Sulfonylpyrroles as Histone Deacetylase Inhibitors
The invention relates to compounds of formula (I) which are effective inhibitors of histone deacetylases.
1 . A compound of formula I
in which
R1 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R2 is hydrogen or 1-4C-alkyl,
R3 is hydrogen or 1-4C-alkyl,
R4 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R5 is hydrogen, 1-4C-alkyl, halogen, or 1-4C-alkoxy,
R6 is -T1-Q1, in which
T1 is a bond, or 1-4C-alkylene,
Q1 is naphthyl, HAR, or R61- and/or R62-substituted AR, in which
AR is naphthyl, or HAR, in which
HAR is a monocyclic or fused bicyclic 5- to 10-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
either
T2 is a bond, and
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, in which
R6111 is halogen, or 1-4C-alkyl,
R6112 is 1-4C-alkyl, and
R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, piperazino, or 4N-(1-4C-alkyl)-piperazino,
or
T2 is 1-4C-alkylene, or 2-4C-alkylene interrupted by oxygen, and
R611 is hydrogen, 1-4C-alkyl, hydroxy-2-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is optionally substituted by R6111 and/or R6112, and is a monocyclic or fused bicyclic 5- to 10-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, in which
R6111 is halogen, or 1-4C-alkyl,
R6112 is 1-4C-alkyl, and
R612 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy-2-4C-alkyl or hydroxy-2-4C-alkyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, thiomorpholino, S-oxo-thiomorpholino, S,S-dioxo-thiomorpholino, piperidino, pyrrolidino, piperazino, 4N-(1-4C-alkyl)-piperazino, imidazolo, pyrrolo, triazolo or pyrazolo,
R62 is 1-4C-alkyl, 1-4C-alkoxy, halogen, cyano, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkylcarbonylamino or 1-4C-alkylsulphonylamino,
R7 is hydroxyl, or Cyc1, in which
Cyc1 is a ring system of formula Ia
in which
A is C (carbon),
B is C (carbon),
R71 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
R72 is hydrogen, halogen, 1-4C-alkyl, or 1-4C-alkoxy,
M with inclusion of A and B is either a ring Ar2 or a ring Har2, in which
Ar2 is a benzene ring,
HAR2 is a monocyclic 5- or 6-membered unsaturated heteroaromatic ring comprising one to three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,
or a salt thereof.
2 . A compound of formula I according to claim 1 ,
in which
R1 is hydrogen, or 1-4C-alkyl,
R2 is hydrogen, or 1-4C-alkyl,
R3 is hydrogen, or 1-4C-alkyl,
R4 is hydrogen, or 1-4C-alkyl,
R5 is hydrogen, or 1-4C-alkyl,
R6 is -T1-Q1, in which
T1 is a bond,
Q1 is naphthyl, HAR, R61-substituted AR, R62-substituted AR, or R61- and R62-substituted AR, in which
AR is naphthyl, or HAR, in which
HAR is either
a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or
a monocyclic 6-membered unsaturated heteroaromatic ring comprising one or two nitrogen atoms, or
a fused bicyclic 9-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or
a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond or 1-4C-alkylene,
R611 is hydrogen, 1-4C-alkyl, phenyl-1-4C-alkyl, or Har1-1-4C-alkyl, in which
Har1 is either
a monocyclic 5-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or
a monocyclic 6-membered unsaturated heteroaromatic ring comprising one or two nitrogen atoms, or
a fused bicyclic 9-membered unsaturated heteroaromatic ring comprising one, two or three heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur, or
a fused bicyclic 10-membered unsaturated heteroaromatic ring comprising one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,
R612 is hydrogen, 1-4C-alkyl, or hydroxy-2-4C-alkyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, piperidino, pyrrolidino, piperazino, or 4N-methyl-piperazino,
R62 is 1-4C-alkyl, 1-4C-alkoxy, or halogen,
R7 is hydroxyl, or 2-aminophenyl,
or a salt thereof.
3 . A compound of formula I according to claim 1 ,
in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, in which
T1 is a bond,
Q1 is naphthyl, HAR, R61-substituted AR, N-methyl-imidazolyl, N-methyl-pyrazolyl, N-methyl-indolyl, mono- or di-methyl-substituted thiazolyl, methyl -substituted N-methyl-imidazolyl, or methyl substituted N-methyl-pyrazolyl, in which
AR is naphthyl, or HAR, in which
HAR is pyridinyl, thiazolyl, benzothiophenyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl or isoquinolinyl,
R61 is 1-4C-alkyl, or -T2-N(R611)R612, in which
T2 is a bond or 1-2C-alkylene,
R611 is hydrogen or 1-4C-alkyl,
R612 is hydrogen or 1-4C-alkyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, piperidino, pyrrolidino, piperazino, or 4N-methyl-piperazino,
R7 is hydroxyl, or 2-aminophenyl,
or a salt thereof.
4 . A compound of formula I according to claim 1 ,
in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, in which
T1 is a bond,
Q1 is naphthyl, HAR, R61-substituted pyridinyl, N-methyl-imidazolyl, N-methyl-pyrazolyl, mono- or di-methyl-substituted thiazolyl, methyl -substituted N-methyl-imidazolyl, or methyl substituted N-methyl-pyrazolyl, in which
HAR is pyridinyl, thiazolyl, benzothiophenyl or benzothiazolyl,
R1 is -T2-N(R611)R612, in which
T2 is a bond or 1-2C-alkylene,
R611 is hydrogen or 1-2C-alkyl,
R612 is hydrogen or 1-2C-alkyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino, piperidino, pyrrolidino, piperazino, or 4N-methyl-piperazino,
R7 is hydroxyl, or 2-aminophenyl,
or a salt thereof.
