Aminocarbonylcarbamate compounds

Patent metadata

Field	Value
Publication number	US-9403761-B2
Application number	US-201514633388-A
Country	US
Kind code	B2
Filing date	Feb 27, 2015
Priority date	Feb 28, 2014
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The present disclosure provides a compound represented by Formula (I) and a pharmaceutically acceptable salt which are effective as a dopamine reuptake inhibitor and a method of using the compound:

wherein X is independently halo, alkyl, alkoxy or nitro; m is 0, 1, 2, 3 or 4; n is 1 or 2; R 1 and R 2 are independently H— or alkyl; R 3 is H—, alkyl or aralkyl; and R 4 is H— or aryl.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
X is independently halo, alkyl, alkoxy or nitro;
m is 0, 1, 2, 3 or 4
n is 1 or 2;
R 1 and R 2 are independently H— or alkyl;
R 3 is H—, alkyl or aralkyl; and
R 4 is H— or aryl,
wherein at least one of R 1 , R 2 , R 3 and R 4 is not H—.

2. The compound or pharmaceutically acceptable salt of claim 1 , wherein X is halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or nitro; R 1 and R 2 are independently H—or C 1 -C 4 alkyl; R 3 is C 1 -C 4 alkyl or C 6 -C 10 aryl-C 1 -C 4 alkyl; and R 4 is H— or C 6 -C 10 aryl.

3. The compound or pharmaceutically acceptable salt of claim 1 , which is a compound of Formula (II):

wherein
X is independently halo, alkyl, alkoxy or nitro;
m is 0, 1, 2, 3 or 4;
n is 1 or 2;
R 1 and R 2 are independently H— or alkyl; and
R 4 is H— or aryl,
wherein at least one of R 1 , R 2 and R 4 is not H—.

4. The compound or pharmaceutically acceptable salt according to claim 3 , wherein X is H—, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or nitro; R 1 and R 2 are independently H— or C 1 -C 4 alkyl; and R 4 is H— or C 6 -C 10 aryl.

5. The compound or pharmaceutically acceptable salt according to claim 3 , wherein m is 1, 2, 3 or 4 and each X is independently halo, methyl, tent-butyl, ethoxy or nitro.

6. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 1 and R 2 are independently H—, methyl or isopropyl.

7. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 4 is H— or phenyl.

8. The compound or pharmaceutically acceptable salt according to claim 3 , wherein R 4 is H—.

9. The compound or pharmaceutically acceptable salt according to claim 3 , wherein n is 1, and R 4 is H—.

10. The compound or pharmaceutically acceptable salt according to claim 3 , which is selected from the group consisting of:
2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;
2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;
2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(3-chlorophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(4-tert-butylphenyl)propyl (aminocarbonyl)carbamate;
2-amino-3-(2-fluorophenyl)propyl (aminocarbonyl)carbamate;
2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and
2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

11. The compound or pharmaceutically acceptable salt according to claim 3 , wherein the compound is a substantially pure stereoisomer.

12. The compound or pharmaceutically acceptable salt according to claim 11 , which is selected from the group consisting of:
(2R)-2-(isopropylamino)-3-phenylpropyl (aminocarbonyl)carbamate;
(2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)carbamate;
(2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)carbamate;
(2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;
(2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)carbamate;
(2R)-2-(methylamino)-3-phenylpropyl (aminocarbonyl)carbamate; and
(2R)-2-amino-3-phenylpropyl (anilinocarbonyl)carbamate.

13. The compound or pharmaceutically acceptable salt according to claim 1 , wherein the salt is hydrochloride.

14. The compound or pharmaceutically acceptable salt of claim 1 , which is a compound of Formula (III):

wherein
X is independently halo, alkyl, alkoxy or nitro;
m is 0, 1, 2, 3 or 4;
n is 1 or 2;
R 1 and R 2 are independently H— or alkyl; and
R 3 is H—, alkyl or aralkyl,
wherein at least one of R 1 , R 2 and R 3 is not H—.

15. The compound or pharmaceutically acceptable salt according to claim 14 , wherein X is H—, halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or nitro; and R 1 and R 2 are independently H— or C 1 -C 4 alkyl.

16. The compound or pharmaceutically acceptable salt according to claim 14 , wherein m is 1, 2, 3 or 4 and each X is independently halo, methyl, tert-butyl, ethoxy or nitro.

17. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 1 and R 2 are independently H—, methyl or isopropyl.

18. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 3 is C 1 -C 4 alkyl or C 6 -C 10 aryl-C 1 -C 4 alkyl.

19. The compound or pharmaceutically acceptable salt according to claim 14 , wherein R 3 is methyl, ethyl or benzyl.

20. The compound or pharmaceutically acceptable salt according to claim 14 , wherein n is 1 and R 3 is H—.

21. The compound or pharmaceutically acceptable salt according to claim 14 , which is selected from the group consisting of:
2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;
2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)methylcarbamate;
2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;
2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;
2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(4-fluorophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(4-methylphenyl)propyl (aminocarbonyl)methylcarbamate;
2-amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl)methylcarbamate; and
2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate.

22. The compound or pharmaceutically acceptable salt according to claim 14 , wherein the compound is a substantially pure stereoisomer.

23. The compound or pharmaceutically acceptable salt according to claim 22 , which is selected from the group consisting of:
(2R)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;
(2R)-2-(dimethylamino)-3-phenylpropyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-phenylpropyl (aminocarbonyl)benzylcarbamate;
(2R)-2-amino-3-phenylpropyl (aminocarbonyl)ethylcarbamate;
(2R)-2-amino-3-(2-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(4-chlorophenyl)propyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(2,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(3,4-dichlorophenyl)propyl (aminocarbonyl)methylcarbamate;
(2S)-2-amino-3-phenylpropyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(4-nitrophenyl)propyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(4-methylphenyl)propyl (aminocarbonyl)methylcarbamate;
(2R)-2-amino-3-(4-ethoxyphenyl)propyl (aminocarbonyl)methylcarbamate; and
(2R)-2-amino-4-phenylbutyl (aminocarbonyl)methylcarbamate.

24. The compound or pharmaceutically acceptable salt according to claim 14 , wherein the salt is hydrochloride.

25.

Assignees

• Sk Biopharmaceuticals Co Ltd

Inventors

• Kang Young-Soon
• Chung Jin-Yong
• Maeng Cheol-Young
• Yi Han-Ju
• Lee Ki-Ho
• Heo Joon
• Chae Eun-Hee
• Shin Yu-Jin

Classifications

• A61K9/0053 Primary

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07C275/60 Primary

  Y being an oxygen atom, e.g. allophanic acids · CPC title

• A61K31/325 Primary

  Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof (thiurams A61K31/145) · CPC title

• A61K31/27 Primary

  of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine · CPC title