Patents Represented by Attorney Scanlon
  • Patent number: 4885291
    Abstract: 7.beta.-Acylamino-1-carba(dethia)-3-cephem-4-carboxylic acids represented by the formula ##STR1## wherein n is 1 or 2; R.sub.1 is C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkyl substituted by hydroxy, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, trifluoromethyl, carboxy, carbamoyl, amino, C.sub.1 -C.sub.4 alkylamino, di-(C.sub.1 -C.sub.4 alkyl)amino, halogen, cyano, phenyl, substituted phenyl as defined above; C.sub.2 -C.sub.6 alkenyl; C.sub.3 -C.sub.7 cycloalkyl; phenyl or substituted phenyl as defined above; or a 5- or 6-membered heterocycle selected from thienyl, furyl, pyrryl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, triazinyl, or pyrazinyl; the benzheterocycles, benzothienyl, benzofuryl, indolyl, benzimidazolyl, or benztriazolyl, and said 5- or 6-membered heterocycle and said benzheterocycle substituted by C.sub.1 -C.sub.4 alkyl, halogen, hydroxy, C.sub.1 -C.sub.
    Type: Grant
    Filed: January 14, 1988
    Date of Patent: December 5, 1989
    Assignee: Eli Lilly and Company
    Inventor: John H. McDonald, III
  • Patent number: 4870169
    Abstract: 1-Benzyl(or substituted benzyl)-3.beta.-[4(S)-aryloxazolidin-2-one-3-yl]-4.beta.-(2-arylvinyl)azet idin-2-ones are provided via cycloaddition of a 4(S)-aryloxazolidin-2-one-3-ylacetyl halide and an imine formed with a benzylamine and a 3-arylacrolein, e.g. cinnamaldehyde. The azetidinones are useful chiral intermediates in an asymmetric synthesis of 1-carba(1-dethia)-3-hydroxy-3-cephem-4-carboxylic acids and esters and to monocyclic .beta.-lactam antibiotics.
    Type: Grant
    Filed: April 22, 1988
    Date of Patent: September 26, 1989
    Assignee: President and Fellows of Harvard College
    Inventors: David A. Evans, Eric B. Sjogren
  • Patent number: 4845229
    Abstract: A stereoselective process for chiral intermediates to 1-carbapenem and 1-carbacephalosporins is provided comprising the use of an N-acyl-(4R)-substituted-1,3-thiazolidine-2-thione as a chiral auxiliary in boron enolate mediated aldol condensation with a protected-.beta.-keto ester aldehyde. E.g., benzyl 3,3-(ethylenedioxy)-4-formylbutyrate is condensed with the boron enolate formed with n-butyryl (4R)-methoxycarbonyl-1,3-thiazolidine-2-thione to provide benzyl 3,3-ethylenedioxy-(5R)-hydroxy-6-[(4R)-methoxycarbonyl-1,3-thiazolidine-2- thione-3-ylcarbonyl]octanoate. Displacement of the thiazolidine-2-thione chiral auxiliary moiety with an O-alkyl, O-acyl or O-aralkyl hydroxyamine provides the corresponding chiral intermediate as the hydroxamate.
    Type: Grant
    Filed: February 26, 1988
    Date of Patent: July 4, 1989
    Assignee: University of Notre Dame du Lac
    Inventors: Chi-nung W. Hsiao, Marvin J. Miller
  • Patent number: 4826992
    Abstract: 2,3-(Dihydro) bicyclic pyrazolidinones are intermediates for bicyclic pyrazolidinone antimicrobials.
    Type: Grant
    Filed: November 24, 1986
    Date of Patent: May 2, 1989
    Assignee: Eli Lilly and Company
    Inventors: Louis N. Jungheim, Sandra K. Sigmund
  • Patent number: 4820815
    Abstract: The invention provides azetidinones of the formula ##STR1## where R.sub.4 is hydrogen, amino or protected amino; R.sup.0 is H when R.sub.4 is amino or protected amino, or C.sub.1 -C.sub.4 alkyl when R.sub.4 is H; R.sub.1 is H, CH.sub.3, --CH.sub.2 --.sub.n Y where Y is OH, protected OH, --CH.sub.2 OH, protected --CH.sub.2 OH, halogen, COOH or protected COOH; n is 1 or 2; --CH.sub.2 --C(O)SR.sub.1 ' where R.sub.1 ' is e.g., C.sub.1 -C.sub.4 alkyl; R.sub.2 is H or protecting group and R.sub.3 is e.g., alkyl or phenyl. The azetidinones obtained are useful intermediates to carbapenems and carbacephems and monocyclic antibacterials, e.g., .alpha.-(dialkylphosphono)-[[3.beta.-[2-(2-aminothiazol-4-yl)-2-(syn)metho xyiminoacetylamino]azetidin-2-one-1-yl]]acetic acid and pharmaceutically acceptable salts thereof.
