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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 Williams in 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 (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 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 B virus. repeated Virologic failure on antiretroviral combination Combinations of tipranavir with at least one compound of therapy, their 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. HO Base in particular of multiresistant HIV. In most cases, the enhanced therapeutic effect is not attainable by administra tion of either agent alone. In a preferred but not necessary 55 embodiment, the effect of administration of tipranavir and the compound of formula (I) in combination or alternation is synergistic. Even though a combination exhibits additive wherein Base is selected from the group consisting of and not synergistic effects, the combination can still provide thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethy 60 an effect that is different from the separate administration of luracil and 2,6-diaminopurine, or a pharmaceutically accept the two agents. For example, the biodistribution, pharma able salt or prodrug thereof, for the manufacture of a medicament for the prophylaxis or treatment of a viral cokinetics, cytotoxic effects or metabolism of one can be infection in a patient. affected by the other. In a fourth aspect of this invention, there is provided a kit 65 Further aspects of the present invention become apparent of parts for the prophylaxis or treatment of a viral infection to the one skilled in the art from the following detailed in a patient, comprising: description and examples. US 7,244,716 B2 5 Definitions The term “pharmaceutically acceptable salt” means a salt of the corresponding compound which is, within the scope of Sound medical judgment, Suitable for use in contact with 5 the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commen Surate with a reasonable benefit/risk ratio, generally water or HO oil-soluble or dispersible, and effective for their intended use. The term includes pharmaceutically-acceptable acid 10 addition salts and pharmaceutically-acceptable base addition salts. Lists of Suitable salts are found in, e.g., S. M. Birge et F al., J. Pharm. Sci., 1977, 66, pp. 1-19, which is hereby 3'-deoxy-3'-fluorothymidine (FLT) incorporated by reference in its entirety. 15 As used herein, the term “treatment’ means the admin istration of the antivirally active compounds according to this invention in combination or alternation according to the present invention to alleviate or eliminate symptoms of the viral infection and/or to reduce viral load in a patient. As used herein, the term “prevention” or “prophylaxis' means the administration of the antivirally active com 25 pounds according to this invention in combination or alter HO nation according to the present invention post-exposure of the individual to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the 30 virus in the blood. F As used herein, the term “human retrovirus' (HRV) 2',3'-dideoxy-3'-fluorocytidine includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, as well as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) 35 or strains apparent to one skilled in the art, which belong to the same or related viral families and which create similar NH2 physiological effects in humans as various human retrovi USS. 40 NCy N N DETAILED DESCRIPTION OF THE HO INVENTION O 45 The virally active agents according to this invention may be in either free form or in protected format one or more of F the remaining (not previously protected) carboxyl, amino, 2',3'-dideoxy-3'-fluoroadenosine hydroxy, or other reactive groups. The protecting groups 50 may be any of those known in the art. Furthermore, the virally active agents according to this invention may also be used as in form of their pharmacologically acceptable salts O and/or hydrates. 55

HN N According to the first aspect of this invention, there is N provided a novel pharmaceutical composition useful for the treatment of viral infections comprising tipranavir and at 60 ur) HO least one antiviral active compound of formula (I), or a O pharmaceutically acceptable salt or prodrug thereof.

The following known compounds constitute part of the 65 F invention as preferred compounds of the formula (I) to be 2',3'-dideoxy-3'-fluoroguanosine (FLG) combined with tipranavir. US 7,244,716 B2 7 8 including pharmaceutically acceptable salts and prodrugs of nosine, or a pharmaceutically acceptable salt or prodrug the compounds listed above. thereof, and a pharmaceutically acceptable carrier. Preferred prodrugs of FLG are described in WO99/09031 A preferred manufacture comprises tipranavir and and WO 99/41268, which documents in their entirety are 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3'-fluoro-5-O-2- incorporated herein by reference. 5 (L-Valyloxy)-propionylguanosine, or a pharmaceutically The most preferred compound of the formula (I) to be acceptable salt or prodrug thereof, for use in combination or combined with tipranavir according to the aspects of this alternation in the prophylaxis or treatment of a viral infec invention is selected from the group consisting of tion in a patient. (a) 3'-deoxy-3'-fluorothymidine, or a pharmaceutically 10 The advantageous effects of the combination of tipranavir acceptable Salt or prodrug thereof, and and the compound of formula (I) are realized over a wide (b) 2',3'-dideoxy-3'-fluoroguanosine (FLG), or a pharmaceu ratio, like for example in a ratio of between 1:250 to 250:1. tically acceptable salt or prodrug thereof, in particular 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propionylgua Therefore, in the compositions, combinations, kit of parts, nosine, or a pharmaceutically acceptable salt thereof. manufacture and/or the use of the combinations according to The compound of the formula (I) is very most preferably 15 this invention, tipranavir and the at least one compound of selected from the group consisting of 3'-deoxy-3'-fluorothy formula (I) are preferably present in a synergistic ratio. midine and 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propio Usually, this ratio is between about 1:250 to about 250:1. nylguanosine, including pharmaceutically acceptable salts More preferably the ratio is between about 1:50 to about thereof. 