Fluorine-substituted alkyl phenol compounds and their uses

Abstract

The present invention relates to the synthesis of fluorinated forms of alkyl phenol compounds and their subsequent use as pharmaceutical agents. More specifically, alkyl phenol compounds are fluorinated to increase compound volatility such that the compound may be administered to a mammal, such as a human being, by inhalation. The invention also provides an inhaler (or vaporizer), that can be used for administration of the volatile derivatives of fluorine-substituted alkyl phenol compound. Further, different derivatives of fluorine-substituted alkyl phenol compound can be also administered by other routes as described in this document.

1 . A volatile fluorine-substituted alkyl phenol compound. 
   
   
       2 . A compound comprising an alkyl phenol compound that is not an ester and has at least two fluorine groups. 
   
   
       3 . The compound of  claim 1  or  2 , wherein said compound comprises at least two fluorine groups. 
   
   
       4 . The compound of  claim 1  or  2 , comprising an alkyl phenol molecule and a fluorine substitution of a hydrogen at any one or more carbon-hydrogen positions on the molecule. 
   
   
       5 . The compound of  claim 1  or  2 , comprising an akyl phenol and one or more fluorine substitutions at any one or more of the two meta and para position of the aromatic ring of said alkyl phenol. 
   
   
       6 . The compound of  claim 1  or  2 , wherein the alkyls group is butyl. 
   
   
       7 . The compound of  claim 1  or  2 , wherein the alkyl group is isopropyl. 
   
   
       8 . The compound of  claim 1  or  2 , wherein the alkyl phenol is a diakylphenol. 
   
   
       9 . The compound of  claim 1  or  2 , wherein the alkyl phenol is a diisopropylphenol. 
   
   
       10 . The compound of  claim 1  or  2 , wherein the alkyl phenol is a di-sec-butylphenol. 
   
   
       11 . The compound of  claim 1  or  2 , wherein the alkyl phenol is 2,6-diisopropylphenol. 
   
   
       12 . The compound of  claim 1  or  2 , wherein the alkyl phenol is 2,6-di-sec-butylphenol. 
   
   
       13 . A pharmaceutical composition comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       14 . A pharmaceutical composition comprising the composition of  claim 11  and a pharmaceutically acceptable carrier. 
   
   
       15 . A method for anesthetizing a subject comprising administering to subject a pharmaceutically effective amount of the composition described in  claim 12 . 
   
   
       16 . The method according to  claim 15 , wherein said pharmaceutically effective amount is an amount sufficient to achieve a sedation level of at least 2 on the Ramsay scale. 
   
   
       17 . The method according to  claim 15 , wherein said pharmaceutically effective amount is an amount sufficient to achieve a sedation level of at least 3 on the Ramsay scale. 
   
   
       18 . The method according to  claim 15 , wherein said pharmaceutically effective amount is an amount sufficient to achieve a sedation level of at least 4 on the Ramsay scale. 
   
   
       19 . The method according to  claim 15 , wherein said pharmaceutically effective amount is an amount sufficient to achieve a sedation level of at least 5 on the Ramsay scale. 
   
   
       20 . A method for treating a tissue comprising an excess of free oxygen radicals comprising exposing said tissue to an amount of a composition according to  claim 13 , effective to reduce the amount of free radicals in said tissue compared to a tissue not so treated. 
   
   
       21 . The method according to  claim 20 , wherein said tissue is in a patient with a pathology associated with an excess of free oxygen radicals. 
   
   
       22 . The method according to  claim 21 , wherein said pathology is an inflammatory disease. 
   
   
       23 . The method according to  claim 21 , wherein said pathology is a neurological disease. 
   
   
       24 . The method according to  claim 21 , wherein said pathology is cancer. 
   
   
       25 . The method according to  claim 21 , wherein said pathology is a cerebrovascular disease. 
   
   
       26 . The method according to  claim 21 , wherein said method comprises the step of administering said composition by inhalation. 
   
   
       27 . A method of treating a headache, comprising administering a therapeutically effective amount of the composition of  claim 13  or  14  to a patient. 
   
   
       28 . The method according to  claim 27 , wherein said headache is a migraine. 
   
   
       29 . The method according to  claim 27 , wherein said therapeutically effective amount is an amount effective to reduce one or more symptoms of: pain, visual disturbance, auditory disturbance, and nausea. 
   
   
       30 . An inhaler (or vaporizer) comprising:
 (a) a reservoir comprising a volatile fluorine-substituted alkyl phenol;   (b) an opening for placement in the oral or nasal cavity of a patient, and;   (c) a passageway connecting said reservoir and said opening, wherein a vapor form of said fluorine-substituted alkyl phenol passes through said passageway from said reservoir through said opening into the oral or nasal cavity of said patient for inhalation by said patient.   
   
