WO2016116603A1 - Novel phenylphosphates and use thereof as medicaments - Google Patents
Novel phenylphosphates and use thereof as medicaments Download PDFInfo
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- WO2016116603A1 WO2016116603A1 PCT/EP2016/051347 EP2016051347W WO2016116603A1 WO 2016116603 A1 WO2016116603 A1 WO 2016116603A1 EP 2016051347 W EP2016051347 W EP 2016051347W WO 2016116603 A1 WO2016116603 A1 WO 2016116603A1
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- general formula
- radical
- optionally substituted
- compounds
- branched
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- 239000003814 drug Substances 0.000 title claims abstract description 15
- CMPQUABWPXYYSH-UHFFFAOYSA-N phenyl phosphate Chemical class OP(O)(=O)OC1=CC=CC=C1 CMPQUABWPXYYSH-UHFFFAOYSA-N 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 181
- 102000001712 STAT5 Transcription Factor Human genes 0.000 claims abstract description 56
- 108010029477 STAT5 Transcription Factor Proteins 0.000 claims abstract description 56
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- -1 alkoxy radical Chemical class 0.000 claims description 65
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical group NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 44
- 239000002243 precursor Substances 0.000 claims description 40
- 239000004202 carbamide Chemical group 0.000 claims description 22
- 235000013877 carbamide Nutrition 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000003367 polycyclic group Chemical group 0.000 claims description 15
- 238000011275 oncology therapy Methods 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 229910019142 PO4 Inorganic materials 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 claims description 10
- 239000001301 oxygen Substances 0.000 claims description 10
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 9
- 239000012965 benzophenone Substances 0.000 claims description 9
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- QDLAGTHXVHQKRE-UHFFFAOYSA-N lichenxanthone Natural products COC1=CC(O)=C2C(=O)C3=C(C)C=C(OC)C=C3OC2=C1 QDLAGTHXVHQKRE-UHFFFAOYSA-N 0.000 claims description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical group [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000010452 phosphate Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 238000002619 cancer immunotherapy Methods 0.000 claims description 4
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007970 thio esters Chemical class 0.000 claims description 4
- 201000009030 Carcinoma Diseases 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 2
- 150000005840 aryl radicals Chemical class 0.000 claims 2
- OIAQMFOKAXHPNH-UHFFFAOYSA-N 1,2-diphenylbenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1C1=CC=CC=C1 OIAQMFOKAXHPNH-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 15
- 230000005764 inhibitory process Effects 0.000 abstract description 15
- 229940002612 prodrug Drugs 0.000 abstract description 12
- 239000000651 prodrug Substances 0.000 abstract description 12
- 150000003839 salts Chemical class 0.000 abstract description 9
- 230000003993 interaction Effects 0.000 abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 54
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- 238000000034 method Methods 0.000 description 51
- 230000015572 biosynthetic process Effects 0.000 description 47
- 238000003786 synthesis reaction Methods 0.000 description 43
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 230000026731 phosphorylation Effects 0.000 description 23
- 238000006366 phosphorylation reaction Methods 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000000873 masking effect Effects 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- LOLWKWOOTKIJHJ-UHFFFAOYSA-N [4-[(nonanoylamino)methyl]-2-phosphonooxyphenyl] dihydrogen phosphate Chemical compound CCCCCCCCC(=O)NCc1ccc(OP(O)(O)=O)c(OP(O)(O)=O)c1 LOLWKWOOTKIJHJ-UHFFFAOYSA-N 0.000 description 9
- 235000021317 phosphate Nutrition 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000824 cytostatic agent Substances 0.000 description 8
- 230000001085 cytostatic effect Effects 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 229940024874 benzophenone Drugs 0.000 description 7
- 108020001507 fusion proteins Proteins 0.000 description 7
- 102000037865 fusion proteins Human genes 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 238000002875 fluorescence polarization Methods 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- FYZCRINOGJKXQT-UHFFFAOYSA-N (2-phosphonooxyphenyl) dihydrogen phosphate Chemical compound OP(O)(=O)OC1=CC=CC=C1OP(O)(O)=O FYZCRINOGJKXQT-UHFFFAOYSA-N 0.000 description 5
- HKBJBMDIUUKWGG-UHFFFAOYSA-N 6-methyl-2-phosphonooxy-3-propan-2-ylbenzoic acid Chemical compound C(C)(C)C=1C(=C(C(=O)O)C(=CC=1)C)OP(=O)(O)O HKBJBMDIUUKWGG-UHFFFAOYSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- FLLCGDMAXOLXOB-UHFFFAOYSA-N [4-[(8-methylnonanoylamino)methyl]-2-phosphonooxyphenyl] dihydrogen phosphate Chemical compound CC(C)CCCCCCC(=O)NCc1ccc(OP(O)(O)=O)c(OP(O)(O)=O)c1 FLLCGDMAXOLXOB-UHFFFAOYSA-N 0.000 description 5
- 239000004305 biphenyl Substances 0.000 description 5
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- GBZVNKQWXLVYNG-UHFFFAOYSA-N (3-phosphonooxyphenyl) dihydrogen phosphate Chemical compound OP(O)(=O)OC1=CC=CC(OP(O)(O)=O)=C1 GBZVNKQWXLVYNG-UHFFFAOYSA-N 0.000 description 4
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 4
- DTMZHINTUWVLBA-UHFFFAOYSA-N 6-[2-[(3,4-dihydroxyphenyl)methylamino]-2-oxoethoxy]-N-phenylnaphthalene-2-carboxamide Chemical class OC1=C(O)C=C(CNC(=O)COC2=CC=C3C=C(C=CC3=C2)C(=O)NC2=CC=CC=C2)C=C1 DTMZHINTUWVLBA-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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- NHNQCKHMXJEHKA-UHFFFAOYSA-N 1-phosphonooxynaphthalene-2-carboxylic acid Chemical compound P(=O)(O)(O)OC1=C(C=CC2=CC=CC=C12)C(=O)O NHNQCKHMXJEHKA-UHFFFAOYSA-N 0.000 description 3
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- KFIMLORFYLXGBF-UHFFFAOYSA-N 4-methyl-2-phosphonooxybenzoic acid Chemical compound CC1=CC(=C(C(=O)O)C=C1)OP(=O)(O)O KFIMLORFYLXGBF-UHFFFAOYSA-N 0.000 description 3
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- QLZHNIAADXEJJP-UHFFFAOYSA-N Phenylphosphonic acid Chemical class OP(O)(=O)C1=CC=CC=C1 QLZHNIAADXEJJP-UHFFFAOYSA-N 0.000 description 3
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
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- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- NQRYGPXAYYDKJB-UHFFFAOYSA-N phenyl hydrogen phosphonate Chemical class OP(=O)OC1=CC=CC=C1 NQRYGPXAYYDKJB-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Definitions
- the present invention relates to novel phenyl phosphates and naphthyl phosphates, their prodrugs and their (pharmaceutically) acceptable salts and their use as drugs for the selective inhibition of the STAT5 protein, in particular for use in cancer therapy.
- Some types of cancer are known to be poorly responsive to treatment with cytotoxic drugs from the outset. But even in patients with actually treatable cancers, the therapy may fail after some time. One possible reason is resistance, which makes the tumor cells insensitive to cytostatics. Some underlying biological processes are known.
- STAT5b the intracellular Signal Transducer and Activator of Transcription 5 (also referred to as transcription factor STAT5) STAT5b is biologically well-validated and provides a desirable target for the treatment of leukemias and other cancers, such as breast cancer and head and neck cancer ( Nat., Rev. Feb. 4 (2): 97-105.) STAT5 inhibitors are also of particular interest to patients receiving have become resistant to inhibitors of protein kinase Bcr-Abl.
- Glivec also called Gleevec or Imatinib, Novartis
- Tasigna Nilotinib, Novartis
- Sprycel Desatinib, Bristol-Myers Squibb
- Bosulif Bosutinib, Pfizer
- Iclusig Iclusig
- STAT5 proteins There are two STAT5 proteins that are 93% identical in their amino acid sequence. They have redundant and non-redundant functions. Recent scientific evidence suggests that in particular the selective inhibition of STAT5b (without inhibition of STAT5a) could be therapeutically valuable for the treatment of Bcr-Abl-dependent leukemias. (Schaller-Schoenitz M, Barzan D, Williamson AJ, Griffiths JR, Dallmann I, Battmer K, et al., BCR-ABL affects STAT5A and STAT5B differentially., PLoS One 2014, 9 (5): e97243). At the present time, however, no inhibitors of the STAT5 protein are commercially available - it is considered a very sophisticated target.
- STAT5 inhibitors which selectively and directly inhibit the STAT5 protein and can be used in conjunction with the use in a combination of multifactorial therapy, in particular for cancer therapy.
- Previously known STAT5 inhibitors are used in the concentration range of about 3 ⁇ - 50 ⁇ .
- the object of the present invention is therefore to eliminate or minimize the disadvantages known from the prior art and to provide novel chemical compounds which inhibit the transcription factor STAT5, in particular STAT5b, as selectively and potently as possible, in particular for use in cancer therapy provide.
- n 1 or 2
- n is an integer from 0 to 4,
- p is an integer from 0 to 2
- X is O, S, NR 2 or CH 2 ,
- R 1 is H, an optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched alkoxyl radical, a given substituted and / or polycyclic C 5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzophenone, Benzylben- zol-, fluorenyl and triphenylmethane est, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyloses, in particular selected from the group dibenzofuran, xanthene, carbazole and Phenothi- azine radical.
- n 1 or 2
- v is an integer from 0 to 4,
- Y is carboxyl, carbamoyl, carbonate, carbamide, carbamate or urea
- R 3 is H, an optionally substituted and / or branched C 1 - to C 20 -alkyl radical, an optionally substituted and / or branched C 1 - to C 10 -alkoxyl radical, an optionally substituted aryl radical,
- R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, in particular F and Cl, and L Jm
- n is an integer from 0 to 4,
- X is O, S, NR 2 or CH 2 ,
- R is H, an optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched alkoxyl group, a optionally substituted and / or polycyclic C 5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzo phenone, Benzylbenzol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyloses, in particular selected from the group dibenzofuran, xanthene, carbazole, and phenothiazine radical.
- novel compounds of the general formula (I) and novel compounds of the general formula (II) inhibit the STAT5 protein by a selective and specific interaction.
- the advantage of the compounds according to the general formula (I) and compounds of the general formula (II) for use in cancer therapy is that these compounds have at least 50-fold higher activity for the selective inhibition of the STAT5 protein than currently known compounds.
- the compounds according to the general formula (I) and compounds of the general formula (II) for the protein STAT5b compared to STAT5a preferably have a activity which is more than 30 times higher than STAT5a, compared to STAT5a.
- the compounds of the general formula (I) or (II) according to the invention can be used to selectively investigate the function of STAT5b and STAT5a in their natural environment, in particular in genetically unmodified biological systems.
- the selectivity of the compounds of general formula (I) and (II) according to the invention for STAT5b compared to STAT5a is not an exclusion criterion for the substances described in this application.
- a comparable strong activity of the substances against both STAT5 proteins or even preferential inhibition of STAT5a to STAT5b by the substances could also be observed.
- “Inhibition of the STAT5 protein” in the context of the present invention means that by interaction of the STAT5 protein, preferably the STAT5b protein with a low molecular weight compound, preferably the novel phosphates or phosphonates of the general formula (I) or the general formula (II) the phosphorylation of STAT5b on Tyr699 or the phosphorylation of STAT5a on Tyr694 is inhibited
- the STAT5 protein preferably the STAT5b protein
- loses its capacity through interaction with the phosphates or phosphonates according to the invention of the general formula (I) or Formula (II) has the ability to interact with cancer-causing binding partners (eg, proteins) and, at the same time, advantageously induces the initiation of apoptosis (for example, by stimulated caspase activity.)
- Caspases are the most important apoptosis enzymes in animals (programmed cell death).
- the compounds of the formula (I) or general formula (II) according to the invention have a mean inhibitory concentration (IC 50 ) in the range from 10 nmol / L to 500 / mol / L relative to the STAT5b protein , preferably in the range of 100 nmol / L to 100 / mol / L.
- IC 50 mean inhibitory concentration
- low molecular weight organic compounds are understood as meaning molecular compounds which are composed primarily of the elements carbon, hydrogen, oxygen and nitrogen and preferably have a molecular weight in the range from 100 to 1200 g / mol, in particular from 150 to 750 g / mol , especially 200 to 650 g / mol.
- Low molecular weight organic compounds have the significant advantage over large molecules (e.g., nucleotide-based inhibitors such as antisense oligonucleotides or RNA oligonucleotides) of having much better handleability and stability under physiological conditions. Furthermore, low molecular weight, organic compounds are usually cell-like and therefore easier to apply in the cell or an organism.
- the compounds of the general formula (I) particularly advantageously have an IC 50 in the submicromolar, more preferably in the nanomolar concentration range.
- R is a hydrophobic substituent chosen from H, an optionally branched C 3 -Ci2-alkyl radical, such as, n-propyl, / so-propyl, n-butyl, / 'so-butyl, ie / f-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, / ' so-octyl, n-nonyl, / ' so-nonyl, n-dodecyl radical, an optionally polycyclic and / or substituted five-membered or six-membered ring heterocycle and an optionally polycyclic and / or substituted aryl radical.
- R is a hydrophobic substituent chosen from H, an optionally branched C 3 -Ci2-alkyl radical, such as, n-propyl, / so-propyl, n-but
- a "polycyclic aryl radical or heterocycle” is to be understood as meaning a conjugated system which contains at least two arylenes (for example phenylene, naphthylene) which are directly connected to one another, ie in conjugation with one another via an electron donor (for example, nitrogen, oxygen, CH 2 ) directly connected to one another and thus bring about the planarity of the system, such as in a fluorenyl, benzophenone, benzylbenzene, xanthene, carbazole, phenoxyphenyl, phenothiazine or triphenylmethane radical.
- arylenes for example phenylene, naphthylene
- an electron donor for example, nitrogen, oxygen, CH 2
- compounds of the general formula (I) or of the formula (II) in which the substituent R has an optionally polycyclic and / or substituted aryl radical very particularly preferably a fluorenyl, phenyl, biphenyl, naphthalenyl, benzophenone, Benzylbenzene residue is a particularly high binding affinity to the STAT5 protein (ie low IC 50 value).
- such compounds of general formula (I) or of formula (II) wherein R is as defined above have an IC 50 value in the range of 10 nmol / L to 1.5 / mol / L over the STAT5 protein to, more preferably in the range of 50 nmol / L to 1 / mol / L.
- R is an optionally branched C 3 -C 0 -alkyl radical, in particular selected from n-propyl, / so-propyl, n-butyl, / 'so-butyl, ie / f-butyl , n-pentyl, n-hexyl, n-heptyl, ie / f-heptyl, n-octyl, / 'so-octyl, sec-octyl-n-nonyl, /' so-nonyl, sec nonyl group.
- Such substituted compounds of the general formula (I) or of the formula (II) in which R is as defined above have an IC 50 value in the range from 250 nmol / L to 2 / mol / L compared to the STAT5 protein. more preferably in the range of 80 nmol / L to 3 / mol / L.
- L has a substituent R 1 which deviates from H. It was now surprisingly found that, in particular in the case of the defined R 1, in more detail above for R, a is optionally substituted and / or branched C 3 to C 2 alkyl, low IC 50 - values are reached. This is proof of the high binding affinity of these compounds.
- the compound of the general formula (II) according to the invention is adapted in such a way that two phosphate groups or phosphonate groups on the naphthyl derivative are located on the phenyl ring of the phenylphosphate so that n is 2.
- these compounds particularly advantageously have an IC 50 in the submicromolar, more preferably in the nanomolar concentration range.
- novel phenylphosphates of the general formula (I) and novel naphthylphosphates of the formula (II) are:
- n 1 or 2
- Also useful in the present invention are compounds such as pharmacologically acceptable salts, prodrugs, enantiomers, diastereomers, racemic mixtures, crystalline forms, amorphous forms and solvates comprising a novel compound of general formula (I) or formula (II), respectively Use as a drug in cancer therapy and the treatment of cystic fibrosis includes.
- the compounds of the general formula (I) or of the formula (II) can also be present according to the invention in the form of their pharmacologically acceptable salts.
- a pharmacologically acceptable salt is to be understood as meaning chemical compounds of a novel compound of the formula (I) or formula (II) of positively and negatively charged ions which, for example, depend on the substituents of the phosphate or phosphonate according to the invention Treatment with a weak, pharmaceutically acceptable acid or base can be obtained.
- the pharmaceutically acceptable salts are preferably composed of the corresponding base of the compounds of the formula (I) or of the formula (II) and singly or multiply positively charged counterion, in particular selected from alkali metal and alkaline earth metal ions, such as sodium, potassium, calcium , - or magnesium salts. Also preferred are pharmacologically acceptable salts of the compounds of general formula (I) or (II) ammonium salts with ammonia or organic amines, such as mono- or di-lower alkylamines, e.g.
- the present invention also encompasses pharmacologically acceptable prodrugs of compounds of the general formula (I) and of the formula (II).
- prodrugs are esters, ethers or amides of compounds of the general formula (I) or (II) or other compounds which metabolize in the organism to compounds of the general formula (I) or (II).
- the invention also provides precursor compounds (also prodrugs) of compounds according to the general formula (I) of the general formula (IIIa) or (IIIb):
- n 1 or 2
- p is an integer from 0 to 2
- n is an integer from 0 to 4,
- X is O, S, NR 2 or CH 2 ,
- R 1 is H, an optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched alkoxyl radical, an optionally substituted and / or polycyclic C 5 to C 5 -aryl radical, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzophenone, Benzylben- zol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyloses, in particular selected from the group dibenzofuran, Xanthene, carbazole and phenothiazine moiety,
- a "polycyclic aryl radical or heterocycle” is to be understood as meaning a conjugated system which contains at least two arylenes (for example phenylene, naphthylene) which are directly connected to one another, ie in conjugation with one another via an electron donor (for example, nitrogen, oxygen, CH 2 ) directly connected to one another and thus bring about the planarity of the system, such as in a fluorenyl, benzophenone, benzylbenzene, xanthene, carbazole, phenoxyphenyl, phenothiazine or triphenylmethane radical, wherein: the masking group R ° is selected from H, Ci-6-alkyl radical and 0 , wherein 0 is an integer from 0 to 3,
- Y is selected from carboxyl, carbamoyl, cabonate, carbamide, carbamate, urea, thioester,
- Ci -6 - alkyl e.g. cyclopentyl, cyclohexyl.
- C 6- io-aryl especially phenyl
- a and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy.
- Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy.
- the invention also provides precursor compounds (also prodrugs) of the general formula (IVa) or (IVb) of compounds according to the general formula (II):
- n 1 or 2
- v is an integer from 0 to 4,
- Y is carboxyl, carbamoyl, cabonate, carbamide, carbamate or urea
- R 3 is H, an optionally substituted and / or branched, or cyclic C 1 to C 10 -alkyl radical (for example cyclopentyl, cyclohexyl or cycloheptyl), an optionally substituted and / or branched C 1 to C 10 -alkoxyl radical, an optionally substituted aryl radical, R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, especially F and Cl, and * - - where:
- n is an integer from 0 to 4,
- X is O, S, NR 2 or CH 2 ,
- R 1 is H, an optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched alkoxyl group, an optionally substituted and / or polycyclic C5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzo phenone, Benzylbenzol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyloses, in particular selected from the group dibenzofuran, Xanthene, carbazole and phenothiazine residues.
- the masking group R ° is selected from H, Ci-6-Alkylrest and J °, wherein
- 0 is an integer from 0 to 3
- Y is selected from carboxyl, carbamoyl, cabonate, carbamide, carbamate, urea, thioester,
- R 4 is an optionally branched and / or substituted Ci -6 alkyl group or a C 6 - o-l aryl, in particular phenyl, and wherein the variables of the cyclizing masking group ⁇ - ( ⁇ ) ⁇ ⁇ have the following meanings:
- a and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy. It is particularly advantageous for precursor compounds of the general formula (IIIa) and (IIIb) to exhibit increased cell permeability over compounds of the general formula (I) or (II) since negative charges of the phosphate group or of the phosphonate group are masked.
- Cell permeability defined according to the invention as intracellular transport of a low molecular weight compound, wherein the membrane and cell integrity is not disturbed.
- Possible models for the intracellular transport of low molecular weight compounds are known to the person skilled in the art and include inter alia endocytosis (Hällbrink et al., 2001) or receptor-mediated uptake (Tyagi et al., 2001).
- endocytosis Hallbrink et al., 2001
- receptor-mediated uptake Tyagi et al., 2001
- the novel compounds according to the invention are preferably cell-permeable compounds which penetrate into a cell by passage of the lipid bilayer, the cell permeability of the compounds according to the invention not being restricted to specific cells.
- prodrug refers to a pharmacologically inactive or poorly active precursor compound of the compounds of general formula (I) or (II) as defined above, wherein the precursor compound forms a covalent bond between the compound of general formula (I).
- the precursor compound is first in vivo, preferably intracellular, by a chemical modification under physiological conditions (ie by metabolism or metabolization) in the organism into the corresponding pharmacologically active compound of general formula (I). It can also be provided that the prodrug is converted by chemical or biochemical methods in an ex vivo environment into the corresponding pharmacologically active form of a novel compound according to the general formula (I) or the formula (II) becomes.
- Prodrugs can be administered both orally and intravenously to a patient.
- the half-life is preferably a maximum of 10 to 600 minutes.
- the masking group R ° is preferably a C 1 -C 4 -alkoxymethyl group, in particular an acetyl, propionyl, n-butanoyl, isobutanoyl, sec-butanoyl or pivaloyloxymethyl group, a C 1 -C 4 -alkoxycarbonyloxymethyl group, in particular a propyl, n-butyl Butyl, isobutyl, sec-butyl or tert-butyl Oxycarbonyloxymethyl distr, sulfur-containing alkyl groups, in particular S-acyl-2-thioethyl (SATE), S-acylthiopropyl (SATP) or hydroxyethyl disufanylethyl groups ("dithiodiethyl" or DTE), wherein the cleavability of the phosphonic acid esters can be influenced by suitable substituents.
- Examples of particularly preferred phosphonic acid masking groups R ° are iso
- Typical examples of the precursor compounds of the general formula (IIIa) and (IIIb) according to the invention are:
- cyclic phosphonic acid esters are described in which ⁇ - ( ⁇ ) ⁇ ⁇ together preferably an optionally substituted 1-aryl-propane-1, 3-dioxy group or 2- (3-chlorophenyl) - [1, 3,2] dioxaphosphinane.
- Masking groups may also be selected such that steric hindrance around a functional group, especially the phosphonic acid group, is minimized so that the rate of bioconversion is increased and thereby the maximum plasma concentration is reached more quickly.
- precursor compounds of the general formula (IIIa, b) or (IVa, b) are reacted by reaction of a compound of the general formula (I) or (II) with a suitable masking agent (for example an organic acid or Lewis acid).
- a suitable masking agent for example an organic acid or Lewis acid.
- precursor compounds of the general formula (IIIa) or (IVa) are synthesized by reacting compounds of the general formula (I) or (II) according to Method 6.
- precursor compounds of general formula (IIIb) or (IVb) are synthesized by adding open-chain compounds of general formula (I) or (II) with the addition of organic acids or Lewis acids to the corresponding compound of general formula (IIIb) or (IVb) are cyclized.
- the precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention are preferably pH-labile compounds, ie. Molecules with a high stability in the pH range of 7.0 to 7.5, which are much more labile in the range around pH 7.4, so that the precursor compound disintegrate after a certain (predetermined) half-life and the corresponding pharmaceutically active compound of the general Release formula (I).
- prodrugs are sought which have half-lives of between 0.1 and 20 h in the range of pH 6.4.
- Detailed pharmacokinetic measurements allow the final selection of suitable sequestering agents for the synthesis of precursor compounds of the general formula (IIIa, b) or (IVa, b).
- the precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention are cell-permeable, they preferably have such a stability that they are not split intracellularly until they have passed the cell membrane.
- the precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention also have the particular advantage that the corresponding pharmaceutically active compounds of general formula (I) or (II), depending on the individual needs of the patient intracellularly be released.
- the precursor compounds of the general formulas (IIIa, b) or (IVa, b) according to the invention are particularly preferably cleaved after passage of the lipid bilayer in the cells by intracellular esterases. For example, when oxyalkyl groups are used (for example when pivaloyloxymethyl is used), the remaining part of the molecule subsequently breaks down alkylaldehyde (for example formaldehyde) with the release of the active substance.
- alkylaldehyde for example formal
- novel compounds of the formula (I) in particular a phenyl phosphate, and / or a novel compound of the formula (II), in particular a naphthyl phosphate, into an organism depends on the structure of the compound.
- a particularly advantageous property of the novel compounds of the formula (I) or of the formula (II) over conventional nucleotide-based inhibitors is that they are low-molecular-weight, organic compounds in the sense of the invention, for example a bioavailability largely independent of the gastric pH exhibit.
- compounds containing a novel compound according to the general formula (I) and / or the formula (II) are administered to an organism by oral or parenteral administration and absorbed via the mucous membranes.
- pharmaceutical formulations are suitable, for example, in the form of a tablet, capsule or liquid or rectally in the form of suppositories.
- organisms in the context of the present invention are preferably selected from the group of mammals, it being possible with very particular preference for the compounds according to the general formula (I) or (II) to be administered to a human.
- the invention also relates to the compounds of the invention according to the general formula (I), in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa , b) for use in the treatment of carcinoma or multiple sclerosis.
- the general formula (I) in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa , b) for use in the treatment of carcinoma or multiple sclerosis.
- Another object of the invention relates to a pharmaceutical formulation comprising a therapeutically effective amount of at least one novel compound according to the general formula (I), in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa, b), in particular for use in cancer therapy.
- a pharmaceutical formulation comprising a therapeutically effective amount of at least one novel compound according to the general formula (I), in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa, b), in particular for use in cancer therapy.
- novel compounds according to the general formula (I) or the formula (II) and / or their specified precursor compounds according to the general formula (IIIa, b) or (IVa, b) in the pharmaceutical formulation as the only pharmacological gically active ingredient or in combination with at least one cytostatic used to broaden eg the spectrum of action or to prevent development of resistance.
- at least one cytostatic used to broaden eg the spectrum of action or to prevent development of resistance.
- additive or synergistic effects are obtained, ie the effectiveness of the mixture is greater than the effectiveness of the individual components.
- a pharmaceutical formulation according to the invention comprising the compound according to the general formula (I) or the formula (II) and / or their precursor compounds according to the general formula (IIIa, b) or (IVa, b) in combination with at least one cytostatic.
- a pharmaceutical formulation according to the invention thus offers the particular advantage that the formation of resistance in a cytostatic treatment is prevented or at least significantly delayed.
- cytostatics are: folic acid antagonists (eg methotrexate, pemetrexed), pyrimidine analogs (eg 5-fluorouracil, gemcitabine), purine analogs (eg pentostatin, azathioprine) and N- or C-terminally protected oligopeptides (eg bortezomib).
- folic acid antagonists eg methotrexate, pemetrexed
- pyrimidine analogs eg 5-fluorouracil, gemcitabine
- purine analogs eg pentostatin, azathioprine
- N- or C-terminally protected oligopeptides eg bortezomib
- the compound of the invention according to the general formula (I) or the formula (II) and / or precursor compounds according to the general formula (IIIa, b) or (IVa, b) can be administered orally in the form of tablets, capsules, Liquids or syrups may be administered rectally in the form of suppositories or intravenously.
- Preferred fillers for the production of tablets, coated tablets, dragées and hard gelatine capsules are, for example, lactose, starch and derivatives thereof, talc, stearic acids and their salts.
- Preferred excipients for the production of gelatin capsules are, for example, vegetable oils, waxes, fats and liquid polyalcohols.
- suitable excipients for the preparation of solutions or syrups such as, for example, water, pharmaceutically acceptable polyalcohols, sucrose, invert sugar and glucose.
- drug carriers for injection solutions are, for example, selected from water, pharmaceutically acceptable salt solutions, alcohols, polyalcohols, glycerol and vegetable oils.
- the combination of a compound of the invention according to the general formula (I) and the formula (II) and / or one of the precursor compounds given according to the invention in the selective inhibition of the STAT5 protein can advantageously lead to superadditive ("synergistic") effects.
- superadditive for example, the following effects are possible, which exceed the expected effects: reduced application concentration and / or or extended spectrum of activity and / or increased activity of the individual compounds (ie active ingredients) and pharmaceutical formulations
- the pharmaceutical formulation according to the invention therefore comprises the compound according to the general formula (I) in combination with one or more compounds of the formula (II).
- the present invention further encompasses a method for reducing the functionality of the STAT5 protein in a cell or an organism comprising administering a compound of the invention according to the general formula (I) or (II) and / or a corresponding precursor compound of the general Formula (IIIa / b) or (IVa, b) in a physiologically active concentration for inhibiting the STAT5 protein, said compounds selectively interact with the STAT5 protein.
- the invention also encompasses the use of a compound according to the invention according to the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b) or (IVa, b) for the treatment of disease states which are elevated with an STAT5 signaling, especially cancer.
- the invention also encompasses a method of treatment in cancer therapy by administering an effective dose of an inhibitor of the transcription factor STAT5, in particular a compound according to the invention of the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b ) or (IVa, b).
- the method of treatment in this case comprises the application of a pharmaceutical formulation comprising at least one of a compound according to the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b) or (IVa, b) in a physiologically effective concentration.
- the pharmaceutical formulation for the application is solid or liquid, for example. In the form of a tablet, capsule or liquid or rectally in the form of suppositories, so that the pharmaceutical formulation of an organism administered by oral or parenteral administration and resorbed via the mucous membranes.
- an organism for such a treatment are, for example, mammals, such as humans, into consideration.
