Synthesis of cyclopropyl indoles and cyclohepta[B]indoles, pharmaceutical compositions containing them and method of using them

Patent metadata

Field	Value
Publication number	US-10174008-B2
Application number	US-201515545858-A
Country	US
Kind code	B2
Filing date	Dec 3, 2015
Priority date	Dec 3, 2014
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Methods of making indole analogs using a rhodium-containing catalyst are described, along with methods of using the compounds to treat hyperglycemic, hyperlipidemic, or autoimmune disorders in mammals, and corresponding pharmaceutical compositions. Disclosed herein is a method of making indoles. The method comprises contacting a reactant of formula I wherein E is a protecting group, —SO2-Aryl, or —SO2-substituted-Aryl; and R and R2 are independently selected from the group consisting of hydrogen, halo, C1-C12-alkyl and aryl; with a rhodium(1)-containing catalyst.

First claim

What is claimed is:

1. A method of making indoles, the method comprising:
contacting a reactant of formula I:

wherein E is a protecting group, —SO 2 -Aryl, or —SO 2 -substituted-Aryl; and
R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 12 -alkyl, and aryl;
with a rhodium(I)-containing catalyst, in the presence or absence of an alkene-containing co-reactant, for a time and at a temperature to yield a product mixture comprising a compound selected from the group consisting of formula (II), (III), and (IV):

wherein R 1 , R 2 , and E are as defined previously, and R 3 is hydrogen in the absence of the alkene-containing co-reactant, and R 3 is a substituent corresponding to the alkene-containing co-reactant in the presence of the alkene-containing co-reactant.

2. The method of claim 1 , which yields a product mixture comprising a compound of formula (II).

3. The method of claim 1 , which yields a product mixture comprising a compound of formula (III).

4. The method of claim 1 , which yields a product mixture comprising a compound of formula (IV).

5. The method of claim 1 , conducted in the absence of the alpha-alkene-containing co-reactant.

6. The method of claim 1 , wherein the alkene-containing co-reactant is present and is selected from the group consisting of:

wherein R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, C 1 -C 12 -alkyl, C 1 -C 12 -alkyloxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl; and E is a protecting group.

7. The method of claim 1 , wherein the rhodium(I)-containing catalyst comprises [Rh(CO) 2 Cl] 2 .

8. The method of claim 7 , which yields a product mixture comprising a compound of formula (II).

9. The method of claim 7 , which yields a product mixture comprising a compound of formula (III).

10. The method of claim 7 , which yields a product mixture comprising a compound of formula (IV).

11. The method of claim 7 , conducted in the absence of the alpha-alkene-containing co-reactant.

12. The method of claim 7 , wherein the alkene-containing co-reactant is present and is selected from the group consisting of:

wherein R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, C 1 -C 12 -alkyl, C 1 -C 12 -alkyloxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl; and E is a protecting group.

13. The method of claim 1 , wherein the reactant of formula I is contacted with the catalyst in the presence of carbon monoxide.

14. The method of claim 13 , which yields a product mixture comprising a compound of formula (II).

15. The method of claim 13 , which yields a product mixture comprising a compound of formula (III).

16. The method of claim 13 , which yields a product mixture comprising a compound of formula (IV).

17. The method of claim 13 , conducted in the absence of the alpha-alkene-containing co-reactant.

18. The method of claim 13 , wherein the alkene-containing co-reactant is present and is selected from the group consisting of:

wherein R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, C 1 -C 12 -alkyl, C 1 -C 12 -alkyloxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl; and E is a protecting group.

19. A method of treating hyperglycemic, hyperlipidemic, or autoimmune disorders in mammals, wherein the autoimmune disorders are selected from the group consisting of arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease, the method comprising administering to a mammal an anti-hyperglycemic-effective, anti-hyperlipidemic-effective, or anti-autoimmune-effective amount of one or more compounds selected from the group consisting of:

wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 12 -alkyl, and aryl; and R 3 is selected from the group consisting of:

wherein R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, C 1 -C 12 -alkyl, C 1 -C 12 -alkyloxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl; E is a protecting group or a hydrogen atom;
or a pharmaceutically suitable salt thereof.

20. A pharmaceutical composition for treating hyperglycemic, hyperlipidemic, or autoimmune disorders in mammals, wherein the autoimmune disorders are selected from the group consisting of arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease, the composition comprising an anti-hyperglycemic-effective, anti-hyperlipidemic-effective, or anti-autoimmune-effective amount of one or more of the compounds selected from the group consisting of:

wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, halo, C 1 -C 12 -alkyl, and aryl; and R 3 is selected from the group consisting of:

wherein R 4 , R 5 , and R 6 are each independently selected from the group consisting of hydrogen, C 1 -C 12 -alkyl, C 1 -C 12 -alkyloxy, C 1 -C 12 -haloalkyl, and C 1 -C 12 -hydroxyalkyl; E is a protecting group or a hydrogen atom;
or a pharmaceutically suitable salt thereof;
in combination with a pharmaceutically suitable carrier.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Tang Weiping
• Li Xiaoxun

Classifications

• C07B51/00

  Introduction of protecting groups or activating groups, not provided for in the preceding groups · CPC title

• C07B37/10

  Cyclisation · CPC title

• B01J31/4046

  containing rhodium · CPC title

• B01J31/2265

  Carbenes or carbynes, i.e.(image) · CPC title

• B01J2231/325

  Cyclopropanations · CPC title