CARBAPENEMS AND 1-METHYLCARBAPENEMS HAVING A 2-HETEROARYLIUMALIPHATIC SUBSTITUENT

Abstract: Carbapenems and 1-methylcarbapenems having the formula: wherein - R¹ and R² are independently H, CH₃. CH₃CH₂-, (CH₃)₂CH-, HOCH₂, CH₃CH(OH)-, (CH₃)₂C(OH)-, FCH₂-, F₂CH, F₃C-, CH₃CH(F)-, CH₃CF₂-, or (CH₃)₂C(F)-; R³ is H- or CH₃; L is a bridging group comprising substituted or unsubsti­ tuted C₁-C₆ straight, C₂-C₆ branched or C₃-C₇ cycloalkyl groups wherein the substituents are selected from C₁-C₆ alkyl, O-C₁-C₆ alkyl, S-C₁-C₆ alkyl, CF₃, N(C₁-C₆ alkyl)₂; is a quaternary, monocyclic or bicyclic substituted or unsubstituted, heteroaryl group containing (a) when monocyclic, up to 3 heteroatoms and up to 6 total ring atoms, or (b) when bicyclic, up to 5 heteroatoms and 9-10 ring atoms, which is optionally substituted with one or more groups; and Y is a carboxy-containing group; their preparation and antibiotic use are disclosed.

Description: BACKGROUND OF THE INVENTION The present invention is concerned with 1-methylcarbapenem antibiotics having a quaternary mono- or bicyclic heteroarylium alkyl group which is internally alkylated in the 2-position. Thienamycin is a known carbapenem, broad spectrum antibiotic of the formula: Other derivatives of A are also known. The present internally alkylated mono- or bicyclic 2-quaternary heteroarylalkyl substituted carbapenems are believed to have an antibiotic spectrum comparable to A . BRIEF DESCRIPTION OF DISCLOSURES IN THE ART Sankyo U.S. Pat. No. 4,377,591 and Japanese patent publications 56-199682 and 56-60852 Shionogi Japanese patent publications 57-145086 and 57-145087; and Roche U.K. patent publication 2 092 147A, all describe azabicycloheptene antibiotics having a 2-position substituent joined through a thioalkylene bridge. U.S. Pat. No. 4,189,493 to Bristol-Myers discloses externally alkylated heteroarylium alkylthioazabicycloheptene antibiotics. U.S. Pat. No. 4,465,672, U.S. Pat. No. 4, 260,627 and U.S. Pat. No. 4,267,188, all assigned to Merck & Co., Inc., disclose 2,6-substituted-1-carba-2-penem-3-carboxylic acids wherein the 2-substituent can be substituted or unsubstituted alkyl or aryl. However, none of the above 2 references specifically describe the carbapenem compounds of the present invention. GB-A- 2 119 371 describes carbapenem derivatives wherein the 2-position is substituted by a heteroarylalkylenethio unit. Compounds having a methyl group in the 1-position are not disclosed in this document. EP-B-0 007 614 shows the equivalence for some few penem and carbapenem derivatives whose substituent in the 2-position is always linked to the basic penem or carbapenem structure via a sulfur atom. DETAILED DESCRIPTION OT THE INVENTION The invention is embodied in a compound having the formula wherein: R³ is methyl; R² is H; R¹ is is substituted or unsubstituted pyridinium, pyridazinium, pyrimidinium, pyrazinium, pyrazolium, triazolium, imidiazolium, thiazolium, oxazolium or isoxazolium, which is optionally substituted by one or more of the groups independently selected from OH, NH₂, NHCH₃, OCH₃, COO-C₁-C₃ alkyl, C(O)NHOH, phenyl, N(CH₃)₂, C(O)CH₃, C(O)N(CH₃)OH, SO₃H, SCH₃, CHO, COOH, S(O)CH₃, SO₂CH₃, SO₂NH₂, SO₂NHCH₃, CN, CSNH₂, CONH₂, CONH(CH₃), CH=N-OH, up to C₆ alkenyl, C₁-C₆ alkyl, which alkyl group is optionally substituted by one or more of the groups independently selected from OH, NH₂, NHCH₃, OCH₃ -COO-C₁-C₃ alkyl, C(O)NHOH, N(CH₃)₂, C(O)CH₃, C(O)-N(CH₃)OH, SO₃H, SCH₃, CHO, COOH, S(O)CH₃, SO₂CH₃, SO₂NH₂, SO₂NHCH₃, CN, CSNH₂, CH-N-OH, CONH₂ and CONH(CH₃); L is -CH₂-, -CH₂CH₂- or -CH(CH₃)CH₂-; and Y is i) -COOH, a pharmaceutically acceptable ester or salt thereof; ii) COOR