NZ622127B2 - Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals - Google Patents
Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals Download PDFInfo
- Publication number
- NZ622127B2 NZ622127B2 NZ622127A NZ62212712A NZ622127B2 NZ 622127 B2 NZ622127 B2 NZ 622127B2 NZ 622127 A NZ622127 A NZ 622127A NZ 62212712 A NZ62212712 A NZ 62212712A NZ 622127 B2 NZ622127 B2 NZ 622127B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- series consisting
- phenyl
- chromanyloxy
- formula
- Prior art date
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- 239000003814 drug Substances 0.000 title claims description 18
- XFZODDHRWKDGLV-UHFFFAOYSA-N 2-(3,4-dihydro-2h-chromen-6-yloxy)-1,3-thiazole Chemical class C1=C2CCCOC2=CC=C1OC1=NC=CS1 XFZODDHRWKDGLV-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 486
- 238000011282 treatment Methods 0.000 claims abstract description 41
- 206010019280 Heart failures Diseases 0.000 claims abstract description 37
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 17
- 208000006011 Stroke Diseases 0.000 claims abstract description 15
- 102000001794 Sodium-Calcium Exchanger Human genes 0.000 claims abstract description 11
- 108010040240 Sodium-Calcium Exchanger Proteins 0.000 claims abstract description 11
- 239000003112 inhibitor Substances 0.000 claims abstract description 10
- -1 phenyl-O- Chemical class 0.000 claims description 625
- 125000001424 substituent group Chemical group 0.000 claims description 258
- 229910052757 nitrogen Inorganic materials 0.000 claims description 140
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 124
- 239000001257 hydrogen Substances 0.000 claims description 122
- 229910052739 hydrogen Inorganic materials 0.000 claims description 122
- 229910052736 halogen Inorganic materials 0.000 claims description 102
- 150000002367 halogens Chemical class 0.000 claims description 102
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 88
- 125000004432 carbon atom Chemical group C* 0.000 claims description 88
- 239000011737 fluorine Substances 0.000 claims description 88
- 229910052731 fluorine Inorganic materials 0.000 claims description 88
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 87
- 239000000203 mixture Substances 0.000 claims description 82
- 150000003839 salts Chemical class 0.000 claims description 80
- 125000005842 heteroatom Chemical group 0.000 claims description 79
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 72
- 125000000623 heterocyclic group Chemical group 0.000 claims description 67
- 229910052717 sulfur Inorganic materials 0.000 claims description 59
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 58
- 238000000034 method Methods 0.000 claims description 58
- 229910052760 oxygen Inorganic materials 0.000 claims description 58
- 239000001301 oxygen Substances 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 55
- 239000011593 sulfur Substances 0.000 claims description 55
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 40
- 125000002950 monocyclic group Chemical group 0.000 claims description 39
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- 125000002619 bicyclic group Chemical group 0.000 claims description 35
- 125000001153 fluoro group Chemical group F* 0.000 claims description 33
- 229920006395 saturated elastomer Polymers 0.000 claims description 30
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 22
- 229910052740 iodine Inorganic materials 0.000 claims description 20
- 230000008569 process Effects 0.000 claims description 20
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 19
- 230000005764 inhibitory process Effects 0.000 claims description 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000035939 shock Effects 0.000 claims description 9
- 206010020772 Hypertension Diseases 0.000 claims description 8
- 206010012289 Dementia Diseases 0.000 claims description 7
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 7
- 201000006370 kidney failure Diseases 0.000 claims description 7
- 208000031225 myocardial ischemia Diseases 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- UBNWPQXLFRMMEI-GQCTYLIASA-N 5-[3-[(e)-3-(3-hydroxy-2-methoxycarbonylphenoxy)prop-1-enyl]phenyl]-1,2-oxazole-3-carboxylic acid Chemical compound COC(=O)C1=C(O)C=CC=C1OC\C=C\C1=CC=CC(C=2ON=C(C=2)C(O)=O)=C1 UBNWPQXLFRMMEI-GQCTYLIASA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000006793 arrhythmia Effects 0.000 abstract description 8
- KFMCNOLLOWMPHN-UHFFFAOYSA-N 2-[[2-(2-methylphenyl)-3,4-dihydro-2h-chromen-6-yl]oxy]-n-[2-(2-oxoimidazolidin-1-yl)ethyl]-1,3-thiazole-5-carboxamide Chemical compound CC1=CC=CC=C1C1OC2=CC=C(OC=3SC(=CN=3)C(=O)NCCN3C(NCC3)=O)C=C2CC1 KFMCNOLLOWMPHN-UHFFFAOYSA-N 0.000 abstract 1
- HYQZOWKBOUKHIQ-UHFFFAOYSA-N n-[[2-[(2-phenyl-3,4-dihydro-2h-chromen-6-yl)oxy]-1,3-thiazol-5-yl]methyl]-1-pyridin-4-ylmethanamine Chemical compound C=1N=C(OC=2C=C3CCC(OC3=CC=2)C=2C=CC=CC=2)SC=1CNCC1=CC=NC=C1 HYQZOWKBOUKHIQ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 238000001819 mass spectrum Methods 0.000 description 79
- 239000002253 acid Substances 0.000 description 77
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 72
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 71
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 67
- 235000002639 sodium chloride Nutrition 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 63
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 56
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000002904 solvent Substances 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 125000004043 oxo group Chemical group O=* 0.000 description 43
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 41
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical group C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- 239000003480 eluent Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 25
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 206010007559 Cardiac failure congestive Diseases 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 21
- 239000011575 calcium Substances 0.000 description 19
- NRYCMMCUURADTR-UHFFFAOYSA-N 1,2-oxazol-3-ylmethanamine Chemical compound NCC=1C=CON=1 NRYCMMCUURADTR-UHFFFAOYSA-N 0.000 description 18
- IJVLVRYLIMQVDD-UHFFFAOYSA-N 1,3-thiazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CS1 IJVLVRYLIMQVDD-UHFFFAOYSA-N 0.000 description 18
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 18
- 201000010099 disease Diseases 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 17
