(19) TZZ¥ _T

(11) EP 3 494 972 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 12.06.2019 Bulletin 2019/24 A61K 31/513 (2006.01) A61K 31/5365 (2006.01) A61K 45/06 (2006.01) A61K 9/00 (2006.01) (21) Application number: 19151897.6

(22) Date of filing: 24.01.2011

(84) Designated Contracting States: (72) Inventor: UNDERWOOD, Mark Richard AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Research Triangle Park, NC North Carolina 27709 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO (US) PL PT RO RS SE SI SK SM TR Designated Extension States: (74) Representative: Gladwin, Amanda Rachel BA ME GlaxoSmithKline Global Patents (CN925.1) (30) Priority: 27.01.2010 US 29858910 P 980 Great West Road Brentford, Middlesex TW8 9GS (GB) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: Remarks: 18161536.0 / 3 351 249 This application was filed on 15.01.2019 as a 15164931.6 / 2 932 970 divisional application to the application mentioned 11737484.3 / 2 531 027 under INID code 62.

(71) Applicant: VIIV Healthcare Company Wilmington, DE 19808 (US)

(54) COMBINATIONS OF AND FOR THE TREAETMENT OF HIV

(57) The present invention relates to combinations of compounds comprising HIV integrase inhibitors and other therapeutic agents. Such combinations are useful in the inhibition of HIV replication, the prevention and/or treatment of infection by HIV, and in the treatment of AIDS and/or ARC. EP 3 494 972 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 3 494 972 A1 2

Description compounds in the treatment of HIV infection and related conditions can result in potentiated antiviral activity, re- BACKGROUND OF THE INVENTION duced toxicity, delayed progression to resistance, and increased drug efficacy. Combinations administered in a [0001] The human immunodeficiency virus ("HIV") is 5 single dosage unit can result in increased patient com- the causative agent for acquired immunodeficiency syn- pliance as the pill burden is reduced and dosing sched- drome ("AIDS"), a disease characterized by the destruc- ules are simplified. However, not all compounds are suit- tion of the immune system, particularly of CD4 + T-cells, able for administration in combinations. Factors that in- with attendant susceptibility to opportunistic , fluence the feasibility of combinations include the chem- and its precursor AIDS-related complex ("ARC"), a syn- 10 ical instability of the compounds, size of the dosage unit, drome characterized by symptoms such as persistent potential for antagonistic or merely additive activities of generalized lymphadenopathy, fever and weight loss. the combined compounds, and difficulties in achieving a HIV is a retrovirus; the conversion of its RNA to DNA is suitable formulation. accomplished through the action of the enzyme reverse [0007] There is continued need to find therapeutic transcriptase. Compounds that inhibit the function of re- 15 agents suitable for use in combination and feasible phar- verse transcriptase inhibit replication of HIV in infected maceutical compositions to treat HIV infection. Due to cells. Such compounds are useful in the prevention or their high potency and pharmacokinetic profile, certain treatment of HIV infection in humans. HIV integrase inhibitors are attractive as components in [0002] In addition to CD4, HIV requires a co-receptor combination therapy. for entry into target cells. The chemokine receptors func- 20 tion together with CD4 as co-receptors for HIV. The BRIEF DESCRIPTION OF THE FIGURES chemokine receptors CXCR4 and CCR5 have been iden- tified as the main co-receptors for HIV-1. CCR5 acts as [0008] a major co-receptor for fusion and entry of macrophage- 25 tropic HIV into host cells. These chemokine receptors Figure 1: Inhibition of HIV-1IIIB by a compound of are thought to play an essential role in the establishment formula (I), GSK1349572A, in combination with and dissemination of an HIV infection. Therefore, CCR5 (ABC). antagonists are thought to be useful as therapeutic Figure 2: Inhibition of HIV-1IIIB by a compound of agents active against HIV. formula (I), GSK1349572A, in combination with efa- [0003] As in the case of several other retroviruses, HIV 30 virenz (EFV). encodes the production of a protease which carries out Figure 3: Inhibition of HIV-1IIIB by a compound of post-translational cleavage of precursor polypeptides in formula (I), GSK1349572A, in combination with lopi- a process necessary for the formation of infectious viri- navir (LPV) ons. These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse35 SUMMARY OF THE INVENTION transcriptase), an endonuclease, HIV protease, and gag, which encodes the core-proteins of the virion. [0009] The present invention relates to combinations [0004] One focus of anti-viral drug design has been to of compounds comprising HIV integrase inhibitors and create compounds which inhibit the formation of infec- other therapeutic agents. Such combinations are useful tious virions by interfering with the processing of viral 40 in the inhibition of HIV replication, the prevention and/or polyprotein precursors. Processing of these precursor treatmentof infection byHIV, andin the treatment of AIDS proteins requires the action of virus-encoded proteases and/or ARC. The present invention also features phar- which are essential for replication. The anti-viral potential maceutical compositions containing HIV integrase inhib- of HIV protease inhibition has been demonstrated using itors. peptidyl inhibitors. 45 [0005] A required step in HIV replication in human T- DETAILED DESCRIPTION OF THE INVENTION cells is the insertion by virally-encoded integrase of pro- viral DNA into the host cell genome. Integration is be- [0010] The present invention relates to combinations lieved to be mediated by integrase in a process involving comprising a compound of the following formula (I), (II), assembly of a stable nucleoprotein complex with viral 50 or (III): DNA sequences, cleavage of two nucleotides from the 3’ termini of the linear proviral DNA and covalent joining of the recessed 3’ OH termini of the proviral DNA at a staggered cut made at the host target site. The repair synthesis of the resultant gap may be accomplished by 55 cellular enzymes. Inhibitors of HIV integrase can be ef- fective in treating AIDS and inhibiting viral replication. [0006] Administration of combinations of therapeutic

