Crystalline spirocyclic compound, a dosage form containing, a method for using in treatment of disease, and a method for recrystallizing

Abstract

There is a crystalline compound of (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 that exhibits an XRPD pattern having a characteristic peak at 19.05±0.20 (° 2θ). There is also a pharmaceutical composition containing the compound. There is also a dosage form containing the crystalline compound and one or more pharmaceutically acceptable excipients. There is also a method for crystallizing/recrystallizing the compound. There is also a method for treating or preventing a disease with the compound.

1 . A crystalline compound of (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 that exhibits an XRPD pattern with characteristic peaks at the following: 
       
         
           
                 
                 
                 
               
                     
                 
                   Peak position (°2θ) 
                   d space (Å) 
                   Intensity (%) 
                 
                     
                 
                     
                 
                 
                 
                 
               
                    8.78 ± 0.20 
                   10.077 ± 0.235  
                   90 
                 
                   14.87 ± 0.20 
                   5.956 ± 0.081 
                   71 
                 
                   15.39 ± 0.20 
                   5.757 ± 0.075 
                   72 
                 
                   15.61 ± 0.20 
                   5.677 ± 0.073 
                   78 
                 
                   18.45 ± 0.20 
                   4.809 ± 0.052 
                   70 
                 
                   19.05 ± 0.20 
                   4.658 ± 0.049 
                   100. 
                 
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . A crystalline compound of (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 that exhibits an XRPD pattern having a characteristic peak at 19.05±0.20 (° 2θ). 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . A pharmaceutical composition suitable for administration to a patient, comprising: the crystalline compound of  claim 1  and one or more pharmaceutically acceptable excipients. 
     
     
         6 . (canceled) 
     
     
         7 . A method of lowering peripheral serotonin in a patient in need thereof, comprising administering to the patient an effective amount of the crystalline compound of  claim 1 . 
     
     
         8 . A method of treating or preventing a disease in a patient, wherein the disease is selected from the group consisting of bone disease, cardiovascular disease, metabolic disease, pulmonary disease, gastrointestinal disease, liver disease, cancer, and inflammatory disease, the method comprising administering to said patient a therapeutically effective amount of the crystalline compound of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein the disease is cardiovascular disease, and wherein the cardiovascular disease is pulmonary arterial hypertension (PAH). 
     
     
         10 . The method of  claim 9 , wherein the PAH is associated pulmonary arterial hypertension (APAH). 
     
     
         11 . The method of  claim 8 , wherein the disease is cancer, wherein the cancer is carotenoid cancer. 
     
     
         12 . The method of  claim 8 , wherein the disease is gastrointestinal disease, wherein the gastrointestinal disease is carcinoid syndrome. 
     
     
         13 . A dosage form suitable for administration to a patient, the dosage form comprising: the crystalline compound of  claim 1  is present in a proportion that is 90 wt % or more by weight of any (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 present. 
     
     
         14 . The dosage form of  claim 13 , wherein the crystalline compound is present in a proportion that is 95 wt % or more by weight of any (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 present. 
     
     
         15 . A dosage form suitable for administration to a patient, the dosage form comprising: the crystalline compound of  claim 1  in a proportion that is about 20 wt % or more by weight of the dosage form. 
     
     
         16 . The dosage form of  claim 13 , wherein the dosage form has an immediate release profile. 
     
     
         17 . The dosage form of  claim 13 , wherein the dosage form is an inhalant. 
     
     
         18 . A method of crystallizing or recrystallizing (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, comprising:
 (A) contacting the (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 with an amount of heptane sufficient to form a suspension thereof; and 
 (B) removing the heptane from the suspension or filtrating the suspension to form crystalline (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. 
 
     
     
         19 . A method of crystallizing or recrystallizing (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, comprising:
 (A) dissolving the (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 in an amount of methyl tert-butyl ether following by introducing an amount of heptane sufficient to form a suspension thereof; and 
 (B) removing the heptane from the suspension or filtrating the suspension to form crystalline (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.