US20180311257A1 - Selective hdac8 inhibitors and their uses - Google Patents

Selective hdac8 inhibitors and their uses Download PDF

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US20180311257A1
US20180311257A1 US15/771,550 US201615771550A US2018311257A1 US 20180311257 A1 US20180311257 A1 US 20180311257A1 US 201615771550 A US201615771550 A US 201615771550A US 2018311257 A1 US2018311257 A1 US 2018311257A1
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alkyl
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Franz-Josef Meyer-Almes
Christian MEYNERS
Alexander KLEINSCHEK
Patricia HAUS
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Hochschule Darmstadt
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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to small molecule compounds based on benzopyrimido- or benzoimidazo-thiazin-imine as well as their (synthesis) intermediates and their use as HDAC inhibitors, in particular HDAC8 inhibitors.
  • the present invention also relates to the use of said compounds in the treatment of cancer and as therapeutic agents for eukaryotic parasites and respective methods of treatment.
  • cancer is still one of the most threatening diseases in common societies. 13% of the worldwide deaths (7.9 million people) in 2007 were caused by cancer. As the second most common cause of death (USA), exceeded only by heart diseases, cancer remains a burden to the health and even the funds off many societies (see e.g. Cancer Facts & Figures 2009).
  • the start of a cancer disease can be caused by environmental influences or the incorporation of toxins into a healthy cell, leading to several damages in its DNA.
  • Cancer cells are characterized by their out-of-control growth, their invasion into different tissues and the extensive spreading over the whole body through bloodstream and lymph system migration. Conventionally, cancer is treated by a mixture of chemotherapy, surgery and radiation, depending on the individual type of cancer. For a long time DNA crosslinking agents like cisplatin were applied in treatments with chemotherapy to induce apoptosis.
  • HDACs histone deacetylases
  • the DNA is structurally tensely packed by forming nucleosomes, which comprise of multiple units of a protein octamer and attached convoluted DNA.
  • nucleosomes which comprise of multiple units of a protein octamer and attached convoluted DNA.
  • Those proteins called histones, have a strong influence on the accessibility for transcriptional proteins by binding the DNA over acetylated histone-lysine residues.
  • Acetylated lysine residues form tense structures with the negatively charged backbone of the DNA leading to reduced gene expression.
  • HDACs play a great role in controlling the acetylation state of lysine residues located at the ends of histones. Occurring as a natural substrate, acetylated lysines become deacetylated by HDACs resulting in reduced gene expression due to a less accessible DNA structure. The loss of acetylations can be restored by the antagonistic histone acetyl-transferases (HATs).
  • HATs antagonistic histone acetyl-transferases
  • HDACs are associated with several diseases and vice versa are valid targets for cancer treatments (Bieliauskas and Pflum, 2008).
  • HDAC proteins In humans, the overall family of HDAC proteins contains 18 different members separated into four classes by their homology to yeast proteins, cellular localization and the structure of their active sites.
  • Class I comprises of HDAC-1, -2, -3 and -8 which are homologue to the yeast protein RPD3 and retain mostly located in the nucleus.
  • Class II HDAC members are divided into the further subclasses IIa and IIb.
  • Class IIa Includes HDAC-4, -5, -7 and -9 which are homologue to yeast HDA1-deacetylase and contain one active site.
  • HDAC IIb members HDAC-6 and -10 contain two active sites. However HDAC-10 carries only one completely functional active site while the second C-terminally localized domain lacks important residues of the active site.
  • Class IIa members have the possibility of shuttling between cytoplasm and the nucleus.
  • HDAC IIb members are localized in the cytoplasm.
  • the Class IV member HDAC-11 shares a similar catalytic domain with Class I and H members. Yet, no substrate could be identified for this protein.
  • All Class I, II and IV members are zinc-dependent deacetylases.
  • Class III proteins are NAD + dependent and denoted as Sirtuins due to their yeast homologue SirT2 (Finnin et al., 1999; Schrump 2009; Marks and Xu, 2009).
