Patents Assigned to Antibioticos
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Patent number: 6635458Abstract: Enzymatic process for the preparation of cephalosporanic 7&bgr;-(4-carboxybutanamide) acid by using the modified enzyme D-aminoacid oxidase of Trigonopsis variabilis produced in Escherichia coli. The process for the expression of the enzyme comprises: (I) isolating the DNA corresponding to gene which codes for the enzyme D-aminoacid oxidase; (II) removing the intron which is contained in said gene; (III) inserting the DNA fragment obtained into the plasmide which is capable of replication in Escherichia coli; (IV) fusing at the extremity 5′ of the structural region of the gene a synthetic assembler which contains a nucleotide sequence which codes for six histidines; (V) transforming a strain of Escherichia coli with the resulting recombinant plasmide; (VI) cultivating the transformed cells of Escherichia coli; and (VII) recovering the enzyme D-aminoacid oxidase of the former cultivation operation through affinity chromatography.Type: GrantFiled: July 15, 1999Date of Patent: October 21, 2003Assignee: Antibioticos, S.A.U.Inventors: Jose Luis Garcia Lopez, Estrella Cortes Rubio, Jorge Alonso Palacios, Encarnacion Mellado Duran, Bruno Diez Garcia, Jose Manuel Guisan Seijas, Franciso Salto Maldonado, Barredo Fuente
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Patent number: 6558921Abstract: An isolated DNA having the promoter sequence of the hex gene of P. chrysogenum or a DNA fragment that is hybridizable to the complement of the promoter sequence under stringent conditions and is capable of directing expression of DNA downstream of the fragment in P. chrysogenum. Also a process for promoting expression of a coding sequence of interest in a microorganism using the isolated DNA and a process to block expression of a gene of interest in a microorganism using the isolated DNA are disclosed.Type: GrantFiled: August 2, 2000Date of Patent: May 6, 2003Assignee: Antibioticos, S.A.Inventors: Jose Luis Barredo Fuente, Marta Rodriguez Saiz, Alfonso J. Collados de la Vieja, Migeul Angel Moreno Valle, Francisco Salto Maldonado, Bruno Diez Garcia
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Publication number: 20030004336Abstract: A process for the preparation of Cefuroxime acid (1), which comprises the following steps: (1) Extraction of deacetyl 7-glutaryl ACA (II) aqueous solution at acid pH with organic solvents (for example according to the procedures disclosed in U.S. Pat. No. 5,801,241); (2) drying the resulting solution while preventing lactonization of the intermediate; (3) carbamoylation of the hydroxymethyl group at the 3-position by reaction with chlorosulfonyl isocyanate or similar products; (7) extraction of the carbamoyl derivative from step 3 with water at neutral pH; (8) enzymatic hydrolysis of the amide at the 7-position of the cephalosporanic ring with glutaryl acylase; (6) acylation of the amino group by condensation with 2-furanyl(sin-methoxyimino)acetic acid chloride or mixed anhydride.Type: ApplicationFiled: August 22, 2002Publication date: January 2, 2003Applicant: Antibioticos S.p.A.Inventors: Enrico Siviero, Walter Cabri, Daniele Mario Terrassan
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Patent number: 6458558Abstract: A process for the preparation of Cefuroxime acid (I), which comprises the following steps: (1) Extraction of deacetyl 7-glutaryl ACA (II) aqueous solution at acid pH with organic solvents (for example according to the procedures disclosed in U.S. Pat. No. 5,801,241); (2) drying the resulting solution while preventing lactonization of the intermediate; (3) carbamoylation of the hydroxymethyl group at the 3-position by reaction with chlorosulfonyl isocyanate or similar products; (7) extraction of the carbamoyl derivative from step 3 with water at neutral pH; (8) enzymatic hydrolysis of the amide at the 7-position of the cephalosporanic ring with glutaryl acylase; (6) acylation of the amnino group by condensation with 2-furanyl(sin-methoxyimino)acetic acid chloride or mixed anhydride.Type: GrantFiled: February 11, 2002Date of Patent: October 1, 2002Assignee: Antibioticos S.p.A.Inventors: Enrico Siviero, Walter Cabri, Daniele Mario Terrassan
