TREATMENTS
Described herein are compounds, combinations of compounds, compositions, formulations, and methods of treating viruses, viral load, and manifestations of viral infections.
1 . A method of reducing viral load comprising:
administering to a subject in need thereof an effective amount of a composition including a compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl, or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms;
A is selected from the group consisting of —CH 2 NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —, —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —;
each R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; and
X 1 and X 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl.
2 . A method of reducing viral load comprising:
administering to a subject in need thereof an effective amount of a composition including a compound of Formula 5:
or tautomers, stereoisomers and pharmaceutically acceptable salts thereof,
wherein:
X 1 , X 2 and X 3 are independently H, halogen, nitrile, hydroxyl, or C 1-6 alkyl;
Y is —NR N1 S(O) 2 —, —NR N1 C(O)—, —O(CR 1 2 ) n —, —NR N1 (CR 1 2 ) m —, —C(O)O—, —OC(O)—, —S(O) 2 —, —C(O)—, —NR N1 C(O)O—, C 1-6 alkylene, aryl, or heteroaryl;
Z is a direct bond or C 1-6 alkylene;
R is H, halogen, cyano, OR 3 , C 1-6 alkyl, acyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R may form a ring of 5 to 7 member atoms with R N1 or R 1 , wherein the ring may contain up to 2 heteroatoms selected from N, O, and S, the ring being either saturated or unsaturated;
R N1 is H or C 1-6 alkyl or forms a ring with R;
R 1 is H, F, or Me or forms a ring with R;
R 3 is H or C 1-6 alkyl;
n is an integer from 0 to 6; and
m is an integer from 1 to 6.
3 . The method of claim 1 or 2 , wherein the viral load is a result of a coronavirus.
4 . A method of treating viral conjunctivitis comprising:
topically administering to a subject in need thereof an effective amount of a composition including a compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl, or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms;
A is selected from the group consisting of —CH 2 NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —;
each R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; and
X 1 and X 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl.
5 . A method of treating viral conjunctivitis comprising:
topically administering to a subject in need thereof an effective amount of a composition including a compound of Formula 5:
or tautomers, stereoisomers and pharmaceutically acceptable salts thereof,
wherein:
X 1 , X 2 and X 3 are independently H, halogen, nitrile, hydroxyl, or C 1-6 alkyl;
Y is —NR N1 S(O) 2 —, —NR N1 C(O)—, —O(CR 1 2 ) n —, —NR N1 (CR 1 2 ) m —, —C(O)O—, (O), —S(O) 2 —, —C(O)—, —NR N1 C(O)O—, C 1-6 alkylene, aryl, or heteroaryl;
Z is a direct bond or C 1-6 alkylene;
R is H, halogen, cyano, OR 3 , C 1-6 alkyl, acyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R may form a ring of 5 to 7 member atoms with R N1 or R 1 , wherein the ring may contain up to 2 heteroatoms selected from N, O, and S, the ring being either saturated or unsaturated;
R N1 is H or C 1-6 alkyl or forms a ring with R;
R 1 is H, F, or Me or forms a ring with R;
R 3 is H or C 1-6 alkyl;
n is an integer from 0 to 6; and
m is an integer from 1 to 6.
6 . The method of claim 4 or 5 , wherein the viral conjunctivitis is a result a coronavirus.
7 . A method of treating pulmonary manifestations of a viral infection comprising:
administering to a subject in need thereof an effective amount of a composition including a compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl, or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms;
A is selected from the group consisting of —CH 2 NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —;
each R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; and
X 1 and X 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl.
8 . A method of treating pulmonary manifestations of a viral infection comprising:
administering to a subject in need thereof an effective amount of a composition including a compound of Formula 5:
or tautomers, stereoisomers and pharmaceutically acceptable salts thereof,
wherein:
X 1 , X 2 and X 3 are independently H, halogen, nitrile, hydroxyl, or C 1-6 alkyl;
Y is —NR N1 S(O) 2 —, —NR N1 C(O)—, —(CR 1 2 ) n —, —NR N1 (CR 1 2 ) m —, —C(O)O—, —OC(O)—, —S(O) 2 —, —C(O)—, —NR N1 C(O)O—, C 1-6 alkylene, aryl, or heteroaryl;
Z is a direct bond or C 1-6 alkylene;
R is H, halogen, cyano, OR 3 , C 1-6 alkyl, acyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R may form a ring of 5 to 7 member atoms with R N1 or R 1 , wherein the ring may contain up to 2 heteroatoms selected from N, O, and S, the ring being either saturated or unsaturated;
R N1 is H or C 1-6 alkyl or forms a ring with R;
R 1 is H, F, or Me or forms a ring with R;
R 3 is H or C 1-6 alkyl;
n is an integer from 0 to 6; and
m is an integer from 1 to 6.
9 . The method of claim 7 or 8 , wherein the virus is a coronavirus.
10 . The method of claim 7 or 8 , wherein the administering is via inhalation.
11 . The method of any preceding claim, further comprising administering at least one antiviral compound.
12 . The method of any preceding claim, wherein the pulmonary manifestations are swelling, inflammation, fibrosis, or a combination thereof.
13 . The method of any preceding claim, further comprising administering a ROCK/JAK inhibitor or a JAK inhibitor.
14 . The method of claim 13 , wherein the JAK inhibitor is tofacitinib, decernotinib, INCB18424, baricitinib, CYT387, GLPG0634, AC-430, axitinib, ruxolitinib, fibotinib, or peficitinib.
15 . A composition comprising:
a compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 and R 2 are independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl, or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a ring of 3, 4, 5, 6, 7 or 8 member atoms;
A is selected from the group consisting of —CH 2 NH—, —CH(R 10 )—, —C(CH 3 )(R 10 )—, —CH 2 CH 2 —CH(R 10 )CH 2 —, —CH 2 CH 2 CH(R 10 )—, —CH 2 CH(R 10 )—, and —C(CH 3 )(R 10 )CH 2 —;
each R 10 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, amino, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, any of which may be optionally substituted; and
X 1 and X 2 are independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, amino, nitro, cyano, carbonyl, carbonylamino, alkoxy, aryloxy, sulfonyl, sulfonamido, thioalkyl, and carboxyl; and
at least one JAK inhibitor.
16 . A composition comprising:
a compound of Formula 5:
or tautomers, stereoisomers and pharmaceutically acceptable salts thereof,
wherein:
X 1 , X 2 and X 3 are independently H, halogen, nitrile, hydroxyl, or C 1-6 alkyl;
Y is —NR N1 S(O) 2 —, —NR N1 C(O)—, —(CR 1 2 ) n —, —NR N1 (CR 1 2 ) m —, —C(O)O—, —OC(O)—, —S(O) 2 —, —C(O)—, —NR N1 C(O)O—, C 1-6 alkylene, aryl, or heteroaryl;
Z is a direct bond or C 1-6 alkylene;
R is H, halogen, cyano, OR 3 , C 1-6 alkyl, acyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R may form a ring of 5 to 7 member atoms with R N1 or R 1 , wherein the ring may contain up to 2 heteroatoms selected from N, O, and S, the ring being either saturated or unsaturated;
R N1 is H or C 1-6 alkyl or forms a ring with R;
R 1 is H, F, or Me or forms a ring with R;
R 3 is H or C 1-6 alkyl;
n is an integer from 0 to 6; and
m is an integer from 1 to 6; and
at least one JAK inhibitor.
17 . The composition of claim 15 or 16 , wherein the composition is prepared as a powder for inhalation.
18 . The composition of claim 15 or 16 , wherein the composition is prepared for topical administration.
19 . A method or composition as described herein.