US2016024075A1PendingUtilityA1
Indole and benzofuran fused isoquinuclidene derivatives and processes for preparing them
Est. expiryJan 25, 2032(~5.5 yrs left)· nominal 20-yr term from priority
Inventors:Robert M. Moriarty
C07D 453/00C07D 471/22C07D 491/22
51
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Claims
Abstract
Provided herein are indole and benzofuran fused isoquinuclidene derivatives. Also provided herein are processes, preferably enantioselective processes, for preparing such derivatives including processes for preparing (−) and (+) noribogaine or a salt thereof, in substantially enantiomerically pure forms.
Claims
exact text as granted — not AI-modified1 - 10 . (canceled)
11 . A compound of Formula (I)-j or (VI)-j:
or a salt or enantiomer thereof wherein
k is 1, 2, or 3;
each R 1 is independently selected from the group consisting of hydrogen, halo, amino, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cyano, nitro, -N 3 , and -CO 2 H or an ester thereof, wherein the alkyl, alkoxy, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkoxy, and —CO 2 H or an ester thereof;
R 2 is hydrogen or C(R 2 ) 2 is a keto group;
R 3 is selected from the group consisting of hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, or the alkylnyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof;
each R 4 independently is selected from the group consisting of hydrogen, hydroxy, —SR 41 , —OR 42 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, C 1 -C 6 alkoxy, amino, hydroxy, cyano, nitro, —NHCOCH 3 , —N 3 , and —CO 2 H or an ester thereof, or the 2 R 4 groups together with the carbon atom to which they are bonded to form a keto (C═O) group, a Schiff base (=NR 43 ), a vinylidene moiety of formula =CR 48 R 49 , or form a cyclic ketal or thioketal, which cyclic ketal or thioketal is of formula:
each R 41 is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, halo, amino, —N 3 , hydroxy, C 1 -C 6 alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, C 2 -C 10 heteroaryl, C 3 -C 8 cycloalkyl, and C 3 -C 8 heterocyclyl;
each R 42 is independently selected from the group consisting of C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, C 2 -C 10 heteroaryl, C 3 -C 8 heterocyclyl, halo, amino, -N 3 , hydroxy, C 1 -C 6 alkoxy, silyl, nitro, cyano, and CO 2 H or an ester thereof, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;
where X in both occurrences is either oxygen or sulfur;
m is 1, 2, 3, or 4;
n is 1 or 2;
R 43 is selected from the group consisting of C 6 -C 10 aryl and C 2 -C 10 heteroaryl;
R 44 is selected from the group consisting of C 1 -C 6 alkyl and C 6 -C 10 aryl;
R 48 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl, wherein the alkyl, alkenyl, or the alkynyl group is optionally substituted with 1-3 substituents selected from the group consisting of keto, C 1 -C 6 alkoxy, amino, hydroxy, cyano, nitro, -NHCOCH 3 , and -CO 2 H or an ester thereof;
R 49 is hydrogen or C 1 -C 6 alkyl; and
R 51 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof;
wherein the C 14 content of a compound of Formula (I), that is ibogaine, ibogamine, noribogaine, or methoxy ibogaine is less than 0.9 ppt.
12 . The compound of claim 11 , of Formula (IA):
wherein k and R 1 , R 2 , R 3 , R 4 , and R 51 are defined as in claim 11 .
13 . The compound of claim 11 , of Formula (IIA):
wherein k and R 1 , R 2 , R 4 , and R 51 are defined as in claim 11 .
14 . The compound of claim 11 , of Formula (IIIA):
wherein k and R 1 , R 3 , R 4 , and R 51 are defined as in claim 11 .
15 . The compound of claim 11 , of Formula (IVA):
wherein R 11 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
k is 1 or 2;
and R 1 , R 2 , R 3 , R 4 , and R 51 are defined as in claim 11 .
16 . The compound of claim 11 , of Formula (IVC) or (VIA):
wherein R 11 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof, and phenyl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkoxy;
k is 1 or 2;
and R 1 , R 2 , R 3 , R 4 , and R 51 are defined as in claim 11 .
17 . An isolated enantiomer of a compound of any one of claims 11 - 16 in substantial enantiomeric excess.