  • HDACs are involved in different non-redundant processes, which are tissue specific. Knock-out of HDAC-1, -2, -3 or -7 in mice are lethal in early embryonic states due to aberrant angiogenesis or cell cycle control. Mice with knock-out for HDAC-4, -5, -6, or -9 are viable with occurring abnormalities in cardiovascular, bone and muscle development. In cancer tissue a single knock-down of one HDAC results in specific symptoms. For example, HDAC-2 knock-down in colon cancer cells induces growth arrest, while lagging this effect in osteosarcoma or breast-cancer.
  • HDACi's histone deacetylase inhibitors
  • hydroxamates are the most enlightened group until today.
  • their structure consists of a variable cap group and a metal-binding hydroxamic acid group. Both parts are connected through an aliphatic linker.
  • This schedule is basically in accordance to the natural substrate which complexes the zinc in the active site with an acetyl group instead of the hydroxamic acid.
  • One of the first potent hydroxamate HDACi's was isolated from Streptomyces bydroscopicus : Trichostation A (TSA) (Kim et al., 2000). Based on this structure, a second very potent HDACi was synthesized: Vorinostat (SAHA) (Butler et al., 2000). SAHA was one of the first HDACi that passed all clinical trials and was applied for treatment of cutaneous T-cell lymphoma (CTCL).
  • TSAHA Trichostation A
  • HDA8 to be involved in various cancer diseases like T-cell lymphoma (Balasubramanian et al., 2008; U.S. Pat. No. 8,906,954), neuroblastoma (Oehme et al., 2009), urothelial cancer (Niegisch et al., 2013) and breast cancer (Park et al., 2011) as well as in neural crest development (Haberland et al., 2009).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen; halogen, such as I, Cl, Br, F, NO 2 , CN, SO 3 , N(R 10 ) 2 , O—X, S—X, NR 8 —X, —NR 10 C( ⁇ O)—X, S( ⁇ O)—X, S( ⁇ O) 2 —X, NHS( ⁇ O) 2 —X, C 1 -C 6 alkyl-X, C 2 -C 6 alkenyl-X, C 2 -C 6 alkynyl-X, C 1 -C 6 heteroalkyl-X, C 1 -C 6 fluoroalkyl-X, partially fluorinated C 1 -C 6 alkyl-X, C 1 -C 6 alkyl-O—X, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR
  • X is hydrogen, or a substituted or unsubstituted group selected from aryl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 3 alkylaminoC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkylaminoC 1 -C 3 alkoxy, C 2 -C 5 heterocycloalkylC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 2 alkyl, CN, NO 2 , SO 3 , CO 2 R 9 , C( ⁇ O)R 9 , S—R 9 , S( ⁇ O)—R 9 , S( ⁇ O) 2 —R 9 , NR 10 C( ⁇ O)—R 9 , C( ⁇ O)N(R 10 ) 2 , S( ⁇ O) 2 N(
  • R 8 is selected from hydrogen, C 1 -C 6 alkyl, phenyl or benzyl;
  • R 9 is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, C 2 -C 5 heterocycloalkyl, aryl, and heteroaryl;
  • R 10 and R 11 are each independently selected from hydrogen, or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl;
  • HDAC histone deacetylase
  • C 1 -C 6 alkyl-X C 2 -C 6 alkenyl-X, C 2 -C 6 alkynyl-X, C 1 -C 6 heteroalkyl-X, C 1 -C 6 fluoroalkyl-X, partially fluorinated C 1 -C 6 alkyl-X, C 1 -C 6 alkyl-O—X, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR 8 —X, C 1 -C 3 alkyl-NR 8 —C 1 -C 3 alkyl —X, C 1 -C 6 alkyl-C( ⁇ O)NR 8 —X, C 1 -C 3 alkyl-C( ⁇ O)NR 8 —C 1 -C 3 alkyl-X, C 1 -C 6 alkyl-NR 8 C( ⁇ O)—X, C 1 -C 3 alkyl-C( ⁇ O)NR 8
  • X is hydrogen, or a substituted or unsubstituted group selected from aryl, heteroaryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 3 alkylaminoC 1 -C 3 alkoxy, hydroxyC 1 -C 3 alkylaminoC 1 -C 3 alkoxy, C 2 -C 5 heterocycloalkylC 1 -C 3 alkoxy, C 2 -C 8 heterocycloalkylC 1 -C 2 alkyl, CN, NO 2 , SO 3 , CO 2 R 9 , C( ⁇ O)R 9 , S—R 9 , S( ⁇ O)—R 9 , S( ⁇ O) 2 —R 9 , NR 10 C( ⁇ O)—R 9 , C( ⁇ O)N(R 10 ) 2 , S( ⁇ O) 2 N(
  • R 8 is selected from hydrogen, C 1 -C 6 alkyl, phenyl or benzyl;
  • R 9 is a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl;
  • R 10 and R 11 are each independently selected from hydrogen, or a substituted or unsubstituted group selected from C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, partially fluorinated C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, and heteroaryl;
  • HDAC histone deacetylase
  • this object is solved by a compound according to the invention or pharmaceutical composition of the present invention for use in the treatment of cancer.