- the invention also relates to novel compounds according to the general formula (I) or (II) and the corresponding precursor compounds of the general formula (IIIa, b) or (IVa, b) or a mixture for use as a medicament, in particular for an application in cancer therapy.
- the dosage of the novel compounds according to the general formula (I) or (II) but also the precursor compounds of the general formula (IIIa, b) or (IVa, b) depends on various factors, for example the method of administration, the age, weight and health, including the type of organism to be treated.
- the novel compounds of the formula (I) and formula (II) are used individually or as a mixture thereof as medicaments for use in cancer therapy.
- the invention also includes the use of the previously described precursor compounds of the general formula (IIIa, b) and (IVa, b), pharmacologically acceptable salts, enantiomers, diastereomers, racemic mixtures, crystalline forms, amorphous forms and solvates, each containing a novel compound of general formula (I) or (II).
- the invention therefore also relates to the use of the novel compounds of the general formula (I) or formula (II) or a mixture of this kind for the preparation of a pharmaceutical formulation for use in cancer therapy.
- the novel compounds of formula (I) or formula (II) are administered to a patient in an amount of about 0.1-30 mg / kg of body weight per day, and ideally in an amount of 0.5-15 mg / kg of body weight per day.
- the correct dosage is determined both by examining the efficacy of the compound in the cell proliferation - can be determined by determining the patient's toxicity.
- phenylphosphonates or naphthylphosphonates for the selective and potent inhibition of the transcription factor STAT5, in particular STAT5b, since these compounds are not cleaved by enzymes, in particular phosphatases, in the body, in particular in the cell, and are therefore much more stable than the physiological conditions.
- phenylphosphonates or naphthylphosphonates and the corresponding prodrugs thereof have a high long-term stability under physiological conditions and show a very good therapeutic effect over a long period of time.
- the present invention also encompasses the use of a compound of the general formula (I) and / or formula (II) or their precursor compounds according to the invention for the preparation of a pharmaceutical formulation, in particular for use in cancer therapy.
- the invention also provides the use of a compound of the general formula (I) and / or formula (II) or their precursor compounds according to the invention in combination with a cancer immunotherapy for use in the treatment of cancer, wherein advantageously the resistance formation (ie resistance of a Tumors or tumor cells compared to the treatment method used) compared to the treatment methods reduced, in particular is suppressed.
- Cancer immunotherapy methods differentiate between active and passive immunization.
- active immunization the patient is given substances that are supposed to trigger an immune response in his immune system.
- Passive immunization uses antibodies or antibody fragments.
- leukocytes are removed from the patient, cultured ex vivo, and then injected back into the patient.
- the further treatment of cancers is made much more difficult by resistance formation.
- a treatment method with a compound of the general formula (I) and / or formula (II) or its precursor compounds according to the invention thus offers the particular advantage that resistance formation in cancer immunotherapy, in particular the cytostatic treatment, is prevented or at least significantly delayed.
- cytostatics are: folic acid antagonists (eg methotrexate, pemetrexed), pyrimidine analogs (eg 5-fluorouracil, gemcitabine), purine analogs (eg pentostatin, azathioprine) and N- or C-terminally protected oligopeptides (eg bortezomib).
- the present invention is applicable to both the human and veterinary fields.
- patient as used herein thus refers to organisms to be treated, especially humans and animals.
- IR spectra were recorded on a FT-IR spectrometer FT / IR-4100 type A from Jasco as a film or with potassium bromide compacts.
- the molar mass was determined using a high-resolution mass spectrometer with electrospray ionization (HR-ESI-MS) from Bruker-Daltonics.
- Fig. 1 shows the synthesis scheme for access to compound (13).
- Fig. 2 shows the scheme of induced signal transduction via STATs by activated cell surface receptors and non-receptor tyrosine kinases such as Src or Bcr-Abl.
- a small-molecule ligand of the SH2 domain (symbolized by the triangle) of a STAT protein inhibits signal transduction via the STAT protein in question by inhibiting phosphorylation on the conserved tyrosine residue C-terminal of the transactivation domain.
- the illustration is based on the literature reference. 31
- Fig. 3 shows the selective inhibition of STAT5b tyrosine phosphorylation by 17, the pivaloyloxymethyl ester of 13.
- Figure 4e) shows the quantification of the pSTAT5a GFP bands (STAT5a-GFP fusion protein phosphorylated on STAT5a Tyr694) normalized against STAT5a-GFP (STAT5a-GFP fusion protein independent of the phosphorylation state on STAT5a Tyr694). The error bars indicate the standard deviation of two independent experiments.
- Fig. 5 f the inhibition of tyrosine phosphorylation of endogenous STAT5 by 0.3 ⁇ - 10 ⁇ 17 in K562 cells.
- the negative control compound 18 (10 ⁇ ) does not inhibit the phosphorylation of endogenous STAT5.
- Upper blot with phosphorylation-dependent STAT5 antibody. It recognizes endogenous STAT5b and STAT5a only when phosphorylated on Tyr699 (STAT5b) or Tyr694 (STATa).
- Second-highest blot with phosphorylation-independent STAT5 antibody. It recognizes STAT5a and STAT5b independently of phosphorylation on Tyr699 (STAT5b) and Tyr694 (STAT5a), respectively.
- Lower blot with antibody to actin.
- Fig. 5 g) shows the quantification of the endogenous pSTAT5 bands normalized against endogenous STAT5 independent of the phosphorylation state. The error bars indicate the standard deviation of four independent experiments.
- Fig. 6 h the time dependence of tyrosine phosphorylation of the STAT5b-GFP fusion protein by 17 in K562 cells transfected with STAT5b-GFP. The cells were treated with 10 ⁇ M 17 for the indicated times.
- Upper blot with phosphorylation-dependent STAT5 antibody. This recognizes STAT5b only if it is phosphorylated on Tyr699.
- Second-highest blot with phosphorylation-independent STAT5 antibody. This recognizes STAT5b independently of phosphorylation on Tyr699.
- a separate gel was made to check for uniform transfection using the GFP tag.
- Figure 7 shows the binding of the BODIPY-FL-labeled derivative of compound (31) as compound (10) to a STAT5 protein derivative (native STAT5b, STAT5b point mutant Arg618Ala, Arg618Lys and Trp641Ala, native STAT5a) by increasing fluorescence polarization ,
- STAT5b The analysis of the substance activities against STAT5b was carried out according to the principle of fluorescence polarization and follows the published procedure. ' 3 "51 To obtain the STAT5b protein, the human STAT5b nucleotides coding for amino acids 136-703 were amplified by PCR and cloned into the Fsel / Ascl sites of a modified pQE70 vector . The protein was expressed from E. coli Rosetta (Novagen).
- the STAT5b protein 120 nmol / L was incubated with the peptide 5-carboxyfluorescein-GY (P0 3 H 2 ) LVLDKW (10 nM) in the following buffer: 10 mmol / L Hepes, pH 7.5, 1 mmol / L EDTA, 0.1% Nonidet P-40, 50 mmol / L NaCl, 1 mmol / L dithiothreitol, and 2% DMSO. After incubation at room temperature for 30-120 minutes, fluorescence polarization was measured in the presence of the test substances (Tecan Infinite F500).
- K562 cells are cultured in RPMI 1640 medium (Invitrogen) containing 10% FBS (Gibco Life Technologies), 2 mM L-glutamine (PAA Laboratories) and penicillin / streptomycin (PAA Laboratories). Cells are transfected with either STAT5a-GFP or STAT5b-GFP plasmid using Fugene HD Transfection Reagent (Promega). After 24 h, the cells are treated for 4 h with test substance or DMSO (final DMSO concentration: 0.2%).
- the cells are harvested and lysed with lysis buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM Na 4 P 2 O 7 , 10% glycerol, 1% Triton X-100, 1 mM EDTA, 100 ng / ml aprotinin, 1 M Na 3 P0 4 , 10 mM NaF and 1 mM PMSF).
- lysis buffer 50 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM Na 4 P 2 O 7 , 10% glycerol, 1% Triton X-100, 1 mM EDTA, 100 ng / ml aprotinin, 1 M Na 3 P0 4 , 10 mM NaF and 1 mM PMSF.
- SDS-PAGE polyacrylamide gel
- a membrane was incubated with Stat5 antibodies (anti-pSTAT5, recognizes Stat5a pTyr694 and STAT5b pTyr699, cell signaling, anti-total Stat5, cell signaling, anti- ⁇ -actin, cell signaling).
- the other membrane is incubated with anti-GFP (cell signaling) followed by anti- ⁇ -actin to check for uniform transformation.
- Primary bound antibody membranes are incubated with secondary antibody ( ⁇ -rabbit HRP secondary antibody, Dako).
- the signals are detected after addition of Western Lightning Plus chemiluminescence reagent (Perkin-Elmer) with an ImageQuant image system (GE Healthcare).
- the quantitative analysis was carried out with the software ImageJ (NIH). (Schneider CA, Rasband WS, Eliceiri KW, NIH Image to ImageJ: 25 years of image analysis, Nature methods 2012, 9 (7): 671-675)
- BnO-P-OBn O 31 b was prepared starting from 31 a according to method 2.
- the crude product was purified by column chromatography (2% to 4% methanol in dichloromethane). Yield: 90%.
- 31 was prepared starting from 31 b according to method 3.
- 32b was prepared from 32a according to method 2.
- the crude product was purified by column chromatography (1% to 2% methanol in dichloromethane). Yield: 99%
- 32 was prepared starting from 32b according to method 3.
- FIG. 1 shows the synthesis scheme for the access to compound (13), wherein the following reactants are added in the individual reaction stages a) to h) to the correspondingly obtained intermediates: a) benzyl bromide, KHCO 3 , DMF, 4h; b) ethyl bromoacetate, K 2 C0 3 , DMF, 1 h; c) Pd / C, H 2 , EtOH, 1 h; d) aniline, EDC, HOBt, DMF, 16h; e) 1 M NaOH, THF, 1 h; f) 4- (aminomethyl) benzene-1,2-diol, EDC, HOBt, triethylamine, DMF, 16h; g) dibenzyl phosphite, CCI 4 , diisopropylethylamine, DMAP, 1 h; h) Pd / C, H 2 , EtOH, 1 h.
- the compound (13f) is recovered from 14 (0.28 g, 0.63 mmol) according to Method 1.
- the crude product was purified by column chromatography (dichloromethane / acetone 20: 1 ⁇ 9: 1).
- the product is obtained as an oil (0.485 g, 80%).
- IR [KBr]: v [cm "1 ] 3645, 3633, 3625, 3604, 3592, 3583, 3572, 3563, 3426, 3308, 3062, 3023, 2924, 2897, 1768, 1667, 1660, 1652, 1629, 1600, 1539, 1506, 1478, 1456, 1441, 1393, 1321, 1274, 1203, 1173, 1157, 1124, 1081, 1018, 1001, 880, 813, 741, 695, 596, 511, 499, 475, 456;
- 13 is prepared from 13f (0.3 g, 0.31 mmol) prepared according to Method 2. Lyophilization gave the product as a white solid (0.178 g, 95%).
- UV / Vis: ⁇ [nm] 301, 250, 238, 201
- the BODIPY-FL labeled derivative of compound (31) was synthesized as compound (10).
- Compound (10) serves as an indicator of direct binding assay based on fluorescence polarization.
- the compound (10) is obtained via five synthesis steps.
- the binding of the substance to a protein is detected by the increase in fluorescence polarization.
- the STAT5b point mutants Arg618Ala, Arg618Lys and Trp641Ala are significantly less the affinity of the wild-type protein (see Figure 7).
- Wild-type STAT5a also binds much weaker at compound 10 than wild-type STAT5b. This demonstrates the markedly high selectivity of catechol bisphosphates for STAT5b.
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Abstract
The present invention relates to novel phenylphosphates and naphthylphosphates, to the prodrugs thereof and to the (pharmaceutically) acceptable salts thereof, and to the use thereof as medicaments for the selective inhibition of the STAT5 protein, especially for use in cancer treatment. Advantageously, the novel compounds according to the general formula (I) and (II) inhibit the STAT5 protein by selective and specific interaction, these compounds having an activity at least 50 times higher for the selective inhibition of the STAT5 protein than currently known compounds.
Description
Neuartige Phenylphosphate und deren Verwendung als Arzneimittel Novel phenylphosphates and their use as pharmaceuticals
Die vorliegende Erfindung betrifft neuartige Phenylphosphate und Naphthylphosphate, deren Prodrugs und deren (pharmazeutisch) akzeptable Salze sowie deren Verwendung als Arzneimittel für die selektive Inhibierung des STAT5-Proteins, insbesondere für die Anwendung in der Krebstherapie. The present invention relates to novel phenyl phosphates and naphthyl phosphates, their prodrugs and their (pharmaceutically) acceptable salts and their use as drugs for the selective inhibition of the STAT5 protein, in particular for use in cancer therapy.
Von einigen Krebsarten weiß man, dass sie von vornherein schlecht auf eine Behandlung mit Zytostatika ansprechen. Aber auch bei Patienten mit eigentlich gut behandelbaren Krebsarten kann die Therapie nach einiger Zeit versagen. Ein möglicher Grund sind Resistenzen, wodurch die Tumorzellen gegen Zytostatika unempfindlich werden. Einige dahinter stehende biologische Prozesse sind bekannt. Some types of cancer are known to be poorly responsive to treatment with cytotoxic drugs from the outset. But even in patients with actually treatable cancers, the therapy may fail after some time. One possible reason is resistance, which makes the tumor cells insensitive to cytostatics. Some underlying biological processes are known.
So konnte gezeigt werden, dass die Behandlung verschiedener Tumorzelllinien mit Zytostatika zu einer verstärkten Expression zellulärer Proteine führt, die zum Schutz und zur Stabilisierung der korrekten Faltung von Rezeptoren, Enzymen und zellulären Strukturproteinen wichtig sind. Thus, it has been shown that the treatment of different tumor cell lines with cytostatics leads to an increased expression of cellular proteins, which are important for the protection and stabilization of the correct folding of receptors, enzymes and cellular structural proteins.
Hierbei ist das intrazelluläre STAT5b-Protein (Signal Transducer and Activator of Transcription 5; hiernach auch Transkriptionsfaktor STAT5) biologisch hervorragend validiert und bietet ein wünschenswertes Target für die Behandlung von Leukämien und anderer Krebsarten, wie zum Beispiel Brustkrebs und Krebs des Kopf- und Nackenbereichs (H. Yu, R. Jove, The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 2004 Feb;4(2):97- 105.)STAT5-Hemmstoffe sind zudem von besonders großem Interesse bei Patienten, die gegen Hemmstoffe der Proteinkinase Bcr-Abl resistent geworden sind. Zu diesen Medikamenten zählen unter anderem Glivec (auch Gleevec oder Imatinib genannt, Fa. Novartis), Tasigna (Nilotinib, Fa. Novartis), Sprycel (Dasatinib, Fa. Bristol-Myers Squibb), Bosulif (Bo- sutinib, Fa. Pfizer), oder Iclusig (Ponatinib, Fa. Ariad Pharmaceuticals). Here, the intracellular Signal Transducer and Activator of Transcription 5 (also referred to as transcription factor STAT5) STAT5b is biologically well-validated and provides a desirable target for the treatment of leukemias and other cancers, such as breast cancer and head and neck cancer ( Nat., Rev. Feb. 4 (2): 97-105.) STAT5 inhibitors are also of particular interest to patients receiving have become resistant to inhibitors of protein kinase Bcr-Abl. These drugs include, among others, Glivec (also called Gleevec or Imatinib, Novartis), Tasigna (Nilotinib, Novartis), Sprycel (Dasatinib, Bristol-Myers Squibb), Bosulif (Bosutinib, Pfizer). , or Iclusig (Ponatinib, Ariad Pharmaceuticals).
Es existieren zwei STAT5-Proteine, die in ihrer Aminosäuresequenz zu 93% identisch sind. Sie besitzen redundante und nicht-redundate Funktionen. Jüngste wissenschaftliche Erkenntnisse weisen darauf hin, dass insbesondere die selektive Hemmung von STAT5b (ohne Hemmung von STAT5a) therapeutisch wertvoll für die Behandlung Bcr-Abl-abhängiger Leukämien sein könnte. (Schaller-Schönitz M, Barzan D, Williamson AJ, Griffiths JR, Dallmann I, Battmer K, et at. BCR-ABL affects STAT5A and STAT5B differentially. PLoS One 2014, 9(5): e97243).
Zum gegenwärtigen Zeitpunkt sind allerdings noch keine Hemmstoffe für das STAT5-Protein kommerziell verfügbar - es gilt als sehr anspruchsvolles Target. There are two STAT5 proteins that are 93% identical in their amino acid sequence. They have redundant and non-redundant functions. Recent scientific evidence suggests that in particular the selective inhibition of STAT5b (without inhibition of STAT5a) could be therapeutically valuable for the treatment of Bcr-Abl-dependent leukemias. (Schaller-Schoenitz M, Barzan D, Williamson AJ, Griffiths JR, Dallmann I, Battmer K, et al., BCR-ABL affects STAT5A and STAT5B differentially., PLoS One 2014, 9 (5): e97243). At the present time, however, no inhibitors of the STAT5 protein are commercially available - it is considered a very sophisticated target.
Weiterhin sind bislang überhaupt keine Verbindungen bekannt, die STAT5b mit Selektivität gegenüber STAT5a hemmen. Furthermore, so far no compounds are known which inhibit STAT5b with selectivity to STAT5a.
Es besteht daher ein ausgeprägtes Interesse und ein großer Bedarf an effizienteren STAT5- Inhibitoren, die das STAT5-Protein selektiv und direkt inhibieren und in Zusammenhang mit der Anwendung in einer multifaktoriellen Kombinationstherapie, insbesondere für die Krebstherapie eingesetzt werden können. Bisher bekannte STAT5-lnhibitoren werden im Konzentrationsbereich von ca. 3 μΜ - 50 μΜ eingesetzt. There is therefore a strong interest and a great need for more efficient STAT5 inhibitors, which selectively and directly inhibit the STAT5 protein and can be used in conjunction with the use in a combination of multifactorial therapy, in particular for cancer therapy. Previously known STAT5 inhibitors are used in the concentration range of about 3 μΜ - 50 μΜ.
Der vorliegenden Erfindung liegt daher die Aufgabe zu Grunde, die aus dem Stand der Technik bekannten Nachteile zu beseitigen bzw. zu minimieren und neuartige chemische Verbindungen bereitzustellen, die den Transkriptionsfaktor STAT5, insbesondere STAT5b, möglichst selektiv und potent inhibieren, insbesondere zur Anwendung in der Krebstherapie bereitzustellen. The object of the present invention is therefore to eliminate or minimize the disadvantages known from the prior art and to provide novel chemical compounds which inhibit the transcription factor STAT5, in particular STAT5b, as selectively and potently as possible, in particular for use in cancer therapy provide.
Zur Lösung der Aufgabe werden neuartige Verbindungen gemäß der allgemeinen Formel (I), nachfolgend entsprechend Phenylphosphate bzw. Phenylphosphonate genannt, angegeben: To solve the problem novel compounds according to the general formula (I), hereinafter called according to phenyl phosphates or phenyl phosphonates given:
(i) n 1 oder 2 ist, (i) n is 1 or 2,
m eine ganze Zahl von 0 bis 4 ist, m is an integer from 0 to 4,
p eine ganze Zahl von 0 bis 2 ist, p is an integer from 0 to 2,
der Linker L ist C(R2)2, O, NR2, NR2C(=0), NR2C(=0)CH2, NR2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci0-Alkoxylrest, the linker L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, an optionally substituted and / or branched Q to C 5 alkyl radical, optionally substituted and / or branched Ci to Q 0 alkoxyl,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R1 ist H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein gegebenen-
falls substituierter und/oder polyzyklischer C5 bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyl-, Biphenyl-, Naphthalinyl-, Benzophenon-, Benzylben- zol-, Fluorenyl- und Triphenylmethan- est, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Dibenzofuran-, Xanthen-, Carbazol- und Phenothi- azin-Rest. R 1 is H, an optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched alkoxyl radical, a given substituted and / or polycyclic C 5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzophenone, Benzylben- zol-, fluorenyl and triphenylmethane est, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyklus, in particular selected from the group dibenzofuran, xanthene, carbazole and Phenothi- azine radical.
Die Aufgabe der Erfindung wird weiterhin gelöst durch neuartige Verbindungen der allgemeinen Formel (II), nachfolgend entsprechend Naphthylphosphate bzw. Naphthylphosphonate genannt: The object of the invention is further achieved by novel compounds of general formula (II), hereinafter called according to Naphthylphosphate or Naphthylphosphonate:
wobei die Variablen die folgende nachstehende Bedeutung haben: where the variables have the following meaning:
n ist 1 oder 2, n is 1 or 2,
v eine ganze Zahl von 0 bis 4 ist, v is an integer from 0 to 4,
- Y ist Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat oder Urea, Y is carboxyl, carbamoyl, carbonate, carbamide, carbamate or urea,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
R3 ist H, ein gegebenenfalls substituierter und/oder verzweigter Ci bis Ci0-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter i bis Ci0-Alkoxylrest, ein gegebenenfalls substituierter Arylrest, R 3 is H, an optionally substituted and / or branched C 1 - to C 20 -alkyl radical, an optionally substituted and / or branched C 1 - to C 10 -alkoxyl radical, an optionally substituted aryl radical,
R5, R6, R7 und R8 sind unabhängig voneinander ausgewählt aus H, Halogen, insbe- sondere F und CI, und L Jm R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, in particular F and Cl, and L Jm
wobei: in which:
m eine ganze Zahl von 0 bis 4 ist, m is an integer from 0 to 4,
- der Linker L ist C(R2)2, O, NR2, NR2C(=0), NR2C(=0)CH2, NR2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Ci bis C10- Alkoxylrest, - the linker L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched Ci to C1 0 - alkoxyl group,
- X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R ist H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein
gegebenenfalls substituierter und/oder polyzyklischer C5 bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyl-, Biphenyl-, Naphthalinyl-, Benzo- phenon-, Benzylbenzol-, Fluorenyl- und Triphenylmethan-Rest, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Dibenzofuran-, Xanthen-, Carbazol- und Phenothiazin-Rest. R is H, an optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched alkoxyl group, a optionally substituted and / or polycyclic C 5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzo phenone, Benzylbenzol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyklus, in particular selected from the group dibenzofuran, xanthene, carbazole, and phenothiazine radical.
Vorteilhaft inhibieren die neuartigen Verbindungen gemäß der allgemeinen Formel (I) und neuartige Verbindungen der allgemeinen Formel (II) das STAT5-Protein durch eine selektive und spezifische Interaktion. Advantageously, the novel compounds of the general formula (I) and novel compounds of the general formula (II) inhibit the STAT5 protein by a selective and specific interaction.
Der Vorteil der Verbindungen gemäß der allgemeinen Formel (I) und Verbindungen der allgemeinen Formel (II) für die Anwendung in der Krebstherapie besteht darin, dass diese Verbindungen eine mindestens 50fach höhere Aktivität für die selektive Inhibierung des STAT5- Proteins aufweisen als derzeit bekannte Verbindungen. The advantage of the compounds according to the general formula (I) and compounds of the general formula (II) for use in cancer therapy is that these compounds have at least 50-fold higher activity for the selective inhibition of the STAT5 protein than currently known compounds.
Einzigartig ist die Selektivität der Verbindungen gemäß der allgemeinen Formel (I) und Verbindungen der allgemeinen Formel (II) für das Protein STAT5b gegenüber STAT5a. Bevorzugt weisen die erfindungsgemäßen Verbindungen gegenüber STAT5b eine mehr als 30- fach höhere Aktivität auf, als gegen STAT5a. Nach einer bevorzugten Ausgestaltung der Erfindung können die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) bzw. (II) verwendet werden, um selektiv die Funktion von STAT5b und STAT5a in deren natürlicher Umgebung, insbesondere in genetisch nicht modifizierten biologischen Systemen, zu untersuchen. Unique is the selectivity of the compounds according to the general formula (I) and compounds of the general formula (II) for the protein STAT5b compared to STAT5a. The compounds according to the invention preferably have a activity which is more than 30 times higher than STAT5a, compared to STAT5a. According to a preferred embodiment of the invention, the compounds of the general formula (I) or (II) according to the invention can be used to selectively investigate the function of STAT5b and STAT5a in their natural environment, in particular in genetically unmodified biological systems.
So weisen die Verbindungen der allgemeinen Formel (I) und die Verbindungen der allgemeinen Formel (II) insbesondere gegenüber dem STAT5b-Protein besonders vorteilhaft bereits eine Aktivität im submikromolaren Wirkstoff konzentrationsbereich auf. Nach einer bevorzugten Ausgestaltung der vorliegenden Erfindung werden die neuartigen Phenylphosphate der Formel (I) und Naphthylphosphate der Formel (II) mit einer Wirkstoffkonzentration im Bereich von 1 nmol/L bis 1000 /jmol/L, bevorzugt im Bereich von 10 nmol/L bis 100 /jmol/L, besonders bevorzugt 100 nmol/L bis 50 /jmol/L eingesetzt. Thus, the compounds of the general formula (I) and the compounds of the general formula (II), in particular with respect to the STAT5b protein, particularly advantageously already have an activity in the submicromolar active ingredient concentration range. According to a preferred embodiment of the present invention, the novel phenylphosphates of the formula (I) and naphthylphosphates of the formula (II) having an active ingredient concentration in the range from 1 nmol / L to 1000 / mol / L, preferably in the range of 10 nmol / L to 100 / mol / L, more preferably 100 nmol / L to 50 / mol / L used.
Die Selektivität der erfindungsgemäßen Verbindungen der allgemeinen Formel (I) und (II) für STAT5b gegenüber STAT5a ist aber kein Ausschlusskriterium für die in dieser Anmeldung beschriebenen Substanzen. Eine vergleichbare starke Aktivität der Substanzen gegen beide
STAT5-Proteine oder sogar bevorzugte Hemmung von STAT5a gegenüber STAT5b durch die Substanzen konnte ebenfalls beobachtet werden. However, the selectivity of the compounds of general formula (I) and (II) according to the invention for STAT5b compared to STAT5a is not an exclusion criterion for the substances described in this application. A comparable strong activity of the substances against both STAT5 proteins or even preferential inhibition of STAT5a to STAT5b by the substances could also be observed.
„Inhibierung des STAT5-Proteins" bedeutet im Sinne der vorliegenden Erfindung, dass durch Interaktion des STAT5-Proteins, vorzugsweise des STAT5b-Proteins mit einer niedermolekularen Verbindung, bevorzugt den neuartigen Phosphaten bzw. Phosphonaten der allgemeinen Formel (I) bzw. der allgemeinen Formel (II) die Phosphorylierung von STAT5b an Tyr699 bzw. die Phosphorylierung von STAT5a an Tyr694 inhibiert wird. Besonders Vorteilhaft verliert das STAT5-Protein, vorzugsweise das STAT5b-Protein, durch Interaktion mit den erfindungsgemäßen Phosphaten bzw. Phosphonaten der allgemeinen Formel (I) bzw. Formel (II) die Fähigkeit zur Interaktion mit krebsauslösenden Bindungspartnern (bspw. Proteinen) und zugleich wird vorteilhaft die Einleitung der Apoptose induziert (bspw. durch stimulierte Aktivität von Caspasen). Caspasen sind in Tieren die wichtigsten Enzyme der Apoptose (programmierter Zelltod). "Inhibition of the STAT5 protein" in the context of the present invention means that by interaction of the STAT5 protein, preferably the STAT5b protein with a low molecular weight compound, preferably the novel phosphates or phosphonates of the general formula (I) or the general formula (II) the phosphorylation of STAT5b on Tyr699 or the phosphorylation of STAT5a on Tyr694 is inhibited Particularly advantageously, the STAT5 protein, preferably the STAT5b protein, loses its capacity through interaction with the phosphates or phosphonates according to the invention of the general formula (I) or Formula (II) has the ability to interact with cancer-causing binding partners (eg, proteins) and, at the same time, advantageously induces the initiation of apoptosis (for example, by stimulated caspase activity.) Caspases are the most important apoptosis enzymes in animals (programmed cell death).
Bei in vitro Versuchen wurde nun gefunden, dass die erfindungsgemäßen Verbindungen der Formel (I) bzw. allgemeinen Formel (II) gegenüber dem STAT5b-Protein eine mittlere inhibitorische Konzentration (IC50) im Bereich von 10 nmol/L bis 500 /jmol/L, bevorzugt im Bereich von 100 nmol/L bis 100 /jmol/L aufweisen. In in vitro experiments, it has now been found that the compounds of the formula (I) or general formula (II) according to the invention have a mean inhibitory concentration (IC 50 ) in the range from 10 nmol / L to 500 / mol / L relative to the STAT5b protein , preferably in the range of 100 nmol / L to 100 / mol / L.
Als niedermolekulare, organische Verbindung werden im Sinne der Erfindung molekulare Verbindungen verstanden, die primär aus den Elementen Kohlenstoff, Wasserstoff, Sauerstoff und Stickstoff aufgebaut sind und vorzugsweise ein Molekulargewicht im Bereich von 100 bis 1200 g/mol, insbesondere von 150 bis 750 g/mol, vor allem 200 bis 650 g/mol aufweisen. For the purposes of the invention, low molecular weight organic compounds are understood as meaning molecular compounds which are composed primarily of the elements carbon, hydrogen, oxygen and nitrogen and preferably have a molecular weight in the range from 100 to 1200 g / mol, in particular from 150 to 750 g / mol , especially 200 to 650 g / mol.
