; -OR ³ ; -OCO2R ³ radical; -OCOR ³ ; -OCONR ³ R ⁴ ; -OS (O) 2 R ⁹ ; O; -NR ³ R ⁴ radical; CONR ³ R ⁴ - radical; -NR CO2R ^{3 4} radical; -NR ³ CONR ³ R ⁴ radical; -NR ³ S (O) R ⁹ &gt; -SR ³ ; -S (O) R ⁹ ; -S (O) 2 R ⁹

-2197904; -SO ₃ R ³ ; -CO2R group of the formula ^3, -CONR ³ R ⁴ radical; -CN; or phenyl optionally substituted with 1-3 fluoro, chloro, bromo, C 1-6 alkyl, -OR ³ , -NR ³ R ⁴ , -SO ³ R ³ , -CO ₂ R ³ or -CONR ³ R ⁴ wherein R ³ , R ⁴ and R ⁹ are as defined above; or at another point in the ring, R ^{5 may be} attached to the ring of formula (b) to form a fused heterocyclic or heteroaromatic ring which may contain additional oxygen and / or sulfur and / or nitrogen atoms as heteroatoms;

Ar is a straight or branched alkylene group containing from 1 to 6 carbon atoms;

R ² * is hydrogen, anionic charge, or a conventional, easily removable, carboxyl protecting group, provided that when R 1 is hydrogen or protecting group, a counterion is present;

the group of formula (b) is a substituted or unsubstituted, mono-, bi- or polycyclic aromatic heterocyclic group containing at least one nitrogen atom in the ring, one of the carbon atoms of which is attached to A and the nitrogen atom of the ring is quaternized with R ⁵ *. with the exception of the pyridinium ion substituted on the ring carbon atoms with 1 to 4 carbon atoms and attached to the ring A via the carbon atoms of the ring -

The compounds of formula (I) are prepared as described in Scheme A and, respectively, in Scheme B, respectively. A compound of formula III wherein R '* and R® are as defined above, R ² ' is a protecting group, in an organic solvent, such as dichloromethane, acetonitrile or dimethylformamide, with about equimolar amounts of R 0 -L, such as p- toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-triisopropylbenzenesulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, diphenylphosphate, toluene, benzenesulfonyl chloride, etc. wherein L is a suitable leaving group, such as toluene-s.sulfonyloxy, ρ-nitrobenzenesulfonyloxy, diphenoxyphosphinyloxy and the like. The reagent R 0 -L is prepared by known and conventional methods. Preferably, the reaction is carried out with a base such as diisopropylethylamine, triethylamine, 4- (dimethylamine) pyridine and the like to introduce the leaving group into the 2-position of the compound of formula (III). as such, at a temperature of -20 to -40 ° C, more preferably 0 ° C. In the intermediate of formula IV, the leaving group L may also be halogen. To prepare such an intermediate, the starting compound of formula (III) is reacted with a halogenating agent in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran, etc., a base such as diisopropylethylamine, triethylamine, 4- (dimethylamino) pyridine and the like. . presence. The halogenating agent is, for example, O ₃ PCl ₂ , O ₃ PBr ₂ , (OO) ₃ PBr ₂ , oxalyl chloride and the like.

The intermediate of formula (IV) is isolated if desired, but is conveniently used without further isolation or purification for the next step.

The intermediate of formula (IV) is then subjected to a conventional reaction in which the leaving group L is replaced by a desired group. Thus, the intermediate of formula (IV) is reacted with about an equimolar amount of a heteroaralkyl mercaptan of formula (VIII), wherein A is a straight or branched alkylene group having from 1 to 6 carbon atoms, and a group of formula (b) is mono-, bi or a polycyclic aromatic heterocyclic group containing a quaternary nitrogen atom in the ring and a carbon atom of the ring being attached to the A group. The reaction is carried out in an inert organic solvent such as dioxane, dimethylformamide, dimethyl sulfoxide or acetonitrile, a base such as diisopropylethylamine, triethylamine, sodium bicarbonate, potassium carbonate or 4- (dimethylamino) pyridine. presence. The temperature for this reaction is not critical, but is preferably between -40 ° C and 25 ° C. It is particularly preferred to carry out the reaction under cooling, for example from 0 ° C to -10 ° C.

The ring nitrogen of the heteroaralkyl group of intermediate (II) is quaternized by reacting compound (II) in an inert organic solvent with at least equivalent or at most about 50% molar excess of the alkylating agent (IX). Wherein R ⁵ is as defined above, X 'is a conventional leaving group such as halogen, such as chlorine, bromine or iodine, particularly preferably iodine, or a sulfonate ester group such as mesylate, tosylate or triflate. Suitable non-reactive organic solvents are, for example, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetone, dimethylsulfoxide or dimethylformamide. Temperatures for the alkylation reaction are not critical and values between 0 and 40 ° C are preferred. It is particularly preferred to carry out this reaction step at room temperature.

The intermediate of formula (tartalmaz) contains a counterion X 'which is derived, for example, from the alkylating agent used and which may be replaced by another counterion, which is more pharmaceutically acceptable, for example, at this step of the process or at a later step. after deprotection. Against3

-3197904 can be removed simultaneously with the deprotection.

