EP2751114A1 - 6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine - Google Patents

6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

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Publication number
EP2751114A1
EP2751114A1 EP12766291.4A EP12766291A EP2751114A1 EP 2751114 A1 EP2751114 A1 EP 2751114A1 EP 12766291 A EP12766291 A EP 12766291A EP 2751114 A1 EP2751114 A1 EP 2751114A1
Authority
EP
European Patent Office
Prior art keywords
compounds
formula
alkyl
group
triazolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP12766291.4A
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German (de)
English (en)
Inventor
Norbert Schmees
Joachim Kuhnke
Bernard Haendler
Philip Lienau
Amaury Ernesto FERNANDEZ-MONTALVAN
Pascale Lejeune
Stephan Siegel
William Scott
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Bayer Intellectual Property GmbH
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Bayer Intellectual Property GmbH
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Publication date
Application filed by Bayer Intellectual Property GmbH filed Critical Bayer Intellectual Property GmbH
Publication of EP2751114A1 publication Critical patent/EP2751114A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel 6 ⁇ -thieno [3,2-f] [l, 2,4] triazolo [4,3-a] [l, 4] diazepines, especially for therapeutic purposes, containing pharmaceutical agents
  • the human BET family (bromodomain and extra C-terminal domain family) has four members (BRD2, BRD3, BRD4 and BRDT) containing two related bromodomains and one extra-terminal domain (Wu and Chiang, J. Biol. Chem., 2007 , 282: 13141-13145).
  • the bromodomains are protein regions that recognize acetylated lysine residues. Such acetylated lysines are often found at the N-terminal end of histones (eg, histone 3 or histone 4) and are features for open chromatin structure and active gene transcription (Kuo and Allis, Bioessays, 1998, 20: 615-626 ).
  • bromodomains can recognize additional acetylated proteins.
  • BRD4 binds to RelA, resulting in the stimulation of NF- ⁇ and transcriptional activity of inflammatory genes (Huang et al., Mol. Cell. Biol., 2009, 29: 1375-1387).
  • the extra-terminal domain of BRD2, BRD3 and BRD4 interacts with several proteins that have a role in chromatin modulation and the regulation of gene expression (Rahman et al., Mol. Cell Biol, 2011, 31: 2641-2652).
  • BET proteins play an important role in cell growth and cell cycle. Biol. Cell, 2009, 20: 4899-4909; Yang et al., Mol. Cell. Biol, 2008, 28: 967-976 ). BRD4 is essential for the transcription elongation and recruits the
  • BRD2 and BRD4 knockout mice die prematurely during embryogenesis (Gyuris et al., Biochim Biophys Acta, 2009, 1789: 413-421, Houzelstein et al, Mol. Cell Biol, 2002, 22: 3794-3802). Heterozygous BRD4 mice have various growth defects attributable to reduced cell proliferation (Houzelstein et al., Mol. Cell. Biol., 2002, 22: 3794-3802). BET proteins play an important role in various tumor types.
  • the fusion between the BET proteins BRD3 or BRD4 and NUT results in an aggressive form of squamous cell carcinoma called NUT midline carcinoma (French, Cancer Genet., Cytogenet., 2010, 203: 16- 20).
  • the fusion protein prevents cell differentiation and promotes proliferation (Yan et al., J. Biol. Chem., 2011, 286: 27663-27675).
  • the growth of derived in vivo models is inhibited by a BRD4 inhibitor (Filippakopoulos et al, Nature, 2010, 468: 1067-1073).
  • BRD4 plays an important role in this tumor (Zuber et al., Nature, 2011, doi: 10.1038). Reduction of BRD4 expression leads to selective cell cycle arrest and apoptosis. Treatment with a BRD4 inhibitor prevents the proliferation of an AML xenograft in vivo. Amplification of the DNA region containing the BRD4 gene was detected in primary breast tumors (Kadota et al., Cancer Res, 2009, 69: 7357-7365). Also for BRD2 there is data related to a role in tumors. A transgenic mouse expressing BRD2 selectively in B cells develops B-cell lymphomas and leukemias (Greenwall et al., Blood, 2005, 103: 1475-1484).
  • BET proteins are also involved in viral infections.
  • BRD4 binds to the E2 protein of various papillomaviruses and is important for survival of the viruses in latently infected cells (Wu et al., Genes Dev., 2006, 20: 2383-2396).
  • the herpesvirus responsible for the Kaposi's sarcoma interacts with various BET proteins, what for the
  • BRD4 also plays an important role in the replication of HIV (Bisgrove et al, Proc Natl Acad., USA, 2007, 104: 13690-13695).
  • BET proteins are also involved in inflammatory processes.
  • BRD2-hypomorphic mice show reduced inflammation in adipose tissue (Wang et al., Biochem J., 2009, 425: 71-83).
  • the infiltration of macrophages into white adipose tissue is also reduced in BRD2-deficient mice (Wang et al., Biochem J., 2009, 425: 71-83).
  • BRD4 regulates a number of genes involved in inflammation.
  • Macrophages prevent a BRD4 inhibitor from expression of inflammatory genes, such as IL-1 or IL-6 (Nicodeme et al, Nature, 2010, 468: 1119-1123). These data demonstrate that BET proteins play an essential role in various pathologies. It is therefore important to find potent and selective inhibitors that prevent the interaction between the BET proteins and acetylated proteins. These new inhibitors should also have appropriate pharmacokinetic properties that allow patients to inhibit these interactions.
  • EP0638560 discloses inter alia 6 // -thieno [3,2- [1,2,4] triazolo [4,3-a] [1,4] diazepines for the treatment of osteoporosis.
  • position 6 of the ring system also substituted esters and amides are provided, wherein as substituents no bridged elements or spiro elements are disclosed.
  • US 5,712,274 discloses 6 // thieno [3,2- [1,2,4] triazolo [4,3-a] [l, 4] diazepines for the treatment of inflammation. In position 6 of the ring system are also provided with heterocycles substituted amides or ring closures on the amide nitrogen.