  • this object is solved by a compound according to the invention or pharmaceutical composition of the present invention for use as therapeutic agent against eukaryotic parasites.
  • this object is solved by a compound according to the invention or pharmaceutical composition of the present invention for use in the treatment of infections with eukaryotic parasites.
  • this object is solved by a method of treatment of cancer, comprising the step of
  • this object is solved by a method of an infection with eukaryotic parasites, comprising the step of
  • the present invention provides a class of small molecule compounds and their use as HDAC inhibitors.
  • a compound of the present invention is a compound having the general formula I or II or III or IV.
  • a compound of the present invention is a compound having the general formula I or II
  • a compound of the present invention is a compound having the general formula III or IV:
  • a compound of the present invention having general formula III or IV is a compound which is an intermediate/a synthesis intermediate of a compound having general formula I or II.
  • C 1 -C 6 alkyl examples are: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
  • C 2 -C 6 alkenyl examples are: ethenyl, 1-methyl-ethenyl, cis-2-methyl-ethenyl, trans-2-methyl-ethenyl, cis-1,2-dimethyl-ethenyl, trans-1,2-dimethyl-ethenyl, cis-1-propenyl, trans-1-propenyl, 2-propenyl, cis-1-buthenyl, trans-1-buthenyl, cis-2-buthenyl, trans-2-buthenyl, or 3-buthenyl.
  • C 2 -C 6 alkynyl examples are: ethynyl, 1-propynyl, 2-propynyl, 3-methyl-1-propynyl, 3,3-dimethyl-1-propynyl, 1-methyl-2-propynyl, 1,1-dimethyl-2-propynyl, 1-buthynyl, 2-buthynyl, or 3-buthynyl.
  • C 3 -C 10 cycloalkyl examples are: cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • C 1 -C 6 alkoxy examples are: methoxy, ethoxy, or propoxy.
  • C 2 -C 10 heteracycloalkyl examples are: quinolizinyl, dioxinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazinyl, tetrahydropyridinyl, piperazinyl, oxazinanonyl, dihydropyrrolyl, dihydroimidazolyl, tetrahydrofuranyl, tetrahydropyranyl, dihydrooxazolyl, oxiranyl, pyrrolidinyl, pyrazolidinyl, dihydrothienyl, imidazolidinonyl, pyrrolidinonyl, dihydrofuranonyl, dioxolanonyl, thiazolidinyl, piperidinonyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, or tetrahydro
  • heteroaryl examples are: pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, 7-azaindolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofura
  • Si 1 -Si 3 silyl examples are: trimethylsilyl, triethylsilyl, triisopropylsilyl, or tert-butyldimethylsilyl.
  • Si 2 -Si 4 siloxane examples are: dimethylsiloxy, ethylmethylsiloxy, diisopropylsiloxy, di-tert-butylsiloxy, (trimethylsiloxy)dimethylsilyl.
