3-(2-amino-ethyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-alkylidene-1,3-dihydro-indol-2-one derivatives as selective sphingosine kinase 2 inhibitors

Patent metadata

Field	Value
Publication number	US-9598384-B2
Application number	US-201514933042-A
Country	US
Kind code	B2
Filing date	Nov 5, 2015
Priority date	Feb 10, 2012
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

3-(2-amino-ethyl)-5-[3-(4-substituted-phenyl)-alkylidene)-thiazolidine-2,4-dione and 1-(2-amino-ethyl)-3-alkylidene-1,3-dihydro-indol-2-one and derivatives thereof are provided for use as selective SphK2 inhibitors and for use in the treatment of human diseases, such as cancer.

First claim

We claim:

1. A compound of Formula II:

wherein,
R 10 is selected from the group consisting of: C 3 -C 14 alkyl, C 3 -C 14 alkoxyl;
R 11 , R 12 , R 13 and R 14 may be the same or different and are independently selected from: H, C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
R 15 , R 16 , R 17 and R 18 may be the same or different and are independently selected from the group consisting of: C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
X is C 1 -C 4 alkyl;
Y is C 1 -C 4 alkyl;
and
W is NR 19 R 20 where R 19 and R 20 may be the same or different and are selected from the group consisting of: H, C 1 -C 4 alkyl; a saturated heterocycle comprising N bonded directly to Y, and an unsubstituted or substituted guanidine moiety.

2. The compound of claim 1 , wherein said saturated heterocycle is selected from the group consisting of morpholine, piperidine, piperazine, and pyrrolidine.

3. A method of treating diseases or conditions by inhibiting positive SphK2 activity in a patient in need thereof, comprising the step of administering to said patient a sufficient quantity of at least one compound of Formula II:

wherein,
in Formula II:
R 10 is selected from the group consisting of: C 3 -C 14 alkyl, C 3 -C 14 alkoxyl;
R 11 , R 12 , R 13 and R 14 may be the same or different and are independently selected from: H, C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
R 15 , R 16 , R 17 and R 18 may be the same or different and are independently selected from the group consisting of: C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
X is C 1 -C 4 alkyl;
Y is C 1 -C 1 alkyl;

and
W is NR 19 R 20 where R 19 and R 20 may be the same or different and are selected from the group consisting of: H, C 1 -C 1 alkyl; a saturated heterocycle comprising N bonded directly to Y, and an unsubstituted or substituted guanidine moiety.

4. The method of claim 3 , wherein said saturated heterocycle is selected from the group consisting of morpholine, pipieridine, piperazine, and pyrrolidine.

5. The method of claim 3 , wherein said disease or condition associated with positive SphK2 activity is selected from the group consisting of: cancer, arthrosclerosis, arthritis, diabetes, obesity, osteoporosis, inflammatory diseases and Alzheimer's disease.

6. A method of inhibiting SphK2, comprising the step of exposing said SphK2 to at least one compound of Formula II:

wherein,
in Formula II:
R 10 is selected from the group consisting of: C 3 -C 14 alkyl, C 3 -C 14 alkoxyl;
R 11 , R 12 , R 13 and R 14 may be the same or different and are independently selected from: H, C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
R 15 , R 16 , R 17 and R 18 may be the same or different and are independently selected from the group consisting of: C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
X is C 1 -C 4 alkyl;
Y is C 1 -C 1 alkyl;

and
W is NR 19 R 20 where R 19 and R 20 may be the same or different and are selected from the group consisting of: H, C 1 -C 4 alkyl; a saturated heterocycle comprising N bonded directly to Y, and an unsubstituted or substituted guanidine moiety.

7. The method of claim 6 , wherein said saturated heterocycle is selected from the group consisting of morpholine, pipieridine, piperazine, and pyrrolidine.

8. The method of claim 6 , wherein said SphK2 is present in a cell.

9. The method of claim 8 , wherein said cell is selected from the group consisting of a cancer cell, cardiocyte cell, epithelial cell, pancreatic cell, and neuronal cell, and said method includes a step of exposing said cell to said at least one compound of Formula II.

10. A method of inhibiting growth or killing or damaging cancer cells, comprising the step of exposing said cancer cells to a compound of Formula II:

wherein,
W is NR 7 R 8 where R 7 and R 8 may be the same or different and are independently selected from H; C 1 -C 4 alkyl; a saturated heterocycle comprising N bonded directly to Y; and an unsubstituted or substituted guanidine moiety;
and wherein

in Formula II:
R 10 is selected from the group consisting of: C 3 -C 14 alkyl, C 3 -C 14 alkoxyl;
R 11 , R 12 , R 13 and R 14 may be the same or different and are independently selected from: H, C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
R 15 , R 16 , R 17 and R 18 may be the same or different and are independently selected from the group consisting of: C 1 -C 8 alkyl, C 1 -C 8 alkoxyl, C 1 -C 8 alkylcarbonyl, halogen, hydroxyl, amino, nitro, and cyano;
X is C 1 -C 4 alkyl;
Y is C 1 -C 1 alkyl;

and
W is NR 19 R 20 where R 19 and R 20 may be the same or different and are selected from the group consisting of: H, C 1 -C 4 alkyl; a saturated heterocycle comprising N bonded directly to Y, and an unsubstituted or substituted guanidine moiety.

11. The method of claim 10 , wherein said saturated heterocycle is selected from the group consisting of morpholine, pipieridine, piperazine, and pyrrolidine.

12. The method of claim 10 , wherein said cancer cells are of a type selected from the group consisting of: leukemia, lymphoma, sarcoma, neuroblastoma, lung cancer, skin cancer, head squamous cell carcinoma, neck squamous cell carcinoma, prostate cancer, colon cancer, breast cancer, ovarian cancer, cervical cancer, brain cancer, bladder cancer, and pancreatic cancer.

Assignees

• Univ Virginia Commonwealth

Inventors

• Zhang Shijun
• Spiegel Sarah

Classifications

• C07D277/34 Primary

  Oxygen atoms · CPC title

• C07D209/34

  in position 2 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title