  • Example 50 discloses, for example, a ring closure via the amide nitrogen to the morpholine. Bridged elements or spiro elements are not included or disclosed.
  • inhibitory effects on proteins of the BRD family or utility in cancers are not disclosed.
  • EP0934940 discloses 6 // thieno [3,2- /] [1,2,4] triazolo [4,3-a] [1,4] diazepme for the treatment of inflammation.
  • position 6 of the ring system also substituted esters and amides are provided wherein no bridged elements or spiro elements are disclosed as substituents.
  • EP0989131 claims 6 / i-thieno [3,2- [1,2,4] triazolo [4,3-a] [1,4] diazepines bearing in position 6 of the ring system a carboxyalkyl side chain with amide function in which the nitrogen atom carries a hydrogen atom and the radical R 3 .
  • R 3 may also have the meaning of an aromatic or heteroaromatic radical. Heterocycles via the amide nitrogen, bridged elements or spiro elements are not intended to be significant for R 3 .
  • the compounds are disclosed for use in inflammatory and allergic diseases in which cell adhesion plays a role.
  • EP1887008 discloses 6 - / - thieno [3,2 - /] [l, 2,4] triazolo [4,3-a] [1,4] diazepms with substituted Ci-C6-alkyl esters in position 6 of the ring system, wherein the Alkyl ester is bonded via an alkylene group to the ring system. As substituents of the alkyl ester also heterocycles such as morpholine are provided. Amides in position 6, ring closures via the amide nitrogen, bridged elements or spiro elements are not included or disclosed. The use of the compounds described is in the field of inflammatory diseases.
  • EP2239264 discloses 6 // -thieno [3,2- [1,2,4] triazolo [4,3-a] [1,4] diazepines for the treatment of cancers. The mechanism of action is called the inhibition of the BRD protein family.
  • position 6 of the ring system (R 4 ) exclusively primary amides are provided ie the amide nitrogen carries a hydrogen atom.
  • R 9 is a possible substituent of the amide nitrogen.
  • R 9 does not include the meaning of bridged elements, spiro-elements, or ring-ends via the amide nitrogen.
  • JQ-1 acts as a potent binder on the BET protein family and has anti-proliferative properties mediated by it.
  • JQl is Comparative Example VI in the present application. Applicant sees JQl as the closest prior art because JQI refers to the same target and indications as the substances of the invention.
  • WO2011 / 054553, WO2011 / 054843, WO2011 / 054844 and WO2011 / 054845 disclose 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepines as bromodomain inhibitors.
  • WO2011 / 054553 relates to a single benzodiazepine and its
  • WO2011 / 054843 relates to various individual substances, including a benzodiazepine, and their use in inflammatory diseases or
  • the compounds according to the invention differ from the compounds of WO2011 / 054845 in that the benzene fused to the diazepine is replaced by thiophene and in position 6 of the diazepine there is provided an amide residue which contains at most one cycle. Bridged elements or spiro elements are not provided in WO2011 / 054845 in position 6 of the ring system.
  • the compounds of the invention differ from the closest prior art 6 // -thieno [3,2- /] [l, 2,4] triazolo [4,3-a] [1,4] diazepames described in WO2009 / 084693 have been disclosed as BRD4 inhibitors by containing saturated optionally substituted carbo or heterocyclic amides with a spiro element and / or a bridged element.
  • the object of the present invention is to provide new structures for the therapy of human and animal diseases.
  • Tumors are suitable and have advantages over known in the art structures.
  • the structures according to the invention should have a pharmacokinetics suitable for the prophylaxis and therapy of tumor diseases and have pharmacokinetic advantages over structures known in the prior art. It has surprisingly been found that the compounds of the formula (I) according to the invention can have advantageous pharmacokinetic properties. It is preferable to provide structures for the treatment of diseases which additionally also have one, more preferably several or even all of the following properties:
  • X is a bond and Y is a nitrogen atom or
  • X is the group -NH- and Y is the group -CH-, and
  • R 1 and R 2 are independently hydrogen or a Ci-Cö-alkyl group
  • n 0 or 1
  • n 0 or 1
  • o 0 or 1
  • p 0 or 1
  • R S1 and R S1 independently of one another represent hydrogen or a C 1 -C 6 -alkyl group, or
  • R S2 together with R S1 forms a keto group -C (O) -
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are attached form a saturated 3- to 8-membered carbocycle or heterocycle, optionally
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 4 , R 5 , R 6 and / or R 7 are independently stand for
  • R 8 is a C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy group, with the proviso that
  • R b1 and R b2 form a bridge as defined for compounds of the formula (I),
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are attached form a saturated 3- to 8-membered carbo- or heterocycle, or
  • R b1 and R b2 form a bridge as defined for compounds of the formula (I),
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 3- to 8-membered carbo- or heterocycle, as well as their diastereomers, racemates and physiologically tolerated salts, particularly good for the therapy of Diseases are suitable and solve the task of the invention.
  • the compounds of the invention prevent the interaction between BRD4 and an acetylated histone 4 peptide and inhibit the growth of cancer cells. They thus represent new structures for the therapy of human and animal diseases, in particular of cancers.
  • the invention is based on the following definitions: alkyl:
  • Alkyl is a linear or branched, saturated, monovalent hydrocarbon radical having generally 1 to 6 (C 1 -C 6 -alkyl), preferably 1 to 4 (C 1 -C 4 -alkyl), and particularly preferably 1 to 3 carbon atoms (C 1 -C 4) 3- alkyl).
  • Alkoxy represents a linear or branched, saturated alkyl ether radical of the formula -O-alkyl having generally 1 to 6 (C 1 -C 6 -alkoxy), preferably 1 to 4 (C 1 -C 4 -alkoxy), and particularly preferably 1 to 3 ( C 1 -C 3 -alkoxy) carbon atoms.
  • Alkoxyalkyl is an alkoxy-substituted alkyl radical.
