Substituted ureas and methods of making and using same
The invention relates to substituted ureas, and compositions comprising the same, which in certain embodiments are useful for treating and/or preventing pain in a subject in need thereof.
1. A compound of formula (I), or a salt, enantiomer, diastereoisomer, or tautomer thereof:
wherein:
A is selected from the group consisting of
B′ is selected from the group consisting of
and B 2 is H;
R 1 and R 2 are independently selected from the group consisting of H, CH 3 , and CH 3 substituted with at least one selected from the group consisting of fluoro, chloro, cyano, hydroxyl and nitro;
R 3 is selected from the group consisting of H and CH 3 ,
X is selected from the group consisting of S, O, and N—R 3 ;
each occurrence of R is independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, and substituted phenyl;
each occurrence of m is independently selected from the group consisting of 0, 1, 2 and 3;
n is selected from the group consisting of 1, 2 and 3; and
each occurrence of p is independently selected from the group consisting of 0, 1, 2 and 3.
2. The compound of claim 1 , wherein A is
3. The compound of claim 1 , wherein A is
4. The compound of claim 1 , wherein B 1 is
5. The compound of claim 1 , wherein B 1 is
6. The compound of claim 1 , wherein B 1 is
7. The compound of claim 1 , wherein A is selected from the group consisting of 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, 5-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 8-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl, 5-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 7-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 8-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl, 5-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 7-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 8-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl, 5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, 6-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl, and 8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl.
8. The compound of claim 1 , wherein B 2 is H, and wherein B 1 is selected from the group consisting of 3-thienyl, 2-thienyl, 2-chloro-4-fluorophenyl, 4-chloro-2-fluorophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, and phenyl.
9. A compound selected from the group consisting of:
1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;
3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;
1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;
3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;
3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea-;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((R)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((S)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea; and
1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
or a salt, enantiomer, diastereoisomer, or tautomer thereof.
10. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of claim 1 .
11. A method of treating or ameliorating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (I), or a salt, enantiomer, diastereoisomer or tautomer thereof:
wherein:
A is selected from the group consisting of
B 1 is selected from the group consisting of
and B 2 is H;
R 1 and R 2 are independently selected from the group consisting of H, CH 3 , and CH 3 substituted with at least one selected from the group consisting of fluoro, chloro, cyano, hydroxyl and nitro;
R 3 is selected from the group consisting of H and CH 3 ;
X is selected from the group consisting of S, O, and N—R 3 ;
each occurrence of R is independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, and substituted phenyl;
each occurrence of m is independently selected from the group consisting of 0, 1, 2 and 3;
n is selected from the group consisting of 1, 2 and 3; and
each occurrence of p is independently selected from the group consisting of 0, 1, 2 and 3.
12. A method of treating or ameliorating pain in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound selected from the group of:
1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-3-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;
3-(2-(Dimethylamino)-2-(thiophen-3-yl)ethyl)-1-methyl-1-(1,2,3,4-tetrahydronaphthalen-1-yl)urea;
1-(2-(Dimethylamino)-2-phenylethyl)-3-(1,2,3,4-tetrahydronaphthalen-2-yl)urea;
3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(S)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;
3-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-1-methyl-1-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((R)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(5-hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-((S)-7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(R)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-(2-Dimethylamino-2-thiophen-3-yl-ethyl)-3-(S)-1,2,3,4-tetrahydro-naphthalen-2-yl-urea;
1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-((R)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((R)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
1-((S)-3-(dimethylamino)-3-(thiophen-3-yl)propyl)-3-((S)-1,2,3,4-tetrahydronaphthalen-2-yl)urea;
or a salt, enantiomer, diastereoisomer, or tautomer thereof.
13. The method of claim 11 , wherein the at least one compound is a MOR agonist.
14. The method of claim 11 , wherein the at least one compound decreases cyclic adenosine monophosphate (cAMP) levels in the subject.
15. The method of claim 11 , wherein the at least one compound does not significantly induce recruitment, binding to, or association with a β-arrestin.
16. The method of claim 11 , wherein the at least one compound does not significantly cause at least one side effect selected from the group consisting of tachyphylaxis, respiratory depression, constipation, nausea, emesis, withdrawal, dependence, and addiction.
17. The method of claim 11 , wherein the pain comprises at least one pain type selected from the group consisting of chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, and allodynia.
18. The method of claim 12 , wherein the pain comprises at least one pain type selected from the group consisting of chronic pain, neuropathic pain, nociceptive pain, hyperalgesia, and allodynia.