US2020361936A1PendingUtilityA1
Morphinan derivatives and use thereof
Est. expiryJan 2, 2037(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:Laykea Tafesse
C07D 471/08A61K 31/485C07B 2200/05A61P 25/04
67
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Claims
Abstract
The application is directed to compounds of formula (I): and pharmaceutically acceptable salts, radiolabeled isomers, solvates, or hydrates thereof, wherein R1, R2, R3, X, and n are defined as set forth in the specification. The application is also directed to compounds of formulae II, I-a, I-a1, I-a2, I-b, and I-b1 and the pharmaceutically acceptable salts, radiolabeled isomers, solvates, and hydrates thereof. The application is also directed to use of Compounds of the present disclosure to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain Compounds of the present disclosure are especially useful for treating pain. In one embodiment, Compounds of the present disclosure exhibit less opioid-induced side effects (such as, euphoria or drug-liking).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (I):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof: wherein
R 1 is C 1-3 alkyl or (C 3-6 cycloalkyl)C 1-3 alkyl;
R 2 is —OH, C 1-3 alkyl, C 1-3 alkoxy, —C 1-3 alkyl-N(R 4 )(R 5 ), or —N(R 4 )(R 5 );
R 3 is H, —OH, —N(R 4 )(R 5 ), or C 1-3 alkoxy;
R 4 and R 5 , each independently, are H or C 1-3 alkyl;
X is —CH 2 —, —C(O)—, or —S(O) 2 —;
n is 0, 1, or 2;
provided that when R 1 is (cyclobutyl)methyl and R 3 is —OH, then R 2 is not —N(R 4 )(R 5 ).
2 . The compound of claim 1 , wherein said compound is a compound of formula (I-a):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
3 . The compound of any one of claims 1 and 2 , wherein said compound is a compound of formula (I-a1):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
4 . The compound of any one of claims 1 and 2 , wherein said compound is a compound of formula (I-a2):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
5 . The compound of claim 1 , wherein said compound is a compound of formula (I-b):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
6 . The compound of any one of claims 1 and 5 , wherein said compound is a compound of formula (I-b1):
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
7 . The compound of any one of claims 1 to 6 , wherein R is C 1-3 alkyl.
8 . The compound of any one of claims 1 to 7 , wherein R 2 is —OH, C 1-3 alkoxy, —C 1-3 alkyl-N(R 4 )(R 5 ), or —N(R 4 )(R 5 ).
9 . The compound of any one of claims 1 to 8 , wherein R 2 is —OH or —N(R 4 )(R 5 ).
10 . The compound of any one of claims 8 and 9 , wherein one of R 4 and R 5 is H, the other is H or C 1-3 alkyl.
11 . The compound of any one of claims 1 to 10 , wherein X is —CH 2 — or —C(O)—.
12 . The compound of any one of claims 1 to 11 , wherein n is 0 or 1.
13 . The compound of any one of claims 1 to 12 , wherein R 3 is H, —OH, or C 1-3 alkoxy.
14 . The compound of any one of claims 1 to 13 , wherein R 3 is H or —OH.
15 . The compound of claim 1 , wherein said compound is a compound of formula (II), or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof:
Wherein
R 1 is C 1-3 alkyl or (C 3-6 cycloalkyl)C 1-3 alkyl;
R 2 is —OH, —C 1-3 alkyl-N(R 4 )(R 5 ), or —N(R 4 )(R 5 );
R 3 is H, —OH, or C 1-3 alkoxy;
R 4 and R 5 , each independently, are H or C 1-3 alkyl;
provided that when R 1 is (cyclobutyl)methyl and R 3 is —OH, then R 2 is not —N(R 4 )(R 5 ).
16 . The compound of claim 1 or 15 , wherein R 1 is C 1-3 alkyl or (cyclopropyl)C 1-3 alkyl
17 . The compound of claim 16 , wherein R 1 is methyl or (cyclopropyl)methyl.
18 . The compound of any one of claims 1 and 15 - 17 , wherein R 2 is —OH or —N(R 4 )(R 5 ).
19 . The compound of any one of claims 15 to 18 , wherein R 2 is —N(R 4 )(R 5 ), and at least one of R 4 and R 5 is H.