  • C 1 -alkoxy-C 1 -alkyl means that the alkoxy moiety has n carbon atoms and the alkyl moiety via which the moiety is attached has m carbon atoms.
  • Alkylcarbonyl is the group -C (O) -alkyl having generally 1 to 6, preferably 1 to 4, and particularly preferably 1 to 3 carbon atoms in the alkyl moiety.
  • Examples include:
  • Heteroatoms are oxygen, nitrogen or sulfur atoms.
  • Carbocycle
  • Carbocycle stands for a monocyclic, saturated, hydrocarbon ring having generally 3 to 8 carbon atoms, preferably 4 to 6 carbon atoms.
  • heterocycle stands for a monocyclic, saturated, hydrocarbon ring having generally 3 to 8 carbon atoms, preferably 4 to 6 carbon atoms.
  • Heterocycle represents a non-aromatic monocyclic ring having 3 to 8 ring atoms, wherein at least one ring atom is a heteroatom or a hetero group.
  • heteroatoms nitrogen atoms, oxygen atoms and / or sulfur atoms may occur.
  • hetero groups -S (O) -, -S (O) 2- or -N ⁇ O " ) - may occur.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • Haloalkyl is an alkyl radical having at least one halogen substituent.
  • Difiuormethyl trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 5,5,5,4,4-pentafluoropentyl or 5,5,5,4,4,3,3-H tafiuorpentyl.
  • perfluorinated alkyl radicals such as trifluoromethyl or pentafluoroethyl.
  • Haloalkoxy is an alkoxy radical having at least one halogen substituent.
  • Cycle includes carbocyclic and heterocyclic rings
  • a preferred subgroup are compounds according to formula (I) in which
  • X is a bond and Y is a nitrogen atom or
  • X is the group -NH- and Y is the group -CH-, and
  • R 1 and R 2 independently represent hydrogen or a C 1 -C 3 -alkyl group, and m is 0 or 1, and
  • n 0 or 1
  • o 0 or 1
  • p 0 or 1
  • R S1 and R sl independently of one another are hydrogen or a C 1 -C 3 -alkyl group, or R 2S together with R 5S forms a keto group -C (O) -, or
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are attached form a saturated 4- to 6-membered carbo or heterocycle, optionally
  • a keto group -C (O) - may contain, and
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 4 , R 5 , R 6 and / or R 7 are independently are hydrogen, a C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy group or the group -C (O) -R 8 with R 8 being a C 1 -C 4 -alkyl or C 1 -C 4 -alkoxy group
  • R bl and R b2 form a bridge, as they are for the preferred subgroup of
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 4- to 6-membered carbo- or heterocycle
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 4- to 6-membered carbo- or heterocycle
  • X is a bond and Y is a nitrogen atom or
  • X is the group -NH- and Y is the group -CH-, and
  • R 1 and R 2 are a Ci-C3-alkyl group
  • n 0 or 1
  • n 0 or 1
  • o 0 or 1
  • p 0 or 1
  • R S1 and R S1 are hydrogen, or
  • R S2 together with R S1 forms a keto group -C (O) -, or
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are attached forms a saturated 4- to 6-membered carbo- or heterocycle having an oxygen atom as heteroatom, which is optionally substituted by halogen, hydroxy and / or by a carbon atom.
  • C3-alkyl and / or C1-C3-alkoxy may be mono- or polysubstituted by identical or different substituents, and
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 6 and / or R 7 are hydrogen or a Ci-C3-alkyl or C1-C3-
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 4- to 6-membered carbo- or heterocycle having an oxygen atom as the heteroatom
  • R bl and R b2 form a bridge as defined for the more preferred subgroup of compounds of formula (I)
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 4- to 6-membered carbo- or heterocycle having an oxygen atom as the heteroatom
  • X is a bond and Y is a nitrogen atom
  • R 1 and R 2 are a methyl group
  • n 0 or 1
  • n 0 or 1
  • o 0 or 1
  • p 0 or 1
  • R S2 together with R S1 forms a keto group -C (O) -, or
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated 4- to 6-membered heterocycle having an oxygen atom as the heteroatom, optionally with halogen, hydroxy and / or with a C 1 -C 3 -alkyl - and / or C1-C3-
  • Alkoxy may be mono- or polysubstituted by identical or different substituents
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge -CHR 6 -CHR 7 -,
  • R 6 and / or R 7 are hydrogen or a C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy group, with the proviso
  • R b1 and R b2 form a bridge as defined for the very preferred subgroup of compounds of formula (I),
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated, 4- to 6-membered heterocycle with an oxygen atom as heteroatom,
  • R bl and R b2 form a bridge, as they are for the very preferred subgroup of
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are bonded form a saturated, 4- to 6-membered heterocycle having an oxygen atom as heteroatom,
  • X is either a bond and Y is a nitrogen atom or
  • X is a bond and Y is a nitrogen atom.
  • R 1 and R 2 independently of one another represent hydrogen or a C 1 -C 6 -alkyl group.
  • R 1 and R 2 independently of one another represent hydrogen or a C 1 -C 3 -alkyl group.
  • R 1 and R 2 is a Ci-C3-alkyl group.
  • R 1 and R 2 represent a methyl group.
  • R 1 and R 2 represent a methyl group.
  • n, o and p are 0 or 1
  • R S1 and R S1 independently of one another represent hydrogen or a C 1 -C 6 -alkyl group, or
  • R S2 together with R S1 forms a keto group -C (O) -
  • R S2 together with R S1 and the carbonyl to which R S1 and R S2 are attached form a saturated 3- to 8-membered carbo or heterocycle, optionally
  • R S1 and R S1 independently of one another represent hydrogen or a C 1 -C 3 -alkyl group, or
  • R S2 together with R S1 forms a keto group -C (O) -, or
  • R S2 together with R S1 and the carbon atom to which R S1 and R S2 are attached form a saturated 4- to 6-membered carbo or heterocycle, optionally
  • (ii) may contain a keto group -C (O) -.