  • the compounds of the present invention are provided as inhibitors of enzymes of the histone deacetylase (HDAC) family.
  • HDAC histone deacetylase
  • the compounds of the present invention selectively inhibit HDAC8.
  • An inhibitor is “selective” as used herein if its potency (which is proportional to the inverse of K i or IC 50 values) against HDAC8 is at least 10 times higher compared to each of the other HDAC isoform.
  • the compounds of the present invention are based on benzopyrimido- or benzoimidazo-thiazin-imine.
  • n is more than 1, such as 2, 3, 4, 5, 6 or 7,
  • R 1 and/or R 2 of each C atom are different from each other.
  • a compound of the present invention is not P2742 (ND 404,182; 6H-6-Imino-(2,3,4,5-tetrahydropyrimido)[1,2-c]-[1,3]benzothiazine) with the following formula:
  • the compound has general formula II and
  • the compound is selected from:
  • the compound is selected from 13b, 13c, 13d, 13e, 13f, 13g, 13h, 13i, 13j, 13k, 13l and 13m, more preferably 13b, 13c, 13d, 13e, 13f, 13g, 13h, 13j, 13k, 13l and 13m, more preferably 13b, 13c, 13d, 13e, 13f, 13g, 13h, 13j, 13k, 13l and 13m
  • the compounds of the present invention are based on benzopyrimido- or benzoimidazo-thiones.
  • the compound has general formula III and
  • the compound is compound 12x (“KA192”).
  • the compound has general formula m and
  • the compound is compound 12h.
  • the compound has general formula m and
  • the compound is compound 12g.
  • the compound has general formula III and
  • the compound is compound 12k.
  • the compound has general formula III and
  • the compound is compound 12t.
  • the compound having general formula III is selected from compound 12x (KA192), 12g, 12k, 12t and 12h.
  • the compound has general formula IV and
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising
  • the pharmaceutical composition can optionally comprise a further agent or drug, such as cytostatic compound(s).
  • the pharmaceutical composition is used in a combination therapy together with other anti-cancer drug(s).
  • the pharmaceutical composition is for oral application/administration.
  • the present invention provides a compound according to the present invention or the pharmaceutical composition according to the present invention for use in the treatment of cancer.
  • the cancer is selected from
  • HDA8 to be involved in various cancer diseases like T-cell lymphoma (Balasubramanian et al., 2008; U.S. Pat. No. 8,906,954), neuroblastoma (Oehme et al., 2009), urothelial cancer (Niegisch et al., 2013) and breast cancer (Park et al., 2011) as well as in neural crest development (Haberland et al., 2009).
  • the present invention provides a compound according to the present invention or the pharmaceutical composition according to the present invention for use as therapeutic agent against eukaryotic parasites.
  • the present invention provides a compound according to the present invention or the pharmaceutical composition according to the present invention for use in the treatment of infections with eukaryotic parasites.
  • the eukaryotic parasites are preferably Schistosoma mansoni or Plasmodium falciparum.
  • the compound or pharmaceutical composition of the present invention are used in combination with further agent(s) or drug(s), such as cytostatic compound(s).
  • compound or pharmaceutical composition of the present invention are used in a combination therapy together with other anti-cancer drug(s).
  • the medical use of the present invention comprises the administration of a therapeutically effective amount of a compound of the present invention or of a pharmaceutical composition of the present invention.
  • the present invention provides a method of treatment of cancer.
  • Said treatment method comprises the step of administering to a subject a therapeutically effective amount of a compound according to the invention or a pharmaceutical composition of the invention.
  • a “therapeutically effective amount” of a compound according to the invention preferably refers to the amount necessary to achieve the therapeutic outcome.
  • the dosage of the compounds according to the invention is carried out in the order of magnitude customary for histone deacetylases inhibitors.
  • the customary dose in the case of systemic therapy may be between 0.03 and 60 mg/kg body weight per day, (i. v.) may be between 0.03 and 60 mg/kg/h.
