HDAC inhibitors and therapeutic methods using the same

Patent metadata

Field	Value
Publication number	US-RE47009-E
Application number	US-201215182061-A
Country	US
Kind code	E1
Filing date	Jan 31, 2012
Priority date	Feb 1, 2011
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed.

First claim

What is claimed:

1. A compound having a structural formula
Cap-L-M
wherein Cap is selected from the group consisting of

wherein ring

 is an aliphatic or aromatic five or six membered ring,
W, X, Y, and Z independently are selected from the group consisting of null, C(R 1 ) 2 , O, S, and NR 1 ,
ring

 is an aliphatic or aromatic six membered ring,
wherein D, E, F, and G independently are selected from the group consisting of C(R 1 ) 2 , O, and S,
or ring

 is an aliphatic or aromatic five membered ring, wherein D, E, F, and G are selected from the group consisting of null, C(R 1 ) 2 , and NR 1 ,
R 1 , independently, is selected from the group consisting of null, hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 1-6 perfluoroalkyl, C 1-6 perfluoroalkoxy, aryl, heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, C 1-6 alkyleneheterocycloalkyl, C 1-6 alkylenecycloalkyl,

 OR a , halo, N(R a ) 2 , SR a , SOR a , SO 2 R a , CN, C(═O)R a , CF 3 , OCF 3 , NO 2 , OC(═O)R a , SO 2 N(R a ) 2 , OSO 2 CF 3 , C(═O)OR a , C(═O)N(R a ) 2 , C 1-6 alkyleneN(R a ) 2 , C 1-6 alkyleneC(═O)R a , C 1-6 alkyleneOR a , C 1-6 alkyleneSR a , C 1-6 alkyleneNR a SO 2 R a , C 1-6 alkyleneSOR a , C 1-6 alkyleneCN, C 1-6 heteroalkyleneCN, C 1-6 alkyleneC(═O)OR a , C 1-6 alkyleneOC(═O)N(R a ) 2 , C 1-6 alkyleneNR a C(═O)OR a , C 1-6 alkyleneNR a C(═O)R a , C 1-6 alkylene C(═O)N(R a ) 2 C 1-6 alkyleneC(═O)N(R a ) 2 , C 1-6 alkyleneOC 1-6 alkyleneC(═O)OR a , C(═O)NR a SO 2 R a , C(═O)C 1-6 alkylenearyl, C(═O)NR a C 1-6 alkyleneOR a , OC 1-6 alkyleneC(═O)OR a , OC 1-6 alkyleneN(R a ) 2 , OC 1-6 alkyleneOR a , OC 1-6 alkyleneNR a C(═O)OR a , NR a C 1-6 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-6 alkyl) 2 , and NR a (SO 2 C 1-6 alkyl), and
R a , independently, is selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 alkyleneNH 2 , C 1-6 alkyleneNH(C 1-6 alkyl), C 1-6 alkyleneN(C 1-6 alkyl) 2 , C 1-6 alkyleneNH(C 1-6 alkyl) 2 , C 1-6 alkyleneNHC(═O)(C 1-6 alkyl), C 1-6 alkyleneC(═O)NH 2 , C 1-6 alkyleneOH, C 1-6 alkyleneCN, C 1-6 heteroalkyleneCN, C 1-6 alkyleneOC 1-6 alkyl, C 1-6 alkyleneSH, C 1-6 alkyleneSC 1-6 alkyl, C 1-6 alkyleneNH(SO 2 C 1-6 alkyl), aryl, heteroaryl, C 3-8 cycloalkyl, and C 3-10 heterocycloalkyl,
wherein linker L is attached to any atom D, E, F, or G, and

wherein ring

 is an aliphatic or aromatic five or six membered ring,
E, F, W, X, Y, Z, R 1 , and R a are as defined above, and

wherein A is C, N, O, S, B, or P, and L is attached to A,
R 2 , R 3 and R 4 independently are selected from the group consisting of null, hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 1-6 perfluoroalkyl, C 1-6 perfluoroalkoxy, aryl, heteroaryl, C 3-10 cycloalkyl, C 3-8 heterocycloalkyl, C 1-6 alkylenearyl, C 1-6 alkyleneheteroaryl, C 1-6 alkyleneheterocycloalkyl, C 1-6 alkylenecycloalkyl,