2 3 EP 3 494 972 A1 4

[0014] A chemical name of the compound of formula (III) is (4aS,13aR)-N-[2,4-difluorophenyl)methyl]-10-hy- droxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro- 1H-pyrido [1,2-a]pyrrolo[1’,2’:3,4,]imidazo[1,2-d]pyra- 5 zine-8-carboxamide. [0015] The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharma- 10 cological activity thereof and is nontoxic when adminis- tered in doses sufficient to deliver a therapeutic amount of the antiviral agent. [0016] The term "treatment" as used herein refers to the alleviation of symptoms of a particular disorder in a 15 patient, or the improvement of an ascertainable meas- urement associated with a particular disorder, and may include the suppression of symptom recurrence in an asymptomatic patient such as a patient in whom a viral infection has become latent. Treatment may include 20 prophylaxis which refers to preventing a disease or con- dition or preventing the occurrence of symptoms of such a disease or condition, in a patient. As used herein, the term "patient" refers to a mammal, including a human. [0017] As used herein, the term "subject" refers to a 25 patient, animal or a biological sample. [0018] Pharmaceutically acceptable salts of the com- pounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hy- or a pharmaceutically acceptable salt thereof, and one 30 drochloric, hydrobromic, sulfuric, nitric, perchloric, fumar- or more therapeutic agents selected from the group con- ic, maleic, phosphoric, glycollic, lactic, salicyclic, succin- sisting of nucleotide reverse transcriptase inhibitors, nu- ic, toluene-p-sulfonic, tartaric, acetic, citric, methanesul- cleoside reverse transcriptase inhibitors (NRTIs), non- fonic, ethanesulfonic, formic, benzoic, malonic, naphtha- nucleoside reverse transcriptase inhibitors (NNRTIs), lene-2-sulfonic and benzenesulfonic acids. Other acids, protease inhibitors, CCR5 antagonists, CXCR4 antago- 35 such as oxalic, while not in themselves pharmaceutically nists, fusion inhibitors, maturation inhibitors, and inte- acceptable, may be employed in the preparation of salts grase inhibitors. useful as intermediates in obtaining the compounds of [0011] The present invention relates to methods of the invention and their pharmaceutically acceptable acid treatment of HIV infection, AIDS, and AIDS related con- addition salts. Salts derived from appropriate bases in- ditions by administering to a subject a compound of for- 40 clude alkali metal (e.g. sodium), alkaline earth metal + mula (I), (II), or (III) and one or more therapeutic agents (e.g., magnesium), ammonium, NW 4 (wherein W is C 1-4 selected from the group consisting of nucleotide reverse alkyl) and other amine salts. An advandtageous salt is transcriptase inhibitors, nucleoside reverse transcriptase sodium salt. inhibitors (NRTIs), non-nucleoside reverse transcriptase [0019] Salts of the compounds of the present invention inhibitors (NNRTIs), protease inhibitors, CCR5 antago- 45 may be made by methods known to a person skilled in nists, CXCR4 antagonists, fusion inhibitors, maturation the art. For example, treatment of a compound of the inhibitors, and integrase inhibitors. present invention with an appropriate base or acid in an [0012] A compound of formula (I) is also known as appropriate solvent can yield the corresponding salt. GSK1349572. A chemical name of the compound of for- [0020] The present invention relates to methods of mula (I) is (4R, 12aS)-N-[2,4-flurophenyl)methyl]-50 treating or preventing viral infection, for example an HIV 3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-di- infection, in a human comprising administering to the hu- oxo-2H-pyrido [1’,2’:4,5]pyrazino [2,1-b] [1,3] oxazine-9- man a therapeutically effective amount of a compound carboxamide. of formula (I), (II), or (III) or a pharmaceutically acceptable [0013] A chemical name of the compound of formula salt thereof in combination with one or more therapeutic (II) is (3S, 11aR)-N-[(2,4-difluorophenyl)methyl]-55 agents selected from the group consisting of nucleotide 2,3,5,7,11,11a-hexahydro-6-hydroxy-3-methyl-5,7-di- reverse transcriptase inhibitors, nucleoside reverse tran- oxo-oxazolo [3,2-a] pyrido [1,2-d] pyrazine-8-carboxam- scriptase inhibitors (NRTIs), non-nucleoside reverse ide. transcriptase inhibitors (NNRTIs), protease inhibitors,