  • the customary dose in the case of systemic therapy is between 0.3 and 30 mg/kg per day, (i. v.) is between 0.3 and 30 mg/kg/h.
  • the choice of the optimal dosage regime and duration of medication, particularly the optimal dose and manner of administration of the active compounds necessary in each case can be determined by a person skilled in the art on the basis of his/her expert knowledge.
  • the cancer is selected from
  • the treatment method of the invention comprises
  • the present invention provides a method of treatment of an infection with eukaryotic parasites.
  • Said treatment method comprises the step of
  • a “therapeutically effective amount” of a compound according to the invention preferably refers to the amount necessary to achieve the therapeutic outcome.
  • the eukaryotic parasites are preferably Schistosoma mansoni or Plasmodium falciparum.
  • the present invention discloses novel HDAC inhibitors. Furthermore, the present invention discloses pharmaceutical compositions comprising HDAC inhibitor(s) and exemplary treatment regimens for various diseases. These especially include cancer and infections with eukaryotic parasites.
  • HDACi's histone deacetylase inhibitors
  • This schedule is basically in accordance to the natural substrate which complexes the zinc in the active site with an acetyl group instead of the hydroxamic acid.
  • One of the first potent hydroxamate HDACi's was isolated from Streptomyces bydroscopicus : Trichostation A (TSA) (Kim et al., 2000). Based on this structure, a second very potent HDACi was synthesized: Vorinostat (SAHA) (Butler et al., 2000). SAHA was one of the first HDACi that passed all clinical trials and was applied for treatment of cutaneous T-cell lymphoma (CTCL).
  • TSAHA Trichostation A
  • CTCL cutaneous T-cell lymphoma
  • HDA8 to be involved in various cancer diseases like T-cell lymphoma (Balasubramanian et al., 2008; U.S. Pat. No. 8,906,954), neuroblastoma (Oehme et al., 2009), urothelial cancer (Niegisch et al., 2013) and breast cancer (Park et al., 2011) as well as in neural crest development (Haberland et al., 2009).
  • the class of compounds discloses herein are more potent and selective inhibitors for HDAC8 when compared to the known HDAC8-selective inhibitor PCI-34051, and also more effective on cancer cell lines.
  • compounds of general formula III or IV which can be intermediates/synthesis intermediates of the compounds having general formula I or II, are selective HDAC8 inhibitors, which in addition show higher cell stability.
  • 12x increases SMC3 acetylation much stronger than the imine compounds 13a and 13l (see FIG. 6C ) indicating an increased inhibition of HDAC8 within cells.
  • FIG. 1 Structure of HDAC inhibitors.
  • FIG. 2 Characterization of compounds of the invention.
  • FIG. 3 Inhibition of HDACs 1, 5, 7 and 8 by compounds of the invention.
  • the HDAC activity was investigated using a colorimetric assay as described by Wegener et al (2009) using 50 ⁇ M of the substrate Boc-Lys(Ac)-AMC for HDAC1 or 20 ⁇ M of the substrate Boc-Lys(TFA)-AMC for HDAC5, 7 and 8.
  • the IC 50 -values of P2742 were determined to be 3.0 ⁇ M for HDAC1, 0.11 ⁇ M for HDAC5, 0.24 ⁇ M for HDAC7 and 0.012 ⁇ M for HDAC8.
  • the IC 50 -values were 20 ⁇ M for HDAC1, 13 ⁇ M for HDAC5, 0.51 ⁇ M for HDAC7 and 0.20 ⁇ M for HDAC8.
  • the compound KA090 showed IC 50 -values of 34 ⁇ M for HDAC1, 12 ⁇ M for HDAC5, 2.1 ⁇ M for HDAC7 and 0.071 ⁇ M for HDAC8.
  • the IC 50 -values of KA091 were 7.9 ⁇ M for HDAC1, 1.0 ⁇ M for HDAC5, 0.080 ⁇ M for HDAC7 and 0.0055 I M for HDAC8.
  • FIG. 4 Inhibition of HDAC8 and cell proliferation of cancer cells by further compounds of the invention.