The carboxy protecting group R ² 'is removed from the intermediate of formula (Γ) by conventional methods such as solvolysis, chemical reduction or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is removed by catalytic hydrogenation, the intermediate of formula (Γ) is used in a solvent such as dioxane, water, ethanol or tetrahydrofuran. , in a mixture of aqueous dipotassium hydrogen phosphate and isopropanol, and the like. with hydrogen at 100-400 kPa, hydrogenation catalysts such as palladium on carbon, palladium hydroxide, platinum oxide and the like. in the presence of 0 to 50 ° C for 0.24 to 4 hours.

For example, when R ² 'is an o-nitrobenzyl group, photolysis can also be used to remove it. Protecting groups such as 2,2,2-trichloroethyl can be removed by slight reduction with zinc. The allyl protecting group may be removed using a catalyst consisting of palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, dichloromethane or diethyl ether. Similarly, other carboxyl protecting groups may be removed by methods known to those skilled in the art.

Finally, compounds of Formula (Γ) wherein R ² 'forms a physiologically hydrolyzable ester group such as acetoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl may be administered directly to the treated subject. without deprotection, since these esters hydrolyze in vivo under physiological conditions.

The above known process has several disadvantages. For example, it consists of several steps and it may be advantageous to reduce the number of steps. Total production is quite low; and quaternization is performed with the carbapenem compound itself. It would be desirable to provide a novel process for the preparation of compounds of formula (I) which (1) consists of fewer steps, (2) provides higher yields, and (3) allows first the quaternized amine to be formed and only one at a later stage, to the carbapenem ring system, finally.

(4) more readily provide quaternary amine-containing products from a variety of amines, including spatial inhibitors and low pKb amines.

Accordingly, the present invention provides a process for the preparation of carbapenem side chain derivatives of formula (IA) having a chemotherapeutic, preferably antibacterial activity, having a 2-terminal pyridinium group; in formula IA

R ¹ is C 1-4 alkyl substituted by hydroxy

^R5 and ^R6 are independently C1-4 alkyl,

R ¹⁵ is C 1-4 alkyl or hydrogen,

A is a C 1-4 alkylene group.

Such a process is already known for preparing similar chemical structure as the above-mentioned, but a hydrogen atom, R ⁶ of formula (I) compounds of the invention at the priority date JEJE even in Hungarian? published later than the date of filing of the patent, the Hungarian Patent No. 192,431. The present invention provides a novel process for the preparation of novel compounds having beneficial effects not described in prior patents.

In the process of the present invention, an intermediate of formula IV wherein R ¹ and R ¹⁵ are as defined above, R ² 'is a conventional, easily removable carboxy protecting group, L is a conventional leaving group such as toluenesulfonyloxy, p-nitrobenzene sulfonyloxy, diphenoxyphosphinyloxy or halogen, in the presence of an inert solvent and a base, with a thiol of the formula VII wherein A, R ⁵ and R ⁶ are as defined above and X ^- is a counterhenylone, and the resulting compound of formula (IA ') wherein R ¹ , R ² ' R ⁵ , R ⁶ , R ' ⁵ , A and X- are as defined above is optionally deprotected. R ² '.

Thus, the process of the present invention provides carbapenem derivatives of formula (IA) and (IA ') and pharmaceutically acceptable salts thereof, as well as intermediates of formula (VII). '

The carbapenem compounds of formula IA are effective antibacterial agents or valuable intermediates in the preparation of such antibacterial agents.

Compounds of formula IA contain the carbapenem ring system of formula X and may therefore be referred to as 1-carba-2-penem-3-carboxylic acid derivatives. However, the compounds may also be considered to contain the basic structure of formula (XI) and may be referred to herein as the 7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid derivatives. Although the invention encompasses the preparation of any compound wherein the relative stereochemistry of the 5,6-proton is either cis or trans, 5R, 6S (trans) stereochemistry is preferred.

In the above schematic description of the process according to the invention, the term "conventional, easily removable carboxyl protecting group" refers to a known ester group which is used to protect a carboxyl group in the reaction steps described below and which may be removed by methods that do not result in major damage, such as chemical or enzymatic hydrolysis, treatment with reducing agents under mild conditions, ultraviolet light

-4197904 by irradiation or by catalytic hydrogenation. Examples of such ester protecting groups are benzhydryl, allyl, p-nitrobenzyl, 2-naphthylmethylbenzyl, trichloroethyl, silyl such as trimethylsilyl, phenacyl, p-methoxy. benzyl, acetonyl, ο-nitrobenzyl, 4-pyridylmethyl, and C 1-6 alkyl such as methyl, ethyl or tert-butyl. These protecting groups include those which undergo hydrolysis under physiological conditions. Examples include pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and methoxymethyl. A particularly preferred carboxyl protecting group is the p-nitrobenzyl group which is readily removed by catalytic hydrogenation. 15

Of the compounds of the formula (IA) obtainable by the process of the present invention, the group -CH ₂ - in the A position is particularly preferred.

R ¹⁵ is methyl, R ¹ stands for a generally compounds of formula CH ₃ CH (OH) group (IA) 20 well, of stereoisomers is the 5R, 6S, 8R compound absolute configuration.

The pharmaceutically acceptable salts mentioned above include non-toxic acid addition salts, for example, with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and the like. and acid addition salts with organic acids such as maleic acid, acetic acid, citric acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and malic acid. The acid addition salts of the compounds of formula (IA) may also be represented by the formula (IB) wherein R ² is hydrogen or a protecting group and X ^- represents the anion of the acid. The X ^- counter anion can be selected to provide a pharmaceutically acceptable salt for therapeutic treatment. 40 In this case, however, when the compound of formula (I) is used as an intermediate, X ^- can be toxic anion. In this case the ion can be subsequently removed or exchanged for a pharmaceutically acceptable anion, in order to obtain the final product can be felhasznál- ^b therapeutically.

