Dialkyl tryptamines and their therapeutic uses

Abstract

The disclosure relates to a compound of formula (I): The disclosure also relates to a compound of formula (Ia): The disclosure relates to compositions comprising, consisting essentially of, or consisting of a compound of formula (I) or formula (Ia) and an excipient. The disclosure also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) or formula (Ia) where the excipient is a pharmaceutically acceptable carrier. The disclosure further relates to therapeutic uses of compounds of formula (I) or formula (Ia).

The claimed invention is: 
     
         1 . A method of administering psilocin comprising:
 administering a therapeutically effective amount of a psilocin prodrug of formula (I) or formula (Ia) to a subject in need thereof, 
 wherein the ratio of psilocin plasma concentration (A) to psilocin prodrug concentration (B) is greater than 10 at 1 hr. after the administration of the psilocin prodrug of formula (I) or formula (Ia); wherein formula (I) is:
                     
 wherein: 
 R 1  and R 2  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl; 
 one of R 3  and R 4  is hydrogen and the other of R 3  and R 4  is —OR 5 , —OC(O)R 5 , —OC(O)OR 5 , and —OSO 2 R 5 ; 
 R 5  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and 
 R 6 , R 7 , and R 8  are each independently selected from hydrogen or a C 1 -C 6  alkyl, or a pharmaceutically acceptable acid-addition salt thereof; and formula (Ia) is:
                     
 wherein: 
 R 1a  and R 2a  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl; 
 R 3a  and R 4a  are each independently selected from hydrogen, —OR 5a , —OC(O)R 5a , —OC(O)OR 5a , and —OSO 2 R 5a ; 
 R 5a  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and 
 R 6a , R 7a  and R 8a  are each independently selected from hydrogen or a C 1 -C 6  alkyl; 
 R 9a  is hydrogen; and 
 X 2-  is a pharmaceutically-acceptable dianion. 
 
 
     
     
         2 . The method of  claim 1 , wherein the therapeutically effective amount of the psilocin prodrug of formula (I) or formula (Ia) is administrated as an oral dosage composition. 
     
     
         3 . The method of  claim 1 , wherein the ratio of psilocin plasma concentration (A) to psilocin prodrug concentration (B) is greater than 20 at 1 hr. after the administration of the psilocin prodrug of formula (I) or formula (Ia). 
     
     
         4 . The method of  claim 1 , wherein the ratio of B:A does not exceed 0.1 at any time after 0.1 hours following the administration of the psilocin prodrug of formula (I) or formula (Ia). 
     
     
         5 . The method of  claim 1 , wherein the psilocin prodrug is a psilocin prodrug of formula (I). 
     
     
         6 . The method of  claim 1 , wherein the psilocin prodrug is a psilocin prodrug of formula (Ia). 
     
     
         7 . The method of  claim 5 , wherein the psilocin prodrug of formula (I) is 4-acetoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method of  claim 6 , wherein the psilocin prodrug of formula (Ia) is a pharmaceutically acceptable dianion salt of 4-acetoxy-N,N-dimethyltryptamine. 
     
     
         9 . The method of  claim 1 , wherein 1 to 70 mg of the psilocin prodrug of formula (I) or formula (Ia) is administered to produce a maximum plasma concentration (Cmax) of psilocin of greater than 10 ng/mL within 0.1 to 1.0 hours after administration of the psilocin prodrug of formula (I) or formula (Ia). 
     
     
         10 . The method of  claim 1 , wherein 1 to 5 mg of the psilocin prodrug of formula (I) or formula (Ia) is administered. 
     
     
         11 . The method of  claim 1 , wherein 5 to 50 mg of the psilocin prodrug of formula (I) or formula (Ia) is administered. 
     
     
         12 . The method of  claim 1 , wherein 10 to 30 mg of the psilocin prodrug of formula (I) or formula (Ia) is administered. 
     
     
         13 . The method of  claim 1 , wherein the plasma concentration of the psilocin prodrug of formula (I) or formula (Ia) is less than 2 ng/mL at the psilocin Tmax. 
     