 OR a , halo, N(R a ) 2 , SR a , SOR a , SO 2 R a , CN, C(═O)R a , OC(═O)R a , C(═O)OR a , C 1-6 alkyleneN(R a ) 2 , C 1-6 alkyleneOR a , C 1-6 alkyleneSR a , C 1-6 alkyleneC(═O)OR a , C(═O)N(R a ) 2 , C(═O)NR a C 1-6 alkyleneOR a , OC 1-6 alkyleneC(═O)OR a , OC 1-6 alkyleneN(R a ) 2 , OC 1-6 alkyleneOR a , OC 1-6 alkyleneNR a C(═O)OR a , NR a C 1-6 alkyleneN(R a ) 2 , NR a C(═O)R a , NR a C(═O)N(R a ) 2 , N(SO 2 C 1-6 alkyl) 2 , NR a (SO 2 C 1-6 alkyl), nitro, and SO 2 N(R a ) 2 , and
R a is defined above; wherein at least one of E, F, W, X, Y, and Z is NR 1 ;
L is selected from the group consisting of null, C 1-8 alkylene, R a substituted C 1-8 alkylene, NR a , C(═O), aryl, C(═O)aryl, C(═O)C 1-6 alkylene, C 1-8 alkyleneNR a , C 1-6 alkylenearyleneC 1-6 alkylene, C 2-6 alkenylene, C 4-8 alkdienylene, C 1-6 alkylenearylene, C 1-6 alkyleneheteroarylene, R a substituted C 1-6 alkyleneheteroarylene, and C 2-6 alkenylenearyleneC 1-6 alkylene, and R a is defined above CH 2 —C 6 H 5 ;
M is

 selected from the group consisting of —C(═O)N(R b )OH,
—O(CH 2 ) 1-6 C(═O)N(R b )OR b ,
—N(R b )(CH 2 ) 1-6 C(═O)N(R b )OR b ,
—N(R b )(CH 2 ) 1-6 C(═O)N(R b )OR b ,
arylC(═O)NHOH,
—N(OH)C(═O)R b ,
heteroarylC(═O)NHOH,
—C 3-6 cycloalkylN—C(═O)CH 2 SH,
—B(OR b ) 2 ,
SO 2 NHR b ,
—NHSO 2 NHR b ,
NHSO 2 C 1-6 alkyl,
—SO 2 C 1-6 alkyl,
—SR c ,

—C(═O)R e ,
—P(═O)(OR f ) 2 ,
—NH—P(═O)(OR f ) 2 ,

—C(═O)(C(R b ) 2 ) 1-6 SH,
—C(═O)C(═O)NHR b ,
—C(═O)NHN(R b ) 2 ,
—C(═O)NH(CH 2 ) 1-3 N(R b ) 2 ,

—S—(C═O)C 1-6 alkyl,
C 3-10 heterocycloalkyl optionally substituted with oxo (═O), thioxo (═S), or both,
aryl optionally substituted with one or more of C 1-6 alkyl, —C(═O)R d , —NH 2 , and —SH,
heteroaryl optionally substituted with —NH 2 , —SH, or both,
—N(H)C(═O)SH,
—NHC(═O)NHR d ,
—NHC(═O)CH 2 R d ,
—NHC(═O)(CH 2 ) 1-6 SH,
—NHC(═O)CH 2 Hal,
—NHC(═S)NHR d ,
—NHC(═S)CH 2 R d ,
—C(═S)NHR d ,
—C(═S)CH 2 R d ,
—NHC(═S)CH 2 R d ,
—NHC(═S)CH 2 Hal, and
—(C═O)C 1-6 alkyl;
R b , independently, is selected from the group consisting of hydrogen, (C═O)CH 3 , C 1-6 alkyl, CF 3 , CH 2 F, and aryl, or two R b groups are taken together with the carbon to which they attached to form a C 3-8 cycloalkyl group;
R c is selected from hydrogen or (C═O)CH 3 ;
R d is NH 2 or OH;
R e is selected from the group consisting of OH, N(R b ) 2 , NH(OCH 3 ), N(CH 3 )OH, C 1-6 alkyl, CF 3 , aryl, heteroaryl, C 3-8 cycloalkyl, NHSO 2 CH 3 , NHSO 2 CF 3 , and C 1-6 haloalkyl;
R f independently is hydrogen, methyl, or ethyl; and
Hal is halo,
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.

2. The compound of claim 1 wherein the bicyclic ring system

is selected from a residue of the group consisting of thionaphthene, isothionaphthene, indole, indolenine, 1H-isoindole, cyclopenta[b]pyridine, pyrano[3,4-b]pyrrole, indazole, benzisoxazole, benzoxazole, anthranil, naphthalene, tetralin, decalin, 2H-1-

Assignees

• Childrens Hospital Philadelphia
• The Trustees Of The Univ Of Illinois

Inventors

• Kozikowski Alan
• Kalin Jay Hans
• Butler Kyle Vincent
• Bergman Joel
• Hancock Wayne W

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0455

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• A61K49/0002

  General or multifunctional contrast agents, e.g. chelated agents · CPC title