Niedermolekulare, organische Verbindungen weisen gegenüber großen Molekülen (bspw. Nukleotid-basierende Inhibitoren wie Antisense-Oligonukleotide oder RNA-Oligonukleotide) den signifikanten Vorteil auf, dass diese eine wesentlich bessere Handhabbarkeit und Stabilität unter physiologischen Bedingungen aufweisen. Ferner sind niedermolekulare, organische Verbindungen zumeist zellgängig und daher leichter in die Zelle oder einen Organismus zu applizieren. Low molecular weight organic compounds have the significant advantage over large molecules (e.g., nucleotide-based inhibitors such as antisense oligonucleotides or RNA oligonucleotides) of having much better handleability and stability under physiological conditions. Furthermore, low molecular weight, organic compounds are usually cell-like and therefore easier to apply in the cell or an organism.
Nach einer bevorzugten Ausgestaltung der vorliegenden Erfindung ist die Verbindung der allgemeinen Formel (I) derart angepasst, dass zwei Phosphatgruppen bzw. Phosphonat- gruppen am Phenylring des Phenylphosphats lokalisiert sind, sodass n = 2 ist.
Durch diese Anpassung des Phenylphosphats bzw. des Phenylphosphonats, weisen die Verbindungen der allgemeinen Formel (I) besonders vorteilhaft eine IC50 im submikromola- ren, besonders bevorzugt im nanomolaren Konzentrationsbereich auf. According to a preferred embodiment of the present invention, the compound of the general formula (I) is adapted such that two phosphate groups or phosphonate groups are located on the phenyl ring of the phenyl phosphate, so that n = 2. As a result of this adaptation of the phenylphosphate or of the phenylphosphonate, the compounds of the general formula (I) particularly advantageously have an IC 50 in the submicromolar, more preferably in the nanomolar concentration range.
Nach einer besonders bevorzugten Ausgestaltung der vorliegenden Erfindung sind die Verbindungen der allgemeinen Formel (I) als Bisphosphate, d.h. Q ist Sauerstoff (O) und n=2, ausgestaltet, da insbesondere diese Verbindungen selektiv gegenüber dem STAT5b-Protein eine Aktivität im submikromolaren Wirkstoffkonzentrationsbereich aufweisen, ohne die Funktion des STAT5a-Proteins in diesem Konzentrationsbereich wirksam zu inhibieren. According to a particularly preferred embodiment of the present invention, the compounds of general formula (I) are as bisphosphates, i. Q is oxygen (O) and n = 2, since in particular these compounds have an activity in the submicromolar drug concentration range selectively relative to the STAT5b protein, without effectively inhibiting the function of the STAT5a protein in this concentration range.
Alternativ kann vorgesehen sein, dass die Verbindung der allgemeinen Formel (I) lediglich eine Phosphatgruppen bzw. Phosphonatgruppen am Phenylring des Phenylphosphats lokalisiert aufweist, sodass n = 1 ist. Dabei wurde überraschend gefunden, dass insbesondere derartige Verbindungen bei denen zusätzlich am Phenylring ausschließlich eine oder keine Carboxylgruppe (p ist 1 oder 0) lokalisiert ist, eine besonders hohe Selektivität gegenüber dem STAT5b-Protein aufweisen, sodass vorteilhaft eine Aktivität im submikromolaren Wirkstoffkonzentrationsbereich ermittelt werden konnte. Ganz besonders bevorzugt ist p = 1. Alternatively it can be provided that the compound of the general formula (I) has only one phosphate group or phosphonate groups localized on the phenyl ring of the phenyl phosphate, so that n = 1. It was surprisingly found that in particular those compounds in which only one or no carboxyl group (p is 1 or 0) is located on the phenyl ring, have a particularly high selectivity to the STAT5b protein, so that advantageously an activity in the submicromolar drug concentration range could be determined , Most preferably, p = 1.
Nach einer ganz besonderes bevorzugten Ausgestaltung weisen Verbindungen der Formel (I) mit lediglich einer Phosphatgruppen bzw. Phosphonatgruppen am Phenylring (n = 1 ) die Carboxylgruppe in ortho-Position zur Phosphatgruppen bzw. Phosphonatgruppen auf. In a very particular preferred embodiment, compounds of the formula (I) having only one phosphate group or phosphonate groups on the phenyl ring (n = 1) have the carboxyl group in the ortho position to the phosphate groups or phosphonate groups.
Die Bindungsaffinität der Verbindung der allgemeinen Formel (I) oder der Verbindung der Formel (II) zum STAT5-Protein wird u.a. von der Art des Substituenten R bestimmt. Bevorzugt ist R ein hydrophober Substituent ausgewählt aus H, einem gegebenenfalls verzweigten C3-Ci2-Alkylrest, wie bspw. n-Propyl-, /so-Propyl, n-Butyl-, /'so-Butyl, ie/f-Butyl, n-Pentyl-, n- Hexyl, n-Heptyl-, n-Oktyl-, /'so-Oktyl-, n-Nonyl-, /'so-Nonyl-, n-Dodecyl-Rest, einem gegebenenfalls polyzyklischen und/oder substituierten Fünfring- oder Sechsring-Hetrozyklus und einem gegebenenfalls polyzyklischen und/oder substituierten Arylrest. The binding affinity of the compound of the general formula (I) or the compound of the formula (II) for the STAT5 protein is determined inter alia by the nature of the substituent R. Preferably, R is a hydrophobic substituent chosen from H, an optionally branched C 3 -Ci2-alkyl radical, such as, n-propyl, / so-propyl, n-butyl, / 'so-butyl, ie / f-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, / ' so-octyl, n-nonyl, / ' so-nonyl, n-dodecyl radical, an optionally polycyclic and / or substituted five-membered or six-membered ring heterocycle and an optionally polycyclic and / or substituted aryl radical.
Unter einem„polyzyklischen Arylrest bzw. Heterozyklus" im Sinne dieser Erfindung soll ein konjugiertes System verstanden werden, das mindestens zwei Arylene (bspw. Phenylen, Naphthylen) enthält, die direkt miteinander verbunden sind, d.h. in Konjugation miteinander stehen. Dabei können die Arylene auch über einen Elektronendonator (bspw. Stickstoff, Sauerstoff, CH2) direkt miteinander verbunden sein und damit die Planarität des Systems herbeiführen, wie bspw. bei einem Fluorenyl-, Benzophenon-, Benzylbenzol-, Xanthen-, Carbazol-, Phenoxyphenyl-, Phenothiazin- oder Triphenylmethan-Rest.
Insbesondere zeigten Verbindungen der allgemeinen Formel (I) bzw. der Formel (II), bei denen der Substituent R ein gegebenenfalls polyzyklischer und/oder substituierter Arylrest, ganz besonders bevorzugt ein Fluorenyl-, Phenyl-, Biphenyl-, Naphthalinyl-, Benzophenon-, Benzylbenzol-Rest ist eine besonders hohe Bindungsaffinität zum STAT5-Protein (d.h. niedriger IC50-Wert). Vorzugsweise weisen derartige Verbindungen der allgemeinen Formel (I) bzw. der Formel (II) bei denen R wie vorstehend definiert ist, gegenüber dem STAT5-Protein einen IC50-Wert im Bereich von 10 nmol/L bis 1 ,5 /jmol/L auf, besonders bevorzugt im Bereich von 50 nmol/L bis 1 /jmol/L. For the purposes of this invention, a "polycyclic aryl radical or heterocycle" is to be understood as meaning a conjugated system which contains at least two arylenes (for example phenylene, naphthylene) which are directly connected to one another, ie in conjugation with one another via an electron donor (for example, nitrogen, oxygen, CH 2 ) directly connected to one another and thus bring about the planarity of the system, such as in a fluorenyl, benzophenone, benzylbenzene, xanthene, carbazole, phenoxyphenyl, phenothiazine or triphenylmethane radical. In particular, compounds of the general formula (I) or of the formula (II) in which the substituent R has an optionally polycyclic and / or substituted aryl radical, very particularly preferably a fluorenyl, phenyl, biphenyl, naphthalenyl, benzophenone, Benzylbenzene residue is a particularly high binding affinity to the STAT5 protein (ie low IC 50 value). Preferably, such compounds of general formula (I) or of formula (II) wherein R is as defined above, have an IC 50 value in the range of 10 nmol / L to 1.5 / mol / L over the STAT5 protein to, more preferably in the range of 50 nmol / L to 1 / mol / L.
Nach einer alternativ bevorzugten Ausgestaltung der vorliegenden Erfindung ist R ein gegebenenfalls verzweigter C3-Ci0-Alkylrest, insbesondere ausgewählt aus n-Propyl-, /so-Propyl, n-Butyl-, /'so-Butyl, ie/f-Butyl, n-Pentyl-, n-Hexyl, n-Heptyl-, ie/f-Heptyl, n-Oktyl-, /'so-Oktyl-, sec-Oktyl-n-Nonyl-, /'so-Nonyl-, sec-Nonyl-Gruppe. Derart substituierte Verbindungen der allgemeinen Formel (I) bzw. der Formel (II), bei denen R wie vorstehend definiert ist, weisen gegenüber dem STAT5-Protein einen IC50-Wert im Bereich von 250 nmol/L bis 2 /jmol/L, besonders bevorzugt im Bereich von 80 nmol/L bis 3 /jmol/L auf. According to an alternatively preferred embodiment of the present invention R is an optionally branched C 3 -C 0 -alkyl radical, in particular selected from n-propyl, / so-propyl, n-butyl, / 'so-butyl, ie / f-butyl , n-pentyl, n-hexyl, n-heptyl, ie / f-heptyl, n-octyl, / 'so-octyl, sec-octyl-n-nonyl, /' so-nonyl, sec nonyl group. Such substituted compounds of the general formula (I) or of the formula (II) in which R is as defined above have an IC 50 value in the range from 250 nmol / L to 2 / mol / L compared to the STAT5 protein. more preferably in the range of 80 nmol / L to 3 / mol / L.
Ganz besonders bevorzugt sind Verbindungen der allgemeinen Formel (I) bzw. der Formel (II), bei denen R2 ein Wasserstoff (H) ist. Very particular preference is given to compounds of the general formula (I) or of the formula (II) in which R 2 is a hydrogen (H).
Bei Verbindungen der allgemeinen Formel (I) bzw. der Formel (II) kann vorgesehen sein, dass L einen von H abweichenden Substituenten R1 aufweist. Dabei wurde nun überraschend gefunden, dass insbesondere im Fall das R1, wie vorstehend für R näher definiert, ein gegebenenfalls substituierter und/oder verzweigter C3 bis Ci2-Alkylrest ist, niedrige IC50- Werte erreicht werden. Dies ist ein Beleg für die hohe Bindungsaffinität dieser Verbindungen. In the case of compounds of the general formula (I) or of the formula (II), it may be provided that L has a substituent R 1 which deviates from H. It was now surprisingly found that, in particular in the case of the defined R 1, in more detail above for R, a is optionally substituted and / or branched C 3 to C 2 alkyl, low IC 50 - values are reached. This is proof of the high binding affinity of these compounds.
Es kann auch zweckdienlich sein, dass die erfindungsgemäße Verbindung der allgemeinen Formel (II) derart angepasst ist, dass an dem Naphthylderivat zwei Phosphatgruppen bzw. Phosphonatgruppen am Phenylring des Phenylphosphats lokalisiert sind, sodass n 2 ist. It may also be expedient that the compound of the general formula (II) according to the invention is adapted in such a way that two phosphate groups or phosphonate groups on the naphthyl derivative are located on the phenyl ring of the phenylphosphate so that n is 2.
Durch diese Anpassung des Naphthylderivats der allgemeinen Formel (II), weisen diese Verbindungen besonders vorteilhaft eine IC50 im submikromolaren, besonders bevorzugt im nanomolaren Konzentrationsbereich auf. As a result of this adaptation of the naphthyl derivative of the general formula (II), these compounds particularly advantageously have an IC 50 in the submicromolar, more preferably in the nanomolar concentration range.
Nach einer besonders bevorzugten Ausgestaltung der vorliegenden Erfindung sind die Verbindungen der allgemeinen Formel (II) als Bisphosphate, d.h. Q ist O und n=2, ausgestaltet, da insbesondere diese Verbindungen selektiv gegenüber dem STAT5b-Protein eine Aktivität
im submikromolaren Wirkstoffkonzentrationsbereich aufweisen, ohne die Funktion des STAT5a-Proteins in diesem Konzentrationsbereich wirksam zu inhibieren. According to a particularly preferred embodiment of the present invention, the compounds of the general formula (II) as bisphosphates, ie Q is O and n = 2, designed, since in particular these compounds selectively against the STAT5b protein activity in the submicromolar drug concentration range without effectively inhibiting the function of the STAT5a protein in this concentration range.
Typische Beispiele für neuartige Phenylphosphate der allgemeinen Formel (I) und neuartige Naphthylphosphate der Formel (II) (mit dem jeweiligen Mittelwert der IC50 gegenüber dem STAT5b-Protein in /jmol/L und Standardabweichung) sind: Typical examples of novel phenylphosphates of the general formula (I) and novel naphthylphosphates of the formula (II) (with the respective mean value of the IC 50 in relation to the STAT5b protein in / mol / L and standard deviation) are:
2.45 ± 0.05 ICM = 26.69 ± 3.04 ICM = 59.42 ± 3.50
Typische Vertreter für neuartige Phenylphosphonate der allgemeinen Formel (I) mit n = 1 oder 2 und entsprechend p = 0 oder 1 sind: 2.45 ± 0.05 IC M = 26.69 ± 3.04 IC M = 59.42 ± 3.50 Typical representatives of novel phenylphosphonates of the general formula (I) where n = 1 or 2 and correspondingly p = 0 or 1 are:
2 2
für alle Substanzen gilt: n = 1 oder 2 for all substances: n = 1 or 2
Dem gegenüber zeigten typische Vergleichsverbindungen, wie bspw. die nachstehenden Verbindungen, keine (messbare) inhibitorische Aktivität gegenüber dem STAT5-Protein: In contrast, typical comparison compounds, such as the compounds below, showed no (measurable) inhibitory activity on the STAT5 protein:
6 ± 2% Inhibition 0% Inhibition 6 ± 2% inhibition 0% inhibition
bei 100 μΜ bei 200 pM at 100 μΜ at 200 pM
Von der vorliegenden Erfindung sind auch Verbindungen wie pharmakologisch akzeptable Salze, Prodrugs, Enantiomere, Diastereomere, racemische Gemische, kristalline Formen, amorphe Formen und Solvate, aufweisend eine neuartige Verbindung gemäß der allgemeinen Formel (I) bzw. der Formel (II), für die Verwendung als Arzneimittel in der Krebstherapie und die Behandlung von Mukoviszidose mitumfasst.
Die Verbindungen der allgemeinen Formel (I) bzw. der Formel (II) können erfindungsgemäß auch in Form ihrer pharmakologisch akzeptablen Salze vorliegen. Unter einem pharmakologisch akzeptablen Salz sind im Sinne der vorliegenden Erfindung chemische Verbindungen einer neuartigen Verbindung gemäß Formel (I) bzw. Formel (II) aus positiv und negativ geladenen Ionen zu verstehen, die in Abhängigkeit der Substituenten des erfindungsgemäßen Phosphats bzw. Phosphonats bspw. durch Behandlung mit einer schwachen, pharmazeutisch akzeptablen Säure oder Base erhalten werden können. Also useful in the present invention are compounds such as pharmacologically acceptable salts, prodrugs, enantiomers, diastereomers, racemic mixtures, crystalline forms, amorphous forms and solvates comprising a novel compound of general formula (I) or formula (II), respectively Use as a drug in cancer therapy and the treatment of cystic fibrosis includes. The compounds of the general formula (I) or of the formula (II) can also be present according to the invention in the form of their pharmacologically acceptable salts. For the purposes of the present invention, a pharmacologically acceptable salt is to be understood as meaning chemical compounds of a novel compound of the formula (I) or formula (II) of positively and negatively charged ions which, for example, depend on the substituents of the phosphate or phosphonate according to the invention Treatment with a weak, pharmaceutically acceptable acid or base can be obtained.
Bevorzugt sind die pharmazeutisch akzeptablen Salze zusammengesetzt aus der korrespondierenden Base der Verbindungen der Formel (I) bzw. der Formel (II) und einfach- oder mehrfach positiv geladenen Gegenion, insbesondere ausgewählt aus Alkalimetall- und Erdalkalimetallionen, wie Natrium-, Kalium-, Calcium,- oder Magnesiumsalze. Außerdem bevorzugt sind pharmakologisch akzeptable Salze von die Verbindungen der allgemeinen Formel (I) bzw. (II) Ammoniumsalze mit Ammoniak oder organischen Aminen, wie bspw. Mono- oder Diniederalkylaminen, z.B. Methylamin, Aethylamin, Dimethylamin oder Diäthyla- min, oder mit gegebenenfalls niederalkylierten Mono- oder Di(hydroxylalkyl)-aminen, oder mit Tri(hydroxyalkyl-)aminen, z.B. 2-Aminoäthanol, 2-(Diäthylamino)-athanol, 2,2'- Iminodiäthanol, N-Methyl-2,2'-iminodiäthanol oder 2,2',2"-Nitrilotri-äthanol. The pharmaceutically acceptable salts are preferably composed of the corresponding base of the compounds of the formula (I) or of the formula (II) and singly or multiply positively charged counterion, in particular selected from alkali metal and alkaline earth metal ions, such as sodium, potassium, calcium , - or magnesium salts. Also preferred are pharmacologically acceptable salts of the compounds of general formula (I) or (II) ammonium salts with ammonia or organic amines, such as mono- or di-lower alkylamines, e.g. Methylamine, ethylamine, dimethylamine or diethylamine, or with optionally lower alkylated mono- or di (hydroxyalkyl) -amines, or with tri (hydroxyalkyl) -amines, e.g. 2-aminoethanol, 2- (diethylamino) ethanol, 2,2'-iminodiethanol, N-methyl-2,2'-iminodiethanol or 2,2 ', 2 "-nitrilotri-ethanol.
Zur Erleichterung der Resorbierbarkeit erfindungsgemäßer Verbindungen oder um insbesondere eine Zersetzung von oral verabreichten Verbindungen im Magen-Darmtrakt zu verhindern, kann es von Vorteil sein gewisse funktionelle Gruppen einer pharmazeutisch aktiven Verbindung durch die Umsetzung mit einem pharmazeutisch geeigneten Maskierungsmittel zumindest temporär zu maskieren. To facilitate the resorbability of compounds of the invention or in particular to prevent decomposition of orally administered compounds in the gastrointestinal tract, it may be advantageous to at least temporarily mask certain functional groups of a pharmaceutically active compound by reaction with a pharmaceutically acceptable sequestrant.
Von der vorliegenden Erfindung sind auch pharmakologisch unbedenkliche Prodrugs von Verbindungen der allgemeinen Formel (I) und der Formel (II) umfasst. Als Prodrugs werden beispielsweise Ester, Ether oder Amide von Verbindungen der allgemeinen Formel (I) bzw. (II) oder sonstige Verbindungen bezeichnet, die im Organismus zu Verbindungen der allgemeinen Formel (I) bzw. (II) metabolisieren. The present invention also encompasses pharmacologically acceptable prodrugs of compounds of the general formula (I) and of the formula (II). Examples of prodrugs are esters, ethers or amides of compounds of the general formula (I) or (II) or other compounds which metabolize in the organism to compounds of the general formula (I) or (II).
Gegenstand der Erfindung sind auch Vorläuferverbindungen (auch Prodrugs) von Verbindungen gemäß der allgemeinen Formel (I) der allgemeinen Formel (lila) bzw. (Illb):
The invention also provides precursor compounds (also prodrugs) of compounds according to the general formula (I) of the general formula (IIIa) or (IIIb):
wobei die Variablen n, m, L, X und 1 die gleiche Bedeutung wie vorstehend definiert haben: n ist 1 oder 2, where the variables n, m, L, X and 1 have the same meaning as defined above: n is 1 or 2,
p ist eine ganze Zahl von 0 bis 2, p is an integer from 0 to 2,
m ist eine ganze Zahl von 0 bis 4, m is an integer from 0 to 4,
- L ist C(R2)2, O, N R2, NR2C(=0), NR2C(=0)CH2, NR2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Ci bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Ci bis Ci0-Alkoxylrest, - L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, an optionally substituted and / or branched C 1 to C 5 -alkyl radical, an optionally substituted and / or branched C 1 to C 10 -alkoxyl radical,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
- X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R1 ist H , ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein gegebenenfalls substituierter und/oder polyzyklischer C5 bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyl-, Biphenyl-, Naphthalinyl-, Benzophenon-, Benzylben- zol-, Fluorenyl- und Triphenylmethan-Rest, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Dibenzofuran-, Xanthen-, Carbazol- und Phenothi- azin-Rest, R 1 is H, an optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched alkoxyl radical, an optionally substituted and / or polycyclic C 5 to C 5 -aryl radical, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzophenone, Benzylben- zol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyklus, in particular selected from the group dibenzofuran, Xanthene, carbazole and phenothiazine moiety,
Unter einem„polyzyklischen Arylrest bzw. Heterozyklus" im Sinne dieser Erfindung soll ein konjugiertes System verstanden werden, das mindestens zwei Arylene (bspw. Phenylen, Naphthylen) enthält, die direkt miteinander verbunden sind, d.h. in Konjugation miteinander stehen. Dabei können die Arylene auch über einen Elektronendonator (bspw. Stickstoff, Sauerstoff, CH2) direkt miteinander verbunden sein und damit die Planarität des Systems herbeiführen, wie bspw. bei einem Fluorenyl-, Benzophenon-, Benzylbenzol-, Xanthen-, Carbazol-, Phenoxyphenyl-, Phenothiazin- oder Triphenylmethan-Rest, wobei: die Maskierungsgruppe R° ausgewählt ist aus H, Ci-6-Alkylrest und 0 , wobei
0 eine ganze Zahl von 0 bis 3 ist, For the purposes of this invention, a "polycyclic aryl radical or heterocycle" is to be understood as meaning a conjugated system which contains at least two arylenes (for example phenylene, naphthylene) which are directly connected to one another, ie in conjugation with one another via an electron donor (for example, nitrogen, oxygen, CH 2 ) directly connected to one another and thus bring about the planarity of the system, such as in a fluorenyl, benzophenone, benzylbenzene, xanthene, carbazole, phenoxyphenyl, phenothiazine or triphenylmethane radical, wherein: the masking group R ° is selected from H, Ci-6-alkyl radical and 0 , wherein 0 is an integer from 0 to 3,
- Y ist ausgewählt aus Carboxyl, Carbamoyl, Cabonat, Carbamid, Carbamat, Urea, Thioester, Y is selected from carboxyl, carbamoyl, cabonate, carbamide, carbamate, urea, thioester,
4 ist ein gegebenenfalls verzweigter oder zyklischer und/oder substituierter Ci-6- Alkylrest (bspw. Cyclopentyl, Cyclohexyl) oder ein C6-io-Arylrest, insbesondere Phenyl, und wobei die Variablen der zyklisierenden Maskierungsgruppe ΟΑ-(·)ΓΒΟ die folgende Bedeutung aufweisen: 4 is an optionally branched or cyclic and / or substituted Ci -6 - alkyl (e.g. cyclopentyl, cyclohexyl.) Or a C 6- io-aryl, especially phenyl, and wherein the variables of the cyclizing masking group ΟΑ- (·) Γ ΒΟ the have the following meaning:
1 0 oder 1 ist, 1 is 0 or 1,
A und B unabhängig voneinander CH2, CH-Ar, Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat, Urea, wobei Ar ein gegebenenfalls substituierter Arylrest, insbesondere Phenyl- oder Pyridinrest, ist, der insbesondere substituiert ist mit Halogen (F, Cl, Br), OH, einem Ci-6-Alkylrest oder einem Ci-6-Alkoxyrest. A and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy.
Gegenstand der Erfindung sind auch Vorläuferverbindungen (auch Prodrugs) der allgemeinen Formel (IVa) bzw. (IVb) von Verbindungen gemäß der allgemeinen Formel (II): The invention also provides precursor compounds (also prodrugs) of the general formula (IVa) or (IVb) of compounds according to the general formula (II):
(IVa) (IVb) wobei die Variablen die folgende nachstehende Bedeutung haben: (IVa) (IVb) where the variables have the following meanings:
n ist 1 oder 2, n is 1 or 2,
v eine ganze Zahl von 0 bis 4 ist, v is an integer from 0 to 4,
- Y ist Carboxyl, Carbamoyl, Cabonat, Carbamid, Carbamat oder Urea, Y is carboxyl, carbamoyl, cabonate, carbamide, carbamate or urea,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
R3 ist H, ein gegebenenfalls substituierter und/oder verzweigter, oder zyklischer Ci bis Cio-Alkylrest (bspw. Cyclopentyl, Cyclohexyl oder Cycloheptyl), ein gegebenenfalls substituierter und/oder verzweigter Ci bis Ci0-Alkoxylrest, ein gegebenenfalls substituierter Arylrest,
R5, R6, R7 und R8 sind unabhängig voneinander ausgewählt aus H, Halogen, insbe- sondere F und Cl, und *- -™ wobei: R 3 is H, an optionally substituted and / or branched, or cyclic C 1 to C 10 -alkyl radical (for example cyclopentyl, cyclohexyl or cycloheptyl), an optionally substituted and / or branched C 1 to C 10 -alkoxyl radical, an optionally substituted aryl radical, R 5 , R 6 , R 7 and R 8 are independently selected from H, halogen, especially F and Cl, and * - - where:
m eine ganze Zahl von 0 bis 4 ist, m is an integer from 0 to 4,
- der Linker L ist C(R2)2, O, NR2, NR2C(=0), NR2C(=0)CH2, NR2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Ci bis C10- Alkoxylrest, - the linker L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched Ci to C 10 - alkoxy radical,
- X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R1 ist H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein gegebenenfalls substituierter und/oder polyzyklischer C5 bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyl-, Biphenyl-, Naphthalinyl-, Benzo- phenon-, Benzylbenzol-, Fluorenyl- und Triphenylmethan-Rest, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Dibenzofuran-, Xanthen-, Carbazol- und Phenothiazin-Rest. wobei: die Maskierungsgruppe R° ausgewählt ist aus H, Ci-6-Alkylrest und J° , wobeiR 1 is H, an optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched alkoxyl group, an optionally substituted and / or polycyclic C5 to C 5 aryl, in particular selected from the group phenyl, biphenyl, naphthalenyl, benzo phenone, Benzylbenzol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyklus, in particular selected from the group dibenzofuran, Xanthene, carbazole and phenothiazine residues. wherein: the masking group R ° is selected from H, Ci-6-Alkylrest and J °, wherein
0 eine ganze Zahl von 0 bis 3 ist, 0 is an integer from 0 to 3,
- Y ausgewählt ist aus Carboxyl, Carbamoyl, Cabonat, Carbamid, Carbamat, Urea, Thioester, Y is selected from carboxyl, carbamoyl, cabonate, carbamide, carbamate, urea, thioester,
R4 ein gegebenenfalls verzweigter und/oder substituierter Ci-6-Alkylrest oder ein C6- -lo-Arylrest, insbesondere Phenyl, ist und wobei die Variablen der zyklisierenden Maskierungsgruppe ΟΑ-(·)ΓΒΟ die folgende Bedeutung aufweisen: R 4 is an optionally branched and / or substituted Ci -6 alkyl group or a C 6 - o-l aryl, in particular phenyl, and wherein the variables of the cyclizing masking group ΟΑ- (·) Γ ΒΟ have the following meanings:
1 0 oder 1 ist, 1 is 0 or 1,
A und B unabhängig voneinander CH2, CH-Ar, Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat, Urea, wobei Ar ein gegebenenfalls substituierter Arylrest, insbesondere Phenyl- oder Pyridinrest, ist, der insbesondere substituiert ist mit Halogen (F, Cl, Br), OH, einem Ci-6-Alkylrest oder einem Ci-6-Alkoxyrest.
Besonders vorteilhaft weisen Vorläuferverbindungen der allgemeinen Formel (lila) und (lllb) gegenüber Verbindungen der allgemeinen Formel (I) bzw. (II) eine erhöhte Zellpermeabilität auf, da negative Ladungen der Phosphatgruppe bzw. der Phosphonatgruppe maskiert sind. A and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy. It is particularly advantageous for precursor compounds of the general formula (IIIa) and (IIIb) to exhibit increased cell permeability over compounds of the general formula (I) or (II) since negative charges of the phosphate group or of the phosphonate group are masked.
Zellpermeabilität (Zellmembranpassage) definiert sich erfindungsgemäß als intrazellulärer Transport einer niedermolekularen Verbindung, wobei die Membran- und Zellintegrität nicht gestört wird. Mögliche Modelle für den intrazellulären Transport niedermolekularer Verbindung sind dem Fachmann bekannt und sind unter anderem die Endozytose (Hällbrink et al., 2001 ) oder die rezeptorvermittelte Aufnahme (Tyagi et al., 2001 ). Per definitionem von zell- permeablen Verbindungen erfolgt ihre Translokalisation rezeptor-, energie- und temperaturunabhängig (Thoren et al., 2000). Bevorzugt sind die neuartigen erfindungsgemäßen Verbindungen zellpermeablen Verbindungen, die durch Passage der Lipiddoppelschicht in eine Zelle eindringen, wobei die Zellpermeabilität der erfindungsgemäßen Verbindungen nicht auf bestimmte Zellen beschränkt ist. Cell permeability (cell membrane passage) defined according to the invention as intracellular transport of a low molecular weight compound, wherein the membrane and cell integrity is not disturbed. Possible models for the intracellular transport of low molecular weight compounds are known to the person skilled in the art and include inter alia endocytosis (Hällbrink et al., 2001) or receptor-mediated uptake (Tyagi et al., 2001). By definition of cell-permeable compounds, their translocation takes place receptor-, energy- and temperature-independent (Thoren et al., 2000). The novel compounds according to the invention are preferably cell-permeable compounds which penetrate into a cell by passage of the lipid bilayer, the cell permeability of the compounds according to the invention not being restricted to specific cells.
