WO2007092802A1 - Method for treating hiv infection through co-administration of tipranavir and gs 9137 - Google Patents

Method for treating hiv infection through co-administration of tipranavir and gs 9137 Download PDF

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Publication number
WO2007092802A1
WO2007092802A1 PCT/US2007/061591 US2007061591W WO2007092802A1 WO 2007092802 A1 WO2007092802 A1 WO 2007092802A1 US 2007061591 W US2007061591 W US 2007061591W WO 2007092802 A1 WO2007092802 A1 WO 2007092802A1
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Prior art keywords
tipranavir
administration
hiv infection
ritonavir
treating hiv
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PCT/US2007/061591
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French (fr)
Inventor
Peter James Piliero
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Publication of WO2007092802A1 publication Critical patent/WO2007092802A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • TECHNICAL FIELD The present invention relates to a method for treating HIV infection through coadministration of tipranavir and GS 9137.
  • Tipranavir (also known as PNU 140690) is a non-peptidic HIV protease inhibitor which is useful for the treatment of HIV infection. Tipranavir has the following structural formula,
  • tipranavir The synthesis of tipranavir and the manner in which it may be used to treat HIV infection are described in U.S. Patent 5,852,195 and published International Application WO9530670.
  • GS 9137 also known as JTK-303, is an oral HIV integrase inhibitor and is useful for the treatment of HIV infection.
  • GS 9137 has the following chemical structure:
  • Ritonavir is an HIV protease inhibitor. Chemically it is ((2S,3S,5S)-5-(N-(N-((N-Methyl- N-((2-isopropyl-4-thiazoly)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5- thiazoly)methoxycarbonyl) amino)- 1,6-dipheny 1-3 -hydroxy hexane). It has the following structural formula.
  • Ritonavir is currently marketed only by Abbott Laboratories, as Norvir® capsules and oral solution. The synthesis of Ritonavir is described by U.S. Patent 5,541,206 and granted European Patent EP 0 674 513 Bl .
  • Ritonavir is a known inhibitor of Cytochrome P450 monooxygenase (hereinafter called "CYP"). While not approved for this purpose, ritonavir can thus be used to improve the pharmacokinetics of other drugs which are metabolized by CYP. Such use is described by U.S. Patent 6,037,157 and the corresponding WO9701349. The use ritonavir for the purpose of improving the pharmacokinetics of tipranavir is described in US Patent 6,147,095 and the corresponding WO0025784.
  • the invention provides an improved method for the treatment of HIV infection, especially infection by HIV-I, wherein tipranavir and GS 9137 are co-administered.
  • the invention further comprises pharmaceutical compositions comprising both tipranavir and etravire in a single dosage form.
  • a patient suffering from HIV infection is treated for such infection by means of the co-administration of tipranavir and GS 9137, optionally in further co-administration with additional anti- viral agents.
  • tipranavir and GS 9137 may be co- administered by way of separate dosage forms or they may optionally be combined in a single dosage form and administered simultaneously by this means.
  • tipranavir is co- administered not only with GS 9137 but also with an inhibitor of Cytochrome P450 monooxygenase (hereinafter called "CYP").
  • CYP Cytochrome P450 monooxygenase
  • the amount of the CYP inhibitor administered should be sufficient to inhibit the metabolism of tipranavir by CYP and thereby facilitate attainment of a therapeutically effective blood level of tipranav ⁇ r.
  • the preferred CYP inhibitor for this purpose is ritonavir, which may be employed in the manner described by U.S. Patent 6,147,095 and the corresponding WO0025784.
  • the invention also includes pharmaceutical compositions comprising both tipranavir and GS 9137, optionally in further combination with a CYP inhibitor, preferably ritonavir, as a single dosage form.
  • the invention further includes is a kit of parts comprising at least two dosage forms, one comprising tipranavir and the other GS 9137, wherein the kit optionally further includes a third dosage form comprising a CYP inhibitor, preferably ritonavir.
  • tipranavir, GS 9137 and CYP inhibitors, particularly ritonavir into appropriate pharmaceutical dosage forms.
  • the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
  • tipranavir For tipranavir, the most convenient and therefore preferable route of administration will be the oral route. Dosage forms suitable for the oral administration of tipranavir are known per se, having been described by U.S. Patent 5,852,195 and published International Application WO9530670. Exemplary fill formulations for soft gelatin capsules are described by US Patent 6,231,887, WO9906024, WO9906043 and WO9906044.
  • tipranavir When tipranavir is to be administered orally, an effective amount is from about 0.1 mg to 100 mg per kg of body weight per day. For adults, the preferred orally-administered dose of tipranavir is 500 mg, co-administcrcd with 200 mg low-dose ritonavir, twice daily. Commercially available ritonavir, such as that sold by Abbott Laboratories under the brand name Norvir®, may be used.
  • GS 9137 For GS 9137, the most convenient and therefore preferable route of administration will also be the oral route. Dosage forms suitable for the oral administration of GS 9137 are known per se, having been described by published International Application WO2005113508. In general, for the purpose of practicing the present invention, an effective daily amount of GS 9137 would be from 0.01 mg to 1 g.
  • tipranavir with co-administered CYP inhibitor such as ritonavir
  • GS 9137 as well as any additionally co-administered antiviral agents would be readily determined by those skilled in the art and would be dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
  • the co-administration of tipranavir, CYP inhibitor and GS 9137 in accordance with the invention may be accompanied by the further co-administration of additional antiviral agents.
  • Said other antiretroviral compounds may be known, antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g.
  • zidovudine (3'-azido-3'- deoxythymidine, AZT), didanosine (dideoxy inosine; ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (3 '-thia-2'-3 '-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transciptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (ll-cyclopropyl-5,l l-dihydro-4-methyl-6H-dipyrido[3,- 2-b: 2', 3'-e][l,4]diazepin-6-one), tacrine (tetrahydroaminoacridine)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method for treating HIV infection through co-administration of tipranavir and GS 9137.

