Sphingosine kinase inhibitors
View Patent ↗Sphingosine kinases are enzymes that catalyze the biosynthesis of sphingosine-1-phosphate. The invention provides compounds that are effective for inhibition of sphingosine kinase type 1, sphingosine kinase type 2, or both. Certain compounds are selective for sphingosine kinase type 2 relative to sphingosine kinase type 1. Compounds of the invention can be used in treatment of a range of diseases wherein increasing the level of sphingosine-1-phosphate in blood is medically indicated. Diseases that can be treated by administration of an effective dose of a compound of the invention include a neoplastic disease that involves excess vascular growth; macular degeneration or diabetic retinopathy; an allergic disease such as asthma, an inflammatory disease of the eye such as uveitis, scleritis, or vitritis; an inflammatory disease of the kidney; a fibrotic disease; atherosclerosis; or pulmonary arterial hypertension. A compound of the invention can be used to improve the integrity of a vascular barrier in a disease where the vascular barrier is disrupted, such as cancer or Alzheimer's disease.
1. A compound of formula (IA)
wherein
X is phenyl;
R 1 and R 2 are independently selected from the group consisting of H, OH, —(C 1 -C 6 )alkyl-OH, halo, NH 2 , NOH, NHOH, and CN;
or R 1 and R 2 , if bound to adjacent carbon atoms, in combination with the existing carbon-carbon bond represent a double bond between the adjacent carbon atoms;
R 3 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )haloalkyl, CN, and halo;
R 4 is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )haloalkyl, CN, and halo,
wherein one of R 3 and R 4 —CF 3 ;
m=0 or 1;
W is CH 2 , O or, NH;
V is selected from the group consisting of H, (C 1 -C 10 )alkyl, (C 2 -C 12 )alkenyl, —(C 1 -C 10 )alkyl-(C 6 -C 10 )aryl, —(C 2 -C 12 )alkenyl-(C 6 -C 10 )aryl, —(C 1 -C 10 )alkyl-(C 6 -C 10 )aryl-(C 1 -C 10 )alkyl, —(C 1 -C 10 )alkyl-(C 3 -C 8 )cycloalkyl, and —(C 1 -C 10 )alkyl-heterocyclyl containing from 1 to 3 ring heteroatoms selected from N, O, and S;
wherein any aryl is optionally fused to (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl, or heterocyclyl containing from 1 to 3 ring heteroatoms selected from N, O, and S
wherein any alkyl, alkenyl, cycloalkyl, heterocyclyl, or aryl is optionally substituted by 1-4 substituents independently selected from the group consisting of F, Cl, Br, (C 1 -C 6 )alkyl, —O—(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )haloalkyl, and CN;
Y 1 , Y 2 , and Y 3 are independently selected from the group consisting of C, N, NH, O, and S;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein
m is 1; and
Y 1 is N; Y 2 is N and Y 3 is O; or Y 2 is O and Y 3 is N, such that the ring comprising Y 1 , Y 2 , and Y 3 is an oxadiazole ring.
3. The compound of claim 2 , wherein R 1 and R 2 are independently selected from the group consisting of H, OH, CH 2 OH, F, and Cl.
4. The compound of claim 1 , according to formula (IB)
wherein:
R 1 and R 2 are H, or when m=1, one of R 1 and R 2 can be OH;
R 3 is (C 1 -C 4 )alkyl, cyclopropyl, (C 1 -C 2 )fluoroalkyl, cyano, or halo;
R 4 is H, (C 1 -C 4 )alkyl, cyclopropyl, (C 1 -C 2 )fluoroalkyl, cyano, or halo,
wherein one of R 3 and R 4 —CF 3 ;
m=0 or 1;
each of Y 1 , Y 2 , and Y 3 , is independently selected from a group consisting of C, N, NH, O, and S, so as to form a 5-membered heteroaryl ring comprising at least two carbon atoms;
X is phenyl;
W is O or CH 2 ;
V is (C 5 -C 10 )alkyl;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 , wherein the ring comprising Y 1 , Y 2 , and Y 3 , is an oxadiazole or thiadiazole ring.
6. The compound of claim 4 , wherein R 1 and R 2 are both hydrogen.
7. The compound of claim 4 wherein m is 1 and R 2 is OH.
8. A compound that is:
or a pharmaceutically acceptable salt thereof.
9. A compound or a pharmaceutically acceptable salt thereof selected from the following table:
10. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
11. A method of inhibiting a sphingosine kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of claim 1 .
12. A method according to claim 11 wherein the sphingosine kinase is sphingosine kinase type 2 or a combination of sphingosine kinase type 1 and sphingosine kinase type 2.