wherein R is a conventional removable carboxy protecting group; iii) COOM wherein M is an alkali metal; or iv) COO⁻ provided that when Y is other than iv) a counterion Z⁻ is present. When L is then all stereoisomers are included as mixtures or as separate isomers. Representative examples of preferred pyridinium groups are those having the formulae Representative examples of preferred monocyclic other then pyridinium are those having the following formulae: Preferred emdodiments of the internally alkylated subject compounds are given by the following formula. The compounds of Formula I include inner (Zwitterion) salts when Y is COO⁻, eg. or, when Y is other than COO⁻, salts with an external, physiologically acceptable counterion, Z⁻, eg. R oa is a pharmaceutically acceptable ester, eg., pivaloyloxymethyl, phthalidyl, phtalimidomethyl, acetoxymethyl, ethoxycarbonyloxyethyl, pivaloyloxyethyl, 4-methyl-2-oxo-1,3-dioxolen-5-yl-methyl or salt group; and Z⁻ is C1⁻, Br⁻, I⁻, OH⁻, H₂O - / 3, CH₃CO - / 2 and the like. The inner salts are preferred. Compounds of Formula I include the stereoisomers as mixtures and as separate isomers. Compounds having the stereochemistry shown below are preferred: where contains a chiral center, the side chain chirality leads to diastereometric products. The products can be separated by conventional methods, used as mixtures, or synthesized stereospecifically. The compounds of the present invention are valuable antibiotics, active against various Gram-positive and Gram-negative bacteria and accordingly find utility in human and veterinary medicine. Representative pathogens which are sensitive to antibiotics I include: Staphyloccus aureus , Escherichia coli , Klebsiella Pneumoniae , Bacillus subtilis , Salmonella typhosa , Pseudomonas and Bacterium proteus . The antibacterials of the invention are not limited to utility as medicaments; they may be used in all manner of industry, for example: additives to animal feed, preservation of food, disinfectants, and in other industrial systems where control of bacterial growth is desired. For example, they may be employed in aqueous compositions in concentrations ranging from 0.1 to 100 parts of antibiotic per million parts of solution in order to destroy or inhibit the growth of harmful bacteria on medical and dental equipment and as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growth of harmful bacteria. The compounds of this invention may be used in any of a variety of pharmaceutical preparations. They may be employed in capsule, powder form, in liquid solution, or in suspension. They may be administered by a variety of means; those of principal interest include: topically or parenterally by injection (intravenously or intramuscularly). Compositions for injection, a preferred route of delivery, may be prepared in unit dosage form in ampules, or in multidose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents. Alternatively, the active ingredient may be in powder form for reconstitution, at the time of delivery, with a suitable vehicle, such as sterile water. Topical applications may be formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints, or powders. The dosage to be administered depends to a large extent upon the condition and size of the subject being treated as well as the route and frequency of administration -- the parenteral route by injection being preferred for generalized infections. Such matters, however, are left to the routine discretion of the therapist according to principles of treatment well known in the antibiotic art. In general, a daily dosage consists of from about 5 to about 600 mg of active