Combination pharmaceutical agents as RSV inhibitors
The present invention relates to pharmaceutical agents administered to a subject either in combination or in series for the treatment of a Respiratory Syncytial Virus (RSV) infection, wherein treatment comprises administering a compound effective to inhibit the function of the RSV and an additional compound or combinations of compounds having anti-RSV activity.
1. A method of treating a human respiratory syncytial virus infection in a subject in need thereof, comprising administering to the subject a compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) CN;
4) Optionally substituted —C 1 -C 8 alkyl; and
5) Optionally substituted —C 1 -C 8 alkyl —O—R 11 ;
R 2 and R 5 are each independently selected from the group consisting of:
1) Hydrogen; and
2) Optionally substituted —C 1 -C 8 alkyl;
A is selected from the group below:
R 3 is hydrogen or R 11 ;
R 4 is selected from the group consisting of:
1) Optionally substituted —C 3 -C 12 cycloalkyl;
2) Optionally substituted —C 3 -C 12 cycloalkenyl;
3) Optionally substituted 3- to 12-membered heterocyclyl;
4) Optionally substituted aryl;
5) Optionally substituted heteroaryl;
6) Optionally substituted aryl-O—;
7) Optionally substituted heteroaryl-O;
8) Optionally substituted aryl-C 1 -C 4 -alkyl; and
9) Optionally substituted heteroaryl-C 1 -C 4 -alkyl;
each R 6 is the same or different and independently selected from hydrogen, halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —NHC 1 -C 8 alkyl, optionally substituted —S—(—C 1 -C 8 alkyl), optionally substituted —SO 2 —(—C 1 -C 8 alkyl), — optionally substituted —SO 2 —NH—(—C 1 -C 8 alkyl), optionally substituted —NH—SO 2 —(—C 1 -C 8 alkyl), —CO 2 R 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 11 and R 12 are each independently is selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted —C 3 -C 8 cycloalkenyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;
R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 —alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl; optionally substituted —C 3 -C 8 -cycloalkyl, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 , and optionally substituted —C 1 -C 8 -alkoxy; alternatively, R 13 and R 14 are taken together with the nitrogen they attached to form a heterocyclic ring; and n is 0, 1, 2, 3 or 4;
and a second anti-respiratory syncytial virus agent,
wherein the compound of Formula I and the second agent are administered in a combined amount which is therapeutically effective.
2. The method of claim 1 , wherein the compound of Formula (I) is represented by Formula Ib,
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein R 4 is selected from one of the following by removal of one hydrogen atom:
wherein each of the above shown is optionally substituted when possible.
4. The method of claim 1 , wherein R 4 is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halo, —CH 3 , —CF 3 , —OCF 3 , —CN, —NH 2 , —OH, —CH 2 N(CH 3 ) 2 , —C(O)CH 3 , optionally substituted —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—(C 1 -C 6 )alkyl-(C 1 -C 6 )alkoxy, optionally substituted —SO 2 —(C 1 -C 6 )alkyl, optionally substituted —SO 2 —NH—(C 1 -C 6 )alkyl, optionally substituted —NH—SO 2 —(C 1 -C 6 )alkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 1 -C 8 -alkenyl, optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted —C 3 -C 8 -cycloalkenyl, and optionally substituted —C 1 -C 8 -alkoxy.
5. The method of claim 1 , wherein R 4 is substituted by 1 to 3 substituents independently selected from the group consisting of CH 3 , CN, fluoro, chloro, CH 3 O—, CH 3 C(O)—, CH 3 OCH 2 —, CH 3 OCH 2 CH 2 O—, —CF 3 , CF 3 O—,
6. The method of claim 1 , wherein the compound of Formula I is represented by Formula IIa-1, IIa-2, IIb-1, or IIb-2, or a pharmaceutically acceptable salt thereof,
wherein R 2 , R 3 , R 4 , R 5 , R 6 , n and A are as defined in claim 1 .
7. The method of claim 1 , wherein the compound of Formula I is represented by Formula IV-1, IV-2, IV-3, or IV-4 or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and n are as defined in claim 1 .
8. The method of claim 1 , wherein the compound of Formula I is selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Example
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9. The method of claim 1 , wherein the second anti-respiratory syncytial virus agent is selected from the group consisting of an anti-RSV antibody, a fusion inhibitor, an N-protein inhibitor, a nucleoside or non-nucleoside RSV L polymerase inhibitor, an IMPDH inhibitor, an siRNA, and an interferon.
10. The method of claim 9 , wherein the second anti-respiratory syncytial virus agent is selected from the group consist of RSV-IGIV, palivizumab, motavizumab, MK-1654, I-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-di sulfonic-acid (RFI-641), 4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonic acid,disodium salt (CL387626), 2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol (TMC-353121), 5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol (VP-14637, MDT-637), N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (05), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[r,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxyoxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-0-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [1,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403), N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido) benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide, 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide,4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ-27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Taribavirin, viramidine), (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-(chloromethyl)-4-fluoro-2-((isobutyryloxy)methyl)tetrahydrofuran-3-yl isobutyrate, (2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1 (2H)-yl)-2-(chloromethyl)-4-fluoro-2(hydroxymethyl)tetrahydrofuran-3-yl isobutyrate,((2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1-(2H)-yl)-2-(chloromethyl)-4-fluoro-3-hydroxytetrahydrofuran-2-yl)methyl triphosphate, 4-amino-1-((2R,3R,4R,5R)-5-(chloromethyl)-3-fluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one, 1,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type Iinterferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide, 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomide),N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CClO (CG-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against the G protein (mAb 131-2G), ALN-RSVO1, ALN-RSV02, Medi-559, Medi-534 and Medi-557, JNJ-53718678, AK-0529, RV521, BTA585, MIV-323, PC786, JNJ-64417184, ALS-8176, ALS-8112, ALX-0171, or a pharmaceutically acceptable salt of any of the foregoing.
11. The method of claim 1 , wherein the compound of Formula I or salt thereof and the second anti-respiratory syncytial virus agent are administered in a single composition or as separate compositions.
12. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
13. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
14. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
15. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
16. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
17. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
18. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
19. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.
20. The method of claim 8 , wherein the compound of Formula (I) has the formula
or a pharmaceutically acceptable salt thereof.