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 239000002243 precursor Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 15
- 125000000524 functional group Chemical group 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 229910052791 calcium Inorganic materials 0.000 description 13
- 230000003834 intracellular effect Effects 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 102100035088 Sodium/calcium exchanger 1 Human genes 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 238000002347 injection Methods 0.000 description 12
- 239000007924 injection Substances 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 206010003658 Atrial Fibrillation Diseases 0.000 description 11
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 210000002216 heart Anatomy 0.000 description 11
- 108010067207 sodium-calcium exchanger 1 Proteins 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 125000004430 oxygen atom Chemical group O* 0.000 description 10
- 238000007363 ring formation reaction Methods 0.000 description 10
- 125000005302 thiazolylmethyl group Chemical group [H]C1=C([H])N=C(S1)C([H])([H])* 0.000 description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 9
- 239000012131 assay buffer Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 239000000975 dye Substances 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 230000002441 reversible effect Effects 0.000 description 9
- 125000004434 sulfur atom Chemical group 0.000 description 9
- 230000002861 ventricular Effects 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229910001424 calcium ion Inorganic materials 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 239000012047 saturated solution Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000002560 therapeutic procedure Methods 0.000 description 8
- BNYCHCAYYYRJSH-UHFFFAOYSA-N 1h-pyrazole-5-carboxamide Chemical compound NC(=O)C1=CC=NN1 BNYCHCAYYYRJSH-UHFFFAOYSA-N 0.000 description 7
- SHUBKLFAGAHOIS-UHFFFAOYSA-N 3-hydroxy-3,4-dihydrochromen-2-one Chemical compound C1=CC=C2OC(=O)C(O)CC2=C1 SHUBKLFAGAHOIS-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000012442 inert solvent Substances 0.000 description 7
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 229930192474 thiophene Natural products 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- LSJVQKDTVCDSPE-UHFFFAOYSA-N 1h-pyrazole-5-sulfonamide Chemical compound NS(=O)(=O)C=1C=CNN=1 LSJVQKDTVCDSPE-UHFFFAOYSA-N 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 150000002430 hydrocarbons Chemical group 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 125000003386 piperidinyl group Chemical group 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 6
- 229940080818 propionamide Drugs 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910001415 sodium ion Inorganic materials 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- PODSUMUEKRUDEI-UHFFFAOYSA-N 1-(2-aminoethyl)imidazolidin-2-one Chemical compound NCCN1CCNC1=O PODSUMUEKRUDEI-UHFFFAOYSA-N 0.000 description 5
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 description 5
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
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- 239000002600 sunflower oil Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- MBYLVOKEDDQJDY-UHFFFAOYSA-N tris(2-aminoethyl)amine Chemical compound NCCN(CCN)CCN MBYLVOKEDDQJDY-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 208000003663 ventricular fibrillation Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
- C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
- C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
Abstract
Provided are substituted 2-(chroman-6-yloxy)-thiazole compounds of the general formula I, where the variables are as defined in the specification. Examples of the compounds include 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid [2-(2-oxo-imidazolidin-1-yl)ethyl]-amide and [2-(2-Phenyl-chroman-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine. The compounds sodium-calcium exchanger (NCX) inhibitors. The compounds may be useful in the treatment of arrhythmias, heart failure and stroke. man-6-yloxy)-thiazol-5-ylmethyl]-pyridin-4-ylmethyl-amine. The compounds sodium-calcium exchanger (NCX) inhibitors. The compounds may be useful in the treatment of arrhythmias, heart failure and stroke.
Description
Substituted 2-(chromanyloxy)-thiazoles and their use as pharmaceuticals
The present invention relates to substituted 2-(chromanyloxy)-thiazoles of the
formula I,
Ar O
in which Ar, R2, R3 and R4 are as defined below. The compounds of the formula I
are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-
calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse
disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias,
heart failure and stroke. The invention furthermore relates to processes for the
preparation of the compounds of the formula I, their use as pharmaceuticals, and
pharmaceutical compositions comprising them.
Over the last decade major pharmacologic advances have been realized in the
management of heart failure (HF), or congestive heart failure (CHF). Beta-blockers
and inhibitors of the renin-angiotensin-aldosterone system have been found to have
a favorable effect in CHF with regard to mortality and improvement of symptoms (K.
Dickstein et al., Eur. J. Heart Fail. 10 (2008): 933-989). Nevertheless, morbidity and
mortality have remained unacceptably high. The number of patients with CHF, and in
particular more severe forms of CHF, is even growing, in part paradoxically because
of the success of these treatment approaches. Thus, there is still a need for agents
that can help improve CHF outcome and enhance quality of life. Blockers of the
sodium-calcium exchanger (NCX), a transport protein which is involved in the
regulation of cellular calcium and sodium levels, have the potential to improve the
prognosis of CHF and quality of life.
The function of the NCX is to extrude calcium in cardiomyocytes and other cell types
such as neurons. In CHF, the NCX was shown to be upregulated, thus unloading the
cell from calcium and further decreasing myocardial contractility (M. Flesch et al.,
Circulation 94 (1996): 992-1002; G. Hasenfuss et al., Circulation 99 (1999): 641-648).
Pump failure in CHF is not only due to irreversible structural changes and loss of
myocardium, but also due to adverse functional changes including a disturbance of
the intracellular calcium homeostasis. The latter can be treated by inhibition of the
NCX. Three subtypes of the NCX have been described. In the heart, predominantly
subtype 1 is expressed.