ingredient per kg of body weight of the subject in one or more treatments per day. A preferred daily dosage for adult humans lies in the range of from about 10 to 240 mg of active ingredient per kg of body weight. Another factor influencing the precise dosage regimen, apart from the nature of the infection and peculiar identity of the individual being treated, is the molecular weight of the chosen species of this invention (I). The compositions for human delivery per unit dosage, whether liquid or solid, may contain from 0.1% to 99% of active material, the preferred range being from about 10-60%. The composition will generally contain from about 15 mg to about 1500 mg of the active ingredient; however, in general, it is preferable to employ a dosage amount in the range of from about 250 mg to 1000 mg. In parenteral administration, the unit dosage is usually the pure compound I in sterile water solution or in the form of a soluble powder intended for solution. The preferred method of administration of the formula I antibiotic is parenteral by i.v. infusion, i.v. bolus, or i.m. injection. For adults, 5-50 mg of Formula I antibiotic per kg of body weight given 2, 3, or 4 times per day is preferred. Preferred dosage is 250 mg to 1000 mg of the Formula I antibiotic given two (b.i.d.) three (t.i.d.) or four (q.i.d.) times per day. More specifically, for mild infections, and particularly urinary tract infections, a dose of 250 mg t.i.d. or q.i.d. is recommended. For moderate infections against highly susceptible gram positive and gram negative organisms, a dose of 500 mg t.i.d. or q.i.d. is recommended. For severe, life-threatening infections against organisms at the upper limits of sensitivity to the antibiotic, a dose of 1000 t.i.d. or q.i.d. is recommended. For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 times per day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usually recommended. Antibiotic compounds of Formula I are of the broad class known as carbapenems or 1-carbade-thiapenems. Certain of these carbapenems are susceptible to attack by a renal enzyme known as dehydropeptidase (DHP). This attack or degradation may reduce the efficacy of the carbapenem antibiotic. Inhibitors of DHP and their use with carbapenem antibiotics are disclosed in the prior art [see published European Patent Applications No. 79102616.4 filed July 24, 1979 (Patent Number 10573); 79102615.6, filed July 24, 1979 (publication no. 0007614); and No. 82107174.3, filed August 9, 1980 (publication no. 72014)]. The present I compounds may, where DHP inhibition is desired or necessary, be combined or used with the appropriate DHP inhibitor as described in the aforesaid published applications. The cited European patent applications 1.) define the procedure for determining DHP susceptibility of the present carbapenems and 2.) disclose suitable inhibitors, combination compositions and methods of treatment. A preferred weight ratio of I compound:DHP inhibitor in the combination compositions is about 1:1. A preferred DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethyl-cyclopropanecarboxamide)-2-heptenoic acid or a useful salt thereof. These combination compositions and their use is another embodiment of the present invention. The compounds of Formula I may be prepared by any convenient process. Methods of Preparation 1) L = -CH₂, a) Further elaboration of A . Option 1 . (X=OH) Option 2 . (X=OH) Alternate Preparations of A 1. 2. 3. 