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United States Patent (10) Patent No.: US 7,244,716 B2 Klaes Et Al

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United States Patent (10) Patent No.: US 7,244,716 B2 Klaes Et Al USOO724471.6B2 (12) United States Patent (10) Patent No.: US 7,244,716 B2 Klaes et al. (45) Date of Patent: Jul. 17, 2007 (54) PHARMACEUTICAL COMPOSITION OF 2001/0036920 A1* 11/2001 Hirschman ................... 514f14 ANTIVIRAL AGENTS FOREIGN PATENT DOCUMENTS (75) Inventors: Heinz-Gerd Klaes, Gau-Bickelheim WO WO 88.00050 1, 1988 (DE); Elena Koundourakis, Danbury, WO WO 91/O1137 2, 1991 CT (US); Hernan Valdez, Somers, NY WO WO 99,09031 2, 1999 (US); Douglas Lytle Mayers, WO WO 99,41268 8, 1999 Newtown, CT (US) WO WOOO, 51641 9, 2000 (73) Assignee: Boehringer Ingelheim International OTHER PUBLICATIONS GmbH, Ingelheim (DE) Roy M. Gulicket al; New drugs for HIV therapy: AIDS (2002) vol. (*)c Notice:- r Stil tO E. state th SMR t Erik16 No. De 4 Clercq;pp. S135-S144; New Developments Lippincott Williamsin Anti-HIV & Wilkins. Chemotherapy; patent 1s extended or adjusted under Current Medicinal Chemistry (2001) vol. 8 pp. 1543-1572; U.S.C. 154(b) by 0 days. Bentham Science Publishers Ltd. (21) Appl. No.: 10/809,060 * cited by examiner (22) Filed: Mar 25, 2004 Primary Examiner Patrick Lewis 9 (74) Attorney, Agent, or Firm Michael P. Morris; (65) Prior Publication Data Mary-Ellen M. Devlin US 2004/O235779 A1 Nov. 25, 2004 (57) ABSTRACT (30) Foreign Application Priority Data In accordance with the present invention there is provided a Mar. 27, 2003 (EP) .................................. O3OO7OO1 pharmaceutical composition useful for the treatment or Jul. 17, 2003 (EP) ... ... O3O16224 prophylaxis of viral infections comprising tipranavir and at Dec. 20, 2003 (EP) .................................. O3O29507 least one antiviral active compound of formula (I) (51) Int. Cl. AOIN 43/04 (2006.01) I A6 IK3I/70 (2006.01) HO Base CO7H 19/00 (2006.01) CO7H 9/048 (2006.01) (52) U.S. Cl. ............................ 514/49; 514/42: 514/45; 514743 F (58) Field of Classification Search .................. 514/42, See application file for complete serie 45, 49 wherein Base is selected from the group consisting of pp p ry. thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy (56) References Cited luracil and 2,6-diaminopurine, or a pharmaceutically accept able salt or prodrug thereof. U.S. PATENT DOCUMENTS 6,147,095 A 11/2000 Ferry et al. 20 Claims, No Drawings US 7,244,716 B2 1. 2 PHARMACEUTICAL COMPOSITION OF antiretroviral drugs and cannot obtain two active drugs to ANTIVIRAL AGENTS form the core of a new, effective antiretroviral drug regimen. Tipranavir is a known agent for the treatment of HIV RELATED APPLICATIONS infection. 5 Tipranavir, also known as U-140690 and PNU-140690, is This application claims priority to European Application an HIV protease inhibitor. Chemically, tipranavir is (6R)-3- No. 03029507.5, filed Dec. 20, 2003: European Application ((1R)-1-3-((5-trifluoromethyl)(2-pyridyl) No. 03016224.2, filed Jul. 17, 2003; and European Appli sulfonyl)amino)phenylpropyl)-4-hydroxy-6-(2-phenyl cation No. 03007001.5, filed Mar. 27, 2003, each of which 10 ethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one or (R-(R*, is hereby incorporated by reference in its entirety. R*)-N-3-1-5,6-dihydro-4-hydroxy-2-oxo-6-(2- FIELD OF THE INVENTION phenylethyl)-6-prop yl-2H-pyran-3-ylpropylphenyl-5- (trifluoromethyl)-2-pyridinesulfonamide) and has the The present invention relates to a pharmaceutical com following structural formula: position useful for the treatment of viral infections compris 15 ing tipranavir and at least one antiviral active compound of formula (I). Furthermore the present invention relates to a use of tipranavir in combination or alternation with a com pound of formula (I) in the prophylaxis or treatment of a viral infection in a patient. The present invention also relates to a use of tipranavir in combination with a compound of formula (I) for the manufacture of a medicament for the prophylaxis or treatment of a viral infection in a patient. In addition the present invention relates to a kit of parts and to 25 a manufacture for the prophylaxis or treatment of a viral Tipranavir and methods for its synthesis and use in the infection in a patient. treatment of HIV are described in WO95/30670 and cor responding U.S. Pat. No. 5,852,195. Pharmaceutical formu BACKGROUND OF THE INVENTION 30 lations suitable for the oral administration of tipranavir are described in WO 99/06043 and WO 99/06044, and the Human immunodeficiency virus (HIV) is recognized as corresponding U.S. Pat. Nos. 6,121,313 and 6,231,887. the causative agent in AIDS. As tipranavir is metabolized relatively rapidly by the Current therapies for HIV infection focus on inhibiting cytochromes P450, especially the Cyp3A4 isoform, it is the activity of viral enzymes which are essential to the life 35 preferred to co-administer an inhibitor of Cyp3A4 in order cycle of the virus. The agents that are presently in use fall to obtain therapeutically effective blood levels of tipranavir. mainly into three classes, designated Nucleoside Reverse The use of ritonavir