50:1. The most preferred ratio is between about 1:20 to about 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propionylgua 20:1, which includes the ratios 1:18, 1:16, 1:14, 1:12, 1:10: nosine is a preferred prodrug of FLG and can be depicted by 1:8; 1:6; 1:5; 1:4; 1:3; 1:2,5; 1:2: 1:15; 1:12; 1:1: 12:1; the following structure 15:1;2:1; 2,5:1; 3:1; 4:1; 5:1; 6:1; 8:1; 10:1, 12:1, 14:1, 16:1, 18:1 and all ranges in between. 25 If a further therapeutic agent is added, ratios will be adjusted accordingly. It will be appreciated that the amount of pharmaceutical composition according to the invention required for use in treatment or prophylaxis will vary not only with the par 30 ticular compound selected but also with the route of admin HN istration, the nature and severity of the condition for which treatment or prophylaxis is required, the age, weight and condition of the patient, concomitant medication and will be 35 ultimately at the discretion of the attendant physician or veterinarian. In general however the active compounds are The synthesis of 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- included in the pharmaceutically acceptable carrier in an propionylguanosine, also named as 21.3'-dideoxy-3'- amount Sufficient to deliver to a patient a therapeutically fluoro-5-O-2-(L-Valyloxy)-propionylguanosine, is effective amount of compound to inhibit viral replication in described in the WO99/09031 and especially in example 32 40 therein. Vivo, especially HIV replication, without causing serious Therefore, a preferred pharmaceutical composition useful toxic effects in the treated patient. By “inhibitory amount” is for the treatment of viral infections comprises tipranavir and meant an amount of active ingredient Sufficient to exert an 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3'-fluoro-5-O-2- inhibitory effect as measured by, for example, an assay Such (L-Valyloxy)-propionylguanosine, or a pharmaceutically 45 as the ones described herein. A suitable dose will preferably be in the range of from about 0.05 to about 200 mg/kg of acceptable salt or prodrug thereof. body weight per day. Furthermore, tipranavir in combination or alternation with preferably 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3- The desired dose may conveniently be presented in a fluoro-5-O-2-(L-Valyloxy)-propionylguanosine, or a phar single dose or as divided dose administered at appropriate 50 intervals, for example as two, three, four or more doses per maceutically acceptable salt or prodrug thereof, is used in day. the prophylaxis or treatment of a viral infection in a patient. The pharmaceutical composition according to the present Also preferred is the use of tipranavir in combination with 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3'-fluoro-5-O-2- invention is conveniently administered in unit dosage form; (L-Valyloxy)-propionylguanosine, or a pharmaceutically 55 for example containing 5 to 3000 mg, conveniently 5 to acceptable salt or prodrug thereof, for the manufacture of a 1000 mg of active ingredient(s) per unit dosage form. medicament for the prophylaxis or treatment of a viral The pharmaceutical acceptable carrier(s) must be “accept infection in a patient. able' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the A preferred kit of parts for the prophylaxis or treatment of 60 a viral infection in a patient, comprises: recipient thereof. (a) a first containment containing a pharmaceutical compo Examples of pharmaceutically acceptable carriers are sition comprising tipranavir and a pharmaceutically magnesium Stearate, chalk, starch, lactose, wax, gum or acceptable carrier, and gelatin. Carriers which are Suited to achieve a Sustained (b) a second containment containing a pharmaceutical com 65 release, for example natural or synthetic polymers or lipo position comprising 3'-deoxy-3'-fluorothymidine or Somes, are known to the one skilled in the art. Pharmaceu 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propionylgua tically acceptable carriers also comprise liquid carriers and US 7,244,716 B2 10 diluents, for example water, alcohol, glycerine or oil, which Furthermore, tipranavir in combination with ritonavir and serve as a base for liquid formulations, such as Solutions, in combination or alternation with preferably 3'-deoxy-3- Suspensions or emulsions. fluorothymidine or 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- The compositions referred to above may conveniently be propionylguanosine, or a pharmaceutically acceptable salt presented for use in the form of a pharmaceutical formula or prodrug thereof, is used in the prophylaxis or treatment of tion and therefore pharmaceutical formulations comprising a a viral infection in a patient. composition as defined above together with a pharmaceuti Also preferred is the use of tipranavir in combination with cally acceptable carrier comprise a further aspect of the ritonavir and 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3- invention. 10 fluoro-5-O-2-(L-Valyloxy)-propionylguanosine, or a phar The individual components of Such compositions may be maceutically acceptable salt or prodrug thereof, for the administered either in combination, i.e. simultaneously, or in manufacture of a medicament for the prophylaxis or treat alternation, i.e. sequentially, in separate or combined phar ment of a viral infection in a patient. maceutical formulations. A preferred kit of parts for the prophylaxis or treatment of When tipranavir is used in combination with a compound 15 a viral infection in a patient, comprises: of the formula (I) against the same virus the dose of each (a) a first containment containing a pharmaceutical compo compound may be either the same as or differ from that sition comprising tipranavir and ritonavir and a pharma when the compound is used alone. Appropriate doses will be ceutically acceptable carrier, and (b) a second containment containing a pharmaceutical com readily appreciated by those skilled in the art. position comprising 3'-deoxy-3'-fluorothymidine or The compositions according to this invention preferably 