Der Begriff „Prodrug" wie hierin verwendet, bezieht sich auf eine pharmakologisch inaktive oder wenig aktive Vorläuferverbindung der Verbindungen der allgemeinen Formel (I) bzw. (II) wie oben definiert, wobei die Vorläuferverbindung eine kovalente Bindung zwischen der Verbindung der allgemeinen Formel (I) bzw. (II) und einer abspaltbaren Maskierungsgruppe aufweist. Die Vorläuferverbindung wird erst in vivo, vorzugsweise intrazellulär, durch eine chemische Modifizierung unter physiologischen Bedingungen (d.h. durch Verstoffwechselung oder Metabolisierung) im Organismus in die entsprechende pharmakologisch aktive Verbindung der allgemeinen Formel (I) bzw. (II) umgewandelt. Dabei kann auch vorgesehen sein, dass die Prodrug durch chemische oder biochemische Methoden in einer ex vivo Umgebung in die entsprechend pharmakologisch aktive Form einer neuartigen Verbindung gemäß der allgemeinen Formel (I) bzw. der Formel (II) überführt wird. The term "prodrug" as used herein refers to a pharmacologically inactive or poorly active precursor compound of the compounds of general formula (I) or (II) as defined above, wherein the precursor compound forms a covalent bond between the compound of general formula (I The precursor compound is first in vivo, preferably intracellular, by a chemical modification under physiological conditions (ie by metabolism or metabolization) in the organism into the corresponding pharmacologically active compound of general formula (I). It can also be provided that the prodrug is converted by chemical or biochemical methods in an ex vivo environment into the corresponding pharmacologically active form of a novel compound according to the general formula (I) or the formula (II) becomes.
Prodrugs können dabei sowohl oral als auch intravenös einem Patienten verabreicht werden. Bei intravenöser Verabreichung beträgt die Halbwertszeit vorzugsweise maximal 10 bis 600 Minuten. Prodrugs can be administered both orally and intravenously to a patient. When administered intravenously, the half-life is preferably a maximum of 10 to 600 minutes.
Aus dem Stand der Technik ist eine Vielzahl in-vivo spaltbarer Gruppen bekannt, welche als Phosphonsäure- und Phosphorsäureester-maskierende Gruppen dienen können (J. E. Starret et al. Journal of Medicinal Chemistry 1994, 37, 1857; H. T. Serafinowska et al. Journal of Medicinal Chemistry 1995, 38, 1372; J. P. Krise und V. J. Stella in Advanced Drug Delivery Reviews 1996, 19, 287; S. Freeman und K. C. Ross in Progress in Medicinal Chemistry 1997, 34, 1 1 1 ; P. Ettmayer et al. Journal of Medicinal Chemistry 2004, 47, 2393 sowie die darin zitierte Referenzliteratur).
Bevorzugt ist die Maskierungsgruppe R° eine Ci-C4-Alkoxymethylgruppe, insbesondere eine Acetyl-, Propionyl-, n-Butanoyl-, Isobutanoyl-, sec-Butanoyl- oder Pivaloyloxymethylgruppe, eine CrC4-Alkoxycarbonyloxymethylgruppe, insbesondere eine Propyl-, n-Butyl-, Isobutyl-, sec-Butyl- oder tert-Butyl-Oxycarbonyloxymethylgruppe, schwefelhaltige Alkylgruppen, insbesondere S-Acyl-2-thioethyl- (SATE), S-Acylthiopropyl (SATP) oder Hydroxyethyl- disufanylethyl-Gruppen ("Dithiodiethyl" oder DTE), wobei die Spaltbarkeit der Phosphonsäureester durch geeignete Substituenten beeinflusst werden kann. Beispiele für besonders bevorzugte Phosphonsäure-maskierende Gruppen R° sind Isopropyloxycarbony- loxymethyl), Benzyl (Bn) und Pivaloyloxymethyl (Piv). A variety of in vivo cleavable groups are known in the art which can serve as phosphonic acid and phosphoric acid ester masking groups (JE Starret et al., Journal of Medicinal Chemistry 1994, 37, 1857, HT Serafinowska et al., Journal of Medicinal Chem., 1995, 38, 1372, JP Crisis and VJ Stella in Advanced Drug Delivery Reviews 1996, 19, 287, S. Freeman and KC Ross in Progress in Medicinal Chemistry 1997, 34, 11, Ettmayer et al., Journal of Medicinal Chemistry 2004, 47, 2393 and the references cited therein). The masking group R ° is preferably a C 1 -C 4 -alkoxymethyl group, in particular an acetyl, propionyl, n-butanoyl, isobutanoyl, sec-butanoyl or pivaloyloxymethyl group, a C 1 -C 4 -alkoxycarbonyloxymethyl group, in particular a propyl, n-butyl Butyl, isobutyl, sec-butyl or tert-butyl Oxycarbonyloxymethylgruppe, sulfur-containing alkyl groups, in particular S-acyl-2-thioethyl (SATE), S-acylthiopropyl (SATP) or hydroxyethyl disufanylethyl groups ("dithiodiethyl" or DTE), wherein the cleavability of the phosphonic acid esters can be influenced by suitable substituents. Examples of particularly preferred phosphonic acid masking groups R ° are isopropyloxycarbonyloxymethyl), benzyl (Bn) and pivaloyloxymethyl (Piv).
Typische Beispiele für die erfindungsgemäßen Vorläuferverbindungen der allgemeinen Formel (lila) und (lllb) sind: Typical examples of the precursor compounds of the general formula (IIIa) and (IIIb) according to the invention are:
Des Weiteren werden auch zyklische Phosphonsäureester beschrieben, worin ΟΑ-(·)ΓΒΟ zusammen bevorzugt eine gegebenenfalls substituierte 1 -Aryl-propan-1 ,3-dioxy-Gruppe oder 2-(3-chlorophenyl)-[1 ,3,2]dioxaphosphinan sind.
Maskierungsgruppen (Phosphonsäure-maskierende Gruppen) können auch derart ausgewählt sein, dass die sterische Hinderung um eine funktionelle Gruppe, insbesondere die Phosphonsäuregruppe) minimiert ist, so dass die Geschwindigkeit der biologischen Umwandlung erhöht ist und dadurch die maximale Plasmakonzentration schneller erreicht wird. Furthermore, cyclic phosphonic acid esters are described in which ΟΑ- (·) Γ ΒΟ together preferably an optionally substituted 1-aryl-propane-1, 3-dioxy group or 2- (3-chlorophenyl) - [1, 3,2] dioxaphosphinane. Masking groups (phosphonic acid masking groups) may also be selected such that steric hindrance around a functional group, especially the phosphonic acid group, is minimized so that the rate of bioconversion is increased and thereby the maximum plasma concentration is reached more quickly.
Generell werden Vorläuferverbindungen der allgemeinen Formel (llla,b) oder (IVa,b) durch Reaktion einer Verbindung der allgemeinen Formel (I) bzw. (II) mit einem geeigneten Maskierungsmittel (bspw. einer organischen Säure oder Lewissäure) umgesetzt. In general, precursor compounds of the general formula (IIIa, b) or (IVa, b) are reacted by reaction of a compound of the general formula (I) or (II) with a suitable masking agent (for example an organic acid or Lewis acid).
Nach einer bevorzugen Ausgestaltung der vorliegenden Erfindung werden Vorläuferverbindungen der allgemeinen Formel (lila) oder (IVa) synthetisiert, indem Verbindungen der allgemeinen Formel (I) bzw. (II) gemäß Methode 6 umgesetzt werden. According to a preferred embodiment of the present invention, precursor compounds of the general formula (IIIa) or (IVa) are synthesized by reacting compounds of the general formula (I) or (II) according to Method 6.
Nach einer alternativ bevorzugten Ausgestaltung der vorliegenden Erfindung werden Vorläuferverbindungen der allgemeinen Formel (lllb) oder (IVb) synthetisiert, indem offenkettige Verbindungen der allgemeinen Formel (I) bzw. (II) unter Zugabe von organischen Säuren oder Lewissäuren zu der entsprechenden Verbindung der allgemeinen Formel (lllb) bzw. (IVb) zyklisiert werden. According to an alternatively preferred embodiment of the present invention, precursor compounds of general formula (IIIb) or (IVb) are synthesized by adding open-chain compounds of general formula (I) or (II) with the addition of organic acids or Lewis acids to the corresponding compound of general formula (IIIb) or (IVb) are cyclized.
Bevorzugt sind die erfindungsgemäßen Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b) pH-labile Verbindungen, d.h. Moleküle mit einer hohen Stabilität im pH-Bereich von 7,0 bis 7,5, die im Bereich um pH 7,4 wesentlich labiler sind, so dass die Vorläuferverbindung nach einer gewissen (vorgegebenen) Halbwertszeit zerfallen und die entsprechend pharmazeutisch aktive Verbindung der allgemeinen Formel (I) freisetzen. Aus therapeutischen Überlegungen werden Prodrugs angestrebt, die im Bereich von pH 6.4 Halbwertszeiten zwischen 0,1 und 20 h aufweisen. Detaillierte pharmakokinetische Messungen ermöglichen dazu die endgültige Auswahl geeigneter Maskierungsmittel für die Synthese von Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b). The precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention are preferably pH-labile compounds, ie. Molecules with a high stability in the pH range of 7.0 to 7.5, which are much more labile in the range around pH 7.4, so that the precursor compound disintegrate after a certain (predetermined) half-life and the corresponding pharmaceutically active compound of the general Release formula (I). For therapeutic reasons, prodrugs are sought which have half-lives of between 0.1 and 20 h in the range of pH 6.4. Detailed pharmacokinetic measurements allow the final selection of suitable sequestering agents for the synthesis of precursor compounds of the general formula (IIIa, b) or (IVa, b).
Da die erfindungsgemäßen Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b) zellpermeabel sind, weisen sie bevorzugt eine derartige Stabilität auf, dass sie erst nach dem Passieren der Zellmembran intrazellulär gespaltet werden. Dabei weisen die erfindungsgemäßen Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b) insbesondere auch den Vorteil auf, dass die entsprechend pharmazeutisch aktiven Verbindungen der allgemeinen Formel (I) bzw. (II) je nach individuellem Bedarf der Patienten intrazellulär freigesetzt werden.
Besonders bevorzugt werden die erfindungsgemäßen Vorläuferverbindungen der allgemeinen Formeln (llla,b) bzw. (IVa,b) nach Passage der Lipiddoppelschicht in den Zellen durch intrazelluläre Esterasen gespalten. Beispielsweise spaltet bei dem Einsatz von Oxyal- kylgruppen (bspw. bei Verwendung von Pivaloyloxymethyl) der verbleibende Molekülteil nachfolgend Alkylaldehyd (bspw. Formaldehyd) ab unter Freisetzung der aktiven Substanz. Since the precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention are cell-permeable, they preferably have such a stability that they are not split intracellularly until they have passed the cell membrane. In this case, the precursor compounds of the general formula (IIIa, b) or (IVa, b) according to the invention also have the particular advantage that the corresponding pharmaceutically active compounds of general formula (I) or (II), depending on the individual needs of the patient intracellularly be released. The precursor compounds of the general formulas (IIIa, b) or (IVa, b) according to the invention are particularly preferably cleaved after passage of the lipid bilayer in the cells by intracellular esterases. For example, when oxyalkyl groups are used (for example when pivaloyloxymethyl is used), the remaining part of the molecule subsequently breaks down alkylaldehyde (for example formaldehyde) with the release of the active substance.
Die Möglichkeit der Applikation einer Verbindung, aufweisend eine neuartige Verbindung der Formel (I), insbesondere ein Phenylphosphat, und/oder eine neuartige Verbindung der Formel (II), insbesondere ein Naphthylphosphat, in einen Organismus hängt von der Struktur der Verbindung ab. Eine besonders vorteilhafte Eigenschaft der neuartigen Verbindungen der Formel (I) bzw. der Formel (II) gegenüber konventionellen Nukleotid-basierten Inhibitoren ist, dass sie als niedermolekulare, organische Verbindungen im Sinne der Erfindung eine bspw. vom Magen-pH-Wert weitgehend unabhängige Bioverfügbarkeit aufweisen. Nach einer besonders bevorzugten Ausgestaltung der vorliegenden Erfindung werden Verbindungen, enthaltend eine neuartige Verbindung gemäß der allgemeinen Formel (I) und/oder der Formel (II), einem Organismus durch orale oder parentale Applikation verabreicht und über die Schleimhäute resorbiert. Für die orale Applikation eignen sich pharmazeutische Formulierungen bspw. in Form als Tablette, Kapsel oder Flüssigkeit oder rektal in Form von Sup- positorien. Beispiele für Organismen im Sinne der vorliegenden Erfindung sind vorzugsweise ausgewählt aus der Gruppe der Säugetiere, wobei die Verbindungen gemäß der allgemeinen Formel (I) bzw. (II) ganz besonders bevorzugt einem Menschen appliziert werden kann. The possibility of applying a compound comprising a novel compound of the formula (I), in particular a phenyl phosphate, and / or a novel compound of the formula (II), in particular a naphthyl phosphate, into an organism depends on the structure of the compound. A particularly advantageous property of the novel compounds of the formula (I) or of the formula (II) over conventional nucleotide-based inhibitors is that they are low-molecular-weight, organic compounds in the sense of the invention, for example a bioavailability largely independent of the gastric pH exhibit. According to a particularly preferred embodiment of the present invention, compounds containing a novel compound according to the general formula (I) and / or the formula (II) are administered to an organism by oral or parenteral administration and absorbed via the mucous membranes. For oral administration, pharmaceutical formulations are suitable, for example, in the form of a tablet, capsule or liquid or rectally in the form of suppositories. Examples of organisms in the context of the present invention are preferably selected from the group of mammals, it being possible with very particular preference for the compounds according to the general formula (I) or (II) to be administered to a human.
Gegenstand der Erfindung sind auch die erfindungsgemäßen Verbindungen gemäß der allgemeinen Formel (I), insbesondere ein Phenylphosphat, und/oder der Formel (II), insbesondere ein Naphthylphosphat, und/oder Vorläuferverbindungen gemäß der allgemeinen Formel (llla,b) bzw. (IVa,b) zur Verwendung zur Behandlung von Karzinomen oder Multiple Sklerose. The invention also relates to the compounds of the invention according to the general formula (I), in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa , b) for use in the treatment of carcinoma or multiple sclerosis.
Ein weiterer Gegenstand der Erfindung betrifft eine pharmazeutische Formulierung, enthaltend eine therapeutisch wirksame Menge mindestens einer neuartigen Verbindung gemäß der allgemeinen Formel (I), insbesondere ein Phenylphosphat, und/oder der Formel (II), insbesondere ein Naphthylphosphat, und/oder Vorläuferverbindungen gemäß der allgemeinen Formel (llla,b) bzw. (IVa,b), insbesondere für eine Anwendung in der Krebstherapie. Another object of the invention relates to a pharmaceutical formulation comprising a therapeutically effective amount of at least one novel compound according to the general formula (I), in particular a phenyl phosphate, and / or the formula (II), in particular a naphthyl phosphate, and / or precursor compounds according to the general formula (IIIa, b) or (IVa, b), in particular for use in cancer therapy.
Dabei können die neuartigen Verbindungen gemäß der allgemeinen Formel (I) bzw. der Formel (II) und/oder deren angegebene Vorläuferverbindungen gemäß der allgemeinen Formel (llla,b) bzw. (IVa,b) in der pharmazeutischen Formulierung als einzig pharmakolo-
gisch aktiver Wirkstoff oder auch in Kombination mit mindestens einem Zytostatikum verwendet werden, um so z.B. das Wirkungsspektrum zu verbreitern oder Resistenzentwicklungen vorzubeugen. In vielen Fällen erhält man dabei additive oder synergistische Effekte, d.h. die Wirksamkeit der Mischung ist größer als die Wirksamkeit der Einzelkomponenten. In this case, the novel compounds according to the general formula (I) or the formula (II) and / or their specified precursor compounds according to the general formula (IIIa, b) or (IVa, b) in the pharmaceutical formulation as the only pharmacological gically active ingredient or in combination with at least one cytostatic used to broaden eg the spectrum of action or to prevent development of resistance. In many cases, additive or synergistic effects are obtained, ie the effectiveness of the mixture is greater than the effectiveness of the individual components.
Besonders bevorzugt ist allerdings eine erfindungsgemäße pharmazeutische Formulierung, enthaltend die Verbindung gemäß der allgemeinen Formel (I) bzw. der Formel (II) und/oder deren Vorläuferverbindungen gemäß der allgemeinen Formel (llla,b) bzw. (IVa,b) in Kombination mit mindestens einem Zytostatikum. Eine solche erfindungsgemäße pharmazeutische Formulierung bietet somit den besonderen Vorteil, dass die Resistenzbildung bei einer Zy- tostatikabehandlung verhindert oder zumindest deutlich verzögert ist. Beispiele für Zytostatika sind: Folsäureantagonisten (bspw. Methotrexat, Pemetrexed), Pyrimidinanaloga (bspw. 5- Fluoruracil, Gemcitabin), Purinanaloga (bspw. Pentostatin, Azathioprin) und N- bzw. C- terminal geschützte Oligopeptide (bspw. Bortezomib). However, particularly preferred is a pharmaceutical formulation according to the invention comprising the compound according to the general formula (I) or the formula (II) and / or their precursor compounds according to the general formula (IIIa, b) or (IVa, b) in combination with at least one cytostatic. Such a pharmaceutical formulation according to the invention thus offers the particular advantage that the formation of resistance in a cytostatic treatment is prevented or at least significantly delayed. Examples of cytostatics are: folic acid antagonists (eg methotrexate, pemetrexed), pyrimidine analogs (eg 5-fluorouracil, gemcitabine), purine analogs (eg pentostatin, azathioprine) and N- or C-terminally protected oligopeptides (eg bortezomib).
Wie oben beschrieben, kann die erfindungsgemäße Verbindung gemäß der allgemeinen Formel (I) bzw. der Formel (II) und/oder Vorläuferverbindungen gemäß der allgemeinen Formel (llla,b) bzw. (IVa,b) oral in Form von Tabletten, Kapseln, Flüssigkeiten oder Sirup, rektal in Form von Suppositorien oder intravenös verabreicht werden. As described above, the compound of the invention according to the general formula (I) or the formula (II) and / or precursor compounds according to the general formula (IIIa, b) or (IVa, b) can be administered orally in the form of tablets, capsules, Liquids or syrups may be administered rectally in the form of suppositories or intravenously.
Bevorzugte Füllstoffe zur Herstellung von Tabletten, beschichteten Tabletten, Dragees und Hartgelatinekapseln sind bspw. Laktose, Stärke und deren Derivate, Talk, Stearinsäuren und deren Salze. Preferred fillers for the production of tablets, coated tablets, dragées and hard gelatine capsules are, for example, lactose, starch and derivatives thereof, talc, stearic acids and their salts.
Bevorzugte Hilfsstoffe zur Herstellung von Gelatinekapseln sind bspw. Pflanzenöle, Wachse, Fette und flüssige Polyalkoholen. Preferred excipients for the production of gelatin capsules are, for example, vegetable oils, waxes, fats and liquid polyalcohols.
Der Fachmann kennt geeignete Arzneistoffträger zur Herstellung von Lösungen oder Sirupen, wie bspw. Wasser, pharmazeutisch akzeptable Polyalkoholen, Saccharose, Invertzucker und Glusose. The person skilled in the art knows suitable excipients for the preparation of solutions or syrups, such as, for example, water, pharmaceutically acceptable polyalcohols, sucrose, invert sugar and glucose.
Dabei sind dem Fachmann Arzneistoffträger für Injektionslösungen grundsätzlich bekannt, und sind bspw. ausgewählt aus Wasser, pharmazeutisch akzeptable Salzlösungen, Alkoholen, Polyalkoholen, Glycerin und Pflanzenölen. In this case, those skilled in the art are generally familiar with drug carriers for injection solutions, and are, for example, selected from water, pharmaceutically acceptable salt solutions, alcohols, polyalcohols, glycerol and vegetable oils.
In Abhängigkeit von der Art des zu behandelnden Karzinoms, kann die Kombination einer erfindungsgemäßen Verbindung gemäß der allgemeinen Formel (I) und der Formel (II)
und/oder eine der erfindungsgemäß entsprechend angegebenen Vorläuferverbindungen bei der selektiven Inhibierung des STAT5-Proteins vorteilhaft zu überadditiven („synergistischen") Effekten führen. So sind bspw. die folgenden Effekte möglich, die über die eigentlich zu erwartenden Effekte hinausgehen: verringerte Anwendungskonzentration und/oder erweitertes Wirkungsspektrum und/oder erhöhte Wirksamkeit der einzelnen Verbindungen (d.h. Wirkstoffe) und pharmazeutischen Formulierungen. In einer bevorzugten Ausgestaltung der vorliegenden Erfindung weist die erfindungsgemäße pharmazeutische Formulierung demnach die Verbindung gemäß der allgemeinen Formel (I) in Kombination mit einer oder mehrerer Verbindungen der Formel (II) auf. Depending on the nature of the carcinoma to be treated, the combination of a compound of the invention according to the general formula (I) and the formula (II) and / or one of the precursor compounds given according to the invention in the selective inhibition of the STAT5 protein can advantageously lead to superadditive ("synergistic") effects.For example, the following effects are possible, which exceed the expected effects: reduced application concentration and / or or extended spectrum of activity and / or increased activity of the individual compounds (ie active ingredients) and pharmaceutical formulations In a preferred embodiment of the present invention, the pharmaceutical formulation according to the invention therefore comprises the compound according to the general formula (I) in combination with one or more compounds of the formula (II).
Durch die vorliegende Erfindung wird ferner eine Methode zur Verringerung der Funktionalität des STAT5-Proteins in einer Zelle oder einem Organismus mitumfasst, umfassend die Applikation einer erfindungsgemäßen Verbindung gemäß der allgemeinen Formel (I) bzw. (II) und/oder einer entsprechenden Vorläuferverbindung der allgemeinen Formel (llla/b) bzw. (IVa,b) in einer physiologisch wirksamen Konzentration zur Inhibierung des STAT5-Proteins, wobei die angegebenen Verbindungen selektiv mit dem STAT5-Protein interagieren. The present invention further encompasses a method for reducing the functionality of the STAT5 protein in a cell or an organism comprising administering a compound of the invention according to the general formula (I) or (II) and / or a corresponding precursor compound of the general Formula (IIIa / b) or (IVa, b) in a physiologically active concentration for inhibiting the STAT5 protein, said compounds selectively interact with the STAT5 protein.
Die Erfindung umfasst auch die Anwendung einer erfindungsgemäßen Verbindung gemäß der allgemeinen Formel (I) bzw. (II) und/oder einer Vorläuferverbindung der allgemeinen Formel (llla,b) bzw. (IVa,b) zur Behandlung von Krankheitszuständen, die mit einem erhöhten STAT5-Signaling, insbesondere Krebs einhergehen. The invention also encompasses the use of a compound according to the invention according to the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b) or (IVa, b) for the treatment of disease states which are elevated with an STAT5 signaling, especially cancer.
Die Erfindung umfasst auch eine Methode zur Behandlung bei der Krebstherapie durch Verabreichung einer effektiven Dosis eines Inhibitors des Transkriptionsfaktor STAT5, insbesondere einer erfindungsgemäßen Verbindung gemäß der allgemeinen Formel (I) bzw. (II) und/oder einer Vorläuferverbindung der allgemeinen Formel (llla,b) bzw. (IVa,b). The invention also encompasses a method of treatment in cancer therapy by administering an effective dose of an inhibitor of the transcription factor STAT5, in particular a compound according to the invention of the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b ) or (IVa, b).
Die Methode zur Behandlung umfasst dabei die Applikation einer pharmazeutischen Formulierung, enthaltend mindestens eine einer Verbindung gemäß der allgemeinen Formel (I) bzw. (II) und/oder einer Vorläuferverbindung der allgemeinen Formel (llla,b) bzw. (IVa,b) in einer physiologisch wirksamen Konzentration. Nach einer bevorzugten Ausgestaltung der Erfindung, insbesondere für die Behandlung bei der Krebstherapie, ist die pharmazeutische Formulierung für die Applikation fest oder flüssig, bspw. in Form als Tablette, Kapsel oder Flüssigkeit oder rektal in Form von Suppositorien, so dass die pharmazeutischen Formulierung einem Organismus durch orale oder parenterale Applikation verabreicht und über die Schleimhäute resorbiert wird. Vorzugsweise werden die Verbindung gemäß der allgemeinen Formel (I) bzw. (II) und/oder einer Vorläuferverbindung der allgemeinen Formel (llla,b) bzw. (IVa,b) in einer Menge von etwa 0,1-30 mg/kg Körpergewicht pro Tag verabreicht und ideal-
erweise in einer Menge von 0,5-15 mg/kg Körpergewicht pro Tag. Als Organismus für eine derartige Behandlung kommen bspw. Säugetiere, wie der Mensch, in Betracht. The method of treatment in this case comprises the application of a pharmaceutical formulation comprising at least one of a compound according to the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b) or (IVa, b) in a physiologically effective concentration. According to a preferred embodiment of the invention, in particular for the treatment in cancer therapy, the pharmaceutical formulation for the application is solid or liquid, for example. In the form of a tablet, capsule or liquid or rectally in the form of suppositories, so that the pharmaceutical formulation of an organism administered by oral or parenteral administration and resorbed via the mucous membranes. Preferably, the compound according to the general formula (I) or (II) and / or a precursor compound of the general formula (IIIa, b) or (IVa, b) in an amount of about 0.1-30 mg / kg body weight administered daily and ideally in an amount of 0.5-15 mg / kg body weight per day. As an organism for such a treatment are, for example, mammals, such as humans, into consideration.
Gegenstand der Erfindung sind auch neuartige Verbindungen gemäß der allgemeinen Formel (I) bzw. (II) und der entsprechenden Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b) oder eines Gemisches zur Verwendung als Arzneimittel, insbesondere für eine Anwendung in der Krebstherapie. The invention also relates to novel compounds according to the general formula (I) or (II) and the corresponding precursor compounds of the general formula (IIIa, b) or (IVa, b) or a mixture for use as a medicament, in particular for an application in cancer therapy.
Nach einer bevorzugten Ausgestaltung der vorliegenden Erfindung werden daher neuartige Verbindungen gemäß der allgemeinen Formel (I) bzw. (II) oder Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (Iva,b) oder eines Gemisches zur Herstellung einer pharmazeutischen Formulierung, insbesondere für eine Anwendung in der Krebstherapie verwendet. According to a preferred embodiment of the present invention are therefore novel compounds according to the general formula (I) or (II) or precursor compounds of the general formula (IIIa, b) or (Iva, b) or a mixture for the preparation of a pharmaceutical formulation, in particular used for an application in cancer therapy.
Die Dosierung der neuartigen Verbindungen gemäß der allgemeinen Formel (I) bzw. (II) aber auch der Vorläuferverbindungen der allgemeinen Formel (llla,b) bzw. (IVa,b) hängt von verschiedenen Faktoren ab, bspw. der Verabreichungsmethode, dem Alter, dem Gewicht sowie der Gesundheit, einschließlich der Art des zu behandelnden Organismus. The dosage of the novel compounds according to the general formula (I) or (II) but also the precursor compounds of the general formula (IIIa, b) or (IVa, b) depends on various factors, for example the method of administration, the age, weight and health, including the type of organism to be treated.
Nach einer bevorzugten Ausgestaltung der vorliegenden Erfindung werden die neuartigen Verbindungen der Formel (I) und Formel (II) einzeln oder als Gemisch dieser als Arzneimittel für eine Anwendung in der Krebstherapie verwendet. Erfindungsgemäß wird dabei auch die Verwendung der zuvor beschriebenen Vorläuferverbindungen der allgemeinen Formel (llla,b) und (IVa,b), pharmakologisch akzeptabler Salze, Enantiomere, Diastereomere, racemischer Gemische, kristalliner Formen, amorpher Formen und Solvater, jeweils enthaltend eine neuartige Verbindung der allgemeinen Formel (I) bzw. (II) mitumfasst. According to a preferred embodiment of the present invention, the novel compounds of the formula (I) and formula (II) are used individually or as a mixture thereof as medicaments for use in cancer therapy. The invention also includes the use of the previously described precursor compounds of the general formula (IIIa, b) and (IVa, b), pharmacologically acceptable salts, enantiomers, diastereomers, racemic mixtures, crystalline forms, amorphous forms and solvates, each containing a novel compound of general formula (I) or (II).
Gegenstand der Erfindung ist daher auch die Verwendung der neuartigen Verbindungen der allgemeinen Formel (I) bzw. Formel (II) oder eines Gemisches derart zur Herstellung einer pharmazeutischen Formulierung für eine Anwendung in der Krebstherapie. The invention therefore also relates to the use of the novel compounds of the general formula (I) or formula (II) or a mixture of this kind for the preparation of a pharmaceutical formulation for use in cancer therapy.
Vorzugsweise werden die neuartigen Verbindungen der Formel (I) bzw. Formel (II) einem Patienten in einer Menge von etwa 0,1-30 mg/kg Körpergewicht pro Tag verabreicht und idealerweise in einer Menge von 0,5-15 mg/kg Körpergewicht pro Tag. Der Fachmann wird erkennen, dass, wenn eine weitere Verbindung, bspw. in Kombination mit einer Vorläuferverbindungen der allgemeinen Formel (llla,b) und (IVa,b) eingesetzt wird, die korrekte Dosierung sowohl anhand der Untersuchung der Wirksamkeit der Verbindung in den Zellprolife-
rationsassays als auch durch Bestimmung der Toxizität beim Patienten ermittelt werden kann. Preferably, the novel compounds of formula (I) or formula (II) are administered to a patient in an amount of about 0.1-30 mg / kg of body weight per day, and ideally in an amount of 0.5-15 mg / kg of body weight per day. Those skilled in the art will recognize that when another compound is used, for example, in combination with a precursor compound of the general formula (IIIa, b) and (IVa, b), the correct dosage is determined both by examining the efficacy of the compound in the cell proliferation - can be determined by determining the patient's toxicity.