In the process of the invention, the intermediate of formula (IV) is used. This type of compound No. 38 869 ₃ q public European Patent withdrawn and the Patent Publication No. 54917 European explained and the general preparation methods described in these locations may be used. In the formula, L is a conventional leaving group gg (defined in the European Patent Publication No. 38,869 as "X") such as chlorine, bromine, iodine, benzenesulfonyloxy, ρ-toluenesulfonyloxy, p-nitrobenzene, sulfonyloxy, methane sulfonyloxy, trifluoromethane sulfonyloxy, diphenyl ^{phosphinyl-00} alkyloxy or di (trichloroethoxy) -foszfiniloxi group.

The preferred leaving group is diphenoxyphosphinyloxy.

In general, the intermediates of formula (IV) are prepared by reacting 65 of a compound of formula (III) wherein R ¹ , R ¹⁵ and R ² 'are as defined above with a suitable acylating agent of formula R 0 -L, and whereby the compound of formula IV is formed in situ.

The preferred intermediate of formula (IV) wherein L is diphenoxy-phosphinyloxy is prepared by reacting a ketoester of formula (III) in an inert organic solvent such as dichloromethane, acetonitrile or dimethylformamide with about equimolar amount of chlorophosphoryl acid in the presence of a base such as diisopropylethylamine, triethylamine, 4- (dimethylamino) pyridine or the like, at a temperature of from -20 ° C to + 40 ° C, particularly preferably from about 0 ° C. If desired, the resulting compound of formula (IV) may be isolated, but may conveniently be used as a starting material for the process of the invention without isolation or purification.

The process of the invention the carbapenem intermediate of formula (IV) with a quaternary ammonium thiol compound of formula (VII) wherein A, R ⁵ and R ⁶ substituents are as defined above, and X- is a counter anion. The reaction is carried out in an inert solvent such as acetonitrile, acetonitrile-dimethylformamide, tetrahydrofuran, tetrahydrofuran / water, acetonitrile / water or acetone in the presence of a base. The type of base used is not critical. Suitable bases include, for example, sodium hydroxide, diisopropylethylamine, 1,8-diazabicyclo [5.4.0.] Undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, and tri ( C 1-4 alkyl) amines such as triethylamine, tributylamine or tripropylamine.

The intermediate of formula (IV) may be reacted over a wide range of temperatures with the thiol of formula (VII), for example at a temperature of -15 ° C to room temperature, but preferably at a temperature of -15 ° C to + 15 ° C.

The carbapenem compound formed by the reaction of the thiol of formula VII with the intermediate of formula IV 'also contains a counter anion (e.g., an anion of (C ₆ H ₅ O) ₂ PO ₂ , Cl' or a quaternary thiol). That counter-anion can be replaced by another counter-anion by conventional methods, for example, one that is more therapeutically beneficial. Alternatively, the counter-anion can be removed simultaneously with the deprotection. In the case where the quaternized carbapenem compound and the counter-anion form an insoluble product, the product may crystallize upon formation so that the pure product can be isolated by filtration,

After formation of the desired carbapenem compound, R ² 'protecting the carboxyl group of the compound of formula IA' was added.

In the case of -5197904, it can be removed by conventional techniques such as solvolysis, chemical reduction, or hydrogenation. When a protecting group such as p-nitrobenzyl, benzyl, benzhydryl or 2-naphthylmethyl is used, which can be removed by catalytic hydrogenation, the compound of formula (IA ') may be used in a solvent such as dioxane, water. and ethanol, tetrahydrofuran, diethyl ether and buffer solution, tetrahydrofuran, aqueous dipotassium hydrogen phosphate solution and isopropanol, may be hydrogenated at 100-400 kPa, hydrogenation catalyst such as palladium on carbon, palladium hydroxide, etc. in the presence of 0 to 50 ^h at a temperature of generally from 0.24 to 4 hours.

If the R ² groups are p-nitrobenzyl groups. powder, then we can use photolysis to remove it. Protecting groups such as 2,2,2-trichloroethyl can be removed by slight reduction with zinc. When the protecting group is an allyl group, it may be removed using a catalyst consisting of a mixture of a palladium compound and triphenylphosphine in a suitable aprotic solvent such as tetrahydrofuran, dichloromethane or diethyl ether.

Similarly, other conventional carboxyl protecting groups may be removed by methods known to those skilled in the art. Finally, as already mentioned, those compounds of formula (IA *) wherein R ² is a physiologically bridgeable ester group such as ethoxymethyl, phthalidyl, indanyl, pivaloyloxymethyl, methoxymethyl and the like. without removing the protecting group, it can be administered directly to the treated subject since these esters hydrolyze in vivo under physiological conditions.

It is understood that when the R ¹ , R ⁸ , R ⁵ or R ¹⁵ substituent or quaternary heteroaromatic moiety which is attached to the A substituent contains a functional group which may interfere with the reaction to be carried out, then this functional group will be protected by a conventional protecting group. and then remove the protecting group to form the desired protecting group again. Suitable protecting groups and methods for their introduction and removal are known to those skilled in the art.