  • R S1 and R S1 are hydrogen, or
  • R S2 together with R S1 forms a keto group -C (O) -, or
  • R S2 forms together with R S1 and the carbonyl to which R S1 and R S2 are attached, a saturated 4- to 6-membered carbo- or heterocycle having an oxygen atom as heteroatom, which is optionally substituted by halogen, hydroxy and / or by a carbon atom.
  • C3-alkyl and / or C1-C3-alkoxy may be mono- or polysubstituted by identical or different substituents.
  • the general formula (I) very preferably
  • R S2 together with R S1 is a keto group -C (O) -, or
  • R S1 and R S2 are attached R S2 together with R S1 and the Kohlenstoffatonyan form a saturated 4- to 6-membered heterocycle having an oxygen atom as the hetero atom, optionally substituted by halogen, hydroxy and / or with a Ci-C3-alkyl and / or C1-C3 alkoxy may be mono- or polysubstituted by identical or different substituents.
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 4 , R 5 , R 6 and / or R 7 are independently are hydrogen, a Ci-Cö-alkyl or Ci-Cö-alkoxy group or the group -C (0) -R 8 with R 8 standing for a Ci-Cö-alkyl or Ci-Cö-alkoxy group.
  • R 3 , R 4 , R 5 , R 6 and / or R 7 are independently are hydrogen, a Ci-Cö-alkyl or Ci-Cö-alkoxy group or the group -C (0) -R 8 with R 8 standing for a Ci-Cö-alkyl or Ci-Cö-alkoxy group.
  • R 8 standing for a Ci-Cö-alkyl or Ci-Cö-alkoxy group.
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 4 , R 5 , R 6 and / or R 7 are independently represent hydrogen, one
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge consisting of one of the groups
  • R 3 , R 6 and / or R 7 are hydrogen or a C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy group or the group -C (O) -R 8 where R 8 is a C 1 -C 4 -alkyl or C 1 -C 4 alkoxy group.
  • R bl and R b2 are hydrogen, or
  • R bl and R b2 form a bridge -CHR 6 -CHR 7 -,
  • R 6 and / or R 7 are hydrogen or a Ci-C3-alkyl or C1-C3-
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced, irrespective of the particular combinations of radicals indicated, by any definitions of radicals of other combinations.
  • Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts and of the formula (I) encompassed by formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts. Also to be considered as encompassed by the present invention is the use of the salts of the compounds of the invention.
  • Salts which are preferred within the scope of the present invention are physiologically acceptable salts of the compounds according to the invention. However, also included are salts which are not suitable for pharmaceutical applications themselves but can be used, for example, for the isolation or purification of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.
  • Another object of the present invention are medicaments containing the
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred within the scope of the present invention.
  • the compounds of the invention may exist in different stereoisomeric forms depending on their structure, i. in the form of configurational isomers or optionally also as conformational isomers.
  • the compounds of the invention have at position 6 a uniformly configured center of asymmetry. They can therefore be present as pure diastereomers or mixtures thereof if one or more of the substituents described in the formula (I) contains a further asymmetric element, for example a chiral
  • the present invention therefore also encompasses diastereomers and their respective mixtures. From such mixtures, the pure diastereomers can be isolated stereoisomerically in a known manner; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or dural phase. If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.
  • the present invention also encompasses all suitable isotopic variants of the compounds according to the invention.
  • An isotopic variant of a compound according to the invention is understood to mean a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), ⁇ (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 C, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of a compound of the invention may be useful, for example for the study of the mechanism of action or distribution of active ingredient in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes in particular are suitable for this purpose.
  • incorporation of isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose; Such modifications of the compounds of the invention may therefore optionally also constitute a preferred embodiment of the present invention.
  • Isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by using appropriate isotopic modifications of the respective reagents and / or starting compounds.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).
  • the compounds according to the invention can act systemically and / or locally.
  • it may be applied in a suitable manner, such as, for example, orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally).
  • a resorption step e.g., intravenously, intraarterially, intracardially, intraspinal, or intralumbar
  • absorption e.g., intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally.
  • parenteral administration are suitable as application forms u.a. Injection and
  • Infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.
  • Inhalation medicines i.a.
  • Ophthalmic preparations vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as patches), milk, pastes, foams, scattering powders, implants or stents.
  • the compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients.
  • adjuvants include, among others.
  • Carriers e.g., microcrystalline cellulose, lactose, mannitol
  • solvents e.g., liquid polyethylene glycols
  • emulsifiers e.g., emulsifiers and dispersing or wetting agents
  • binders e.g., polyvinylpyrrolidone
  • synthetic and natural polymers e.g., albumin
  • stabilizers e.g.
  • Antioxidants such as ascorbic acid
  • dyes eg, inorganic pigments such as iron oxides
  • flavor and / or odoriferous agents are pharmaceutical compositions containing the compounds of the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.
  • the formulation of the compounds according to the invention into pharmaceutical preparations is carried out in a manner known per se by converting the active substance (s) into the desired administration form with the auxiliaries customary in galenicals.
  • auxiliaries customary in galenicals.
  • excipients for example, vehicles, fillers, disintegrants,
  • Binders humectants, lubricants, and ⁇ , diluents, solvents, cosolvents, emulsifiers, solubilizers, flavoring agents, colorants, preservatives, stabilizers, wetting agents, salts for changing the osmotic pressure or buffers are used.
  • the pharmaceutical formulations can be any suitable pharmaceutical formulations.
  • auxiliaries may be, for example, salts, saccharides (mono-, di-, tri-, oligo- and / or polysaccharides), proteins, amino acids, peptides, fats, waxes, oils,
  • Hydrocarbons and derivatives thereof, wherein the excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • excipients may be of natural origin or may be obtained synthetically or partially synthetically.
  • oral or oral administration in particular tablets, dragees, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions come into question.
  • the present invention relates to the compounds of the invention.
