Peripherally acting opioid compounds
View Patent ↗The invention relates to a compound of Formula I, II, III, IV or a pharmaceutically acceptable ester or prodrug thereof:
1. A compound of Formula I, II, III, IV or a pharmaceutically acceptable salt thereof:
Wherein:
u is 0, 1 or 2;
t is 0, 1, 2, 3, 4, 5, or 6;
X is S or O;
Y ⊖ is a pharmaceutically acceptable counterion;
R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
Each R 2 , R 3 , R 4 , R 6 , R 8 , and R 11 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively, R 4 , and R 11 together with the atoms they are attached form one optionally substituted rings; alternatively R 2 and R 3 together with the carbon they are attached to form a C═X group or a vinyl group; alternatively, two R 11 groups together with the carbon atom to which they are attached form a C═X or a vinyl group;
wherein each R 20 and R 21 is independently selected from hydrogen, halogen, -alkyl, substituted alkyl, aryl or substituted aryl;
R 5 is alkyl, substituted alkyl, aryl or substituted aryl;
R 7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
R 10 is selected from Table A;
TABLE A
Wherein s is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, 5, 6, or 7;
q is 0, 1, 2, 3, 4, or 5;
Each R 100 , R 101 , R 102 , R 103 , R 104 , and R 105 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl.
2. A compound of Formula V or VI, or a pharmaceutically acceptable salt thereof:
Wherein t is 0, 1, 2, 3, or 4;
Y ⊖ is a pharmaceutically acceptable counterion;
R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
Each R 4 and R 11 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively two R 11 groups together with the carbon atom to which they are attached form a C═X or a vinyl group;
wherein each R 20 and R 21 is independently selected from hydrogen, halogen, alkyl, substituted alkyl, aryl or substituted aryl;
X is S or O;
R 5 is alkyl, substituted alkyl, aryl or substituted aryl;
R 7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;
R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;
R 10 is selected from Table A:
TABLE A
Wherein s is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, 5, 6, or 7;
q is 0, 1, 2, 3, 4, or 5;
Each R 100 , R 101 , R 102 , R 103 , R 104 , and R 105 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl.
3. A compound according to claim 1 selected from Table B:
TABLE B
No
Compound
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
Wherein R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; and,
R 10 is selected from Table A:
Wherein s is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, 5, 6, or 7;
q is 0, 1, 2, 3, 4, or 5;
Each R 100 , R 101 , R 102 , R 103 , R 104 , and R 105 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl.
4. A compound according to claim 3 wherein R 10 is selected from:
Wherein s is 0, 1, 2, or 3;
p is 0, 1, 2, 3, 4, 5, 6, or 7;
q is 0, 1, 2, 3, 4, or 5;
Each R 100 , R 101 , R 102 , R 103 , R 104 , and R 105 is independently selected from hydrogen, halogen, —OR 20 , —SR 20 , —NR 20 R 21 , —C(O)R 20 , —C(O)OR 20 , —C(O)NR 20 R 21 , —N(R 20 )C(O)R 21 , —CF 3 , —CN, —NO 2 , —N 3 , acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl.
5. A compound according to claim 1 wherein R 1 is selected from, —(CH 2 ) a —CH═CH 2 , —CH 3 , —CH 2 —CH 2 -Phenyl or —(CH 2 ) a —CH═C(CH 3 ) 2 wherein a is independently 0, 1, 2 or 3.
6. A compound according to claim 1 wherein u is 1.
7. A compound according to claim 1 wherein X is oxygen.
8. A compound selected from Table C:
TABLE C
No
Compound
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
.