Patents Assigned to NaPro BioTherapeutics, Inc.
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Patent number: 6770670Abstract: A pharmaceutical formulation of paclitaxel and polyethoxylated castor oil is disclosed to be relatively acidified to a pH of less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment of cancer, A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which paclitaxel is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the paclitaxel before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.Type: GrantFiled: October 4, 2001Date of Patent: August 3, 2004Assignee: NaPro BioTherapeutics, Inc.Inventors: David Carver, Timothy Prout, Hernita Ewald, Robyn Elliott, Paul Handreck
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Patent number: 6653501Abstract: A method is provided for processing a solution having optical isomers to obtain a (2R,3S) target isomer: wherein P1 is H or a hydroxyl protecting group, R1 is H, an alkyl group, an olefinic group or an aromatic group, and R2 is H or R3CO, where R3 is an alkyl group, an olefinic group, an aromatic group, an O-alkyl group, an O-olefinic group or an O-aromatic group, provided that R1 is not H when R3 is Ph and P1 is H. The method includes passing the solution through a chromatographic stationary phase, such as S,S Whelk-O, that has a greater affinity for one of the target isomer and an optical isomer thereof. A portion of the solution with the target isomer is then collected. The solution may be a racemic mixture of (±)-N-CBZ-3-phenylisoserine ethyl ester.Type: GrantFiled: June 27, 2001Date of Patent: November 25, 2003Assignee: NaPro BioTherapeutics, Inc.Inventors: James D. McChesney, Herbert R. Brinkman, Siead Zegar, David Baehr
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Patent number: 6509484Abstract: The present invention relates to chemical compounds that are useful in the production of taxanes. The chemical compounds according to the present invention have a generalized formula: wherein R1 is +NH3X− where X is deprotonated organic acid such as deprotonated trifluoroacetic acid, and wherein R2 may be acetyl or hydrogen, and P1 may be hydrogen or a hydroxyl protecting group, such as benzyloxymethyl.Type: GrantFiled: May 22, 2001Date of Patent: January 21, 2003Assignee: NaPro BioTherapeutics, Inc.Inventors: Charles S. Swindell, Nancy Krauss
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Patent number: 6495705Abstract: The present invention describes a process for producing 10-deacetyl baccatin III from a solution containing a solvent reactive with hydrazine hydrate and a spectrum of taxanes. The solution is contacted with hydrazine hydrate thereby converting some taxanes therein into 10-deacetyl baccatin III. The process can target taxanes having an ester functionality on at least one of the C-10 and C-13 positions. The hydrazine hydrate cleaves the ester functionality of the taxane solute, The process may be used to produce 10-deacetyl baccatin III from a biomass extract by contacting the biomass extract with a mixture of a solvent and a hydrazine hydrate. The solvent may have a functional group that is cleaved by hydrazine. Acetate solvents are contemplated.Type: GrantFiled: July 5, 2001Date of Patent: December 17, 2002Assignee: NaPro BioTherapeutics, Inc.Inventors: Madhavi C. Chander, James D. McChesney
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Patent number: 6479679Abstract: The present invention relates to a method of producing paclitaxel from a protected coupled ester compound having a formula: wherein P1 is a hydrogenatable protecting group, comprising the steps of deprotecting the 7-O-position, 3′-N-position and 2′-O-position thereof in the presence of an acid to form a first intermediate compound having a formula: wherein HA is said acid, and benzoylating the first intermediate compound at the 3′-N-position thereby to produce paclitaxel.Type: GrantFiled: April 25, 2001Date of Patent: November 12, 2002Assignee: NaPro BioTherapeutics, Inc.Inventors: Jan Zygmunt, James D. McChesney
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Patent number: 6452025Abstract: The present invention relates to a method of producing paclitaxel from a protected coupled ester compound having a formula: wherein P1 is a hydrogenatable protecting group, comprising deprotecting the 7-O-position and 3′-N-position of the protected coupled ester compound to form a first intermediate compound, benzoylating the first intermediate compound at the 3′-N-position thereby to form a second intermediate compound, and deprotecting the second intermediate compound by replacing P1 with hydrogen in the presence of an acid. The present invention also provides chemical compounds useful in the production of paclitaxel.Type: GrantFiled: April 25, 2001Date of Patent: September 17, 2002Assignee: NaPro BioTherapeutics, Inc.Inventors: Jan Zygmunt, James D. McChesney