Like other beta-lactam antibiotics. For compounds of formula (IA), the compounds of formula (IA) may also be prepared by known methods to produce pharmaceutically acceptable salts which are substantially equivalent in activity to the corresponding compounds of formula (IA). For example, the compound of formula (IA) containing the anionic charged carboxylic acid at position 3 may be dissolved in a suitable inert solvent and an equivalent amount of a pharmaceutically acceptable acid may be added. The desired acid addition salt can be obtained by conventional methods such as precipitation with solvent 6, lyophilization, etc. we can win.

Some of the compounds of formula IA may be in the form of optical isomers as well as epimeric mixtures thereof. The invention relates to the preparation of all such mixtures of optical isomers and epimers. For example, if

The substituent at the 6-position may be hydroxyethyl in the R or S configuration. The invention encompasses both the resulting isomers and their epimeric mixtures.

The thiol of formula (VII) can be prepared from the (XIII) thioacetate of the formula wherein A and R ⁶ are attached as above same, and CH ₃ -CO-SA- side chain of the pyridyl ring is a carbon atom. The thioacetate of formula (XIII) may kvaternerezzük that the inert organic solvent such as diethyl ether, dichloromethane, dioxane, benzene, xylene, toluene or mixtures thereof with a suitable (IX) with an alkylating agent of the formula wherein R ⁵ * is X 'above is a conventional leaving group such as halogen (chlorine, bromine or iodine, preferably iodine) or a sulfonate ester such as mesylate, tosylate or triflate. The temperature used in the alkylation reaction is not critical, preferably between 0 and 40 ° C.

Prior to reaction with the carbapenem intermediate of formula (IV), the quaternized thioacetate is subjected to acidic or basic hydrolysis to form the quaternary thiol of formula (VII). This hydrolysis is conveniently carried out immediately prior to coupling with the compound of formula (IV) in order to minimize the degradation of the relatively unstable thiol of formula (VII).

By suitable choice of solvents, the preparation of the compound of formula (I) from the compound of formula (IIP) is carried out without isolation of the various intermediates by a so-called "unique" process.

The compounds of formula (IA) and their pharmaceutically acceptable salts, which are obtainable by the process of the present invention, are disclosed in U.S. Patent No. 425,755, supra. Like the carbapenem derivatives of the general formula (I) disclosed in the German patent, they are valuable antibiotics which are at least equivalent in pharmacological properties to the similar pyridinium methylthiocarbapenem substituted on the carbon atoms of the pyridinium ring.

The compounds of formula (IA) and their salts are mainly active against Gram-positive and Gram-negative bacteria and can be used, for example, in the following uses: as an additive in growth in animal feed; as a preservative in foodstuffs; as a bactericide for industrial applications such as aqueous paints or chalk suspensions of paper mills

-6197904 for inhibiting bacterial growth; and as a disinfectant for medical or dental instruments to kill or inhibit the growth of harmful bacteria. However, the compounds are particularly useful for the treatment of infections caused by Gram-positive or Gram-negative bacteria in humans and animals.

The pharmaceutically effective compounds of formula I may be used alone or in the form of pharmaceutical compositions. The pharmaceutical compositions contain, in addition to the active carbapenem compound, a pharmaceutically acceptable carrier or diluent. The compounds may be administered to the subject in a variety of ways, most notably oral, topical or parenteral (e.g., intravenous or muscular injection). The pharmaceutical compositions may be solid, such as capsules, tablets, powders, etc., or liquid, such as solutions, suspensions, or emulsions. Administration is preferably by injection. To this end, the compositions may be presented in unit dosage form and may be packaged in ampoules, or in multiples of a single dose. Formulations for injection may also contain adjuvants such as suspending, stabilizing and dispersing agents. The formulations may be formulated for immediate use or may be in powder form for constitution with a suitable vehicle, such as sterile water, prior to administration.

The dosage employed will depend to a large extent on the compound to be administered, the composition employed, the mode of administration, the subject being treated and the condition thereof, and the nature of the disease. The choice of the preferred dosage and route of administration is the responsibility of the attending physician. Generally, however, the parenteral or oral dose to mammals or humans is about 5 to 200 mg / kg / day. Treatment is usually by administering several daily doses, for example three to four times a day.

The invention is illustrated in detail by the following examples.

Example 1 (5R, 6S) -3 - [(1,3-Dimethyl-pyridinium-4-yl) methylthio] -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3,2.0] hept-2-ene-2-carboxylate - (Compound XXIII containing R) and - (4R, 5R, 6S) -3 - [(1,3-dimethylpyridinium) -4-yl) methylthio] -6- [1- (R) -hydroxyethyl] -4-methyl. Preparation of til-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (compound of formula XXIII wherein R is methyl)

A. Preparation of 4- (hydroxymethyl) -3-methylpyridine (The procedure is illustrated in Scheme C)

V. Boekelheide and W.J. Linn (JACS, 76, 1286 (1954)) used the general procedure for hydroxymethylpyridines. Accordingly, a solution of 46.0 g (0.43 mol) of freshly distilled 3,4-lutidine in 120 ml of glacial acetic acid was cooled to 0 ° C and 64 ml of 30% hydrogen peroxide was added dropwise. The resulting solution was heated to 75 ° C (oil bath temperature) and maintained at this temperature for 3 hours. An additional 20 mL of 30% hydrogen peroxide was added and heating continued for 18 hours. Finally, 20 ml of 30% hydrogen peroxide was added again and the reaction mixture was heated at 75 ° C for an additional 3 hours. The solution was then concentrated to a volume of about 100 mL under vacuum pump water, 50 mL of water was added to the concentrate, and the mixture was concentrated to about half its volume. The resulting mixture was cooled to 0-5 ° C and basified to about pH 10 with cold 40% aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane (5 times), and the combined extracts were dried over anhydrous sodium carbonate and sodium sulfate and evaporated on a film evaporator. The residual yellow solution was diluted with hexane, and the precipitated solid was filtered and dried in vacuo. 48.0 g (83%) of 3,4-wayidine N-oxide are obtained in the form of an off-white solid.