    Type: Grant
    Filed: September 1, 1987
    Date of Patent: April 11, 1989
    Assignee: University of Notre Dame du Lac
    Inventor: Marvin J. Miller
  • Patent number: 4820816
    Abstract: 7.beta.-Acylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxyli c acid antibiotic compounds, esters and salts thereof, and the corresponding 7-amino and protected 7-amino 1-carbacephalosporins are provided. The 3-trifluoromethylsulfonyloxy-substituted 1-carbacephalosporins also are useful in a process for preparing 3-halo-1-carbacephalosporins which comprises reacting a 3-triflate ester with a lithium halide in an aprotic polar solvent.
    Type: Grant
    Filed: August 17, 1988
    Date of Patent: April 11, 1989
    Assignee: President and Fellows of Harvard College
    Inventors: David A. Evans, Eric B. Sjogren
  • Patent number: 4820832
    Abstract: A process for preparing 7.beta.-acylamino (or 7.beta.-protected amino)-3-H-1-carba(1-dethia)-3-cephem-4-carboxylic acid esters and the corresponding cephalosporins is provided. 7.beta.-Acylamino (or 7.beta.-protected amino)-3-halo (or 3-sulfonyl ester)-1-carba(dethia)-3-cephem carboxylic acid esters and the corresponding cephalosporins are reduced with Pd(O) and a tetra-C.sub.2 -C.sub.6 alkyl stannane and, when a 3-sulfonyloxy ester is reduced, the process is carried out in the presence of an alkali metal halide. 3-Sulfonyloxy-3-cephem esters such as 3-mesylate, 3-tosylate and 3-triflate are employed.
    Type: Grant
    Filed: March 23, 1988
    Date of Patent: April 11, 1989
    Assignee: Eli Lilly and Company
    Inventors: Gwendolyn K. Cook, John H. McDonald, III
  • Patent number: 4795815
    Abstract: 1,2,4-Trisubstituted diazolidinones are intermediates to bicyclic pyrazolidinone antimicrobial compounds.
    Type: Grant
    Filed: October 29, 1987
    Date of Patent: January 3, 1989
    Assignee: Eli Lilly and Company
    Inventor: Robert J. Ternansky
  • Patent number: 4791106
    Abstract: 7.beta.-Acylamino-3-alkoxycarbonyl-(and 3-keto)-1-carba(1-dethia)-3-cephem-4-carboxylic acids and derivatives and related 3-substituted compounds are provided as antibiotics useful for treating infections in man and animals. Pharmaceutical formulations comprising the antibiotics and intermediates a process for their preparation are provided. Exemplary compounds provided are 7.beta.-[D-(2-phenyl-2-aminoacetyl)amino]-3-methoxycarbonyl-1-carba(1-deth ia)-3-cephem-4-carboxylic acid and 7.beta.-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-acetyl-1-carb a(1-dethia)-3-cephem-4-carboxylic acid.
    Type: Grant
    Filed: June 26, 1987
    Date of Patent: December 13, 1988
    Assignee: Eli Lilly and Company
    Inventor: John E. Munroe
  • Patent number: 4782144
    Abstract: Crystalline p-nitrobenzyl 7.beta.-phenoxyacetylamino-3-hydroxy-1-carba(dethia)-3-cephem-4-carboxylat e and the crystalline mono-acetic acid solvate thereof are provided by mixing a carboxylic acid or a sulfonic acid with a solution of the 3-hydroxy ester in DMF or DMAC. Acetic acid provides the crystalline acetic acid solvate while other acids provide crystalline non-solvated 3-hydroxy ester. The crystalline forms are useful purified intermediates to antibiotics.