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Patent number: 6448417Abstract: The present invention relates to a method of producing paclitaxel or a paclitaxel analog comprising the esterification of C-7, C-10 di-CBZ 10-deacetylbaccatin III with an N-carbamate protected, C-2-protected 3-phenyl isoserine side chain. The C-7, C-10 carbobenzyloxy groups are then replaced with hydrogen and an acyl group is substituted at the C-3′ nitrogen. The resulting compound is acylated at the C-10 hydroxyl position, and deprotected at the C-2′ position by replacing the hydroxyl protecting group with hydrogen to produce paclitaxel or a paclitaxel analog. The present invention also relates to alternative methods of acylating a 10-hydroxy paclitaxel analog. The first method comprises dissolving a 10-hydroxy paclitaxel analog in an acceptable ether solvent therefor to form a first solution at a first temperature.Type: GrantFiled: January 11, 2001Date of Patent: September 10, 2002Assignee: NaPro BioTherapeutics, Inc.Inventors: Nicholas J. Sisti, Herbert R. Brinkman, James D. McChesney, Medhavi C. Chander, Xian Liang, Jan Zygmunt
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Patent number: 6358996Abstract: A chemical compound comprising an isotopically labeled analog of a standard taxane molecule, wherein said isotopically labeled analog is synthetically formed to have incorporated therein at a selected position a stable isotope of an element existing at said selected positon in said standard taxane molecule, said isotope having amass different form a mass of a mass of a most abundantly occurring isotope of said element in nature, such that said isotopically labeled analog has a molecular weight different form a molecular weight of said standard taxane molecule.Type: GrantFiled: June 9, 2000Date of Patent: March 19, 2002Assignee: NaPro BioTherapeutics, Inc.Inventors: Michael S. Alexander, James D. McChesney, Jan Zygmunt
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Patent number: 6306894Abstract: A pharmaceutical formulation of paclitaxel and polyethoxylated castor oil is disclosed to be relatively acidified to a pH of less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment of cancer. A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which paclitaxel is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the paclitaxel before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.Type: GrantFiled: May 3, 2000Date of Patent: October 23, 2001Assignee: NaPro Biotherapeutics, Inc.Inventors: David Carver, Timothy Prout, Hernita Ewald, Robyn Elliott, Paul Handreck
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Patent number: 6307088Abstract: The present invention concerns alkyl esters of &bgr;-amino acid derivatives which are useful in the synthesis of taxol and analogs.Type: GrantFiled: April 11, 2000Date of Patent: October 23, 2001Assignees: NaPro BioTherapeutics, Inc., Bryn Mawr CollegeInventors: Charles S. Swindell, Nancy Krauss
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Patent number: 6281368Abstract: A process for producing 10-deacetyl baccatin III from an acidic solution containing a spectrum of taxanes, comprising contacting the acidic solution containing the spectrum of taxanes with a hydrazine hydrate, thereby to convert into 10-deacetyl baccatin III some taxanes in said solution that are not 10-deacetyl baccatin III.Type: GrantFiled: March 16, 2000Date of Patent: August 28, 2001Assignee: NaPro BioTherapeutics, Inc.Inventors: James D. McChesney, Madhavi C. Chander, Douglas L. Rodenburg
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Patent number: 6143902Abstract: A chemic compound having the formula: ##STR1## wherein P.sub.1 is a hydroxyl protecting group, R.sub.1 is an alkyl group, an olefinic group, an aromatic group, Ph, PhCH.sub.2, an O-alkyl group, an O-olefinic group, an O-aromatic group, O--Ph, or O--CH.sub.2 Ph, and wherein Z is an N-imido group. In particular, P.sub.1 may be selected from the group consisting of benzyl, benzyloxymethyl and benzoyl, and Z may be a heterocyclic N-imido group, preferably having 5 to 7 atoms in the ring and alternatively substituted with at least one electron withdrawing group, preferably selected from the group consisting of a chloro group, a fluoro group and a nitro group. In particular, it is contemplated that Z may be succinimido, phthalimido, 5-norbornene-2,3-dicarboxyimido, maleimido and substituted derivatives thereof.Type: GrantFiled: June 21, 1999Date of Patent: November 7, 2000Assignee: NaPro BioTherapeutics, Inc.Inventors: Jan Zygmunt, James D. McChesney, Madhavi C. Chander
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Patent number: 6140359Abstract: A pharmaceutical formulation of paclitaxel (also known as taxol) and polyethoxylated castor oil is disclosed to be relatively acidified to a pH of less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment of cancer. A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which taxol is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the paclitaxel before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.Type: GrantFiled: July 19, 1999Date of Patent: October 31, 2000Assignee: NaPro Biotherapeutics, Inc.Inventors: David Carver, Timothy Prout, Hernita Ewald, Robyn Elliott, Paul Handreck
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Patent number: 6136999Abstract: A chemical compound having the formula: ##STR1## wherein P.sub.1 is a hydroxyl protecting group, R.sub.1 may be H or electron withdrawing group, R.sub.2 may be H or electron withdrawing group, R.sub.3 may be H or electron withdrawing group, R.sub.4 may be H or electron withdrawing group, R.sub.5 may be H or electron withdrawing group, R.sub.6 may be an alkyl group, an olefinic group, an aromatic group, Ph, PhCH.sub.2, an O-alkyl group, an O-olefinic group, an O-aromatic group, O--Ph, or O--CH.sub.2 Ph.Type: GrantFiled: June 21, 1999Date of Patent: October 24, 2000Assignee: NaPro BioTherapeutics, Inc.Inventors: Madhavi C. Chander, James D. McChesney, Jan Zygmunt