18 . The compound of claim 11 of Formula (VA):
wherein the substituents are as tabulated below:
R 1
R 11
C(R 2 ) 2
R 45
R 46
R 47
H, 4-Me, 6-Me, 7-
Bn
C═O
CR 45 CR 46 is
—
—
Me, 4-OH, 6-OH, 7-
C═O
OH, 4-OMe, 6-
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
C═O
CR 45 CR 46 is
—
—
Me, 4-OH, 6-OH, 7-
C═CR 48 H, R 48
OH, 4-OMe, 6-
is Me, Et, Pr,
OMe, or 7-OMe
Bu
H, 4-Me, 6-Me, 7-
Bn
CH 2
CR 45 CR 46 is
—
—
Me, 4-OH, 6-OH, 7-
C═CR 48 H, R 48
OH, 4-OMe, 6-
is Me, Et, Pr,
OMe, or 7-OMe
Bu
H, 4-Me, 6-Me, 7-
Bn
C═O
CH═CHR 47
OH
H, or C 1 -C 4 alkyl optionally
Me, 4-OH, 6-OH, 7-
substituted with an OMe group, OH
OH, 4-OMe, 6-
group, an amide, or with an amino
OMe, or 7-OMe
group
H, 4-Me, 6-Me, 7-
Bn
C═O
C≡CR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
C═O
CH 2 CH 2 R 47
H
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
C═O
CH 2 CH 2 R 47
OH
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
CH═CHR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
C≡CR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
CH 2 CH 2 R 47
H
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
CH 2 CH 2 R 47
OH
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
C═O
CH═CHR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
C═O
C≡CR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
C═O
CH 2 CH 2 R 47
H
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
C═O
CH 2 CH 2 R 47
OH
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
CH 2
CH═CHR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
CH 2
C≡CR 47
OH
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
CH 2
CH 2 CH 2 R 47
H
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
H
CH 2
CH 2 CH 2 R 47
OH
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide,
OH, 4-OMe, 6-
or with an amino group
OMe, or 7-OMe
19 . The compound of claim 11 of Formula (VIC):
wherein the substituents are as tabulated below:
R 1
R 11
C(R 2 ) 2
R 45
R 47
H, 4-Me, 6-Me, 7-
Bn
C═O
CH═CHR 47
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
C═O
C≡CR 47
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
C═O
CH 2 CH 2 R 47
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide, or
OH, 4-OMe, 6-
with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
CH═CHR 47
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
C≡CR 47
H or C 1 -C 4 alkyl optionally substituted
Me, 4-OH, 6-OH, 7-
with an OMe group, OH group, an
OH, 4-OMe, 6-
amide, or with an amino group
OMe, or 7-OMe
H, 4-Me, 6-Me, 7-
Bn
CH 2
CH 2 CH 2 R 47
C 1 -C 4 alkyl optionally substituted with
Me, 4-OH, 6-OH, 7-
an OMe group, OH group, an amide, or
OH, 4-OMe, 6-
with an amino group
OMe, or 7-OMe
20 . The compound of claim 11 , wherein R 51 is C 1 -C 6 alkyl optionally substituted with 1-3 substituents selected from the group consisting of keto, halo, amino, hydroxy, cyano, nitro, —N 3 , and —CO 2 H or an ester thereof.
21 . The compound of claim 11 , wherein R 1 is a non-hydrogen substituent, and k is 2.
22 . The compound of claim 11 , wherein R 1 is a non-hydrogen substituent, and k is 3.
23 . The compound of claim 18 , wherein R 47 is CH 2 OMe, (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, (CH 2 ) 4 OMe), CH 2 OH, (CH 2 ) 2 0H, (CH 2 ) 3 OH, (CH 2 ) 4 OH), (CH 2 ) 2 NHCOMe, (CH 2 ) 3 NHCOMe, (CH 2 ) 4 NHCCOMe),
24 . The compound of claim 18 , wherein R 47 is methyl, ethyl, propyl, or butyl each optionally substituted with an OMe group, OH group, an amide, or with an amino group.
25 . The compound of claim 19 , wherein R 47 is CH 2 OMe, (CH 2 ) 2 OMe, (CH 2 ) 3 OMe, (CH 2 ) 4 OMe), CH 2 OH, (CH 2 ) 2 OH, (CH 2 ) 3 OH, (CH 2 ) 4 OH), (CH 2 ) 2 NHCOMe, (CH 2 ) 3 NHCOMe, (CH 2 ) 4 NHCCOMe),
26 . The compound of claim 18 , wherein R 47 is methyl, ethyl, propyl, or butyl each optionally substituted with an OMe group, OH group, an amide, or with an amino group.Join the waitlist — get patent alerts
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