Besonders vorteilhaft werden Phenylphosphonate bzw. Naphthylphosphonate zur selektiven und potenten Inhibierung des Transkriptionsfaktors STAT5, insbesondere STAT5b eingesetzt, da diese Verbindungen im Körper, insbesondere in der Zelle nicht durch Enzyme, insbesondere Phosphatasen, gespalten werden und daher gegenüber den physiologischen Bedingungen wesentlich stabiler sind. Mithin weisen insbesondere Phenylphosphonate bzw. Naphthylphosphonate und die entsprechenden Prodrugs daraus unter physiologischen Bedingungen eine hohe Langzeitstabilität auf und zeigen über einen langen Zeitraum eine sehr gute therapeutische Wirkung. It is particularly advantageous to use phenylphosphonates or naphthylphosphonates for the selective and potent inhibition of the transcription factor STAT5, in particular STAT5b, since these compounds are not cleaved by enzymes, in particular phosphatases, in the body, in particular in the cell, and are therefore much more stable than the physiological conditions. Thus, especially phenylphosphonates or naphthylphosphonates and the corresponding prodrugs thereof have a high long-term stability under physiological conditions and show a very good therapeutic effect over a long period of time.
Die vorliegende Erfindung umfasst auch die Verwendung einer erfindungsgemäßen Verbindung der allgemeinen Formel (I) und/oder Formel (II) bzw. deren Vorläuferverbindungen zur Herstellung einer pharmazeutischen Formulierung, insbesondere für eine Anwendung in der Krebstherapie. The present invention also encompasses the use of a compound of the general formula (I) and / or formula (II) or their precursor compounds according to the invention for the preparation of a pharmaceutical formulation, in particular for use in cancer therapy.
Gegenstand der Erfindung ist auch die Verwendung einer erfindungsgemäßen Verbindung der allgemeinen Formel (I) und/oder Formel (II) bzw. deren erfindungsgemäß angegebener Vorläuferverbindungen in Kombination mit einer Krebsimmunotherapie zur Verwendung bei der Behandlung von Krebserkrankungen, wobei vorteilhaft die Resistenzbildung (d.h. Widerstandsfähigkeit eines Tumors bzw. Tumorzellen gegenüber die eingesetzten Behandlungsmethode) gegenüber der Behandlungsmethoden vermindert, insbesondere unterdrückt wird. The invention also provides the use of a compound of the general formula (I) and / or formula (II) or their precursor compounds according to the invention in combination with a cancer immunotherapy for use in the treatment of cancer, wherein advantageously the resistance formation (ie resistance of a Tumors or tumor cells compared to the treatment method used) compared to the treatment methods reduced, in particular is suppressed.
Klassische Methoden zur Behandlung bei Krebserkrankungen sind bspw. die operative Tumorentfernung (Resektion), die Chemotherapie und die Strahlentherapie, wobei häufig zwei oder gar alle drei Behandlungsmethoden gleichzeitig bei einem Organismus angewendet werden. Bei den Krebsimmunotherapiemethoden unterscheidet man zwischen der aktiven und der passiven Immunisierung. Bei der aktiven Immunisierung bekommt der Patient Substanzen verabreicht, die in seinem Immunsystem eine Immunantwort auslösen sollen. Bei der passiven Immunisierung kommen Antikörper oder Antikörper-Fragmente zum Einsatz. Bei der adoptiven Immuntherapie werden dem Patienten Leukozyten entnommen, ex vivo kultiviert und anschließend wieder dem Patienten injiziert. Werden bei der Behandlung aber nicht alle Zellen des Tumors und seiner Metastasen vernichtet, so ist die weitere Behandlung von Krebserkrankungen durch Resistenzbildung deutlich erschwert.
Eine Behandlungsmethode mit einer erfindungsgemäßen Verbindung der allgemeinen Formel (I) und/oder Formel (II) bzw. deren Vorläuferverbindungen bietet somit den besonderen Vorteil, dass die Resistenzbildung bei der Krebsimmunotherapie, insbesondere der Zytosta- tikabehandlung, verhindert oder zumindest deutlich verzögert ist. Beispiele für Zytostatika sind: Folsäureantagonisten (bspw. Methotrexat, Pemetrexed), Pyrimidinanaloga (bspw. 5- Fluoruracil, Gemcitabin), Purinanaloga (bspw. Pentostatin, Azathioprin) und N- bzw. C- terminal geschützte Oligopeptide (bspw. Bortezomib). Classical methods for the treatment of cancers include, for example, surgical removal of the tumor (resection), chemotherapy and radiation therapy, where frequently two or even all three treatment methods are used simultaneously in one organism. Cancer immunotherapy methods differentiate between active and passive immunization. In active immunization, the patient is given substances that are supposed to trigger an immune response in his immune system. Passive immunization uses antibodies or antibody fragments. In adoptive immunotherapy, leukocytes are removed from the patient, cultured ex vivo, and then injected back into the patient. However, if not all cells of the tumor and its metastases are destroyed in the treatment, the further treatment of cancers is made much more difficult by resistance formation. A treatment method with a compound of the general formula (I) and / or formula (II) or its precursor compounds according to the invention thus offers the particular advantage that resistance formation in cancer immunotherapy, in particular the cytostatic treatment, is prevented or at least significantly delayed. Examples of cytostatics are: folic acid antagonists (eg methotrexate, pemetrexed), pyrimidine analogs (eg 5-fluorouracil, gemcitabine), purine analogs (eg pentostatin, azathioprine) and N- or C-terminally protected oligopeptides (eg bortezomib).
Es versteht sich, dass die vorstehend genannten und die nachstehend noch zu erläuternden Beispiele der Erfindung nicht nur in der jeweils angegebenen Kombination, sondern auch in anderen Kombinationen oder in Alleinstellung verwendbar sind, ohne den Rahmen der Erfindung zu verlassen. It is understood that the examples of the invention mentioned above and those yet to be explained can be used not only in the particular combination given, but also in other combinations or in isolation, without departing from the scope of the invention.
Die vorliegende Erfindung ist sowohl für den humanmedizinischen als auch den veterinärmedizinischen Bereich einsetzbar. Der Begriff „Patient" wie hierin verwendet bezieht sich folglich auf zu behandelnde Organismen, insbesondere Menschen und Tiere. The present invention is applicable to both the human and veterinary fields. The term "patient" as used herein thus refers to organisms to be treated, especially humans and animals.
Die in der Beschreibung und den Ansprüchen offenbarten Merkmale der Erfindung können sowohl einzeln als auch in beliebiger Kombination für die Verwirklichung der Erfindung in ihren verschiedenen Ausführungsformen von Bedeutung sein. The features of the invention disclosed in the specification and the claims may be of importance both individually and in any combination for the realization of the invention in its various embodiments.
Weitere Merkmale und Vorteile der Erfindung sollen anhand folgender Ausführungsbeispiele näher erläutert werden, ohne die Erfindung auf diese zu beschränken. Further features and advantages of the invention will become apparent from the following embodiments, without limiting the invention to these.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) bzw. (II) sind auf verschiedenen Wegen zugänglich. Die im Folgenden beschriebenen Herstellungsverfahren bilden ebenfalls einen Teil der vorliegenden Erfindung. The compounds of general formula (I) or (II) according to the invention are accessible in various ways. The manufacturing methods described below also form part of the present invention.
Die obigen Formeln und die oben geschilderten Synthesestufen sind in Schema 1 zusam- mengefasst. The above formulas and the synthetic steps described above are summarized in Scheme 1.
Allgemeine Angaben General Information
Zur Aufnahme der 1H- und 13C-NMR-Spektren wurde ein Spektrometer der Firma Varian (1H: 300 MHz; 13C: 75 MHz) oder der Firma Bruker (1H: 400 MHz; 13C: 101 MHz) verwendet. Als innerer Standard für die chemische Verschiebung δ, angegeben in ppm, diente das jeweils verwendete Lösungsmittel.
Die Bestimmung der Schmelzpunkte erfolgte am Mikroheiztischmikroskop der Firma Büchi. Die Werte sind nicht korrigiert angegeben. To record the 1 H and 13 C NMR spectra, a Varian spectrometer ( 1 H: 300 MHz, 13 C: 75 MHz) or Bruker ( 1 H: 400 MHz, 13 C: 101 MHz) was used , The internal standard for the chemical shift δ, expressed in ppm, was the solvent used in each case. The determination of the melting points was carried out on the microheating microscope of Buchi. The values are not corrected.
Die IR-Spektren wurden an einem FT-IR-Spektrometer FT/IR-4100 Typ A der Firma Jasco als Film oder mit Kaliumbromid-Presslingen aufgenommen. The IR spectra were recorded on a FT-IR spectrometer FT / IR-4100 type A from Jasco as a film or with potassium bromide compacts.
Die Bestimmung der molaren Masse erfolgte mit einem hochauflösenden Massenspektrome- ter mit Elektrosprayionisation (HR-ESI-MS) der Firma Bruker-Daltonics. The molar mass was determined using a high-resolution mass spectrometer with electrospray ionization (HR-ESI-MS) from Bruker-Daltonics.
Dabei zeigt: Showing:
Fig. 1 das Syntheseschema für den Zugang zu Verbindung (13). Fig. 1 shows the synthesis scheme for access to compound (13).
Fig. 2 das Schema der induzierten Signaltransduktion über STATs durch aktivierte Zelloberflächenrezeptoren und Nicht-Rezeptortyrosinkinasen wie Src oder Bcr-Abl. Ein niedermolekularer Ligand der SH2-Domäne (symbolisiert durch das Dreieck) eines STAT-Proteins hemmt die Signaltransduktion über das betreffende STAT-Protein, indem es die Phosphorylierung am konservierten Tyrosinrest C-terminal von der Transaktivierungsdomäne hemmt. Die Abbilddung ist an die Literaturreferenz angelehnt.31 Fig. 2 shows the scheme of induced signal transduction via STATs by activated cell surface receptors and non-receptor tyrosine kinases such as Src or Bcr-Abl. A small-molecule ligand of the SH2 domain (symbolized by the triangle) of a STAT protein inhibits signal transduction via the STAT protein in question by inhibiting phosphorylation on the conserved tyrosine residue C-terminal of the transactivation domain. The illustration is based on the literature reference. 31
Fig. 3 die selektive Hemmung der STAT5b Tyrosinphosphorylierung durch 17, den Pivaloy- loxymethylester von 13. a) Struktur von 17 und der Negativkontrollverbindung 18. b) Hemmung der Tyrosinphosphorylierung des STAT5b-GFP-Fusionsproteins durch 0,3 μΜ - 10 μΜFig. 3 shows the selective inhibition of STAT5b tyrosine phosphorylation by 17, the pivaloyloxymethyl ester of 13. a) Structure of 17 and the negative control compound 18. b) Inhibition of tyrosine phosphorylation of the STAT5b-GFP fusion protein by 0.3 μΜ-10 μΜ
17 in K562-Zellen, die mit STAT5b-GFP transfiziert wurden. Die Negativkontrollverbindung17 in K562 cells transfected with STAT5b-GFP. The negative control compound
18 (10 μΜ) hemmt die STAT5b-Phosphorylierung nicht. Oberer Blot: mit phosphorylierungs- abhängigem STAT5-Antikörper. Dieser erkennt STAT5b und STAT5a nur dann, wenn diese an Tyr699 (STAT5b) bzw. Tyr694 (STATa) phosphoryliert sind. Zweitoberster Blot: mit phos- phorylierungsunabhängigem STAT5-Antikörper. Dieser erkennt STAT5a und STAT5b unabhängig von der Phosphorylierung an Tyr699 (STAT5b) bzw. Tyr694 (STAT5a). Die Identität des STAT5-GFP-Proteins ergibt sich aus dem Konstrukt, mit dem die Zellen transfiziert wurden. 18 (10 μΜ) does not inhibit STAT5b phosphorylation. Upper blot: with phosphorylation-dependent STAT5 antibody. This recognizes STAT5b and STAT5a only if they are phosphorylated on Tyr699 (STAT5b) or Tyr694 (STATa). Second-highest blot: with phosphorylation-independent STAT5 antibody. It recognizes STAT5a and STAT5b independently of phosphorylation on Tyr699 (STAT5b) and Tyr694 (STAT5a), respectively. The identity of the STAT5-GFP protein results from the construct with which the cells were transfected.
Ein getrenntes Gel wurde angefertigt, um die gleichmäßige Transfektion mittels des GFP- Tags zu überprüfen. Der entsprechende Blot wurde zunächst mit anti-GFP-Antikörper inkubiert (dritter Blot von oben), und danach mit anti-Actin Antikörper (unterster Blot).
c) Quantifizierung der pSTAT5b-GFP-Banden (STAT5b-GFP-Fusionsprotein, das an STAT5b Tyr699 phosphoryliert ist), normalisiert gegen STAT5b-GFP (STAT5b-GFP- Fusionsprotein unabhängig vom Phosphorylierungszustand an STAT5b Tyr699). Die Fehlerbalken geben die Standardabweichung zweier unabhängiger Experimente an. A separate gel was made to check for uniform transfection using the GFP tag. The corresponding blot was first incubated with anti-GFP antibody (third blot from above) and then with anti-actin antibody (lowest blot). c) Quantification of the pSTAT5b-GFP bands (STAT5b-GFP fusion protein phosphorylated on STAT5b Tyr699), normalized against STAT5b-GFP (STAT5b-GFP fusion protein independent of the phosphorylation state on STAT5b Tyr699). The error bars indicate the standard deviation of two independent experiments.
Fig. 4 in d) Die STAT5a Tyrosinphosphorylierung durch 0,3 μΜ - 10 μΜ 17 in K562-Zellen, die mit STAT5b-GFP transfiziert wurden, ist nicht inhibiert. Ein getrenntes Gel wurde angefertigt, um die gleichmäßige Transfektion mittels des GFP-Tags zu überprüfen. Die Negativkontrollverbindung 18 (10 μΜ) hemmt die STAT5a-Phosphorylierung auch nicht. Zur Erklärung der Blots siehe Legende unter b). Fig. 4 e) zeigt die Quantifizierung der pSTAT5a-GFP- Banden (STAT5a-GFP-Fusionsprotein, das an STAT5a Tyr694 phosphoryliert ist), normalisiert gegen STAT5a-GFP (STAT5a-GFP-Fusionsprotein unabhängig vom Phosphorylierungszustand an STAT5a Tyr694). Die Fehlerbalken geben die Standardabweichung zweier unabhängiger Experimente an. Figure 4 in d) STAT5a tyrosine phosphorylation by 0.3 μΜ - 10 μΜ 17 in K562 cells transfected with STAT5b-GFP is not inhibited. A separate gel was made to check for uniform transfection using the GFP tag. The negative control compound 18 (10 μΜ) also does not inhibit STAT5a phosphorylation. For explanation of the blots see legend under b). Figure 4e) shows the quantification of the pSTAT5a GFP bands (STAT5a-GFP fusion protein phosphorylated on STAT5a Tyr694) normalized against STAT5a-GFP (STAT5a-GFP fusion protein independent of the phosphorylation state on STAT5a Tyr694). The error bars indicate the standard deviation of two independent experiments.
Fig. 5 f) die Hemmung der Tyrosinphosphorylierung von endogenem STAT5 durch 0,3 μΜ - 10 μΜ 17 in K562-Zellen. Die Negativkontrollverbindung 18 (10 μΜ) hemmt die Phosphorylierung von endogenem STAT5 nicht. Oberer Blot: mit phosphorylierungsabhängigem STAT5-Antikörper. Dieser erkennt endogenes STAT5b und STAT5a nur dann, wenn diese an Tyr699 (STAT5b) bzw. Tyr694 (STATa) phosphoryliert sind. Zweitoberster Blot: mit phos- phorylierungsunabhängigem STAT5-Antikörper. Dieser erkennt STAT5a und STAT5b unabhängig von der Phosphorylierung an Tyr699 (STAT5b) bzw. Tyr694 (STAT5a). Unterer Blot: mit Antikörper gegen Actin. Fig. 5 g) zeigt die Quantifizierung der endogenen pSTAT5- Banden normalisiert gegen endogenes STAT5 unabhängig vom Phosphorylierungszustand. Die Fehlerbalken geben die Standardabweichung von vier unabhängigen Experimenten an. Fig. 5 f) the inhibition of tyrosine phosphorylation of endogenous STAT5 by 0.3 μΜ - 10 μΜ 17 in K562 cells. The negative control compound 18 (10 μΜ) does not inhibit the phosphorylation of endogenous STAT5. Upper blot: with phosphorylation-dependent STAT5 antibody. It recognizes endogenous STAT5b and STAT5a only when phosphorylated on Tyr699 (STAT5b) or Tyr694 (STATa). Second-highest blot: with phosphorylation-independent STAT5 antibody. It recognizes STAT5a and STAT5b independently of phosphorylation on Tyr699 (STAT5b) and Tyr694 (STAT5a), respectively. Lower blot: with antibody to actin. Fig. 5 g) shows the quantification of the endogenous pSTAT5 bands normalized against endogenous STAT5 independent of the phosphorylation state. The error bars indicate the standard deviation of four independent experiments.
Fig. 6 h) die Zeitabhängigkeit der Tyrosinphosphorylierung des STAT5b-GFP- Fusionsproteins durch 17 in K562-Zellen, die mit STAT5b-GFP transfiziert wurden. Die Zellen wurden für die angegebenen Zeiten mit 10 μΜ 17 behandelt. Oberer Blot: mit phosphorylierungsabhängigem STAT5-Antikörper. Dieser erkennt STAT5b nur dann, wenn es an Tyr699 phosphoryliert ist. Zweitoberster Blot: mit phosphorylierungsunabhängigem STAT5- Antikörper. Dieser erkennt STAT5b unabhängig von der Phosphorylierung an Tyr699. Ein getrenntes Gel wurde angefertigt, um die gleichmäßige Transfektion mittels des GFP-Tags zu überprüfen. Der entsprechende Blot wurde zunächst mit anti-GFP-Antikörper inkubiert (dritter Blot von oben), und danach mit anti-Actin Antikörper (unterster Blot).
Fig. 7 die Bindung des BODIPY-FL-markierten Derivats von Verbindung (31 ) als Verbindung (10) an ein STAT5-Proteinderivat (natives STAT5b, STAT5b-Punktmutanten Arg618Ala, Arg618Lys und Trp641Ala, natives STAT5a) wird durch die Erhöhung der Fluoreszenzpolarisation festgestellt. Fig. 6 h) the time dependence of tyrosine phosphorylation of the STAT5b-GFP fusion protein by 17 in K562 cells transfected with STAT5b-GFP. The cells were treated with 10 μM 17 for the indicated times. Upper blot: with phosphorylation-dependent STAT5 antibody. This recognizes STAT5b only if it is phosphorylated on Tyr699. Second-highest blot: with phosphorylation-independent STAT5 antibody. This recognizes STAT5b independently of phosphorylation on Tyr699. A separate gel was made to check for uniform transfection using the GFP tag. The corresponding blot was first incubated with anti-GFP antibody (third blot from above) and then with anti-actin antibody (lowest blot). Figure 7 shows the binding of the BODIPY-FL-labeled derivative of compound (31) as compound (10) to a STAT5 protein derivative (native STAT5b, STAT5b point mutant Arg618Ala, Arg618Lys and Trp641Ala, native STAT5a) by increasing fluorescence polarization ,
Allgemeine Synthesevorschriften General Synthesis Instructions
KHC03 (1.2 mmol) und Benzylbromid (1 .5 mmol) wurden zu einer Lösung des Benzoesäurederivates (1 mmol) in 4 mL trockenem DMF gegeben und bei 40°C für 3-4 h gerührt. Nach Beendigung der Reaktion werden 10 mL Wasser und mit Ethylacetat (2 x 20 mL) extrahiert. Die organische Phase wird mit 5% NaHC03 gewaschen und Na2S04 getrocknet. Nach Ab- destillation des Losungsmitttels im Vakuum wird das Rohprodukt ohne weitere Reinigung in der Folgereaktion eingesetzt.'11 KHC0 3 (1.2 mmol) and benzyl bromide (1 .5 mmol) were added to a solution of the benzoic acid derivative (1 mmol) in 4 mL of dry DMF and stirred at 40 ° C for 3-4 h. After completion of the reaction, 10 mL of water and extracted with ethyl acetate (2 x 20 mL). The organic phase is washed with 5% NaHC0 3 and Na 2 S0 4 dried. After the solvent has been distilled off in vacuo, the crude product is used in the subsequent reaction without further purification. 11
Methode 2: Umsetzung einwertiger aromatische Alkohole zu Phosphodibenzylestern
Method 2: Reaction of Monovalent Aromatic Alcohols to Phosphodibenzyl Esters
Zu einer gerührten Lösung des aromatischen Alkohols (1 mmol) in trockenem Acetonitril (8 mL) werden CCI4 (5 mmol), Diethylisopropylamin (DIPEA) (2.1 mmol) und eine katalyti- sche Menge Dimethylaminopyridin (DMAP) gegeben.'21 Danach wird bei 0°C tropfenweise Dibenzylphosphit (1.5 mmol) zugegeben und die Mischung für 30-60 Minuten gerührt. Nach Beendigung der Reaktion werden 2 mL einer 0.5 mol/L KH2P04 Lösung zugegeben. Die Reaktionsmischung wird wiederholt mit Ethylacetat extrahiert. Die vereinigten organischen Phasen werden mit 5% NaCI Lösung und Wasser gewaschen und danach über Na2S04 getrocknet. Nach Destillation des Lösungsmittels im Vakuum wird das Produkt durch Flash- Chromatographie gereinigt. To a stirred solution of the aromatic alcohol (1 mmol) in dry acetonitrile (8 mL) is added CCI 4 (5 mmol), diethylisopropylamine (DIPEA) (2.1 mmol) and a catalytic amount of dimethylaminopyridine (DMAP). 21 After dropwise at 0 ° C dibenzyl phosphite (1.5 mmol) is added and the mixture stirred for 30-60 minutes. After completion of the reaction, 2 mL of a 0.5 mol / L KH 2 P0 4 solution are added. The reaction mixture is repeatedly extracted with ethyl acetate. The combined organic phases are washed with 5% NaCl solution and water and then dried over Na 2 S0 4 . After distillation of the solvent in vacuo, the product is purified by flash chromatography.
Diese Methode wird in analoger Form für zweiwertige aromatische Alkohole angewandt. Dabei werden jedoch nur 0.5 mmol des zweiwertigen aromatischen Alkohols eingesetzt.
Methode 3: Spaltung der Phosphodibenzylester durch Hydrogenolyse
This method is used in analogous form for dihydric aromatic alcohols. However, only 0.5 mmol of the dihydric aromatic alcohol are used. Method 3: Cleavage of the Phosphodibenzylester by Hydrogenolysis
Zu einer Lösung von Phosphodibenzylester (100 mg) in absolutem Ethanol (20 mL) werden 10% Pd auf Kohle (15 mg) unter einer inerten Atmosphäre gegeben. Durch wiederholtes Anlegen von Vakuum und Füllen des Gasraums mit Wasserstoff wird eine Wasserstoffatmosphäre erzeugt. Nach Beendigung der Reaktion wird die Reaktionsmischung über Celite filtriert und das Celite mehrfach mit Ethanol gewaschen. Nach Entfernung des Lösungsmittels im Vakuum werden die Phosphorsäurederivate in Wasser gelöst und mit Dichlormethan gewaschen. Nach Lyophilisation werden die Produkte in quantitativer Ausbeute und in hochreiner Form erhalten. To a solution of phosphodibenzyl ester (100 mg) in absolute ethanol (20 mL) is added 10% Pd on carbon (15 mg) under an inert atmosphere. By repeatedly applying vacuum and filling the gas space with hydrogen, a hydrogen atmosphere is generated. After completion of the reaction, the reaction mixture is filtered through Celite and the celite washed several times with ethanol. After removal of the solvent in vacuo, the phosphoric acid derivatives are dissolved in water and washed with dichloromethane. After lyophilization, the products are obtained in quantitative yield and in a highly pure form.
Methode 4: Amidkupplung Method 4: Amide coupling
Zu einer Lösung der Carbonsäure (1 mmol) mit wasserfreiem DMF (10 mL) werden bei 0°C EDC (1 mmol) und HOBT (1 mmol) gegeben. Die Reaktionsmischung wird erst für 30 Minuten bei 0°C, und dann für 90 Minuten bei Raumtemperatur gerührt. Triethylamin (3 mmol) und das zu kuppelnde Amin (1 mmol) werden zugegeben und über Nacht bei Raumtemperatur gerührt. Nach Zugabe von Wasser (100 mL) wird das Produkt durch Zugabe von Ethyl- acetat (2x30 mL) extrahiert. Die vereinigten organischen Phasen werden mit gesättigter NaHC03-Lösung gewaschen und über Na2S04 getrocknet. Nach Destillation des Lösungsmittels im Vakuum wird das Produkt säulenchromatographisch gereinigt. To a solution of the carboxylic acid (1 mmol) with anhydrous DMF (10 mL) at 0 ° C is added EDC (1 mmol) and HOBT (1 mmol). The reaction mixture is stirred for 30 minutes at 0 ° C, and then for 90 minutes at room temperature. Triethylamine (3 mmol) and the amine to be coupled (1 mmol) are added and stirred overnight at room temperature. After addition of water (100 ml), the product is extracted by adding ethyl acetate (2 x 30 ml). The combined organic phases are washed with saturated NaHC0 3 solution and dried over Na 2 S0 4 . After distillation of the solvent in vacuo, the product is purified by column chromatography.
Methode 5: Spaltung von Methylphenylethern zu Phenolen Method 5: Cleavage of Methylphenyl Ethers to Phenols
Zu einer Lösung des Methylphenylethern (1 mmol) in 2 mL trockenem Dichlormethan wird bei 0°C eine 1 M Lösung von BBr3 in Dichlormethan (3 mmol) zugegeben und über Nacht bei Raumtemperatur gerührt. Nach Beendigung der Reaktion wird die Reaktionsmischung zweimal mit 2 mL Methanol versetzt und anschließend flüchtige Bestandteile im Vakuum entfernt. Die Rohprodukte werden säulenchromatographisch gereinigt.
Methode 6: Umsetzung von Phosphorsäureestern in die entsprechenden Pivaloyloxyme- thylester To a solution of the Methylphenylethern (1 mmol) in 2 mL of dry dichloromethane at 0 ° C, a 1 M solution of BBr 3 in dichloromethane (3 mmol) was added and stirred overnight at room temperature. After completion of the reaction, the reaction mixture is mixed twice with 2 ml of methanol and then volatiles are removed in vacuo. The crude products are purified by column chromatography. Method 6: Reaction of phosphoric esters in the corresponding Pivaloyloxyme-
0.1 mmol Phosphorsäurester werden in Acetonitril suspendiert. Diisopropylamin (4 äq / Phosphorsäureesterfunktion) und Pivaloyloxymethyliodid (4 äq. / Phosphorsäureesterfunktion) werden bei Raumtemperatur zugegeben. Die Mischung wird über Nacht bei Raumtemperatur gerührt. Nach Entfernung der flüchtigen Komponenten im Vakuum wird das Produkt säulenchromatographisch gereinigt. 0.1 mmol of phosphoric acid ester are suspended in acetonitrile. Diisopropylamine (4 eq / phosphoric acid ester function) and pivaloyloxymethyl iodide (4 eq / phosphoric ester function) are added at room temperature. The mixture is stirred overnight at room temperature. After removal of the volatile components in vacuo, the product is purified by column chromatography.
Methode 7: Analyse der Substanzaktivitäten mittels Fluoreszenzpolarisations-AssaysMethod 7: Analysis of the substance activities by fluorescence polarization assays
Die Analyse der Substanzaktivitäten gegen STAT5b erfolgte nach dem Prinzip der Fluoreszenzpolarisation und folgt dem publizierten Verfahren.'3"51 Zur Gewinnung des STAT5b- Proteins wurden die für die Aminosäuren 136-703 kodierenden Nukleotide menschlichen STAT5b durch PCR amplifiziert und in die Fsel/Ascl Schnittstellen eines modifizierten pQE70-Vektors kloniert. Das Protein wurde exprimiert aus E. coli Rosetta (Novagen) wie beschrieben,'6"71 durch Affinitätschromatographie gereinigt und dialysiert gegen einen Puffer der folgenden Zusammensetzung: 50 mmol/L Hepes (pH 7.5), 100 mmol/L NaCI, 10% glyce- rol, 1 mmol/L EDTA, 1 mmol/L DTT, und 0.1 % Nonidet P-40 Ersatzstoff. Das STAT5b Protein (120 nmol/L) wurde mit dem Peptid 5-carboxyfluorescein-GY(P03H2)LVLDKW (10 nM) inkubiert in dem folgenden Puffer: 10 mmol/L Hepes, pH 7.5, 1 mmol/L EDTA, 0.1 % Nonidet P-40, 50 mmol/L NaCI, 1 mmol/L dithiothreitol, und 2% DMSO. Nach Inkubation bei Raumtemperatur für 30-120 Minuten wurde die Fluoreszenzpolarisation in Gegenwart der Testsubstanzen gemessen (Tecan Infinite F500). The analysis of the substance activities against STAT5b was carried out according to the principle of fluorescence polarization and follows the published procedure. ' 3 "51 To obtain the STAT5b protein, the human STAT5b nucleotides coding for amino acids 136-703 were amplified by PCR and cloned into the Fsel / Ascl sites of a modified pQE70 vector .The protein was expressed from E. coli Rosetta (Novagen). as described, '6' 71 purified by affinity chromatography and dialyzed against a buffer of the following composition: 50 mmol / L Hepes (pH 7.5), 100 mmol / L NaCl, 10% glycerol, 1 mmol / L EDTA, 1 mmol / L DTT, and 0.1% Nonidet P-40 Substitute. The STAT5b protein (120 nmol / L) was incubated with the peptide 5-carboxyfluorescein-GY (P0 3 H 2 ) LVLDKW (10 nM) in the following buffer: 10 mmol / L Hepes, pH 7.5, 1 mmol / L EDTA, 0.1% Nonidet P-40, 50 mmol / L NaCl, 1 mmol / L dithiothreitol, and 2% DMSO. After incubation at room temperature for 30-120 minutes, fluorescence polarization was measured in the presence of the test substances (Tecan Infinite F500).