Through the NCX, calcium is exchanged for sodium, and extracellular sodium is the
driving force for the exchanger. The stoichiometry of the exchanger is that three
sodium ions enter the cell for the extrusion of one calcium ion. This stoichiometry
causes a positive inward current which is depolarizing in nature. The depolarizing
current, if of a sufficient size, could induce afterdepolarizations of the ventricular and
atrial action potential. Afterdepolarizations are oscillations of the electric membrane
potential and can occur during (early afterdepolarizations, EADs) or after (delayed
afterdepolarizations, DADs) the cardiac action potential. The occurrence of EADs is
associated with a prolonged ventricular action potential (visible as prolonged QT
interval in the electrocardiogram (ECG)), which is a common feature of the failing
heart. Afterdepolarizations are believed to be the major trigger of cardiac arrhythmias,
which therefore are also called triggered activity (D. M. Bers et al., Ann. N. Y. Acad.
Sci. 1080 (2006): 165-177; K. R. Sipido et al., Pflugers Arch. 430 (1995): 871-878; A.
O. Verkerk et al., Circulation 104 (2001): 2728-2733; C. Pott et al., Current Drug
Targets 12 (2011): 737-747; G. Antoons et al., Pharmacol. Ther. 134 (2012): 26-42).
The premature beats arising from the NCX-induced depolarizing currents can cause
more complex and irreversible arrhythmias such as episodes of tachycardia,
ventricular flutter or ventricular fibrillation.
Patients with pump failure, or heart failure, typically suffer from arrhythmias and
arrhythmic death. About 50% of the cardiac mortality in CHF is due to arrhythmic
death. NCX blockade is therefore a means of improving pump failure and associated
symptoms as well as of reducing arrhythmic death. Current positive inotropic drugs
are associated with proarrhythmic effects that either increase mortality, such as in the
case of phosphodiesterase inhibitors, or annihilate the positive effects achieved by
an improvement of pump failure by the positive inotropic effect (J. T. Parissis et al.,
Curr. Opin. Crit. Care 16 (2010): 432-441). On the other hand, a number of clinically
useful antiarrhythmic drugs have a negative inotropic effect on the heart worsening
the symptoms of heart failure. NCX blockers are therapeutically unique in that they
can address the two major problems of CHF, pump failure and arrhythmias.
NCX blockade is particularly interesting for advanced stages of CHF, like NYHA
Classes III and IV according to the New York Heart Association Functional
Classification of heart failure, in which the therapeutic options, i.e. beta-blockers,
inhibitors of the renin angiotensin-aldosterone system, diuretics and vasodilators,
already are fully exploited. Elderly patients progressing to end-stage HF present a
new emerging population. In this late stage a vasodilator effect is no more desirable
in a considerable part of the patients because blood pressure is already lowered as a
consequence of pump failure. Phosphodiesterase inhibitors as positive inotropic
drugs not only suffer from the drawback of being proarrhythmic, but also from a
vasodilator effect.
Atrial fibrillation (AF) is the most frequent arrhythmia. AF affects about 6.8 million
patients in the US and the European Union, and its prevalence is strongly rising
because of the aging of the population and of the successful treatment of myocardial
infarction, coronary artery disease and congestive heart failure. AF causes about
25% of all strokes, and increases mortality. Also in AF, upregulation of the NCX has
been demonstrated (U. Schotten et al., Cardiovasc. Res. 53 (2002): 192-201).
Upregulation of the NCX can be involved in the induction of AF by the
arrhythmogenic activity of the NCX and in its maintenance, and hence NCX blockers
have therapeutically favorable effects in the therapy and prevention of AF. Since AF
is an increasing disease in the aging population and is frequently associated with
heart failure in up to about 45% of patients (I. Savelieva et al., Europace. 5 Suppl 1
(2004): S5-S19), NCX blockers would be particularly favorable in patients with AF
and CHF.
Since NCX blockers also exert a positive inotropic effect in the atria, they may be
particularly favorable in diastolic heart failure where ventricular filling is the major
problem as a consequence of ventricular stiffening. A more vigorous atrial contraction
would improve ventricular filling in diastolic heart failure.
Since a reduced cardiac output has deleterious effects on the perfusion of organs
such as the kidney, brain and heart, inhibition of the NCX, which increases the
contractility of the heart, is able to improve perfusion of the brain, heart and kidney
for a therapy or prevention of stroke, dementia and Alzheimer's disease, renal failure
and cardiac ischemia. Since the NCX is also involved in salt sensitive hypertension,
its inhibition is also suited for the treatment of hypertension.
Inhibitors of the NCX are also suited for the therapy and prevention of life threatening
conditions in which inotropic support is required to maintain a sufficient level of blood
supply. This includes all forms of shock, hemodynamic shock, cardiogenic shock and
septic shock. Inhibitors of the NCX are particularly suited to treat these conditions
because they are neutral on heart rate and lack the proarrhythmic or vasodilator or
vasoconstrictor properties of other inotropic drugs.
In stroke, NCX blockers have the potential of improving the outcome since in
neuronal hypoxia, as occurs in stroke, the NCX reverses its transport direction to
reverse mode, and loads the cells with calcium leading to a calcium overload. This
leads to accelerated cell death due to excessive intracellular calcium concentrations.
Moreover, a low cardiac output can lead to brain ischemia favoring stroke. NCX
blockers will increase cardiac output and raise brain perfusion. Hence, NCX blockers
have a potential in the therapy and prevention of stroke (T. Matsuda et al., J.
Pharmacol. Exp. Ther. 298 (2001): 249-2569.
Certain compounds capable of inhibiting the NCX have already been described, e.g.
in EP 0978506, JP 2008/189592, , , WO
03/006452, WO 02/32883, WO 97/09306. However, there still is a need for further
compounds which inhibit the NCX and are suitable for use as pharmaceuticals in the
treatment of the mentioned disease states. It has now been found that the
compounds of the formula I are excellent inhibitors of the sodium-calcium exchanger
(NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and have a
favorable property profile for such use.