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Patent number: 6417352Abstract: The invention relates to the process for the isolation of a pharmaceutically acceptable alkali metal salt of clavulanic acid from a fermentation broth containing impure clavulanic acid comprising the steps of filtration of the fermented broth, extraction of the clavulanic acid to a water immiscible or partly water immiscible solvent at pH from 1.2-2, precipitation of an alkali metal salt A of clavulanic acid by addition of a solution of an alkali metal alkylalkanoate, characterized by the following steps: before the filtration the fermented broth containing clavulanic acid is diluted with water, a flocculating agent is added and the pH is adjusted to 3-5 for further purification the alkali metal salt A of clavulanic acid is converted to clavulanic acid by addition of an inorganic acid and is extracted into a water immiscible or partly water immiscible solvent a solution of a different alkali metal B alkyl alkanoate is added and the alkali metal salt B of clavulanic acid is precipitated.Type: GrantFiled: February 10, 2000Date of Patent: July 9, 2002Assignee: CIPAN-Companhia Industrial Produtora de Antibioticos, S.A.Inventor: Joaquim P. Cardoso
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Patent number: 6300095Abstract: The invention relates to promoters of the genes glutamate dehydrogenase, &bgr;-acetylhexosaminidase and &ggr;-actin and their use in systems of expression, secretion and anti-sense of filamentary fungi. The invention also relates to the use of the promoters of the genes which code: (I) glutamate dehydrogenase NADP depending (EC.1.4.1.4) of Penicillium chrysogenum, (II) &ggr;-N-actylhexosaminidase (EC.3.2.1.52) of Penicillium chrysogenum and (III) &ggr;-actin of Penicillium chrysogenum and Acrimonium chrysogenum, which can be used for the construction of potent vectors of expression and secretion useful both for P. chrysogenum and for A. chrysogenum and related species. These promoters can also be used for blocking the genic expression through anti-sense construction. Under the control of the above mentioned promoters, it is possible to conduct the expression of other genes in filamentary fungi, thereby increasing the production of antibiotics and/or proteins inherent to the same.Type: GrantFiled: May 14, 1999Date of Patent: October 9, 2001Assignee: Antibioticos, S.A.Inventors: Jose Luis Barredo Fuente, Marta Rodriguez Saiz, Alfonso J. Collados De La Vieja, Migeul Angel Moreno Valle, Francisco Salto Maldonado, Bruno Diez Garcia
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Patent number: 6251655Abstract: An isolated DNA encoding phenyl acetyl-CoA-ligase and a process of increasing the production of penicillin G in a strain of Penicillium chrysogenum by transforming the strain with the isolated DNA. Also vectors and host organisms having the isolated DNA.Type: GrantFiled: October 28, 1998Date of Patent: June 26, 2001Assignee: Antibioticos S.A.Inventors: Baltasar Minambres Rodriguez, Honorina Martinez Blanco, Elias Rodriguez Olivera, Belen Garcia Alonso, Jose Manuel Fernandez Canon, Jose Luis Barredo Fuente, Bruno Diez Garcia, Carmen Schleissner Sanchez, Miguel Angel Moreno Valle, Francisco Salto Maldonado, Jose Maria Luengo Rodriguez
