Morphinan Derivatives for the Treatment of Drug Overdose
The instant application relates to morphinan derivatives of Formula I with sustained effectiveness in treating drug toxicity and overdose:
1 . A method of treating an opioid toxicity or overdose in a subject in need thereof comprising administrating a first opioid receptor antagonist followed by a compound of Formula I:
or a pharmaceutically acceptable salt, ester or prodrug thereof wherein;
R 1 is —(CH 2 ) n -c-C 3 H 5 , —(CH 2 ) n -c-C 4 H 7 , —(CH 2 ) n -c-C 5 H 9 , —(CH 2 ) n —CH═CH 2 or —(CH 2 ) n —CH═C(CH 3 ) 2 wherein n is independently 0, 1, 2 or 3;
R 2 is —CONH 2 or —CSNH 2 ;
R 3 and R 4 are independently H, —OH or together R 3 and R 4 form an —O— or —S— group;
R 5 is H or C 1 -C 8 alkyl; and
R 6 and R 7 are independently H, —OH, OCH 3 or together R 6 and R 7 form a ═O or ═CH 2 group.
2 . The method according to claim 1 , wherein said first opioid receptor antagonist is naloxone.
3 . The method according to any one of claim 1 , wherein said drug toxicity or overdose is resulting from opioid administration to a non-dependent patient.
4 . The method according to claim 3 , wherein said subject is an opioid experienced non-dependent opioid user.
5 . The method according to claim 2 , wherein said administration of compound of Formula I is preceded by said naloxone administration.
6 . The method according to claim 5 , wherein said naloxone administration reduces symptoms of overdose or toxicity prior to administration of compounds of Formula I.
7 . The method according to any one of claim 1 , wherein said compound of Formula I is administered in a daily dose of about 3 to about 20 mg/day.
8 . The method according to claim 7 , wherein said daily dose is about 10 mg/day.
9 . The method according to claim 1 , wherein administration of a compound of Formula I reduces symptoms of opioid toxicity or overdose over a period of at least about 15 to about 30 minutes.
10 . The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least one hour.
11 . The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least two hours.
12 . The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least three hours.
13 . The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least four hours.
14 . The method according to claim 9 , wherein symptoms of opioid toxicity or overdose are reduced for a period of at least eight hours.
15 . The method according to any one of claim 9 , wherein said administration comprises about 3 mg to about 20 mg of a compound of Formula I.
16 . The method according to any one of claim 9 , wherein said symptoms of overdose is selected from decreased respiratory rate, decreased respiratory depth, apnea, comotosis, hypoxia, delirium hypotension, bradycardia, decreased body temperature, urinary retention and pupil miosis.
17 . The method according to claim 2 , wherein naloxone is administered concurrently with a compound of Formula I.