US2007099983A1PendingUtilityA1
Aminocyclohexyl ether compounds and uses thereof
Est. expiryMay 2, 2023(expired)· nominal 20-yr term from priority
Inventors:G. Dean BarrettLewis Siu Leung ChoiDough ChouGrace JungBertrand M. C. PlouvierYuzhong LiuJeff ZhuTao Sheng
A61P 9/06A61K 31/455A61K 31/519A61P 43/00A61K 31/40C07D 207/12A61P 9/00A61K 31/4965
52
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Claims
Abstract
Aminocyclohexyl ether compounds are disclosed. The compounds of the present invention may be incorporated in compositions and kits. The present invention also discloses uses for the compounds and compositions, including the treatment of arrhythmia.
Claims
exact text as granted — not AI-modified1 - 100 . (canceled)
101 . A method of stereoselectively making an aminocyclohexyl ether comprising:
reacting a compound of formula (55), or a compound of formula (74), with a compound of formula (56), to form a compound of formula (57), or a compound of formula (75), respectively, wherein R 1 and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II): and wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and wherein O-J is a leaving group.
102 . A method of making a compound of formula (55) or formula (74):
wherein the method comprises:
alkylating a compound of formula (53),
or a compound of formula (84),
with a compound of formula (54),
to form the compound of formula (55) or the compound of formula (74); respectively; and
optionally protecting a compound of formula (53),
or a compound of formula (84),
before said alkylating step;
wherein O-Q is a leaving group that reacts with —OH in formula (53) or formula (84) to form the compound of formula (55) or the compound of formula (74), such that the stereochemical configuration of the compound of formula (53) or the compound of formula (84) is retained in the compound of formula (55) or the compound of formula (74), respectively;
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and
wherein O-J is a leaving group.
103 . A method of making a compound of formula (74) or formula (55):
wherein the method comprises:
activating a compound of formula (73),
or a compound of formula (94),
with a hydroxy activating reagent to form the compound of formula (74) or the compound of formula (55), respectively;
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and
wherein O-J is a leaving group.
104 . A method of making a compound of formula (73):
wherein the method comprises:
hydrogenating and hydrogenolyzing a compound of formula (72),
to form the compound of formula (73);
wherein X is a halide; and
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen.
105 . A method of making a compound of formula (72):
wherein the method comprises:
alkylating a compound of formula (51),
with a compound of formula (54),
to form the compound of formula (72);
wherein X is a halide
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and
wherein O-Q is a leaving group that reacts with —OH in the compound of formula (51) to form the compound of formula (72), such that the stereochemical configuration of the compound of formula (51) is retained in the compound of formula (72).
106 . A method of making a compound of formula (93):
wherein the method comprises:
alkylating a compound of formula (92),
with a compound of formula (54),
to form the compound of formula (93);
wherein Pro is a protecting group;
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy, and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen; and
wherein O-Q is a leaving group that reacts with —OH in the compound of formula (92) to form the compound of formula (93), such that the stereochemical configuration of the compound of formula (92) is retained in the compound of formula (93).
107 . A method of making a compound of formula (92):
wherein the method comprises:
hydrogenating and hydrogenolyzing a compound of formula (91),
to form the compound of formula (92);
wherein Pro is a protecting group; and
wherein X is a halide.
108 . A method of making a compound of formula (53):
wherein the method comprises:
hydrogenating and hydrogenolyzing a compound of formula (52),
to form the compound of formula (53);
wherein X is a halide; and
wherein O-J is a leaving group.
109 . A method of making a compound of formula (52):
wherein the method comprises:
activating a compound of formula (51),
with a hydroxy activating reagent to form the compound of formula (52);
wherein X is a halide; and
wherein O-J is a leaving group.
110 . A method of making a compound of formula (99):
wherein the method comprises:
activating a compound of formula (92),
with a hydroxy activating reagent to form the compound of formula (99);
wherein Pro is a protecting group; and
wherein O-J is a leaving group.
111 . A method of making a compound of formula (53) or a compound of formula (84):
wherein the method comprises:
removing a functional group G or G 1 from a compound of formula (85),
or a compound of formula (86),
respectively, to form the compound of formula (53) or the compound of formula (84), respectively;
wherein O-J is a leaving group.