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propionylgua also comprise at least one pharmaceutically acceptable car nosine, or a pharmaceutically acceptable salt or prodrug rier. thereof, and a pharmaceutically acceptable carrier. According to the third aspect of this invention, the com Another preferred kit of parts for the prophylaxis or bination of tipranavir and at least one compound of the 25 treatment of a viral infection in a patient, comprises: formula (I) is used for the manufacture of a medicament for (a) a first containment containing a pharmaceutical compo the prophylaxis or the treatment of a viral infection in a sition comprising tipranavir and a pharmaceutically patient. acceptable carrier, and According to one embodiment, this medicament may be 30 (b) a second containment containing a pharmaceutical com a unit dosage form, which is preferably useful in combina position comprising ritonavir and a pharmaceutically tion therapy, such as capsules or tablets. The unit dosage acceptable carrier, and form contains a pharmaceutical composition according to (c) a third containment containing a pharmaceutical com position comprising 3'-deoxy-3'-fluorothymidine or this invention, i.e. tipranavir in combination with at least one 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)-propionylgua compound of the formula (I), with at least one pharmaceu 35 nosine, or a pharmaceutically acceptable salt or prodrug tically acceptable carrier. thereof, and a pharmaceutically acceptable carrier. Therefore, another object of this invention also comprises A preferred manufacture comprises tipranavir, ritonavir bringing tipranavir and at least a compound of the formula and a compound of the formula (I) selected from the group (I) together in conjunction or association with a pharmaceu 40 consisting of 3'-deoxy-3'-fluorothymidine or 3'-deoxy-3- tically acceptable carrier. fluoro-5-O-2-(L-Valyloxy)-propionylguanosine, or a phar According to another embodiment, this medicament is a maceutically acceptable salt thereof, for use in combination multiple dosage form, preferably a kit of parts, which is or alternation in the prophylaxis or treatment of a viral especially useful in alternation and/or combination therapy infection in a patient. to flexibly suit the individual therapeutic needs of the 45 In said combinations, compositions, kit of parts, manu patient. factures, which comprise tipranavir, ritonavir and at least It is known, e.g. WO 00/25784, that various doses of one compound of the formula (I) the ratio and the amount of ritonavir have substantial and significant effects on tipranavir and ritonavir present in these combinations are tipranavir by elevating, or enhancing, plasma concentrations 50 preferably chosen to achieve therapeutically effective of tipranavir. This pharmacokinetic may plasma levels of tipranavir. Upper limits, lower limits and offer the following advantages: therapeutically preferred areas of dosage regimens are enhanced antiviral activity of tipranavir, known from scientific literature, e.g. WO 00/25784, and reduction of the administered tipranavir dose, may be optimized in view of the combination with the improved safety profile. 55 compounds of the formula (I) according to known methods. Therefore, according to one embodiment the combina tions, compositions, kit of parts, manufactures of this inven According to further embodiments the combinations, tion and the uses thereof, which comprise tipranavir and at compositions, kit of parts, manufactures of this invention least one compound of the formula (I), or a pharmaceutically and the uses thereof comprise a combination selected from 60 the group consisting of: salt or prodrug thereof, further comprise ritonavir. a compound of the formula (I), tipranavir and one, two or Following this, a preferred pharmaceutical composition more further NRTIs: useful for the treatment of viral infections comprises a compound of the formula (I), tipranavir, a NNRTI and tipranavir in combination with ritonavir and 3'-deoxy-3- optionally one, two or more further NRTIs: fluorothymidine or 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- 65 a compound of the formula (I), tipranavir, an entry propionylguanosine, or a pharmaceutically acceptable salt inhibitor and optionally one, two or more further or prodrug thereof. NRTIs: US 7,244,716 B2 11 12 a compound of the formula (I), tipranavir, a NNRTI, an According to still further embodiments the combinations, and optionally one, two or more further compositions, kit of parts, manufactures of this invention NRTIs: and the uses thereof comprise a combination selected from a compound of the formula (I), tipranavir, an integrase the group consisting of a compound of the formula (I), inhibitor and optionally one, two or more further tipranavir and a further antiviral agent. In these still further NRTIs: embodiments tipranavir may advantageously be combined a compound of the formula (I), tipranavir, a NNRTI, an with ritonavir as described hereinbefore. and optionally one, two or more A further antiviral agent may be selected from the group further NRTIs. 10 of the maturation inhibitors, antisense compounds or pro In the above listed combinations, compositions, kit of tease inhibitors, other than tipranavir. Examples of further parts, manufactures and uses thereof tipranavir may advan antivirals are PA-457 (Panacos), KPC-2 (Kucera Pharm.), tageously be combined with ritonavir as described herein HGTV-43 (Enzo Biochem), (VX-478, Agen before. erase), (Reyataz), Sulfate (MK-639, 15 In the foregoing and in the following, the term “further Crixivan), Lexiva ( calcium, GW-433908 or NRTI' refers to a nucleoside reverse transcriptase inhibitor, 908, VX-175), +Ritonavir (ABT-378/r, Kaletra), or a pharmaceutically acceptable salt or prodrug thereof, Mesylate (Viracept), (Invirase, For other than the selected compound of the formula (I). tovase), AG-1776 (JE-2147, KNI-764; Nippon Mining Examples of further NRTIs are Sulfate (Ziagen), Holdings), AG-1859 (Pfizer), DPC-681/684 (BMS), (ddI, Videx), (Emtriva), Lamivu GS224338 (4338; Gilead Sciences), KNI-272 (Nippon dine (3TC, Epivir), (d4t, Zerit), Tenofovir diso Mining Holdings), Nar-DG-35 (Narhex), P(PL)-100 proxil fumarate (nucleotide, bis (POC) PMPA, Viread), (P-1946; Procyon Biopharma), P-1946 (Procyon Biop (ddc, Hivid), (AZT, Retrovir), harma), R-944 (Hoffmann-LaRoche), RO-0334649 (Hoff 25 mann-LaRoche), TMC-114 (Johnson & Johnson), VX-385 (DAPD; Gilead Sciences), (ACH (GW-640385; GSK/Vertex), VX-478 (Vertex/GSK). 