     
         14 . A method of treating a disorder comprising:
 administering a therapeutically effective amount of a psilocin prodrug of formula (I) or formula (Ia) to a subject in need thereof, 
 wherein the ratio of a psilocin plasma concentration (A) to a psilocin prodrug concentration (B) is greater than 10 at 1 hr. after the administration of the psilocin prodrug of formula (I) or formula (Ia), wherein formula (I) is:
                     
 wherein:
 R 1  and R 2  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl; 
 one of R 3  and R 4  is hydrogen and the other of R 3  and R 4  is —OR 5 , —OC(O)R 5 , —OC(O)OR 5 , and —OSO 2 R 5 ; 
 R 5  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and 
 R 6 , R 7 , and R 8  are each independently selected from hydrogen or a C 1 -C 6  alkyl; 
 
 or a pharmaceutically acceptable acid-addition salt thereof; and formula (Ia) is:
                     
 
 
 wherein: 
 R 1a  and R 2a  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl; 
 R 3a  and R 4a  are each independently selected from hydrogen, —OR 5a , —OC(O)R 5a , —OC(O)OR 5a , and —OSO 2 R 5a ; 
 R 5a  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and 
 R 6a , R 7a  and R 8a  are each independently selected from hydrogen or a C 1 -C 6  alkyl; 
 R 9a  is hydrogen; and 
 X 2-  is a pharmaceutically-acceptable dianion. 
 
 
     
     
         15 . The method of  claim 14 , wherein the disorder is selected from the group consisting of anxiety, post-traumatic stress disorder, inflammation, pain, and a neurological disorder. 
     
     
         16 . A method of treating a neurological disorder comprising administering an oral dosage form comprising a therapeutically effective amount of a psilocin prodrug of formula (I) or formula (Ia), wherein the plasma concentration of the psilocin prodrug of formula (I) or formula (Ia) is less than 1 ng/mL within 30 minutes after administration of the psilocin prodrug of formula (I) or formula (Ia); wherein formula (I) is:
                       wherein:   R 1  and R 2  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl;   one of R 3  and R 4  is hydrogen and the other of R 3  and R 4  is —OR 5 , —OC(O)R 5 , —OC(O)OR 5 , and —OSO 2 R 5 ;   R 5  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and   R 6 , R 7 , and R 8  are each independently selected from hydrogen or a C 1 -C 6  alkyl; 
or a pharmaceutically acceptable acid-addition salt thereof; and formula (Ia) is:
                     
 wherein 
 R 1a  and R 2a  are each independently a C 1 -C 6  alkyl or a C 2 -C 6  alkenyl; 
 R 3a  and R 4a  are each independently selected from hydrogen, —OR 5a , —OC(O)R 5a , —OC(O)OR 5a , and —OSO 2 R 5a ; 
 R 5a  is a C 1 -C 6  alkyl or a substituted or unsubstituted aryl; and 
 R 6a , R 7a  and R 8a  are each independently selected from hydrogen or a C 1 -C 6  alkyl; 
 R 9a  is hydrogen; and 
 X 2-  is a pharmaceutically-acceptable dianion. 
 
     
     
         17 . The method of  claim 16 , wherein the psilocin prodrug of formula (I) is 4-acetoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 1 , wherein formula (Ia) is with the proviso that when R 3a  is —OC(O)R 5a  and R 4a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are methyl or one of R 1a  and R 2a  is ethyl and the other of R 1a  and R 2a  is propyl; and
 with the proviso that when R 4a  is —OR 5a  and R 3a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are propyl or both R 1a  and R 2a  are allyl. 
 
     
     
         19 . The method of  claim 14 , wherein formula (Ia) is with the proviso that when R 3a  is —OC(O)R 5a  and R 4a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are methyl or one of R 1a  and R 2a  is ethyl and the other of R 1a  and R 2a  is propyl; and
 with the proviso that when R 4a  is —OR 5a  and R 3a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are propyl or both R 1a  and R 2a  are allyl. 
 
     
     
         20 . The method of  claim 16 , wherein formula (Ia) is with the proviso that when R 3a  is —OC(O)R 5a  and R 4a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are methyl or one of R 1a  and R 2a  is ethyl and the other of R 1a  and R 2a  is propyl; and
 with the proviso that when R 4a  is —OR 5a  and R 3a , R 6a , R 7a , R 8a , and R 9a  are hydrogen, then R 5a  is not methyl when either both R 1a  and R 2a  are propyl or both R 1a  and R 2a  are allyl.