  • HDAC8 activity was investigated using a colorimetric assay as described by Wegener et al (2009) using 20 ⁇ M of the substrate Boc-Lys(TFA)-AMC. Increasing concentrations of the thions 12x and 12h inhibit HDAC8 with different potencies.
  • FIG. 5 PCA-Analysis of chemical descriptors characterising compounds of the benzothiazinimine series. Each sphere represents one chemical entity labeled by its code number.
  • FIG. 6 HDAC8 inhibition increases the acetylation level of SMC3, a specific substrate of HDAC8.
  • FIG. 7 HPLC-MS of representative compounds (13e, 13g, 13i).
  • Mass spectra were acquired either in positive or in negative mode scanning over the mass range of 105-1500.
  • the purities of the final compounds were determined using an Agilent 1200 series HPLC system using a C-18 column (Waters Sunfire C18 3.5 ⁇ m, 2.1 mm ⁇ 100 mm) and were found to be >95%. Flash column chromatography was conducted using silica gel (Merck Kieselgel 60, No. 9385, 230-400 mesh ASTM).
  • JURKAT Human T cell leukemia cell line JURKAT (ATCC® TIB152TM)
  • Human breast cancer cell line MCF-7 (ATCC@ HTB22TM)
  • DMEM Dulbecco's modified Eagle's medium
  • 2-Bromobenzaldehyde (10a) (924 mg, 5.00 mmol) was subjected to general procedure, using ethane-1,2-diamine (367 ⁇ L, 330 mg, 5.50 mmol), K 2 CO 3 (2.07 g, 15.0 mmol) and 12 (1.74 g, 6.85 mmol).
  • 2-(2-bromophenyl)-4,5-dihydro-1H-imidazole (11b) was received as orange oil (926 mg, 4.11 mmol, 82%).
  • 2-Bromo-5-chlorobenzaldehyde (10c) (878 mg, 4.00 mmol) was subjected to general procedure, using ethane-1,2-diamine (294 ⁇ L, 265 mg, 4.40 mmol K 2 CO 3 (1.66 g, 12.0 mmol) and I 2 (1.27 g, 5.00 mmol).
  • 2-(2-bromo-5-chlorophenyl)-4,5-dihydro-1H-imidazole (11c) was received as yellowish solid (876 mg, 3.38 mmol, 84%).
  • 2-Bromo-5-chlorobenzaldehyde (10c) (878 g, 4.00 mmol) was subjected to general procedure, using propane-1,3-diamine (367 ml, 327 mg, 4.41 mmol), K 2 CO 3 (1.66 g, 12.0 mmol) and I 2 (1.30 g, 5.12 mmol).
  • 2-(2-Bromo-5-chlorophenyl)-1,4,5,6-tetrahydropyrimidine (11e) was received as yellow solid (992.7 mg, 3.63 mmol, 91%).
  • 2,4-Difluorobenzaldehyde (10f) (1.43 g, 10.0 mmol) was subjected to general procedure, using propane-1,3-diamine (916 ⁇ L, 815 mg, 11.0 mmol), K 2 CO 3 (4.15 g, 30.0 mmol) and I 2 (3.18 g, 12.5 mmol).
  • 2-(2,4-Difluorophenyl)-1,4,5,6-tetrahydropyrimidine (11f) was received as brown solid (1.73 g, 8.80 mmol, 88%).
  • 2,3-Difluorobenzaldehyde (10h) (1.43 g, 10.0 mmol) was subjected to general procedure, using propane-1,3-diamine (916 ⁇ l, 815 mg, 11.0 mmol), K 2 CO 3 (4.15 g, 30.0 mmol) and I 2 (3.16 g, 12.5 mmol).
  • 2-(2,3-Difluorophenyl)-1,4,5,6-tetrahydropyrimidine (11h) was received as brown solid (1.35 mg, 6.89 mmol, 69%).