   
       31 . The inhaler according to  claim 30 , wherein said alkyl is butyl. 
   
   
       32 . The inhaler according to  claim 30 , wherein the alkyl is isopropyl. 
   
   
       33 . The inhaler according to  claim 30 , wherein the alkyl phenol is a dialkylphenol. 
   
   
       34 . The inhaler according to  claim 30 , wherein the alkyl phenol is a diisopropylphenol. 
   
   
       35 . The inhaler according to  claim 30 , wherein the alkyl phenol is a di-sec-butylphenol. 
   
   
       36 . The inhaler according to  claim 30 , wherein the alkyl phenol is 2,6-diisopropylphenol. 
   
   
       37 . The inhaler according to  claim 30 , wherein the alkyl phenol is 2,6-di-sec-butylphenol. 
   
   
       38 . The inhaler according to  claim 30 , wherein the reservoir comprises a liquid form of said volatile fluorine-substituted alkyl phenol. 
   
   
       39 . The inhaler according to  claim 30 , wherein said reservoir comprises an absorbable material comprising said fluorine-substituted alkyl phenol. 
   
   
       40 . A process for preparation of a compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is a C 1  to C 6  linear or branched alkyl, C 1  to C 6  linear or branched fluoroalkyl containing at least one fluorine atom provided that when R 1  and R 5  are both alkyl, R 1  is not equal to R 5    
     comprising the steps of:
 i) reacting an alkyl phenol of the formula: 
 
     
       
         
         
             
             
         
       
       with a halogenation agent to give a haloalkyl phenol of the formula: 
     
     
       
         
         
             
             
         
       
       wherein R 1  is a C 1  to C 6  linear or branched alkyl, C 1  to C 6  linear or branched fluoroalkyl containing at least one fluorine atom provided that when R 1  and R 5  are both alkyl, R 1  is not equal to R 5 ; and 
       wherein X=Cl, Br or I; and 
       ii) reacting the said haloalkyl phenol with a fluoroalkylating agent to give a fluoroalkyl phenol of the formula: 
     
     
       
         
         
             
             
         
       
       wherein Ry= 
     
     
       
         
         
             
             
         
       
     
     and
 wherein R a , R b  and R c  are each independently H, F, straight or branched alkyl chain containing at least one fluorine atom. 
 
   
   
       41 . The process according to  claim 40 , wherein R 1  is selected from the group consisting of CH 3  (methyl), CH 2 CH 3  (ethyl), CH(CH 3 ) 2  (isopropyl), CH 2 CH 2 CH 3  (n-propyl), or CH(CH 3 )CH 2 CH 3  (sec-butyl), CF 3  (trifluoromethyl), CF 2 CF 3  (pentafluoroethyl), CF 2 CF 2 CF 3  (septafluoro-n-propyl), R 2  and R 4  are H (hydrogen) and R 3  and R 5  are independently selected from H, CF 3 , CF 2 CF 3  or CF 2 CF 2 CF 3 . 
   
   
       42 . The process of  claim 40 , wherein said fluoralkyl is selected from the group consisting of 6-trifluoromethyl-2-sec-butylphenol, 6-trifluoromethyl-2-isopropylphenol, 6-Pentafluoroethyl-2-isopropylphenol and 6-Heptafluoro-n-propyl-2-isopropylphenol. 
   
   
       43 . The process of  claim 40 , wherein the said halogenating agent is a bromination or iodination agent. 
   
   
       44 . The process of  claim 43 , wherein the said halogenating agent is selected from the group consisting essentially of Br 2  and CuI. 
   
   
       45 . The process of  claim 43 , wherein the said halogenating agent is CuI. 
   
   
       46 . The process of  claim 40  wherein the said fluoroalkylating agent is selected from the group consisting essentially of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate, sodium heptafluorobutyrate and CF 3 CF 2 COONa (perfluoro sodium propionate). 
   
   
       47 . The process of  claim 46  wherein the said fluoroalkylating agent is methyl 2,2-difluoro-2-(fluorosulfonyl)acetate. 
   
   
       48 . The process of  claim 46  wherein the said fluoroalkylating agent is perfluoro sodium propionate. 
   
   
       49 . The process of  claims 40 ,  41  and  42  further comprising the step of substituting at least one hydrogen atom in the aromatic ring of the fluoroalkyl phenol with a fluorine atom. 
   
   
       50 . The process of  claims 40  and  41 , wherein R 1  and R 5  are both alkyl groups provided that R 1  is not equal to R 5 . 
   
   
       51 . The process of  claims 40  and  41 , wherein said R 1  and said R 5  are interchangeably alkyl and fluoroalkyl.