The resulting 3,4-lutidine N-oxide was added portionwise to 60 ml of acetic anhydride and the resulting dark orange solution was heated in a water bath at about 90 ° C for 1 hour. Excess acetic anhydride was distilled off under reduced pressure and the residue was fractionated in vacuo. 39.0 g of a boiling point of 90-120 ° C / 13 Pa were isolated. The resulting oil was chromatographed on silica gel using ethyl acetate / petroleum ether 2: 3 as eluent. 19.0 g (30%) of 4- (acetoxymethyl) -3-methylpyridine were obtained in the form of an oil. Infrared spectrum: 1745 cm ^-1 .

The resulting 4- (acetoxymethyl) -3-methylpyridine was taken up in 100 ml of 10% aqueous hydrochloric acid and refluxed for 1 hour. The solution was cooled to 0 ° C, basified with solid potassium carbonate and extracted with dichloromethane (3 x 100 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated. 11.0 g of an off-white solid are obtained, m.p. 70-72 ° C. This material was triturated with cold ether to give 9.5 g (67%) of pure 4- (hydroxymethyl) -3-methylpyridine as a white solid, mp 77-80 ° C. 81-82 ° C [W.L.F. Armarego, B.A. Milloy,

S.C. Sharma, J. Chem. Soc., 1972, 2485]. 'HMMR spectrum (deuterochloroform) delta *

8.27, 7.41 (AB quartet, J = 5 Hz, 2H), 8.18 (singlet, 1H), 5.63 (broad singlet, -OH), 4.67 (singlet, CH ₂ ), 2 , 20 (singlet, CH ₃ ). Infrared spectrum (nujol): 3170 cm ^{-1 * * * V.} B. Preparation of 4- (Acetylthiomethyl) -3-methylpyridine

-7197904 (Process Scheme D) To an ice-cold solution of triphenylphosphine (17.04 g, 0.065 mol) in dry tetrahydrofuran (250 ml) was added diisopropyl ester of azodicarboxylic acid (12.8 ml, 0.065 mol) and the resulting suspension was stirred at 0 ° C for 1 hour. A solution of 4.0 g (0.0325 mol) of 4- (hydroxymethyl) -3-methylpyridine in 100 ml of anhydrous tetrahydrofuran was added dropwise and 4.64 ml (0.065 mol) of freshly distilled thioacetic acid were added. The resulting reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for an additional 1 hour. The resulting orange solution was concentrated on a rotary evaporator and diluted with petroleum ether. The mixture was filtered and the filtrate was evaporated. The residual orange oil was chromatographed on silica gel, eluting first with hexane and then with ethyl acetate / hexane with a 10% to 50% increase in ethyl acetate. Distillation of the resulting oil (7.0 g) gave the pure title compound (6.0 g, 100%) as a yellow oil, b.p. (air bath temperature) 95-110 ° C / 0.1 torr.

'HMMR (deuterochloroform) delta *

8.40, 7.20 (AB quartet, J = 5 Hz, 2H), 8.37 (singlet, 1H), 4.08 (singlet, CH ₂ ), 2.35 (singlet, CH ₃ ), 2, 32 (singlet, CH ₃ ). IR: 1695 cm @ -1.

C. Preparation of 4- (Acetyl 1-thiomethyl) -1,3-dimethylpyridinium (trifluoromethanesulfonate) (Process Scheme E) 2.95 g (0.016 mole) of 4- (acetyl). To an ice-cold solution of thiomethyl) -3-methylpyridine in 10 mL of dichloromethane was added dropwise 4.60 mL (0.04 mol) of trifluoromethanesulfonic acid methyl ester and the reaction mixture was stirred for 1 hour under nitrogen at 0 ° C. The reaction mixture was then evaporated to dryness and the residue triturated with ether. The resulting solid was filtered and dried in vacuo to afford 4.0 g (72%) of the title product as a white solid.

'HMMR (deuterochloroform) delta' values'

8.72 (s, 1H), 8.58, 7.87 (AB quartet, J = 6Hz, 2H), 4.39 (s, _N-CH3), 4.17 (s, CH _2); 2.53 (singlet, CH ₃ ), 2.36 (singlet, CH ₃ ).

IR: 1700 ^cm-first

D. (5R, 6S) -3 - [(1,3-Dimethylpyridinium-4-yl) methylthio] -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [ 3.2.0] Preparation of hept-2-ene-2-carboxylate (The procedure is illustrated in Scheme F) To a solution of 0.324 g (0.008 mol) of sodium hydroxide in 10 ml of water was added ice-cold, nitrogen purged, 1.40 g (0.004 mol).