  • 2,3-Difluorobenzaldehyde (10h) (1.43 g, 10.0 mmol) was subjected to general procedure, using ethane-1,2-diamine (735 ⁇ L, 661 mg, 11.0 mmol K 2 CO 3 (4.13 g, 30.1 mmol) and I 2 (3.19 g, 12.6 mmol).
  • 2-(2,3-difluorophenyl)-4,5-dihydro-1H-imidazole (11i) was received as yellowish solid (1.55 g, 8.51 mmol, 85%).
  • 2-(2-Bromo-6-fluorophenyl)-1,4,5,6-tetrahydropyrimidine (11j) was received as yellowish solid (2.14 mg, 8.32 mmol, 83%).
  • 2-Fluoro-4-methylbenzaldehyde (10k) (1.38 g, 10.0 mmol) was subjected to general procedure, using propane-1,3-diamine (916 ⁇ l, 815 mg, 11.0 mmol), K 2 CO 3 (4.15 g, 30.0 mmol) and I 2 (3.19 g, 12.6 mmol).
  • 2-(2-Fluoro-4-methylphenyl)-1,4,5,6-tetrahydropyrimidine (11k) was received as brown viscous oil (1.93 mg, 10.0 mmol, quant.).
  • 2-Bromo-5-fluorobenzaldehyde (101) (2.04 g, 10.0 mmol) was subjected to general procedure, using propane-1,3-diamine (916 ⁇ l, 815 mg, 11.0 mmol), K 2 CO 3 (4.15 g, 30.0 mmol) and I 2 (3.18 g, 12.5 mmol).
  • 2-(2-Bromo-5-fluorophenyl)-1,4,5,6-tetrahydropyrimidine (11l) was received as colorless solid (1.93 mg, 7.49 mmol, 75%).
  • 2-Fluoro-6-methylbenzaldehyde (10m) (1.01 g, 7.30 mmol) was subjected to general procedure, using propane-1,3-diamine (663 ⁇ l, 590 mg, 7.75 mmol), K 2 CO 3 (2.99 g, 21.7 mmol) and I 2 (2.30 g, 9.06 mmol).
  • 2-(2-Fluoro-4-methylphenyl)-1,4,5,6-tetrahydropyrimidine (11m) was received as yellowish solid (1.13 mg, 5.87 mmol, 80%).
  • 2-Fluoro-5-methylbenzaldehyde (10n) (1.38 g, 10.0 mmol) was subjected to general procedure, using ethane-1,2-diamine (734 ⁇ L, 660 mg, 11.0 mmol), K 2 CO 3 (4.15 g, 30.1 mmol) and I 2 (3.20 g, 12.6 mmol).
  • 2-(2-Fluoro-5methylphenyl)-4,5-dihydro-1H-imidazole (11n) was received as yellowish solid (1.71 g, 9.57 mmol, 96%).
  • HDAC1 The activity of HDAC1 was determined by a colorimetric assay as described by Wegener et al (2003). 1 nM of HDAC1 was incubated with increasing concentrations of the respective compound for 30 minutes at 30° C. The reaction was initiated by addition of 50 ⁇ M of the substrate Boc-Lys(Ac)-AMC. After an incubation of 60 minutes the reaction was stopped by addition of 20 ⁇ M SAHA and the deacetylated substrate was converted into a fluorescent product by the addition of trypsin.
  • HDAC4 The activity of HDAC4 was determined by a colorimetric assay as described by Wegener et al. (2003). 1 nM of HDAC4 was incubated with increasing concentrations of the respective compound for 30 minutes at 30° C. The reaction was initiated by addition of 20 ⁇ M of the substrate Boc-Lys(trifluoracetyl)-AMC. After an incubation of 60 minutes the reaction was stopped by addition of 20 ⁇ M SAHA and the deacetylated substrate was converted into a fluorescent product by the addition of trypsin.
  • HDAC activity was investigated using a colorimetric assay as described by Wegener et al. (2003) using 50 ⁇ M of the substrate Boc-Lys(Ac)-AMC for HDAC1 or 20 ⁇ M of the substrate Boc-Lys(TFA)-AMC for HDAC5, 7 and 8.
