Patents Assigned to Sarawak Medichem Pharmaceuticals, Inc.
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Patent number: 6420571Abstract: The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy -10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10 -propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy -6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (−)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.Type: GrantFiled: July 31, 2001Date of Patent: July 16, 2002Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Ze-Qi Xu, Hongwei Yuan, Jennifer Crabb, Raghu Samy, Ailing Li, Hua Cao
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Patent number: 6369241Abstract: The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (−)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.Type: GrantFiled: April 25, 2000Date of Patent: April 9, 2002Assignee: Sarawak Medichem Pharmaceuticals, Inc.Inventors: Ze-Qi Xu, Hongwei Yuan, Jennifer Crabb, Raghu Samy, Ailing Li, Hua Cao
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Publication number: 20020013480Abstract: The present invention relates to methods for preparing 2,2-dimethyl-5-acyloxy-10-propyl-2H,8H-benzo[ 1,2-b:3,4-b ′]dipyran-8-one (5) and 2,2-dimethyl-5-hydroxy- 10-propyl-2H,8H-benzo[1,2-b:3,4-b ′]dipyran-8-one (6) and their use as intermediates for the synthesis of antiviral calanolide compounds. For example, Fries rearrangement on compound 5 or Friedel-Crafts reaction on 6, yields intermediate 2,2-dimethyl-5-hydroxy-6-propionyl-10-propyl-2H,8H-benzo[1,2-b:3,4-b′]dipyran-8-one (4), which, in turn, can be converted to (+)-calanolide A and (−)-calanolide B. The coupling of compound 6 with the appropriate chiral molecule under Mitsunobu or nucleophilic displacement leads to the asymmetric synthesis of antiviral calanolide compounds.Type: ApplicationFiled: July 31, 2001Publication date: January 31, 2002Applicant: Sarawak Medichem Pharmaceuticals, Inc.Inventors: Ze-Qi Xu, Hongwei Yuan, Jennifer Crabb, Raghu Samy, Ailing Li, Hua Cao
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Publication number: 20020013478Abstract: Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.Type: ApplicationFiled: March 21, 2001Publication date: January 31, 2002Applicant: Sarawak Medichem Pharmaceuticals,Inc.Inventors: Ze-Qi Xu, Michael T. Flavin, David Zembower
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Publication number: 20010027209Abstract: Calanolides and analogues thereof that demonstrate potent mycobacterium activity are provided. Also provided is a method of using calanolides and analogues thereof for treating or preventing mycobacterium infections. The calanolides and analogues thereof provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.Type: ApplicationFiled: December 11, 2000Publication date: October 4, 2001Applicant: Sarawak Medichem Pharmaceuticals, Inc.Inventors: Ze-Qi Xu, Yuh Meei Lin, Michael T. Flavin
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Patent number: 6277879Abstract: Calanolide analogues that demonstrate potent antiviral activity against many viruses are provided. Also provided is a method of using calanolide analogues for treating or preventing viral infections. The calanolide analogues provided are obtained via syntheses employing chromene 4 and chromanone 7 as key intermediates.Type: GrantFiled: October 15, 1998Date of Patent: August 21, 2001Assignee: Sarawak Medichem Pharmaceuticals, Inc.Inventors: Ze-Qi Xu, Michael T. Flavin, David Zembower
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Patent number: 6160131Abstract: An efficient and scalable method is reported for the isolation of costatolide (2), an HIV-1-specific nonnucleoside reverse transcriptase inhibitor (NNRTI), from the latex of Calophyllum plants such as C. teysmannii var. inophylloide. An overall yield of 10.6% of costatolide, with a purity of 96%, was obtained by repetitive recrystallization of the latex from a single organic solvent after the oily material was removed by treatment with hexane. A second major component of the latex, soulattrolide (3), another HIV-1 NNRTI, was also isolated. Both compounds were characterized by spectroscopic and chromatographic analyses and their in vitro anti-HIV activities were also confirmed. The results suggest that sufficient supplies of costatolide can be obtained in a relatively low-cost manner from natural sources.Type: GrantFiled: December 17, 1998Date of Patent: December 12, 2000Assignee: Sarawak Medichem Pharmaceuticals, Inc.Inventors: Yuh-Meei Lin, Herbert M. Anderson, Tuah R. Jenta, Michael J. Williams, Michael T. Flavin, Ze-Qi Xu