Thus, a subject of the present invention are the compounds of the formula I, in any of
their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and the
pharmaceutically acceptable salts thereof,
Ar O
wherein
Ar is selected from the series consisting of phenyl and a 5-membered or 6-
membered monocyclic aromatic heterocycle, which are all unsubstituted or
substituted by one or more identical or different substituents R1, wherein the
heterocycle comprises 1 or 2 identical or different ring heteroatoms selected from the
series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon
atom;
R1 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl,
1 6 3 7
(C -C )-cycloalkyl-(C -C )-alkyl-, phenyl, Het1, HO-, (C -C )-alkyl-O-, (C -C )-
3 7 1 4 1 6 3 7
cycloalkyl-O-, (C -C )-cycloalkyl-(C -C )-alkyl-O-, phenyl-O-, Het1-O- and (C -C )-
3 7 1 4 1 6
alkyl-S(O) -, and two groups R1 bonded to adjacent ring carbon atoms in Ar, together
with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-
unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one or more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)-CH -, R7-
C(O)-NH-CH - and R7-S(O) -NH-CH -;
2 2 2
R3 is selected from the series consisting of hydrogen, halogen, (C -C )-alkyl and (C -
1 4 1
C )-alkyl-O-;
R4 is hydrogen or one or more identical or different substituents selected from the
series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O-;
1 4 1 4
R5 and R6 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl, phenyl, Het1 and
1 6 3 7 6 10
Het2, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or
different substituents R10, and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all
3 7 6 10
are unsubstituted or substituted by one or more identical or different substituents R11,
or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-
membered to 10-membered, monocyclic or bicyclic, saturated or partially unsaturated
heterocycle which, in addition to the nitrogen atom carrying R5 and R6, comprises 0
or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen
and sulfur, and which is unsubstituted or substituted by one ore more identical or
different substituents R12;
R7 is selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl, phenyl,
1 6 3 7
Het2 and Het3, wherein (C -C )-alkyl, (C -C )-cycloalkyl and Het2 all are
1 6 3 7
unsubstituted or substituted by one or more identical or different substituents R10,
and phenyl and Het3 all are unsubstituted or substituted by one or more identical or
different substituents R13;
R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, (C -C )-alkyl-S(O) -, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)-,
1 6 n
R19-O-C(O)- and R16-N(R17)-S(O) -;
R11 and R12 are independently of one another selected from the series consisting of
(C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-
1 4 1 4 1 4 1 4
alkyl-, R14, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-,
HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, (C -C )-alkyl-S(O) -,
2 2 2 2 1 6 n
R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-
S(O) -;
R13 is selected from the series consisting of halogen, (C -C )-alkyl, HO-, (C -C )-
1 4 1 4
alkyl-O- and R16-N(R17)-, and two substituents R13 bonded to adjacent ring carbon
atoms in R7, together with the carbon atoms carrying them, can form a 5-membered
to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different
ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur,
and which is unsubstituted or substituted by one or more identical or different
substituents selected from the series consisting of fluorine and (C -C )-alkyl;
R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated,
partially unsaturated or aromatic and comprises 0, 1, 2, 3 or 4 identical or different
ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur,
and which is unsubstituted or substituted by one or more identical or different
substituents R20;
R15 and R18 are independently of one another selected from the series consisting of
(C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, phenyl-(C -C )-
1 6 3 7 3 7 1 4 1 4
alkyl- and Het1-(C -C )-alkyl-;
R16 and R17 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, phenyl-
1 6 3 7 3 7 1 4
(C -C )-alkyl- and Het1-(C -C )-alkyl-,
1 4 1 4
or the groups R16 and R17, together with the nitrogen atom carrying them, form a 4-
membered to 7-membered, monocyclic saturated heterocycle which, in addition to
the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one ore more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, phenyl-(C -C )-alkyl- and Het1-(C -C )-
3 7 1 4 1 4 1 4
alkyl-;
R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
(C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-
3 7 1 6
S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, (C -C )-alkyl-S(O) -, R16-
2 2 2 2 1 6 n
N(R17)-, R18-C(O)-N(R17)-, R18-O-C(O)-N(R17)-, NC-, R18-C(O)-, R16-N(R17)-
C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -;
Het1 is a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1
or 2 identical or different ring heteroatoms selected from the series consisting of
nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more
identical or different substituents selected from the series consisting of halogen, (C -
C )-alkyl and (C -C )-alkyl-O-;
4 1 4
Het2 is a 4-membered to 10-membered monocyclic or bicyclic, saturated or partially
unsaturated heterocycle comprising 1 or 2 identical or different ring heteroatoms
selected from the series consisting of nitrogen, oxygen and sulfur;
Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle
comprising 1 or 2 identical or different ring heteroatoms selected from the series
consisting of nitrogen, oxygen and sulfur;
n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are
independent of one another;
wherein all phenyl groups, unless specified otherwise, are unsubstituted or
substituted by one or more identical or different substituents selected from the series
consisting of halogen, (C -C )-alkyl and -O-(C -C )-alkyl;
1 4 1 4
wherein all cycloalkyl and bicycloalkyl groups, independently of any other
substituents which can be present on a cycloalkyl or bicycloalkyl group, can be
substituted by one or more identical substituents selected from the series consisting
of fluorine and (C -C )-alkyl;
wherein all alkyl groups, independently of any other substituents which can be
present on an alkyl group, can be substituted by one ore more fluorine substituents.
The groups R2 and R3 in the compounds of the formula I and all other compounds in
which the groups R2 and R3 occur and in the respective formulae are not bonded to
a specific ring atom, can be bonded to any of the two carbon atoms of the thiazole
ring system depicted in formula I which have a free binding site, i.e. to the carbon
atoms in ring positions 4 and 5 of the thiazole ring system, as is indicated by the
bonds originating at R2 and R3 which are not directed to a specific carbon atom. One
of the groups R2 and R3 is bonded to the carbon atom in ring position 4 of the
thiazole ring system, and the other of the groups R2 and R3 is bonded to the carbon
atom in ring position 5 of the thiazole ring system. This applies accordingly to other
groups in compounds referred to herein whose binding position is not fixed in their
formulae, such as the group Y in the compounds of the formulae III and IV, for
example.
Likewise, groups R4 in the compounds of the formula I and all other compounds in
which groups R4 occur, which are different from hydrogen, can be bonded to any
carbon atoms of the chroman ring system depicted in formula I which have a free
binding site, i.e. to carbon atoms in ring positions 2, 3, 4, 5, 7 and 8 of the chroman
ring system, as is indicated by the bond originating at R4 which is not directed to a
specific carbon atom of the chroman ring. In all free binding sites of the carbon atoms
in ring positions 2, 3, 4, 5, 7 and 8 of the chroman ring system which are not
occupied by groups R4 different from hydrogen, hydrogen atoms are present. I.e., if
in a compound of the formula I no group R4 is present which is different from
hydrogen, the carbon atoms in ring positions 2, 5, 7 and 8 of the chroman ring
system carry one hydrogen atom, and the carbon atoms in ring positions 3 and 4 of
the chroman ring system carry two hydrogen atoms. If substituents R4 are present,
i.e. atoms or groups representing R4 which are different from hydrogen, one or more
of the said hydrogen atoms are replaced by the substituents R4.
If structural elements such as groups, substituents or numbers, for example, can
occur several times in the compounds of the formula I, they are all independent of
each other and can in each case have any of the indicated meanings, and they can
in each case be identical to or different from any other such element. In a
dialkylamino group, for example, the alkyl groups can be identical or different.
Alkyl groups, i.e. saturated hydrocarbon residues, can be linear (straight-chain) or
branched. This also applies if these groups are substituted or are part of another
group, for example an alkyl-O- group (alkyloxy group, alkoxy group) or an HO-
substituted alkyl group (HO-alkyl-, hydroxyalkyl group). Depending on the respective
definition, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6, or 1,
2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1. Examples of alkyl are methyl, ethyl, propyl
including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-
butyl, pentyl including n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl,
and hexyl including n-hexyl, 3,3-dimethylbutyl and isohexyl. Examples of
alkyl-O- groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
tert-butoxy, n-pentoxy. Examples of alkyl-S(O) - are methylsulfanyl- (CH -S-),
methanesulfinyl- (CH -S(O)-), methanesulfonyl (CH -S(O) -), ethylsulfanyl-
3 3 2
(CH -CH -S-), ethanesulfinyl- (CH -CH -S(O)-), ethanesulfonyl (CH -CH -S(O) -), 1-
3 2 3 2 3 2 2
methylethylsulfanyl- ((CH ) CH-S-), 1-methylethanesulfinyl- ((CH ) CH-S(O)-), 1-
3 2 3 2
methylethanesulfonyl ((CH ) CH-S(O) -). In one embodiment of the invention, the
3 2 2
number n is selected from the series consisting of 0 and 2, wherein all numbers n are
independent of each other and can be identical or different. In another embodiment
the number n in any of its occurrences, independent of its meaning in other
occurrences, is 0. In another embodiment the number n in any of its occurrences,
independent of its meaning in other occurrences, is 2.
A substituted alkyl group can be substituted in any positions, provided that the
respective compound is sufficiently stable and is suitable as a pharmaceutical active
compound. The prerequisite that a specific group and a compound of the formula I
are sufficiently stable and suitable as a pharmaceutical active compound, applies in
general with respect to the definitions of all groups in the compounds of the formula I.
As examples of substituted alkyl groups, specifically of HO-(C -C )-alkyl groups, for
example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-
hydroxypropyl, 3-hydroxypropyl, 1-hydroxymethylethyl, 2-hydroxymethylethyl,
1-hydroxybutyl, 4-hydroxybutyl, 2-hydroxymethylpropyl or 2-hydroxy
methylpropyl may be mentioned. An alkyl group which, independently of any other
substituents, can be substituted by one or more fluorine substituents, can be
unsubstituted by fluorine substituents, i.e. not carry fluorine substituents, or
substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or
by 1, 2, 3, 4 or 5 fluorine substituents, or by 1, 2 or 3 fluorine substituents, which can
be located in any positions. For example, in a fluoro-substituted alkyl group one or
more methyl groups can carry three fluorine substituents each and be present as
trifluoromethyl groups, and/or one or more methylene groups (CH ) can carry two
fluorine substituents each and be present as difluoromethylene groups. The
explanations with respect to the substitution of a group by fluorine also apply if the
group additionally carries other substituents and/or is part of another group, for
example of an alkyl-O- group. Examples of fluoro-substituted alkyl groups are
trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4-trifluorobutyl
and heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O- groups are
trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy.
Examples of fluoro-substituted alkyl-S(O) - groups are trifluoromethylsulfanyl-
(CF -S-), trifluoromethanesulfinyl- (CF -S(O)-) and trifluoromethanesulfonyl
(CF -S(O) -). With respect to all groups or substituents in the compounds of the
formula I which can be an alkyl group which can generally contain one or more
fluorine substituents, as an example of groups or substituents containing fluorine-
substituted alkyl which may be included in the definition of the group or substituent,
the group CF (trifluoromethyl), or respective groups such as CF -O- or CF -S-, may
3 3 3
be mentioned.