4. Option 3 . (X=Cl, Br, I, etc.) Q = -Cl, -Br, or the like; R⁵ = H; M, M' = Li, Cu, MgX, Zn, Na or the like; X, R³ = as defined previously; R OP = as defined previously; R P , R P ' = triorganosilyl, allyloxycarbonyl, p-nitro-benzyloxylcarbonyl, etc.; strong base = LiNiPr₂, LiN(TMS)₂, KH, etc.; Z = -OEt; activating agent = O₂, MoOPH, Cl₂, Br₂, I₂, BrSO₂Ar, etc.; activating agent (OH) = ClSO₂CH₃, ClSO₂Ar, TMSI, ØP₃/CCl₄ etc., possilby followed by displacement with halogen; R N = triorganolsilyl, 2) L = -CH₂CH₂- or a) b) c) d) e) All variables are as defined above. The following examples illustrate the preparation of compounds of Formula I. The temperature is in degrees Celsius unless otherwise indicated. EXAMPLE 1 (intermediate product) Step A : A solution of 11 (12 mg, 0.018 mmol) in toluene (1 ml) is heated at reflux under nitrogen for one hour and then concentrated to a colorless oil. Preparative thin layer chromatography on silica gel (plate eluted with 1:1 ethyl acetate-hexane and extracted with 1:1 ethyl acetate-methylene chloride) gives the carbapenem 13 (5 mg, 70% yield). NMR (CDCl₃) 5.98 (m, -CH₂C H =CH₂), 5.39 (m, CH₂CH=C H ₂), 4.80 (m, -C H ₂CH=CH₂), 4.47 (m, C H ₂OH), 4.22 (m, H₅+H₈), 3.25 (m, H₁, H₆+OH), 1.26 and 1.21 (sd, 1-CH₃ and CH₃CHO-), 0.9 (C(CH₃)₃), 0.07 (Si(CH₃)₂) in ppm downfield from TMS. IR (CH₂Cl₂ solution) 1775, 1710 cm⁻¹. UV (dioxane) max = 283 nm/ MS (FAB). EXAMPLE 2 Step A : A solution of dihydroxycarbapenem 14 (48 mg, 0.18 mmol) and p-toluene sulfonic anhydride (55 mg, 0.18 mmol) in anhydrous methylene chloride (5 ml) is cooled to 0°C and triethylamine (20 mg, 0.20 mmol) is added slowly by syringe. The resulting solution is stirred at 0°C for 1 hour, then is diluted with methylene chloride (20 ml) and washed quickly with cold pH 7 phosphate buffer and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to provide crude tosylate 15 which is carried on without further purification. Step B : An ice cold solution of tosylate 15 (84 mg, 0.20 mmol) in anhydrous acetonitrile (5 ml) is treated with pyridine (40 mg, 0.50 mmol). The mixture is stirred at 0°C for 15 minutes, then allowed to warm to room temperature. After standing three hours the solution is concentrated in vacuo to give crude 16 . This material is suspended in a mixture of methylene chloride (2 ml) and ethyl acetate (2 ml). To this mixture is added a solution of potassium ethylhexanoate in ethyl acetate (0.40 ml of 0.5M solution, 0.20 mmol), triphenylphosphine (3.4 mg, 0.014 mmol) and tetrakis(triphenylphosphine)-palladium[0] (0.5 mg, 0.0005 mmol). The reaction mixture is stirred under nitrogen at ambient temperature for 2 hours, then is concentrated in vacuo . The residue is partitioned between water (5 ml) and ethyl ether (5 ml). The aqueous phase is separated and washed with an additional portion of ether, then is concentrated in vacuo and chromatographed on two RPS plates (eluting with ethanol/water). The U.V. active band is removed from the plates and extracted with 4:1 acetonitrile/water. This solution is washed four times with hexanes, then concentrated in vacuo and lyophilized to yield compound 17 . EXAMPLE 3 An ice cold solution of tosylate 15 (84 mg, 0.20 mmol) in anhydrous acetonitrile (5 ml) is treated with 3-aminopyridine (25 mg, 0.26 mmol). The mixture is stirred at 0°C for 15 minutes, then allowed to warm to room temperature. After standing three hours the solution is concentrated in vacuo to give crude 18 . This material is suspended in a mixture of methylene chloride (2 ml) and ethyl acetate (2 ml). To this mixture is added a solution of potassium ethylhexanoate in ethyl acetate (0.40 ml of 0.5M solution, 0.20 mmol), triphenylphosphine (3.4 mg, 0.014 mmol) and tetrakis(triphenylphosphine)-palladium[0] (0.5 mg, 0.0005 mmol). The reaction mixture is stirred under nitrogen at ambient temperature for 2 hours, then