US2023041584A1PendingUtilityA1
Novel prodrugs and conjugates of dimethyltryptamine
Est. expiryJun 9, 2041(~14.9 yrs left)· nominal 20-yr term from priority
C07D 209/12C07D 209/08C07D 209/14C07D 209/16C07D 401/06A61P 25/24C07F 9/5728C07D 403/06A61K 31/4045A61K 31/675A61P 25/00A61P 25/22
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Claims
Abstract
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R8, R9, X, Y, Z, W, and m are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Claims
exact text as granted — not AI-modifiedWhat is claimed:
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof;
wherein,
R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;
X, Y and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl;
R′, R 3 , R 4 , R 5 and R 6 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 , —(C═O)(CH 2 ) n (NH 2 ), —(C)CH(NH 2 )(CH 3 ), —(C═O)CH(NH 2 ), (CH 2 ) n (NH)(C═NH), or —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 ;
R 7 and R 8 are independently hydrogen or alkyl;
R 9 is hydrogen, alkyl, or halogen;
L and M are independently alkyl or aryl;
W is oxygen, sulfur or NR 6 ;
n is an integer from 2-7; and
m is an integer from 1-4,
wherein at least one of R′, R 3 , R 4 , and R 5 and R 6 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or
2 . The compound of claim 1 , wherein R 1 and R 2 are independently C 1 -C 6 alkyl.
3 . The compound of claim 1 or 2 , wherein R 1 and R 2 are independently methyl, ethyl, propyl, and isopropyl.
4 . The compound of any one of claims 1 - 3 , wherein R 1 and R 2 are methyl.
5 . The compound of any one of claims 1 - 4 , wherein X, Y and Z are H.
6 . The compound of any one of claims 1 - 5 , wherein R 8 is hydrogen.
7 . The compound of any one of claims 1 - 6 , wherein R 8 is alkyl.
8 . The compound of any one of claims 1 - 7 , wherein R 8 is C 1 -C 6 alkyl.
9 . The compound of any one of claims 1 - 8 , wherein R 9 is a halogen.
10 . The compound of any one of claims 1 - 9 , wherein R 9 is Br.
11 . The compound of any one of claims 1 - 8 , wherein R 9 is alkyl.
12 . The compound of any one of claims 1 - 8 or 11 , wherein R 9 is C 1 -C 6 alkyl.
13 . The compound of any one of claims 1 - 8 , wherein R 7 and R 8 are independently hydrogen or C 1 -C 8 alkyl and R 9 is hydrogen, halogen, or C 1 -C 8 alkyl.
14 . The compound of claim 13 , wherein the halogen is bromine.
15 . The compound of claim 13 , wherein said C 1 -C 8 alkyl is substituted with at least one of hydroxyl, thiol and halogen.
16 . The compound of any one of claims 1 - 15 , wherein m is 1.
17 . The compound of any one of claims 1 - 15 , wherein m is 2.
18 . The compound of claim 1 , wherein X, Y and Z are hydrogen; W is NR 6 ; and R 6 is —(C═O)— alkyl or —(C═O)(CH 2 ) n (NH 2 ).
19 . The compound of claim 1 , wherein two of X, Y and Z are hydrogen.
20 . The compound of claim 19 , wherein the non-hydrogen X, Y or Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
21 . The compound of claim 1 , wherein X and Y are hydrogen; Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
22 . The compound of claim 1 , wherein X and Z are hydrogen; Y is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
23 . The compound of claim 1 , wherein Y and Z are hydrogen; X is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
24 . The compound of any one of claims 1 - 23 , wherein R 5 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).
25 . The compound of any one of claims 1 - 24 , wherein R 4 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).
26 . The compound of any one of claims 1 - 25 , wherein R 3 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).
27 . The compound of any one of claims 1 - 26 , wherein R 6 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).
28 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)(CH 2 ) n (NH 2 ) and n is 3.
29 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), and n is 4.
30 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 and n is 3.
31 . The compound of any one of claims 1 - 23 , wherein at least one of R′, R 3 , R 4 , R 5 and R 6 is —(C═O)CH(NH)(CH 2 ) n (C═NH)—NH 2 and n is 2.
32 . The compound of any one of claims 1 - 31 , wherein L is methyl or isopropyl and M is alkyl or aryl.
33 . The compound of any one of claims 1 - 32 , wherein W is NR 6 and R 6 is hydrogen or alkyl.
34 . A compound of claim 1 , which is a salt of the Formula (IV):
wherein R 10 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or
A is a pharmaceutically acceptable anion.
35 . The compound of any one of claims 1 - 34 , wherein the compound is a compound shown in Table 1, Table 2, Table 3, or Table 4.
36 . A compound of Formula (III):
or a pharmaceutically acceptable salt thereof;
wherein,
R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;
X, Y and Z are independently hydrogen, halogen, —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl,
R′, R 3 , R 4 , and R 5 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 ) (CH 2 ) n (NH)(C═NH)—NH 2 , —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or
R 7 and R 8 are independently hydrogen or alkyl;
R 9 is hydrogen, alkyl or halogen;
L and M are independently alkyl or aryl;
n is an integer from 2-7; and
m is an integer from 1-4,
wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or
37 . The compound of claim 36 , wherein R 1 and R 2 are independently C 1 -C 6 alkyl.
38 . The compound of claim 36 or 37 , wherein R 1 and R 2 are independently methyl, ethyl, propyl, and isopropyl.
39 . The compound of any one of claims 36 - 38 , wherein R 1 and R 2 are methyl.
40 . The compound of any one of claims 36 - 39 , wherein X, Y and Z are H.
41 . The compound of any one of claims 36 - 40 , wherein R 8 is hydrogen.