The above explanations with respect to alkyl groups apply correspondingly to alkyl
groups which in the definition of a group in the compounds of the formula I are
bonded to two adjacent groups, or linked to two groups, and may be regarded as
divalent alkyl groups (alkanediyl groups), like in the case of the alkyl part of a
substituted alkyl group. Thus, such groups can also be linear or branched, the bonds
to the adjacent groups can be located in any positions and can start from the same
carbon atom or from different carbon atoms, and they can be unsubstituted or
substituted by fluorine substituents independently of any other substituents.
Examples of such divalent alkyl groups are -CH -, -CH -CH -, -CH -CH -CH -,
2 2 2 2 2 2
-CH -CH -CH -CH -, -CH(CH )-, -C(CH ) -, -CH(CH )-CH -, -CH -CH(CH )-,
2 2 2 2 3 3 2 3 2 2 3
-C(CH ) -CH -, -CH -C(CH ) -. Examples of fluoro-substituted alkanediyl groups,
3 2 2 2 3 2
which can contain 1, 2, 3, 4, 5 or 6 fluorine substituents, for example, are -CHF-,
-CF -, -CF -CH -, -CH -CF -, -CF -CF -, -CF(CH )-, -C(CF ) -, -C(CH ) -CF -,
2 2 2 2 2 2 2 3 3 2 3 2 2
-CF -C(CH ) -.
2 3 2
The number of ring carbon atoms in a (C -C )-cycloalkyl group can be 3, 4, 5, 6 or 7.
Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl. The number of ring carbon atoms in a (C -C )-bicycloalkyl group can be
6 10
6, 7, 8, 9 or 10. The two cycles in a bicycloalkyl group can have one, two to more ring
carbon atoms in common and can be fused or form a bridged bicycle or a spirocycle.
Examples of bicycloalkyl are bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl,
bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl and
bicyclo[4,4.0]decyl. Bicycloalkyl groups can be bonded via any ring carbon atom.
Cycloalkyl and bicycloalkyl groups which, independently of any other substituents,
can be substituted by one or more (C -C )-alkyl substituents, can be unsubstituted by
alkyl substituents, i.e. not carry alkyl substituents, or substituted, for example by 1, 2,
3 or 4 identical or different (C -C )-alkyl substituents, for example by methyl groups,
which substituents can be located in any positions. Examples of such alkyl-
substituted cycloalkyl groups and bicycloalkyl groups are 1-methylcyclopropyl, 2,2-
dimethylcyclopropyl, 1-methylcyclopentyl, 2,3-dimethylcyclopentyl, 1-
methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl,
3,3,5,5-tetramethylcyclohexyl, 7,7-dimethylbicyclo[2.2.1]heptyl, 6,6-
dimethylbicyclo[3.1.1]heptyl and 1,7,7-trimethylbicyclo[2.2.1]heptyl. Cycloalkyl groups
and bicycloalkyl groups which, independently of any other substituents, can be
substituted by one or more fluorine substituents, can be unsubstituted by fluorine
substituents, i.e. not carry fluorine substituents, or substituted, for example by 1, 2, 3,
4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or by 1, 2, 3, 4, 5 or 6 fluorine
substituents, or by 1, 2 or 3 fluorine substituents. The fluorine substituents can be
located in any positions of the cycloalkyl group or bicycloalkyl groups and can also be
located in an alkyl substituent. Examples of fluoro-substituted cycloalkyl groups and
bicycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3-
difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl, 3,3,4,4,5,5-
hexafluorocyclohexyl, 1-fluorobicyclo[2.2.2]octyl and 1,4-difluorobicyclo[2.2.2]octyl.
Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl.
Examples of the group (C -C )-cycloalkyl-(C -C )-alkyl- are cyclopropylmethyl-,
3 7 1 4
cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1-
cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-
cyclopentylethyl-, 2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1-
cycloheptylethyl-, 2-cycloheptylethyl-. In one embodiment of the invention, a (C -C )-
cycloalkyl-(C -C )-alkyl- group in any one or more occurrences of such a group,
independently of any other occurrences, is a (C -C )-cycloalkyl-(C -C )-alkyl- group,
3 7 1 2
in another embodiment a (C -C )-cycloalkyl-CH - group. In the group (C -C )-
3 7 2 3 7
cycloalkyl-(C -C )-alkyl-, and likewise in all other groups, the terminal hyphen
denotes the free bond via which the group is bonded, and thus indicates via which
subgroup a group composed of subgroups is bonded.
In substituted phenyl groups, including phenyl groups representing Ar and R14, the
substituents can be located in any positions. In monosubstituted phenyl groups, the
substituent can be located in position 2, in position 3 or in position 4. In disubstituted
phenyl groups, the substituents can be located in positions 2 and 3, in positions 2
and 4, in positions 2 and 5, in positions 2 and 6, in positions 3 and 4, or in positions 3
and 5. In trisubstituted phenyl groups, the substituents can be located in positions 2,
3 and 4, in positions 2, 3 and 5, in positions 2, 3 and 6, in positions 2, 4 and 5, in
positions 2, 4 and 6, or in positions 3, 4 and 5. If a phenyl group carries four
substituents, some of which can be fluorine atoms, for example, the substituents can
be located in positions 2, 3, 4 and 5, in positions 2, 3, 4 and 6, or in positions 2, 3, 5
and 6. If a polysubstituted phenyl group or any other polysubstituted group carries
different substituents, each substituent can be located in any suitable position, and
the present invention comprises all positional isomers. The number of substituents in
a substituted phenyl group can be 1, 2, 3, 4 or 5. In one embodiment of the invention,
the number of substituents in a substituted phenyl group, like the number of
substituents in any other substituted group which can carry one or more substituents,
is 1, 2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in
another embodiment 1, where the number of substituents in any occurrence of such
a substituted group is independent of the number of substituents in other
occurrences.