  • the IC 50 -values of P2742 were determined to be 3.0 j ⁇ M for HDAC1, 0.11 ⁇ M for HDAC5, 0.24 ⁇ M for HDAC7 and 0.012 ⁇ M for HDAC8.
  • the IC 50 -values were 20 ⁇ M for HDAC1, 13 ⁇ M for HDAC5, 0.51 ⁇ M for HDAC7 and 0.20 ⁇ M for HDAC8.
  • the compound KA090 showed IC 50 -values of 34 ⁇ M for HDAC1, 12 g ⁇ M for HDAC5, 2.1 ⁇ M for HDAC7 and 0.071 ⁇ M for HDAC8.
  • the IC 50 -values of KA091 were 7.9 ⁇ M for HDAC1, 1.0 ⁇ M for HDAC5, 0.080 ⁇ M for HDAC7 and 0.0055 ⁇ M for HDAC8.
  • IC 50 ( ⁇ M) Cp HDAC1 HDAC2 HDAC3 HDAC4 HDAC5 HDAC6 HDAC7 HDAC8 13a 3.6 ⁇ 0.8 32 ⁇ 1.5 >50 8.6 ⁇ 1.5 0.11 ⁇ 0.01 6.7 ⁇ 0.8 0.22 ⁇ 0.02 0.011 ⁇ 0.001 13b >50 >50 >50 >50 >50 >50 >50 >50 1.3 ⁇ 0.7 4.4 ⁇ 0.8 13c 21 ⁇ 1 >50 >50 >50 >50 13 ⁇ 1 32 ⁇ 18 0.5 ⁇ 0.2 0.18 ⁇ 0.02 13d 34 ⁇ 2 >50 >50 >50 >50 12 ⁇ 1 14 ⁇ 1 2.0 ⁇ 0.5 0.072 ⁇ 0.003 13e 7.9 ⁇ 0.2 >50 20 ⁇ 1 5.7 ⁇ 0.3 1.0 ⁇ 0.1 1.2 ⁇ 0.4 0.08 ⁇ 0.02 0.0059 ⁇ 0.0003 13f 2.9
  • GI 50 -values of compounds of the invention on different cell lines in ⁇ M The growth inhibition of the cancer cell lines was determined using the resazurin assay.
  • GI 50 ( ⁇ M) Cpd SK-UT-1 MCF7 JURKAT 13a 736 ⁇ 659 >1000 63 ⁇ 8 13b 343 ⁇ 191 213 ⁇ 50 558 ⁇ 342 13c 64 ⁇ 7 60 ⁇ 6 67 ⁇ 8 13d 106 ⁇ 21 200 ⁇ 58 153 ⁇ 28 13e >1000 >1000 56 ⁇ 9 13f 147 ⁇ 73 >1000 33 ⁇ 3 13g 76 ⁇ 7 >1000 30 ⁇ 3 13h >1000 >1000 42 ⁇ 3 13i 109 ⁇ 29 16 ⁇ 3 24 ⁇ 3 13j 16 ⁇ 3 11 ⁇ 3 17 ⁇ 3 13k 45 ⁇ 16 44 ⁇ 12 36 ⁇ 4 13l 24 ⁇ 5 79 ⁇ 11 16 ⁇ 2 13m 35 ⁇ 2 179 ⁇ 66 23 ⁇ 2
  • the imine function is crucial for very strong inhibition of HDAC8, because the corresponding thione intermediates 12a-m are substantially less potent against this enzyme (see Table 1). Furthermore, the ring size of the nitrogen heterocycle had a tremendous impact on potency: As demonstrated by the direct comparison of three matching pairs of imine compounds (13a/13b, 13e/13c, 13h/13i), the 3,4-dihydrobenzo[e]pyrimido[1,2-c][1,3]thiazin-6(2H)-imines were at least 30 times more potent than the corresponding 2H-benzo[e]imidazo[1,2-c][1,3]thiazin-5(3H)-imines.

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