for this purpose is described in U.S. Pat. Transcriptase Inhibitors (NRTIs). Non-nucleoside Reverse No. 6,147,095. The use for this purpose of other inhibitors Transcriptase Inhibitors (NNRTIs), and Protease Inhibitors 40 of Cyp3A4 is also possible. (PIs). Presently, combination therapies, i.e. the selection of Furthermore Compounds of the Formula (I) two or more antiretroviral agents taken together to make up a "drug cocktail.” are the preferred treatment for HIV infection. Combination therapies have been shown to reduce HO Base the incidence of opportunistic infections and to increase 45 Survival time. Typically, the drug cocktail combines drugs from different classes, so as to attack the virus at several stages in the replication process. This approach has been shown to reduce the likelihood of the development of virus forms that are resistant to a given drug or class of drugs. 50 Treatment failure with rebound of the amount of HIV wherein Base is selected from the group consisting of which can be measured in the blood is common for patients thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy treated with combination antiretroviral regimens. Resistance luracil and 2,6-diaminopurine, or a pharmaceutically accept to the drugs in the drug regimen develops as the virus 55 able salt or prodrug thereof, are described in the WO 88/00050 and WO91701137 for the therapeutic and prophy replicates in the presence of these drugs. Because of struc lactic control and treatment of AIDS, HIV infections, hepa tural similarities of the drugs within an antiretroviral class, titis B virus (HBV) infections and retrovirus infections in cross resistance is commonly seen to the other members of animals and man. These nucleoside compounds are trans that class (for example Virologic failure on a regimen formed by cells or enzymes to triphosphates which inhibit containing an NNRTI will lead to cross resistance to the 60 the reverse transcriptase of retrovirus as well as the activity other first generation NNRTI agents). As patients experience of DNA dependent polymerase of hepatitis B virus. repeated Virologic failure on antiretroviral combination Combinations of tipranavir with at least one compound of therapy, their viruses develop broad multi-class antiretrovi the formula (I) which exhibit potent therapeutic activity ral drug resistance which limits the effectiveness of the next 65 against HIV and HBV would greatly aid in the development round of antiretroviral therapy. Many highly treatment expe of new combination therapy against human retroviral (HRV) rienced patients have been exposed to all three classes of infections and HBV. US 7,244,716 B2 3 4 SUMMARY OF THE INVENTION (a) a first containment containing a pharmaceutical compo sition comprising tipranavir and at least one pharmaceu In one aspect, the present invention provides a novel tically acceptable carrier, and pharmaceutical composition useful for the treatment or (b) a second containment containing a pharmaceutical com prophylaxis of viral infections comprising tipranavir and at position comprising an antiviral active compound of least one antiviral active compound of formula (I) formula (I) HO Base 10 HO Base 15 wherein Base is selected from the group consisting of thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy wherein Base is selected from the group consisting of luracil and 2,6-diaminopurine, or a pharmaceutically accept thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy able salt or prodrug thereof. luracil and 2,6-diaminopurine, or a pharmaceutically accept The pharmaceutical compositions of the present invention able salt or prodrug thereof, and at least one pharmaceuti are useful in therapy, in particular as antivirals, especially in cally acceptable carrier. the treatment or prophylaxis of human retroviral (HRV) In a fifth aspect of this invention, there is provided a infections. 25 manufacture comprising tipranavir and at least one antiviral In a second aspect, there is provided a use of tipranavir in active compound of formula (I) combination or alternation with at least one antiviral active compound of formula (I) 30 HO Base HO Base 35 wherein Base is selected from the group consisting of thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy wherein Base is selected from the group consisting of 40 thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy luracil and 2,6-diaminopurine, or a pharmaceutically accept luracil and 2,6-diaminopurine, or a pharmaceutically accept able salt or prodrug thereof, for use in combination or able salt or prodrug thereof, in the prophylaxis or treatment alternation in the prophylaxis or treatment of a viral infec of a viral infection in a patient. tion in patient. In a third aspect, there is provided a use of tipranavir in 45 With the combination of tipranavir and a compound of the combination with at least one antiviral active compound of formula (I) according to this invention, including its use in formula (I) prophylaxis and treatment, the person skilled in the art can achieve an advantageous therapeutic effect to inhibit viral 50 replication, especially of human retrovirus (HRV) and HBV.
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