IP Library › Patent Application 19064963

Patent Application

App. No. 19/064,963

PRODRUGS OF RILUZOLE AND THEIR METHOD OF USE

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Patent No.: US None
App. No.: 19/064,963

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Abstract

Pharmaceutical compositions of the invention include substituted riluzole prodrugs useful for the treatment of cancers including melanoma, breast cancer, brain cancer, and prostate cancer through the release of riluzole. Prodrugs of riluzole have enhanced stability to hepatic metabolism and are delivered into systemic circulation by oral administration, and then cleaved to release riluzole in the plasma via either an enzymatic or general biophysical release process.

Claims (304)

1 . A compound having formula (I):

including enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes thereof, wherein:

R 1 is selected from the group consisting of C 1 -C 6 fluoroalkyl, OR 2 , (CR 6a R 6b ) m NHR 7 , CR 10a R 10b NR 11 R 12 ,

R 2 is selected from the group consisting of CH 2 (CH 2 ) n NR 3a R 3b ,

R 3a and R 3b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and CO 2 R 4 ;

R 3a and R 3b cannot both be C 1 -C 6 alkyl;

R 3a and R 3b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR, S, and SO 2 ;

n is 1 or 2;

R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted phenyl, and optionally substituted benzyl;

R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

R 6a and R 6b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 7 branched alkyl, optionally substituted C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

R 6a and R 6b are taken together with the atom to which they are bound to form an optionally substituted 6 membered ring;

m is 1, 2, or 3;

R 7 is selected from the group consisting of COCR 8a R 8b (NHR 9 ),

R 8a and R 8b are at each occurrence independently selected from the group consisting of hydrogen, CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH(OH)CH 3 , CH 2 Ph, CH 2 (4-OH-Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 ;

R 9 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

Y is at each occurrence independently selected from the group consisting of H 2 or O;

R 10a and R 10b are at each occurrence independently selected from the group consisting of hydrogen, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (4-OH-Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 (CCH), CH 2 (cyclohexyl), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 ;

R 10a and R 10b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;

R 11 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 2 -C 6 alkynyl;

R 10a and R 11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R 12 is not hydrogen;

R 10b and R 11 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom, and R 12 is not hydrogen;

R 12 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, COCR 13a R 13b NR 15a R 15b , COCR 13a R 13b OR 14 SO 2 CR 13a R 13b NR 15a R 15b , COCR 13a R 13b NHSO 2 R 15a

and (CR 19a R 19b ) q NHR 20 , and when R 12 is hydrogen, R 11 cannot be hydrogen;

R 11 and R 12 are taken together with the atom to which they are bound to form an optionally substituted four to six membered saturated heterocyclic ring containing a nitrogen atom and optionally containing an additional heteroatom from the group consisting of N and O;

R 13a and R 13b are at each occurrence independently selected from the group consisting of hydrogen, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 ;

R 13a and R 13b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated carbocyclic ring;

R 13a and R 13b are taken together with the atom to which they are bound to form an optionally substituted six membered saturated heterocyclic ring with one 0 atom within the ring;

R 13a and R 14 are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;

R 13a and Ru 15a are taken together with the atoms to which they are bound to form an optionally substituted four to six membered ring containing one nitrogen atom;

Y 1 is at each occurrence independently selected from the group consisting of H 2 , O, and —H/—OCH 2 Ph;

R 14 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

R 15a and R 15b are at each occurrence independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl C 1 -C 6 fluoroalkyl, COR 21 , CH 2 R 21 , SO 2 R 22 , an optionally substituted four to six membered saturated heterocyclic ring containing a heteroatom selected from the group consisting of NR 24 and O, COCHR 23 NH 2 ,

R 15a and R 15b are taken together with the atom to which they are bound to form an optionally substituted three to six membered saturated heterocyclic ring consisting of two to five carbon atoms and a member selected from the group consisting of O, NR, S, and SO 2 ;

R 16 is at each occurrence independently selected from the group consisting of CH 2 , O, C═O, and NH;

R 17 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

R 18 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

R 17 and R 18 are taken together with the atoms to which they are bound to form an optionally substituted five or six membered ring containing two nitrogen atoms;

R 19a and R 19b are at each occurrence independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 7 branched alkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 2 -C 6 alkenyl, and optionally substituted C 2 -C 6 alkynyl;

R 19a and R 19b are taken together with the atom to which they are bound to form an optionally substituted 3 to 6 membered carbocyclic ring;

R 20 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, and C 2 -C 6 alkynyl;

q is 1, or 2;

R 21 is at each occurrence independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 fluoroalkyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 22 is at each occurrence independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl;

R 23 is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CCH, CH(CH 3 ) 2 , CH 2 CH(CH 3 ) 2 , CH(CH 3 )CH 2 CH 3 , CH 2 OH, CH 2 OCH 2 Ph, CH 2 CH 2 OCH 2 Ph, CH(OH)CH 3 , CH 2 Ph, CH 2 (cyclohexyl), CH 2 (4-OH-Ph), (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 )NH, CH 2 (3-indole), CH 2 (5-imidazole), CH 2 CO 2 H, CH 2 CH 2 CO 2 H, CH 2 CONH 2 , and CH 2 CH 2 CONH 2 ;

R 24 is at each occurrence independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, COR 25 , and SO 2 —C 1-6 alkyl;

R 25 is at each occurrence independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 branched alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, C 1 -C 6 alkoxy, and C 1 -C 6 alkylamino.

2 . The compound of claim 1 having the formula (II)