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Patent number: 6110699Abstract: Alternative process for obtaining 6-aminopenicillanic acid. The process comprises replacing the stages of extraction with organic solvents and isolation and separation of the intermediate penicillin salt as a solid by a process of ultrafiltration of the culture broth in at least 2 successive stages. The first stage has a cut-off for molecular weights of 20,000 Dalton and the second, 2000 Dalton. Subsequent to the enzyme conversion stage the products from that stage are subjected to a series of anionic exchange chromatography steps.Type: GrantFiled: February 25, 1998Date of Patent: August 29, 2000Assignee: Antibioticos, S.A.Inventors: Manuel Oliver Ruiz, Nieves Fraile Yecora, Emiliano Gonzalez De Prado, Alejandro Vitaller Alba, Francisco Salto Maldonado
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Patent number: 6100393Abstract: Process for purifying 7-substituted aminodeacetoxycephalosporins through the use of filter membranes. A process for purification by ultrafiltration and/or nanofiltration with a cut-off for molecular weights over 10,000 Dalton and preferably over 2000 Dalton is described. For example cephalosporin-G of increased purity, represented by a 6-8% increase in the HPLC titre, with a reduction of 50% in absorbance, is obtained using this technique. The invention makes it possible for the purified products to be used directly in the synthesis of other antibiotic compounds without the need for intermediate isolation.Type: GrantFiled: February 25, 1998Date of Patent: August 8, 2000Assignee: Antibioticos, S.A.Inventors: Juan Francisco Lopez Ortiz, Oscar Ferrero Barruego, Emiliano Gonzalez de Prado, Alejandro Vitaller Alba, Francisco Salto Maldonado
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Patent number: 6100052Abstract: A batch fermentation is carried out continuously or semicontinuously using strain of Streptomyces clavuligerus for the production of clavulanic acid. The fermentation process is carried out with strict control of the soluble phosphate in the medium both at the beginning and throughout the process.Type: GrantFiled: September 15, 1997Date of Patent: August 8, 2000Assignee: Antibioticos, S.A.Inventors: Carmelita Rodriguez Otero, Miguel Angel Moreno Valle, Manuel Jesus Lopez Nieto, Alfonso Juan Collados De La Vieja, Alejandro Vitaller Alba
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Patent number: 6005101Abstract: A compound having the following general formula (I): ##STR1## where R is a hydrogen atom; a linear or branched C.sub.1 -C.sub.4 alkyl group, unsubstituted or substituted by at least a phenyl group or at least a hydrogen atom; a benzyl group substituted by at least a linear or branched C.sub.1 -C.sub.4 alkyl or alkoxy group or a nitro group; a silyl substituted by at least a linear or branched, unsubstituted or substituted C.sub.1 -C.sub.4 alkyl group; n is 0 or 1; and Y is a radical of formula ##STR2## wherein A is H, OH, Cl, CH.sub.2, CH.sub.2 X, where X is F, Cl, Br, I, OH or OR' and R' is COCH.sub.3 or a linear or branched, unsubstituted or substituted C.sub.1 -C.sub.4 alkyl group and - - - represents a single or a double bond, with the proviso that when n=0 and R is H, R' is not a methyl group.Type: GrantFiled: February 3, 1998Date of Patent: December 21, 1999Assignee: Antibioticos S.p.A.Inventors: Loris Sogli, Davide Longoni, Giovanni Pozzi, Enrico Siviero, Daniele Mario Terrassan, Ermanno Bernasconi, Francisco Salto
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Patent number: 5945414Abstract: Cefazolin, cefazedone, cefoperazone, cefamandole, cefatrizine or ceftriaxone is prepared by reacting glutaryl 7-ACA of the formula: ##STR1## with a compound of formula (II):R--SH (II)wherein R is 5-methyl-1,3,4-thiadiazol-2-yl, 1H-1,2,3-triazol-4-yl, 1-methyl-tetrazol-5-yl or1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl group, and R.sup.1 and R.sup.2 are both hydrogen and the other is an acyl group, in an aqueous solution in an amount of 3-5 mols per mol of glutaryl 7-ACA to about 90.degree. C. and for a time from about 2 to about 10 hours;optionally recovering the excess of the compound of formula (II), thereby preparing a compound of formula (III) in an aqueous solution: ##STR2## wherein R is as above defined and optionally deacylating said compound of formula (III); andconverting the resulting compound of formula (I) ##STR3## wherein R, R.sup.1 and R.sup.2 are as defined above in the presence of a non-chlorinated solvent into one of said cephalosporins.Type: GrantFiled: December 2, 1997Date of Patent: August 31, 1999Assignee: Antibioticos S.p.A.Inventors: Loris Sogli, Daniele Terrassan, Ermanno Bernasconi, Francisco Salto