Description

Method for Treating HIV Infection Through Co-Administration of Tipranavir and GS 9137
CROSS-REFERENCE TO RELATED APPLICATIONS The benefit of US Provisional Patent Application No. 60/743,261 filed on February 9, 2006 is hereby claimed.
BACKGROUND OF THE INVENTION
1. TECHNICAL FIELD The present invention relates to a method for treating HIV infection through coadministration of tipranavir and GS 9137.
2. BACKGROUND INFORMATION
Tipranavir (also known as PNU 140690) is a non-peptidic HIV protease inhibitor which is useful for the treatment of HIV infection. Tipranavir has the following structural formula,
Figure imgf000002_0001
and is known by the following chemical names:
2-Pyridinesulfonamide, N-[3-[(lR)-l-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-(2- phenylethyl)-6-propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)- (Preferred CA INDEX NAME)
2-Pyridinesulfonamide, N-[3-[l-[5,6-dihydro-4-hydroxy-2-oxo-6-(2- phenylethyl)-6- propyl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-, [R-(R* , R*)]- (Other CA INDEX NAME) 3'-[(I R)- 1 -[(6R)-5 ,6-Dihydro-4-hy droxy-2-oxo-6-phenylemyl-6-propyl-2H-pyran-
3yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonanilide
(USP Dictionary of USAN and International Drug Names, 2004 Ed.).
The synthesis of tipranavir and the manner in which it may be used to treat HIV infection are described in U.S. Patent 5,852,195 and published International Application WO9530670.
GS 9137, also known as JTK-303, is an oral HIV integrase inhibitor and is useful for the treatment of HIV infection. GS 9137 has the following chemical structure:
Figure imgf000003_0001
The synthesis of GS 9137 and the manner in which it may be used to treat HIV infection are described in published International Application WO20051 13508.
Ritonavir is an HIV protease inhibitor. Chemically it is ((2S,3S,5S)-5-(N-(N-((N-Methyl- N-((2-isopropyl-4-thiazoly)methyl)amino)carbonyl)valinyl)amino)-2-(N-((5- thiazoly)methoxycarbonyl) amino)- 1,6-dipheny 1-3 -hydroxy hexane). It has the following structural formula.
Figure imgf000003_0002
Ritonavir is currently marketed only by Abbott Laboratories, as Norvir® capsules and oral solution. The synthesis of Ritonavir is described by U.S. Patent 5,541,206 and granted European Patent EP 0 674 513 Bl . Ritonavir is a known inhibitor of Cytochrome P450 monooxygenase (hereinafter called "CYP"). While not approved for this purpose, ritonavir can thus be used to improve the pharmacokinetics of other drugs which are metabolized by CYP. Such use is described by U.S. Patent 6,037,157 and the corresponding WO9701349. The use ritonavir for the purpose of improving the pharmacokinetics of tipranavir is described in US Patent 6,147,095 and the corresponding WO0025784.
BRIEF SUMMARY OF THE INVENTION
The invention provides an improved method for the treatment of HIV infection, especially infection by HIV-I, wherein tipranavir and GS 9137 are co-administered. The invention further comprises pharmaceutical compositions comprising both tipranavir and etravire in a single dosage form.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the invention, a patient suffering from HIV infection, especially infection by HlV-I, is treated for such infection by means of the co-administration of tipranavir and GS 9137, optionally in further co-administration with additional anti- viral agents.
For the purpose of carrying out the invention, tipranavir and GS 9137 may be co- administered by way of separate dosage forms or they may optionally be combined in a single dosage form and administered simultaneously by this means.