    Type: Grant
    Filed: September 14, 1987
    Date of Patent: November 1, 1988
    Assignee: Eli Lilly and Company
    Inventor: John P. Gardner
  • Patent number: 4778884
    Abstract: 7.beta.-Acylamino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxyli c acid antibiotic compounds, esters and salts thereof, and the corresponding 7-amino and protected 7-amino 1-carbacephalosporins are provided. The 3-trifluoromethylsulfonyloxy-substituted 1-carbacephalosporins also are useful in a process for preparing 3-halo-1-carbacephalosporins which comprises reacting a 3-triflate ester with a lithium halide in an aprotic polar solvent.
    Type: Grant
    Filed: February 25, 1987
    Date of Patent: October 18, 1988
    Assignee: President & Fellows of Harvard College
    Inventors: David A. Evans, Eric B. Sjogren
  • Patent number: 4775752
    Abstract: A process for preparing a .beta.-keto ester of the formula ##STR1## is provided which comprises cycloaddition of an (S)-4-aryloxazolidin-2-one-3-ylacetyl halide with an imine formed with a benzyl amine and an m-alkoxycinnamaldehyde to form the azetidinone ##STR2## hydrogenation of the azetidinone to the 4-[2-(m-alkoxyphenyl)-ethyl]substituted azetidinone; reduction of the hydrogenation product with Li-NH.sub.3 and t-butyl alcohol to form the 3-aminoazetidinone. ##STR3## and N-acylation of the 3-aminoazetidinone followed by ozonolysis of the cyclodiene group; wherein, e.g. alk, is methyl, Ar is phenyl and R.sub.1 is phenoxymethyl.
    Type: Grant
    Filed: September 21, 1987
    Date of Patent: October 4, 1988
    Assignee: The President and Fellows of Harvard College
    Inventors: David A. Evans, Eric B. Sjogren
  • Patent number: 4772694
    Abstract: 2,5-Disubstituted oxazolidin-4-one-3-ylacetyl chlorides and 1,2,5-substituted imidazolidin-4-one-3-yl-acetyl chlorides function as chiral auxiliary moieties in the asymmetric cycloaddition with aldimines to provide cis-azetidinones. The azetidinones are useful intermediates in the preparation of antibiotics.
    Type: Grant
    Filed: July 24, 1986
    Date of Patent: September 20, 1988
    Assignee: Eli Lilly and Company
    Inventor: Robin D. G. Cooper
  • Patent number: 4769325
    Abstract: 2-(Allenyl)penicillins antibiotics and intermediates thereto are disclosed. A process for making the 2-(allenyl)penicillins and the starting materials for the process are also disclosed.
    Type: Grant
    Filed: July 28, 1986
    Date of Patent: September 6, 1988
    Inventors: Jack E. Baldwin, Amit Basak
  • Patent number: 4753881
    Abstract: Deacetoxycephalosporin C synthetase is provided in purified form via chromatography of crude cell-free extracts over a weak anion exchange resin followed by gel filtration and hydroxylapatite chromatography, all carried out in the presence of glycerol, a C.sub.1 -C.sub.3 alkyl monohydric alcohol, e.g., ethanol, a sulfhydryl containing reducing agent, e.g., dithiothreitol, and ascorbate. The purified enzyme which possesses both expandase and hydroxylase activities can be further purified by chromatography over a strong anion exchange resin.
    Type: Grant
    Filed: September 10, 1986
    Date of Patent: June 28, 1988
    Assignee: Eli Lilly and Company
    Inventors: Wu-Kuang Yeh, Joe E. Dotzlaf
  • Patent number: 4751296
    Abstract: A process for 4-halomethylazetidin-2-ones is provided which comprises mixing in an inert solvent a positive halogen reagent in the presence of a weak base with a .beta.,.gamma.-unsaturated O-acylhydroxamate of the formula ##STR1## wherein R is protected amino, lower alkyl or phenyl substituted lower alkyl, R.sub.2 is a substituent such as lower alkyl which may be substituted by formyl, hydroxy, halogen, etc., and R.sub.1 is alkoxy, benzyloxy, etc. When R is a protected amino group, the process provides cis-4-halomethylazetidin-2-ones, while when R is alkyl or phenylalkyl, the trans isomer is obtained. The 4-halomethylazetidinones are useful intermediates for known antibiotic compounds.