126443; Achillion Pharm.), GS-7340 (Gilead Sciences), The combinations, compositions, kit of parts, manufac INK-20 (thioether phospholipid formulation of AZT Kucera tures of this invention and the uses thereof of the above Pharm.), MIV-310 (Medivir AB), MIV-210 (Medivir AB), mentioned embodiments may be combined with further (racemic FTC; Pharmasset), Reverset (RVT, 30 active ingredients. D-D4FC, DPC-817; Pharmasset), SPD-754 ((-)doTC; Examples of such further active ingredients are acyclic Shire Pharm), BCH-13520 (Shire Pharm) and BCH-10618 nucleosides Such as acyclovir, ganciclovir, interferons such (Shire Pharm). as alpha-, beta- and gamma-interferon; glucuronation inhibi In the foregoing and in the following, the term “NNRTI' 35 tors such as probenecid; nucleoside transport inhibitors such refers to a non nucleoside reverse transcriptase inhibitor, or as dipyridamole; immunomodulators such as interleukin II a pharmaceutically acceptable Salt or prodrug thereof. (IL2) and granulocyte macrophage colony stimulating factor Examples of NNRTIs are (Rescriptor), (GM-CSF), erythropoietin, ampligen, thymomodulin, thy (DMP-266, Sustiva), (BIRG-587, mopentin, , glycosylation inhibitors such as Viramune), (+)- and B (Advanced Life Sci 40 2-deoxy-D-glucose, castanospermine, 1-deoxynojirimycin; ences), (AG 1549, S-1153; Pfizer), GW-695634 and inhibitors of HIV binding to CD4 receptors such as (GW-8248; GSK), MIV-150 (Medivir), MV026048 soluble CD4, CD4 fragments, CD4-hybrid molecules and (R-1495; Medivir AB/Roche), NV-05 (Idenix Pharm.), inhibitors of the HIV aspartyl protease such as L-735,524. R-278474 (Johnson & Johnson), RS-1588 (Idenix Pharm.), 45 The compounds, or their pharmaceutically acceptable TMC-120/125 (Johnson & Johnson), TMC-125 (R-165335: derivative or salts thereof, can also be mixed with other Johnson & Johnson), UC-781 (Biosyn Inc.) and YM-215389 active materials that do not impair the desired action, or with (Yamanoushi). materials that Supplement the desired action, such as anti In the foregoing and in the following, the term "entry biotics, antifungals, antiinflammatorics, protease inhibitors, inhibitor refers to an entry inhibitor, including fusion 50 or other nucleoside or non-nucleoside antiviral agents, as inhibitors, inhibitors of the CD4 receptor, inhibitors of the discussed in more detail above. CCR5 co-receptor and inhibitors of the CXCR4 co-receptor, In general, during alternation therapy, an effective dosage or a pharmaceutically acceptable salt or prodrug thereof. of each agent is administered serially, whereas in combina Examples of entry inhibitors are AMD-070 (AMD-11070; 55 tion therapy, an effective dosage of two or more agents are AnorMed), BlockAide/CR (ADVENTRX Pharm.), BMS administered together. The dosages will depend on Such 806 (BMS-378806; BMS), Enfurvirtide (T-20, R698, factors as absorption, biodistribution, metabolism and excre Fuzeon), KRH-1636 (Kureha Pharmaceuticals), ONO-4128 tion rates for each drug as well as other factors known to (GW-873140, AK-602, E-913; ONO Pharmaceuticals), Pro those of skill in the art. It is to be noted that dosage values 140 (Progenics Pharm), PRO-542 (Progenics Pharm.), 60 will also vary with the severity of the condition to be SCH-D (SCH-417690; Schering-Plough), T-1249 (R724: alleviated. It is to be further understood that for any par Roche?Trimeris), TAK-220 (Takeda Chem. Ind.), TNX-355 ticular Subject, specific dosage regimens and Schedules (Tanox) and UK-427,857 (Pfizer). should be adjusted over time according to the individual Examples of integrase inhibitors are L-870810 (Merck & 65 need and the professional judgment of the person adminis Co.), c-2507 (Merck & Co.) and S(RSC)-1838 (Shionogi/ tering or Supervising the administration of the compositions. GSK). Examples of Suitable dosage ranges for tipranavir, com US 7,244,716 B2 13 14 pounds of formula (I), preferably 3'-deoxy-3'-fluorothymi coated according to methods well known in the art. Oral dine, ritonavir, further NRTIs and other antivirals can be liquid preparations may be in the form of, for example, found in the scientific literature. Many examples of suitable aqueous or oily suspensions, solutions, emulsions, syrups or dosage ranges for other compounds described herein are also elixirs, or may be presented as a dry product for constitution found in the public literature or can be identified using with water or other suitable vehicle before use. Such liquid known procedures. These dosage ranges can be modified as preparations may contain conventional additives such as desired to achieve a desired result. Suspending agents, emulsifying agents, non-aqueous It has been recognized that drug-resistant variants of HIV vehicles (which may include edible oils), or preservatives. can emerge after prolonged treatment with an antiviral 10 The pharmaceutical composition according to the inven agent. Drug resistance most typically occurs by mutation of tion may also be formulated for parenteral administration a gene that encodes for an enzyme used in the viral life (e.g. by injection, for example bolus injection or continuous cycle, and most typically in the case of HIV, in either the infusion) and may be presented in unit dose form in reverse transcriptase or protease genes. It has been demon ampoules, pre-filled Syringes, Small Volume infusion or in strated that the efficacy of a drug against HIV infection can 15 multi-dose containers with an added preservative. The com be prolonged, augmented, or restored by administering the positions may take Such forms as Suspensions, Solutions, or compound in combination or alternation with a second, and emulsions in oily or aqueous vehicles, and may contain perhaps third, antiviral compound that induces a different formulatory agents such as Suspending, stabilizing and/or mutation(s) from that selected for by the principle drug. dispersing agents. Alternatively, the active ingredient(s) may Alternatively, the , biodistribution, or be in powder form, obtained by aseptic isolation of sterile other parameter of the drug can be altered by such combi solid or by lyophilisation from solution, for constitution with nation or alternation therapy. In general, combination a Suitable vehicle, e.g. sterile, pyrogen-free water, before therapy is typically preferred over alternation therapy SC. because it induces-multiple simultaneous stresses on the 25 Pharmaceutical formulations suitable for rectal adminis virus. In the case of administering the antiviral compounds tration wherein the carrier is a solid are most preferably in alternation, i.e. sequentially, the time gap between admin presented as unit dose Suppositories. Suitable carriers istering the first compound and the second compound is include cocoa butter and other materials commonly used in preferably not too long in order to achieve a beneficial effect. 