5 . A compound of formula I according to claim 1 ,
in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, in which
T1 is a bond,
Q1 is naphthyl, HAR, 2-(R61)-pyridin-3-yl, 1-methyl-pyrazol-4-yl, 1-methyl-imidazol-4-yl, 1,2-dimethyl-imidazol-4-yl, or 2,4-dimethyl-thiazol-5-yl, in which
HAR is pyridin-3-yl, benzothiophen-2-yl or benzothiazol-6-yl,
R61 is -T2-N(R611)R612, in which
T2 is a bond or methylene,
R611 is hydrogen or methyl,
R612 is hydrogen or methyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
R7 is hydroxyl, or 2-aminophenyl,
or a salt thereof.
6 . A compound of formula I according to claim 1 ,
in which
R1 is hydrogen,
R2 is hydrogen,
R3 is hydrogen,
R4 is hydrogen,
R5 is hydrogen,
R6 is -T1-Q1, in which
T1 is a bond,
Q1 is naphthyl, HAR, or 2-(R61)-pyridin-3-yl, in which
HAR is pyridinyl,
R61 is -T2-N(R611)R612, in which
T2 is a bond or methylene,
R611 is hydrogen or methyl,
R612 is hydrogen or methyl,
or R611 and R612 together and with inclusion of the nitrogen atom, to which they are bonded, form a heterocyclic ring Het1, in which
Het1 is morpholino,
R7 is hydroxyl, or 2-aminophenyl,
or a salt thereof.
7 . A compound of formula I according to claim 1 which is selected from the group consisting of
(E)-N-Hydroxy-3-[1-(naphthalene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-(2-Amino-phenyl)-3-[1-(naphthalene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-Hydroxy-3-[1-(pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-Hydroxy-3-[1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-(2-Amino-phenyl)-3-[1-(benzo[b]thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-(2-Amino-phenyl)-3-[1-(benzothiazole-6-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-Hydroxy-3-[1-(1-methyl-1H-imidazole-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-N-Hydroxy-3-[1-(1-methyl-1H-pyrazole-4-sulfonyl)-1H-pyrrol-3-yl]-acrylamide,
(E)-3-[1-(Benzo[b]thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,
(E)-3-[1-(Benzothiazole-6-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,
(E)-3-[1-(2,4-Dimethyl-thiazole-5-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide,
(E)-3-[1-(1,2-Dimethyl-1H-imidazole-4-sulfonyl)-1H-pyrrol-3-yl]-N-hydroxy-acrylamide, and salts
thereof.
8 . (canceled)
9 . A pharmaceutical composition comprising one or more compounds as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient and/or auxiliary.
10 . A method of treating a disease responsive or sensitive to inhibition of histone deacetylase activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
11 . (canceled)
12 . A method for treating, preventing or ameliorating hyperproliferative diseases of benign or malignant behaviour and/or disorders responsive to induction of apoptosis, in a patient comprising to said patient a therapeutically effective and tolerable amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.
13 . A method for treating benign and/or malignant neoplasia in a patient comprising administering to said patient a therapeutically effective and tolerable amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, optionally, simultaneously, sequentially or separately with one or more further therapeutic agents.
14 . A combination comprising
a first active ingredient, which is at least one compound according to claim 1 or a salt thereof, and
a second active ingredient, which is at least one anti-cancer agent selected from the group consisting of chemotherapeutic anti-cancer agents and target-specific anti-cancer agents,
for separate, sequential, simultaneous, concurrent or chronologically staggered use in therapy.
15 . A method for treating, preventing or ameliorating hyperproliferative diseases and/or disorders responsive to induction of apoptosis in a patient comprising administering separately, simultaneously, concurrently, sequentially or chronologically staggered to said patient in need thereof
an amount of a first active compound, which is a compound according to claim 1 or a salt thereof, and
an amount of at least one second active compound, said second active compound being an anti-cancer agent selected from the group consisting of chemotherapeutic anti-cancer agents and target-specific anti-cancer agents, wherein the amounts of the first active compound and said second active compound result in a therapeutic effect.
16 . The combination according to claim 14 , in which said chemotherapeutic anti-cancer agents are selected from the group consisting of (i) alkylating/carbamylating agents; (ii) platinum derivatives; (iii) antimitotic agents/tubulin inhibitors; (iv) topoisomerase inhibitors including; (v) pyrimidine antagonists; (vi) purin antagonists; and (vii) folic acid antagonists.
17 . The combination according to claim 14 , in which said target-specific anti-cancer agents are selected from the group consisting of (i) kinase inhibitors; (ii) proteasome inhibitors; (iii) histone deacetylase inhibitors; (iv) heat shock protein 90 inhibitors; (v) vascular targeting agents (VAT) anti-angiogenic drugs, and KDR tyrosine kinase inhibitors; (vi) monoclonal antibodies, mutants and conjugates of monoclonal antibodies, and antibody fragments; (vii) oligonucleotide based therapeutics; (viii) Toll-like receptor/TLR 9 agonists, TLR 7 agonists, or TLR 7/8 agonists; (ix) protease inhibitors; (x) hormonal therapeutics; xi bleomycin; (xii) retinoids; (xiii) DNA methyltransferase inhibitors; (xiv) alanosine; (xv) cytokines; (xvi) interferons; and (xvii) death receptor agonists.
18 . The combination according to claim 14 , in which said cancer is selected from the group consisting of
cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, stomach, skin, ureter, vagina and vulva;
inherited cancers, retinomblastoma and Wilms tumor;
leukemia, lymphoma, non-Hodgkins disease, chronic and acute myeloid leukaemia, acute lymphoblastic leukemia, Hodgkins disease, multiple myeloma and T-cell lymphoma;
myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site and AIDS related malignancies.
19 . A method of treating a disease different to malignant neoplasia in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.