4- (acetylthiomethyl) -1,3-dimethylpyridinium trifluoromethanesulfonate and the mixture was stirred at 0 ° C for 1 hour under nitrogen. The pH was adjusted to 7.2-7.3 with 10% aqueous potassium dihydrogen phosphate solution and the resulting solution was added dropwise with 1.45 g of enol phosphate 8 (0.0025 mol) in 20 ml of tetrahydrofuran. , for ice-cold solution. The reaction mixture was stirred at 0 ° C for 1 hour and then charged into a pressure-proof apparatus. 20 ml of ether, 25 ml of 0.1 M phosphate buffer (pH 7.4) and 1.4 g of 10% palladium on carbon were added and the mixture was hydrogenated at 45 psi for 1 hour. The reaction mixture was filtered through Celite filtration aid, and the filter was washed with additional ether and pH 7.4 phosphate buffer. The aqueous phase was separated and the remaining solvents were removed in vacuo. The resulting aqueous solution was applied to a reverse phase column (C ₁₈ Bondapak) up the column with water and then eluted with water containing 10% acetonitrile. Lyophilization of the appropriate fractions afforded 0.9 g of an orange solid, which was subjected to another chromatography using water followed by 2% acetonitrile in water. Lyophilization gave 0.25 g (57%) of the pure title compound as a yellow solid.

'HMMR (deuterium oxide) delta *

8.55 (singlet, 1H), 8.53-3.96 (AB quartet, J = 6.8 Hz, 2H), 4.30-3.99 (multiplet, 2H), 4.27 (singlet, 5H) ), 3.35 (doublet of doublets, J = 2.8 Hz, J ₂ = 6.0 Hz, 1H), 3.05 (doublet, J = 8.8 Hz, 2H), 2.50 (singlet) , 3H), 1.23 (doublet, J = 6.3 Hz, 3H).

Infrared (potassium bromide pellet): 1755, 1590 cm ^-1 .

Ultraviolet spectrum (phosphate buffer, pH = 7):

λ _καχ = 295 nm (ε = / 180).

E. (4R, 5R, 6S) -3 - [(1,3-Dimethylpyridinium-4-yl) methylthio] -6- [1- (R) -hydroxyethyl] -4-methyl-7- oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (The procedure is illustrated in Scheme G), to a solution of 0.906 g (0.0025 mole) of bicyclic ketone in 10 ml of acetonitrile was treated successively with Diphenyl chlorophosphate (0.00263 mole), diisopropyl elylamine (0.457 mL, 0.00263 mole) and 4- (dimethylamino) pyridine (0.3 mg) were added. After 50 minutes, the reaction mixture was diluted with cold ethyl acetate and washed with cold water and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated at room temperature. Enol phosphate was obtained as an off-white foam. This foam was taken up in 20 ml of tetrahydrofuran, cooled to -30 ° C under nitrogen, and treated with an aqueous solution of thiolate (prepared as described previously from 0.3 g (7.5 mmol) of sodium hydroxide and 1.3 g). g (3.76 mmol) of thioacetate in 10 mL of water). The reaction mixture was stirred at -30 ° C for 30 minutes, then at 0 ° C for 75 minutes and finally transferred to a pressure bottle containing 20 ml of ether, 30 ml of 0.1 M phosphate buffer (pH 7.4) and It contained 1.5 g of 10% palladium on carbon catalyst. The reaction mixture was hydrogenated at 45 psi for 1 hour, then filtered through Celite, the aqueous phase separated and evaporated in vacuo. The resulting solution was applied to a reverse phase (C, _g BondaPak) column and the column eluted with water. Lyophilization of the appropriate fractions gave 1.2 g of a yellow solid. This was chromatographed again, eluting with water followed by 4% water in water with an increased content of acetonitrile. Lyophilization gave 0.250 g (28%) of the pure title compound as a yellow solid.

'HMMR spectrum (deuterium oxide) delta *

8.53 (singlet, 1H), 8.49, 7.81 (AB quartet, J = 6.2 Hz, 2H), 4.38-3.98 (multiplet, 4H), 4.27 (singlet, 3H) ), 3.49-3.18 (multiplet, 2H), 2.51 (singlet, 3H), 1.25 (doublet, J = 6.7 Hz, 3H), 1.16 (doublet, J = 7) , 6 Hz, 3H). Infrared (potassium bromide pellet): 1750, 1595 cm ^H.

Ultraviolet spectrum (phosphate buffer, pH = 7):

? max = 292 nm (? 7930 nm).

Example 2 (5R, 6S) -3 - [(1,6-Dimethylpyridinyl-2-yl) methylthio] -6- [1- (R) -hydroxyethyl] -4R-methyl-7-oxo -1-Azabicyclo [3.2.0] bept-2-ene-2-carboxylate - Compound XXIV

A. (1,6-Dimethyl-pyridinium-2-yl) -methyl-thiol (trifluoromethanesulfonate) salt (This procedure is illustrated in Scheme H).

A solution of 1.0 g (5.52 mmol) of (6-methylpyridin-2-yl) methylthioacetate in 5 mL of anhydrous ether in 0.74 mL (6.5 mmol) of trifluoromethane sulfonic acid methyl ester was added. and the reaction mixture was stirred at 23 ° C for 4 hours. The ether was decanted off, the white solid was washed twice with 2 mL of ether and dissolved in 15 mL (90.0 mmol) of 6N hydrochloric acid. The resulting solution was kept at 70 ° C for 4 hours under nitrogen and then concentrated under reduced pressure. Remaining traces of hydrochloric acid from the remaining yellow syrupy material were removed by distillation with 2x10 mL water, and the crude product was removed by chromatography on a 2.2 x 13.0 cm reverse phase column (PrepPak C-18) using water as the eluent. The appropriate fractions were combined and lyophilized. This gave 1.43 g (85.4%) of the title compound as a white powder. IR (KBr) _m ax values:

2565 (SH), 1626 (pyridinium), 1585 (pyridinium) cm ^-1

Ultraviolet spectrum (water) - λmax - 278 nm (ε = 7355).