is concentrated in vacuo . The residue is partitioned between water (5 ml) and ethyl ether (5 ml). The aqueous phase is separated and washed with an additional portion of ether, then is concentrated in vacuo and chromatographed on two RPS plates (eluting with ethanol/water). The U.V. active band is removed from the plates and extracted with 4:1 acetonitrile/water. This solution is washed four times with hexanes, then concentrated in vacuo and lyophilized to yield compound 19 . EXAMPLE 4 An ice cold solution of tosylate 15 (84 mg, 0.20 mmol) in anhydrous acetonitrile (5 ml) is treated with 4-dimethylaminopyridine (25 mg, 0.20 mmol). The mixture is stirred at 0°C for 15 minutes, then allowed to warm to room temperature. After standing three hours the solution is concentrated in vacuo to give crude 20 . This material is suspended in a mixture of methylene chloride (2 ml) and ethyl acetate (2 ml). To this mixture is added a solution of potassium ethylhexanoate in ethyl acetate (0.40 ml of 0.5M solution, 0.20 mmol), triphenylphosphine (3.4 mg, 0.014 mmol) and tetrakis(triphenylphosphine)-palladium[0] (0.5 mg, 0.0005 mmol). The reaction mixture is stirred under nitrogen at ambient temperature for 2 hours, then is concentrated in vacuo . The residue is partitioned between water (5 ml) and ethyl ether (5 ml). The aqueous phase is separated and washed with an additional portion of ether, then is concentrated in vacuo and chromatographed on two RPS plates (eluting with ethanol/water). The U.V. active band is removed from the plates and extracted with 4:1 acetonitrile/water. This solution is washed four times with hexanes, then concentrated in vacuo and lyophilized to yield compound 21 .

Claims: A compound having the formula: wherein: R³ is methyl; R² is H; R¹ is is substituted or unsubstituted pyridinium, pyridazinium, pyrimidinium, pyrazinium, pyrazolium, triazolium, imidazolium, thiazolium, oxazolium or isoxazolium, which is optionally substituted by one or more of the groups independently selected from OH, NH₂, NHCH₃, OCH₃, COO-C₁-C₃ alkyl, C(O)NHOH, phenyl, N(CH₃)₂, C(O)CH₃, C(O)N(CH₃)OH, SO₃H, SCH₃, CHO, COOH, S(O)CH₃, SO₂CH₃, SO₂NH₂, SO₂NHCH₃, CN, CSNH₂, CONH₂, CONH(CH₃), CH=N-OH, up to C₆ alkenyl, C₁-C₆ alkyl, which alkyl group is optionally substituted by one or more of the groups independently selected from OH, NH₂, NHCH₃, OCH₃, -COO-C₁-C₃ alkyl, C(O)NHOH, N(CH₃)₂, C(O)CH₃, C(O)-N(CH₃)OH, SO₃H, SCH₃, CHO, COOH, S(O)CH₃, SO₂CH₃, SO₂NH₂, SO₂NHCH₃, CN, CSNH₂, CH-N-OH, CONH₂ and CONH(CH₃); L is -CH₂-, -CH₂CH₂- or -CH(CH₃)CH₂-; and Y is i) -COOH, a pharmaceutically acceptable ester or salt thereof; ii) COOR wherein R is a conventional removable carboxy protecting group; iii) COOM wherein M is an alkali metal; or iv) COO⁻ provided that when Y is other than iv) a counterion Z⁻ is present. A compound of Claim 1 having the stereochemical configuration The combination of a compound of Claim 1 and a DHP inhibitor. A combination of Claim 3 wherein the DHP inhibitor is 7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid. A pharmaceutical composition for antibiotic use comprising an antibacterially effective amount of a compound of Claim 1, an inhibitorily effective amount of a DHP inhibitor, and, optionally, a pharmaceutically acceptable carrier. A pharmaceutical composition for antibiotic use comprising an antibacterially effective amount of a compound of Claim 1, and, optionally, a pharmaceutically acceptable carrier.

Inventors: CHRISTENSEN, BURTON G., HECK, JAMES V., SALZMANN, THOMAS N.
Applicants: MERCK & CO. INC.
Application year: 1985
Main classification: C07D487
IPC codes: A61K31, A61P31, C07D477, C07D487