42 . The compound of any one of claims 36 - 41 , wherein R 8 is alkyl.
43 . The compound of any one of claims 36 - 42 , wherein R 8 is C 1 -C 6 alkyl.
44 . The compound of any one of claims 36 - 43 , wherein R 9 is hydrogen.
45 . The compound of any one of claims 36 - 43 , wherein R 9 is alkyl.
46 . The compound of claim 45 , R 9 is C 1 -C 6 alkyl.
47 . The compound of any one of claims 36 - 46 , wherein R 7 and R 8 are independently hydrogen or C 1 -C 8 alkyl and R 9 is hydrogen, halogen or C 1 -C 8 alkyl.
48 . The compound of claim 47 , wherein the C 1 -C 8 alkyl is substituted with at 1-3 groups including hydroxyl, thiol or halogen.
49 . The compound of any one of claims 36 - 48 , wherein m is 1.
50 . The compound of any one of claims 36 - 48 , wherein m is 2.
51 . The compound of any one of claims 1 - 39 or 41 - 50 , wherein two of X, Y and Z are hydrogen.
52 . The compound of claim 51 , wherein the non-hydrogen X, Y or Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
53 . The compound of claim 36 , wherein X and Y are hydrogen; Z is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
54 . The compound of claim 36 , wherein X and Z are hydrogen; Y is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
55 . The compound of claim 36 , wherein Y and Z are hydrogen; X is —O—, —S—, —NR A —, or —(P═O)—OR A (—OR′), wherein R A is hydrogen or alkyl.
56 . The compound of any one of claims 36 - 55 , wherein R 4 is —(C═O)-alkyl, or —(C═O)(CH 2 ) n (NH 2 ).
57 . The compound of any one of claims 36 - 56 , wherein R 5 is —(C═O)-alkyl or —(C═O)(CH 2 ) n (NH 2 ).
58 . The compound of any one of claims 36 - 57 , wherein R 3 is —(C═O)-alkyl, or —(C═O)(CH 2 ) n (NH 2 ).
59 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)(CH 2 ) n (NH 2 ) and n is 3.
60 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ) and n is 4.
61 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 and n is 3.
62 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)—NH 2 and n is 2.
63 . The compound of any one of claims 36 - 55 , wherein at least one of R′, R 3 , R 4 , and R 5 is
64 . The compound of any one of claims 36 - 63 , in salt form, of the Formula (V):
wherein R 10 is —(C═O)-alkyl, —(C═O)CHR 7 (NH 2 ), —(C═O)(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH 2 ), —(C═O)CH(NH 2 )(CH 2 ) n (NH)(C═NH)—NH 2 , —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 or
and
wherein A is a pharmaceutically acceptable anion.
65 . The compound claim 64 , wherein L is methyl or isopropyl and M is alkyl or aryl.
66 . A pharmaceutical composition comprising the compound of any one of claims 1 - 65 and a pharmaceutically acceptable excipient.
67 . A compound as shown in Table 2, wherein X and Y are hydrogen and R 3 and R 4 are absent.
68 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is hydrogen.
69 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is Me.
70 . A compound as shown in Table 2, wherein X is hydrogen, R 3 is absent, Y is O, and R 4 is Ac.
71 . A compound as shown in Table 2, wherein X is O, R 3 is hydrogen, Y is hydrogen, and R 4 is absent.
72 . A compound as shown in Table 2, wherein X is O, R 3 is Me, Y is hydrogen, and R 4 is absent.
73 . A compound as shown in Table 2, wherein X is O, R 3 is Ac, Y is hydrogen, and R 4 is absent.
74 . A compound of the formula:
75 . A compound of the formula:
76 . A compound of the formula
77 . A compound of the formula:
78 . A compound of Formula (VI):
R 1 and R 2 are independently hydrogen, alkyl, cycloalkyl, or R 1 and R 2 together with the atoms to which they are attached form a heterocycle;
R 3 , R 4 , R 5 and R 6 are independently absent, hydrogen, alkyl, —(C═O)-alkyl, —(C═O)CHR 7 , —(C═O)(CH 2 ) n (NH 2 ), —(C)CH(NH 2 )(CH 3 ), —(C═O)CH(NH 2 ), (CH 2 ) n (NH)(C═NH), or —(C═O)(CH 2 ) n (NH)(C═NH)—NH 2 ;
X is carbon or nitrogen;
W is carbon, oxygen, or nitrogen; and
Z is hydrogen, deuterium, or oxygen.
79 . The compound of claim 78 , having the following chemical formula:
80 . A compound selected from the formulae:
81 . A phosphonooxymethyl prodrug according to claim 1 of the Formula (VIII):
wherein
Ru and R 12 are pharmaceutically acceptable salt and are independently H, D, Na + , K + , NH 4 + ; or
R 1 and R 12 are independently a pharmaceutically acceptable salt, hydrogen, deuterium, alkyl, substituted alkyl, cycloalkyl, or R 11 and R 12 together with the atoms to which they are attached form an alkyl, cycloalkyl, heterocycles and are ether, hemiaminal ketal and amino acid, wherein the pharmaceutically acceptable salt is Na + , K + , NH 4 + .
82 . A pharmaceutical composition comprising a compound of any one of claims 1 - 65 or 67 - 81 and a pharmaceutically acceptable excipient.
83 . An oral dosage form comprising the pharmaceutical composition of claim 66 or 82 .
84 . A method of treating post-traumatic stress disorder (PTSD) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.
85 . A method of treating depression in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.
86 . The method of claim 85 , wherein the depression is major depressive disorder (MDD) or treatment-resistant depression (TRD).
87 . A method of treating an anxiety disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 65 or 67 - 81 or a pharmaceutical composition of claims 66 , 82 or 83 to the subject.Cited by (0)
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