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Patent number: 5847116Abstract: A process is described for preparing 3-exomethylene cephalosporanic acid derivatives for use in the synthesis of cephalosporin antibiotics such as ceftibuten. The process comprises electrochemical reduction of a compound of the formula (IV) ##STR1## wherein: R.sup.3 is ##STR2## is an optional sulfoxide group; n is 2 or 3; R.sup.1 is H and R is H or NHR.sup.2, where R.sup.2 is H or a protecting group selected from C.sub.6 H.sub.5 CH.sub.2 OC(O)--, C.sub.6 H.sub.5 C(O)-- or C.sub.1 -C.sub.6 alkoxy-C(O)--; or wherein R and R.sup.1 together with the carbon atom to which they are attached comprise --C(O)--, and produces the desired 3-exomethylene compounds with low levels of the corresponding 3-methyl tautomers.Type: GrantFiled: December 13, 1996Date of Patent: December 8, 1998Assignees: Schering Corporation, AntibioticosInventors: Derek Walker, Junning Lee, Charles R. Martin, Haiyan Zhang, Loris Sogli, Ermanno Bernasconi, Vinod Parakkal Menon
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Patent number: 5750682Abstract: There are disclosed new compounds of formula (I), wherein R is: a hydrogen atom: a linear or branched C1-C4 alkyl group, unsubstituted or substituted by at least a phenyl group or at least a hydrogen atom: a benzyl group substituted by at least a linear or branched C1-C4 alkyl or alkoxy group or a nitro group; a silyl substituted by at least a linear or branched, unsubstituted or substituted C1-C4 alkyl group; n is 0 or 1; and Y is a radical of formula (II), wherein A is H, OH, Cl, CH2, CH2X, where X is F, Cl, Br, I, OH or OR' and R' is COCH3 or a linear or branched, unsubstituted or substituted C1-C4 alkyl group and . . . represents a single or a double bond, with the proviso that when n=0 and R is H, R' is not a methyl group; and processes for obtaining them.Type: GrantFiled: March 13, 1996Date of Patent: May 12, 1998Assignee: Antibioticos S.p.A.Inventors: Loris Sogli, Davide Longoni, Giovanni Pozzi, Enrico Siviero, Daniele Mario Terrassan, Ermanno Bernasconi, Francisco Salto
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Patent number: 5424196Abstract: Transformation of Cephalosporin C or its derivatives and salts into 7-aminocephalosporanic acid or its derivatives by an enzymatic two stage process with enzymes immobilized on a solid matrix.Type: GrantFiled: January 3, 1994Date of Patent: June 13, 1995Assignee: Antibioticos S.p.A.Inventors: Stefano Cambiaghi, Sergio Tomaselli, Roberto Verga
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Patent number: 5387679Abstract: The present invention relates to a process for preparing a compound of formula (I) ##STR1## wherein R is an heterocyclic group which contains at least one nitrogen atom with or without oxygen or sulphur and R.sup.1 and R.sup.2 are both hydrogen atoms or one of them is an hydrogen atom and the other is an acyl group; the process comprising reacting a compound of formula (II) ##STR2## wherein R.sup.1 and R.sup.2 are each as defined above, and wherein, if necessary, any reactive group is protected by a suitable protective group, or a salt thereof, with a compound of formula (III)R--SH (III)wherein R is as defined above, or a salt thereof, in the presence of an acid and of a compound of formula (IV) ##STR3## wherein each of R.sup.3 and R.sup.4 is a C.sub.1 -C.sub.4 alkyl group or R.sup.3 and R.sup.4 taken together are a C.sub.2 or C.sub.3 alkylene chain and, if necessary, removing the protective groups possibly present.Type: GrantFiled: March 15, 1993Date of Patent: February 7, 1995Assignee: Antibioticos S.p.A.Inventors: Loris Sogli, Daniele Terrassan, Giuseppe Ribaldone