Methode 8: Analyse der zellulären Substanzaktivitäten Method 8: Analysis of cellular substance activities
Humanes Volllängen STAT5a und STAT5b wurden aus K562 cDNA PCR-amplifiziert, und in einen Expressionsvektor basierend auf pCS2 kloniert. Dieser Expressionsvektor hat einen C- terminalen GFP-Tag. Daher werden in der Zelle die Fusionproteine STAT5a-GFP bzw. STAT5b-GFP gebildet. Full length human STAT5a and STAT5b were PCR amplified from K562 cDNA and cloned into an expression vector based on pCS2. This expression vector has a C-terminal GFP tag. Therefore, the fusion proteins STAT5a-GFP and STAT5b-GFP are formed in the cell.
K562 Zellen werrden in RPMI 1640 Medium (Invitrogen) kultiviert, das 10% FBS (Gibco Life Technologies), 2 mM L-Glutamin (PAA Laboratories) und Penicillin/Streptomycin (PAA Laboratories) enthält. Die Zellen werden transfiziert, entweder mit STAT5a-GFP, oder mit STAT5b-GFP-Plasmid, unter Verwendung von Fugene HD Transfection Reagent (Promega). Nach 24 h werden die Zellen für 4 h mit Testsubstanz oder DMSO behandelt (finale DMSO Konzentration: 0.2 %). Die Zellen werden geerntet und mit Lysepuffer lysiert (50 mM Tris-HCI pH 7.5, 150 mM NaCI, 10 mM Na4P207, 10% glycerol, 1 % Triton X-100, 1 mM EDTA, 100
ng/ml Aprotinin, 1 m Na3P04, 10 mM NaF and 1 mM PMSF). Die Komponenten der Zelllysa- te werden auf einem Polyacrylamidgel (SDS-PAGE) aufgetrennt, dann auf eine Nitrocellulo- se-Membran transferiert. Für jedes Experiment wurden zwei Gele und Membranen präpariert. Eine Membran wurde mit Stat5-Antikörpern inkubiert (anti-pSTAT5, erkennt Stat5a pTyr694 und STAT5b pTyr699, Cell Signaling; anti-total Stat5, Cell Signaling; anti-ß-actin, Cell Signaling). Die andere Membran wird mit anti-GFP (Cell Signaling) gefolgt von anti-ß- actin inkubiert, um die gleichmäßige Transformation zu überprüfen. Membranen mit gebundenem Primärantikörper werden mit sekundärem Antikörper (α-rabbit-HRP secondary antibody, Dako) inkubiert. Die Signale werden nach Zugabe von Western Lightning Plus Chemi- lumineszenz-Reagenz (Perkin-Elmer) mit einem ImageQuant Imagesystem (GE Healthcare) detektiert. Die quantitative Analyse erfolgte mit der Software ImageJ (NIH). (Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nature methods 2012, 9(7): 671 -675 ) K562 cells are cultured in RPMI 1640 medium (Invitrogen) containing 10% FBS (Gibco Life Technologies), 2 mM L-glutamine (PAA Laboratories) and penicillin / streptomycin (PAA Laboratories). Cells are transfected with either STAT5a-GFP or STAT5b-GFP plasmid using Fugene HD Transfection Reagent (Promega). After 24 h, the cells are treated for 4 h with test substance or DMSO (final DMSO concentration: 0.2%). The cells are harvested and lysed with lysis buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 10 mM Na 4 P 2 O 7 , 10% glycerol, 1% Triton X-100, 1 mM EDTA, 100 ng / ml aprotinin, 1 M Na 3 P0 4 , 10 mM NaF and 1 mM PMSF). The components of the cell lysates are separated on a polyacrylamide gel (SDS-PAGE), then transferred to a nitrocellulose membrane. For each experiment, two gels and membranes were prepared. A membrane was incubated with Stat5 antibodies (anti-pSTAT5, recognizes Stat5a pTyr694 and STAT5b pTyr699, cell signaling, anti-total Stat5, cell signaling, anti-β-actin, cell signaling). The other membrane is incubated with anti-GFP (cell signaling) followed by anti-β-actin to check for uniform transformation. Primary bound antibody membranes are incubated with secondary antibody (α-rabbit HRP secondary antibody, Dako). The signals are detected after addition of Western Lightning Plus chemiluminescence reagent (Perkin-Elmer) with an ImageQuant image system (GE Healthcare). The quantitative analysis was carried out with the software ImageJ (NIH). (Schneider CA, Rasband WS, Eliceiri KW, NIH Image to ImageJ: 25 years of image analysis, Nature methods 2012, 9 (7): 671-675)
Beispiel 1 : Synthese von (4-Methyl-2-(phosphonooxy)benzoesäure) (4) Example 1: Synthesis of (4-methyl-2- (phosphonooxy) benzoic acid) (4)
Synthese von (Benzyl-2-hvdroxy-4-methylbenzoat) (4a) Synthesis of (benzyl-2-hydroxy-4-methylbenzoate) (4a)
4a 4a
4a wurde gemäß Methode 1 hergestellt (Ausbeute: 94%) 4a was prepared according to method 1 (yield: 94%)
1H-NMR (400 MHz, CDCI3): δ [ppm] = 2.35 (s, 3H, CH3), 5.38 (s, 2H, Bn-CH2), 6.69 (d, J = 8, 1 H, Ar-H), 6.81 (s, 1 H, Ar-H), 7.36-7.46 (m, 5H, Bn-H), 7.77 (d, J = 8, 1 H, Ar-H), 10.71 (s, 1 H, OH) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 2.35 (s, 3H, CH 3 ) , 5.38 (s, 2H, Bn-CH 2 ) , 6.69 (d, J = 8, 1 H, Ar-H) , 6.81 (s , 1H, Ar-H), 7.36-7.46 (m, 5H, Bn-H), 7.77 (d, J = 8, 1H, Ar-H), 10.71 (s, 1H, OH)
13C-NMR (100 MHz, CDCI3): δ [ppm] = 22.00, 66.84, 109.95, 1 17.85, 120.59, 128.34, 128.59, 128.81 , 129.92, 135.62, 147.31 , 161.86, 170.08 13 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 22.00 , 66.84 , 109.95 , 1 17.85, 120.59, 128.34, 128.59, 128.81, 129.92, 135.62, 147.31, 161.86, 170.08
MS (ESI) gefunden: [M-H]" m/z = 241.1 , berechnet für Ci5H1403: 241.1 MS (ESI) found: [MH] " m / z = 241.1, calculated for Ci 5 H 14 0 3 : 241.1
UV/Vis λ [nm] = 306.5 (Int = 0.71 ), 247.5 (Int = 1.93) UV / Vis λ [nm] = 306.5 (Int = 0.71), 247.5 (Int = 1.93)
Synthese von (Benzyl-2-(bis(benzyloxy)phosphoryloxy)-4-methylbenzoat) (4b) Synthesis of (benzyl-2- (bis (benzyloxy) phosphoryloxy) -4-methylbenzoate) (4b)
4b
4b wurde gemäß Methode 2 hergestellt. Das Rohprodukt wurde säulenchromatographisch gereinigt (Ethylacetat: Hexan 30:70). Ausbeute: 55% 4b 4b was prepared according to method 2. The crude product was purified by column chromatography (ethyl acetate: hexane 30:70). Yield: 55%
1H-NMR (400 MHz, CDCI3): δ [ppm] = 2.32 (s, 3H, CH3), 5.12 (d, J = 8.8, 4H, P-Bn-CH2), 5.23 (s, 2H, Bn-CH2), 7.01 (d, J = 8.4, 1 H, Ar-H), 7.20 (s, 1 H, Ar-H), 7.26-7.35 (m, 13H, Bn-H), 7.40-7.42 (m, 2H, Bn-H), 7.82 (d, J = 7.6, 1 H, Ar-H) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 2.32 (s, 3H, CH 3 ) , 5.12 (d, J = 8.8, 4H, P-Bn-CH 2 ) , 5.23 (s, 2H , Bn-CH2), 7:01 (d, J = 8.4, 1 H, Ar-H), 7.20 (s, 1 H, Ar-H), 7:26 to 7:35 (m, 13H, Bn-H), 7.40- 7.42 (m, 2H, Bn-H), 7.82 (d, J = 7.6, 1H, Ar-H)
13C-NMR (100 MHz, CDCI3): δ [ppm] = 21 .57, 66.80, 70.13 (d, J = 5.9), 120.02, 1 17.85, 122.30 (d, J = 2.9), 125.88, 128.15, 128.29, 128.36, 128.61 , 128.64, 131 .94, 135.76 (d, J = 7.4), 136.08, 145.12, 149.91 , 164.68 13 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 21 .57 , 66.80 , 70.13 (d, J = 5.9), 120.02 , 1 17.85, 122.30 (d, J = 2.9), 125.88, 128.15, 128.29, 128.36, 128.61, 128.64, 131.94, 135.76 (d, J = 7.4), 136.08, 145.12, 149.91, 164.68
31P-NMR (162 MHz, CDCI3): δ [ppm] = -6.05 (s, 1 P) 3 1 P-NMR (162 MHz, CDCl 3 ): δ [ppm] = -6.05 (s, 1 P)
MS (ESI) gefunden: [M+H]+ m/z = 503.1 , berechnet für C29H27O6P: 503.0 MS (ESI) found: [M + H] + m / z = 503.1, calculated for C29H27O6P: 503.0
UV/Vis λ [nm] = 384.5 (Int = 2.43), 247.5 (Int = 1.69) UV / Vis λ [nm] = 384.5 (Int = 2.43), 247.5 (Int = 1.69)
Synthese von (4-Methyl-2-(phosphonooxy)benzoesäure) (4) Synthesis of (4-methyl-2- (phosphonooxy) benzoic acid) (4)
4 wurde gemäß Methode 3 hergestellt und in Form weißer Kristalle erhalten. Ausbeute: 81 % 1H-NMR (400 MHz, D20): δ [ppm] = 2.21 (s, 3H, CH3), 6.73 (d, J = 7.6, 1 H, Ar-H), 7.14 (d, J = 8.0, 1 H, Ar-H), 7.26 (s, 1 H, Ar-H) 4 was prepared according to Method 3 and obtained in the form of white crystals. Yield: 81% 1 H-NMR (400 MHz, D 2 O): δ [ppm] = 2.21 (s, 3H, CH 3 ) , 6.73 (d, J = 7.6, 1 H, Ar-H) , 7.14 ( d, J = 8.0, 1H, Ar-H) , 7.26 (s, 1H, Ar-H)
13C-NMR (100 MHz, D20): δ [ppm] = 17.97, 1 16.95 (d, J = 3.0), 1 18.92, 124.78 (d, J = 7.3), 125.15, 137.73, 147.77 (d, I = 5.9), 174.70 13 C-NMR (100 MHz, D 2 O): δ [ppm] = 17.97 , 1 16.95 (d, J = 3.0) , 1 18.92 , 124.78 (d, J = 7.3) , 125.15 , 137.73 , 147.77 (d, I = 5.9) , 174.70
31P-NMR (162 MHz, D20): δ [ppm] = 1 .00 (s, 1 P) 3 1 P-NMR (162 MHz, D 2 O): δ [ppm] = 1 .00 (s, 1 P)
HRMS (ESI) gefunden: [M-H]" m/z = 231.0064, berechnet für C8H906P: 231 .0064 HRMS (ESI) found: [MH] "m / z = 231.0064, calculated for C 8 H 9 0 6 P: 231 .0064
UV/Vis λ [nm] = 283.0 (Int = 1 .35), 240.5 (Int = 2.99) UV / Vis λ [nm] = 283.0 (Int = 1 .35), 240.5 (Int = 2.99)
Beispiel 2: Synthese von 3-lsopropyl-6-methyl-2-(phosphonooxy)benzoesäure (8)Example 2: Synthesis of 3-isopropyl-6-methyl-2- (phosphonooxy) benzoic acid (8)
Synthese von Benz -2-hvdroxy-3-isopropyl-6-methylbenzoat (8a) Synthesis of Benz -2-hydroxypropyl-3-isopropyl-6-methylbenzoate (8a)
8a
8a wurde gemäß Methode 1 hergestellt. Ausbeute: 99% 8a 8a was prepared according to method 1. Yield: 99%
1H NMR (300 MHz, CDCI3) δ = 1 .1 1 - 1 .19 (d, J=6.8, 5H), 2.19 - 2.26 (s, 3H), 3.59 - 3.77 (h, J=6.8, 6.8, 6.8, 6.8, 6.8, 1 H), 5.38 - 5.45 (s, 2H), 6.75 - 6.85 (d, J=7.9, 1 H), 7.17 - 7.29 (m, 1 H), 7.32 - 7.49 (m, 4H), 10.71 - 10.78 (s, 1 H). 1 H NMR (300 MHz, CDCl 3 ) δ = 1 .1 1 - 1 .19 (d, J = 6.8, 5H), 2.19-2.26 (s, 3H), 3.59-3.77 (h, J = 6.8, 6.8 , 6.8, 6.8, 6.8, 1H), 5.38 - 5.45 (s, 2H), 6.75 - 6.85 (d, J = 7.9, 1H), 7.17 - 7.29 (m, 1H), 7.32 - 7.49 (m, 4H), 10.71 - 10.78 (s, 1H).
13C-NMR (75 MHz, CDCI3): δ [ppm] = 16.06, 24.49, 30.44, 67.69, 1 12.05, 1 16.05, 123.90, 13 C-NMR (75 MHz, CDCl 3 ): δ [ppm] = 16.06, 24.49, 30.44, 67.69, 1 12.05, 1 16.05, 123.90,
128.75, 128.81 , 128.83, 135.18, 149.17, 159.47, 171 .67 128.75, 128.81, 128.83, 135.18, 149.17, 159.47, 171.67
MS (ESI) gefunden: [M-H]" m/z = 283.0, berechnet für Ci4H1203: 283.1 MS (ESI) found: [MH] " m / z = 283.0, calculated for Ci 4 H 12 0 3 : 283.1
Synthese von Benzyl 2-((bis(benzyloxy)phosphoryl)oxy)-3-isopropyl-6-methylbenzoat (8b) Synthesis of Benzyl 2 - ((bis (benzyloxy) phosphoryl) oxy) -3-isopropyl-6-methylbenzoate (8b)
8a 8b 8a 8b
8b wurde gemäß Methode 2 hergestellt. Das Rohprodukt wurde säulenchromatographisch gereinigt (Ethylacetat: Hexan 30:70). Ausbeute: 90% 8b was prepared according to method 2. The crude product was purified by column chromatography (ethyl acetate: hexane 30:70). Yield: 90%
1H NMR (400 MHz, CDCI3) δ = 1.15 (d, J=6.8, 6H), 2.31 (s, 3H), 2.96 (hept, J=6.7, 1 H), 4.99 - 5.08 (m, 4H), 5.23 (s, 2H), 7.06 (dd, J=8.0, 1.2, 1 H), 7.18 (d, J=8.0, 1 H), 7.23 - 7.43 (m, 15H). 1 H NMR (400 MHz, CDCl 3 ) δ = 1.15 (d, J = 6.8, 6H), 2.31 (s, 3H), 2.96 (hept, J = 6.7, 1H), 4.99 - 5.08 (m, 4H) , 5.23 (s, 2H), 7.06 (dd, J = 8.0, 1.2, 1H), 7.18 (d, J = 8.0, 1H), 7.23 - 7.43 (m, 15H).
31P NMR (162 MHz, CDCI3) δ = -5.06 31 P NMR (162 MHz, CDCl 3 ) δ = -5.06
MS (ESI) gefunden: [M+Na]+ m/z = 567.4, berechnet für C28H2506P: 567.6 MS (ESI) found: [M + Na] + m / z = 567.4, calculated for C 28 H 25 0 6 P: 567.6
Synthese von 3-lsopropyl-6-methyl-2-(phosphonooxy)benzoesäure (8) Synthesis of 3-isopropyl-6-methyl-2- (phosphonooxy) benzoic acid (8)
8 wurde gemäß Methode 3 hergestellt. Ausbeute: 89% 8 was prepared according to method 3. Yield: 89%
1H NMR (400 MHz, DMSO) δ = 1.14 (d, J=6.8, 6H), 2.25 (s, 3H), 2.96 (hept, J=7.1 , 1 H), 7.03 (d, J=7.9, 1 H), 7.18 (d, J=8.0, 1 H). 1 H NMR (400 MHz, DMSO) δ = 1.14 (d, J = 6.8, 6H), 2.25 (s, 3H), 2.96 (hept, J = 7.1, 1H), 7.03 (d, J = 7.9, 1 H), 7.18 (d, J = 8.0, 1 H).
13C NMR (75 MHz, DMSO) δ = 16.74, 23.84, 30.05, 121.04, 128.17 (d, J=2.5), 129.00, 131 .41 , 143.98, 145.84, 168.19.
31P NMR (162 MHz, DMSO) δ = -3.78 13 C NMR (75 MHz, DMSO) δ = 16.74, 23.84, 30.05, 121.04, 128.17 (d, J = 2.5), 129.00, 131.41, 143.98, 145.84, 168.19. 31 P NMR (162 MHz, DMSO) δ = -3.78
HRMS (ESI) gefunden: [M+Na]+ m/z = 297.0499, berechnet für CnH15Na06 HRMS (ESI) found: [M + Na] + m / z = 297.0499, calculated for CnH 15 Na0 6
Beispiel 3: Synthese von (2-(Phosphonooxy)-1 -naphthoesäure) (12) Example 3: Synthesis of (2- (phosphonooxy) -1-naphthoic acid) (12)
Synthese von -hydroxy-1 -naphthoat) (12a) Synthesis of -hydroxy-1-naphthoate) (12a)
12a 12a
12a wurde gemäß Methode 1 als farbloses Öl hergestellt. Ausbeute: 99%. 12a was prepared according to Method 1 as a colorless oil. Yield: 99%.
1H-NMR (400 MHz, CDCI3): δ [ppm] = 5.58 (s, 2H, Bn-CH2), 7.17 (d, J = 12.4, 1 H, Ar-H), 7.33- 7.55 (m, 7H, Bn-H, Ar-H), 7.75 (dd, J = 12.4, 9.2, 1 H, Ar-H), 7.90 (d, J = 12.0, 1 H, Ar-H), 8.80 (d, , J = 1 1.6, 1 H, Ar-H), 12.27 (s, 1 H, OH) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 5.58 (s, 2H, Bn-CH 2 ) , 7.17 (d, J = 12.4, 1 H, Ar-H) , 7.33-7.55 (m , 7H, Bn-H, Ar-H), 7.75 (dd, J = 12.4, 9.2, 1H, Ar-H), 7.90 (d, J = 12.0, 1H, Ar-H), 8.80 (d, , J = 1.6, 1H, Ar-H), 12.27 (s, 1H, OH)
13C-NMR (100 MHz, CDCI3): δ [ppm] = 67.66, 104.75, 123.77, 125.47, 128.56, 128.66, 128.72, 128.81 , 128.92, 129.23, 131.97, 135.39, 137.15, 164.71 , 172.30 13 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 67.66, 104.75, 123.77 , 125.47, 128.56, 128.66, 128.72, 128.81, 128.92, 129.23, 131.97, 135.39, 137.15, 164.71, 172.30
MS (ESI) gefunden: [M+Na]+ m/z = 301 .1 , berechnet für Ci8H1403: 301.1 MS (ESI) found: [M + Na] + m / z = 301 .1, calculated for Ci 8 H 14 0 3 : 301.1
UV/Vis λ [nm] = 340.5 (Int = 0.50), 306.0 (Int = 0.63), 233.5 (Int = 2.40) UV / Vis λ [nm] = 340.5 (Int = 0.50), 306.0 (Int = 0.63), 233.5 (Int = 2.40)
Synthese von (Benzyl 2-(bis(benzyloxy)phosphoryloxy)-1 -naphthoat) (12b) Synthesis of (benzyl 2- (bis (benzyloxy) phosphoryloxy) -1-naphthoate) (12b)
12b 12b
12b wurde gemäß Methode 2 hergestellt. Das Rohprodukt wurde säulenchromatographisch gereinigt (Ethylacetat: Hexan 20:80). Ausbeute: 50%, farbloses Öl. 12b was prepared according to method 2. The crude product was purified by column chromatography (ethyl acetate: hexane 20:80). Yield: 50%, colorless oil.
1H-NMR (400 MHz, CDCI3): δ [ppm] = 5.00-5.12 (m, 4H, P-Bn-CH2), 5.43 (s, 2H, Bn-CH2), 7.24-7.62 (m, 19H, Bn-H, Ar-H), 7.40-7.42 (m, 2H, Bn-H), 7.82-7.89 (m, 3H, Ar-H) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 5.00-5.12 (m, 4H, P-Bn-CH 2 ) , 5.43 (s, 2H, Bn-CH 2 ) , 7.24-7.62 (m , 19H, Bn-H, Ar-H), 7.40-7.42 (m, 2H, Bn-H), 7.82-7.89 (m, 3H, Ar-H).
13C-NMR (100 MHz, CDCI3): δ [ppm] = 67.36, 70.26 (d, J = 8.1 ), 1 19.47 (d, J = 2.9), 121.21 (d, J = 10.2) 124.85, 126.01 , 127.99, 128.07, 128.14, 128.32, 128.50, 128.62, 128.64, 128.70, 128.72, 130.84 (d, J = 5.1 ) , 135.42, 135.52, 145.91 (d, J = 8.7), 166.34 1 3 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 67.36 , 70.26 (d, J = 8.1), 1 19.47 (d, J = 2.9), 121.21 (d, J = 10.2) 124.85, 126.01 , 127.99, 128.07, 128.14, 128.32, 128.50, 128.62, 128.64, 128.70, 128.72, 130.84 (d, J = 5.1), 135.42, 135.52, 145.91 (d, J = 8.7), 166.34
31 31
P-NMR (162 MHz, CDCI3): δ [ppm] = -5.73 (s, 1 P)
MS (ESI) gefunden: [M+Na]+ m/z = 561 .2, berechnet für C32H27O6P: 561 .2 UV/Vis λ [nm] = 321.5 (Int = 0.13), 282.0 (Int = 0.58), 232.0 (Int = 2.65) P-NMR (162 MHz, CDCl 3 ): δ [ppm] = -5.73 (s, 1 P) MS (ESI) found: [M + Na] + m / z = 561.2, calculated for C32H27O6P: 561.2 UV / Vis λ [nm] = 321.5 (Int = 0.13), 282.0 (Int = 0.58), 232.0 (Int = 2.65)
Synthese von (2-(Phosphonooxy)-1 -naphthoesäure) (12) Synthesis of (2- (phosphonooxy) -1-naphthoic acid) (12)
12 12
12 wurde gemäß Methode 3 hergestellt und als weißes Pulver erhalten. Ausbeute: 90% 1H-NMR (400 MHz, D20): δ [ppm] = 7.8 (t, J = 7.6, 1 H, Ar-H), 7.55-7.60 (m, 2H, Ar-H), 7.81 (d, J = 8.4, 1 H, Ar-H), 7.95 (dd, J = 26.4, 10, 2H, Ar-H) 12 was prepared according to Method 3 and obtained as a white powder. Yield: 90% 1 H-NMR (400 MHz, D 2 O): δ [ppm] = 7.8 (t, J = 7.6, 1 H, Ar-H) , 7.55-7.60 (m, 2H, Ar-H) , 7.81 (d, J = 8.4, 1H, Ar-H), 7.95 (dd, J = 26.4, 10, 2H, Ar-H)
13C-NMR (100 MHz, D20): δ [ppm] = 120.21 , 122.55 (d, J = 7.3), 124.35, 125.23, 127.43, 128.08, 129.56, 129.95, 130.32, 145.97 (d, J = 5.8), 167.51 13 C-NMR (100 MHz, D 2 O): δ [ppm] = 120.21 , 122.55 (d, J = 7.3) , 124.35 , 125.23 , 127.43 , 128.08 , 129.56 , 129.95 , 130.32 , 145.97 (d, J = 5.8 ), 167.51
31P-NMR (162 MHz, D20): δ [ppm] = -4.56 (s, 1 P) 3 1 P-NMR (162 MHz, D 2 O): δ [ppm] = -4.56 (s, 1 P)
HRMS (ESI) gefunden: [M-H]" m/z = 267.006, berechnet für CnH906P: 267.0064 HRMS (ESI) found: [MH] "m / z = 267,006, calculated for CnH 9 0 6 P: 267.0064
UV/Vis λ [nm] = 290.0 (Int = 0.15), 278.0 (Int = 0.18), 223.0 (Int = 2.46) UV / Vis λ [nm] = 290.0 (Int = 0.15), 278.0 (Int = 0.18), 223.0 (Int = 2.46)
Beispiel 4: Synthese von (1 -(Phosphonooxy)-2-naphthoesäure) (13) Example 4: Synthesis of (1 - (phosphonooxy) -2-naphthoic acid) (13)
Synthese von (Benzyl-1 -hydroxy-2-naphthoat) (13a) Synthesis of (benzyl-1-hydroxy-2-naphthoate) (13a)
13a 13a
13a wurde gemäß Methode 1 hergestellt und als farbloses Öl erhalten. Ausbeute: 62% 13a was prepared according to method 1 and obtained as a colorless oil. Yield: 62%
1H-NMR (400 MHz, CDCI3): δ [ppm] = 5.45 (s, 2H, Bn-CH2), 7.27 (d, J = 9.6, 1 H, Ar-H), 7.36- 7.63 (m, 7H, Ar-H), 7.77 (d, J = 8.4, 1 H, Ar-H), 7.82 (d, J = 8.4, 1 H, Ar-H), 8.43 (d, J = 8.8, 1 H, Ar-H), 1 1 .98 (s, 1 H, OH) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 5.45 (s, 2H, Bn-CH 2 ) , 7.27 (d, J = 9.6 , 1H, Ar-H) , 7.36-7.63 (m , 7H, Ar-H), 7.77 (d, J = 8.4, 1H, Ar-H), 7.82 (d, J = 8.4, 1H, Ar-H), 8.43 (d, J = 8.8, 1H , Ar-H), 1 1 .98 (s, 1H, OH)
13C-NMR (100 MHz, CDCI3): δ [ppm] = 67.10, 105.74, 1 18.75, 124.04, 124.43, 124.98, 125.91 , 127.60, 128.40, 128.65, 128.85, 129.59, 135.61 , 137.40, 161.29, 170.96 13 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 67.10 , 105.74 , 1 18.75, 124.04, 124.43, 124.98, 125.91, 127.60, 128.40, 128.65, 128.85, 129.59, 135.61, 137.40, 161.29, 170.96
MS (ESI) gefunden: [M+K]+ m/z = 301 .1 , berechnet für C18H1402: 301.3
UV/Vis λ [nm] = 365.5 (Int = 0.52), 343.0 (Int = 0.56), 288.5 (Int = 0.54), 279.5 (Int = 0.58), 256.5 (Int = 3.21 ), 249.0 (Int = 3.14) MS (ESI) found: [M + K] + m / z = 301 .1, calculated for C1 8 H 14 0 2 : 301.3 UV / Vis λ [nm] = 365.5 (Int = 0.52), 343.0 (Int = 0.56), 288.5 (Int = 0.54), 279.5 (Int = 0.58), 256.5 (Int = 3.21), 249.0 (Int = 3.14)
Synthese von (Benzyl-1 -(bis(benzyloxy)phosphoryloxy)-2-naphthoat) (13b) Synthesis of (benzyl-1 - (bis (benzyloxy) phosphoryloxy) -2-naphthoate) (13b)
13b wurde gemäß Methode 2 hergestellt. Das Rohprodukt wurde säulenchromatographisch gereinigt (Ethylacetat: Hexan 20:80). Ausbeute: 59%, farbloses Öl. 13b was prepared according to method 2. The crude product was purified by column chromatography (ethyl acetate: hexane 20:80). Yield: 59%, colorless oil.
