Endothelin receptor antagonists
View Patent ↗This invention relates to novel endothelin receptor antagonists, derivatives, acceptable acid addition salts, solvates, hydrates and polymorphs thereof. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by compounds that block the endothelin signaling pathway that leads to vasoconstriction and in particular those diseases or conditions beneficially treated by endothelin receptor antagonists.
1. A method of treating a subject suffering from disease or condition selected from pulmonary arterial hypertension, interstitial lung disease, pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and Eisenmenger's syndrome, comprising the step of administering to said patient an effective amount of a compound of the formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
each Y is independently selected from hydrogen or deuterium, and Y 2a is additionally selected from OH;
each Z is independently selected from hydrogen, deuterium, and fluorine; and
at least one Y or Z is deuterium.
2. The method of claim 1 , wherein the disease or condition is pulmonary arterial hypertension.
3. The method of claim 2 , comprising the additional step of co-administering to the patient a second therapeutic agent selected from epoprostenol treprostinil, iloprost, and beraprost.
4. The method of claim 1 , comprising the additional step of co-administering to the patient a second therapeutic agent, wherein the second therapeutic agent is sildenafil and the disease or condition is pulmonary arterial hypertension or Eisenmenger's syndrome.
5. The method of claim 1 , wherein each Y 1 of formula (I) is simultaneously deuterium.
6. The method of claim 1 , wherein each Y 1 of formula (I) is simultaneously hydrogen.
7. The method according to claim 1 , wherein Y 2b , Y 2c , Y 2d ,Y 2e , Y 2f , Y 2g ,Y 2h , and Y 2i of formula (I) are the same.
8. The method of claim 7 , wherein Y 2a , Y 2b , Y 2c , Y 2d , Y 2e , Y 2f , Y 2g , Y 2h , and Y 2i of formula (I) are the same.
9. The method of claim 7 , wherein Y 2a of formula (I) is OH.
10. The method of claim 7 , wherein Y 2b , Y 2c , Y 2d , Y 2e , Y 2f , Y 2g , Y 2h , and Y 2i of formula (I) are simultaneously deuterium.
11. The method of claim 7 , wherein Y 2b , Y 2c , Y 2d , Y 2e , Y 2f , Y 2g , Y 2h , and Y 2i f formula (I) are simultaneously hydrogen.
12. The method according to any one of claims 1 or 5 to 11 , wherein Z 1a and Z 1b of formula (I) are simultaneously deuterium.
13. The method according to any one of claims 1 or 5 to 11 , wherein Z 1a and Z 1b of formula (I) are simultaneously hydrogen.
14. The method according to any one of claims 1 or 5 to 11 , wherein Z 1a and Z 1b of formula (I) are simultaneously fluorine.
15. The method of claim 1 , wherein the compound is selected from any one of the compounds below:
or a pharmaceutically acceptable salt thereof.
16. The method according to claim 1 , wherein for compounds of formula (I) any atom not specified as deuterium is present in its natural isotopic abundance.
17. The method according to claim 1 , wherein the compound of formula (I) is selected from:
or a pharmaceutically acceptable salt of any of the foregoing.