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Twenty-seven novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel acid moieties at C-7 that were synthesized using nucleophilic aromatic substitution reactions and Stille couplings. The most interesting compound (6) displayed an MIC(90) against MRSA of 3.7 microg/mL, and an average PD(50) of 3.9 mg/kg.

Forty-five novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel cinnamic acid moieties at C-7 that were synthesized using a key Heck reaction followed by nucleophilic aromatic substitution reactions. The most active compound ( 41 ) displayed an MIC 90 against MRSA of 1.0 μg/mL, and a PD 50 of 0.8 mg/kg. Compound 14 was found to be very safe in a mouse model of acute toxicity.

Sixteen novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds were synthesized using substituted thiopyridones, generated either by cyclization of functionalized precursors, or by direct alkylation of the enolate of 2-methyl substituted pyrones. The most active compound in vitro against a strain of MRSA (A27223) displayed an MIC of 0.5 μg/mL. The most efficacious compound in vivo had a PD50 of 2.1 mg/kg.

A practical synthesis of the anti-methicillin resistant Staphylococcus aureus cephem (6R-trans)-E-7-[[[[2,5-dichloro-4-[3-[(carboxymethyl)amino]-3-oxo-1-propenyl]phenyl]-thio]-acetyl]amino]-4-[[(2-carboxy-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-en-3-yl)methyl]thio]-2,6-dimethyl-1-[3-(4-methylmorpholino-4-yl)propyl]-1-pyridinium, hydroxide, inner salt (BMS-247243) was developed. A process was developed for the interchange of the iodide counterion in 3a to chloride 3b that was essential for an efficient synthesis of the C-3 side chain 4-mercaptopyridone 6b. Use of catalytic Bu4NCl in the reaction of chlorocinnamide 14 with the Li-salt of methylthioglycolate formed the methyl ester of the C-7 side chain 12b in high yield. Reaction with the dianion of thioglycolic acid gave an increased level of the corresponding Michael addition byproduct that led to lower quality thermodynamic product 12b by the reverse reaction. Cephem nucleus 16 was acylated with the acid chloride of acid 12b in a biphasic system to circum...

Regiospecific synthesis of alkylated A ring of arotinoids has been achieved by using Me3Al-TMSOSO2CF3 as a key reagent for conversion of carbonyl to a geminal dimethyl functionality.

A series of thymidine analogues substituted with alkoxy groups of the C-4 position of the furan ring were synthesized. Among these compounds, the methoxy analogue 9 was the most potent inhibitor of herpes simplex virus type 1 thymidine kinase.

A novel synthetic methodology for the hydroxymethyl substituted acyclic acetal functionality was developed, The rationally designed phosphonate analogue 3 of ganciclovir monophosphate was highly active against human cytomegalovirus.

The synthesis of 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]-2,6-diaminopurine ( 2 ) is described. This compound exhibited good inhibitory activity against HIV replication in MT-4 cells.

Regiospecific synthesis of alkylated A ring of arotinoids has been achieved by using Me3Al-TMSOSO2CF3 as a key reagent for conversion of carbonyl to a geminal dimethyl functionality.

Ten diacids were synthesized via a simple regio- and stereoselective aldol reaction. All of these compounds were good to excellent inhibitors of 14 kDa human platelet PLA2, and many of these derivatives displayed activity in a phorbol-ester induced mouse ear edema assay. One of the new compounds reported here was selected for further development as a potential antipsoriasis agent.

Sixteen novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds were synthesized using substituted thiopyridones, generated either by cyclization of functionalized precursors, or by direct alkylation of the enolate of 2-methyl substituted pyrones. The most active compound in vitro against a strain of MRSA (A27223) displayed an MIC of 0.5 μg/mL. The most efficacious compound in vivo had a PD50 of 2.1 mg/kg.

The synthesis of 9-[(2R,5R)-2,5-dihydro-5-(phosphonomethoxy)-2-furanyl]-2,6-diaminopurine ( 2 ) is described. This compound exhibited good inhibitory activity against HIV replication in MT-4 cells.

Phosphonate analogues of d4T and d4A monophosphates have been synthesized using stereocontrolled addition of dimethyl hydroxymethylphosphonate to furanoid glycals. The new phosphonates exhibited a potent activity against HIV.