In heterocyclic groups, including the groups Het1, Het2 and Het3, heterocycles
representing Ar and R14 and other heterocyclic rings which can be present in the
compounds of the formula I, such as rings formed by two group together with the
atom or atoms carrying them, the hetero ring members can be present in any
combination and located in any suitable ring positions, provided that the resulting
group and the compound of the formula I are suitable and sufficiently stable as a
pharmaceutical active compound. In one embodiment of the invention, two oxygen
atoms in any heterocyclic ring in the compounds of the formula I cannot be present in
adjacent ring positions. In another embodiment of the invention, two hetero ring
members selected from the series consisting of oxygen atoms and sulfur atoms
cannot be present in adjacent ring positions in any heterocyclic ring in the
compounds of the formula I. In another embodiment of the invention, two hetero ring
members selected from the series consisting of nitrogen atoms carrying an exocyclic
group like a hydrogen atom or a substituent, sulfur atoms and oxygen atoms cannot
be present in adjacent ring positions in any heterocyclic ring in the compounds of the
formula I. In an aromatic heterocyclic ring the choice of hetero ring members is
limited by the prerequisite that the ring is aromatic, i.e. it comprises a cyclic system of
six delocalized pi electrons. Monocyclic aromatic heterocycles are 5-membered or 6-
membered rings and, in the case of a 5-membered ring, comprise one ring
heteroatom selected from the series consisting of oxygen, sulfur and nitrogen,
wherein this ring nitrogen carries an exocyclic group like a hydrogen atom or a
substituent, and optionally one or more further ring nitrogen atoms, and, in the case
of a 6-membered ring, comprise one or more nitrogen atoms as ring heteroatoms,
but no oxygen atoms and sulfur atoms as ring heteroatoms. Unless specified
otherwise in the definition of the group, heterocyclic groups can be bonded via any
suitable ring atom, i.e. any ring atom which carries a hydrogen atom or a substituent,
including ring carbon atoms and ring nitrogen atoms. In one embodiment of the
invention, any of the heterocyclic groups occurring in the compounds of the formula I
in any of its occurrences, is independently of its other occurrences and independently
of any other heterocyclic group, bonded via a ring carbon atom, and in another
embodiment via a ring nitrogen atom, if applicable. In substituted heterocyclic groups,
the substituents can be located in any positions.
The number of ring heteroatoms which can be present in a heterocyclic group in the
compounds of the formula I, the number of cycles, i.e. whether the heterocyclic group
can be monocyclic and/or bicyclic, the number of ring members which can be present,
and the degree of saturation, i.e. whether the heterocyclic group is saturated and
does not contain a double bond within the ring, or whether it is partially unsaturated
and contains one or more, for example one or two, double bonds within the ring but is
not aromatic, or whether it is aromatic and thus contains two double bonds within the
ring in the case of a 5-membered monocyclic aromatic heterocycle, three double
bonds within the ring in the case of a 6-membered monocyclic aromatic heterocycle,
four double bonds within the ring in the case of 9-membered bicyclic aromatic
heterocycle, and five double bonds within the ring in the case of 10-membered
aromatic heterocycle, is specified in the definitions of the individual groups in the
compounds of the formula I. The two cycles in a bicyclic heterocyclic group can have
one, two or more ring atoms in common and can be fused or form a bridged bicycle
or a spirocycle. As examples of heterocyclic ring systems, from which heterocyclic
groups in the compounds of the formula I can be derived, and from any one or more
of which any of the heterocyclic groups in the compounds of the formula I is selected
in one embodiment of the invention, provided that the ring system is comprised by
the definition of the group, oxetane, thietane, azetidine, furan, tetrahydrofuran,
thiophene, tetrahydrothiophene, pyrrole, pyrroline, pyrrolidine, 1,3-dioxole, 1,3-
dioxolane, isoxazole ([1,2]oxazole), isoxazoline, isoxazolidine, oxazole ([1,3]oxazole),
oxazoline, oxazolidine, isothiazole ([1,2]thiazole), isothiazoline, isothiazolidine,
thiazole ([1,3]thiazole), thiazoline, thiazolidine, pyrazole, pyrazoline, pyrazolidine,
imidazole, imidazoline, imidazolidine, [1,2,3]triazole, [1,2,4]triazole, [1,2,4]oxadiazole,
[1,3,4]oxadiazole, 1,2,5-oxadiazole, [1,2,4]thiadiazole, 1H-tetrazole, pyran,
tetrahydropyran, thiopyran, tetrahydrothiopyran, 2,3-dihydro[1,4]dioxine, 1,4-dioxane,
pyridine, 1,2,5,6-tetrahydropyridine, piperidine, morpholine, thiomorpholine,
piperazine, pyridazine, pyrimidine, pyrazine, [1,2,4]triazine, oxepane, thiepane,
azepane, [1,3]diazepane, [1,4]diazepane, [1,4]oxazepane, [1,4]thiazepanel, azocane,
3-azabicyclo[3.1.0]hexane, octahydrocyclopenta[b]pyrrole,
octahydrocyclopenta[c]pyrrole, 2-azaspiro[4.4]nonane, 7-azabicyclo[2.2.1]heptane,
2,7-diazaspiro[4.4]nonane, octahydropyrrolo[3,4-b]pyrrole, 6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazole, imidazo[2,1-b]thiazole, 6,7-dihydro-5H-thiazolo[3,2-
a]pyrimidine, benzofuran, isobenzofuran, benzothiophene (benzo[b]thiophene), 1H-
indole, 2,3-dihydro-1H-indole, octahydroindole, 2H-isoindole, octahydroisoindole,
benzo[1,3]dioxole, benzoxazole, benzthiazole, 1H-benzimidazole, imidazo[1,2-
a]pyridine, [1,2,4]triazolo[4,3-a]pyridine, chroman, isochroman, thiochroman,
benzo[1,4]dioxane, 3,4-dihydro-2H-benzo[1,4]oxazine, 3,4-dihydro-2H-
benzo[1,4]thiazine, 2-azaspiro[4.5]decane, 3-azabicyclo[3.2.2]nonane, quinoline,
1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, isoquinoline, 1,2,3,4,-
tetrahydroisoquinoline, 5,6,7,8-tetrahydroisoquinoline, 2,7-diazaspiro[4.5]decane,
2,8-diazaspiro[4.5]decane, cinnoline, quinazoline, quinoxaline, phthalazine and
[1,8]naphthyridine may be mentioned, which can all be unsubstituted or substituted in
any suitable positions as specified in the definition of the respective group in the
compounds of the formula I, wherein the given degree of unsaturation is by way of
example only, and in the individual groups also ring systems with a higher or lower
degree of saturation, or hydrogenation, or of unsaturation can be present as specified
in the definition of the group.
