Prodrugs of NH-acidic compounds
View Patent ↗The invention provides a method of sustained delivery of a lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug by administering to a patient an effective amount of a prodrug compound of the invention wherein upon administration to the patient, release of the parent drug from the prodrug is sustained release. Prodrug compounds suitable for use in the methods of the invention are labile conjugates of parent drugs that are derivatized through carbonyl linked prodrug moieties. The prodrug compounds of the invention can be used to treat any condition for which the lactam, imide, amide, sulfonamide, carbamate or urea containing parent drug is useful as a treatment.
1. A compound of having the formula:
wherein
represents a single or double bond;
R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 ;
Each R A and R B independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Each R 3 , R 4 and R 5 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 , —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u —, —S(O) 2 [C(R 30 )(R 31 )] u —, —O[C(R 30 )(R 31 )] u —, —N(R 30 )—, —N(R 30 )[C(R 31 )(R 32 )] u —, or —[C(R 30 )(R 31 )] u , or —C(O)[C(R 30 )(R 31 )] u —;
Each u is independently 1, 2, 3, 4, 5, 6 or 7;
D is selected from absent, —O—, —NR 33 , —C(R 34 )(R 35 )—, —S—, —S(O)—,—S(O) 2 —, or —C(O)—;
Each R 30 , R 31 , R 32 , R 33 , R 34 , and R 35 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
R 2 is selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
each G 3 and G 4 is independently selected from —N—, —C(R 10 )—[C(R 10 )(R 11 )] a —, wherein
a is 0, 1 or 2;
m and q are independently selected from 0, 1, and 2;
X 20 is —C(R 10 )— or —N—; and,
p is selected 0, 1, 2 or 3.
2. A compound of claim 1 having the formula:
wherein
represents a single or double bond;
R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , —C(R A )(R B )—OC(O)NR 20 R 21 ;
Each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
Each R 3 , R 4 and R 5 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 , —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl;
Each R 10 and R 11 is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R 10 and R 11 together with the atoms to which they are attached and any intervening atoms may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring;
A is selected from absent, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkenyl, —S—, —O—, —S(O)—, —S(O) 2 —, —S[C(R 30 )(R 31 )] u —, —S(O)[C(R 30 )(R 31 )] u —, —S(O) 2 [C(R 30 )(R 31 )] u —, —O[C(R 30 )(R 31 )] u —, —N(R 30 )—, —N(R 30 )[C(R 31 )(R 32 )] u —, or —[C(R 30 )(R 31 )] u , or —C(O)[C(R 30 )(R 31 )] u —,
Each u is independently 1, 2, 3, 4, 5, 6 or 7;
D is selected from absent, —O—, —NR 33 , —C(R 34 )(R 35 )—, —S—, —S(O)—, —S(O) 2 —, or —C(O)—;
Each R 30 , R 31 , R 32 R 33 , R 34 , and R 35 is independently selected from absent, hydrogen, halogen, —OR 10 , —SR 10 , —NR 10 R 11 —, —C(O)R 10 , optionally substituted aliphatic, optionally substituted aryl or optionally substituted heterocyclyl; and,
R 2 , p, r, m and q are as defined in claim 1 .
3. A compound of Formula XIIC:
wherein represents a single or double bond;
R 1 is selected from —C(R A )(R B )—OC(O)OR 20 , —C(R A )(R B )—OC(O)R 20 , or —C(R A )(R B )—OC(O)NR 20 R 21 ;
wherein each R A and R B is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;
each R 20 and R 21 is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; and,
w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11.
4. A compound of Table H or a pharmaceutically acceptable salt thereof:
TABLE H
No
Structure
1100.
1101.
1102.
1103.
1104.
1105.
1106.
1107.
1108.
1109.
1110.
1111.
1112.
1113.
1114.
1115.
1116.
1117.
1118.
1119.
1120.
1121.
1122.
1123.
1124.
1125.
1126.
1127.
1128.
1129.
1130.
1131.
1132.
1133.
1134.
1135.
1136.
1137.
1138.
1139.
1140.
1141.
1142.
1143.
1144.
1145.
1146.
1147.
1148.
1149.
1150.
1151.
1152.
1153.
1154.
1155.
1156.
1157.
1158.
1159.
1160.
1161.
1162.
1163.
1164.
1165.
1166.
1167.
5. A compound of Table I or a pharmaceutically acceptable salt thereof:
No
Structure
1200.
1201.
1202.
1203.
1204.
1205.
1206.
1207.
1208.
1209.
1210.
1211.
1212.
1213.
1214.
1215.
1216.
1217.
1218.
1219.
1220.
1221.
1222.
1223.
1224.
1225.
1226.
1227.
1228.
1229.
1230.
1231.
1232.
1233.
1234.
1235.
1236.
1237.
1238.
1239.
1240.
1241.
1242.
1243.
1244.
1245.
1246.
1247.
1248.
1249.
1250.
1251.
1252.
1253.
1254.
1255.
1256.
1257.
1258.
1259.
1260.
1261.
1262.
1263.
1264.
1265.
1266.
1267.
.