Analysis: Calculated for C ₉ H ₂ NO ₃ S ₂ F ₃ : C 35.64%, H 3.99%, N 4.62%, S 21.14%;

Found: C 35.49%, H 4.05%, N 4.56%,

S, 20.99%.

B. (5R, 6S) -3 - [(1,6-Dimethylpyridinium-2-yl) methylthio] -6- [1- (R) -hydroxyethyl] -4R-methyl-7-oxo 1-Azabicyclo [3.2.0] hept-2-ene-2-carboxylate (This procedure is illustrated in Scheme I).

1.11 g (3.06 mmol) of (5R, 6S) -3,7-dioxo-6- [1- (R) -hydroxyethyl] -4RS-methyl-1-azabicyclo [3.2.0] heptane- To a solution of 2R-carboxylic acid (p-nitrobenzyl) ester (R) S in 86 (14) in 90 mL of anhydrous acetonitrile at 5 ° C under nitrogen was added 0.68 mL (3.3) simultaneously over 10 min. mmol) of chlorophosphoric diphenyl ester, 0.57 ml (3.3 mmol) of diisopropylethylamine. The cold (5 ° C) mixture was stirred for 1 hour, cooled to -30 ° C, and 1.03 (3.4 mmol) (1,6-dimethylpyridinium-2-yl) was added simultaneously over 15 minutes. methylthiol (trifluoromethanesulfonate) salt in 2 mL of anhydrous acetonitrile and 0.59 mL (3.4 mmol) of diisopropylethylamine. The reaction mixture was stirred at -30 ° C for 0.5 h, warmed to 0 ° C and stirred for 1 h, then diluted with 35 mL of cold water. The resulting emulsion was poured onto a 2.5 x 18 cm reverse phase column (PrepPak C-18) and eluted with water containing 25-50% acetonitrile. Lyophilization of the appropriate fractions gave 1.69 g of a sticky yellow solid which was dissolved in 40 ml of wet tetrahydrofuran. To the resulting solution was added 70 ml of ether, 50 ml of 0.2 M potassium dihydrogen phosphate / sodium hydroxide buffer (pH = 7.0) and 1.69 g of 10% palladium on carbon catalyst for 2 hours at 23 ° C. and at 42 psi and filtered through Celite. The two phases were separated, the aqueous phase washed with ether (2 x 20 mL) and evaporated to a volume of 15 mL under high vacuum at a temperature below 23 ° C. The residue was loaded on top of a reverse phase column (PrepPak C-18) and eluted with water containing 4% acetonitrile. Lyophilization of the appropriate fractions afforded 0.23 g of the title compound, which was mixed with 24 mol% potassium sodium diphenyl phosphate. The column was further purified on a 2.5 x 14 cm reverse phase column (PrepPak C-18) using 400 mL of water followed by 200 mL of 10% acetonitrile. Lyophilization of the appropriate fractions gave 1 0.17 g (15.3%) of the title compound as a yellow powder. Infrared spectrum (potassium bromide lozenge) / "" values:

1750 (.beta.-lactam C.dbd.O), 1625 (pyridinium), 1600 (C = O of carboxylate) cm ^1st

HMMR (deuterium oxide) delta values:

1.12 (d, J = 7.2 Hz, linked at C-4 _CH3), 1.24 (d, J = 6.4 Hz, _CH3 CH0H), 2.80 (s, pyridinium the 6- CH ₃ ), 4.18 (CH ₃ attached to the nitrogen atom of the pyridinium group), 4.41 (AB quartet center, CH ₂ S), 7.5-8.4 (protons of the pyridinium group) Ultraviolet spectrum (0.05 M) buffer, pH = 7.0):

/ "" = 278 nm (ε = 11504).

[α] ρ = --256,4 ³ ° (c = 0.22, water).

Measured T / ₂ = 20.8 h at 37 ° C for 10 ^"4 M concentration of a buffer of pH 7.4.

-9197904

Example 3 (5R, 6S) -3 - [(1,6-Dimethylpyridinium-2-yl) methylthio] -6- [1- (R) -hydroxyethyl] -7-oxo-1 Preparation of azabicyclo [3.2.0] hept-2-ene-2-carboxylate (XXV) A. (5R, 6S) -3 - [(1,6-Dimethylpyridinium-2-yl) methylthio ] -6- [1- (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p-nitrobenzyl) ester trifluoromethane sulfonate and diphenylphosphate salt (The procedure is illustrated in Scheme J)

2.14 g (6.14) mmol) of (5R, 6S) -6- (1R-hydroxyethyl) -3,7-dioxo-1-azabicyclo [3.2.0] heptane-2R-carboxylic acid (p- To a cold (5 ° C) solution of nitrobenzyl ester in 18 mL of anhydrous acetonitrile was added 1.37 mL (6.6 mmol) of chlorophosphoric diphenyl ester and 1.15 mL (6.6 mL) of nitrogen. mmol) of diisopropylethylamine at a rate such that the temperature is maintained at 5 ° C (addition for 7-10 minutes). Further, 6 mg (0.05 mmol) of 4- (dimethylamino) pyridine was added and the reaction mixture was stirred for 1.5 hours at 5 ° C and then used as such (solution A). .