Preferably, in accordance with the invention, tipranavir is co- administered not only with GS 9137 but also with an inhibitor of Cytochrome P450 monooxygenase (hereinafter called "CYP"). The amount of the CYP inhibitor administered should be sufficient to inhibit the metabolism of tipranavir by CYP and thereby facilitate attainment of a therapeutically effective blood level of tipranavϊr. The preferred CYP inhibitor for this purpose is ritonavir, which may be employed in the manner described by U.S. Patent 6,147,095 and the corresponding WO0025784.
The invention also includes pharmaceutical compositions comprising both tipranavir and GS 9137, optionally in further combination with a CYP inhibitor, preferably ritonavir, as a single dosage form. The invention further includes is a kit of parts comprising at least two dosage forms, one comprising tipranavir and the other GS 9137, wherein the kit optionally further includes a third dosage form comprising a CYP inhibitor, preferably ritonavir.
Those skilled in the art will know how to formulate tipranavir, GS 9137 and CYP inhibitors, particularly ritonavir, into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
For tipranavir, the most convenient and therefore preferable route of administration will be the oral route. Dosage forms suitable for the oral administration of tipranavir are known per se, having been described by U.S. Patent 5,852,195 and published International Application WO9530670. Exemplary fill formulations for soft gelatin capsules are described by US Patent 6,231,887, WO9906024, WO9906043 and WO9906044.
When tipranavir is to be administered orally, an effective amount is from about 0.1 mg to 100 mg per kg of body weight per day. For adults, the preferred orally-administered dose of tipranavir is 500 mg, co-administcrcd with 200 mg low-dose ritonavir, twice daily. Commercially available ritonavir, such as that sold by Abbott Laboratories under the brand name Norvir®, may be used.
For GS 9137, the most convenient and therefore preferable route of administration will also be the oral route. Dosage forms suitable for the oral administration of GS 9137 are known per se, having been described by published International Application WO2005113508. In general, for the purpose of practicing the present invention, an effective daily amount of GS 9137 would be from 0.01 mg to 1 g.
The exact route of administration, dose, or frequency of administration of tipranavir (with co-administered CYP inhibitor such as ritonavir) and GS 9137, as well as any additionally co-administered antiviral agents would be readily determined by those skilled in the art and would be dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
Optionally, the co-administration of tipranavir, CYP inhibitor and GS 9137 in accordance with the invention may be accompanied by the further co-administration of additional antiviral agents. Said other antiretroviral compounds may be known, antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3'-azido-3'- deoxythymidine, AZT), didanosine (dideoxy inosine; ddl), zalcitabine (dideoxycytidine, ddC) or lamivudine (3 '-thia-2'-3 '-dideoxycytidine, 3TC) and the like; non-nucleoside reverse transciptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (ll-cyclopropyl-5,l l-dihydro-4-methyl-6H-dipyrido[3,- 2-b: 2', 3'-e][l,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TlBO (tetrahydro-imidazo[4,5,l-jk][l,4]-benzodiazepine-2(lH)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5- -methyl-6-(3-methyl-2- butenyl)imidazo-[4,5,l-jk][l,4]benzodiazepine-2(lH)-thione; compounds of the .alpha.- APA (.alpha.-anilino phenyl acetamide) type e.g. .alpha.-[(2-nitro-phenyl)amino]-2,6- dichlorobcnzcnc-acctamidc and the like; TAT-inhibitors, e.g. R.O-5-3335 and the like; protease inhibitors e.g. indinavir, saquinovir, ABT-378 and the like; or immunomodulating agents, e.g. levamisole and the like.