3 5 EP 3 494 972 A1 6

CCR5 antagonists, CXCR4 antagonists, fusion inhibi- raviroc, (Sch-D), TBR-652 (TAK-779), TAK- tors, maturation inhibitors, and integrase inhibitors. The 449, PRO-140, GSK706769, and SCH-532706; fusion combination may be administered simultaneously or se- inhibitors, for example (T-20), T-1249, PRO- quentially. 542, (TNX-355), BMS-378806 (BMS-806), [0021] The compounds of formula (I), (II) and (III) are 5 BMS-488043, KD-247, 5-Helix inhibitors, and HIV attach- particularly suited to the treatment or prophylaxis of HIV ment inhibitors; and maturation inhibitors, for example, infections and associated conditions. Reference herein (PA-344 and PA-457). to treatment may extend to prophylaxis as well as the [0024] The present invention features a combination treatment of established infections, symptoms, and as- comprising a compound of formula (I) sociated clinical conditions such as AIDS related com- 10 plex (ARC), Kaposi’s sarcoma, and AIDS dementia. [0022] Combination therapies comprise the adminis- tration of a compound of the present invention or a phar- maceutically acceptable salt thereof and another phar- maceutically active agent. The active ingredient(s) and 15 pharmaceutically active agents may be administered si- multaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient(s) and or a pharmaceutically acceptable salt thereof, and one pharmaceutically active agent(s) and the relative timings 20 or more therapeutic agents selected from the group con- of administration will be selected in order to achieve the sisting of lamivudine, abacavir, tenofovir, , desired combined therapeutic effect. GSK2248761, lersivirine, , , and [0023] Examples of such therapeutic agents include, . but are not limited to, agents that are effective for the [0025] The present invention also features a combina- treatment of viral infections or associated conditions.25 tion comprising a compound of formula (I) or a pharma- Among these agents are nucleotide reverse tran- ceutically acceptable salt thereof, and one or more ther- scriptase inhibitors, acyclic nucleoside phosphonates, apeutic agents selected from abacavir, efavirenz, or lopi- for example (S)-1-(3-hydroxy-2-phosphonyl-methoxy- navir. The present invention features a combination com- propyl) (HPMPC), [[[2-(6-amino-9H-purin-9- prising of a compound of formula (I) or a pharmaceutically yl)ethoxy] methyl]phosphinylidene] bis(oxymethylene)- 30 acceptable salt thereof, and abacavir. 2,2-dimethyl propanoic acid (bis-POM PMEA, [0026] The present invention features a method of dipivoxil), adefovir, [[(1R)-2-(6-amino-9H-purin-9-yl)-1- treatment of HIV infection comprising administering to a methylethoxy]methyl] phosphonic acid (tenofovir), teno- subject, a compound of formula (I), or a pharmaceutically fovir disoproxil fumarate, and (R)-[[2-(6-Amino-9H-purin- acceptable salt thereof, and one or more therapeutic 9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(iso- 35 agents selected from the group consisting of lamivudine, propoxycarbonyloxymethyl)ester (bis-POC-PMPA); nu- abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, cleoside reverse transcriptase inhibitors, for example 3’- lopinavir, fosamprenavir, and atazanavir. azido-3’-deoxythymidine (AZT, ), 2’,3’-dide- [0027] The present invention features a method of oxycytidine (ddC, ), 2’,3’-dideoxyadenosine, treatment of HIV infection comprising administering to a 2’,3’-dideoxyinosine (ddl, ), 2’,3’-didehydro- 40 subject, a compound of formula (I) or a pharmaceutically thymidine (d4T, ), (-)-cis-1-(2-hydroxymethyl)- acceptable salt thereof, with one or more therapeutic 1,3-oxathiolane 5-yl)-cytosine (lamivudine), cis-1-(2-(hy- agents selected from the group consisting of abacavir, droxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine efavirenz, and lopinavir. The present invention features (FTC, ), (-)-cis-4-[2-amino-6-(cyclo-pro- a method of treatment of HIV infection comprising ad- pylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol 45 ministering to a subject a compound of formula (I) or a (abacavir), fozivudine tidoxil, , , el- pharmaceutically acceptable salt thereof, and abacavir. vucitabine, , and festinavir (OBP-601); pro- [0028] The present invention features a pharmaceuti- tease inhibitors, for example , , nelfina- cal composition comprising a compound of formula (I) or vir, , , fosamprenavir, lopinavir, a pharmaceutically acceptable salt thereof, and one or atazanavir, , , , palinavir, 50 more therapeutic agents selected from the group con- , TMC-310911, DG-17, PPL-100, and SPI-256; sisting of: lamivudine, abacavir, efavirenz, tenofovir, non-nucleoside reverse transcriptase inhibitorsGSK2248761, lersivirine, lopinavir, fosamprenavir, and (NNRTIs), for example , , efa- atazanavir together with a pharmaceutically acceptable virenz, GSK2248761 (IDX-12899), lersivirine (UK- carrier therefor. 453,061), (TMC-278), , , im- 55 [0029] The present invention features a pharmaceuti- munocal, oltipraz, , and RDEA-806; integrase cal composition comprising a compound of formula (I) or inhibitors, for example , , and JTK- a pharmaceutically acceptable salt thereof, and one or 656; CCR5 and/or CXCR4 antagonists, for example, ma- more therapeutic agents selected from the group con-