20 . The compound of any one of claims 1 and 15 - 19 , wherein R 3 is H, —OH, or —OCH 3 .
21 . The compound of any one of claims 1 and 15 - 20 , wherein R 3 is —OH.
22 . The compound of claim 1 , wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
23 . The compound of claim 1 , wherein said compound is selected from the group consisting of
or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
24 . A pharmaceutical composition, comprising a therapeutically effective amount of a compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, and one or more pharmaceutically acceptable carriers or diluent.
25 . A method of treating or preventing a disorder responsive to modulation of one or more opioid receptors in a patient, comprising administering to a patient in need of such treatment or prevention an effective amount of a compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
26 . The method of claim 25 , wherein the disorder is responsive to modulation of μ-opioid receptor or κ-opioid receptor, or to modulation of both the μ-opioid receptor and the κ-opioid receptor.
27 . The method of claim 25 , wherein the disorder is responsive to modulation of the μ-opioid receptor.
28 . The method of claim 25 , wherein the disorder is pain.
29 . The method of claim 25 , wherein said compound or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, is a partial agonist of said one or more opioid receptors.
30 . The method of any one of claims 25 to 29 , wherein said compound or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, is an agonist of μ-opioid receptor or κ-opioid receptor.
31 . The method of treating, alleviating, or preventing pain, constipation, diarrhea, pruritis, an addictive disorder, withdrawal from alcohol addiction, or withdrawal from drug addiction in a patient identified in need of such a treatment or prevention, comprising administering to the patient an effective amount of a compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
32 . The method of claim 31 , wherein the method is for treating, alleviating, or preventing pain.
33 . The method of claim 32 , wherein said pain is acute pain, chronic pain, or surgical pain.
34 . The method of claim 33 , wherein said pain is chronic pain selected from the group consisting of neuropathic pain, postoperative pain, and inflammatory pain.
35 . A method of modulating one or more opioid receptors in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof.
36 . The method of claim 35 , wherein said compound or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof is a partial agonist of the one or more opioid receptors.
37 . The method of claim 35 or 36 , wherein said compound or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, is an agonist of μ-opioid receptor or κ-opioid receptor.
38 . The method of claim 35 , wherein μ- or κ-opioid receptor is modulated, or both of the μ- and the κ-opioid receptors are modulated.
39 . Use of a compound as claimed in any one of claims 1 - 23 in the manufacture of a medicament for treating or preventing a disorder responsive to modulation of one or more opioid receptors.
40 . The use of claim 39 , wherein the disorder is responsive to modulation of μ-opioid receptor or κ-opioid receptor, or to modulation of both μ-opioid receptor and κ-opioid receptor.
41 . The use of claim 39 , wherein said compound is an agonist of μ-opioid receptor or κ-opioid receptor.
42 . The use of any one of claims 39 - 41 , wherein the disorder is pain or constipation.
43 . Use of a compound as claimed in any one of claims 1 - 23 , in the manufacture of a medicament for treating, alleviating, or preventing pain, constipation, diarrhea, pruritis, an addictive disorder, withdrawal from alcohol addiction or withdrawal from drug addiction.
44 . The use of claim 43 , wherein said use is for treating, alleviating, or preventing pain.
45 . The use of claim 44 , wherein said pain is acute pain, chronic pain or surgical pain.
46 . The use of claim 45 , wherein said chronic pain is neuropathic pain, postoperative pain, or inflammatory pain.
47 . A compound as claimed in any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, for use as a medicament.
48 . The compound as claimed in any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, wherein one or more positions in the radiolabeled isomer are independently labeled by 2 H, 3 H, 11 C, 14 C, or a combination thereof.
49 . A method of screening a candidate compound for the ability to bind to an opioid receptor using a radiolabeled isomer of the compound of claim 48 , comprising a) introducing a fixed concentration of the radiolabeled isomer to the receptor to form a complex; b) titrating the complex with a candidate compound; and c) determining the binding of the candidate compound to said receptor.
50 . A kit, comprising a sterile container containing an effective amount of the compound of any one of claims 1 - 23 , or a pharmaceutically acceptable salt, radiolabeled isomer, solvate, or hydrate thereof, and instructions for therapeutic use.Join the waitlist — get patent alerts
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