30 the art, and the Suppositories may be conveniently formed by Preferably, the time gap is less than half a day, most admixture of the active compound(s) with the softened or preferably less than 6 hours. melted carrier(s) followed by chilling and shaping in While it is possible that, for use in therapy, a compound moulds. of the invention may be administered as the raw chemical it When desired the above described formulations adapted is preferable to present the active ingredient as a pharma 35 to give Sustained release of the active ingredient(s) may be ceutical formulation. The invention thus further provides a employed. pharmaceutical formulation comprising tipranavir and a The compositions, combinations, kit of parts, manufac compound of the formula (I) with one or more pharmaceu ture and/or the use of the combinations according to this tically acceptable carriers and, optionally, other therapeutic invention are advantageous in the treatment and/or prophy and/or prophylactic ingredients. 40 laxis of viral infections in a patient, preferably human Pharmaceutical formulations include those suitable for retrovirus (HRV) infections and hepatitis B, in particular oral, rectal, nasal, topical (including buccal and Sub lingual), HIV infections, especially multiresistant HIV infections. transdermal, vaginal or parenteral (including intramuscular, Therefore this invention may offer an aid especially for Sub-cutaneous and intravenous) administration in liquid or 45 highly treatment experienced patients Suffering from multi solid form or in a form suitable for administration by resistant HIV. In addition to the treatment of said diseases, inhalation or insufflation. The formulations may, where the combinations, formulations and compositions according appropriate, be conveniently presented in discrete dosage to this invention can be used prophylactically to prevent or units and may be prepared by any of the methods well retard the progression of clinical illness in individuals who known in the art of pharmacy. All methods include the step 50 are anti-HIV antibody or HIV-antigen positive or who have of bringing into association the active compound(s) with been exposed to HIV. liquid carriers or finely divided solid carriers or both and The compositions, combinations, kit of parts, manufac then, if necessary, shaping the product into the desired ture and/or the use of the combinations according to this formulation. 55 invention may also be beneficial in preventing perinatal Pharmaceutical formulation suitable for oral administra transmission of human retroviral (HRV) infections, in par tion may conveniently be presented as discrete units such as ticular HIV-1, from mother to baby. According to this capsules, including soft gelatin capsules, cachets or tablets method, tipranavir and a compound of the formula (I), each containing a predetermined amount of the active ingre preferably 3'-deoxy-3'-fluorothymidine, and optionally fur dient(s); as a powder or granules; as a solution, a suspension 60 ther active compounds as described hereinbefore or herein or as an emulsion, for example as syrups, elixirs or self after are administered in combination or alternation to the emulsifying delivery systems (SEDDS). The active ingre mother before giving birth. dient(s) may also be presented as a bolus, electuary or paste. The compositions, combinations, kit of parts, manufac Tablets and capsules for oral administration may contain 65 ture and/or the use of the combinations according to this conventional excipients such as binding agents, fillers, lubri invention may also be beneficial in the treatment and/or cants, disintegrants, or wetting agents. The tablets may be prophylaxis of other HIV/AIDS-related conditions such as US 7,244,716 B2

AIDS-related complex (ARC), persistent generalized lym phadenopathy (PGL), AIDS-related neurological conditions, -continued anti-HIV antibody positive and HIV-positive conditions, t d d th Kaposi'ss sarcoma, thrombocytopenia purpurea and oppor compound 2" compound 3' compound 4" compound tunistic infections. 5 T y ity, s tOnawir Therefore, patients to be treated would be especially those FLT TPV Ritonavir MIV-210 individuals: FLT TPV Ritonavir Racivir 1) infected with one or more strains of a human retrovirus as FLT r y ity, SSS. determined by the presence of either measurable viral 10 FIT TPV Ritonavir BCH-13S2O antibody or antigen in the serum; and/or FLT TPV Ritonavir BCH-10618 2) in the case of HIV, having either a asymptomatic HIV FLG PV Air infection or a symptomatic AIDS defining infection such FLG TPV Didanosine8t as i) disseminated histoplasmosis, ii) isopsoriasis, iii) FLG TPV Emtricitabine bronchial and pulmonary candidiasis including pneu- 15 FLG TPV mocystic pneumonia, iv) non-Hodgkin’s lymphoma or V) y Sists Kaposi's sarcoma and being less than sixty years old; or disi having an absolute CD4+ lymphocyte count of less than unnarate 500/mm in the peripheral blood. FLG TPV Zalcitabine The pharmaceutical combination according to this inven- 20 y As tion can be tested for additive and synergistic activity against FLG TPV Elvucitabine HIV according to a number of assays known in scientific and FLG TPV GS-7340 public literature,- 0 including the one described in the WO FL r y E. O 98/44913 and WO 00/51641, which are included herein by FLG TPV Racivir way of reference. 