4 7 EP 3 494 972 A1 8 sistingof: abacavir, efavirenz,and lopinavir, together with carrier therefor. a pharmaceutically acceptable carrier therefor. The [0035] The present invention features a pharmaceuti- present invention features a pharmaceutical composition cal composition comprising a compound of formula (II) comprising a compound of formula (I) or a pharmaceuti- or a pharmaceutically acceptable salt thereof, and one cally acceptable salt thereof, and abacavir together with 5 or more therapeutic agents selected from the group con- a pharmaceutically acceptable carrier therefor. sistingof: abacavir, efavirenz, and lopinavir, togetherwith [0030] The present invention features a combination a pharmaceutically acceptable carrier therefor. The comprising a compound of formula (II) present invention features a pharmaceutical composition comprising a compound of formula (II) or a pharmaceu- 10 tically acceptable salt thereof, and abacavir together with a pharmaceutically acceptable carrier therefor. [0036] The present invention features a combination comprising a compound of formula (III)

15

20

or a pharmaceutically acceptable salt thereof, and one or more therapeutic agents selected from the group con- 25 sisting of lamivudine, abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, lopinavir, fosamprenavir, and atazanavir or a pharmaceutically acceptable salt thereof, and one [0031] The present invention also features a combina- or more therapeutic agents selected from the group con- tion comprising a compound of formula (II) or a pharma- 30 sisting of lamivudine, abacavir, tenofovir, efavirenz, ceutically acceptable salt thereof, and one or more ther- GSK2248761, lersivirine, lopinavir, fosamprenavir, and apeutic agents selected from abacavir, efavirenz, and atazanavir lopinavir. The present invention features a combination [0037] The present invention also features a combina- comprising of a compound of formula (II) or a pharma- tion comprising a compound of formula (III) or a pharma- ceutically acceptable salt thereof, and abacavir. 35 ceutically acceptable salt thereof, and one or more ther- [0032] The present invention features a method of apeutic agents selected from abacavir, efavirenz, and treatment of HIV infection comprising administering to a lopinavir. The present invention also features a combi- subject, a compound of formula (II) or a pharmaceutically nation comprising a compound of formula (III) or a phar- acceptable salt thereof, and one or more therapeutic maceutically acceptable salt thereof, and abacavir. agents selected from the group consisting of lamivudine, 40 [0038] The present invention features a method of abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, treatment of HIV infection comprising administering to a lopinavir, fosamprenavir, and atazanavir. subject,a compound offormula (III) or apharmaceutically [0033] The present invention features a method of acceptable salt thereof, and one or more therapeutic treatment of HIV infection comprising administering to a agents selected from the group consisting of lamivudine, subject, a compound of formula (II) or a pharmaceutically 45 abacavir, tenofovir, efavirenz, GSK2248761, lersivirine, acceptable salt thereof, with one or more therapeutic lopinavir, fosamprenavir, and atazanavir. agents selected from the group consisting of abacavir, [0039] The present invention features a method of efavirenz, and lopinavir. The present invention features treatment of HIV infection comprising administering to a a method of treatment of HIV infection comprising ad- subject, a combination of a compound of formula (III) or ministering to a subject a compound of formula (II) or a 50 a pharmaceutically acceptable salt thereof, with one or pharmaceutically acceptable salt thereof, and abacavir. more therapeutic agents selected from the group con- [0034] The present invention features a pharmaceuti- sisting of abacavir, efavirenz, and lopinavir. The present cal composition comprising a compound of formula (II) invention features a method of treatment of HIV infection or a pharmaceutically acceptable salt thereof, and one comprising administering to a subject a compound of for- or more therapeutic agents selected from the group con- 55 mula (III) or a pharmaceutically acceptable salt thereof, sisting of: lamivudine, abacavir, tenofovir, efavirenz, and abacavir. GSK2248761, lersivirine, lopinavir, fosamprenavir, and [0040] The present invention features a pharmaceuti- atazanavir together with a pharmaceutically acceptable cal composition comprising a compound of formula (III)