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Patent number: 6133462Abstract: A compound for use in the production of taxanes and intermediates therefor having the formula: ##STR1## wherein R is an alkyl group.Type: GrantFiled: September 2, 1997Date of Patent: October 17, 2000Assignees: NaPro BioTherapeutics, Inc., Bryn Mawr CollegeInventors: Nicholas J. Sisti, Charles S. Swindell
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Patent number: 6107497Abstract: C7, C10 di-CBZ 10-deacetyl baccatin III of the formula: ##STR1## provides an intermediate for the production of docetaxel. A method of producing this C7, C10 di-CBZ 10-deacetyl Baccatin III is provided. Here, 10-deacetyl Baccatin III is acylated with at least 1.5 equivalents of n-butyl lithium and at least 1.5 equivalents of benzyl chloroformate in tetrahydrofuran. The 10-deacetyl Baccatin III may first be dissolved in tetrahydrofuran after which the n-butyl lithium is added followed by the addition of the benzyl chloroformate. The reaction is preferably at a reduced temperature of less than -20.degree. C. The resulting solution may be quenched with ammonium chloride and reduced to residue. The residue may then be redissolved in an organic solvent, washed, dried and recrystallized to purify the compound.Type: GrantFiled: March 19, 1996Date of Patent: August 22, 2000Assignees: NaPro BioTherapeutics, Inc., Bryn Mawr CollegeInventors: Nicholas J. Sisti, Charles S. Swindell, Madhavi C. Chander
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Patent number: 6066749Abstract: A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran, to form a first solution at a first temperature. The first solution is then cooled to a second temperature, and a lithium base, preferably n-butyl lithium, is added to form an intermediate compound having a lithium alkoxide at the C-10 position thereof. An acylating agent, such as acetyl chloride, is then added. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent and the lithium base. The result is a solution containing C-2' O-protected taxol. This solution may then be washed, concentrated and purified. The present invention is also directed to C-10 lithium alkoxide intermediate compounds for the production of paclitaxel.Type: GrantFiled: May 1, 1998Date of Patent: May 23, 2000Assignee: NaPro BioTherapeutics, Inc.Inventors: Nicholas J. Sisti, Herbert R. Brinkman, James D. McChesney, Madhavi C. Chander, Xian Liang, Jan Zygmunt
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Patent number: 6048990Abstract: A method of acylating C-2' O-protected-10-hydroxy taxol selectively at the C-10 hydroxyl position over the C-7 hydroxy position thereof to produce C-2' O-protected taxol is accomplished first by dissolving C-2' O-protected-10-hydroxy taxol in an acceptable ether solvent therefor, such as tetrahydrofuran. A lithium salt, preferably lithium chloride, is added. A trialkylamine base or pyridine is next added, followed by the addition of an acylating agent, such as acetyl chloride. The resulting solution may be quenched, for example with ammonium chloride, to eliminate excess of the acylating agent. This solution may then be diluted with ethyl acetate to form an organic phase and an aqueous phase, with the organic phase being washed and thereafter reduced. Recrystallization and column chromatography may be employed to purify the C-2' O-protected taxol.Type: GrantFiled: May 1, 1998Date of Patent: April 11, 2000Assignee: NaPro BioTherapeutics, Inc.Inventors: Xian Liang, Jan Zygmunt, Nicholas J. Sisti, Madhavi C. Chander, Herbert R. Brinkman, James D. McChesney
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Patent number: 5977164Abstract: A pharmaceutical formulation of taxol and polyethoxylated castor oil is disclosed to be relatively acidified to pH of less 8.1 and preferably within a pH range of 5 to 7, inclusively, by an acidifying agent. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment cancer. A formulation method is disclosed and includes the step of mixing an acid with a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which taxol is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the taxol before mixing with the carrier solution. A variety of acidifying agents, a preferred one being anhydrous citric acid, are described.Type: GrantFiled: November 26, 1997Date of Patent: November 2, 1999Assignee: NaPro BioTherapeutics, Inc.Inventors: David Carver, Timothy Prout, Hernita Ewald, Robyn Elliott, Paul Handreck
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Patent number: 5972992Abstract: A pharmaceutical formulation of taxol and polyethoxylated castor oil is disclosed to be stabilized by reducing its pH to less than 8.1 and preferably within a pH range of 5 to 7, inclusively. Ethanol is optionally included in the formulation which is adapted for use in a body for the treatment of cancer. A formulation method is disclosed and includes the step of reducing the pH of a carrier material, such as polyethoxylated castor oil, to form a carrier solution after which taxol is added in an amount such that the resulting pH is less than 8.1 and preferably in a pH range of 5 to 7. Ethanol may optionally be slurried with the taxol before mixing with the carrier solution.Type: GrantFiled: February 24, 1998Date of Patent: October 26, 1999Assignee: NaPro Biotherapeutics, Inc.Inventors: David Carver, Timothy Prout, Hernita Ewald, Robyn Elliott, Paul Handreck