The synthesis of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine (3), starting from (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4), is described. Alkylation of trityl derivative 7 with (diethylphosphono)methyl triflate provided phosphonate 8, which was readily converted to mesylate 12 in three steps. Nucleophilic substitution of the mesylate group of 12 by 2-amino-6-chloropurine sodium salt led to (S)-2-amino-6-chloro-9-[3-[(diethyl-phosphono)methoxy]-4-(tetrahydro- 2H-pyran-2-yloxy)butyl]purine (13). Sequential treatment of 13 with trimethylsilyl bromide and then with 2 N HCl furnished 3. Preliminary in vitro screening indicated that 3 exhibited a potent activity against human cytomegalovirus (HCMV) but was not active against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The adenine and cytosine derivatives (14 and 15) did not exhibit activity against HSV-1 and -2 and HCMV.

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.

A novel synthetic methodology for the hydroxymethyl substituted acyclic acetal functionality was developed, The rationally designed phosphonate analogue 3 of ganciclovir monophosphate was highly active against human cytomegalovirus.

Ring-cleaved pleuromutilin derivatives comprised of a [5.3.1] bicyclic core structure have been synthesized and evaluated in vitro as antibacterial agents. Four of the compounds described were found to have MICs ≤ 4 μg/mL against marker strains of Streptococcus pneumoniae and Staphylococcus aureus.

Forty-five novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel cinnamic acid moieties at C-7 that were synthesized using a key Heck reaction followed by nucleophilic aromatic substitution reactions. The most active compound (41) displayed an MIC(90) against MRSA of 1.0 microg/mL, and a PD(50) of 0.8 mg/kg. Compound 14 was found to be very safe in a mouse model of acute toxicity.

Twenty-seven novel cephalosporin derivatives with activity against methicillin-resistant Staphylococcus aureus (MRSA) are described. The compounds contain novel acid moieties at C-7 that were synthesized using nucleophilic aromatic substitution reactions and Stille couplings. The most interesting compound (6) displayed an MIC(90) against MRSA of 3.7 microg/mL, and an average PD(50) of 3.9 mg/kg.

Isosteric phosphonate analogues of acyclovir and ganciclovir monophosphates were synthesized. The new phosponates exhibited good anti-herpes activity.

Novel phosphonate isosteres of acyclovir (ACV) and ganciclovir (DHPG) monophosphates were found to be potent and selective antiherpesvirus agents. In the series of phosphonate analogues of ACV monophosphate, only the guanine analogue 20 exhibited activity against herpesviruses, similar to the structure-activity relationship observed for base modification of ACV analogues. The phosphonate isostere of ACV monophosphate (20) was more effective than ACV in the HSV-1 infected mouse model. The 3'-carba analogues of 9-[3-hydroxy-2-(phosphonomethoxy)propyl]purines/pyrimidines (adenine, HPMPA; guanine, HPMPG; cytosine, HPMPC) are devoid of antiherpesvirus activity. This result confirms that the beta-oxygen atom of the phosphonomethyl ether functionality in HPMP-purines/pyrimidines plays a critical role for activity against herpesviruses.

The synthesis of (S)-9-[4-hydroxy-3-(phosphonomethoxy)butyl]guanine (3), starting from (S)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (4), is described. Alkylation of trityl derivative 7 with (diethylphosphono)methyl triflate provided phosphonate 8, which was readily converted to mesylate 12 in three steps. Nucleophilic substitution of the mesylate group of 12 by 2-amino-6-chloropurine sodium salt led to (S)-2-amino-6-chloro-9-[3-[(diethyl-phosphono)methoxy]-4-(tetrahydro- 2H-pyran-2-yloxy)butyl]purine (13). Sequential treatment of 13 with trimethylsilyl bromide and then with 2 N HCl furnished 3. Preliminary in vitro screening indicated that 3 exhibited a potent activity against human cytomegalovirus (HCMV) but was not active against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). The adenine and cytosine derivatives (14 and 15) did not exhibit activity against HSV-1 and -2 and HCMV.

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.

A novel synthetic methodology for the acyclic acetal functionality was developed. The rationally designed phosphonate analogue (3) of acyclovir monophosphate was active against herpesvirus

The synthesis of 1-α-methyl and 1-β-methyl isomers of 7-(3-phenoxyacetamido-1,3-dimethyl-Δ3-O-2-isocephem-4-carboxylic acids (14a and 14b) is described. Treatment of amine 2 with methacrolein followed by cycloaddition gave 4 which was ozonolyzed to yield the methyl ketones 6. Upon reduction of 6 there was obtained a mixture of isomeric alcohols 8 which were resolved by column chromatography, converted to their mesylates 9, and hydrolyzed to yield 10a and 10b. Conversion of each isomer to the corresponding O-2-isocephems 11a and 11b followed by azide reduction, coupling of the amines to phenoxyacetic acid, and removal of the ester blocking groups gave 14a and 14b. An attempt to prepare the gem-dimethyl compound failed. The structural assignments to 14a and 14b are discussed.

