Claims for Patent: 7,067,551

Summary for Patent: 7,067,551

Title:	Deacetylase inhibitors
Abstract:	The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.
Inventor(s):	Stacy W Remiszewski, Kenneth W Bair, Richard W Versace, Lawrence B Perez, Michael A Green, Lidia C Sambucetti, Sushil Sharma
Assignee:	Secura Bio Inc
Application Number:	US10/984,501
Patent Claims:	1. A method for treating a proliferative disorder in a mammal which comprises administering to said mammal a compound of the formula (I) wherein R1 is H, halo, or a straight chain C1–C6 alkyl; R2 is selected from H, C1–C10 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, C4–C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, —(CH2)nOC(O)R6, amino acyl, HON—C(O)—CH═C(R1)-aryl-alkyl- and —(CH2)nR7; R3 and R4 are the same or different and independently H, C1–C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound represent C═O, C═S, or C═NR8, or R2 together with the nitrogen to which it is bound and R3 together with the carbon to which it is bound can form a C4–C9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R5 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle; n, n1, n2 and n3 are the same or different and independently selected from 0–6, when n is 1–6, each carbon atom can be optionally and independently substituted with R3 and/or R4; X and Y are the same or different and independently selected from H, halo, C1–C4 alkyl, NO2, C(O)R1, OR9, SR9, CN, and NR10R11; R6 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12, and NR13R14; R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14, and NR12SO2R6; R8 is selected from H, OR15, NR13R14, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R9 is selected from C1–C4 alkyl and C(O)-alkyl; R10 and R11 are the same or different and independently selected from H, C1–C4 alkyl, and —C(O)-alkyl; R12 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, C4–C9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R13 and R14 are the same or different and independently selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R13 and R14 together with the nitrogen to which they are bound are C4–C9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R15 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R17 is selected from C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0 to 6; and Z is selected from O, NR13, S and S(O); or a pharmaceutically acceptable salt thereof. 2. A method of claim 1 wherein the compound of formula (I) is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 3. A method for regulating p21 promoter which comprises introducing a compound of the formula (I) wherein R1 is H, halo, or a straight chain C1–C6 alkyl; R2 is selected from H, C1–C10 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, C4–C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, —(CH2)nOC(O)R6, amino acyl, HON—C(O)—CH═C(R1)-aryl-alkyl and —(CH2)nR7; R3 and R4 are the same or different and independently H, C1–C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound represent C═O, C═S, or C═NR8, or R2 together with the nitrogen to which it is bound and R3 together with the carbon to which it is bound can form a C4–C9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R5 is selected from H, C1–C6 alkyl, C4 C9 cycloalkyl, C4–C9 heterocycloalkyl, acyl, aryl heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, non-aromatic polyheterocycle, and mixed aryl and non-aryl polyheterocycle; n, n1, n2 and n3 are the same or different and independently selected from 0–6, when n1 is 1–6, each carbon atom can be optionally and independently substituted with R3 and/or R4; X and Y are the same or different and independently selected from H, halo, C1–C4 alkyl, NO2, C(O)R1, OR9, SR9, CN, and NR10R11; R6 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12, and NR13R14; R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14, and NR12SO2R6; R8 is selected from H, OR15, NR13R14, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R9 is selected from C1–C4 alkyl and C(O)-alkyl; R10 and R11 are the same or different and independently selected from H, C1–C4 alkyl, and —C(O)-alkyl; R12 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, C4–C9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R13 and R14 are the same or different and independently selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R13 and R14 together with the nitrogen to which they are bound are C4–C9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R15 is selected from H, C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R17 is selected from C1–C6 alkyl, C4–C9 cycloalkyl, C4–C9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0 to 6; and Z is selected from O, NR13, S and S(O); or a pharmaceutically acceptable salt thereof, into the environment of a mammalian cell. 4. A method of claim 3 wherein the compound of formula (I) is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 5. A method according to claim 1 wherein the proliferative disorder is selected from breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid cancer, melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and/or neck cancer or bladder cancer; renal, brain or gastric cancer; epidermoid head and/or neck tumor or a mouth tumor; a lung tumor, for example a small cell or non-small cell lung tumor; a gastrointestinal tumor, a colorectal tumor; a genitourinary tumor, a prostate tumor; a hormone-refractory prostate tumor; a proliferative disease that is refractory to the treatment with other chemotherapeutics; a tumor that is refractory to treatment with other chemotherapeutics due to multidrug resistance; hyperproliferative conditions such as leukemias, hyperplasias, fibrosis, pulmonary fibrosis, renal fibrosis, angiogenesis, psoriasis, atherosclerosis and smooth muscle proliferation in the blood vessels, stenosis or restenosis following angioplasty. 6. A method according to claim 1 wherein the compound is selected from N-hydroxy-3-[4-[(2-hydroxyethyl ){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 7. A method of treating a proliferative disorder in a mammal according to claim 1 wherein the proliferative disorder is selected from lung cancer or tumors, non-small cell lung cancer or tumors, colon cancer or tumors, or fibroblasts. 8. A method of treating a proliferative disorder in a mammal according to claim 5 wherein the compound is selected from N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 9. A method of treating a proliferative disorder in a mammal according to claim 7 wherein the compound is selected from N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.