Compositions and methods for combination antiviral therapy

Abstract

The present invention relates to therapeutic combinations of [9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) and (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine, (−)-cis FTC, Emtriva™ and their physiologically functional derivatives. The combinations may be useful in the treatment of HIV infections, including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors. The present invention is also concerned with pharmaceutical compositions and formulations of said combinations of GS-7340 and emtricitabine, and their physiologically functional derivatives, as well as therapeutic methods of use of those compositions and formulations.

1 . A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal a therapeutically effective amount of a combination comprising 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof, and (2R,5S,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.  
   
   
       2 . The method according to  claim 1  wherein the combination comprises GS-7340 and emtricitabine.  
   
   
       3 . The method according to  claim 2  wherein the combination comprises about 150 mg of GS-7340 and about 200 mg of emtricitabine.  
   
   
       4 . The method according to  claim 1  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of about 1:50 to about 50:1 by weight.  
   
   
       5 . The method according to  claim 1  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of about 1:10 to about 10:1 by weight.  
   
   
       6 . The method according to  claim 1  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each present in an amount from about 1 mg to about 1000 mg per unit dosage form.  
   
   
       7 . The method according to  claim 1  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each present in an amount from about 100 mg to about 300 mg per unit dosage form.  
   
   
       8 . A method according to  claim 1  wherein GS-7340 is a fumarate salt.  
   
   
       9 . A method for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises administering to said animal a therapeutically effective amount of a combination comprising 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof, and a compound of the formula:  
     
       
         
         
             
             
         
       
       wherein B is selected from adenine, guanine, cytosine, uracil, thymine, 7-deazaadenine, 7-deazaguanine, 7-deaza-8-azaguanine, 7-deaza-8-azaadenine, inosine, nebularine, nitropyrrole, nitroindole, 2-aminopurine, 2-amino-6-chloropurine, 2,6-diaminopurine, hypoxanthine, pseudouridine, 5-fluorocytosine, 5-chlorocytosine, 5-bromocytosine, 5-iodocytosine, pseudocytosine, pseudoisocytosine, 5-propynylcytosine, isocytosine, isoguanine, 7-deazaguanine, 2-thiopyrimidine, 6-thioguanine, 4-thiothymine, 4-thiouracil, O 6 -methylguanine, N 6 -methyladenine, O 4 -methylthymine, 5,6-dihydrothymine, 5,6-dihydrouracil, 4-methylindole, and a pyrazolo[3,4-D]pyrimidine; and  
       R is selected from H, C 1 -C 18  alkyl, C 1 -C 18  substituted alkyl, C 2 -C 18  alkenyl, C 2 -C 18  substituted alkenyl, C 2 -C 18  alkynyl, C 2 -C 18  substituted alknyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 2 -C 20  heterocycle, C 2 -C 20  substituted heterocycle, phosphonate, phosphophosphonate, diphosphophosphonate, phosphate, diphosphate, triphosphate, polyethyleneoxy, and a prodrug moiety.  
     
   
   
       10 . The method according to  claim 9  wherein the combination comprises a physiologically functional derivative of emtricitabine which is (2R, 5S, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC).  
   
   
       11 . The method according to  claim 1  wherein the combination comprises a physiologically functional derivative of emtricitabine which is a racemic mixture of the enantiomers (2R, 5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one and (2S, 5R, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.  
   
   
       12 . The method according to  claim 1  wherein the combination comprises a physiologically functional derivative of GS-7340 which has the structure:  
     
       
         
         
             
             
         
       
       wherein R 5  is H or CH 3 ; R 6  and R 8  are independently selected from H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 6 -C 20  arylalkyl, and C 6 -C 20  substituted arylalkyl; R 7  is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and where if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group; R 11  is amino, alkylamino, oxo, or dialkylamino; and R 12  is amino or H;  
       or a pharmaceutically acceptable salt or solvate thereof.  
     
   
   
       13 . The method according to  claim 12  wherein R 7  is H, CH 3  or CH(CH 3 ) 2 .  
   
   
       14 . The method according to  claim 12  wherein R 6  is phenyl.  
   
   
       15 . The method according to  claim 12  wherein R 8  is CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 .  
   
   
       16 . The method according to  claim 1  wherein GS-7340 or a physiologically functional derivative thereof, and emtricitabine or a physiologically functional derivative thereof are administered sequentially.  
   
   
       17 . The method according to  claim 1  wherein the combination is administered as a single combined formulation.  
   
   
       18 . The method according to  claim 17  wherein the single combined formulation is administered once per day to an infected human.  
   
   
       19 . The method according to  claim 1  in which said animal is a human.  
   
   
       20 . The method according to  claim 1  wherein the combination further comprises a third active ingredient selected from a protease inhibitor (PI), a nucleoside reverse transcriptase inhibitor (NRTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and an integrase inhibitor.  
   
   
       21 . The method according to  claim 20  wherein the third active ingredient is tenofovir disoproxil fumarate.  
   
   
       22 . The method according to  claim 1  wherein the combination further comprises a pharmaceutically acceptable glidant selected from silicon dioxide, powdered cellulose, microcrystalline cellulose, a metallic stearate, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, corn starch, magnesium carbonate, asbestos free talc, stearowet C, starch, starch 1500, magnesium lauryl sulfate, magnesium oxide, and combinations thereof.  
   
   
       23 . The method according to  claim 22  wherein the metallic stearate is selected from calcium stearate, magnesium stearate, zinc stearate, and combinations thereof.  
   
   
       24 . A pharmaceutical formulation comprising 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) or a physiologically functional derivative thereof and (2R, 5S, cis)-4amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine) or a physiologically functional derivative thereof.  
   