Syntheses and biological activities of 2-phosphonylmethoxy-ethyl (PME) purine analogs are described.

The preparation by total synthesis of a new class of β-lactam antibiotics is reported. Conversion of alcohol 1b to its mesylate 9b followed by hydrolysis of the acetal to the enol 1b and base-catalyzed ring closure gave benzyl 7- β-azido-Δ3-O-2-isocephem-4-carboxylate 8b. Similarly prepared were the 3 -methyl, 3 -benzyl, and 3 -phenethyl analogs (32b–d). Reduction of the azides followed by coupling of the resultant amines with phenoxyacetic acid and removal of the benzyl groups by hydrogenolysis gave the acids 35a–e which exhibited high antibacterial activity. The structural assignments to the O-2-isocephems which were made on the basis of their spectral characteristics (ir, uv, and nmr) are discussed.

Stereoselective syntheses of the 1-β-methylcarbapenem intermediates 9B (R=SPh or OCH3) have been accomplished by an aldol-type stereocontrolled reaction and stereoselective catalytic hydrogenation of an olefinic ester.

The preparation by total synthesis of a saturated cephalosporin analog 7-β-phenoxyacet-amido-3-ethoxy-O-2-isocepham-4-α-carboxylic acid 30, is described. Compound 30 was prepared via cycloaddition of azidoacetyl chloride to the cinnamylidene Schiff base of ethyl 2-amino-3, 3-diethoxypropionate 13b to give the cis-3-azido-4-styryl β-lactam 15b. Ozonolysis of 15b followed by sodium borohydride reduction gave the alcohol 18b. Boron trifluoride treatment of 18b gave ethyl 7-β-azido-3- β-ethoxy-O-2-isocephem-4-carboxylate 27. Reduction of the azido group followed by coupling with phenoxyacetic acid and saponification of the ester gave 30. The mechanism of the cycloaddition reaction and the stereochemical assignments are also discussed.

Treatment of the acid 3 with triethylamine in refluxing tert-butyl alcohol gave the decarboxylated product 4 which was isomerized to the desired Δ3 isomer 5 using DBN. Reduction of the azido functions in 4 and 5 followed by coupling to phenoxyacetic acid and debenzylation gave the acids 11 and 8, respectively. Attempts to prepare dienic cephalosporins failed. The halogenation of 4 and 5 was studied and is discussed.

The synthesis of 7-β-phenoxyacetamido-3-methyl-1-oxo-Δ3-O-2-isocephem-4-carboxylic acid 14 is described. Condensation of amine 2 followed by β -lactam formation and ozonolysis gave the acid 5. This was converted to its trichloroethyl ester 8 and the ketal was hydrolyzed to give 9. Reduction of the azido function followed by amide formation gave 11. The trichloroethyl group was removed and the enol acid 12 closed to yield 13. Hydrogenolysis of the benzyl ester gave 14. The structural assignments to the compounds are discussed.

The synthesis of new carbapenems having various (substituted) quaternary heterocyclic alkylthio groups at the C-2 position is described. The in vitro antibacterial activity and the dehydropeptidase-I susceptibility were examined. Some of these compounds (e.g., 11, 16, 26 and 27) showed an excellent wide spectrum of in vitro antibacterial activity including activity against Pseudomonas aeruginosa and greater stability than imipenem toward the dehydropeptidase-I.

The synthesis of 7-β-phenoxyacetamido-3-methyl-Δ3-2-isocephem-4-carboxylic acid 14b and its corresponding α-sulfoxide 15 and sulfone 17 is described. Treatment of the bismesylates 4a, 4b, and 10 with hydrogen sulfide triethylamine gave the corresponding 7-β-amino-Δ3-2-isocephems 12a–c which were coupled with phenoxyacetic acid to yield the amides 13a–c. Hydrogenolysis of 13b and c gave the acids 14a–b which were active as antibiotics. Compound 14b was oxidized to its sulfoxide 15 with sodium metaperiodate and to its sulfone 17 with m-chloroperbenzoic acid. Conversion of 13c to its sulfoxide 16b followed by halogenation gave the 1α-chloro sulfoxide 18 which was converted to the acid 19. The stereochemical assignments in the 2-isocephem series are discussed.

