Dihydroxypyrimidine carbonic acid derivatives and their use in the treatment, amelioration or prevention of a viral disease
The present invention relates to a compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specific combination therapies are disclosed.
1. A compound having the general formula (Di), (Dii), or (Diii),
wherein
X 1 is O, S or NR*;
X 2 is O or S;
X 3 is O or S;
X 4 is O or S;
X 5 is O or S;
L is —(CH 2 ) m —, —NR*—SO 2 — or —SO 2 —NR*—;
m is 1 to 4;
R 1 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted aryl), —C(O)—O—R** or —P(O)(OR**) 2 , if X 1 is NR* then R 1 and R* can optionally be bound together to form a 5- to 7-membered ring;
R 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R 3 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 4 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 5 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted C 1-6 alkyl);
R 6 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted C 1-6 alkyl);
R* is —H, or —(C 1-6 alkyl); and
R** is —H, —(C 1-6 alkyl), —(C 3-7 cycloalkyl), -(aryl), or —C 1-4 alkyl-(aryl);
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR*R*, —OH, and —O—C 1-6 alkyl; and
wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of —C 1-6 alkyl, -halogen, —CF 3 , —CN, —X 1 —R*, -aryl and —C 1-4 alkyl-aryl,
or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or a mixture thereof,
with the proviso that the following compound
is disclaimed.
2. A pharmaceutical composition comprising a compound having the general formula (Di), (Dii), or (Diii),
wherein
X 1 is O, S or NR*;
X 2 is O or S;
X 3 is O or S;
X 4 is O or S;
X 5 is O or S;
L is —(CH 2 ) m —, —NR*—SO 2 — or —SO 2 —NR*—;
m is 1 to 4;
R 1 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted aryl), —C(O)—O—R** or -—P(O)(OR**) 2 , if X 1 is NR* then R 1 and R* can optionally be bound together to form a 5- to 7-membered ring,
R 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R 3 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 4 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 5 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted C 1-6 alkyl);
R 6 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted C 1-6 alkyl);
R* is —H, or —(C 1-6 alkyl); and
R** is —H, —(C 1-6 alkyl), —(C 3-7 cycloalkyl), -(aryl), or —C 1-4 alkyl-(aryl);
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR*R*, —OH, and —O—C 1-6 alkyl; and
wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of —C 1-6 alkyl, -halogen, —CF 3 , —CN, —X 1 —R*, -aryl and —C 1-4 alkyl-aryl,
or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or a mixture thereof,
and a pharmaceutically acceptable excipient.
3. A compound having the general formula (Di), (Dii), or (Diii),
wherein
X 1 is O, S or NR*;
X 2 is O or S;
X 3 is O or S;
X 4 is O or S;
X 5 is O or S;
L is —(CH 2 ) m —, —NR*—SO 2 — or —SO 2 —NR*—;
m is 1 to 4;
R 1 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted aryl), —C(O)—O—R** or —P(O)(OR**) 2 , if X 1 is NR* then R 1 and R* can optionally be bound together to form a 5- to 7-membered ring;
R 2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R 3 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3 -7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 4 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl);
R 5 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted C 1-6 alkyl);
R 6 is —H, —C(O)-(optionally substituted C 1-6 alkyl), or -(optionally substituted 0 1-6 alkyl);
R* is —H, or —(C 1-6 alkyl); and
R** is —H, —(C 1-6 alkyl), —(C 3-7 cycloalkyl), -(aryl), or —C 1-4 alkyl-(aryl);
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR*R*, —OH, and —O—C 1-6 alkyl; and
wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of —C 1-6 alkyl, -halogen, —CF 3 , —CN, —X 1 —R*, -aryl and —C 1-4 alkyl-aryl,
or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or a mixture thereof,
wherein the compound is for use in the treatment, amelioration or prevention of a viral disease.
4. The compound according to claim 3 , wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, Flaviviridae.
5. The compound according to claim 4 , wherein the viral disease is influenza.
6. A method of treating or ameliorating a viral disease, the method comprising administering to a patient in need thereof an effective amount of a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 , or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug tautomer, racemate, enantiomer, or diastereomer or mixture thereof.
7. The method according to claim 6 , wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, or Flaviviridae.
8. The method according to claim 7 , wherein the viral disease is influenza.
9. The compound according to claim 1 , wherein m is 1 or 2.
10. The compound according to claim 1 , wherein R 1 is —H or -(optionally substituted C 1-6 alkyl).
11. The compound according to claim 1 , wherein R 2 is an optionally substituted aryl, optionally substituted heteroaryl or optionally substituted C 5-7 cycloalkyl.
12. The compound according to claim 1 , wherein R 2 is
and wherein the heterocyclic group, phenyl group, cyclohexyl group or cyclopentyl group can be optionally substituted in any available position by a substituent which is independently selected from —C 1-6 alkyl, halogen, —CF 3 , —CN, —OH, and —O—C 1-6 alkyl.
13. The compound according to claim 1 , wherein L is —(CH 2 ) m — , or —NR* —SO 2 —.
14. The compound according to claim 1 , wherein X 1 is 0 or NR*.
15. The method according to claim 6 , wherein a further antiviral agent is to be administered concurrently or sequentially with the compound according to claim 3 .
16. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) as defined in claim 3 ; and
(ii) at least one polymerase inhibitor which is different from the compound having the general formula (Di), (Dii), or (Diii).
17. The pharmaceutical composition according to claim 16 , wherein the at least one polymerase inhibitor which is different from the compound having the general formula (Di), (Dii), or (Diii) is selected from
(a) a compound having the general formula (A),
wherein
R A* is —H, -Hal, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), —C 1-4 alkyl-(optionally substituted aryl) or —X 1 —R 1 ;
X A1 is O, C(O), C(O)O, OC(O); S, SO, SO 2 , NR A4 , N(R A5 )C(O), or C(O)NR A5 ;
X A2 is O, S, or NR A4 ;
X A3 is O or S;
X A4 is O or S;
R A1 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl);
R A2 is a hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring, wherein the hydrocarbon group can be optionally substituted;
R A3 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), or —C 1-4 alkyl-(optionally substituted aryl) if X A2 is NR A4 then R A3 can also be —OH;
R A4 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl) or if X A1 is NR A4 , then R A4 and R A1 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N or if X A2 is NR A4 , then R A4 and R A3 can be joined together to form a 5- to 7-membered ring, which can optionally contain O, S or further N; and
R A5 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), -C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl); and
R A6 is —H, or —C 1-6 alkyl;
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR A6 R A6 , —OH, and —O—C 1-6 alkyl;
wherein the optional substituent of the cycloalkyl group, the aryl group or the hydrocarbon group is selected from the group consisting of —C 1-6 alkyl, halogen, —CF 3 , —CN, —X A1 —R A5 and —C 1-4 alkyl-aryl;
or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodruq, tautomer, racemate, enantiomer, or diastereomer or a mixture thereof, and
(b) a compound having the general formula (C),
wherein
V C is N, or CR C6 ;
X C1 is O, S, or NR C8 ;
X C2 is NR C5 , N(R C5 )C(O), C(O)NR C5 , O, C(O), C(O)O, OC(O); S, SO, SO 2 , SO 2 N(R C5 ) or N(R C5 )SO 2 ;
R C* is —H, -Hal, -(optionally substituted C 1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C 1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), or —X C2 —R C1 ;
R C1 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S), —C 1-4 alkyl-(optionally substituted mono- or polycyclic group containing 3 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S);
R C2 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl) or if X C1 is NR C ′, then R C2 can also be —OH;
R C3 is —H, —R C7 , or —X C2 —R C7 ;
R C4 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl);
R C5 is —H, -(optionally substituted C 1-6 alkyl), -(optionally substituted C 3-7 cycloalkyl), -(optionally substituted aryl), —C 1-4 alkyl-(optionally substituted C 3-7 cycloalkyl), or —C 1-4 alkyl-(optionally substituted aryl);
R C6 H, —C 1-6 alkyl, -aryl, halogen or CN;
R C7 is -(optionally substituted hydrocarbon group which contains from 5 to 20 carbon atoms and optionally 1 to 4 heteroatoms selected from O, N and S and which contains at least one ring);
R C8 is —H, or —C 1-6 alkyl; and
n C is 0 to 4;
wherein the optional substituent of the alkyl group is selected from the group consisting of halogen, —CN, —NR C5 R C5 , —OH, and —O—C 1-6 alkyl;
wherein the optional substituent of the cycloalkyl group, the aryl group, the mono- or polycyclic group or the hydrocarbon group is selected from the group consisting of —C 1-6 alkyl, halogen, —CF 3 , —CN, —X c2 —R C8 and —C 1-4 alkyl-aryl;
or a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or a mixture thereof.
18. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 ; and
(ii) at least one neuramidase inhibitor.
19. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 ; and
(ii) at least one M2 channel inhibitor.
20. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 ; and
(ii) at least one alpha glucosidase inhibitor.
21. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 ; and
(ii) at least one ligand of another influenza target.
22. A pharmaceutical composition comprising:
(i) a compound having the general formula (Di), (Dii), or (Diii) according to claim 3 ; and
(ii) at least one medicament selected from antibiotics, anti-inflammatory agents, lipoxygenase inhibitors, EP ligands, bradykinin ligands, and cannabinoid ligands.
23. A method of treating or ameliorating a viral disease, the method comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to any of claims 16 to 22 .
24. The method according to claim 23 , wherein the viral disease is caused by Herpesviridae, Retroviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Coronaviridae, Picornaviridae, Togaviridae, or Flaviviridae.
25. The compound according to claim 1 , wherein the compound having the general formula (Di), (Dii), or (Diii) exhibits a % reduction of at least about 30 % at 50 μM in a cytopathic effect (CPE) assay.
26. The compound according to claim 1 , wherein the compound having the general formula (Di), (Dii), or (Diii) exhibits an IC 50 of at least about 40 μM in a fluorescence resonance energy transfer (FRET) endonuclease activity assay.
27. The method according to claim 23 , wherein the viral disease is caused by influenza.
28. A pharmaceutical composition according to any one of claims 16 - 22 , further comprising one or more pharmaceutically acceptable excipients and/or carriers.