Sphingosine 1-phosphate receptor antagonists
The present invention relates to sphingosine-1-phosphate (S1P) receptors and compounds of the general formula: that are useful in the treatment and prevention of conditions associated with such receptors. More specifically, the present invention relates to the synthesis and use of sphingosine 1-phosphate receptor 2 (S1P 2 ) antagonists that are useful in the treatment of cancer, atherosclerosis, diabetic retinopathy, and other inflammatory diseases. Among these inflammatory diseases that could be treated with these S1P 2 antagonist are those characterized by fibrosis including chronic lung disease, chronic kidney and liver disease, chronic heart disease, and skin diseases such as sclerosis/scleroderma. The S1P 2 antagonists can also be used in the treatment of glioblastoma multiforme (brain cancer), pediatric neuroblastoma, and other cancers.
1. A sphingosine-1-phosphate receptor 2 (S1P 2 ) antagonist compound of the formula:
wherein:
R 1 is selected from the group consisting of -allyl, —CH 3 , and —CH 2 CH 2 CH 2 OH,
R 2 is selected from the group consisting of H, —CH 2 CO 2 H, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CONH 2 , and —CH 2 CO 2 Et, and
R 3 is selected from the group consisting of 4-substituted-2,6-dichloropyridine, 4-substituted-2-chloro-6-hydroxyethyl pyridine, 4-substituted-2-chloro-6-hydroxypropyl pyridine, 4-substituted-2-(aminoethyl)-6-chloro pyridine, 4-substituted-2-(aminoethylmethyl)-6-chloro pyridine, and 5-substituted-2,3-dichloro thiophene,
with the proviso that R 1 is not —CH 3 if R 2 is H,
or any physiologically acceptable salts thereof.
2. The compound of claim 1 , wherein:
R 1 is -allyl,
R 2 is H, and
R 3 is 4-substituted-2,6-dichloropyridine,
or any physiologically acceptable salts thereof.
3. The compound of claim 1 , wherein:
R 1 is —CH 3 ,
R 2 is —CH 2 CH 2 OH, and
R 3 is 4-substituted-2,6-dichloropyridine,
or any physiologically acceptable salts thereof.
4. The compound of claim 1 , wherein:
R 1 is —CH 3 ,
R 2 is —CH 2 CH 2 OH,
R 3 is 4-substituted-2-chloro-6-hydroxyethyl pyridine
or any physiologically acceptable salts thereof.
5. The compound of claim 1 , wherein:
R 1 is —CH 3 ,
R 2 is —CH 2 CH 2 OH,
R 3 is 4-substituted-2-chloro-6-hydroxypropyl pyridine,
or any physiologically acceptable salts thereof.
6. A method of treating a subject suffering from lung fibrosis, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
7. A pharmaceutical composition comprising one or more physiologically acceptable carriers or excipients and a sphingosine-1-phosphate receptor 2 (S1P 2 ) antagonist compound of the formula:
wherein:
R 1 is selected from the group consisting of -allyl, —CH 3 , and —CH 2 CH 2 CH 2 OH,
R 2 is selected from the group consisting of H, —CH 2 CO 2 H, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CONH 2 , and —CH 2 CO 2 Et, and
R 3 is selected from the group consisting of 4-substituted-2,6-dichloropyridine, 4-substituted-2-chloro-6-hydroxyethyl pyridine, 4-substituted-2-chloro-6-hydroxypropyl pyridine, 4-substituted-2-(aminoethyl)-6-chloro pyridine, 4-substituted-2-(aminoethylmethyl)-6-chloro pyridine, and 5-substituted-2,3-dichloro thiophene,
with the proviso that R 1 is not —CH 3 if R 2 is H,
or any physiologically acceptable salts thereof.
8. The pharmaceutical composition of claim 7 , wherein:
R 1 is -allyl,
R 2 is H, and
R 3 is 4-substituted-2,6-dichloropyridine.
9. The pharmaceutical composition of claim 7 , wherein:
R 1 is —CH 3 ,
R 2 is —CH 2 CH 2 OH, and
R 3 is 4-substituted-2-chloro-6-hydroxyethyl pyridine.
10. The pharmaceutical composition of claim 7 , further comprising an additional pharmacological agent selected from the group consisting of cytotoxic agents, hormones, non-steroidal anti-inflammatory drugs (NSAIDs), and any mixtures thereof.
11. The pharmaceutical composition of claim 7 , further comprising a steroidal anti-inflammatory drug.
12. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is formulated for administration by a route selected from the group consisting of inhalational, insufflation, oral, buccal, parenteral and rectal.
13. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is formulated for administration by a route selected from the group consisting of inhalational, insufflation, oral, buccal, parenteral and rectal.
14. The pharmaceutical composition of claim 7 , further comprising a chemotherapeutic agent.