Claims

CLAIMS:
1. A method for treating HIV infection which comprises co-administering tipranavir and GS 9137 in therapeutically effective amounts.
2. The use of tipranavir and GS 9137 in the manufacture of a medicament for the treatment of HIV infection.
3. A pharmaceutical composition comprising tipranavir and GS 9137 and a pharmaceutically acceptable carrier.
PCT/US2007/061591 2006-02-09 2007-02-05 Method for treating hiv infection through co-administration of tipranavir and gs 9137 WO2007092802A1 (en)

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US60/743,261 2006-02-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009006203A1 (en) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Therapeutic compositions and the use thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004087139A1 (en) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Antiviral combination of tipranavir and a further antiretroviral compound
WO2004101512A2 (en) * 2003-05-13 2004-11-25 Smithkline Beecham Corporation Naphthyridine integrase inhibitors
WO2005061487A1 (en) * 2003-12-11 2005-07-07 Abbott Laboratories Hiv protease inhibiting compounds
EP1564210A1 (en) * 2002-11-20 2005-08-17 Japan Tobacco Inc. 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors
WO2005113508A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Stable crystal of 4-oxoquinoline compound
WO2005112930A1 (en) * 2004-05-21 2005-12-01 Japan Tobacco Inc. Combinations comprising a 4-isoquinolone derivative and anti-hiv agents

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1564210A1 (en) * 2002-11-20 2005-08-17 Japan Tobacco Inc. 4-oxoquinoline compounds and utilization thereof as hiv integrase inhibitors
WO2004087139A1 (en) * 2003-03-27 2004-10-14 Boehringer Ingelheim International Gmbh Antiviral combination of tipranavir and a further antiretroviral compound
WO2004101512A2 (en) * 2003-05-13 2004-11-25 Smithkline Beecham Corporation Naphthyridine integrase inhibitors
WO2005061487A1 (en) * 2003-12-11 2005-07-07 Abbott Laboratories Hiv protease inhibiting compounds
WO2005113508A1 (en) * 2004-05-20 2005-12-01 Japan Tobacco Inc. Stable crystal of 4-oxoquinoline compound
WO2005112930A1 (en) * 2004-05-21 2005-12-01 Japan Tobacco Inc. Combinations comprising a 4-isoquinolone derivative and anti-hiv agents

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009006203A1 (en) * 2007-06-29 2009-01-08 Gilead Sciences, Inc. Therapeutic compositions and the use thereof

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