1H-NMR (400 MHz, CDCI3): δ [ppm] = 5.06-5.09 (m, 4H, P-Bn-CH2), 5.34 (s, 2H, Bn-CH2), 7.24-7.33 (m, 12H, Ar-H), 7.44 (d, J = 7.6, 2H, Ar-H), 7.51 (t, J = 8.0, 1 H, Ar-H), 7.56 (t, J = 8.0, 1 H, Ar-H), 7.70 (d, J = 8.4, 1 H, Ar-H), 7.85 (dd, J = 21.6, 4.8, 2H, Ar-H), 8.35 (d, 1 H, Ar-H) 1 H-NMR (400 MHz, CDCl 3 ): δ [ppm] = 5.06-5.09 (m, 4H, P-Bn-CH 2 ) , 5.34 (s, 2H, Bn-CH 2 ) , 7.24-7.33 (m , 12H, Ar-H), 7.44 (d, J = 7.6, 2H, Ar-H), 7.51 (t, J = 8.0, 1H, Ar-H), 7.56 (t, J = 8.0, 1H, Ar-H), 7.70 (d, J = 8.4, 1H, Ar-H), 7.85 (dd, J = 21.6, 4.8, 2H, Ar-H), 8.35 (d, 1H, Ar-H)
13C-NMR (100 MHz, CDCI3): δ [ppm] = 67.21 , 70.36 (d, J = 5.1 ), 120.41 (d, J = 4.4), 124.21 , 125.43 (d, J = 1 .5), 126.24 (d, J = 1 .0), 126.25, 127.10, 127.46, 127.49, 127.63, 128.19, 128.29, 128.46, 128.59, 128.62, 128.64, 135.72 (d, J = 7.3), 136.03, 136.53, 146.56 (d, J = 8.8), 165.76 13 C-NMR (100 MHz, CDCl 3 ): δ [ppm] = 67.21 , 70.36 (d, J = 5.1), 120.41 (d, J = 4.4) , 124.21, 125.43 (d, J = 1 .5), 126.24 (d, J = 1 .0), 126.25, 127.10, 127.46, 127.49, 127.63, 128.19, 128.29, 128.46, 128.59, 128.62, 128.64, 135.72 (d, J = 7.3), 136.03, 136.53, 146.56 (d, J = 8.8), 165.76
31P-NMR (162 MHz, CDCI3): δ [ppm] = -4.86 (s, 1 P) 31 P-NMR (162 MHz, CDCl 3 ): δ [ppm] = -4.86 (s, 1 P)
MS (ESI) gefunden: [M+H]+ m/z = 539.2, berechnet für C32H27O6P: 539.2 MS (ESI) found: [M + H] + m / z = 539.2, calculated for C32H27O6P: 539.2
UV/Vis λ [nm] = 333.5 (Int = 0.10), 282.5 (Int = 0.59), 237.0 (Int = 2.72) UV / Vis λ [nm] = 333.5 (Int = 0.10), 282.5 (Int = 0.59), 237.0 (Int = 2.72)
Synthese von (1 -(Phosphonooxy)-2-naphthoesäure) (13) Synthesis of (1 - (phosphonooxy) -2-naphthoic acid) (13)
13 wurde gemäß Methode 3 hergestellt und als weißes Pulver erhalten. Ausbeute: 80% 13 was prepared according to Method 3 and obtained as a white powder. Yield: 80%
1H-NMR (400 MHz, D20): δ [ppm] = 7.56-7.61 (m, 2H, Ar-H), 7.76-7.81 (m, 2H, Ar-H), 7.86- 7.89 (m, 1 H, Ar-H), 8.42-8.44 (d, J = 8.4), 1 H, Ar-H)
31P-NMR (162 MHz, D20): δ [ppm] = 4.00 (s, 1 P) 1 H-NMR (400 MHz, D 2 O): δ [ppm] = 7.56-7.61 (m, 2H, Ar-H), 7.76-7.81 (m, 2H, Ar-H), 7.86- 7.89 (m, 1H, Ar-H), 8.42-8.44 (d, J = 8.4), 1H, Ar-H) 31 P-NMR (162 MHz, D 2 O): δ [ppm] = 4.00 (s, 1 P)
HRMS (ESI) gefunden: [M-H]" m/z = 267,0064, berechnet für CnH806P: 267,0064 HRMS (ESI) found: [MH] "m / z = 267.0064, calculated for C n H 8 0 6 P: 267.0064
Beispiel 5: Synthese von 1 , 2-Phenylenbis(dihydrogenphosphat) (24) Example 5: Synthesis of 1,2-phenylenebis (dihydrogenphosphate) (24)
Synthese von 1 , 2-Phenylentetrabenzylbisphosphat (24a)
Synthesis of 1, 2-phenylentetrabenzylbisphosphate (24a)
Darstellung nach Methode 2. Representation according to method 2.
1H NMR (400 MHz, CDCI3) δ = 7.38 - 7.23 (m, 24H), 7.1 1 - 7.09 (m, 2H), 5.13 - 5.09 (m, 8H). 1 H NMR (400 MHz, CDCl 3 ) δ = 7.38 - 7.23 (m, 24H), 7.1 1 - 7.09 (m, 2H), 5.13 - 5.09 (m, 8H).
13C NMR (101 MHz, CDCI3) δ = 141 .057 (d, J=6.6), 135.48 (d, J=7.4), 128.68, 128.65, 128.08, 125.87, 121 .79, 70.21 (d, J=5.9) 13 C NMR (101 MHz, CDCl 3 ) δ = 141 .057 (d, J = 6.6), 135.48 (d, J = 7.4), 128.68, 128.65, 128.08, 125.87, 121 .79, 70.21 (d, J = 9/5)
31P NMR (162 MHz, CDCI3) δ = - 5.24 (s, 2P) 3 1 P NMR (162 MHz, CDCl 3 ) δ = - 5.24 (s, 2P)
Synthese von 1 , 2-Phenylenbis(dihydrogenphosphat) (24)
Synthesis of 1,2-phenylenebis (dihydrogenphosphate) (24)
Darstellung nach Methode 2. Representation according to method 2.
1H NMR (400 MHz, DMSO) δ = 8.24 (bs, 4H), 7.34 (s, 2H), 7.12 - 7.10 (m, 2H) 1 H NMR (400 MHz, DMSO) δ = 8.24 (bs, 4H), 7.34 (s, 2H), 7.12-7.10 (m, 2H)
13C NMR (101 MHz, DMSO) δ = 142.69, 124.54, 122.17 1 3 C NMR (101 MHz, DMSO) δ = 142.69, 124.54, 122.17
31P NMR (162 MHz, DMSO) δ = - 4.71 (s, 2P) 3 1 P NMR (162 MHz, DMSO) δ = -4.71 (s, 2P)
Beispiel 6: Synthese von 1,3-Phenylenbis(dihydrogenphosphat) (25) Example 6: Synthesis of 1,3-phenylenebis (dihydrogenphosphate) (25)
Synthese von 1 , 3-Phenylentetrabenzylbisphosphat (25a)
Synthesis of 1, 3-phenylentetrabenzylbisphosphate (25a)
Darstellung nach Methode 2. Representation according to method 2.
1H NMR (400 MHz, CDCI3) δ = 7.33 - 7.32 (m, 21 H), 7.20 (t) 7.10 - 7.00 (m, 2H), 5.1 1 5.09 (m, 8H).
13C NMR (101 MHz, CDCI3) δ = 151 .23 (d, J=6.6), 135.39 (d, J=7.3), 130.38, 128.80, 1 H NMR (400 MHz, CDCl 3 ) δ = 7.33-7.32 (m, 21H), 7.20 (t) 7.10-7.00 (m, 2H), 5.1 1 5.09 (m, 8H). 13 C NMR (101 MHz, CDCl 3 ) δ = 151.23 (d, J = 6.6), 135.39 (d, J = 7.3), 130.38, 128.80,
128.73, 128.17, 1 16.83 (d, J=4.4), 1 12.71 , 70.21 (J=5.9) 128.73, 128.17, 1 16.83 (d, J = 4.4), 1 12.71, 70.21 (J = 5.9)
31P NMR (162 MHz, CDCI3) δ = - 5.46 (s, 2P) 31 P NMR (162 MHz, CDCl 3 ) δ = - 5.46 (s, 2P)
Synthese von 1 ,3-Phenylenbis(dihydrogenphosphat) (25) Synthesis of 1,3-phenylenebis (dihydrogenphosphate) (25)
Darstellung nach Methode 2. Representation according to method 2.
1H NMR (300 MHz, DMSO) 5 = 9.10 (bs, 4H), 7.28 (t, J=7.4, 1 H), 6.96 - 6.93 (m, 3H) 1 H NMR (300 MHz, DMSO) 5 = 9.10 (bs, 4H), 7.28 (t, J = 7.4, 1H), 6.96 - 6.93 (m, 3H)
13C NMR (75 MHz, DMSO) δ = 152.37 (d, J=6.1 ), 129.83, 1 15.60 (d, J=4.4 ), 1 12.45 1 3 C NMR (75 MHz, DMSO) δ = 152.37 (d, J = 6.1), 129.83, 1 15.60 (d, J = 4.4), 1 12.45
31P NMR (162 MHz, DMSO) δ = - 5.17 (s, 2P) 3 1 P NMR (162 MHz, DMSO) δ = - 5.17 (s, 2P)
Beispiel 7: Synthese von 2-Methoxy-4-(nonanamidomethyl)phenyldihydrogenphosphat (30) Synthese von Dibenzyl-(2-methoxy-4-(nonanamidomethyl)phenyl)phosphat (30a) Example 7: Synthesis of 2-methoxy-4- (nonanamidomethyl) phenyl dihydrogen phosphate (30) Synthesis of dibenzyl- (2-methoxy-4- (nonanamidomethyl) phenyl) phosphate (30a)
30a wurde aus N-Vanillylnonanamid nach Methode 2 hergestellt. Reaktionszeit: 2 h. Das Rohprodukt wurde saulenchromatographisch gereinigt (Ethylacetat: Hexan 1 :1 bis 2:1 ). Ausbeute: 92% 30a was prepared from N-vanillylnananamide according to method 2. Reaction time: 2 h. The crude product was purified by column chromatography (ethyl acetate: hexane 1: 1 to 2: 1). Yield: 92%
1H NMR (400 MHz, CDCI3) δ = 0.84 - 0.92 (m, 2H), 1.18 - 1 .38 (m, 10H), 1 .59 - 1.71 (m, 1 H NMR (400 MHz, CDCl 3 ) δ = 0.84-0.92 (m, 2H), 1.18-1.38 (m, 10H), 1.59- 1.71 (m,
2H), 2.15 - 2.25 (m, 2H), 3.76 (s, 3H), 4.36 (d, J=5.7, 2H), 5.16 (d, J=7.9, 4H), 5.88 (t, J=5.9,2H), 2.15 - 2.25 (m, 2H), 3.76 (s, 3H), 4.36 (d, J = 5.7, 2H), 5.16 (d, J = 7.9, 4H), 5.88 (t, J = 5.9,
1 H), 6.74 (dd, J=8.2, 2.0, 1 H), 6.84 (s, 0H), 7.12 (dd, J=8.1 , 1.4, 1 H), 7.33 (s, 8H). 1 H), 6.74 (dd, J = 8.2, 2.0, 1 H), 6.84 (s, 0H), 7.12 (dd, J = 8.1, 1.4, 1 H), 7.33 (s, 8H).
13C NMR (101 MHz, CDCI3) δ = 14.20, 22.75, 25.91 , 29.27, 29.44, 29.47, 31.93, 36.90, 13 C NMR (101 MHz, CDCl 3 ) δ = 14.20, 22.75, 25.91, 29.27, 29.44, 29.47, 31.93, 36.90,
43.35, 55.99, 69.92, 69.98, 1 12.49, 120.04, 121 .60, 127.99, 128.61 , δ = 135.78 (d, J=7.4),43.35, 55.99, 69.92, 69.98, 1 12.49, 120.04, 121.60, 127.99, 128.61, δ = 135.78 (d, J = 7.4),
136.70 (d, J=1.6), 139.09 (d, J=7.2), 150.88 (d, J=5.1 ), 173.13. 136.70 (d, J = 1.6), 139.09 (d, J = 7.2), 150.88 (d, J = 5.1), 173.13.
31P NMR (162 MHz, CDCI3) δ = -4.78 (s, 1 P)
Synthese von 2-Methoxy-4-(nonanamidomethyl)phenyldihvdrogenphosphat (30) 31 P NMR (162 MHz, CDCl 3 ) δ = -4.78 (s, 1 P) Synthesis of 2-methoxy-4- (nonanamidomethyl) phenyl dihydrogen phosphate (30)
30 wurde ausgehend von 30a gemäß Methode 3 hergestellt und als weißes Pulver erhalten. Ausbeute: 90%. 30 was prepared from 30a according to Method 3 and obtained as a white powder. Yield: 90%.
1H NMR (400 MHz, DMSO) δ = 0.84 (t, J=6.8, 3H), 1 .23 (s, 10H), 1 .40 - 1 .64 (m, 2H), 2.10 (t, J=7.4, 2H), 3.72 (s, 3H), 4.18 (d, J=5.9, 2H), 6.70 (dd, J=8.2, 2.0, 1 H), 6.88 (s, 1 H), 7.20 (d, J=8.2, 1 H), 8.22 (t, J=5.8, 1 H). 1 H NMR (400 MHz, DMSO) δ = 0.84 (t, J = 6.8, 3H), 1 .23 (s, 10H), 1 .40 - 1 .64 (m, 2H), 2.10 (t, J = 7.4, 2H), 3.72 (s, 3H), 4.18 (d, J = 5.9, 2H), 6.70 (dd, J = 8.2, 2.0, 1 H), 6.88 (s, 1 H), 7.20 (d, J = 8.2, 1 H), 8.22 (t, J = 5.8, 1 H).
31P NMR (162 MHz, DMSO) δ = -4.35 (s, 1 P) 3 1 P NMR (162 MHz, DMSO) δ = -4.35 (s, 1 P)
Beispiel 8: Synthese von 4-(Nonanamidomethyl)-1 ,2-phenylenbis(dihydrogen phosphat) (31 ) Example 8: Synthesis of 4- (nonanamidomethyl) -1,2-phenylenebis (dihydrogen phosphate) (31)
Synthese von N-(3,4-dihvdroxybenzyl)nonanamid (31 a) Synthesis of N- (3,4-dihydroxybenzyl) nonanamide (31a)
31a wurde ausgehend von N-Vanillylnonanamide gemäß Methode 5 hergestellt. Das Rohprodukt wurde säulenchromatographisch (2% bis 5% Methonol in Dichlormethan) gereinigt. Ausbeute: 50 %, weißer Feststoff. 31a was prepared starting from N-vanillylnananamide according to method 5. The crude product was purified by column chromatography (2% to 5% methanol in dichloromethane). Yield: 50%, white solid.
1H NMR (400 MHz, CDCI3 + CD4O) δ = 0.82 (t, J=6.8, 3H), 1.14 - 1 .31 (m, 10H), 1 .56 (p, J=7.4, 2H), 2.13 (t, 2H), 2.84 (s, 3H), 4.19 (s, 2H), 6.57 (dd, J=8.1 , 2.1 , 1 H), 6.70 (d, J=2.1 , 1 H), 6.72 (d, J=8.1 , 1 H). 1 H NMR (400 MHz, CDCl 3 + CD 4 O) δ = 0.82 (t, J = 6.8, 3H), 1.14-1.31 (m, 10H), 1.56 (p, J = 7.4, 2H), 2.13 (t, 2H), 2.84 (s, 3H), 4.19 (s, 2H), 6.57 (dd, J = 8.1, 2.1, 1H), 6.70 (d, J = 2.1, 1 H), 6.72 (d, J = 8.1, 1H).
MS (ESI) gefunden: [M+Na]+ m/z = 302,2, berechnet für Ci6H25NNa03: 302.2 MS found (ESI): [M + Na] + m / z = 302.2, calculated for C 6 H 25 NNa0 3: 302.2
Synthese von Tetrabenzyl(4-(nonanamidomethyl)-1 ,2-phenylen)bis(phosphat) (31 b) Synthesis of tetrabenzyl (4- (nonanamidomethyl) -1,2-phenylene) bis (phosphate) (31b)
O O
BnO-P-OBn O
31 b wurde ausgehend von 31 a gemäß Methode 2 hergestellt. Das Rohprodukt wurde säu- lenchromatographisch gereinigt (2% bis 4% Methanol in Dichlormethan). Ausbeute: 90%. BnO-P-OBn O 31 b was prepared starting from 31 a according to method 2. The crude product was purified by column chromatography (2% to 4% methanol in dichloromethane). Yield: 90%.
1H NMR (400 MHz, cd3od) δ = 0.87 (t, J=6.9, 3H), 1 .17 - 1 .39 (m, 10H), 1 .61 (p, J=7.1 , 2H), 2.21 (t, J=7.5, 2H), 4.28 (s, 2H), 5.00 - 5.16 (m, 8H), 7.09 (dd, J=8.5, 2.1 , 1 H), 7.18 - 7.43 (m, 22H). 1 H NMR (400 MHz, cd 3 od) δ = 0.87 (t, J = 6.9, 3H), 1 .17 - 1 .39 (m, 10H), 1 .61 (p, J = 7.1, 2H), 2.21 (t, J = 7.5, 2H), 4.28 (s, 2H), 5.00 - 5.16 (m, 8H), 7.09 (dd, J = 8.5, 2.1, 1H), 7.18 - 7.43 (m, 22H).
13C NMR (101 MHz, cd3od) δ = 14.44, 23.69, 23.71 , 27.04, 30.29, 30.31 , 30.36, 30.40, 32.98, 37.09, 43.07, 49.63, 71.72, 71.76 (dd, J=5.7, 2.0), 71.80, 106.16, 121 .84, 122.74, 126.13, 129.27, 129.69, 129.84, 129.86, 136.61 (d, J=7.1 ), 139.08, 139.09, 141.51 (d, J=6.2), 142.52 (d, J=6.3), 176.20. 13 C NMR (101 MHz, cd 3 od) δ = 14.44, 23.69, 23.71, 27.04, 30.29, 30.31, 30.36, 30.40, 32.98, 37.09, 43.07, 49.63, 71.72, 71.76 (dd, J = 5.7, 2.0), 71.80, 106.16, 121.84, 122.74, 126.13, 129.27, 129.69, 129.84, 129.86, 136.61 (d, J = 7.1), 139.08, 139.09, 141.51 (d, J = 6.2), 142.52 (d, J = 6.3) , 176.20.
31P NMR (162 MHz, cd3od) δ = -5.60 (1 P), -5.54 (1 P) 3 1 P NMR (162 MHz, cd 3 od) δ = -5.60 (1 P), -5.54 (1 P)
MS (ESI) gefunden: [M+Na]+ m/z = 822.3, berechnet für C44H5iNNa09P2: 822.3 MS (ESI) found: [M + Na] + m / z = 822.3, calculated for C 4 4H5iNNa0 9 P2: 822.3
Synthese von 4-(Nonanamidomethyl)-1 ,2-phenylenbis(dihydrogen Phosphat) (31 ) Synthesis of 4- (nonanamidomethyl) -1,2-phenylenebis (dihydrogen phosphate) (31)
HO HO
HOHO
31 wurde ausgehend von 31 b gemäß Methode 3 hergestellt. 31 was prepared starting from 31 b according to method 3.
1H NMR (400 MHz, DMSO) δ = 0.84 (t, J=6.7, 3H), 1.23 (s, 10H), 1 .49 (t, J=7.2, 2H), 2.09 (t, J=7.5, 2H), 4.16 (d, J=5.8, 2H), 6.50 (bs, 4H), 6.93 (d, J=8.1 , 1 H), 7.04 - 7.31 (m, 2H), 8.26 (t, J=6.1 , 1 H). 1 H NMR (400 MHz, DMSO) δ = 0.84 (t, J = 6.7, 3H), 1.23 (s, 10H), 1 .49 (t, J = 7.2, 2H), 2.09 (t, J = 7.5, 2H), 4.16 (d, J = 5.8, 2H), 6.50 (bs, 4H), 6.93 (d, J = 8.1, 1H), 7.04 - 7.31 (m, 2H), 8.26 (t, J = 6.1, 1 H).
13C NMR (101 MHz, DMSO) δ = 13.97, 22.09, 25.27, 28.60, 28.75, 31.27, 35.36, 38.89, 13 C NMR (101 MHz, DMSO) δ = 13.97, 22.09, 25.27, 28.60, 28.75, 31.27, 35.36, 38.89,
40.14, 41.37, 121.27, 122.09, 122.95, 136.06, 141 .75, 142.81 , 172.12. 40.14, 41.37, 121.27, 122.09, 122.95, 136.06, 141.75, 142.81, 172.12.
HRMS (ESI) gefunden: [M-H]" m/z = 438.1083, berechnet für CieHzeNOgPz: 438.1088 HRMS (ESI) found: [MH] "m / z = 438.1083, calculated for CieHzeNOgPz: 438.1088
Beispiel 9: Synthese von 4-((8-Methylnonanamido)methyl)-1 ,2-phenylenbis(dihydro- genphosphat) (32) Example 9: Synthesis of 4 - ((8-methylnonanamido) methyl) -1,2-phenylenebis (dihydrogenphosphate) (32)
Synthese von N-(3, 4-Dihvdroxybenzyl)-8-methylnonanamid (32a) Synthesis of N- (3,4-Dihydroxybenzyl) -8-methylnonanamide (32a)
32a wurde entsprechend Methode 3 (katalytische Hydrierung der C=C-Doppelbindung) und Methode 5 aus Capsaicin hergestellt. Das Rohprodukt wurde gereinigt durch Säulenchromatographie (2% Methanol in Dichlormethan). Ausbeute: 47% Feststoff. 32a was prepared according to method 3 (catalytic hydrogenation of the C = C double bond) and method 5 from capsaicin. The crude product was purified by column chromatography (2% methanol in dichloromethane). Yield: 47% solids.
1H NMR (300 MHz, CDCI3) δ = 0.84 (d, J=6.6, 6H), 1 .1 1 (d, J=6.3, 2H), 1.23 (s, 6H), 1.48 (dt, J=13.1 , 6.6, 1 H), 1 .60 (s, 2H), 2.20 (s, 3H), 4.26 (s, 2H), 6.16 (s, 1 H), 6.59 (d, J=7.5, 1 H), 6.68 - 6.89 (m, 2H), 7.58 - 8.86 (m, 1 H). 1 H NMR (300 MHz, CDCl 3 ) δ = 0.84 (d, J = 6.6, 6H), 1 .1 1 (d, J = 6.3, 2H), 1.23 (s, 6H), 1.48 (dt, J = 13.1, 6.6, 1H), 1.60 (s, 2H), 2.20 (s, 3H), 4.26 (s, 2H), 6.16 (s, 1H), 6.59 (d, J = 7.5, 1H) , 6.68 - 6.89 (m, 2H), 7.58 - 8.86 (m, 1 H).
13C NMR (75 MHz, CDCI3) δ = 22.75, 25.94, 27.33, 28.05, 29.40, 29.66, 36.93, 39.04, 43.69, 13 C NMR (75 MHz, CDCl 3 ) δ = 22.75, 25.94, 27.33, 28.05, 29.40, 29.66, 36.93, 39.04, 43.69,
1 15.00, 1 15.21 , 1 19.88, 129.91 , 144.33, 144.69, 165.93, 165.97. 1 15.00, 1 15.21, 1 19.88, 129.91, 144.33, 144.69, 165.93, 165.97.
MS (ESI) gefunden: [2M]" m/z = 585.3, berechnet für C34H53N2O6: 585.4 MS (ESI) found: [2M] "m / z = 585.3, calculated for C34H53N2O6: 585.4
Synthese von Tetrabenzyl (4-((8-methylnonanamido) methyl)-1 ,2-phenylen)bisphosphat (32b) Synthesis of tetrabenzyl (4 - ((8-methylnonanamido) methyl) -1,2-phenylene) bisphosphate (32b)
BnBn
32b wurde aus 32a gemäß Methode 2 hergestellt. Das Rohprodukt wurde säulenchromato- graphisch gereinigt (1 % bis 2% Methanol in Dichlormethan). Ausbeute: 99% 32b was prepared from 32a according to method 2. The crude product was purified by column chromatography (1% to 2% methanol in dichloromethane). Yield: 99%
1H NMR (400 MHz, CDCI3) δ = 0.86 (d, J=6.6, 6H), 1.09 - 1 .20 (m, 2H), 1 .20 - 1 .39 (m, 7H), 1 .51 (hept, J=13.2, 6.6, 1 H), 1.57 - 1.73 (m, 2H), 2.17 (dd, J=8.6, 6.8, 2H), 4.31 (d, J=5.6, 2H), 5.03 - 5.16 (m, 8H), 5.70 (t, J=5.7, 1 H), 7.00 (dd, J=8.4, 1 .3, 1 H), 7.17 - 7.21 (m, 1 H), 7.20 - 7.35 (m, 21 H).. 1 H NMR (400 MHz, CDCl 3 ) δ = 0.86 (d, J = 6.6, 6H), 1.09-1.20 (m, 2H), 1.20-1.39 (m, 7H), 1.51 (hept, J = 13.2, 6.6, 1H), 1.57 - 1.73 (m, 2H), 2.17 (dd, J = 8.6, 6.8, 2H), 4.31 (d, J = 5.6, 2H), 5.03 - 5.16 ( m, 8H), 5.70 (t, J = 5.7, 1H), 7.00 (dd, J = 8.4, 1 .3, 1H), 7.17 - 7.21 (m, 1H), 7.20 - 7.35 (m, 21 H)..
13C NMR (101 MHz, CDCI3) δ = 22.77, 25.84, 27.36, 28.07, 29.53, 29.75, 36.84, 39.09, 42.70, 70.23, 70.27, 70.29, 70.33, 77.47, 121 .05 (d, J=2.3), 121 .96 (d, J=2.3), 125.16, 128.15, 128.68, 128.73, 128.75, 135.40, 135.47, 136.64, 140.67 (t, J=6.6), 141.44 (t, J=6.5), 173.09. 13 C NMR (101 MHz, CDCl 3 ) δ = 22.77, 25.84, 27.36, 28.07, 29.53, 29.75, 36.84, 39.09, 42.70, 70.23, 70.27, 70.29, 70.33, 77.47, 121.05 (d, J = 2.3) , 121.96 (d, J = 2.3), 125.16, 128.15, 128.68, 128.73, 128.75, 135.40, 135.47, 136.64, 140.67 (t, J = 6.6), 141.44 (t, J = 6.5), 173.09.
31P NMR (162 MHz, CDCI3) δ = -3,17 (s, 1 P), -3,29 (s, 1 P) 31 P NMR (162 MHz, CDCl 3 ) δ = -3.17 (s, 1 P), -3.29 (s, 1 P)
MS (ESI) gefunden: [M+Na]+ m/z = 836.4, berechnet für C44H5iNNa09P2: 836.3
Synthese von 4-((8-Methylnonanamido)methyl)-1 ,2-phenylenbis(dihvdroge (32) MS (ESI) found: [M + Na] + m / z = 836.4, calculated for C44H 5 iNNa0 9 P2: 836.3 Synthesis of 4 - ((8-methylnonanamido) methyl) -1,2-phenylenebis (dihydrogen (32)
0 0
HO HO
32 wurde ausgehend von 32b gemäß Methode 3 hergestellt. 32 was prepared starting from 32b according to method 3.
1H NMR (300 MHz, DMSO-d6) δ = 0.83 (d, J=6.5, 6H), 1 .04 - 1 .28 (m, 8H), 1.38 - 1 .58 (m, 3H), 2.09 (t, J=7.5, 2H), 4.16 (d, J=5.7, 2H), 6.94 (d, J=8.1 , 1 H), 7.15 - 7.28 (m, 2H), 7.99 (s, 3H), 8.28 (d, J=6.0, 1 H). 1 H NMR (300 MHz, DMSO-d 6 ) δ = 0.83 (d, J = 6.5, 6H), 1 .04 - 1 .28 (m, 8H), 1.38-1 .58 (m, 3H), 2.09 (t, J = 7.5, 2H), 4.16 (d, J = 5.7, 2H), 6.94 (d, J = 8.1, 1H), 7.15 - 7.28 (m, 2H), 7.99 (s, 3H), 8.28 (d, J = 6.0, 1H).
13C NMR (75 MHz, DMSO) δ = 22.55, 25.28, 26.70, 27.39, 28.79, 29.06, 35.38, 38.46, 41 .36, 121 .13, 121.96, 123.05, 136.21 , 141.44, 142.53, 160.63, 172.14. 13 C NMR (75 MHz, DMSO) δ = 22.55, 25.28, 26.70, 27.39, 28.79, 29.06, 35.38, 38.46, 41.36, 121.13, 121.96, 123.05, 136.21, 141.44, 142.53, 160.63, 172.14.
31P NMR (162 MHz, DMSO) δ = -4.68 (s, 1 P), -4.52 (s, 1 P) 3 1 P NMR (162 MHz, DMSO) δ = -4.68 (s, 1 P), -4.52 (s, 1 P)
HRMS (ESI) gefunden: [M-H]" m/z = 452.1247, berechnet für C17H28NO9P2: 452.1245 HRMS (ESI) found: [MH] "m / z = 452.1247, calculated for C17H28NO9P2: 452.1245
Beispiel 10: Synthese von Verbindung (13) Example 10: Synthesis of Compound (13)
Figur 1 zeigt das Syntheseschema für den Zugang zu Verbindung (13), wobei in den einzelnen Reaktionsstufen a) bis h) zu den entsprechend erhaltenen Zwischenstufen folgende Re- aktanden zugegeben werden: a) Benzylbromid, KHCO3, DMF, 4h; b) Ethylbromacetat, K2C03, DMF, 1 h; c) Pd/C, H2, EtOH, 1 h; d) Anilin, EDC, HOBt, DMF, 16h; e) 1 M NaOH, THF, 1 h; f) 4-(Aminomethyl)benzol-1 ,2- diol, EDC, HOBt, Triethylamin, DMF, 16h; g) Dibenzylphosphit, CCI4, Diisopropylethylamin, DMAP, 1 h; h) Pd/C, H2, EtOH, 1 h. FIG. 1 shows the synthesis scheme for the access to compound (13), wherein the following reactants are added in the individual reaction stages a) to h) to the correspondingly obtained intermediates: a) benzyl bromide, KHCO 3 , DMF, 4h; b) ethyl bromoacetate, K 2 C0 3 , DMF, 1 h; c) Pd / C, H 2 , EtOH, 1 h; d) aniline, EDC, HOBt, DMF, 16h; e) 1 M NaOH, THF, 1 h; f) 4- (aminomethyl) benzene-1,2-diol, EDC, HOBt, triethylamine, DMF, 16h; g) dibenzyl phosphite, CCI 4 , diisopropylethylamine, DMAP, 1 h; h) Pd / C, H 2 , EtOH, 1 h.
Synthese von 6-(2-((3,4-dihvdroxybenzyl)amino)-2-oxoethoxy)-N-phenyl-2-naphthamide (14) Synthesis of 6- (2 - ((3,4-dihydroxybenzyl) amino) -2-oxoethoxy) -N-phenyl-2-naphthamides (14)
Die Verbindung (14) wird aus 13e (0.36 g, 1 .12 mmol) und 4-(Aminomethyl)benzol-1 ,2-diol (0.27 g, 1 .23 mmol) gemäß Methode 4 hergestellt. Das Rohprodukt wird säulenchromato- graphisch (Dichlormethan/Methanol 50:1 ) gereinigt. Die Verbindung (14) wird als weißer Feststoff erhalten (0.35 g, 70%).
