Indolopyridines,Benzofuranopyridines and Benzothienopyridines
Compounds of a certain formula (I), in which R1, R2, R3, R4, R5 and X have the meanings indicated in the description, are novel effective compounds with anti-proliferative and/or apoptosis inducing activity.
1 . A compound of formula I
in which
R1 is methyl, ethyl, isopropyl or cyclopropyl,
R2 is methyl, ethyl, halogen, trifluoromethyl, ethoxy or methoxy,
R3 is methyl, ethyl, halogen, trifluoromethyl, ethoxy or methoxy,
R4 is hydrogen,
X is oxygen (O), sulphur (S), or NH,
R5 is hydrogen, methyl, ethyl, halogen, trifluoromethyl, ethoxy or methoxy,
or a salt, stereoisomer or a salt of a stereoisomer thereof.
2 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl or ethyl,
R2 is methyl, chlorine, fluorine, trifluoromethyl or methoxy,
R3 is methyl, chlorine, fluorine, trifluoromethyl or methoxy,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen, methyl, chlorine, fluorine or trifluoromethyl,
or a salt thereof.
3 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
R2 is methyl, chlorine, fluorine, trifluoromethyl or methoxy,
R3 is methyl, chlorine, fluorine, trifluoromethyl or methoxy,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen, methyl or fluorine,
or a salt thereof.
4 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
R2 is methyl, chlorine, fluorine or methoxy,
R3 is methyl, chlorine, fluorine or methoxy,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen, methyl or fluorine,
or a salt thereof.
5 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
R2 is methyl, chlorine, fluorine or methoxy,
R3 is methyl, chlorine, fluorine or methoxy,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen,
or a salt thereof.
6 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
R2 is methyl, chlorine, fluorine or methoxy,
R3 is methyl, chlorine, fluorine or methoxy,
R4 is hydrogen,
X is NH,
R5 is hydrogen,
or a salt thereof.
7 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
R2 is chlorine, fluorine or methoxy,
R3 is chlorine, fluorine or methoxy,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen,
or a salt thereof.
8 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
either
R2 is methoxy, and
R3 is methoxy,
or
R2 is chlorine or fluorine, and
R3 is chlorine or fluorine,
R4 is hydrogen,
X is oxygen, sulphur or NH,
R5 is hydrogen,
or a salt thereof.
9 . A compound according to claim 1 , which is from formula I*
in which
R1 is methyl,
either
R2 is methyl,
R3 is methyl or methoxy,
R4 is hydrogen,
X is NH, and
R5 is hydrogen, methyl, chlorine or fluorine,
or
R2 is methoxy,
R3 is methoxy,
R4 is hydrogen,
X is NH, and
R5 is methyl, chlorine or fluorine,
or a salt thereof.
10 . A compound according to claim 1 , which is from formula I*
in which
R4 is hydrogen, and
R2, R3 and X have any of the following meanings:
X
R2
R3
1.)
NH
Methoxy
Methoxy
2.)
O
Methoxy
Methoxy
3.)
S
methoxy
Methoxy
4.)
NH
chlorine
Chlorine
5.)
O
chlorine
Chlorine
6.)
S
chlorine
Chlorine
7.)
NH
fluorine
Fluorine
8.)
O
fluorine
fluorine
9.)
S
fluorine
fluorine
10.)
NH
chlorine
methoxy
11.)
O
chlorine
methoxy
12.)
S
chlorine
methoxy
13.)
NH
fluorine
methoxy
14.)
O
fluorine
methoxy
15.)
S
fluorine
methoxy
16.)
NH
chlorine
fluorine
17.)
O
chlorine
fluorine
18.)
S
chlorine
fluorine
19.)
NH
methyl
methyl
20.)
O
methyl
methyl
21.)
S
methyl
methyl
22.)
NH
methyl
methoxy
23.)
O
methyl
methoxy
24.)
S
methyl
methoxy
25.)
NH
methyl
chlorine
26.)
O
methyl
chlorine
27.)
S
methyl
chlorine
28.)
NH
methyl
fluorine
29.)
O
methyl
fluorine
30.)
S
methyl
fluorine
or a salt thereof.
11 . A compound of formula I according to claim 1 , which is selected from the group consisting of
(3aS,10R)-10-(3,5-Dimethoxy-phenyl)-2-methyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Dimethoxy-phenyl)-2-methyl-1-thioxo-1,2,4,10-tetrahydro-3aH-9-thia-2,10a-diaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Dichloro-phenyl)-2-methyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Difluoro-phenyl)-2-methyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Dimethyl-phenyl)-2-methyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Dimethoxy-phenyl)-7-fluoro-2-methyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
(3aS,10R)-10-(3,5-Dimethoxy-phenyl)-2,5-dimethyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one
(3aS,10R)-10-(3,5-Dimethoxy-phenyl)-2,7-dimethyl-1-thioxo-1,2,3a,4,9,10-hexahydro-2,9,10a-triaza-cyclopenta[b]fluoren-3-one,
and salts thereof.
12 . (canceled)
13 . A pharmaceutical composition comprising one or more compounds according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or salt of a stereoisomer thereof, together with a pharmaceutically acceptable auxiliary and/or excipient.
14 . (canceled)
15 . A method for treating, preventing or ameliorating (hyper)proliferative diseases and/or disorders responsive to induction of apoptosis, in a mammal comprising administering a therapeutically effective and tolerable amount of one or more compounds according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or salt of a stereoisomer thereof to said mammal in need thereof.
16 . A combination comprising
a first active ingredient, which is at least one compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer or salt of a stereoisomer 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.
17 . 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 pharmaceutically acceptable salt, stereoisomer or salt of a stereoisomer 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.
18 . The combination according to claim 16 , 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; (v) pyrimidine antagonists; (vi) purin antagonists; and (vii) folic acid antagonists.
19 . The combination according to claim 16 , in which said target-specific anti-cancer agents are selected from (i) kinase inhibitors; (ii) proteasome inhibitors; (iii) histone deacetylase inhibitors; (iv) heat shock protein 90 inhibitors; (v) vascular targeting agents (VAT); (vi) monoclonal antibodies; (vii) oligonucleotide based therapeutics; (viii) Toll-like receptor/TLR 9 agonists; (ix) protease inhibitors; (x) hormonal therapeutics; (xi) bleomycin; (xii) retinoids; (xiii) DNA methyltransferase inhibitors; (xiv) alanosine; (xv) cytokines; interferons; and death receptor agonists.
20 . The combination according to claim 16 , 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, retinoblastoma 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.