25 T y Sis, The present invention is illustrated in further detail by the FLG TPV BCH-13S2O following non-limiting examples of combinations according FLG TPV BCH-10618 to this invention, comprising a 1 compound, a 2" com- LG r V Ritonavir yir pound, optionally a 3" compound, optionally a 4" com- 30 FLG TPV Ritonavir Didanosine pound and optionally a 5" compound. FLG TPV Ritonavir isite FLG TPV Ritonavir Lamivudine Table 1 illustrating combinations of a compound of the FLG TPV Ritonavir Stavudine formula (I), tipranavir (TPV) and one, two or more further FLG TPV Ritonavir Tenofovir NRTIS disoproxil 35 lunarate FLG TPV Ritonavir Zalcitabine FLG TPV Ritonavir Zidovudine FLG TPV Ritonavir Amdoxovir compound 2" compound 3" compound 4" compound FLG TPV Ritonavir Elvucitabine FLG TPV Ritonavir GS-7340 FLT TPV Abacavir 40 FLG TPV Ritonavir NK-20 Sulfate FLG TPV Ritonavir MIV-310 TPV Didanosine FLG TPV Ritonavir Racivir TPV Emtricitabine FLG TPV Ritonavir Reverset TPV Lamivudine FLG TPV Ritonavir SPD-754 TPV Stavudine FLG TPV Ritonavir BCH-13S2O TPV Tenofovir FLG TPV Ritonavir BCH-106.18 disoproxil 45 unnarate TPV ZalcitabineZidovudine Table 2 illustrating combinations of a compound of the TPV Amdoxovir formula (I), tipranavir, a NNRTI and optionally one, two or T y Espine more further NRTIS TPV NK-2O TPV MIV-210 TPV Racivir TPV Reverset compound 2" compound 3" compound 4" compound TPV SPD-754 TPV BCH-13S2O 55 FLT TPV Delavirdine TPV BCH-10618 FLT TPV Efavirenz TPV Ritonavir Abacavir FLT TPV Nevirapine Sulfate FLT TPV (+)- TPV Ritonavir Didanosine Calanolide A TPV Ritonavir Emtricitabine or B TPV Ritonavir Lamivudine 60 FLT TPV Capravirine TPV Ritonavir Stavudine FLT TPV GW-695634 TPV Ritonavir Tenofovir FLT TPV MIV-1SO disoproxil FLT TPV MVO26048 fumarate FLT TPV NV-05 TPV Ritonavir Zalcitabine FLT TPV R-278474 TPV Ritonavir Zidovudine FLT TPV RS-1588 TPV Ritonavir Amdoxovir 65 FLT TPV TMC-120,12S TPV Ritonavir Elvucitabine FLT TPV TMC-12S US 7,244,716 B2 17 18

-continued -continued compound 2" compound 3" compound 4" compound compound 2" compound 3" compound 4" compound TPV UC-781 5 FLT TPV UK-427,857 TPV YM-215389 FLT TPV Ritonavir Enfurwirtide TPV itonavir Delavirdine FLT TPV Ritonavir T-1249 TPV onavir Efavirenz FLT TPV Ritonavir AMD-070 TPV onavir Nevirapine FLT TPV Ritonavir Block Aide? CR TPV onavir (+)- FLT TPV Ritonavir BMS 806 Calanolide A 10 FLT TPV Ritonavir KRH-1636 or B FLT TPV Ritonavir ONO-4128 TPV onavir Capravirine FLT TPV Ritonavir Pro-140 TPV onavir GW-695634 FLT TPV Ritonavir PRO-542 TPV onavir MIV-1SO FLT TPV Ritonavir SCH-D TPV onavir MVO26048 FLT TPV Ritonavir TAK-22O TPV onavir NV-05 15 FLT TPV Ritonavir TNX-355 TPV onavir R-278474 FLT TPV Ritonavir UK-427,857 TPV onavir RS-1588 FLG TPV Enfurvirtide TPV onavir TMC-120,12S FLG TPV T-1249 TPV onavir TMC-12S FLG TPV AMD-070 TPV onavir UC-781 FLG TPV BlockAide? CR TPV onavir YM-215389 2O FLG TPV BMS 806 TPV Delavirdine FLG TPV KRH-1636 TPV Efavirenz FLG TPV ONO-4128 TPV Nevirapine FLG TPV Pro-140 TPV (+)- FLG TPV PRO-542 Calanolide A FLG TPV SCH-D or B FLG TPV TAK-220 TPV Capravirine 25 FLG TPV TNX-355 TPV GW-695634 FLG TPV UK-427,857 TPV MIV-1SO FLG TPV Ritonavir Enfurwirtide TPV MVO26048 FLG TPV Ritonavir T-1249 TPV NV-05 FLG TPV Ritonavir AMD-070 TPV R-278474 FLG TPV Ritonavir Block Aide? CR TPV RS-1588 30 FLG TPV Ritonavir BMS 806 TPV TMC-120,12S FLG TPV Ritonavir KRH-1636 TPV TMC-12S FLG TPV Ritonavir ONO-4128 TPV UC-781 FLG TPV Ritonavir Pro-140 TPV YM-215389 FLG TPV Ritonavir PRO-542 TPV itonavir Delavirdine FLG TPV Ritonavir SCH-D TPV onavir Efavirenz 35 FLG TPV Ritonavir TAK-22O TPV onavir Nevirapine FLG TPV Ritonavir TNX-355 TPV onavir (+)- FLG TPV Ritonavir UK-427,857 Calanolide A or B TPV onavir Capravirine TPV onavir GW-695634 40 Table 4 illustrating combinations of a compound of the TPV onavir MIV-1SO formula (I), tipranavir, a NNRTI, an entry inhibitor and TPV onavir MVO26048 TPV onavir NV-05 optionally one, two or more further NRTIs TPV onavir R-278474 TPV onavir RS-1588 TPV onavir TMC-120,12S TPV onavir TMC-12S 45 st 2nd 3rd 4th 5th TPV onavir UC-781 compound compound compound compound compound onavir YM-215389 TPV Delavirdine Enfurwirtide TPV Delavirdine T-1249 TPV Delavirdine AMD-070 Table 3 illustrating combinations of a compound of the 50 FLT TPV Delavirdine BlockAide? CR formula (I), tipranavir, an entry inhibitor and optionally one, TPV Delavirdine BMS 806 two or more further NRTIs TPV Delavirdine KRH-1636 TPV Delavirdine ONO-4128 TPV Delavirdine Pro-140 TPV Delavirdine PRO-542 55 FI TPV Delavirdine SCH-D 1 compound 2" compound 3" compound 4" compound FLT TPV Delavirdine TAK-220 TPV Delavirdine TNX-355 FLT TPV Enfurwirtide TPV Delavirdine UK-427,857 FLT TPV T-1249 TPV Efavirenz Enfurwirtide FLT TPV AMD-070 TPV Efavirenz T-1249 FLT TPV BlockAide? CR TPV Efavirenz AMD-070 FLT TPV BMS 806 60 TPV Efavirenz BlockAide? CR FLT TPV KRH-1636 TPV Efavirenz BMS 806 FLT TPV ONO-4128 TPV Efavirenz KRH-1636 FLT TPV Pro-140 TPV Efavirenz ONO-4128 FLT TPV PRO-542 TPV Efavirenz Pro-140 FLT TPV SCH-D TPV Efavirenz PRO-542 FLT TPV TAK-220 65 FLT TPV Efavirenz SCH-D FLT TPV TNX-355 TPV Efavirenz TAK-220 US 7,244,716 B2 19 20

-continued -continued

2nd 3rd 4th 5th 3. 2nd 3rd 4th 5th compound compound compound compound C O l p O l l d compound compound compound compound

TPV Efavirenz TNX-355 TPV Ritonavir GW-695634 SCH-D TPV Efavirenz UK-427,857 T TPV Ritonavir GW-695634 TAK-22O TPV Nevirapine Enfurvirtide LT TPV Ritonavir GW-695634 TNX-355 TPV Nevirapine T-1249 TPV Ritonavir GW-695634 UK-427,857 TPV Nevirapine AMD-070 TPV Delavirdine Enfurwirtide TPV Nevirapine BlockAide/CR 10 TPV Delavirdine T-1249 TPV Nevirapine BMS 806 TPV Delavirdline AMD-070 TPV Nevirapine KRH-1636 TPV Delavirdine BlockAide? CR TPV Nevirapine ONO-4128 TPV Delavirdline BMS 806 TPV Nevirapine Pro-140 TPV Delavirdline KRH-1636 TPV Nevirapine PRO-542 TPV Delavirdline ONO-4128 TPV Nevirapine SCH-D 15 TPV Delavirdine Pro-140 TPV Nevirapine TAK-220 TPV Delavirdline PRO-542 TPV Nevirapine TNX-355 TPV Delavirdline SCH-D TPV Nevirapine UK-427,857 TPV Delavirdine TAK-220 TPV GW-695634 Enfurwirtide TPV Delavirdline TNX-355 TPV GW-695634 T 1249 TPV Delavirdine UK-427,857 TPV GW-695634 AMD-070 TPV Efavirenz Enfurwirtide TPV GW-695634 BlockAide? CR TPV