5 9 EP 3 494 972 A1 10 or a pharmaceutically acceptable salt thereof, and one methods disclosed in U.S. Patent Nos. 5,519.021; or more therapeutic agents selected from the group con- 5,663,169; 5,811,423; 6,555,133; 6,639,071; or sisting of: lamivudine, abacavir, tenofovir, efavirenz, 6,939,964. GSK2248761, lersivirine, lopinavir, fosamprenavir, and [0052] GSK2248761 may be made by methods dis- atazanavir together with a pharmaceutically acceptable 5 closed in U.S. Patent No. 7,534,809. carrier therefor. [0053] Lersivirine may be made by methods disclosed [0041] The present invention features a pharmaceuti- in U.S. Patent No. 7,109,228. cal composition comprising a compound of formula (III) [0054] Lopinavir may be made by methods disclosed or a pharmaceutically acceptable salt thereof, and one in U.S. Patent No. 5,914,332. or more therapeutic agents selected from the group con- 10 [0055] Fosamprenavir may be made by methods dis- sistingof: abacavir, efavirenz,and lopinavir, together with closed in U.S. Patent Nos. 6,436,989; 6,514,953; or a pharmaceutically acceptable carrier therefor. The 6,281,367. present invention features a pharmaceutical composition [0056] Atazanavir may be made by methods disclosed comprising a compound of formula (III) or a pharmaceu- in U.S. Patent Nos. 5,849,911 or 6,087,383. tically acceptable salt thereof, and abacavir together with 15 [0057] The therapeutic agents of the combinations a pharmaceutically acceptable carrier therefor. may be made according to published methods or by any [0042] The present invention features combinations, method known to those skilled in the art. methods of treatment, and pharmaceutical compositions [0058] In an aspect of the invention, a compound of as described above wherein a pharmaceutically accept- formula (I), (II) or (III) or a pharmaceutically acceptable able salt of a compound of formula (I), (II) or (III) is a20 salt thereof may be formulated into compositions togeth- sodium salt. er with one or more therapeutic agents. The composition [0043] The present invention features combinations, may be pharmaceutical composition, which comprises a methods of treatment, and pharmaceutical compositions compound of formula (I), (II), or (III), one or more thera- as described above wherein one or more therapeutic peutic agents, and a pharmaceutically acceptable carri- agents are a pharmaceutically acceptable salt of said 25 er, adjuvant or vehicle. In one embodiment, the compo- therapeutic agents, for example, abacavir hemisulfate, sition comprises an amount of a combination of the fosamprenavir calcium, atazanavir sulfate, tenofovir dis- present invention effective to treat or prevent viral infec- oproxil sulfate, vicriviroc maleate or bevirimat dimeglu- tion, for example an HIV infection, in a biological sample mine. or in a patient. In another embodiment, combinations of [0044] The present invention features methods of30 the invention and pharmaceutical compositions thereof, treatment as described above wherein the subject is a comprising an amount of a combination of the present human. invention effective to inhibit viral replication or to treat or [0045] The present invention features combinations, prevent a viral infection or disease or disorder, for exam- methods of treatment and pharmaceutical compositions ple an HIV infection, and a pharmaceutically acceptable as described above wherein the combination is admin- 35 carrier, adjuvant or vehicle, may be formulated for ad- istered sequentially. ministration to a patient, for example, for oral administra- [0046] The present invention features combinations, tion. methods of treatment and pharmaceutical compositions [0059] The present invention features combinations as described above wherein the combination is admin- according to the invention for use in medical therapy, for istered simultaneously or concurrently. 40 example for the treatment or prophylaxis of a viral infec- [0047] Compounds of formula (I), (II), and (III) may be tion, for example an HIV infection and associated condi- made by methods disclosed in WO 2006/116764, U.S. tions. The compounds according to the invention are es- 61/193,634 (WO2010/068253) or 61/193,636pecially useful for the treatment of AIDS and related clin- (WO2010/068262), incorporated herein by reference ical conditions such as AIDS related complex (ARC), pro- hereto. 45 gressive generalized lymphadenopathy (PGL), Kaposi’s [0048] Abacavir may be made by methods disclosed sarcoma, thromobocytopenic purpura, AIDS-related in U.S. Patent Nos. 5,034,394; 5,089,500; 6,294,540; neurological conditions such as AIDS dementia complex, 5,641,889; 5,840,990; 5,919,941; 5,808,147; 6,392,085; multiple sclerosis or tropical paraperesis, anti-HIV anti- 6,448,403; 5,917,041; 6,087,501; 5,917,042; 6,555,687; body-positive and HIV-positive conditions, including 6,552,193; 6,870,053; 6,294,540; 6,340,587; 50 orsuch conditions in asymptomatic patients. 6,646,125. [0060] According to another aspect, the present inven- [0049] Lamivudine may be made by methods dis- tion provides a method for the treatment or prevention of closed in U.S. Patent Nos. 5,047,407; 7,119,202; the symptoms or effects of a viral infection in an infected 5,905,082; 5,696,254; 5,663,320; 5,693,787; 6,051,709; patient, for example, a mammal including a human, which or 6,329,522. 55 comprises administering to said patient a pharmaceuti- [0050] Tenofovir may be made by U.S. Patent Nos. cally effective amount of a combination according to the 5,922,695; 5,935,946; 5,977,089; 6,043,230, 6,069,249. invention. According to one aspect of the invention, the [0051] Efavirenz may be made by may be made by viral infection is a retroviral infection, in particular an HIV

