Amino acid derived prodrugs of propofol, compositions and uses thereof

Abstract

The present invention provides propofol prodrugs, methods of making propofol prodrugs, pharmaceutical compositions of propofol prodrugs and methods of using propofol prodrugs and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as migraine headache pain and post-chemotherapy or post-operative surgery nausea and vomiting.

1 - 12 . (canceled) 
   
   
       13 . A compound of Formula (I) is provided: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, wherein: 
       R 1  is selected from the group consisting of hydrogen, (R 5 NH(CHR 4 ) p C(O))—, R 6 —, R 6 C(O)—, and R 6 OC(O)—; 
       R 2  is —OR 7 ; 
       p is 1 or 2; 
       each R 4  is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; or when R 4  and R 5  are attached to adjacent atoms then R 4  and R 5  together with the atoms to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
       R 5  is selected from the group consisting of hydrogen, R 6 —, R 6 C(O)—, and R 6 OC(O)—; 
       R 6  is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl, and heteroarylalkyl; and 
       R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, heteroaryl, substituted heteroaryl, and heteroarylalkyl. 
     
   
   
       14 . The compound of  claim 13 , wherein:
 R 1  is [R 5 NH(CHR 4 ) p C(O)]—;   p is 1;   R 5  is hydrogen; and   R 4  is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkanyl, and substituted heteroarylalkanyl.   
   
   
       15 . The compound of  claim 13 , wherein:
 R 1  is [R 5 NH(CHR 4 ) p C(O)]—;   p is 1;   R 5  is hydrogen; and   R 4  is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, t-butyl, cyclopentyl, cyclohexyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2 , —CH 2 CH 2 CH 2 NHC(NH)NH 2 , phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, and 3-indolylmethyl.   
   
   
       16 . The compound of  claim 13 , wherein R 7  is selected from the group consisting of hydrogen, C 1-4  alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl. 
   
   
       17 . The compound of  claim 15 , wherein R 7  is selected from the group consisting of hydrogen, C 1-4  alkyl, phenyl, substituted phenyl, benzyl, and substituted benzyl. 
   
   
       18 . The compound of  claim 15 , wherein the α-carbon of the N-terminal amino acid residue is of the L-configuration. 
   
   
       19 . The compound of  claim 15 , wherein the α-carbon of the N-terminal amino acid residue is of the D-configuration. 
   
   
       20 . The compound of  claim 15 , wherein the α-carbon of the C-terminal amino acid residue is of the L-configuration. 
   
   
       21 . The compound of  claim 15 , wherein the α-carbon of the C-terminal amino acid residue is of the D-configuration. 
   
   
       22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 13  and a pharmaceutically acceptable vehicle. 
   
   
       23 . The composition of  claim 22 , for treatment of nausea and vomiting comprising a 5-HT 3  antagonist, a corticosteroid, or a combination thereof. 
   
   
       24 . The composition of  claim 23 , wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, and palonosetron; and the corticosteroid is dexamethasone. 
   
   
       25 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to  claim 17  and a pharmaceutically acceptable vehicle. 
   
   
       26 . The composition of  claim 25 , for treatment of nausea and vomiting comprising a 5-HT 3  antagonist, a corticosteroid, or a combination thereof. 
   
   
       27 . The composition of  claim 26 , wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, and palonosetron; and the corticosteroid is dexamethasone. 
   
   
       28 . A method for treating migraine, nausea, vomiting, anxiety, seizures, convulsions, trauma of the central nervous system, and neurodegenerative conditions selected from the group consisting of Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Pick disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 22 . 
   
   
       29 . A method for treating migraine, nausea, vomiting, anxiety, seizures, convulsions, trauma of the central nervous system, and neurodegenerative conditions g selected from the group consisting of Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Pick disease in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 25 . 
   
   
       30 . A method for treating migraine in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 22 . 
   
   
       31 . A method for treating migraine in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 25 . 
   
   
       32 . A method for treating nausea and vomiting in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 22 . 
   
   
       33 . The composition of  claim 32 , comprising a 5-HT 3  antagonist, a corticosteroid, or a combination thereof. 
   
   
       34 . The composition of  claim 33 , wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, and palonosetron; and the corticosteroid is dexamethasone. 
   
   
       35 . A method for treating nausea and vomiting in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition according to  claim 25 . 
   
   
       36 . The composition of  claim 35 , comprising a 5-HT 3  antagonist, a corticosteroid, or a combination thereof. 
   
   
       37 . The composition of  claim 36 , wherein the 5-HT 3  antagonist is selected from the group consisting of ondansetron, granisetron, dolasetron, and palonosetron; and the corticosteroid is dexamethasone.