  • the compounds of the invention can be used for the prophylaxis and treatment of human diseases, in particular tumors.
  • the compounds of the invention can be used in particular to the
  • the compounds of the invention are particularly suitable for the prophylaxis and / or treatment of hyper-proliferative diseases such as
  • BPH benign prostatic hyperplasia
  • tumors of the breast, the respiratory tract, the brain, the reproductive organs, the gastrointestinal tract, the genitourinary tract, the eye, the liver, the skin, the head and neck, the thyroid gland, the parathyroid gland are treatable Bone and connective tissue and metastases of these tumors.
  • hematological tumors are treatable
  • treatable as breast tumors are:
  • tumors of the respiratory tract are treatable
  • tumors of the brain are treatable
  • tumors of the male reproductive organs are treatable:
  • tumors of the female reproductive organs are treatable:
  • Vulvar Carcinomas As tumors of the gastrointestinal tract, for example, are treatable:
  • tumors of the urogenital tract are treatable: bladder carcinomas
  • tumors of the eye are treatable:
  • Intraocular melanomas Intraocular melanomas
  • tumors of the liver are treatable:
  • tumors of the skin are treatable:
  • tumors of the head and neck are treatable:
  • sarcomas are treatable:
  • lymphomas are treatable:
  • AIDS-associated lymphomas Treatable as leukemias for example:
  • the compounds according to the invention can be used for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal
  • the compounds according to the invention can be used particularly advantageously for the prophylaxis and / or therapy of acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular estrogen-alpha-positive and estrogen-alpha-negative breast carcinomas, multiple myelomas or melanomas.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of benign hyperproliferative diseases such as, for example, endometriosis, leiomyoma and benign prostatic hyperplasia.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of systemic inflammatory diseases, in particular LPS-induced endotoxic shock and / or bacteria-induced sepsis.
  • the compounds according to the invention are also suitable for the prophylaxis and / or therapy of inflammatory or autoimmune diseases such as, for example:
  • Pulmonary diseases associated with inflammatory, allergic and / or proliferative processes chronic obstructive pulmonary diseases of any genesis, especially bronchial asthma; Bronchitis of different origin; all forms of restrictive lung diseases, especially allergic alveolitis; all forms of Pulmonary edema, especially toxic pulmonary edema; Sarcoidoses and granulomatoses, especially Boeck's disease
  • Rheumatic diseases / autoimmune diseases / joint diseases associated with inflammatory, allergic and / or proliferative processes all forms of rheumatic diseases, in particular rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica; reactive arthritis; Inflammatory soft tissue diseases of other origin; arthritic symptoms of degenerative joint disease (arthrosis); traumatic arthritis; Collagenoses of any genesis, e.g. systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren's syndrome, Still's syndrome, Felty syndrome
  • Vasculitis Panarteritis nodosa, temporal arteritis, erythema nodosum
  • Dermatological disorders associated with inflammatory, allergic and / or proliferative processes atopic dermatitis; Psoriasis; Pityriasis rubra pilaris; erythematous diseases induced by different noxae, e.g. Blasting, chemicals, burns etc .; bullous dermatoses; Diseases of the lichenoid type; pruritus; Seborrheic dermatitis; rosacea; Pemphigus vulgaris; Erythema exudative multiforme; balanitis; vulvitis; Hair loss such as alopecia areata; cutaneous T-cell lymphomas
  • Kidney diseases associated with inflammatory, allergic and / or proliferative processes nephrotic syndrome; all nephritis
  • Liver diseases associated with inflammatory, allergic and / or proliferative processes acute liver cell decay; acute hepatitis of different causes, e.g. viral, toxic, drug-induced; Chronic aggressive and / or chronic intermittent hepatitis
  • Gastrointestinal disorders associated with inflammatory, allergic and / or proliferative processes regional enteritis (Crohn's disease); Ulcerative colitis; Gastritis; reflux esophagitis; Gastroenteritides of other genesis, e.g. native sprue
  • Proctological diseases associated with inflammatory, allergic and / or proliferative processes analgesic; fissures; Hemorrhoids; idiopathic proctitis Eye diseases associated with inflammatory, allergic and / or proliferative processes: allergic keratitis, uveitis, ulceris; conjunctivitis; blepharitis; Neuritis nervi optici; Chlorioditis; Opthalmia sympathica
  • Neurological diseases associated with inflammatory, allergic and / or proliferative processes brain edema, especially tumor-related cerebral edema; Multiple sclerosis; acute encephalomyelitis; Meningitis; various forms of seizures, e.g. BNS-seizures
  • Blood disorders associated with inflammatory, allergic and / or proliferative processes acquired hemolytic anemia; idiopathic thrombocytopenia
  • Tumor diseases associated with inflammatory, allergic and / or proliferative processes acute lymphoblastic leukemia; malignant lymphomas; Lymphogranulomatosen; lymphosarcoma; extensive metastases, especially in breast, bronchial and prostate cancers
  • Endocrine disorders associated with inflammatory, allergic and / or proliferative processes endocrine orbitopathy; thyrotoxic crisis; Thyreoditis de Quervain; Hashimoto's thyroiditis; Graves' disease
  • Severe states of shock e.g. anaphylactic shock, systemic inflammatory response syndrome (SIRS)
  • SIRS systemic inflammatory response syndrome
  • Emesis associated with inflammatory, allergic and / or proliferative processes e.g. in combination with a 5-HT3 antagonist in cytostatic vomiting
  • Pain of inflammatory genesis e.g. lumbago
  • the compounds according to the invention are also suitable for the treatment of viral diseases, such as infections caused by PapiUoma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
  • viral diseases such as infections caused by PapiUoma viruses, herpes viruses, Epstein-Barr viruses, hepatitis B or C viruses, and human immunodeficiency viruses.
  • the compounds according to the invention are also suitable for the treatment of atherosclerosis, Dyslipidemia, hypercholesterolemia, hypertriglyceridemia, peripheral vascular disease, cardiovascular disease, angina, pectoris, ischemia, stroke, myocardial infarction, angioplasty restenosis, hypertension, thrombosis, obesity, endotoxemia.