   
       25 . The pharmaceutical formulation according to  claim 24  further comprising one or more pharmaceutically acceptable carriers or excipients.  
   
   
       26 . The pharmaceutical formulation according to  claim 25  wherein the pharmaceutically acceptable carriers or excipients are selected from pregelatinized starch, croscarmellose sodium, povidone, lactose monohydrate, microcrystalline cellulose, and magnesium stearate; and combinations thereof.  
   
   
       27 . The pharmaceutical formulation according to  claim 24  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of 1:50 to 50:1 by weight.  
   
   
       28 . The pharmaceutical formulation according to  claim 24  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are present in a ratio of 1:10 to 10:1 by weight.  
   
   
       29 . The pharmaceutical formulation according to  claim 24  in unit dosage form.  
   
   
       30 . The pharmaceutical formulation according to  claim 29  wherein GS-7340 or a physiologically functional derivative thereof and emtricitabine or a physiologically functional derivative thereof are each and individually present in an amount from 100 mg to 1000 mg per unit dosage form.  
   
   
       31 . The pharmaceutical formulation according to  claim 24  comprising GS-7340 and emtricitabine.  
   
   
       32 . The pharmaceutical formulation according to  claim 31  comprising about 150 mg of GS-7340 and about 200 mg of emtricitabine.  
   
   
       33 . The pharmaceutical formulation according to  claim 24  suitable for oral administration.  
   
   
       34 . The pharmaceutical formulation according to  claim 30  in the form of a tablet or capsule.  
   
   
       35 . The pharmaceutical formulation according to  claim 30  suitable for administration once per day to an infected human.  
   
   
       36 . The pharmaceutical formulation according to  claim 24  comprising a physiologically functional derivative of emtricitabine which is (2R, 5S, cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC).  
   
   
       37 . The pharmaceutical formulation according to  claim 24  comprising a physiologically functional derivative of GS-7340 which has the structure:  
     
       
         
         
             
             
         
       
       wherein R 5  is H or CH 3 ; R 6  and R 8  are independently selected from H, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 6 -C 20  aryl, C 6 -C 20  substituted aryl, C 6 -C 20  arylalkyl, and C 6 -C 20  substituted arylalkyl; R 7  is the side chain of any naturally-occurring or pharmaceutically acceptable amino acid and where if the side chain comprises carboxyl, the carboxyl group is optionally esterified with an alkyl or aryl group; R 11  is amino, alkylamino, oxo, or dialkylamino; and R 12  is amino or H;  
       or a pharmaceutically acceptable salt or solvate thereof.  
     
   
   
       38 . The pharmaceutical formulation according to  claim 37  wherein R 7  is H, CH 3  or OH(CH 3 ) 2 .  
   
   
       39 . The pharmaceutical formulation according to  claim 37  wherein R 6  is phenyl.  
   
   
       40 . The pharmaceutical formulation according to  claim 37  wherein R 8  is CH 3 , CH 2 CH 3 , or CH(CH 3 ) 2 .  
   
   
       41 . A patient pack comprising at least one active ingredient selected from 9-[R-2-[[(S)-[[(S)-1-(isopropoxycarbonyl)ethyl]amino]-phenoxyphosphinyl]methoxy]propyl]adenine (GS-7340) and (2R,5S, cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (emtricitabine), and an information insert containing directions on the use of GS-7340 and emtricitabine together in combination.  
   
   
       42 . The patient pack according to  claim 41  comprising a co-formulated pill, tablet, caplet, or capsule of 100 to 1000 mg of GS-7340 and 100 to 1000 mg of emtricitabine.  
   
   
       43 . The patient pack according to  claim 41  comprising a co-formulated pill, tablet, caplet, or capsule of 300 mg of GS-7340 and 200 mg of emtricitabine.  
   
   
       44 . The patient pack according to  claim 41  comprising a separate pill, tablet, caplet, or capsule of 100 to 1000 mg of GS-7340 and 100 to 1000 mg of emtricitabine.  
   
   
       45 . The patient pack according to  claim 44  comprising a separate pill, tablet, caplet, or capsule of 150 mg of GS-7340 and 200 mg of emtricitabine.  
   
   
       46 . A chemically stable combination of GS-7340 and emtricitabine.  
   
   
       47 . The chemically stable combination of  claim 46  wherein the combination is a pharmaceutical dosage form.  
   
   
       48 . The chemically stable combination of  claim 47  wherein the dosage form is oral.  
   
   
       49 . The chemically stable combination of claims  46 - 48  which further comprises a third antiviral agent.  
   
   
       50 . The chemically stable combination of  claim 49  where in the third antiviral agent is an NNRTI or PI.  
   
   
       51 . The chemically stable combination of  claim 50  wherein the third antiviral agent is a PI.  
   
   
       52 . The chemically stable combination of  claim 50  wherein the third antiviral agent is an NNRTI.  
   
   
       53 . The chemically stable combination of  claim 49  wherein the third antiviral agent is selected from Reyataz, Kaletra or Sustiva.  
   
   
       54 . A chemically stable oral pharmaceutical dosage form comprising GS-7340 and emtricitabine.  
   
   
       55 . A chemically stable oral pharmaceutical dosage form comprising GS-7340, emtricitabine and Reyataz.  
   
   
       56 . A chemically stable oral pharmaceutical dosage form comprising GS-7340, emtricitabine and Kaletra.  
   
   
       57 . A chemically stable oral pharmaceutical dosage form comprising GS-7340, emtricitabine and Sustiva.