112 . A method comprising separating a racemic mixture of a compound of formula (53),
and a compound of formula (84),
113 . A method of forming a racemic mixture of a compound of formula (53) and a compound of formula (84):
wherein the method comprises:
activating a compound of formula (83),
with a hydroxy activating reagent to form the racemic mixture of the compound of formula (53) and the compound of formula (84);
wherein O-J is a leaving group.
114 . A method for stereoselectively making an aminocyclohexyl ether of formula (57):
wherein R 1 and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (57), form a ring denoted by formula (II):
and
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen;
wherein the method comprises:
(a) reacting a compound of formula (53),
wherein O-J is a leaving group, with a compound of formula (54),
wherein R 3 , R 4 and R 5 are as defined above and O-Q is a leaving group that reacts with the hydroxy group (—OH) in formula (53) to form a compound of formula (55),
such that the stereochemical configuration of the compound of formula (53) is retained in the compound of formula (55);
(b) optionally protecting the compound of formula (53) before the first reaction; and
(c) reacting the compound of formula (55) with a compound of formula (56),
wherein R 1 and R 2 are as defined above, to form the aminocyclohexyl ether of formula (57).
115 . A method for stereoselectively making an aminocyclohexyl ether of formula (75):
wherein R 1 and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II):
and
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen;
wherein the method comprises:
(a) reacting a compound of formula (84),
wherein O-J is a leaving group, with a compound of formula (54),
wherein R 3 , R 4 and R 5 are as defined above and O-Q is a leaving group that reacts with the hydroxy group (—OH) in the compound of formula (84) to form a compound of formula (74),
such that the stereochemical configuration of the compound of formula (84) is retained in the compound of formula (74);
(b) optionally protecting the compound of formula (84) before the first reaction step (a); and
(c) reacting the compound of formula (74) with a compound of formula (56),
wherein R 1 and R 2 are as defined above, to form the aminocyclohexyl ether of formula (75).
116 . A method for stereoselectively making an aminocyclohexyl ether of formula (75):
wherein R 1 and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II):
and
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen;
wherein the method comprises:
(a) reacting a compound of formula (73),
with a hydroxy activating reagent to form a compound of formula (74),
wherein O-J is a leaving group, and R 3 , R 4 and R 5 are as defined above; and
(b) reacting the product of the first reaction, compound of formula (74) with a compound of formula (56),
wherein R 1 and R 2 are as defined above, to form the aminocyclohexyl ether of formula (75).
117 . A method for stereoselectively making an aminocyclohexyl ether of formula (57):
wherein R 1 and R 2 , when taken together with the nitrogen atom to which they are directly attached in formula (57) or (75), form a ring denoted by formula (II):
and
wherein R 3 , R 4 and R 5 are independently selected from hydrogen, hydroxy and C 1 -C 6 alkoxy, with the proviso that R 3 , R 4 and R 5 cannot all be hydrogen;
wherein the method comprises:
(a) hydrogenating and hydrogenolyzing a compound of formula (91),
to form a compound of formula (92),
wherein Pro is a protecting group and X is a halide;
(b) alkylating the compound of formula (92) with a compound of formula (54),
wherein R 3 , R 4 and R 5 are as defined above and O-Q is a leaving group that reacts with the hydroxy group in formula (92) to form a compound of formula (93),
such that the stereochemical configuration of the compound of formula (92) is retained in the compound of formula (93);
(c) deprotecting the compound of formula (93) to form a compound of formula (94),
(d) activating the compound of formula (94) to form a compound of formula (55),
wherein O-J is a leaving group; and
(e) reacting the compound of formula (55) with a compound of formula (56),
wherein R 1 and R 2 are as defined above, to form the amino cyclohexyl ether of formula (57).
118 . A method of making compound (1) or compound (2):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form compound (1R):
b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R):
c) hydrolyzing compound (2R) under suitable conditions to form compound (3R):
d) reacting compound (3R) with
under suitable conditions to form compound (4R):
e) reacting compound (4R) with
under suitable conditions to form compound (5R);
f) resolving compound (5R) under suitable conditions to form compound (5RRR) and compound (5SSR):
and
g) hydrogenolyzing compound (5RRR) under suitable conditions to form compound (1), as described above, and hydrogenolyzing compound (5SSR) under suitable conditions to form compound (2), as described above.
