Steroids and methods of manufacture

Patent metadata

Field	Value
Publication number	US-11459353-B2
Application number	US-201816637675-A
Country	US
Kind code	B2
Filing date	Aug 16, 2018
Priority date	Aug 16, 2017
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

Abstract

Methods for producing enantiodefined polycyclic compounds, particularly tetracyclic compounds, are provided. More particularly, synthetic methods for producing biologically active enantiodefined steroidal compositions of both natural (“nat-”) and unnatural (“ent-”) absolute stereochemistry are provided. An exemplary method for manufacturing a tetracyclic compound comprises a step of forming a hydrindane intermediate through coupling of a suitably functionalized enyne with a suitably functionalized alkyne and subsequently performing an intramolecular ring-closing reaction to form the tetracyclic compound. Steroidal compounds obtained by this method and methods of using such steroidal compounds in human and/or animal therapeutics and medicines are also provided.

First claim

What is claimed is:

1. A method for manufacturing a tetracyclic compound, the method comprising a step of:
(a) reacting a compound of Formula (Ci) with a compound of Formula (Di) to give a hydrindane of Formula (Ei):

wherein
LG is a leaving group;
Cy is C 3-8 -cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 -aryl, or 5- to 10-membered heteroaryl;
each R M is independently selected from the group consisting of hydrogen, C 1-6 -alkyl, trimethylsilyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, arylalkyl, and —OR MX , wherein R MX is hydrogen, C 1-6 -alkyl, or C 6-10 -aryl;
n is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
m is an integer selected from 0, 1, and 2;
R A is selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, hydroxy, —OR AX , —SR AY , —S(O) 2 NR Z1 R Z2 , —S(O) 2 R Z1 , —S(O)R Z1 , —NR Z1 R Z2 , —N(R Z1 )C(O)R Z2 , —N(R Z1 )S(O) 2 R Z2 , C 6-10 -aryl, and 5- to 10-membered heteroaryl, or two R A together form an oxo,
wherein R AX is C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, —S(O) 2 R Z1 , C 6-10 -aryl, or 5- to 10-membered heteroaryl,
wherein R AY is hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, C 6-10 -aryl, or 5- to 10-membered heteroaryl,
wherein each of R Z1 and R Z2 are independently hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, C 6-10 -aryl, 5- to 10-membered heteroaryl, hydroxy, or C 1-6 -alkoxy;

R 13 is selected from the group consisting of C 1-6 -alkyl and C 6-10 -aryl-C 1-6 -alkyl, wherein the C 6-10 -aryl of R 13 is optionally substituted one or more halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy; and
each R 17 is independently selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, and halogen, or two R 17 together form an oxo,
wherein any C 3-8 -cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6-10 -aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, C 1-6 -alkyl, C 1-6 -haloalkyl, or C 1-6 -alkoxy;

(b) treating the hydrindane of Formula (Ei) to install a carbon and provide a reactive intermediate for B-ring formation; and
(c) performing an intramolecular ring-closing reaction to form the tetracyclic compound.

2. The method of claim 1 , wherein step (b) comprises cyclopropanation of the compound of Formula (Ei) to form a compound of Formula (Fi):

wherein X 1 and X 2 are independently selected from the group consisting of hydrogen, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, halogen, oxygen, —OR Bx , —SR BY , —S(O) 2 NR Z1 R Z2 , —S(O) 2 R Z1 , —S(O)R Z1 , —NR Z1 R Z2 , —N(R Z1 )C(O)R Z2 , —N(R Z1 )S(O) 2 R Z2 , C 6-10 -aryl, 5- to 10-membered heteroaryl, C 6-10 -aryl-C 1-6 -alkyl, C 6-10 -aryl-C 2-6 -alkenyl, and C 6-10 -aryl-C 2-6 -alkynyl,
wherein R BX is C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, C 6-10 -aryl, or 5- to 10-membered heteroaryl,
wherein R BY is hydrogen, C 1-6 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 1-10 -haloalkyl, —C(O)—C 1-10 -alkyl, —C(O)—C 6-10 -aryl, —C(O)-heteroaryl, C 6-10 -aryl, or 5- to 10-membered heteroaryl; and
R DZ is hydrogen or an oxygen protecting group; and

treatment of the compound of Formula Fi with an acid in an organic solvent.

3. The method of claim 1 , wherein step (c) comprises an intramolecular Friedel-Crafts alkylation reaction.

4. The method of claim 1 , wherein the compound of Formula (Ci) is formed by reacting a compound of Formula (Ai) with a compound of Formula (Bi) or a compound of Formula (A′i) with a compound of Formula (B′i):

wherein LG is a leaving group; X is a halogen or pseudohalogen; and M is a metal.

5. The method of claim 1 , wherein each R M is C 1-6 -alkyl.

6. The method of claim 1 , wherein LG is selected from the group consisting of halogen; —O—Ar 1 wherein Ar 1 is a substituted or unsubstituted C 6-10 -aryl or 5- to 10-membered heteroaryl; and —OSO 2 R 1a , wherein R 1a is aryl, alkyl, fluoroalkyl, -fluoroalkyl-O-fluoroalkyl, —N(alkyl) 2 , fluoro, or imidazolyl.

7. The method of claim 2 , wherein the acid is selected from the group consisting of TiCl 4 , SnCl 4 , and BF 3 OEt 2 .

8. The method of claim 2 , wherein the organic solvent is selected from the group consisting of dichloromethane, chlorobenzene, ethylenechloride, 1,2-dichlorobenzene, nitromethane, tetrachlorethane, and mixtures thereof.

9. The method of claim 2 , wherein X 1 or X 2 is halogen.

10. The method of claim 2 , wherein X 1 and X 2 are both halogen.

11. The method of claim 2 , wherein R DZ is selected from the group consisting of methyl, tert-butyloxycarbonyl (BOC), methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), and tribenzylsilyl.

12. The method of claim 1 , wherein the tetracyclic compound is

13. The method of claim 1 , wherein the tetracyclic compound is selected from the group consisting of:

14. The method of claim 1 , wherein the compound of Formula (Di) is selected from the group consisting of:

15. The method of claim 2 , wherein the compound of Formula (Ei) is selected from the group consisting of:

16. The method of claim 2 , wherein X 1 or X 2 is halogen and R DZ is an oxygen protecting group.

17. The method of claim 16 , wherein the oxygen protecting group is selected from the group consisting of methyl, tert-butyloxycarbonyl (BOC), methoxymethyl (MOM), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS), and tribenzylsilyl.

18. The method of claim 2 , wherein X 1 or X 2 is halogen, R DZ is an oxygen protecting group, Cy is a C 6-10 -aryl or a 5- to 10-membered heteroaryl, R 13 is C 1-6 -alkyl and each R 17 is hydrogen.

19. The method of claim 2 , wherein X 1 or X 2 is halogen and R DZ is an oxygen protecting group and the acid is selected from the group consisting of TiCl 4 , SnCl 4 , and BF 3 OEt 2 .

20. The method of claim 2 , w

Assignees

• Dartmouth College

Inventors

• Micalizio Glenn C

Classifications

• C07J11/00 Primary

  Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3 · CPC title

• C07J75/005

  Preparation of steroids by cyclization of non-steroid compounds · CPC title

• C07J15/00

  Stereochemically pure steroids containing carbon, hydrogen, halogen or oxygen having a partially or totally inverted skeleton, e.g. retrosteroids, L-isomers · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/00 Primary

  Drugs for disorders of the nervous system · CPC title