US2011136807A1PendingUtilityA1
Bicyclic compositions and methods for modulating a kinase cascade
Est. expiryJun 29, 2026(expired)· nominal 20-yr term from priority
Inventors:David G. Hangauer, Jr.
A61P 3/10A61P 43/00A61P 9/00A61P 9/10A61P 35/00A61P 3/04A61P 27/02A61P 27/16C07D 413/06C07D 417/12A61P 19/10A61P 19/02C07D 209/42C07D 401/06C07D 413/12C07D 403/06C07D 401/12C07D 403/12A61P 17/06
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Claims
Abstract
The invention relates to compounds and methods for modulating one or more components of a kinase cascade.
Claims
exact text as granted — not AI-modified1 . A compound according to Formula V:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are independently H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, benzyl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, unbranched, or cyclic alkyl;
R 6 , and R 7 are the same or different and are independently H, branched or unbranched, or (CH 2 ) t —Z, wherein Z is aryl, heteroaryl, biaryl, cyclic alkyl, or heterocycle,
or R 6 and R 7 together form a heterocycle;
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H; PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
wherein any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 and R a , R b , and R c is substituted or unsubstituted;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is P.
2 . The compound of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is selected from halogen, boronic acid, hydroxyl, phosphonic acid, sulfamic acid, guanidine, carboxylic acid, aldehyde, amide, and hydroxymethylphosphonic acid.
3 . The compound according to any one of claims 1 - 2 , wherein at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is halogen.
4 . The compound according to any one of claims 1 - 3 , wherein at least one of R 6 and R 7 is
wherein *R 8 is the point of attachment and is (CH 2 ) x , wherein x is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, CH 2 CHOH, CH(CH 3 )(R-isomer), or CH(CH 3 )(S-isomer);
and each of R 9 , R 10 , R 11 , R 12 , and R 13 is the same or different and independently are H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , halogen, P′, aryl, heteroaryl, biaryl, heterobiaryl, heterocycle, or branched, cyclic, or unbranched alkyl,
P′ is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K′, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L′, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M′, or O-aryl-Q′, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K′ is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 22 , NR 22 R 23 , SO 2 R 24 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L′ is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 22 , NR 22 R 23 , SO 2 R 24 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M′ is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 22 , NR 22 R 23 , SO 2 R 24 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q′ is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 22 , NR 22 R 23 , SO 2 R 24 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 22 , R 23 and R 24 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 22 and R 23 taken together with the attached nitrogen atom form a five membered ring;
wherein R a , R b , and R c are the same or different and independently are H, aryl, heteroaryl, biaryl, heterobiaryl, branched, cyclic, or unbranched alkyl;
wherein any of R 9 , R 10 , R 11 , R 12 , and R 13 are substituted or unsubstituted; and
provided that if one of R 1 , R 2 , R 3 , R 4 , or R 5 is not P, then at least one of R 9 , R 10 , R 11 , R 12 , and R 13 is P′.
5 . A compound of Formula VI:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each the same or different and independently are H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, cyclic, or unbranched alkyl;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C4, C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring; and
x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is P.
6 . Use of a compound of Formula V in the manufacture of a medicament for protection against or treatment of hearing loss in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are independently H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, benzyl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, unbranched, or cyclic alkyl;
R 6 , and R 7 are the same or different and are independently H, branched or unbranched, or (CH 2 ) t —Z, wherein Z is aryl, heteroaryl, biaryl, cyclic alkyl, or heterocycle, or R s and R 7 together form a heterocycle;
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
wherein any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 and R a , R b , and R c is substituted or unsubstituted;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is P.
7 . Use of a compound of Formula VII in the manufacture of a medicament for protection against or treatment of a disease selected from osteoporosis, obesity, diabetes, eye disease, stroke, atherosclerosis, neuropathic pain, and hepatitis B in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are independently IL C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, benzyl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, unbranched, or cyclic alkyl;
R 6 , and R 7 are the same or different and are independently H, branched or unbranched, or (CH 2 ) t —Z, wherein Z is aryl, heteroaryl, biaryl, cyclic alkyl, or heterocycle,
or R 6 and R 7 together form a heterocycle;
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
wherein any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 and R a , R b , and R c is substituted or unsubstituted.
8 . Use of a compound of Formula V in the manufacture of a medicament for prevention or treatment of a proliferative disorder in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are independently H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, benzyl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, unbranched, or cyclic alkyl;
R 6 , and R 7 are the same or different and are independently H, branched or unbranched, or (CH 2 ) t —Z, wherein Z is aryl, heteroaryl, biaryl, cyclic alkyl, or heterocycle,
or R 6 and R 7 together form a heterocycle;
t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, or branched, unbranched, or cyclic alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring;
wherein any of R 1 , R 2 , R 3 , R 4 R 5 , R 6 , and R 7 and R a , R b , and R c is substituted or unsubstituted;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is P.
9 . Use of a compound of Formula VI in the manufacture of a medicament for protection against or treatment of hearing loss in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each the same or different and independently are H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, cyclic, or unbranched alkyl;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring; and
x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
provided that at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is P.
10 . Use of a compound of Formula VIII in the manufacture of a medicament for protection against or treatment of a disease selected from osteoporosis, obesity, diabetes, eye disease, stroke, atherosclerosis, neuropathic pain, and hepatitis B in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each the same or different and independently are H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, cyclic, or unbranched alkyl;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring; and
x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
11 . Use of a compound of Formula VIII in the manufacture of a medicament for the prevention or treatment of a proliferative disorder in a subject:
or a salt, solvate, hydrate, or prodrug thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each the same or different and independently are H, C(O)R a , C(O)NR a R b , C(O)OR a , C(O)SR a , OH, OR a , OC(O)R a , OC(O)OR a , NH 2 , NR a R b , NR a C(O)R b , NR a C(O)NR b R c , NR a C(O)OR b , NR a C(O)SR b , NR a S(O)R b , NR a S(O) 2 R b , NR a S(O)OR b , NR a S(O) 2 OR b , NR a P(O)OR b OR c , NR a P(O)OR b R c , NR a P(O)OR b OR c , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , S(O)NR a R b , S(O) 2 NR a R b , P(O)OR a OR b , B(OH) 2 , P, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocycle, and branched, cyclic, or unbranched alkyl;
R a , R b , and R c are the same or different and are independently H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
P is SO 3 H, OSO 3 H, OPO 3 H 2 , OPO 3 H 2 , O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-K, O—C(O)-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-L, NH-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-M, or O-aryl-Q, further wherein lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl is linear or branched alkyl;
K is C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
L is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
M is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
Q is aryl, OH, C(O)NH 2 , COOH, SO 3 H, OSO 3 H, PO 3 H 2 , OPO 3 H 2 , NH 2 , NHR 19 , NR 19 R 20 , SO 2 R 21 , glycoside, lower C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkoxy, or
R 19 , R 20 and R 21 are independently C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl or R 19 and R 20 taken together with the attached nitrogen atom form a five membered ring; and
x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
12 .- 13 . (canceled)
14 . A compound selected from:
or a salt, solvate, hydrate, or prodrug thereof.
15 . Use of a compound according to claim 12 in the manufacture of a medicament for protection against or treatment of a disease selected from osteoporosis, obesity, diabetes, eye disease, stroke, atherosclerosis, neuropathic pain, hepatitis B, and proliferative disorder in a subject.
16 . Use according to any one of claims 6 - 11 and 14 - 15 , wherein the administration of the compound is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
17 . A pharmaceutical composition comprising a compound according to any one of claim 1 - 5 or 14 and a pharmaceutically acceptable excipient.Cited by (0)
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