Method for treating pulmonary arterial hypertension and associated pulmonary arterial hypertension and daily dosing

Abstract

There is a method of treating or preventing pulmonary arterial hypertension (PAH) or associated pulmonary arterial hypertension (APAH) in a patient. The method has the step of systemically administering to the patient a therapeutically effective amount of one or more compounds: (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, or (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, or a combination of the foregoing. There is also a method of treating or preventing PAH or APAH in a patient by systemically administering a therapeutically effective amount of a THP1 inhibitor from about 1 mg/kg/day to about 50 mg/kg/day. There is a method for treating PAH or APAH in a patient with a single daily dose.

What is claimed is: 
     
         1 . A method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient comprising systemically administering to the patient a therapeutically effective amount of a compound selected from the group consisting of (i) (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, (ii) (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and (iii) a combination of the foregoing, wherein the therapeutically effective amount is about 1 mg/kg/day to about 50 mg/kg/day. 
     
     
         2 . The method of  claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally. 
     
     
         3 . The method of  claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally by a dosage form selected from the group consisting of capsules, tablets, powders, and granules. 
     
     
         4 . The method of  claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is administered orally in the form of a liquid. 
     
     
         5 . The method of  claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is administered one to four times per day. 
     
     
         6 . The method of  claim 1 , wherein the compound is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 1 , wherein the compound is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. 
     
     
         8 . The method of  claim 1 , wherein the compound is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 1 , wherein the compound is (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid. 
     
     
         10 . The method of  claim 1 , wherein the compound is in a substantially amorphous form. 
     
     
         11 . The method of  claim 1 , wherein the compound is in a substantially crystalline form. 
     
     
         12 . The method of  claim 11 , wherein the compound is a crystalline polymorph having a XRPD plot corresponding to  FIG.  1   . 
     
     
         13 . The method of  claim 11 , wherein the compound is a crystalline polymorph having a XRPD plot corresponding to Table 1 or Table 2. 
     
     
         14 . The method of  claim 11 , wherein the compound is a crystalline polymorph exhibiting a characteristic XRPD peak at 19.05±0.20 (° 2θ). 
     
     
         15 . The method of  claim 1 , wherein the compound is systemically administered in the form of a composition including the compound and a pharmaceutically acceptable excipient. 
     
     
         16 . A method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient comprising systemically administering to the patient a therapeutically effective amount of a THP1 inhibitor from about 1 mg/kg/day to about mg/kg/day. 
     
     
         17 . A method of treating or preventing pulmonary arterial hypertension or associated pulmonary arterial hypertension in a patient comprising administering to the patient a therapeutically effective amount of a compound selected from the group consisting of (i) (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, (ii) (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroeth-oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and (iii) a combination of the foregoing, wherein the compound or pharmaceutically acceptable salt thereof is administered once per day. 
     
     
         18 . The method of  claim 17 , wherein the compound is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 18 , wherein the compound is a crystalline polymorph having a XRPD plot corresponding to Table 1 or Table 2. 
     
     
         20 . The method of  claim 17 , wherein the compound is (S)-ethyl 8-(2-amino-6-((R)-1-(5-chloro-[1,1′-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate or a pharmaceutically acceptable salt thereof, wherein the compound is a crystalline polymorph having a XRPD plot corresponding to  FIG.  1   , wherein the therapeutically effective amount is about 1 mg/kg/day to about 50 mg/kg/day.