  • the compounds of the invention are also useful in the treatment of neurodegenerative diseases such as multiple sclerosis, Alzheimers disease and Parkinson's disease.
  • the present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas,
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal
  • the present invention further relates to the compounds according to the invention for the prophylaxis and / or therapy of acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular estrogen-alpha-positive and estrogen-alpha-negative breast carcinomas, multiple myelomas or melanoma.
  • Another object of the invention is the use of the compounds of the invention for the manufacture of a medicament.
  • Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of
  • Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or therapy of
  • Leukemias in particular acute myeolemic leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular hormone receptor-negative, hormone receptor-positive or BRCA-associated breast carcinomas, pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung carcinomas .
  • Another object of the present application is the use of the compounds of the invention for the manufacture of a medicament for the prophylaxis and / or treatment of acute myeloid leukemias, prostate cancer, especially androgen receptor-positive prostate cancer, cervical cancer, breast cancer, especially estrogen-alpha positive and estrogen alpha negative Breast cancer, multiple myeloma or melanoma.
  • Another object of the present application is the use of the compound for the prophylaxis and / or therapy of tumor diseases.
  • a further subject of the present application is the use of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias, prostate carcinomas, in particular androgen receptor-positive
  • Prostate cancer cervical carcinoma, breast cancer, in particular of hormone receptor negative, hormone receptor positive or BRCA-associated breast carcinoma,
  • a further subject of the present application is the use of the compounds according to the invention for the prophylaxis and / or therapy of acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, in particular estrogen-alpha-positive and estrogen-alpha-negative breast carcinomas, multiple Myeloma or melanoma.
  • a further subject of the present application are pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or therapy of leukemias, in particular acute myeolemic leukemias,
  • Prostate cancer especially androgen receptor-positive prostate cancer
  • Hormone receptor-positive or BRCA-associated breast cancers pancreatic carcinomas, renal cell carcinomas, hepatocellular carcinomas, melanomas and other skin tumors, non-small cell lung cancers, endometrial carcinomas and colorectal
  • Carcinomas The present application further relates to pharmaceutical formulations in the form of tablets containing one of the compounds according to the invention for the prophylaxis and / or treatment of acute myeloid leukemias, prostate cancers, in particular androgen receptor-positive prostate carcinomas, cervical carcinomas, breast cancers, especially estrogen-alpha-positive and estrogenic alpha-negative breast carcinoma, multiple myeloma or melanoma.
  • Another object of the invention is the use of the compounds of the invention for the treatment of diseases associated with proliferative processes.
  • Another object of the invention is the use of the compounds of the invention for the treatment of benign hyperplasia, inflammatory diseases, autoimmune diseases, sepsis, viral infections, vascular diseases and neurodegenerative conditions
  • the compounds according to the invention can be used alone or as needed in combination with one or more other pharmacologically active substances, as long as this combination does not lead to undesired and unacceptable side effects.
  • Another object of the present invention are therefore pharmaceutical compositions containing a compound of the invention and one or more other active ingredients, in particular for the prophylaxis and / or therapy of the aforementioned diseases.
  • the compounds according to the invention can be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancerous diseases.
  • the combination of the compounds according to the invention with other substances commonly used for cancer therapy or also with radiotherapy is particularly indicated.
  • Suitable combination active ingredients are:
  • Strontium 89 chloride Synthroid, Tamoxifen, Tamsulosin, Tasonermin, Tastolactone, Taxoter, Teceleukin, Temozolomide, Teniposide, Testosterone Propionate, Testred, Thioguanine, Thiotepa, Thyrotropin, Tiludronic Acid, Topotecan, Toremifene, Tositumomab, Tastuzumab, Teosulfan, Tretinoin, Trexal, trimethylmelamine, trimetrexate, triptorelin acetate, triptorelin pamoate, UFT, uridine, valrubicin, vesnarinone, vinblastine, vincristine, vindesine, vinorelbine, virulizine, zinecard, zinitrate, zostrine, zofran; AB 1-007, Acolbifen, Actimmun, Affinitak, Amin
  • the compounds according to the invention can be combined with anti-hyperproliferative agents which can be by way of example-without this enumeration being conclusive:
  • the compounds of the invention may also be combined with biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • biological therapeutics such as antibodies (e.g., Avastin, Rituxan, Erbitux, Herceptin) and recombinant proteins.
  • the compounds according to the invention can also achieve positive effects in combination with other anti-angiogenic therapies, for example with avastin, axitinib, regorafenib, recentin, sorafenib or sunitinib.
  • Combinations with proteasome and mTOR inhibitors as well as antihormones and steroidal metabolic enzyme inhibitors are particularly suitable because of their favorable side effect profile.
  • the following objectives can be pursued with the combination of the compounds according to the invention with other cytostatic or cytotoxic agents:
  • the compounds of the invention may also be used in conjunction with radiotherapy and / or surgical intervention.
  • tert-butyl [(S) ⁇ 1- (4-chlorophenyl) -2,3,9-trimethyl-6-thieno [3,2-y] [1,2,4] triazolo [4, 3-a] [1,4] diazepin-6-yl] acetate is described (Nature 2010, Vol 468, p067ff, P. Filippakopoulos et al.).
  • the cleavage of the tert-butyl ester can be carried out by using strong acids such as trifluoroacetic acid or hydrochloric acid.
  • the exemplary compounds are then obtained by peptide coupling methods known to those skilled in the art.
  • the reagent used was (7-aza-1-benzotriazole-1-yl) -1,3,3-tetramethyluronium hexafluorophosphate (HATU). It should be mentioned only as an example of the reagents known to those skilled in the art (J. American Chem Soc., 1993, 115, 4397).
  • the respective different variations with respect to R1, R2 and Hal for the preparation of the carboxylic acids which were used for the preparation of the compounds according to the invention were described in WO1998 / 11111.