6 11 EP 3 494 972 A1 12 infection. mal, and intravitreal) administration. The compositions [0061] The present invention further includes the use may conveniently be presented in unit dosage form and of a combination according to the invention in the man- may be prepared by any methods well known in the art ufacture of a medicament for simultaneous (concurrent) of pharmacy. Such methods represent a further feature or sequential administration to a subject for the treatment 5 of the present invention and include the step of bringing of a viral infection, in particular and HIV infection. into association the active ingredients with the carrier, [0062] The present invention further provides a meth- which constitutes one or more accessory ingredients. In od for the treatment of a clinical condition in a patient, for general, the compositions are prepared by uniformly and example, a mammal including a human which clinical intimately bringing into association the active ingredients condition includes those which have been discussed10 with liquid carriers or finely divided solid carriers or both, hereinbefore, which comprises treating said patient with and then if necessary shaping the product. a pharmaceutically effective amount of a compound ac- [0068] The present invention further includes a phar- cording to the invention. The present invention also in- maceutical composition as hereinbefore defined wherein cludes a method for the treatment or prophylaxis of any a compound of the present invention or a pharmaceuti- of the aforementioned diseases or conditions. 15 cally acceptablederivative thereof and another therapeu- [0063] Compounds of the present invention may be tic agent are presented separately from one another as administered with an agent known to inhibit or reduce a kit of parts. the metabolism of compounds, for example ritonavir. Ac- [0069] Compositions suitable for transdermal admin- cordingly, the present invention features a method for istration may be presented as discrete patches adapted the treatment or prophylaxis of a disease as hereinbefore 20 to remain in intimate contact with the epidermis of the described by administration of a compound of the present recipient for a prolonged period of time. Such patches invention in combination with a metabolic inhibitor. Such suitably contain the active compound 1) in an optionally combination may be administered simultaneously or se- buffered, aqueous solution or 2) dissolved and/or dis- quentially. persed in an adhesive or 3) dispersed in a polymer. A [0064] In general a suitable dose for each of the above- 25 suitable concentration of the active compound is about mentioned conditions will be in the range of 0.01 to 250 1%to 25%,preferably about 3% to15%. As one particular mg per kilogram body weight of the recipient (e.g. a hu- possibility, the active compound may be delivered from man) per day, in the range of 0.1 to 100 mg per kilogram the patch by electrotransport or iontophoresis as gener- body weight per day; in the range 1 to 30 mg per kilogram ally described in Pharmaceutical Research 3(6), 318 body weight per day; in the range 0.5 to 20 mg per kilo- 30 (1986). gram body weight per day. Unless otherwise indicated, [0070] Pharmaceutical compositions of the present in- all weights of active ingredients are calculated as the vention suitable for oral administration may be presented parent compound of formula (I), (II), or (III) and other as discrete units such as capsules, caplets, cachets or therapeutic agents. For salts thereof, the weights would tablets each containing a predetermined amount of the be increased proportionally. The desired dose may be 35 active ingredients; as a powder or granules; as a solution presented as one, two, three, four, five, six or more sub- or a suspension in an aqueous or non-aqueous liquid; or doses administered at appropriate intervals throughout as an oil-in-water liquid emulsion or a water-in-oil liquid the day. In some cases the desired dose may be given emulsion. The active ingredient may also be presented on alternative days. These sub-doses may be adminis- as a bolus, electuary or paste. tered in unit dosage forms, for example, containing 1 to 40 [0071] A tablet may be made by compression or mold- 2000 mg; 5 to 500 mg; 10 to 400 mg, 20 to 300 mg of ing, optionally with one or more accessory ingredients. each active ingredient per unit dosage form. Compressed tablets may be prepared by compressing [0065] The combinations may be administered to in a suitable machine the active ingredients in a free- achieve peak plasma concentrations of each active in- flowing form such as a powder or granules, optionally gredient. 45 mixed with a binder (e.g. povidone, gelatin, hydroxypro- [0066] While it is possible for the active ingredients to pylmethyl cellulose), lubricant, inert diluent, preservative, be administered alone, it is preferable to present it as a disintegrant (e.g. sodium starch glycollate, cross-linked pharmaceutical composition. The compositions of the povidone, cross-linked sodium carboxymethyl cellulose) present invention comprise an active ingredient, as de- surface-active or dispersing agent. Molded tablets may fined above, together with one or more acceptable car- 50 be made by molding a mixture of the powdered com- riers thereof and one or more additional therapeutic pound moistened with an inert liquid diluent in a suitable agents. Each carrier must be acceptable in the sense of machine. The tablets may optionally be coated or scored being compatible with the other ingredients of the com- and may be formulated so as to provide slow or controlled position and not injurious to the patient. release of the active ingredients therein using, for exam- [0067] Pharmaceutical compositions include those55 ple, hydroxypropylmethyl cellulose in varying proportions suitable for oral, rectal, nasal, topical (including transder- to provide the desired release profile. Tablets may op- mal,buccal and sublingual), vaginal orparenteral (includ- tionally be provided with an enteric coating, to provide ing subcutaneous, intramuscular, intravenous, intrader- release in parts of the gut other than the stomach.