A solution of (6-methylpyridin-2-yl) methylthioacetate (1.23 g, 6.8 mmol) in anhydrous ether (10 mL) under nitrogen was treated with methyl trifluoromethanesulfonic acid methyl ester (0.85 mL, 7.5 mmol). and the mixture was stirred for 1.5 hours at 23 ° C. The ether was decanted off, and the remaining white powder was washed with ether (2 x 10 mL) and dissolved in water (20 mL). The resulting aqueous solution was cooled to 0 ° C under an oxygen-free atmosphere and treated with 3.4 mL (13.6 mmol) of 4N sodium hydroxide. The mixture was stirred at 2 ° C for 1 hour and then adjusted to pH 7.6 with potassium dihydrogen phosphate. The resulting mixture is used as solution B for the remainder of the procedure.

Cold solution (5 ° C) was treated with solution B for 0.5 hour while maintaining the pH between 7.25 and 7.35 by the dropwise addition of 4N sodium hydroxide solution. The reaction mixture was stirred for 0.5 h and then poured onto the top of a 4.0 x 18 cm reverse phase column (PrepPak C-18). The column was eluted with water containing 25-50% acetonitrile. Lyophilization of the appropriate fractions gave the title compound (2.82 g, 80%) as a yellow powder.

(51% (PhO) ₂ PO ;, 49% CF ₃ SO ₃ ).

IR (KBr) A _max:

3700-3000 (OH), 1772 (beta-lactam C = O), 1700 ^ ester C = O), 1625 (pyridinium), 1590 (pyridinium) cm ^-1 .

'HMMR spectrum (deutero-dimethylsulfoxide)

1.15 (doublet, J = 6.2 Hz, CH ₃ CHOH), 2.84 (singlet, CH ₃ attached to the 6-carbon atom of the pyridinium group), 4.16 (singlet, CH ₃ attached to the nitrogen atom of the pyridinium group), 4.79 (singlet, SCH ₂ ), 6.6-7.5 [(PhO) ₂ PO7], 7.5-8.7 (protons of pyridine10 and p-nitrobenzyl).

B. (5R, 6S) -3 - [(1,6-Dimethylpyridinium-2-yl) methylthio] -6-fb (R) -hydroxyethyl] -7-oxo-1-azabicyclo [3.2. 0] hept-2-ene-2-carboxylate (This procedure is illustrated in Scheme K)

0.87 p (1.27 mmol) of (5R, 6S) -3 - [(1,6-dimethylpyridinium-2-yl) methylthio] -6- [1- (R) -hydroxyethyl] -7- oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (p-nitrobenzyl) ester (trifluoromethanesulfonate) and (diphenylphosphate) salt (49: 51) To a solution of 50 ml of wet tetrahydrofuran was added 50 ml of ether, 40 ml of 0.1 M potassium dihydrogen phosphate / sodium hydroxide buffer (pH 7.0) and 0.87 g of 10% palladium on carbon. The mixture was hydrogenated at 23 ° C and 36 psi for 2 hours and then filtered through Celite. The two phases were separated, the aqueous phase washed with ether (2 x 15 mL), concentrated under high vacuum (30 mL), and the residue poured onto a 2.2 x 13 cm reverse phase column (PrepPak C-18). The column was eluted with water. The appropriate fractions were combined and lyophilized. This gave 0.179 g (40%) of the title product as a yellow powder.

IR (KBr)? _M "values:

1755 (beta-lactam C = O), 1628 (pyridinium), 1590 (carboxylate C = O) cm- ¹ 'HMMR (deuterium oxide) delta'

1.25 (doublet, J = 6.4 Hz, C 1 CH ₂ OH), 2.82 (singlet, CH ₃ attached at the 6-position of the pyridinium group), 3.12 (doublet, J = 9.2 Hz, J = 2.9 Hz, H-4), 3.39 (doublet of doublets, J = 6.0 and 2.8 Hz, H-6), 3.7-4.4 (CH ₃ CHOH, H-5, CH ₃ ) to the nitrogen atom of the pyridinium group 4.48 (singlet, CH ₂ S), 7.6-8.4 (protons of the pyridinium group).

Ultraviolet spectrum (water): λ _ηαχ = 279 nm (e = 9628), broadening at 269 nm. [α] 23 = 55.0 ° (c = 0.63, water).

T _1/2 = 12.5 hours, measured at 37 ° C at 10 ~ ⁴ M in pH 7.4 buffer.

Claims (3)

A process for the preparation of a carbapenem derivative of formula IA in this formula A is C 1-4 alkylene, R ¹ is substituted with hydroxy C 1-4 alkyl, ^R5 and ^R6 are independently C1-4 alkyl, R ¹⁵ is a C 1 -C 4 alkyl group or a hydrogen atom, wherein a compound of formula IV ', wherein R ¹ and R ¹⁵ are as defined above, R ² ' is a conventional carboxyl protecting group, preferably p -nitrobenzyl and L is the leaving group, preferably diphenyl-10197904 It represents -phosphinyloxy group - in the presence of a base of thionyl formula (VII): - wherein A, R® and ^R6 is as defined above, X ^- represents a counter anion - or a reactive derivative reagálta- 5 us, and yielded ( IA ') a compound of formula - wherein A, R, R ^5, R ⁶ and R ² * are as defined above - the ^R2 protecting group is removed. 2. A process according to claim 1, wherein the base is sodium hydroxide. Process according to claim 1, characterized in that the reaction is carried out at a temperature of -30 ° C to -20 ° C. 9 sheets of drawing with formulas