Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs
The present disclosure provides tetrahydro-1H-pyrido[3,4-b]indole compounds or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer, N-oxide and/or substituted derivative or, optionally in a pharmaceutical composition, for the modulation of disorders mediated by estrogen, or other disorders as more fully described herein.
1. A process of preparing a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is —CH 2 — or —O—;
Y is
R 1 and R 2 are each hydrogen;
R 3 and R 4 are each independently selected from hydrogen and halo, and when one of R 3 or R 4 is halo, the other of R 3 or R 4 is hydrogen;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 0 -C 4 (C 3 -C 6 cycloalkyl), or C 1 -C 6 heteroalkyl;
R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 0 -C 4 (C 3 -C 6 cycloalkyl);
R 7 is selected from hydrogen and C 1 -C 6 alkyl; and
R 8 is hydrogen,
wherein the process comprises a step of contacting a first amine compound:
with a first aldehyde compound:
in the presence of an acid to provide the compound of Formula I.
2. The process of claim 1 , further comprising a step of contacting a second amine compound:
with a compound R 6 -LG 3 , wherein LG 3 is selected from halide, OTs, OBs, ONs, OMs, triflate, nonaflate, and tresylate,
in the presence of a base to provide the first amine compound:
3. The process of claim 2 , further comprising a step of contacting a third amine compound:
with hydrogen gas at a pressure of about 50 psi in the presence of a catalyst to provide the second amine compound:
4. The process of claim 3 , further comprising a step of contacting a ketone compound:
with (R)-(+)-1-phenylethylamine in the presence of a reducing agent, optionally at a reduced temperature, to provide the third amine compound:
5. The process of claim 1 , further comprising a step of contacting a second aldehyde compound:
with a first azetidine compound:
to provide the first aldehyde compound:
wherein X is —O— and Y is
6. The process of claim 1 , further comprising a step of contacting a third aldehyde compound:
with a first azetidine compound:
to provide the first aldehyde compound:
wherein X is —O— and Y is
7. The process of claim 1 , wherein the first amine compound is:
8. The process of claim 2 , wherein the second amine compound is:
and wherein R 6 -LG 3 is (CH 3 ) 2 CFCH 2 -OTf.
9. The process of claim 8 , further comprising a step of contacting 2-fluoro-2-methylpropanol with trifluoromethanesulfonic anhydride to provide (CH 3 ) 2 CFCH 2 —OTf.
10. The process of claim 9 , further comprising a step of contacting methyl 2-fluoro-2-methylpropionate with lithium aluminum hydride to provide 2-fluoro-2-methylpropanol.
11. The process of claim 1 , wherein the first aldehyde compound is:
12. The process of claim 11 , further comprising a step of contacting 4-fluorobenzaldehdye with 1-propylazetidin-3-ol in the presence of cesium carbonate and N,N-dimethylformamide at elevated temperature to provide:
13. The process of claim 1 , wherein the first aldehyde compound is:
14. The process of claim 13 , further comprising a step of contacting 3-fluoro-4-iodobenzaldehyde with 1-propylazetidin-3-ol in the presence of cesium carbonate and Cu(I) iodide at elevated temperature to provide:
15. The process of claim 12 , further comprising a step of contacting 1-propionylazetidin-3-one with lithium aluminum hydride to provide 1-propylazetidin-3-ol.
16. The process of claim 15 , further comprising a step of contacting 3-azetidinone hydrochloride with propionyl chloride in the presence of diisopropylethylamine to provide 1-propionylazetidin-3-one.
17. The process of claim 1 , wherein the first aldehyde compound is:
18. The process of claim 17 , further comprising a step of contacting 2-(4-formylphenoxy)ethyl methanesulfonate with 3-(fluoromethyl)azetidine hydrochloride in the presence of potassium carbonate at elevated temperature to provide:
19. The process of claim 18 , further comprising a step of contacting 4-(2-hydroxyethoxy)benzaldehyde with mesyl chloride in the presence of triethylamine to provide 2-(4-formylphenoxy)ethyl methanesulfonate.