7 13 EP 3 494 972 A1 14

[0072] Pharmaceutical compositions suitable for topi- agents. cal administration in the mouth include lozenges com- prising the active ingredients in a flavored base, usually Examples sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and 5 Example 1: Biological Activity glycerin, or sucrose and acacia; and mouthwashes com- prising the active ingredient in a suitable liquid carrier. Assays [0073] Pharmaceutical compositions suitable for vag- inal administration may be presented as pessaries, tam- Method pons, creams, gels, pastes, foams or spray. Pharmaceu- 10 tical compositions may contain in addition to the active [0079] Antiviral HIV activity was measured by means ingredient such carriers as are known in the art to be of a tetrazolium-based colorimetric procedure in the hu- appropriate. man T-cell leukemia virus (HTLV-1) transformed cell line [0074] Pharmaceutical compositions for rectal admin- MT-4. Aliquots of test compound were diluted vertically istration may be presented as a suppository with a suit- 15 across a deep-well master assay plate, in medium (RPMI able carrier comprising, for example, cocoa butter or a 1640, 10% vol./vol. fetal bovine serum (FBS), and 10 salicylate or other materials commonly used in the art. mg/mL gentamicin), at concentrations that were approx- The suppositories may be conveniently formed by ad- imately 40-fold higher than the final assay concentration. mixture of the active combination with the softened or Serial dilutions were made at either 1:2 or 1:3.16 ratios. melted carrier(s) followed by chilling and shaping in20 HIV inhibitors were diluted horizontally across master as- molds. say plates, also in concentrations that were approximate- [0075] Pharmaceutical compositions suitable for ly 40-fold higher than the final assay concentration. Small parenteral administration include aqueous and nonaque- aliquots of both the vertically-diluted and the horizontally- ous isotonic sterile injection solutions which may contain diluted compounds were combined in daughter plates antioxidants, buffers, bacteriostats and solutes which25 using an automated 96-well pipetting system (Rapid- render the pharmaceutical composition isotonic with the Plate-96, Zymark Corp.). Checkerboard style dilutions blood of the intended recipient; and aqueous and non- were arranged so that every concentration of test com- aqueous sterile suspensions which may include sus- pound was tested in the presence and absence of every pending agents and thickening agents; and liposomes or concentration of the HIV inhibitors. Anti-HIV activity tests other microparticulate systems which are designed to tar- 30 were performed in triplicate assays, or more, of each get the compound to blood components or one or more combination. Exponentially growing MT-4 cells were har- organs. The pharmaceutical compositions may be pre- vested and centrifuged at 1,000 rpm for 10 minutes in a sented in unit-dose or multi-dose sealed containers, for Jouan centrifuge (Model CR 4 12). Cell pellets were re- example, ampoules and vials, and may be stored in a suspended in fresh medium (RPMI 1640, 20% vol./vol. freeze-dried (lyophilized) condition requiring only the ad- 35 FBS, 20% vol./vol. IL-2, and 10 mg/mL gentamicin) to a dition of the sterile liquid carrier, for example water for density of 1.25 x 10 6 cells/mL. Cell aliquots were infected injection, immediately prior to use. Extemporaneous in- by the addition of HIV-1 (strain IIIB) diluted to give a viral jection solutions and suspensions may be prepared from multiplicity of infection (MOI) of 73 pfU per 1 x 10 4 cells. sterile powders, granules and tablets of the kind previ- A similar cell aliquot was diluted with medium to provide ously described. 40 a mock-infectedcontrol. Cellinfection was allowed topro- [0076] Unit dosage pharmaceutical compositions in- ceed for 1 hour at 37°C in a tissue culture incubator with clude those containing a daily dose or daily subdose of humidified 5% CO2 atmosphere. After the 1 hour incu- the active ingredients, as hereinbefore recited, or an ap- bation the virus/cell suspension was added to each well propriate fraction thereof. of the plates containing pre-diluted compounds. Plates [0077] Pharmaceutical compositions of the present in- 45 were then placed in a tissue culture incubator with hu- vention may be presented as patient packs containing midified 5% CO2 for 5 days. At the end of the incubation one or more courses of treatment in a single package, period, 40 mL of CellTiter 96 MTS reagent (Promega no. for example, a blister pack. It will be understood that the G3581) was added to each well of the incubation plate. administration of the combination of the invention by Plates were incubated at 37°C for 2 to 3 hours to allow means of a single patient pack, or patient packs of each 50 for color development. O.D. was measured at 492 nM composition, is an additional feature of the invention. using a microplate absorbance reader (Tecan no. [0078] It should be understood that in addition to the 20-300). ingredients particularly mentioned above the pharma- ceutical compositions of this invention may include other Virus used agents conventional in the art having regard to the type 55 of pharmaceutical composition in question, for example, [0080] HIV-1 strain IIIB, wild-type laboratory strain, vi- those suitable for oral administration may include such rus titer = 6.896 E4 TCID50/mL. further agents as sweeteners, thickeners and flavoring

8 15 EP 3 494 972 A1 16

Data Analysis 1. A combination comprising a compound of formula (I) [0081] Although some assay formats might theoreti- cally miss antagonism due to combination cytotoxicity, the approach described here should not miss an antag- 5 onistic effect. The readout in the MT-4 cell assay utilizes MTS, a tetrazolium-based staining reagent where chang- es in optical density (O.D.) of the reagent are used to estimate the total cell number remaining after treatment. Final MT-4 cell numbers may decrease due to two effects. 10 First, an HIV-induced cytotoxicity may occur when HIV kills greater than 75% of the MT-4 cells during the 5 days or a pharmaceutically acceptable salt thereof, with following infection. Second, a compound-induced cyto- one or more therapeutic agents selected from the toxicity may occur, where the compound either directly group consisting of abacavir, efavirenz, and lopina- kills the MT-4 cells or prevents cell growth (stasis) over 15 vir. the 5 days in either infected or uninfected cells. In either of these situations the O.D. is low as compared with in- 2. A combination according to 1 wherein the thera- fected cells protected by anti-HIV-1 compounds or rela- peutic agent is abacavir. tive to untreated and uninfected control cells. Since both cytotoxic effects and antagonism of anti-HIV activity20 3. A combination according to 1 or 2 wherein the would lead to lower O.D. we should not miss an antag- pharmaceutically acceptable salt of a compound of onistic effect due to combination cytotoxicity, but could formula (I) is the sodium salt. underestimate synergistic combinations. [0082] Within assay combination cytotoxicity was eval- 4. A combination according to 2 additionally contain- uated by comparing wells containing the uninfected MT- 25 ing lamivudine. 4 cells from the assay plates that contained the highest concentration of test compound or the comparator com- 5. A method of treatment of HIV infection comprising pound, with wells containing HIV-1 infected MT-4 cells administering to a human, a compound of formula (I) under the corresponding highest combination concentra- tions. For each of these values there is one well per assay 30 plate and thus at least 3 wells per combination assay. Although they do not comprise a formal combination cy- totoxicity analysis, the ratio of compound in combinations to compound alone provides a measure of the compound combination cytotoxicity within the concentrations exam- 35 ined. [0083] The interaction of each pair of compound com- binations was analyzed by the methods described by or a pharmaceutically acceptable salt thereof, with Selleseth, D.W. et al. (2003) Antimicrobial Agents and one or more therapeutic agents selected from the Chemotherapy 47:1468-71. Synergy and antagonism 40 group consisting of abacavir, efavirenz, and lopina- are defined as deviations from dosewise additivity, which vir. results when two drugs interact as if they were the same drug. Values for average deviation from additivity in the 6. A method according to 5 wherein the therapeutic range of - 0.1 to - 0.2 indicate weak synergy and values agent is abacavir. that approach - 0.5 would indicate strong synergy of the 45 interaction. Conversely, positive values of 0.1 to 0.2 7. A method according to 5 or 6 wherein the phar- would indicate that a weak antagonism exists between maceutically acceptable salt of a compound of for- the treatments. mula (I) is the sodium salt.

