Details 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):	Remiszewski; Stacy W (Washington Township, NJ), Bair; Kenneth W (Mountain Lakes, NJ), Versace; Richard W (Wanaque, NJ), Perez; Lawrence B (Hackettstown, NJ), Green; Michael A (Easton, PA), Sambucetti; Lidia C (Pacifica, CA), Sharma; Sushil (West Orange, NJ)
Assignee:	Novartis AG (Basel, CH)
Filing Date:	Nov 09, 2004
Application Number:	10/984,501
Claims:	1. A method for treating a proliferative disorder in a mammal which comprises administering to said mammal a compound of the formula (I) ##STR00309## wherein R.sub.1 is H, halo, or a straight chain C.sub.1 C.sub.6 alkyl; R.sub.2 is selected from H, C.sub.1 C.sub.10 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, C.sub.4 C.sub.9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.nC(O)R.sub.6, --(CH.sub.2).sub.nOC(O)R.sub.6, amino acyl, HON--C(O)--CH.dbd.C(R.sub.1)-aryl-alkyl- and --(CH.sub.2).sub.nR.sub.7; R.sub.3 and R.sub.4 are the same or different and independently H, C.sub.1 C.sub.6 alkyl, acyl or acylamino, or R.sub.3 and R.sub.4 together with the carbon to which they are bound represent C.dbd.O, C.dbd.S, or C.dbd.NR.sub.8, or R.sub.2 together with the nitrogen to which it is bound and R.sub.3 together with the carbon to which it is bound can form a C.sub.4 C.sub.9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R.sub.5 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 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, n.sub.1, n.sub.2 and n.sub.3 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 R.sub.3 and/or R.sub.4; X and Y are the same or different and independently selected from H, halo, C.sub.1 C.sub.4 alkyl, NO.sub.2, C(O)R.sub.1, OR.sub.9, SR.sub.9, CN, and NR.sub.10R.sub.11; R.sub.6 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR.sub.12, and NR.sub.13R.sub.14; R.sub.7 is selected from OR.sub.15, SR.sub.15, S(O)R.sub.16, SO.sub.2R.sub.17, NR.sub.13R.sub.14, and NR.sub.12SO.sub.2R.sub.6; R.sub.8 is selected from H, OR.sub.15, NR.sub.13R.sub.14, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.9 is selected from C.sub.1 C.sub.4 alkyl and C(O)-alkyl; R.sub.10 and R.sub.11 are the same or different and independently selected from H, C.sub.1 C.sub.4 alkyl, and --C(O)-alkyl; R.sub.12 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, C.sub.4 C.sub.9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.13 and R.sub.14 are the same or different and independently selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R.sub.13 and R.sub.14 together with the nitrogen to which they are bound are C.sub.4 C.sub.9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R.sub.15 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.mZR.sub.12; R.sub.16 is selected from C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.mZR.sub.12; R.sub.17 is selected from C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR.sub.13R.sub.14; m is an integer selected from 0 to 6; and Z is selected from O, NR.sub.13, 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]ph- enyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-prope- namide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methy- l]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) ##STR00310## wherein R.sub.1 is H, halo, or a straight chain C.sub.1 C.sub.6 alkyl; R.sub.2 is selected from H, C.sub.1 C.sub.10 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, C.sub.4 C.sub.9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.nC(O)R.sub.6, --(CH.sub.2).sub.nOC(O)R.sub.6, amino acyl, HON--C(O)--CH.dbd.C(R.sub.1)-aryl-alkyl and --(CH.sub.2).sub.nR.sub.7; R.sub.3 and R.sub.4 are the same or different and independently H, C.sub.1 C.sub.6 alkyl, acyl or acylamino, or R.sub.3 and R.sub.4 together with the carbon to which they are bound represent C.dbd.O, C.dbd.S, or C.dbd.NR.sub.8, or R.sub.2 together with the nitrogen to which it is bound and R.sub.3 together with the carbon to which it is bound can form a C.sub.4 C.sub.9 heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring; R.sub.5 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 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, n.sub.1, n.sub.2 and n.sub.3 are the same or different and independently selected from 0 6, when n.sub.1 is 1 6, each carbon atom can be optionally and independently substituted with R.sub.3 and/or R.sub.4; X and Y are the same or different and independently selected from H, halo, C.sub.1 C.sub.4 alkyl, NO.sub.2, C(O)R.sub.1, OR.sub.9, SR.sub.9, CN, and NR.sub.10R.sub.11; R.sub.6 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR.sub.12, and NR.sub.13R.sub.14; R.sub.7 is selected from OR.sub.15, SR.sub.15, S(O)R.sub.16, SO.sub.2R.sub.17, NR.sub.13R.sub.14, and NR.sub.12SO.sub.2R.sub.6; R.sub.8 is selected from H, OR.sub.15, NR.sub.13R.sub.14, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.9 is selected from C.sub.1 C.sub.4 alkyl and C(O)-alkyl; R.sub.10 and R.sub.11 are the same or different and independently selected from H, C.sub.1 C.sub.4 alkyl, and --C(O)-alkyl; R.sub.12 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, C.sub.4 C.sub.9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.13 and R.sub.14 are the same or different and independently selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R.sub.13 and R.sub.14 together with the nitrogen to which they are bound are C.sub.4 C.sub.9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R.sub.15 is selected from H, C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.mZR.sub.12; R.sub.16 is selected from C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.mZR.sub.12; R.sub.17 is selected from C.sub.1 C.sub.6 alkyl, C.sub.4 C.sub.9 cycloalkyl, C.sub.4 C.sub.9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR.sub.13R.sub.14; m is an integer selected from 0 to 6; and Z is selected from O, NR.sub.13, 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]ph- enyl]-2E-2-propenamide, N-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-prope- namide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methy- l]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]phen- yl]-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]phe- nyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.