  • Obtained esters were partially synthesized as racemates and cleaved by suitable methods for separation into the enantiomers. For this purpose, known HPLC methods using a chiral stationary phase were used.
  • the respective tert-butyl esters were prepared and separated into their enantiomers.
  • HATU (7-azal / benzotriazole-1-yl) -1,1,3,3-tetramethyluronium
  • the comparative compound used was tert-butyl [(S) -4- (4-ciphenyl) -2,3,9-trimethyl-6-thieno [3,2-y] [1,2,4] triazole [4,3-a] [1,4] diazepin-6-yl] acetate (VI.
  • the organic phase was dried with magnesium sulfate and the solvent removed in vacuo.
  • the title compound was obtained after chromatography on silica gel (eluent methylene chloride / methanol gradient) and RP-HPLC (XBridge C18 5 ⁇ 100x30 mm, eluent water / acetonitrile gradient, 0.2% saturated ammonia solution as an additive). 0.22 g of the title compound were obtained.
  • the organic phase was dried with magnesium sulfate and the solvent removed in vacuo.
  • the title compound was obtained after chromatography on silica gel (eluent methylene chloride / methanol gradient) and RP-HPLC (XBridge C18 5 ⁇ 100x30 mm, eluent water / acetonitrile gradient, 0.1% formic acid as an additive). 0.13 g of the title compound was obtained.
  • the Ac-H4 peptide may be derived from e.g. Biosyntan (Berlin, Germany).
  • each substance typically 11 different concentrations of each substance (0.1 nM, 0.33 nM, 1.1 nM, 3.8 nM, 13 nM, 44 nM, 0.15 ⁇ , 0.51 ⁇ , 1.7 ⁇ , 5.9 ⁇ and 20 ⁇ ) were measured as duplicates on the same microtiter plate.
  • 100-fold concentrated solutions in DMSO were prepared by serial dilutions (1: 3.4) of a 2 mM stock solution in a clear, 384-well microtiter plate (Greiner Bio-One, Frickenhausen, Germany). From this 50 nl were transferred to a black test plate (Greiner Bio-One, Frickenhausen, Germany).
  • the assay was started by adding 2 ⁇ of a 2.5-fold concentrated BRD4 solution (usually 10 to 50 nM final concentration in the 5 ⁇ of the reaction volume) in aqueous assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl). , 0.25 mM CHAPS and 0.05% serum albumin (BSA)] to the substances in the test plate. This was followed by a 10 minute incubation step at 22 ° C for the pre-equilibration of putative complexes between BRD4 and the substances.
  • aqueous assay buffer [50 mM HEPES pH 7.5, 50 mM sodium chloride (NaCl). , 0.25 mM CHAPS and 0.05% serum albumin (BSA)]
  • BRD4 / Ac-H4 complexes were determined by measuring the resonance energy transfer from the streptavidin-Eu cryptate to the anti-6His-XL665 antibody that is in the reaction.
  • the fluorescence emission at 620 nm and 665 nm after excitation at 330-350 nm were measured in a TR-FRET instrument, eg a Rubystar or Pherastar (both from BMG Lab Technologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
  • the ratio of emission at 665 nm and at 622 nm (ratio) was taken as an indicator of the amount of BRD4 / Ac-H4 complexes formed.
  • the data obtained (ratio) were normalized with 0% inhibition equal to the mean of the measurements of a set of controls (typically 32 data points) containing all reagents. Instead of test substances, 50 ⁇ l of DMSO (100%) were used. 100% inhibition was the mean of the measurements from a set of controls (typically 32 data points) containing all reagents except BRD4.
  • the ability of the substances to inhibit the proliferation of various cell lines was determined.
  • Cell viability was determined using the alamarBlue® reagent (Invitrogen). The cells were grown in different densities (MOLM-13, LAPC-4, MDA-MB-231 and MOLP-8: 4000 cells well, VCaP: 16000 cells / well, LNCaP: 2000 cells / well, MCF-7 and HeLa-MaTu : 1000 cells / well, B16F10: 400 cells / well) in ⁇ growth medium seeded on 96well microtiter plates. After an overnight incubation at 37 ° C, the fluorescence values were determined (CI values).
  • the plates were then treated with various dilutions of the substance and incubated for 96 hours (MOLM-13, MCF-7, MDA-MB-231, HeLa-MaTu and B16F10 cells), 120 hours (MOLP-8 cells) and 168 hours (LAPC, VCaP and LNCaP cells) at 37 ° C. Subsequently, the fluorescence values were determined (CO values). For data analysis, the CI values were subtracted from the CO values and the results compared between cells that were different
  • Concentrations are added to the plasma side and bind to plasma proteins.
  • the unbound portion of the test substance passes through the membrane and spreads on both sides until an equilibrium is established (approximately after 6-8h at 37 ° C).
  • the substance concentration on buffer and plasma side determined by LC-MS analysis.
  • both sides are brought to dilution with buffer or plasma on the same matrix (10% plasma) and then precipitated with methanol. From the quotient of the buffer and plasma concentration, the free (unbound) fraction (fu) is calculated.
  • the free (unbound) fraction is calculated.
  • the substance is dialyzed in buffer against buffer to check the non-specific binding to the apparatus and membrane and the adjustment of the equilibrium.
  • the precipitated samples are additionally diluted 1: 100 with ACN / H 2 O (80/20, v / v) + internal standard and corresponding aliquots are measured by means of LCMS.
  • the test substance is added to a control matrix (calibration samples) in 5-9 concentrations corresponding to the determination range of the analytical method, eg 0, 1, 10, 100, 1000, 5000 nM. This is done by weighing solids and dissolving in DMSO (usually in the stock solution). This stock solution is further diluted 1:10 with DMSO (100 ⁇ ).
  • the calibration samples are then added 1: 5 (v / v) with ACN + internal standard (solution A) and processed analogously to the plasma samples.