Efavirenz T-1249 TPV GW-695634 BMS 806 TPV Efavirenz AMD-070 TPV GW-695634 KRH-1636 TPV Efavirenz BlockAide? CR TPV GW-695634 ONO-4128 TPV Efavirenz BMS 806 TPV GW-695634 Pro-140 TPV Efavirenz KRH-1636 TPV GW-695634 PRO-542 TPV Efavirenz ONO-4128 TPV GW-695634 SCH-D 25 TPV Efavirenz Pro-140 TPV GW-695634 TAK-220 TPV Efavirenz PRO-542 TPV GW-695634 TNX-355 TPV Efavirenz SCH-D TPV GW-695634. UK-427,857 TPV Efavirenz TAK-220 TPV Ritonavir Delavirdine Enfurvirtide TPV Efavirenz TNX-355 TPV Ritonavir Delavirdine T-1249 TPV Efavirenz UK-427,857 TPV Ritonavir Delavirdine AMD-070 30 TPV Nevirapine Enfurwirtide TPV Ritonavir Delavirdine BlockAide? CR TPV Nevirapine T-1249 TPV Ritonavir Delavirdine BMS 806 TPV Nevirapine AMD-070 TPV Ritonavir Delavirdine KRH-1636 TPV Nevirapine BlockAide? CR TPV Ritonavir Delavirdine ONO-4128 TPV Nevirapine BMS 806 TPV Ritonavir Delavirdine Pro-140 TPV Nevirapine KRH-1636 TPV Ritonavir Delavirdine PRO-542 35 TPV Nevirapine ONO-4128 TPV Ritonavir Delavirdine SCH-D TPV Nevirapine Pro-140 TPV Ritonavir Delavirdine TAK-220 TPV Nevirapine PRO-542 TPV Ritonavir Delavirdine TNX-355 TPV Nevirapine SCH-D TPV Ritonavir Delavirdine UK-427,857 TPV Nevirapine TAK-220 TPV Ritonavir Efavirenz Enfurvirtide TPV Nevirapine TNX-355 TPV Ritonavir Efavirenz T-1249 TPV 40 Nevirapine UK-427,857 TPV Ritonavir Efavirenz AMD-070 TPV GW-695634 Enfurwirtide TPV Ritonavir Efavirenz BlockAide? CR TPV GW-695634 T 1249 TPV Ritonavir Efavirenz BMS 806 TPV GW-695634 AMD-070 TPV Ritonavir Efavirenz KRH-1636 TPV GW-695634 BlockAide? CR TPV Ritonavir Efavirenz ONO-4128 TPV GW-695634 BMS 806 TPV Ritonavir Efavirenz Pro-140 TPV GW-695634 KRH-1636 TPV Ritonavir Efavirenz PRO-542 45 TPV GW-695634 ONO-4128 TPV Ritonavir Efavirenz SCH-D TPV GW-695634 Pro-140 TPV Ritonavir Efavirenz TAK-220 TPV GW-695634 PRO-542 TPV Ritonavir Efavirenz TNX-355 TPV GW-695634 SCH-D TPV Ritonavir Efavirenz UK-427,857 TPV GW-695634 TAK-220 TPV Ritonavir Nevirapine Enfurvirtide TPV GW-695634 TNX-355 TPV Ritonavir Nevirapine T-1249 50 TPV GW-695634. UK-427,857 TPV Ritonavir Nevirapine AMD-070 TPV Ritonavir Delavirdine Enfurwirtide TPV Ritonavir Nevirapine BlockAide? CR TPV Ritonavir Delavirdine T-1249 TPV Ritonavir Nevirapine BMS 806 TPV Ritonavir Delavirdine AMD-070 TPV Ritonavir Nevirapine KRH-1636 TPV Ritonavir Delavirdine Block Aide? CR TPV Ritonavir Nevirapine ONO-4128 TPV Ritonavir Delavirdine BMS 806 TPV Ritonavir Nevirapine Pro-140 55 TPV Ritonavir Delavirdine KRH-1636 TPV Ritonavir Nevirapine PRO-542 TPV Ritonavir Delavirdine ONO-4128 TPV Ritonavir Nevirapine SCH-D TPV Ritonavir Delavirdine Pro-140 TPV Ritonavir Nevirapine TAK-220 TPV Ritonavir Delavirdine PRO-542 TPV Ritonavir Nevirapine TNX-355 TPV Ritonavir Delavirdine SCH-D TPV Ritonavir Nevirapine UK-427,857 TPV Ritonavir Delavirdine TAK-22O TPV Ritonavir GW-695634 Enfurvirtide TPV Ritonavir Delavirdine TNX-355 TPV Ritonavir GW-695634 T-1249 60 TPV Ritonavir Delavirdine UK-427,857 TPV Ritonavir GW-695634 AMD-070 TPV Ritonavir Efavirenz Enfurwirtide TPV Ritonavir GW-695634 BlockAide? CR TPV Ritonavir Efavirenz T-1249 TPV Ritonavir GW-695634 BMS 806 TPV Ritonavir Efavirenz AMD-070 TPV Ritonavir GW-695634 KRH-1636 TPV Ritonavir Efavirenz Block Aide? CR TPV Ritonavir GW-695634 ONO-4128 TPV Ritonavir Efavirenz BMS 806 TPV Ritonavir GW-695634 Pro-140 65 TPV Ritonavir Efavirenz KRH-1636 TPV Ritonavir GW-695634 PRO-542 TPV Ritonavir Efavirenz ONO-4128 US 7,244,716 B2 21 22

-continued -continued 2nd 3rd 4th 5th 2nd 3rd 4th 5 th compound compound compound compound compound compound compound compound TPV Ritonavir Efavirenz Pro-140 PV Nevirapine S(RSC)-1838 TPV Ritonavir Efavirenz PRO-542 PV (+)- S(RSC)-1838 TPV Ritonavir Efavirenz SCH-D Calanolide TPV Ritonavir Efavirenz TAK-220 A or B TPV Ritonavir Efavirenz TNX-355 PV (+)- C-2SO7 TPV Ritonavir Efavirenz UK-427,857 10 Calanolide TPV Ritonavir Nevirapine Enfurvirtide A or B TPV Ritonavir Nevirapine T-1249 PV (+)- L-870810 TPV Ritonavir Nevirapine AMD-070 Calanolide TPV Ritonavir Nevirapine BlockAide? CR A or B TPV Ritonavir Nevirapine BMS 806 PV Capravirine S(RSC)-1838 TPV Ritonavir Nevirapine KRH-1636 15 PV Capravirine L-870810 TPV Ritonavir Nevirapine ONO-4128 PV Capravirine C-2SO7 TPV Ritonavir Nevirapine Pro-140 PV GW-695634 S(RSC)-1838 TPV Ritonavir Nevirapine PRO-542 PV GW-695634 L-870810 TPV Ritonavir Nevirapine SCH-D PV GW-695634 C-2SO7 TPV Ritonavir Nevirapine TAK-220 PV MIV-1SO S(RSC)-1838 TPV Ritonavir Nevirapine TNX-355 PV MIV-1SO L-870810 TPV Ritonavir Nevirapine UK-427,857 PV MIV-1SO C-2SO7 TPV Ritonavir GW-695634 Enfurvirtide PV MVO26048 S(RSC)-1838 TPV Ritonavir GW-695634 T-1249 PV NV-05 L-870810 TPV Ritonavir GW-695634 AMD-070 PV NV-05 C-2SO7 TPV Ritonavir GW-695634 BlockAide? CR PV NV-05 S(RSC)-1838 TPV Ritonavir GW-695634 BMS 806 PV R-278474 L-870810 TPV Ritonavir GW-695634 KRH-1636 25 PV R-278474 C-2SO7 TPV Ritonavir GW-695634 ONO-4128 PV R-278474 S(RSC)-1838 TPV Ritonavir GW-695634 Pro-140 PV RS-1588 L-870810 TPV Ritonavir GW-695634 PRO-542 PV RS-1588 S(RSC)-1838 TPV Ritonavir GW-695634 SCH-D PV TMC-120/125 S(RSC)-1838 TPV Ritonavir GW-695634 TAK-220 PV TMC-120,125 C-2SO7 TPV Ritonavir GW-695634 TNX-355 30 PV TMC-120,125 L-870810 TPV Ritonavir GW-695634 UK-427,857 PV TMC-12S S(RSC)-1838 PV TMC-12S L-870810 PV TMC-12S C-2SO7 Table 5 illustrating combinations of a compound of the PV UC-781 S(RSC)-1838 formula (I), tipranavir, an integrase inhibitor and optionally PV UC-781 L-870810 35 PV UC-781 C-2SO7 one, two or more further NRTIs PV YM-215389 S(RSC)-1838 PV YM-215389 L-870810 PV YM-215389 C-2SO7 PV Ritonavir Delavirdine L-8708 PV Ritonavir Delavirdine S(RSC) -1838 1st 2nd 4th PV Ritonavir Efavirenz L-8708 40 compound compound compound compound PV Ritonavir Efavirenz S(RSC) -1838 PV Ritonavir Nevirapine L-8708 FLT TPV L-870810 PV Ritonavir Nevirapine -1838 FLT TPV C-2SO7 S(RSC) PV -1838 FLT TPV Ritonavir (+)- S(RSC) S(RSC)- Calanolide A 1838 or B FLT TPV Ritonavir L-870810 45 PV L-8708 FLT TPV Ritonavir Ritonavir (+)- S(RSC)-1838 Calanolide A FLG TPV L-870810 or B FLG TPV C-2SO7 PV Ritonavir Capravirine -1838 FLG TPV RSC) S(RSC)- PV Ritonavir Capravirine 8708 1838 PV Ritonavir GW-695634 -1838 FLG TPV Ritonavir L-870810 RSC) 50 PV Ritonavir GW-695634 8708 FLG TPV Ritonavir S(RSC)-1838 PV