Epoxidation of Δ2-1-carbacephems 2 followed by base treatment gave the allylic alcohols 4. Oxidation of 4 gave the 2-keto-Δ3-carbacephem 9 which could be reduced to the isomeric allylic alcohol 7. Conversion of these intermediates to a series of biologically active cephalosporin analogs 13g–l and 14 is described.

The general synthetic scheme to nuclear analogs of cephalosporins described in previous papers of this series is reviewed and the synthesis of a series of sidechain derivatives is given. Thus, systems of the following type were formed: carbacephems (A), 2-isocephems (B), N-2-isocephems (C), and O-2-isocephems (D). The invitro microbiological activity of these compounds (with appropriate side-chains attached) is given, with comparison to analogous cephalosporins. Systems of type A, B, and C were only prepared with a 3-H or CH3 substituent and had modest antibacterial activity. The O-2-isocephems (D) were prepared with a wide variety of sidechains at 3 and 7 and were found to have biological activity quite comparable to the cephalosporins. A more detailed biological examination (both invitro and invivo) of the O-2-isocephem analog (19i) of cephalothin was made.

The syntheses of N-methyl and N-carboethoxy-7-β-phenoxyacetamido-Δ3-N-2-isocephem-4-carboxylic acids 17a and 17b are reported. Treatment of aldehyde 3c with methylamine followed by reduction of the Schiff base gave 4d which was converted to its trifluoroacetamide 5c. Acid catalyzed elimination of a mole of ethanol from 5c, gave 8b which was converted to the enol 10b via the vinylogous pyrrolidino amide 9b. Reductive removal of the trifluoroacetamide function led to spontaneous ring closure to give 11b. Alternatively treatment of bis-mesylate 12b with ammonia or methylamine gave 13a and 13b, respectively. Treatment of 13b with sodium hydride in DMSO gave 11b. Attempted acylation of 13a gave 14. Reduction of the azido functions in 11b and 14 followed by coupling of the amines to phenoxyacetic acid and reductive removal of the benzyl esters gave 17a and 17b, respectively. The structural assignments are discussed.

Stereoselective syntheses of the 1-β-methylcarbapenem intermediates 9B (R=SPh or OCH3) have been accomplished by an aldol-type stereocontrolled reaction and stereoselective catalytic hydrogenation of an olefinic ester.

Die zunachst dargestellten Zwischenprodukte (II) und (IV) werden uber die Ester (V) in die Carbonsauren (VI) ubergefuhrt; letztere zeigen signifikante antibiotische Aktivitat. Aus (VIb) werden bei Behandlung mit Na-metaperjodat das Sulfoxid und bei Be- . handlung mit m-Chlorperbenzoesaure das Sulfon gewonnen.

The synthesis of 7-β-phenoxyacetamido-3-methyl-1-oxo-Δ3-O-2-isocephem-4-carboxylic acid 14 is described. Condensation of amine 2 followed by β -lactam formation and ozonolysis gave the acid 5. This...

The preparation by total synthesis of a saturated cephalosporin analog 7-β-phenoxyacet-amido-3-ethoxy-O-2-isocepham-4-α-carboxylic acid 30, is described. Compound 30 was prepared via cycloaddition of azidoacetyl chloride to the cinnamylidene Schiff base of ethyl 2-amino-3, 3-diethoxypropionate 13b to give the cis-3-azido-4-styryl β-lactam 15b. Ozonolysis of 15b followed by sodium borohydride reduction gave the alcohol 18b. Boron trifluoride treatment of 18b gave ethyl 7-β-azido-3- β-ethoxy-O-2-isocephem-4-carboxylate 27. Reduction of the azido group followed by coupling with phenoxyacetic acid and saponification of the ester gave 30. The mechanism of the cycloaddition reaction and the stereochemical assignments are also discussed.

The general synthetic scheme to nuclear analogs of cephalosporins described in previous papers of this series is reviewed and the synthesis of a series of sidechain derivatives is given. Thus, syst...

The synthesis of 1-α-methyl and 1-β-methyl isomers of 7-(3-phenoxyacetamido-1,3-dimethyl-Δ3-O-2-isocephem-4-carboxylic acids (14a and 14b) is described. Treatment of amine 2 with methacrolein follo...