  • the calibration series in solvent is analogous to the described plasma calibration.
  • the test substance is prepared in ACN / FhO (50/50, v / v) and the samples are then mixed 1: 5 (v / v) with ACN + internal standard. This series is used to calibrate the diluted samples. From these obtained concentration-time profiles the following PK parameters are calculated:
  • NMRI nude mice were inoculated subcutaneously into the right flank on day 0 with 2 x 10 6 MOLM-13 cells in 0.1 ml of matrigel.
  • the treatment with Comparative Example VI, Embodiment 1 or 2 was started on Day 3 after tumor inoculation.
  • Comparative Example VI was dissolved in 20% HP betacyclodextrins in saline (0.2% NaCl in water).
  • Embodiment 1 and Embodiment 2 were dissolved in 40% PEG400, 5% ethanol, 25% solutol. The substances were administered orally daily for 11 days (Day 3 to Day 14).
  • Comparative Example VI was administered at a daily dose of 70 mg / kg (maximum tolerated dose), or 40 mg / kg.
  • Embodiments 1 and 2 were applied at a daily dose of 200 (highest dose used), 120 and 70 mg / kg, respectively.
  • Comparative Example C1 was dissolved in 20% HP betacyclodextrin in saline (0.2% NaCl in water) and the exemplary embodiment 2 in 40% PEG400, 5% ethanol, 25% solutol. The substances were administered orally for 10 days (Day 2 to Day 11).
  • Comparative Example VI was applied at a dose of 70 mg / kg (maximum tolerated dose) or 55 mg / kg.
  • Embodiment 2 was applied at a dose of 160 or 120 mg / kg.
  • Table 2 shows the results from the binding assay.
  • Tables 3a, 3b and 3c show the results from the cell proliferation assays. Tab. 3a
  • Table 4 shows the results from the determination of plasma protein binding. Tab. 4
  • Example protein binding expressed as% fu
  • Table 5 shows the plasma concentrations determined in the in vivo experiment (mouse) and Table 6 the determined pharmacokinetic parameters.
  • the AUC (o-tiast), nonn, u indicates that Examples 1 and 2 according to the invention have a higher unbounded exposure after single oral administration compared to Comparative Example VI in the mouse activation species.
  • the mouse thus has higher dose-normalized free
  • Table 7 shows the results from the in vivo compatibility test (mouse).
  • Reference compound VI was tolerated at a daily dose of 100 mg / kg in the 7 days. Weight loss was highest at 10% on the 9th day of treatment. When administered twice daily at 100 mg / kg, the substance was not tolerated as 2 substance-related deaths were observed on the 6th day of treatment.
  • the maximum tolerated treatment dose (MTD) at 5 days was 50 mg / kg twice daily, with a maximum body weight loss of 7% at day 6.
  • Embodiments 1 and 2 were well tolerated at all doses tested once or twice a day.
  • the maximum tolerated treatment dose was> 200 mg / kg daily or> 100 mg / kg twice daily after 5 days of treatment. Body weight loss was less than 3% in all groups.
  • the embodiments 1 and 2 showed better compatibility in mice than the comparison substance VI.
  • the maximum tolerated treatment dose for the single daily regimen was> 200 mg / kg for Examples 1 and 2, and 100 mg / kg for Comparative VI.
  • the maximum tolerated treatment dose for twice daily administration was> 100 mg / kg for Examples 1 and 2, and 50 mg / kg for Comparative VI.
  • Comparative Example VI The highest dose of Comparative Example VI was biologically active since 20% T / C was measured on day 14. The low dose was inactive and had a T / C value of 54%. The highest dose (200 mg / kg) of Example 1 inhibited tumor growth (T / C value 39%), the 120 mg / kg dose also showed activity (T / C value 46%) and the lowest dose was inactive ( T / C value 58%). The highest dose (200 mg / kg) of Embodiment 2 was active and had a T / C value of 23%. Lower doses (120 and 70 mg / kg) also had effects on tumor growth (T / C value 46%), but these were not statistically significant. Statistical significance is defined as P ⁇ 0.05.
  • the treatment with Comparative Example VI resulted in a weight loss of 6 and 2% at the 160 and 120 mg / kg dose, respectively.
  • Embodiment 2 resulted in a weight loss of 5 and 2% at the 160 and 120 mg / kg dose, respectively.
  • One mouse (out of 12) died on day 12 in both groups treated with Comparative Example VI.
  • a mouse that had lost over 20% in weight had to be killed on day 10.
  • the treatment had to be interrupted on some days because some mice had more than 10%
  • the highest tolerated dose (MTD) was 55 mg / kg for the
  • Comparative Example VI Comparative Example VI and 120 mg / kg for Embodiment 2. At these doses both substances were significantly active. Comparative Example VI showed a T / C value of 33% and Embodiment 2 a T / C value of 27%.

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Abstract

L'invention concerne 6H-thiéno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazépine, destinée notamment à des applications thérapeutiques, des agents pharmaceutiques et leur utilisation en thérapie, en particulier pour la prophylaxie et la thérapie de maladies tumorales.
EP12766291.4A 2011-09-01 2012-08-27 6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine Withdrawn EP2751114A1 (fr)

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Application Number Priority Date Filing Date Title
DE102011082013A DE102011082013A1 (de) 2011-09-01 2011-09-01 6H-Thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine
PCT/EP2012/066600 WO2013030150A1 (fr) 2011-09-01 2012-08-27 6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine

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EP2751114A1 true EP2751114A1 (fr) 2014-07-09

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TW (1) TW201313725A (fr)
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US20140213575A1 (en) 2014-07-31
UY34308A (es) 2013-04-05
JP2014525421A (ja) 2014-09-29
WO2013030150A1 (fr) 2013-03-07
CA2846692A1 (fr) 2013-03-07
CN103827120A (zh) 2014-05-28
DE102011082013A1 (de) 2013-03-07
TW201313725A (zh) 2013-04-01

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