Schmelzpunkt: 219 - 222 °C Compound (14) is prepared from 13e (0.36 g, 1.12 mmol) and 4- (aminomethyl) benzene-1,2-diol (0.27 g, 1.23 mmol) according to Method 4. The crude product is purified by column chromatography (dichloromethane / methanol 50: 1). The compound (14) is obtained as a white solid (0.35 g, 70%). Melting point: 219 - 222 ° C
1H NMR (400 MHz, DMSO-d6) δ = 4.18 (d, J=6.0, 2H), 4.67 (s, 2H), 6.51 (dd, J=8.0, 2.1, 1H), 6.62 (d, J=8.0, 1H), 6.70 (d, J=2.1, 1H), 7.03 - 7.15 (m, 1H), 7.30 - 7.40 (m, 4H), 7.80 (dd, J=8.6, 1.1, 2H), 7.88 (d, J=8.7, 1H), 7.95- 8.06 (m, 2H), 8.50 (d, J=1.5, 1H), 8.58 (t, J=6.1, 1H), 8.71 (s, 1H), 8.80 (s, 1H), 10.32 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 4.18 (d, J = 6.0, 2H), 4.67 (s, 2H), 6.51 (dd, J = 8.0, 2.1, 1H), 6.62 (d, J = 8.0, 1H), 6.70 (d, J = 2.1, 1H), 7.03 - 7.15 (m, 1H), 7.30 - 7.40 (m, 4H), 7.80 (dd, J = 8.6, 1.1, 2H), 7.88 ( d, J = 8.7, 1H), 7.95-8.06 (m, 2H), 8.50 (d, J = 1.5, 1H), 8.58 (t, J = 6.1, 1H), 8.71 (s, 1H), 8.80 (s , 1H), 10.32 (s, 1H)
13C NMR (101 MHz, DMSO-d6) δ = 41.53, 67.04, 107.20, 115.02, 115.24, 118.25, 119.60, 120.32, 123.55, 125.04, 126.85, 127.66, 127.84, 128.59, 130.06, 130.20, 130.57, 135.66, 139.30, 144.16, 145.06, 157.07, 165.55, 167.07 13 C NMR (101 MHz, DMSO-d 6 ) δ = 41.53, 67.04, 107.20, 115.02, 115.24, 118.25, 119.60, 120.32, 123.55, 125.04, 126.85, 127.66, 127.84, 128.59, 130.06, 130.20, 130.57, 135.66, 139.30, 144.16, 145.06, 157.07, 165.55, 167.07
UV/Vis: λ [nm] = 285, 237, 204; IR [KBr]: v [cm"1] = 3839, 3820, 3802, 3748, 3737, 3673, 3647, 3564, 3417, 2324, 1746, 1736, 1715, 1651, 1630, 1603, 1535, 1506, 1478, 1442, 1393, 1363, 1323, 1273, 1239, 1203, 1173, 1117, 1066, 1022, 948, 906, 885, 858, 812, 756, 691,631,587,505,474,421 UV / Vis: λ [nm] = 285, 237, 204; IR [KBr]: v [cm "1 ] = 3839, 3820, 3802, 3748, 3737, 3673, 3647, 3564, 3417, 2324, 1746, 1736, 1715, 1651, 1630, 1603, 1535, 1506, 1478, 1442, 1393, 1363, 1323, 1273, 1239, 1203, 1173, 1117, 1066, 1022, 948, 906, 885, 858, 812, 756, 691, 635, 585, 544, 7421
HRMS (ESI) gefunden: [M-H] " m/z = 441.1457 berechnet für C26H2i N205 = 441.1456 HRMS (ESI) found: [MH] "m / z = 441.1457 calculated for C 26 H 2 i N 2 0 5 = 441.1456
Synthese von Tetrabenzyl (4-((2-((6-(phenylcarbamoyl) naphthalen-2-yl) oxy) aceta- mido)methyl)-1 ,2-phenylene) bis(phosphate) (13g) Synthesis of tetrabenzyl (4 - ((2 - ((6- (phenylcarbamoyl) naphthalen-2-yl) oxy) acetamido) methyl) -1,2-phenylene) bis (phosphate) (13g)
Die Verbindung (13f) wird aus 14 (0.28 g, 0.63 mmol) gemäß Method 1 gewonnen. Das Rohprodukt wurde säulenchromatographisch gereingt (Dichlormethan/Aceton 20:1 — > 9:1). Das Produkt wird als Öl erhalten (0.485 g, 80%). The compound (13f) is recovered from 14 (0.28 g, 0.63 mmol) according to Method 1. The crude product was purified by column chromatography (dichloromethane / acetone 20: 1 → 9: 1). The product is obtained as an oil (0.485 g, 80%).
1H NMR (400 MHz, CDCI3) δ = 4.35 (d, J=6.1, 2H), 4.55 (s, 2H), 4.96 - 5.10 (m, 8H), 6.83 (dd, J=8.5, 1.6, 1H), 7.00 (d, J=2.2, 1H), 7.07 - 7.34 (m, 27H), 7.61 (dd, J=23.8, 8.8, 2H), 7.78 (d, J=7.3, 2H), 7.88 (dd, J=8.6, 1.8, 1H), 8.27 (d, J=1.8, 1H), 9.02-9.14 (m, 1H) 1 H NMR (400 MHz, CDCl 3 ) δ = 4.35 (d, J = 6.1, 2H), 4.55 (s, 2H), 4.96 - 5.10 (m, 8H), 6.83 (dd, J = 8.5, 1.6, 1H ), 7.00 (d, J = 2.2, 1H), 7.07-7.34 (m, 27H), 7.61 (dd, J = 23.8, 8.8, 2H), 7.78 (d, J = 7.3, 2H), 7.88 (dd, J = 8.6, 1.8, 1H), 8.27 (d, J = 1.8, 1H), 9.02-9.14 (m, 1H)
13C NMR (101 MHz, CDCI3) δ = 41.95, 67.24, 70.11 - 70.28 (m), 107.38, 118.97, 120.44, 121.01 (d, J=2.2), 121.59 (d, J=2.0), 124.16, 124.84, 125.00, 127.19, 127.79, 127.94 (d, J=2.1), 128.42, 128.57 (d, J=1.3), 128.66, 128.87, 130.99, 131.05, 135.13 (dd, J=7.0, 4.1), 135.76, 135.96, 138.73, 140.52 (t, J=6.3), 141.09 (t, J=6.7), 156.26, 166.33, 167.99
31P NMR (162 MHz, CDCI3) δ = -5.53 (s, 1 P), -5.44 (s, 1 P) UV/Vis: λ [nm] = 280, 240 13 C NMR (101 MHz, CDCl 3 ) δ = 41.95, 67.24, 70.11-70.28 (m), 107.38, 118.97, 120.44, 121.01 (d, J = 2.2), 121.59 (d, J = 2.0), 124.16, 124.84 , 125.00, 127.19, 127.79, 127.94 (d, J = 2.1), 128.42, 128.57 (d, J = 1.3), 128.66, 128.87, 130.99, 131.05, 135.13 (dd, J = 7.0, 4.1), 135.76, 135.96, 138.73, 140.52 (t, J = 6.3), 141.09 (t, J = 6.7), 156.26, 166.33, 167.99 31 P NMR (162 MHz, CDCl 3 ) δ = -5.53 (s, 1 P), -5.44 (s, 1 P) UV / Vis: λ [nm] = 280, 240
IR [KBr]: v [cm"1] = 3645, 3633, 3625, 3604, 3592, 3583, 3572, 3563, 3426, 3308, 3062, 3023, 2924, 2897, 1768, 1667, 1660, 1652, 1629, 1600, 1539, 1506, 1478, 1456, 1441, 1393, 1321, 1274, 1203, 1173, 1157, 1124, 1081, 1018, 1001, 880, 813, 741, 695, 596, 511, 499, 475, 456; IR [KBr]: v [cm "1 ] = 3645, 3633, 3625, 3604, 3592, 3583, 3572, 3563, 3426, 3308, 3062, 3023, 2924, 2897, 1768, 1667, 1660, 1652, 1629, 1600, 1539, 1506, 1478, 1456, 1441, 1393, 1321, 1274, 1203, 1173, 1157, 1124, 1081, 1018, 1001, 880, 813, 741, 695, 596, 511, 499, 475, 456;
HRMS (ESI) gefunden: [M+Na] + m/z =985.2621 , berechnet für 054Η48Ν2Ν3ΟιιΡ2 = 985.2626 Synthese 4-((2-((6-(phenylcarbamoyl) naphthalen-2-yl)oxy) acetamido)methyl)-1 ,2- phenylene bisfdihydrogen Phosphate) (13) HRMS (ESI) found: [M + Na] + m / z = 985.2621, calculated for 0 5 4Η48Ν 2 Ν 3 ΟιιΡ2 = 985.2626 Synthesis 4 - ((2 - ((6- (phenylcarbamoyl) naphthalen-2-yl) oxy ) acetamido) methyl) -1, 2- phenylene bis (dihydrogen phosphates) (13)
13 wird aus 13f hergestellt (0.3 g, 0.31 mmol) gemäß Methode 2 hergestellt. Lyophilisation ergab das Produkt als weißen Feststoff (0.178 g, 95%). 13 is prepared from 13f (0.3 g, 0.31 mmol) prepared according to Method 2. Lyophilization gave the product as a white solid (0.178 g, 95%).
Schmelzpunkt: 192 - 194 °C Melting point: 192-194 ° C
1H NMR (400 MHz, DMSO-d6) δ = 4.30 (d, J=6.0, 2H), 4.70 (s, 2H), 6.99 (d, J=8.2, 1H), 7.09 (t, J=7.4, 1 H), 7.21 (d, J=8.3, 1 H), 7.26 (s, 1 H), 7.30 - 7.43 (m, 4H), 7.80 (d, J=7.7, 2H), 7.90 (d, J=8.6, 1H), 7.94-8.07 (m, 2H), 8.50 (s, 1H), 8.76 (t, J=6.1, 1H), 10.34 (s, 1H) 1 H NMR (400 MHz, DMSO-d 6 ) δ = 4.30 (d, J = 6.0, 2H), 4.70 (s, 2H), 6.99 (d, J = 8.2, 1H), 7.09 (t, J = 7.4 , 1H), 7.21 (d, J = 8.3, 1H), 7.26 (s, 1H), 7.30-7.43 (m, 4H), 7.80 (d, J = 7.7, 2H), 7.90 (d, J = 8.6, 1H), 7.94-8.07 (m, 2H), 8.50 (s, 1H), 8.76 (t, J = 6.1, 1H), 10.34 (s, 1H)
13C NMR (101 MHz, DMSO-d6) δ = 41.29, 67.01, 107.26, 119.59, 120.34, 121.32, 122.02, 123.21, 123.56, 125.08, 126.90, 127.69, 127.85, 128.61, 130.25, 130.62, 135.67, 139.32, 141.68, 142.61, 157.05, 165.60, 167.43 13 C NMR (101 MHz, DMSO-d 6 ) δ = 41.29, 67.01, 107.26, 119.59, 120.34, 121.32, 122.02, 123.21, 123.56, 125.08, 126.90, 127.69, 127.85, 128.61, 130.25, 130.62, 135.67, 139.32, 141.68, 142.61, 157.05, 165.60, 167.43
31P NMR (162 MHz, DMSO-d6) δ = -4.66, -4.50 31 P NMR (162 MHz, DMSO-d 6 ) δ = -4.66, -4.50
UV/Vis: λ [nm] = 301 , 250, 238, 201 UV / Vis: λ [nm] = 301, 250, 238, 201
IR [KBr]: v [cm-1] = 3434, 1651, 1631, 1601, 1537, 1510, 1479, 1441, 1394, 1324, 1273, 1236, 1208, 1175, 1122, 1076, 1065, 1020, 977, 951, 914, 842, 823, 753, 692 ,584, 569, 558, 539, 526, 512, 502, 495, 481 , 473
HRMS (ESI) found: [M-H] " m/z = 601.0787, berechnet für C26H23NO11 P2 = 601 .0783 IR [KBr]: v [cm -1 ] = 3434, 1651, 1631, 1601, 1537, 1510, 1479, 1441, 1394, 1324, 1273, 1236, 1208, 1175, 1122, 1076, 1065, 1020, 977, 951, 914, 842, 823, 753, 692, 584, 569, 558, 539, 526, 512, 502, 495, 481, 473 HRMS (ESI) found: [MH] " m / z = 601.0787, calculated for C26H23NO11 P2 = 601 .0783
Synthese ((((4-((2-((6-(phenylcarbamoyl)naphthalen-2-yl)oxy)acetamido)methyl)-1 ,2- phenylene)bis(oxy))bis(oxo-l5-phosphanetriyl))tetrakis(oxy))tetrakis(methylene) tetrakis(2,2- dimethylpropanoate) (1 Synthesis (((4 - ((2 - ((6- (phenylcarbamoyl) -naphthalen-2-yl) oxy) acetamido) methyl) -1, 2-phenylene) bis (oxy)) bis (oxo-l5-phosphanetriyl) ) tetrakis (oxy)) tetrakis (methylene) tetrakis (2,2-dimethylpropanoate) (1
16 wird gemäß Methode 6 aus 13 (40 mg, 0.07 mmol) hergestellt. Nach Säulenchromato- graphischer Reinigung (Hexan / Essigsäureethylester 3:1 — > 2:1 ) wird das Produkt als Öl erhalten (35 mg, 50%). 16 is prepared according to Method 6 from 13 (40 mg, 0.07 mmol). After purification by column chromatography (hexane / ethyl acetate 3: 1 → 2: 1), the product is obtained as an oil (35 mg, 50%).
1H NMR (400 MHz, Chloroform-d) δ = 1.18 (d, J=4.6, 36H), 4.48 (d, J=6.1 , 2H), 4.68 (s, 2H), 5.60 - 5.79 (m, 8H), 6.94 - 7.06 (m, 2H), 7.1 1 - 7.18 (m, 2H), 7.18 - 7.25 (m, 2H), 7.29 (s, 1 H), 7.33 - 7.40 (m, 2H), 7.75 (dd, J=18.0, 7.9, 3H), 7.84 (d, J=9.0, 1 H), 7.91 (dd, J=8.6, 1 .8, 1 H), 8.32 (s, 1 H), 8.44 (d, J=5.4, 1 H) 1 H NMR (400 MHz, chloroform-d) δ = 1.18 (d, J = 4.6, 36H), 4.48 (d, J = 6.1, 2H), 4.68 (s, 2H), 5.60-5.79 (m, 8H) , 6.94 - 7.06 (m, 2H), 7.1 1 - 7.18 (m, 2H), 7.18 - 7.25 (m, 2H), 7.29 (s, 1H), 7.33 - 7.40 (m, 2H), 7.75 (dd, J = 18.0, 7.9, 3H), 7.84 (d, J = 9.0, 1H), 7.91 (dd, J = 8.6, 1 .8, 1H), 8.32 (s, 1H), 8.44 (d, J = 5.4, 1H)
31P NMR (162 MHz, cdcl3) δ = -8.73 (s, 1 P), -9.00 (s, 1 P) 31 P NMR (162 MHz, cdcl 3 ) δ = -8.73 (s, 1 P), -9.00 (s, 1 P)
13C NMR (101 MHz, cdcl3) δ = 26.96, 38.90, 42.19, 67.56, 77.33, 83.35, 83.39, 83.41 , 83.45, 107.75, 1 19.37, 120.46, 121 .37 - 121 .46 (m), 121.96 - 122.05 (m), 124.58, 124.97, 125.65, 127.70, 127.86, 128.81 , 129.24, 131.30, 136.13, 136.65, 138.57, 140.30 (t, J=6.7), 140.86 (t, J=6.9)., 156.60, 156.65, 166.19, 168.15, 176.72, 176.79 13 C NMR (101 MHz, cdcl 3 ) δ = 26.96, 38.90, 42.19, 67.56, 77.33, 83.35, 83.39, 83.41, 83.45, 107.75, 1 19.37, 120.46, 121 .37 - 121 .46 (m), 121.96 - 122.05 (m), 124.58, 124.97, 125.65, 127.70, 127.86, 128.81, 129.24, 131.30, 136.13, 136.65, 138.57, 140.30 (t, J = 6.7), 140.86 (t, J = 6.9)., 156.60, 156.65, 166.19, 168.15, 176.72, 176.79
HRMS (ESI) gefunden: [M+Na]+ m/z = 1081 .3461 , berechnet für CsoH^NzNaO^: 1081.3471 HRMS (ESI) found: [M + Na] + m / z = 1081 .3461, calculated for CsoH ^ NzNaO ^: 1081.3471
Beispiel 11 : Bestimmung der Bindungstasche Example 11: Determination of the binding pocket
Um für die Verbindung (31 ) aus Beispiel 8 die Wirkstoffbindetasche des STAT5b-Proeteins experimentell nachzuweisen, wurde das BODIPY-FL-markierte Derivat von Verbindung (31 ) als Verbindung (10) synthetisiert. Die Verbindung (10) dient als Indikator für die direkte Bindungsuntersuchung basierend auf der Fluoreszenzpolarisation. Die Verbindung (10) wird über fünf Syntheseschritte erhalten.
Die Bindung der Substanz an ein Protein wird durch die Erhöhung der Fluoreszenzpolarisation festgestellt. Es wurde festgestellt, dass die Verbindung (10) gegenüber dem Wildtyp des STAT5b eine Bindungsaffinität von Kd = 862 ± 77 nM aufweist. Die STAT5b-Punktmutanten Arg618Ala, Arg618Lys und Trp641Ala ist erheblich geringer die die Affinität des Wildtyp- Proteins (vgl. Fig. 7). Wildtyp-STAT5a bindet ebenfalls sehr viel schwächer an Verbindung 10 als Wildtyp-STAT5b. Dies belegt die ausgesprochen hohe Selektivität der Catecholbis- phosphate für STAT5b.
In order to experimentally detect the drug binding pocket of the STAT5b protein for compound (31) of Example 8, the BODIPY-FL labeled derivative of compound (31) was synthesized as compound (10). Compound (10) serves as an indicator of direct binding assay based on fluorescence polarization. The compound (10) is obtained via five synthesis steps. The binding of the substance to a protein is detected by the increase in fluorescence polarization. Compound (10) was found to have a binding affinity of K d = 862 ± 77 nM over the wild-type STAT5b. The STAT5b point mutants Arg618Ala, Arg618Lys and Trp641Ala are significantly less the affinity of the wild-type protein (see Figure 7). Wild-type STAT5a also binds much weaker at compound 10 than wild-type STAT5b. This demonstrates the markedly high selectivity of catechol bisphosphates for STAT5b.
Claims
Patentansprüche claims
1 . Verbindungen zur Inhibierung des STAT5-Proteins der allgemeinen Formel (I): 1 . Compounds for inhibiting the STAT5 protein of general formula (I):
(i) (I)
wobei: in which:
n 1 oder 2 ist, n is 1 or 2,
m eine ganze Zahl von 0 bis 4 ist, m is an integer from 0 to 4,
p eine ganze Zahl von 0 bis 2 ist, p is an integer from 0 to 2,
- der Linker L ist C(R2)2, O, N R2, N R2C(=0), NR2C(=0)CH2, N R2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Ci bis Ci0-Alkoxylrest, - the linker L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched C 1 to C 10 -alkoxyl radical,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
- X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R1 ist H , ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein gegebenenfalls substituierter und/oder polyzyklischer C5 bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyh Biphenyl-, Naphthalinyl-, Benzophenon-, Benzylbenzol-, Fluorenyl- und Triphenylmethan-Rest, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Dibenzofuran-, Xanthen-, Carbazol- und Phenothiazin-Rest. R 1 is H, an optionally substituted and / or branched Q to C 5 -alkyl radical, an optionally substituted and / or branched alkoxy radical, an optionally substituted and / or polycyclic C 5 to C 5 -aryl radical, in particular selected from the group of phenylbiphenyl -, naphthalenyl, benzophenone, Benzylbenzol-, fluorenyl, and triphenylmethane radical, or an optionally polycyclic and / or substituted five- or six-membered ring C 5 to Ci 5 -Hetrozyklus, in particular selected from the group dibenzofuran, xanthene, Carbazole and phenothiazine residue.
2. Verbindungen nach Anspruch 1 , dadurch gekennzeichnet, dass n 2 ist. 2. Compounds according to claim 1, characterized in that n is 2.
3. Verbindungen nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass R1 H, C3-i2- Alkylrest, ein Fünfring- oder Sechsring-Heterozyklus oder ein Arylrest ist. 3. Compounds according to claim 1 or 2, characterized in that R 1 is H, C 3 i 2 - alkyl group, a five- or six-membered heterocycle or an aryl radical.
4. Verbindungen nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass R2 H ist.
Verbindung zur Inhibierung des STAT5-Proteins der allgemeinen Formel (II): 4. Compounds according to one of claims 1 to 3, characterized in that R 2 is H. Compound for inhibiting the STAT5 protein of general formula (II):
wobei: in which:
n ist 1 oder 2, n is 1 or 2,
v eine ganze Zahl von 0 bis 4 ist, v is an integer from 0 to 4,
Q Sauerstoff (O), CH2 oder CF2 ist, wobei wenn n = 2 die beiden Q voneinander unabhängig ausgewählt sind, Q is oxygen (O), CH 2 or CF 2 , where if n = 2 the two Qs are independently selected,
- Y ist Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat oder Urea, Y is carboxyl, carbamoyl, carbonate, carbamide, carbamate or urea,
R3 ist H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci0-Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci0-Alkoxylrest, ein gegebenenfalls substituierter Arylrest, R 3 is H, an optionally substituted and / or branched Q to Ci 0 alkyl, an optionally substituted and / or branched Q to Ci 0 -alkoxyl, an optionally substituted aryl radical,
R5 bis R8 sind unabhängig voneinander ausgewählt aus H, Halogen, insbesondere F und Cl, und L Jm R 5 to R 8 are independently selected from H, halogen, especially F and Cl, and L Jm
wobei: in which:
m eine ganze Zahl von 0 bis 4 ist, m is an integer from 0 to 4,
- der Linker L ist C(R2)2, O, NR2, NR2C(=0), NR2C(=0)CH2, NR2C(=0)0, wobei R2 H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter i bis C10- Alkoxylrest, - the linker L is C (R 2) 2, O, NR 2, NR 2 C (= 0), NR 2 C (= 0) CH 2, NR 2 C (= 0) 0, wherein R 2 is H, optionally substituted and / or branched Q to C 5 - alkyl group, an optionally substituted and / or branched i to C 10 - alkoxy radical,
- X ist O, S, NR2 oder CH2, X is O, S, NR 2 or CH 2 ,
R ist H, ein gegebenenfalls substituierter und/oder verzweigter Q bis Ci5- Alkylrest, ein gegebenenfalls substituierter und/oder verzweigter Alkoxylrest, ein gegebenenfalls substituierter und/oder polyzyklischer Cs bis Ci5-Arylrest, insbesondere ausgewählt aus der Gruppe Phenyh Biphenyl-, Naphthalinyl-, Benzophenon-, Benzylbenzol-, Fluorenyl- und Triphenylmethan-Rest, oder ein gegebenenfalls polyzyklischer und/oder substituierter Fünfring- oder Sechsring- C5 bis Ci5-Hetrozyklus, insbesondere ausgewählt aus der Gruppe Diebenzofuran-, Xanthen-, Carbazol- und Phenothiazin-Rest. R is H, an optionally substituted and / or branched Q to Ci 5 - alkyl radical, an optionally substituted and / or branched alkoxy radical, an optionally substituted and / or polycyclic Cs to Ci 5 -aryl radical, in particular selected from the group Phenyh biphenyl-, Naphthalenyl, benzophenone, benzylbenzene, fluorenyl and triphenylmethane radical, or an optionally polycyclic and / or substituted five-membered or six-membered C 5 to C 5 -heterrocycle, in particular selected from the group diebenzofuran, xanthene, carbazole and phenothiazine residue.
Verbindung nach Anspruch 5, dadurch gekennzeichnet, dass n 2 ist.
Compound according to claim 5, characterized in that n is 2.
7. Verbindung nach Anspruch 5 oder 6, dadurch gekennzeichnet, dass R H, C3-12-Alkylrest, ein Fünfring- oder Sechsring-Hetrozyklus oder ein Arylrest ist. 7. A compound according to claim 5 or 6, characterized in that R is H, C3 -12- alkyl radical, a five-membered or six-membered heterocycle or an aryl radical.
8. Verbindung nach einem der Ansprüche 5 bis 6, dadurch gekennzeichnet, dass R2 H ist. 8. A compound according to any one of claims 5 to 6, characterized in that R 2 is H.
9. Vorläuferverbindungen der Verbindungen der allgemeinen Formel (I) gemäß der Ansprüche 1 bis 4 mit der allgemeinen Formel (lila) bzw. (Illb): 9. Precursor compounds of the compounds of the general formula (I) according to Claims 1 to 4 having the general formula (IIIa) or (IIIb):
(lila) (Illb) wobei: (purple) (Illb) where:
R° ausgewählt ist aus H, Ci-6-Alkylrest und
, wobei R ° is selected from H, Ci -6 alkyl, and , in which
0 eine ganze Zahl von 0 bis 3 ist, 0 is an integer from 0 to 3,
- Y ist ausgewählt aus Carboxyl, Carbamoyl, Cabonat, Carbamid, Carbamat, Urea, Thioester, Y is selected from carboxyl, carbamoyl, cabonate, carbamide, carbamate, urea, thioester,
R4 ist ein Ci-6-Alkylrest oder ein C6-io-Arylrest und R 4 is a Ci -6 alkyl group or a C 6- io-aryl, and
wobei: in which:
1 0 oder 1 ist, 1 is 0 or 1,
A und B unabhängig voneinander CH2, CH-Ar, Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat, Urea, wobei Ar ein gegebenenfalls substituierter Arylrest, insbesondere Phenyl- oder Pyridinrest, ist, der insbesondere substituiert ist mit Halogen (F, Cl, Br), OH, einem Ci-6-Alkylrest oder einem Ci-6-Alkoxyrest. A and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy.
10. Vorläuferverbindungen der Verbindungen der allgemeinen Formel (II) gemäß der Ansprüche 5 bis 8 mit der allgemeinen Formel (IVa) bzw. (IVb): 10. Precursor compounds of the compounds of the general formula (II) according to claims 5 to 8 with the general formula (IVa) or (IVb):
R° ausgewählt ist aus H, Ci-6-Alkylrest und 1 J° , wobei R ° is selected from H, Ci -6- Alkylrest and 1 J °, whereby
0 eine ganze Zahl von 0 bis 3 ist, 0 is an integer from 0 to 3,
Y ist ausgewählt aus Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat, Urea, Thioester, Y is selected from carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, thioester,
R4 ist ein Ci-6-Alkylrest oder ein C6-io-Arylrest und R 4 is a Ci -6 alkyl group or a C 6- io-aryl, and
wobei: in which:
1 0 oder 1 ist, 1 is 0 or 1,
A und B unabhängig voneinander CH2, CH-Ar, Carboxyl, Carbamoyl, Carbonat, Carbamid, Carbamat, Urea, wobei Ar ein gegebenenfalls substituierter Arylrest, insbesondere Phenyl- oder Pyridinrest, ist, der insbesondere substituiert ist mit Halogen (F, Cl, Br), OH, einem Ci-6-Alkylrest oder einem Ci-6-Alkoxyrest. A and B independently of one another are CH 2 , CH-Ar, carboxyl, carbamoyl, carbonate, carbamide, carbamate, urea, where Ar is an optionally substituted aryl radical, in particular phenyl or pyridine radical, which is in particular substituted by halogen (F, Cl, Br), OH, a Ci -6- alkyl radical or a Ci -6- alkoxy.
1 1 . Pharmazeutische Formulierung, enthaltend eine wirksame Menge mindestens einer Verbindung gemäß der allgemeinen Formel (I) und/oder eines Naphthylphosphats der Formel (II) ein und/oder Vorläuferverbindungen gemäß der allgemeinen Formel (II la/b) bzw. (IVa/b) zur Behandlung von Karzinomen oder Multiple Sklerose. 1 1. A pharmaceutical formulation comprising an effective amount of at least one compound according to the general formula (I) and / or a naphthyl phosphate of the formula (II) and / or precursor compounds according to the general formula (II la / b) or (IVa / b) Treatment of carcinomas or multiple sclerosis.
12. Verbindung gemäß der allgemeinen Formel (I) und/oder der Formel (II) einzeln oder als Gemisch zur Verwendung als Arzneimittel für eine Anwendung in der Krebstherapie. 12. A compound according to the general formula (I) and / or the formula (II) individually or as a mixture for use as a medicament for an application in cancer therapy.
13. Verwendung einer Verbindung gemäß der allgemeinen Formel (I) und/oder der Formel (II) und/oder einer Vorläuferverbindung gemäß der allgemeinen Formel (lila, b) bzw. (Iva,b) zur Herstellung einer pharmazeutischen Formulierung. 13. Use of a compound according to the general formula (I) and / or the formula (II) and / or a precursor compound according to the general formula (IIIa, b) or (Iva, b) for the preparation of a pharmaceutical formulation.
14. Verwendung einer Verbindung gemäß der allgemeinen Formel (I) und/oder der Formel (II) und/oder einer Vorläuferverbindungen gemäß der allgemeinen Formel (lila, b) bzw. (Iva,b) in Kombination mit einer Krebsimmunotherapie zur Verwendung bei der Behandlung von Krebserkrankungen.
14. Use of a compound according to the general formula (I) and / or the formula (II) and / or a precursor compounds according to the general formula (IIIa, b) or (Iva, b) in combination with a cancer immunotherapy for use in the Treatment of cancer.
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