Ritonavir MIV-1SO RSC) -1838 PV Ritonavir MIV-1SO 8708 PV Ritonavir MVO26048 RSC) -1838 Table 6 illustrating combinations of a compound of the PV Ritonavir NV-05 8708 formula (I), tipranavir, a NNRTI, an integrase inhibitor and PV Ritonavir NV-05 RSC) -1838 55 PV Ritonavir R-278474 8708 optionally one, two or more further NRTIs PV Ritonavir R-278474 RSC) -1838 PV Ritonavir RS-1588 8708 PV Ritonavir RS-1588 RSC) -1838 PV Ritonavir TMC-120,12S RSC) -1838 1st 2nd 3rd 4th 5th PV Ritonavir TMC-120,12S 8708 compound compound compound compound compound PV Ritonavir TMC-12S RSC) -1838 60 PV Ritonavir TMC-12S 8708 FLT TPV Delaviridine L-870810 PV Ritonavir UC-781 RSC) -1838 FLT TPV Delaviridine C-2SO7 PV Ritonavir UC-781 8708 FLT TPV Delaviridine S(RSC)-1838 PV Ritonavir YM-215389 s RSC) -1838 FLT TPV Efavirenz L-870810 PV Ritonavir YM-215389 L-8708 FLT TPV Efavirenz S(RSC)-1838 PV Delavirdine L-870810 FLT TPV Nevirapine L-870810 65 PV Delavirdine S(RSC)-1838 FLT TPV Nevirapine C-2SO7 PV Efavirenz L-870810

US 7,244,716 B2 25 26 8. A method for treating an HIV or hepatitis B viral -continued infection in an individual comprising administering tipranavir in combination or in alternation with at least one st 2nd 3rd 4th antiviral active compound selected from the group consist compound compound compound compound ing of 3'-deoxy-3'-fluorothymidine, 2',3'-dideoxy-3'-fluo FLG TPV ritonavir KPC-2 roguanosine, or 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- FLG TPV ritonavir HGTV-43 propionylguanosine, or a pharmaceutically acceptable salt FLG TPV ritonavir Amprenavir FLG TPV ritonavir Atazanavir or prodrug thereof. FLG TPV ritonavir Indinavir 9. The method according to claim 8, wherein the antiviral Sulfate 10 active compound is 3'-deoxy-3'-fluorothymidine, or a phar FLG TPV ritonavir Lexiva maceutically acceptable salt or prodrug thereof. FLG TPV ritonavir Lopinavir FLG TPV ritonavir Nelfinavir 10. The method according to claim 8, wherein the anti Mesylate viral active compound is 2',3'-dideoxy-3'-fluoroguanosine, FLG TPV ritonavir Saquinavir or a pharmaceutically acceptable salt or prodrug thereof. FLG TPV ritonavir AG-1776 15 FLG TPV ritonavir AG-1859 11. The method according to claim 8, wherein the antiviral FLG TPV ritonavir DPC-681,684 active compound is 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- FLG TPV ritonavir GS224338 propionylguanosine, or a pharmaceutically acceptable salt FLG TPV ritonavir KNI-272 thereof. FLG TPV ritonavir Nar-DG-35 12. The method according to claim 8, wherein tipranavir FLG TPV ritonavir P(PL)-100 FLG TPV ritonavir P-1946 and the antiviral active compound are administered to the FLG TPV ritonavir R-944 individual in combination or in alternation in a ratio between FLG TPV ritonavir RO-0334649 about 1:250 to about 250:1. FLG TPV ritonavir TMC-114 13. The method according to claim 8, wherein tipranavir FLG TPV ritonavir VX-385 FLG TPV ritonavir VX-478 and the antiviral active compound are administered to the 25 individual in combination or in alternation in a ratio between about 1:50 to about 50:1. In the above given Tables 1 to 7 the term “FLG” is 14. The method according to claim 8, wherein tipranavir 2',3'-dideoxy-3'-fluoroguanosine, or a pharmaceutically is administered in combination with ritonavir and in com acceptable salt or prodrug thereof, in particular 3'-deoxy-3- bination or in alternation with the antiviral active compound. fluoro-5-O-2-(L-Valyloxy)-propionylguanosine, or a phar 30 15. The method according to claim 8, wherein tipranavir maceutically acceptable salt thereof. is administered in combination with the antiviral active compound. What is claimed is: 16. A kit for the treatment of an HIV or hepatitis B viral 1. A pharmaceutical composition for the treatment of an infection in an individual, comprising: HIV or hepatitis B viral infection comprising tipranavir and 35 (a) a first containment containing a pharmaceutical com at least one antiviral active compound selected from the position comprising tipranavir and at least one phar group consisting of 3'-deoxy-3'-fluorothymidine, 2',3'- maceutically acceptable carrier, and dideoxy-3'-fluoroguanosine, or 3'-deoxy-3'-fluoro-5-O-2- (b) a second containment containing a pharmaceutical (L-Valyloxy)-propionylguanosine, or a pharmaceutically composition comprising at least one antiviral active acceptable salt or prodrug thereof. 40 compound selected from the group consisting of 2. The pharmaceutical composition according to claim 1, 3'-deoxy-3'-fluorothymidine, 2,3'-dideoxy-3'-fluo wherein the antiviral active compound is 3'-deoxy-3'-fluo roguanosine, or 3'-deoxy-3'-fluoro-5-O-2-(L-Valy rothymidine, or a pharmaceutically acceptable salt or pro loxy)-propionylguanosine, or a pharmaceutically drug thereof. acceptable salt or prodrug thereof, and at least one 45 pharmaceutically acceptable carrier. 3. The pharmaceutical composition according to claim 1, 17. The kit according to claim 16, wherein the antiviral wherein the antiviral active compound is 2',3'-dideoxy-3- active compound is 3'-deoxy-3'-fluorothymidine, or a phar fluoroguanosine, or a pharmaceutically acceptable salt or maceutically acceptable salt or prodrug thereof. prodrug thereof. 18. The kit according to claim 16, wherein the antiviral 4. The pharmaceutical composition according to claim 1, 50 active compound is 2',3'-dideoxy-3'-fluoroguanosine, or a wherein the antiviral active compound is 3'-deoxy-3'-fluoro pharmaceutically acceptable salt or prodrug thereof. 5-O-2-(L-Valyloxy)-propionylguanosine, or a pharmaceu 19. The kit according to claim 16, wherein the antiviral tically acceptable salt thereof. active compound is 3'-deoxy-3'-fluoro-5-O-2-(L-Valyloxy)- 5. The pharmaceutical composition according to claim 1, propionylguanosine, or a pharmaceutically acceptable salt wherein tipranavir and the antiviral active compound are 55 thereof. present in a ratio between about 1:250 to about 250:1. 20. The kit according to claim 16, further comprising a 6. The pharmaceutical composition according to claim 1 containment containing a pharmaceutical composition com further comprising ritonavir. prising ritonavir. 7. The pharmaceutical composition according to claim 1 with at least one pharmaceutically acceptable carrier.