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Patent number: 6043271Abstract: A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing a viral infections using (.+-.)-calanolide or (-)-calanolide is provided.Type: GrantFiled: August 2, 1995Date of Patent: March 28, 2000Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, John D. Rizzo, Alla Kucherenko, Albert Khilevich, Abram Kivovich Sheinkman, Vilayphone Vilaychack, Lin Lin, Wei Chen, William A. Boulanger
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Patent number: 5981770Abstract: A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.Type: GrantFiled: September 5, 1997Date of Patent: November 9, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, Albert Khilevich, David Zembower, John D. Rizzo, Shuyuan Liao, Aye Mar, Lin Lin, Vilayphone Vilaychack, Darko Brankovic, Sergey Dzekhster, Jinjun Liu
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Patent number: 5892060Abstract: A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.Type: GrantFiled: March 1, 1996Date of Patent: April 6, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, Albert Khilevich, David Zembower, John D. Rizzo, Shuyuan Liao, Aye Mar, Lin Lin, Vilayphone Vilaychak, Darko Brankovic, Sergey Dzekhster, Jinjun Liu
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Patent number: 5874591Abstract: A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (.+-.)-calanolide A or (-)-calanolide A is provided.Type: GrantFiled: September 9, 1997Date of Patent: February 23, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, Vilayphone Vilaychack, Lin Lin
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Patent number: 5872264Abstract: A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (.+-.)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.Type: GrantFiled: September 5, 1997Date of Patent: February 16, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, Albert Khilevich, David Zembower, John D. Rizzo, Shuyuan Liao, Aye Mar, Lin Lin, Vilayphone Vilaychack, Darko Brankovic, Sergey Dzekhster, Jinjun Liu
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Patent number: 5869324Abstract: A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (.+-.)-calanolide A or (-)-calanolide A is provided.Type: GrantFiled: September 8, 1997Date of Patent: February 9, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, John D. Rizzo, Alla Kucherenko, Albert Khilevich, Abram Kivovich Sheinkman, Vilayphone Vilaychack, Lin Lin, Wei Chen, William A. Boulanger
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Patent number: 5859050Abstract: A method of preparing (+)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. According to the disclosed method, chromene 4 intermediate was subjected to a chlorotitanium-mediated aldol reaction with acetaldehyde to selectively produce (.+-.)-8a. Separation and enzyme-mediated resolution of (.+-.)-8a produced (+)-8a. Cyclization of (+)-8a under neutral Mitsunobu conditions followed by Luche reduction of (+)-7 produced (+)-calanolide A in high yield and enantiomeric purity. The method of the invention has been extended to produce potent antiviral calanolide A analogues.Type: GrantFiled: September 5, 1997Date of Patent: January 12, 1999Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, Albert Khilevich, David Zembower, John D. Rizzo, Lin Lin
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Patent number: 5847164Abstract: A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (.+-.)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (.+-.)-calanolide A or (-)-calanolide A is provided.Type: GrantFiled: September 9, 1997Date of Patent: December 8, 1998Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, John D. Rizzo, Albert Khilevich, Abram Kivovich Sheinkman
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Patent number: 5840921Abstract: A method of preparing (.+-.)-calanolide A, 1, a potent HIV reverse transcriptase inhibitor, from chromene 4 is provided. Useful intermediates for preparing (+)-calanolide A and its derivatives are also provided. According to the disclosed method, chromene 4 intermediate was reacted with acetaldehyde diethyl acetal or paraldehyde in the presence of an acid catalyst with heating, or a two-step reaction including an aldol reaction with acetaldehyde and cyclization either under acidic conditions or neutral Mitsunobu conditions, to produce chromanone 7. Reduction of chromanone 7 with sodium borohydride, in the presence of cerium trichloride, produced (.+-.)-calanolide A. A method for resolving (.+-.)-calanolide A into its optically active forms by a chiral HPLC system or by enzymatic acylation and hydrolysis is also disclosed. Finally, a method for treating or preventing viral infections using (.+-.)-calanolide A or (-)-calanolide A is provided.Type: GrantFiled: September 9, 1997Date of Patent: November 24, 1998Assignee: Sarawak MediChem Pharmaceuticals, Inc.Inventors: Michael T. Flavin, Ze-Qi Xu, John D. Rizzo, Albert Khilevich