Results 50 8. A method according to 6 additionally containing lamivudine. [0084] A compound of formula (I) was found to be ad- ditive with raltegravir, adefovir, and and was 9. A pharmaceutical composition comprising a com- not affected by the presence of . A compound of pound of formula (I) according to 1 or 2 and one or formula (I) was found to be synergistic with stavudine, 55 more therapeutic agents selected from the group abacavir, efavirenz, nevirapine, lopinavir, amprenavir, consisting of abacavir, efavirenz, and lopinavir to- enfuvirtide. gether with a pharmaceutically acceptable carrier [0085] The invention provides: therefor.

9 17 EP 3 494 972 A1 18

10. A pharmaceutical composition according to 9 6. A combination according to claim 1 wherein the com- wherein the therapeutic agent is abacavir. bination is administered simultaneously.

11. A pharmaceutical composition according to 7 or 7. A combination according to claim 1 wherein the com- 8 wherein the pharmaceutically acceptable salt of a 5 bination is administered sequentially. compound of formula (I) is the sodium salt. 8. A patient pack comprising a combination according 12. A pharmaceutical composition according to 10 to claim 1. additionally containing lamivudine. 10 9. Use of a combination according to claim 1 for the 13. A combination according to any of 1 - 4 wherein manufacture of a medicament for the treatment of the combination is administered simultaneously. HIV infection.

14. A combination according to any of 1 - 4 wherein the combination is administered sequentially. 15

15. A method of treatment according to any of 5 - 8 wherein the compound of formula (I) and the thera- peutic agent(s) are administered simultaneously. 20 16. A method of treatment according to any of 5 - 8 wherein the compound of formula (I) and the thera- peutic agent(s) are administered sequentially.

17.A patient packcomprising a compoundof formula 25 (I) according to 1 and one or more therapeutic agents selected from the group consisting of abacavir, efa- virenz, and lopinavir.

30 Claims

1. A combination comprising a compound of formula (I)

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or a pharmaceutically acceptable salt thereof, and lamivudine. 45 2. A combination according to 1 wherein the pharma- ceutically acceptable salt of a compound of formula (I) is the sodium salt.

3. A combination according to claim 1 for use in medical 50 therapy.

4. A combination according to claim 1 for use in the treatment of HIV infection. 55 5. A pharmaceutical composition comprising a combi- nation according to claim 1 together with a pharma- ceutically acceptable carrier therefor.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 2006116764 A [0047] • US 5696254 A [0049] • US 61193634 B [0047] • US 5663320 A [0049] • WO 2010068253 A [0047] • US 5693787 A [0049] • WO 61193636 A [0047] • US 6051709 A [0049] • WO 2010068262 A [0047] • US 6329522 B [0049] • US 5034394 A [0048] • US 5922695 A [0050] • US 5089500 A [0048] • US 5935946 A [0050] • US 6294540 B [0048] • US 5977089 A [0050] • US 5641889 A [0048] • US 6043230 A [0050] • US 5840990 A [0048] • US 6069249 A [0050] • US 5919941 A [0048] • US 5519021 A [0051] • US 5808147 A [0048] • US 5663169 A [0051] • US 6392085 B [0048] • US 5811423 A [0051] • US 6448403 B [0048] • US 6555133 B [0051] • US 5917041 A [0048] • US 6639071 B [0051] • US 6087501 A [0048] • US 6939964 B [0051] • US 5917042 A [0048] • US 7534809 B [0052] • US 6555687 B [0048] • US 7109228 B [0053] • US 6552193 B [0048] • US 5914332 A [0054] • US 6870053 B [0048] • US 6436989 B [0055] • US 6340587 B [0048] • US 6514953 B [0055] • US 6646125 B [0048] • US 6281367 B [0055] • US 5047407 A [0049] • US 5849911 A [0056] • US 7119202 B [0049] • US 6087383 A [0056] • US 5905082 A [0049]

Non-patent literature cited in the description

• Pharmaceutical Research, 1986, vol. 3 (6), 318 • SELLESETH, D.W. et al. Antimicrobial Agents and [0069] Chemotherapy, 2003, vol. 47, 1468-71 [0083]

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