    Type: Grant
    Filed: August 6, 1986
    Date of Patent: June 14, 1988
    Assignee: University of Notre Dame du Lac
    Inventor: Marvin J. Miller
  • Patent number: 4745201
    Abstract: A stereoselective process for chiral intermediates to 1-carbapenum and 1-carbacephalosporins is provided comprising the use of an N-acyl-(4R)-substituted-1,3-thiazolidine-2-thione as a chiral auxiliary in boron enolate mediated aldol condensation with a protected-.beta.-keto ester aldehyde. E.g., benzyl 3,3-(ethylenedioxy)-4-formylbutyrate is condensed with the boron enolate formed with n-butyryl (4R)-methoxycarbonyl-1,3-thiazolidine-2-thione to provide benzyl 3,3-ethylenedioxy-(5R)-hydroxy-6-[(4R)-methoxycarbonyl-1,3-thiazolidine-2- thione-3-ylcarbonyl]octanoate. Displacement of the thiazolidine-2-thione chiral auxiliary moiety with an O-alkyl, O-acyl or O-aralkyl hydroxyamine provides the corresponding chiral intermediate as the hydroxamate.
    Type: Grant
    Filed: September 25, 1985
    Date of Patent: May 17, 1988
    Assignee: University of Notre Dame du Lac
    Inventors: Chi-nung W. Hsiao, Marvin J. Miller
  • Patent number: 4734495
    Abstract: 1-Benzyl(or substituted benzyl)-3.beta.-[4(S)-aryloxazolidin-2-one-3-yl]-4.beta.-(2-arylvinyl)azet idin-2-ones are provided via cycloaddition of a 4(S)-aryloxazolidin-2-one-3-ylacetyl halide and an imine formed with a benzylamine and a 3-arylacrolein, e.g. cinnamaldehyde. The azetidinones are useful chiral intermediates in an asymmetric synthesis of 1-carba(1-dethia)-3-hydroxy-3-cephem-4-carboxylic acids and esters and to monocyclic .beta.-lactam antibiotics.
    Type: Grant
    Filed: February 11, 1987
    Date of Patent: March 29, 1988
    Assignee: President and Fellows of Harvard College
    Inventors: David A. Evans, Eric B. Sjogren
  • Patent number: 4734498
    Abstract: 3.beta.-Substituted succinimido)azetidinones represented by the formula ##STR1## wherein R and R.sub.1 are e.g. C.sub.1 -C.sub.5 alkanoyloxy, benzoyloxy, substituted benzoyloxy, or benzyloxy, or one of R and R.sub.1 is hydrogen and the other is as defined above; R.sub.2 is C.sub.1 -C.sub.4 alkoxycarbonyl or an arylvinyl group e.g. styrryl or 2-furylvinyl; and R.sub.3 is e.g. protected-carboxymethyl, or an NH protecting group; are provided via stereoselective cycloaddition of imines with chiral auxiliary 3,4-disubstituted succinimidoacetyl chlorides. The chiral auxiliary e.g., 3S,4S-dibenzoyloxy-and 3S,4S-diacetoxysuccinimidoacetyl chloride, is obtained from tartaric acid via anhydride and imide formation with retention of chirality. The chiral azetidinones obtained are useful intermediates to .beta.-lactam antibacterial compounds.
    Type: Grant
    Filed: July 10, 1986
    Date of Patent: March 29, 1988
    Assignee: Eli Lilly and Company
    Inventor: Robin D. G. Cooper
  • Patent number: 4698338
    Abstract: O-Substituted oximinocephalosporins represented by the formula ##STR1## wherein R is a 5-membered or 6-membered heterocycle, preferably amino-substituted, e.g., 2-aminothiazol-4-yl, R.sub.1 is an arylalkyl, aryloxyalkyl, or arylthioalkyl group, especially substituted benzyl; R.sub.2 is a 1,2,4-triazin-3-yl thio group; and M is a salt or a biologically labile ester group; are potent antibacterial agents. Also provided are antibiotic formulations of said compounds and a method for treating infectious diseases in man or animals comprising the administration of said compounds.
    Type: Grant
    Filed: February 19, 1986
    Date of Patent: October 6, 1987
    Assignee: Eli Lilly and Company
    Inventor: Allen S. Katner