DERIVATIVES OF SUBSTITUTED MORPHOLINES AND USES THEREOF
A compound of Formula I includes a stereoisomer thereof and/or a salt thereof; wherein R 1 is a substituted alkane group, a heterocylic group, or a pyridine group; X is hydrogen, a halogen, an amino acid residue, a substituted amino acid residue, an alkyl group, or an ester. Such compounds may be used in pharmaceutical compositions and for the treatment of central nervous system (CNS) disorders:
1 . A method for the treatment of a central nervous system disorder, the method comprising administering to a subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
2 . The method of claim 1 , wherein R 1 is CH 2 , CH 2 CH 2 , CH 3 CH, CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 , (CH 3 ) 2 C, (CH 3 ) 2 CHCH, or (CH 3 ) 3 CCH.
3 . The method of claim 2 , wherein X is an amino acid residue.
4 . The method of claim 3 , wherein the amino acid residue comprises a hydrophobic side chain.
5 . The method of claim 4 , wherein the amino acid residue with a hydrophobic side chain is valine.
6 . The method of claim 5 , wherein R 1 is CH 2 , CH 3 CH, or (CH 3 ) 2 CHCH.
7 . The method of claim 6 , wherein the compound has the following structure:
8 . The method of claim 4 , wherein the amino acid residue with a hydrophobic side chain is phenylalanine.
9 . The method of claim 8 , wherein R 1 is CH 3 CH.
10 . The method of claim 9 , wherein the compound has the following structure:
11 . The method of claim 3 , wherein each of R 3 -R 14 is independently H, F, Cl, Br, I, or alkyl.
12 . The method of claim 11 , wherein each of R 3 -R 14 are each independently H or C 1 -C 6 alkyl.
13 . The method of claim 12 , wherein R 3 -R 14 are all H.
14 . The method of claim 13 , wherein R 1 is CH 2 , CH 2 CH 2 , CH 3 CH, CH 2 CH 2 CH 2 CH 2 , or CH 3 CH 2 CH 2 CH, or (CH 3 ) 3 CCH.
15 . The method of claim 1 , wherein the compound has the following structure:
wherein:
R 15 is H, alkyl, —C(O)OR 17 , or —C(O)R 17 ;
R 16 is H, alkyl, —C(O)OR 17 , or —C(O)R 17 ; and
R 17 is H or alkyl.
16 . The method of claim 15 , wherein R 15 is alkyl and R 16 is H or alkyl.
17 . The method of claim 16 , wherein R 15 is methyl and R 16 is H or methyl.
18 . The method of claim 17 , wherein the compound has the following structure:
19 . The method of claim 17 , wherein R 15 and R 16 are methyl.
20 . The method of claim 19 , wherein the compound has the following structure:
21 . The method of claim 15 , wherein R 15 is —C(O)R 17 , R 16 is H, and R 17 is methyl.
22 . The method of claim 21 , wherein the compound has the following structure:
23 . The method of claim 1 , wherein R 1 is CH 2 or CH 3 CH.
24 . The method of claim 23 , wherein X is an ester.
25 . The method of claim 24 , wherein the compound has the following structure:
26 . The method of claim 1 , wherein the compound has the following structure:
27 . The method of claim 1 , wherein R 1 is a pyridyl group and X is H.
28 . The method of claim 27 , wherein the compound has the following structure:
29 . The method of claim 1 , wherein R 1 is a pyridyl group and X is F, Cl, Br, or I.
30 . The method of claim 29 , wherein the compound has the following structure:
31 . A compound of Formula II, stereoisomer thereof, and/or a salt thereof:
wherein:
L is alkyl, a substituted pyridinecarboxylic acid, or a substituted azanediyl acetate;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl; and
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl.
32 . The compound of claim 31 , wherein L is CH 2 .
33 . The compound of claim 31 that is:
34 . The compound of claim 31 , wherein L is a substituted pyridinecarboxylic acid group.
35 . The compound of claim 34 , wherein the substituted pyridinecarboxylic acid group is a dimethyl pyridine-dicarboxylate.
36 . The compound of claim 31 that is:
37 . The compound of claim 31 , wherein the substituted azanediyl acetate group is a methylazanediyl acetate.
38 . The compound of claim 31 that is:
39 . A method for the treatment of a central nervous system disorder, the method comprising administering to a subject a compound of Formula III, a stereoisomer thereof, and/or a salt thereof:
wherein:
Y is F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, alkyl, or ester;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl; and
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl.
40 . The method of claim 39 , wherein Y is Cl.
41 . The method of claim 39 , wherein the compound has the following structure:
42 . A method for the treatment of a central nervous system disorder, the method comprising administering to a subject a compound of Formula IV, a stereoisomer thereof, and/or a salt thereof:
wherein:
Z is H, F, Cl, Br, I, an amino acid residue, a substituted amino acid residue, or a nitrogen-containing group;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl; and
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl.
43 . The method of claim 42 , wherein Z is a nitrogen-containing group.
44 . The method of claim 43 , wherein the nitrogen-containing group is an amide.
45 . The method of claim 42 , wherein the compound has the following structure:
46 . The method of claim 1 , wherein the disorder is a sleep disorder.
47 . The method of claim 1 , wherein the disorder is narcolepsy.
48 . The method of claim 47 , wherein administration occurs during the inactive or sleep phase.
49 . A method for enhancing cognition in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
50 . The method of claim 49 , wherein the compound has the following structure:
51 . The method of claim 49 , wherein the compound has the following structure:
52 . A method for enhancing memory in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
53 . The method of claim 52 , wherein the compound has the following structure:
54 . The method of claim 51 , wherein the compound has the following structure:
55 . A method for treating psychosis in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
56 . The method of claim 55 , wherein the compound has the following structure:
57 . The method of claim 55 , wherein the compound has the following structure:
58 . A method of treating pain or eliciting an analgesic effect in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
59 . The method of claim 58 , wherein the compound has the following structure:
60 . The method of claim 58 , wherein the compound has the following structure:
61 . A method of treating schizophrenia in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
62 . The method of claim 61 , wherein the compound has the following structure:
63 . The method of claim 61 , wherein the compound has the following structure:
64 . A method of treating a neuropsychiatric disorder in a patient, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
65 . The method of claim 64 , wherein the compound has the following structure:
66 . The method of claim 64 , wherein the compound has the following structure:
67 . A method for treating anxiety in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
68 . The method of claim 67 , wherein the compound has the following structure:
69 . The method of claim 67 , wherein the compound has the following structure:
70 . A method for treating depression in a subject, the method comprising administering to the subject a compound of Formula I, a stereoisomer thereof, or a salt thereof:
wherein:
R 1 is alkyl, heterocyclyl, or a pyridyl;
R 2 is alkyl, aryl, heteroaryl, or heterocyclyl;
R 3 -R 14 are each independently H, F, Cl, Br, I, CN, NO 2 , alkyl, aryl, heteroaryl, or heterocyclyl; and
X is H, halogen, an amino acid residue, a substituted amino acid residue, alkyl, ester.
71 . The method of claim 70 , wherein the compound has the following structure:
72 . The method of claim 70 , wherein the compound has the following structure: