DEUTERIUM-ENRICHED COLCHICINE, THIOCOLCHICINE, AND DERIVATIVES THEREOF; METHODS OF PREPARATION; AND USE THEREOF
Disclosed herein are deuterium-enriched colchicine, thiocolchicine, and derivatives thereof. The deuterium-enriched compounds are useful as, an antiproliferative agent, a muscle relaxant, an anti-inflammatory agent, or an anti-gout agent.
1 . A deuterium-enriched compound of Formula I,
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
X is —O— or —S—;
R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3m , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c , are each independently hydrogen or deuterium; and
R 3 is
R 3m , wherein R 3m is hydrogen, deuterium, or C(R 3a )(R 3b )(R 3c ) wherein R 3a , R 3b , R 3c , are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium; and
the stereocenter of Formula I indicated by “*” can be racemic, a mixture of R and S enriched in either the R or S isomer, in the R configuration, or in the S configuration;
provided that
when R 3 is R 3m , the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3m , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %;
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %; and
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3g , R 3h , R 3i , R 3j , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
2 . The deuterium-enriched compound of claim 1 , wherein
R 3 is C(R 3a )(R 3b )(R 3c ) wherein R 3a , R 3b , R 3c are each independently hydrogen or deuterium; and
X is —O—.
3 . The deuterium-enriched compound of claim 1 , wherein
R 3 is C(R 3a )(R 3b )(R 3c ) wherein R 3a , R 3b , R 3c are each independently hydrogen or deuterium; and
X is —S—.
4 . The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
5 . The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
6 . The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
7 . The deuterium-enriched compound of claim 1 , wherein the abundance of deuterium in at least one of R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
8 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is hydrogen or deuterium, and wherein
the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in at least one of R 10a , R 10b , and R 10c is at least 50 mol %.
9 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is hydrogen or deuterium, and wherein
the abundance of deuterium in R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in R 10a , R 10b , and R 10c is at least 50 mol %.
10 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is
and wherein
the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 50 mol %;
the abundance of deuterium in at least one of R 10a , R 10b , and R 10c is at least 50 mol %;
or
the abundance of deuterium in at least one of R 3a , R 3b , R 3c , R 3d , R 3f , R 3h , and R 3j is at least 50 mol %.
11 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is
and wherein
the abundance of deuterium in R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in R 7a , R 7b , and R 7c is at least 50 mol %;
the abundance of deuterium in R 10a , R 10b , and R 10c is at least 50 mol %; or
the abundance of deuterium in R 3a , R 3b , R 3c , R 3d , R 3f , R 3h , and R 3j is at least 50 mol %.
12 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is
and wherein
the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 50 mol %;
the abundance of deuterium in at least one of R 10a , R 10b and R 10c is at least 50 mol %;
or
the abundance of deuterium in at least one of R 3a , R 3b , R 3f , R 3h and R 3j is at least 50 mol %.
13 . The deuterium-enriched compound of claim 1 , wherein R 3 is R 3m wherein R 3m is
and wherein
the abundance of deuterium in R 1a , R 1b and R 1c is at least 50 mol %;
the abundance of deuterium in R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in R 7a , R 7b , and R 7c is at least 50 mol %;
the abundance of deuterium in R 10a , R 10b , and R 10c is at least 50 mol %; or
the abundance of deuterium in R 3a , R 3b , R 3f , R 3h , and R 3j is at least 50 mol %.
14 . The deuterium-enriched compound of claim 2 , wherein
the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in at least one of R 10a , R 10b and R 10c is at least 50 mol %.
15 . The deuterium-enriched compound of claim 2 , wherein
the abundance of deuterium in R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in R 10a , R 10b and R 10c is at least 50 mol %.
16 . The deuterium-enriched compound of claim 3 , wherein
the abundance of deuterium in at least one of R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in at least one of R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in at least one of R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in at least one of R 10a , R 10b , and R 10c is at least 50 mol %.
17 . The deuterium-enriched compound of claim 3 , wherein
the abundance of deuterium in R 1a , R 1b , and R 1c is at least 50 mol %;
the abundance of deuterium in R 2a , R 2b , and R 2c is at least 50 mol %;
the abundance of deuterium in R 7a , R 7b , and R 7c is at least 50 mol %; or
the abundance of deuterium in R 10a , R 10b , and R 10c is at least 50 mol %.
18 . The deuterium-enriched compound of claim 1 , wherein the stereocenter indicated by “*” is in the S configuration.
19 . A pharmaceutical composition, comprising a deuterium-enriched compound of Formula I and a pharmaceutically acceptable excipient,
wherein the deuterium-enriched compound of Formula I is
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
X is —O— or —S—;
R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3m , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c , are each independently hydrogen or deuterium; and
R 3 is
R 3m , wherein R 3m is hydrogen, deuterium, or C(R 3a )(R 3b )(R 3c ) wherein R 3a , R 3b , R 3c , are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3c , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium; and
the stereocenter of Formula I indicated by “*” can be racemic, a mixture of R and S enriched in either the R or S isomer, in the R configuration, or in the S configuration;
provided that
when R 3 is R 3m , the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3m , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %;
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %; and
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.
20 . A method of treating a patient in need of a muscle relaxant, anti-inflammatory or anti-gout agent, comprising administering to the patient a deuterium-enriched compound of Formula I, optionally in combination with a pharmaceutically acceptable excipient,
wherein the deuterium-enriched compound of Formula I is
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
X is —O— or —S—;
R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3m , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c , are each independently hydrogen or deuterium; and
R 3 is
R 3m , wherein R 3m is hydrogen, deuterium, or C(R 3a )(R 3b )(R 3c ) wherein R 3a , R 3b , R 3c , are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium, or
wherein R 3a , R 3b , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k are each independently hydrogen or deuterium; and
the stereocenter of Formula I indicated by “*” can be racemic, a mixture of R and S enriched in either the R or S isomer, in the R configuration, or in the S configuration;
provided that
when R 3 is R 3m , the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3m , R 7a , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %;
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %; and
when R 3 is
the abundance of deuterium in at least one of R 1a , R 1b , R 1c , R 2a , R 2b , R 2c , R 3a , R 3b , R 3f , R 3g , R 3h , R 3i , R 3j , R 3k , R 7a , R 7b , R 7c , R 10a , R 10b , and R 10c is at least 3, 5, 10, 20, 40, 60, 80, 90, 95, 98, or 99 mol %.