119 . A method of making compound (5RRR) or compound (5SSR):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form compound (1R):
b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R):
c) hydrolyzing compound (2R) under suitable conditions to form compound (3R):
d) reacting compound (3R) with
under suitable conditions to form compound (4R):
e) reacting compound (4R) with
under suitable conditions to form compound (5R);
and
f) resolving compound (5R) under suitable conditions to form compound (5RRR) and compound (5SSR), as described above.
120 . The method of claim 119 further comprising:
reacting compound (5RRR) under suitable conditions to form compound (17):
121 . A method of making compound (5R):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form compound (1R):
b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R):
c) hydrolyzing compound (2R) under suitable conditions to form compound (3R):
d) reacting compound (3R) with
under suitable conditions to form compound (4R):
and
e) reacting compound (4R) with
under suitable conditions to form compound (5R), as described above.
122 . The method of claim 121 further comprising:
reducing compound (5R) under suitable conditions to form compound (4):
123 . The method of claim 121 further comprising:
reacting compound (5R) under suitable conditions to form compound (12):
124 . A method of making compound (4R):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form compound (1R):
b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R):
c) hydrolyzing compound (2R) under suitable conditions to form compound (3R):
and
d) reacting compound (3R) with
under suitable conditions to form compound (4R), as described above.
125 . A method of making compound (3R):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form compound (1R):
b) reacting compound (1R) with benzyl bromide under suitable conditions to form compound (2R):
and
c) hydrolyzing compound (2R) under suitable conditions to form compound (3R), as described above.
126 . A method of making compound (1):
wherein the method comprises hydrogenolyzing compound (5RRR):
under suitable conditions to form compound (1), as described above.
127 . The method of claim 126 further comprising, prior to the hydrogenolyzing step,
resolving compound (5R): under suitable conditions to form compound (5RRR), as described above.
128 . The method of claim 127 further comprising, prior to the resolving step,
reacting compound (4R): with under suitable conditions to form compound (5R), as described above.
129 . The method of claim 128 further comprising, prior to the reacting step,
reacting compound (3R): with under suitable conditions to form compound (4R), as described above.
130 . The method of claim 129 further comprising, prior to the reaction of compound (3R) with
hydrolyzing compound (2R):
under suitable conditions to form compound (3R), as described above.
131 . A method of making compound (2):
wherein the method comprises hydrogenolyzing compound (5SSR):
under suitable conditions to form compound (2), as described above.
132 . The method of claim 131 further comprising, prior to the hydrogenolyzing step,
resolving compound (5R): under suitable conditions to form compound (5SSR), as described above.
133 . The method of claim 132 further comprising, prior to the resolving step,
reacting compound (4R): with under suitable conditions to form compound (5R), as described above.
134 . The method of claim 133 further comprising, prior to the reacting step,
reacting compound (3R): with under suitable conditions to form compound (4R), as described above.
135 . The method of claim 134 further comprising, prior to the reaction of compound (3R) with
hydrolyzing compound (2R):
under suitable conditions to form compound (3R), as described above.
136 . A method of making compound (6) or compound (7):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form the following compound:
b) reacting the compound formed in step a) with benzyl bromide under suitable conditions to form the following compound:
c) hydrolyzing the compound formed in step b) under suitable conditions to form the following compound:
d) reacting the compound formed in step c) with
under suitable conditions to form the following compound:
e) reacting the compound formed in step d) with
under suitable conditions to form the following compound:
f) resolving the compound formed in step e) under suitable conditions to form the following compounds:
and
g) hydrogenolyzing the following compound formed in step f):
under suitable conditions to form compound (6), as described above;
and hydrogenolyzing the following compound formed in step f):
under suitable conditions to form compound (7), as described above.
137 . The method of claim 136 further comprising:
reducing the compound formed in step e) under suitable conditions to form compound (5):
138 . A method of making compound (3):
wherein the method comprises:
a) reacting
with (Boc) 2 O under suitable conditions to form the following compound:
b) reacting the compound formed in step a) with benzyl bromide under suitable conditions to form the following compound:
c) hydrolyzing the compound formed in step b) under suitable conditions to form the following compound:
d) reacting the compound formed in step c) with
under suitable conditions to form the following compound:
e) reacting the compound formed in step d) with
under suitable conditions to form the following compound:
f) hydrogenolyzing the following compound formed in step e):
under suitable conditions to form compound (3), as described above.
139 . The compound (5RRR):
140 . The compound (5SSR):
141 . The compound (5R):
142 . The compound (4R):Join the waitlist — get patent alerts
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