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Patent number: 5354667Abstract: A process for the production of an E. coli strain producing high yields of 7.beta.-(4-carboxybutanamido) cephalosporin acylase, comprises: (a) digesting the DNA of a microorganism whose DNA includes the sequence encoding 7.beta.-(4-carboxybutanamido) cephalosporin acylase, and forming a plasmidic library; (b) transforming, with the sequences in the plasmidic library, an auxotrophic E. coli host; (c) selecting for transformed E. coli hosts containing the acylase sequence by growth on a suitable medium; (d) isolating the vector containing the acylase sequence, digesting the vector, and ligating the DNA sequences obtained into an E. coli vector under control of an E. coli promoter; (e) repeating selection procedure of step (c) ; (f) using the vectors from the selected E. coli hosts to transform an E. coli host lacking substantial .beta.-lactamase activity. 7-Aminocephalosporanic acid and its derivatives can be prepared by reaction of substrates like 7.beta.-(4-carboxybutanamido) cephalosporanic acid with 7.beta.Type: GrantFiled: August 5, 1991Date of Patent: October 11, 1994Assignee: Antibioticos, S.p.A.Inventors: Christian Croux, Javier C. Perez, Jose L. B. Fuentes, Francisco S. Maldonado
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Patent number: 5229509Abstract: The process comprises a series of stages essentially comprising the protection of the functional groups of the side chain of Ampicillin, esterification of the acid group, oxidation to sulphoxide, expansion of the thiazole ring to a thiazine ring, ozonolysis of the exomethylene cefam derivative obtained, substitution of the hydroxyl group by chlorine and de-protection of the functional groups, in which the order of some stages can be varied without affecting the final result.Type: GrantFiled: March 11, 1992Date of Patent: July 20, 1993Assignee: Antibioticos, S.A.Inventors: Rosa M. Nieves Elvira, Santiago Conde Ruzafa, Jose R. Fernandez Lizarbe
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Patent number: 5006471Abstract: A drug resistant strain of P.chrysogenum has said drug resistance conferred by heterologous DNA, in particular a heterologous gene(s) under the control of a Penicillium control sequence(s). Drug resistance is especially to sulfonamides, or to trimethoprim or methotrexate by a gene derived from plasmid R388. A vector capable of conferring resistance to methotrexate or sulfonamide on P.chrysogenum, comprises at least one said resistance gene under the control of trpC controlling sequences.Type: GrantFiled: March 26, 1987Date of Patent: April 9, 1991Assignee: Antibioticos S.A. of Bravo Murillo 38Inventors: Florentina S. Sanchez, Victor R. Susan, Laura Carramolino-Fitera, Agustin P. A. Ortega
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Patent number: 4898718Abstract: The present invention provides a new biocatalytic reactor to utilize succfully insoluble biocatalysts to carry out enzymatic reactions. It is especially adequate for the processing of enzymatic reactions using gel-like structure insoluble biocatalysts by eliminating the problems of high pressure drops, microbial contamination and mechanical disintegration which arise when conventional packed columns or agitated tanks are used.It is also adequate to utilize rigid insoluble biocatalysts to process enzymatic reactions with viscous or particulate substrates.Type: GrantFiled: March 2, 1987Date of Patent: February 6, 1990Assignee: Cipan-Companhia Industrial Produtora De Antibioticos, S. A.Inventor: Joaquim P. Cardoso