US2023225985A1PendingUtilityA1

Terpenophenolic compounds and their use

Assignee: PHYTOTHERAPEUTIX LTDPriority: Mar 31, 2020Filed: Sep 30, 2022Published: Jul 20, 2023
Est. expiryMar 31, 2040(~13.7 yrs left)· nominal 20-yr term from priority
C07C 39/23A61K 31/05A61P 25/08C07C 37/14C07C 37/003C07C 39/15C07B 2200/09C07C 29/32C07C 33/38C07C 2601/16
60
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Claims

Abstract

The present disclosure describes terpenophenolic compounds and their use in medicine. The present disclosure further describes perrottetinene-like compounds, the manufacture thereof, formulations containing same and their use in medicine. Such compounds include (1′R,2′R)-5′-methyl-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET) or (1′R,2′R)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET-OH).

Claims

exact text as granted — not AI-modified
1 . A method for treating a medical condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound, which is any one selected from the group consisting of:
 5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol having the following structure   
       
         
           
           
               
               
           
         
         4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol having the following structure 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the compound is 5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET) having the following structure 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         3 . The method according to  claim 1 , wherein the compound is 4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET-OH) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         4 . The method according to  claim 1 , wherein the compound is (1′R,2′R)-5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) trans-CBD-PET) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         5 . The method according to  claim 1 , wherein the compound is (1′S,2′S)-5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol) ((+)-cis-CBD-PET) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         6 . The method according to  claim 1 , wherein the compound is (1′R,2′S)-5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) cis-CBD-PET) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof for use as a medicament. 
       
     
     
         7 . The method according to  claim 1 , wherein the compound is (1′S,2′R)-5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol) ((+)-cis-CBD-PET) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         8 . The method according to  claim 1 , wherein the compound is (1′R,2′R)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) trans-CBD-PET-OH) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         9 . The method according to  claim 1 , wherein the compound is (1′S,2′S)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((+) cis CBD-PET-OH) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         10 . The method according to  claim 1 , wherein the compound is (1′R,2′S)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) cis-CBD-PET-OH) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         11 . The method according to  claim 1 , wherein the compound is (1′S,2′R)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((+) cis CBD-PET-OH) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         12 . The method according to  claim 1 , wherein the compound is an o-isomer of trans-CBD-PET having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         13 . The method according to  claim 1 , wherein the compound is o-isomer of trans-CBD-PET-OH having a structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate thereof. 
       
     
     
         14 . The method according to  claim 1 , wherein the compound is present as an isomer with a purity of at least 90% for use as a medicament. 
     
     
         15 . The method according to  claim 1 , wherein the compound is present as a racemic mix of a respective (+) or (−) trans or (+) or (−) cis form for use as a medicament. 
     
     
         16 . The method according to  claim 1 , wherein the compound is a p isomer with a purity of at least 90% for use as a medicament. 
     
     
         17 . The method according to  claim 12 , wherein the compound is an o isomer with a purity of at least 90% for use as a medicament. 
     
     
         18 . The method according to  claim 16 , wherein the isomer of the compound is at greater than 95% purity for use as a medicament. 
     
     
         19 . The method according to  claim 1 , wherein the compound is a mixture of both p and o isomers for use as a medicament. 
     
     
         20 . The method according to  claim 19 , wherein the two isomers forming the mixture of the compound are together present at greater than 95% purity for use as a medicament. 
     
     
         21 - 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising a compound, which is any one selected from the group consisting of:
 (a) 4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET-OH)   
       
         
           
           
               
               
           
         
       
       and
 (b) (1′R,2′R)-4 (4 hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) trans-CBD-PET-OH) 
 
       
         
           
           
               
               
           
         
       
       and
 (c) compound (1′S,2′S)-4 (4 hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((+) cis CBD-PET-OH) 
 
       
         
           
           
               
               
           
         
       
       and
 (d) (1′R,2′S)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((−) cis-CBD-PET-OH) 
 
       
         
           
           
               
               
           
         
       
       and
 (e) (1′S,2′R)-4-(4-hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol ((+) cis CBD-PET-OH) 
 
       
         
           
           
               
               
           
         
       
       and
 (f) an o-isomer of trans-CBD-PET-OH having a structure: 
 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or hydrate of one of (a) through (f) thereof; 
         or 
         (g) 5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol having the following structure 
       
       
         
           
           
               
               
           
         
         together with one or more pharmaceutically acceptable excipient(s). 
       
     
     
         35 .- 44 . (canceled) 
     
     
         45 . A method of manufacturing a perrottetinene-like compound comprising reacting menthadienol with dihydropinosylvin or dihydroresvratrol, suitably in the presence of a Lewis acid. 
     
     
         46 . The method according to  claim 45 , wherein the Lewis acid is a zinc based acid. 
     
     
         47 . The method according to  claim 46 , wherein the zinc based acid is zinc triflate. 
     
     
         48 . The method according to  claim 47 , wherein the initial amount of the zinc triflate is at 0.01-0.05 mole equivalent to menthadienol. 
     
     
         49 . The method according to  claim 45  to  48 , wherein the reaction of menthadienol with dihydropinosylvin or dihydroresvratrol takes place at or under the temperature ranging 80-120° C. 
     
     
         50 . The method according to  claim 45  to  48 , wherein the perrottetinene-like compound is (1′R,2′R)-5′-methyl-4-phenethyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET) when menthadienol is reacted with dihydropinosylvin. 
     
     
         51 . The method according to  claim 45  to  48 , wherein the perrottetinene-like compound is (1′R,2′R)-4 (4 hydroxyphenethyl)-5′-methyl-2′-(prop-1-ene-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (CBD-PET-OH) when menthadienol is reacted with dihydroresvratrol. 
     
     
         52 . The method of  claim 51 , further comprising the step of producing dihydroresvratrol by hydrogenating trans-resveratrol in the presence of palladium on carbon (Pd/C). 
     
     
         53 . The method according to  claim 45 , wherein menthadienol is p-menthadienol

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