As mentioned, the heterocyclic groups can be bonded via any suitable ring atom. For
example, among others can an oxetane and a thietane ring be bonded via positions 2
and 3, an azetidine ring via positions 1, 2 and 3, a furan ring, a tetrahydrofuran ring, a
thiophene ring and a tetrahydrothiophene via positions 2 and 3, a pyrrole ring and a
pyrrolidine ring via positions 1, 2 and 3, an isoxazole ring and an isothiazole ring via
positions 3, 4 and 5, a pyrazole ring via positions 1, 3, 4 and 5, an oxazole ring and a
thiazole ring via positions 2, 4 and 5, an imidazole ring and an imidazolidine ring via
positions 1, 2, 4 and 5, a 1H-tetrazole ring via positions 1 and 3, a tetrahydropyran
and a tetrahydrothiopyran ring via positions 2, 3 and 4, a 1,4-dioxane ring via position
2, a pyridine ring via positions 2, 3 and 4, a piperidine ring via positions 1, 2, 3 and 4,
a morpholine ring and a thiomorpholine ring via positions 2, 3 and 4, a piperazine ring
via positions 1 and 2, a pyrimidine ring via positions 2, 4 and 5, a pyrazine ring via
position 2, an azepane ring via positions 1, 2, 3 and 4, a 3-azabicyclo[3.1.0]hexane
ring via positions 3 and 6, an octahydrocyclopenta[b]pyrrole and an
octahydrocyclopenta[c]pyrrole ring via position 1, a 2-azaspiro[4.4]nonane ring via
position 2, a 7-azabicyclo[2.2.1]heptane ring via position 7, an octahydropyrrolo[3,4-
b]pyrrole ring via positions 1 and 5, a 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole ring
via position 3, an imidazo[2,1-b]thiazole ring via positions 2, 5 and 6, a 6,7-dihydro-
5H-thiazolo[3,2-a]pyrimidine via position 3, a benzofuran ring and a benzothiophene
ring via positions 2, 3, 4, 5, 6 and 7, a 1H-indole ring, a 2,3-dihydro-1H-indole and an
octahydroindole ring via positions 1, 2, 3, 4, 5, 6 and 7, a benzo[1,3]dioxole ring via
positions 4, 5, 6 and 7, a benzoxazole ring and a benzthiazole ring via positions 2, 4,
, 6 and 7, a 1H-benzimidazole ring via positions 1, 2, 4, 5, 6 and 7, an imidazo[1,2-
a]pyridine ring via positions 2 and 3, a [1,2,4]triazolo[4,3-a]pyridine ring via position 3,
a benzo[1,4]dioxane ring via positions 5, 6, 7 and 8, a 3-azabicyclo[3.2.2]nonane ring
via position 3, a quinoline ring via positions 2, 3, 4, 5, 6, 7 and 8, a 1,2,3,4-
tetrahydroquinoline ring via positions 1, 5, 6, 7 and 8, a 5,6,7,8-tetrahydroquinoline
via positions 2, 3 and 4, an isoquinoline ring via positions 1, 3, 4, 5, 6, 7 and 8, a
1,2,3,4-tetrahydroisoquinoline ring via positions 2, 5, 6, 7 and 8, a 5,6,7,8-
tetrahydroisoquinoline ring via positions 1, 3, 4 and 5, a 2,7-diazaspiro[4.5]decane
ring via positions 2 and 7, a 2,8-diazaspiro[4.5]decane ring via positions 2 and 8, for
example, wherein the resulting residues of the heterocyclic groups can all be
unsubstituted or substituted in any suitable positions as specified in the definition of
the respective group in the compounds of the formula I.
Halogen is fluorine, chlorine, bromine or iodine. In one embodiment of the invention,
in any of its occurrences halogen is fluorine, chlorine or bromine, in another
embodiment fluorine or chlorine, in another embodiment fluorine, in another
embodiment chlorine, where all occurrences of halogen are independent of each
other.
An oxo group, i.e. a doubly bonded oxygen atom, when bonded to a carbon atom,
replaces two hydrogen atoms on a carbon atom of the parent system. Thus, if a CH
group is substituted by oxo, it becomes a carbonyl group (C(O), C=O). Oxo groups
can also occur on sulfur atoms, such as on ring sulfur atoms in saturated and
partially unsaturated heterocycles in which generally, besides a ring sulfur atom, also
an S(O) group (S(=O)) and an S(O) group (S(=O) ) can be present as hetero ring
members. An oxo group cannot occur as a substituent on a carbon atom in an
aromatic ring such as in a phenyl group.
The present invention comprises all stereoisomeric forms of the compounds of the
formula I, for example all enantiomers and diastereomers including cis/trans isomers.
The invention likewise comprises mixtures of two or more stereoisomeric forms, for
example mixtures of enantiomers and/or diastereomers including cis/trans isomers,
in all ratios. Asymmetric centers contained in the compounds of the formula I, for
example the carbon atom in position 2 of the chroman ring system or in unsubstituted
or substituted alkyl groups, can all independently of each other have S configuration
or R configuration. The invention relates to enantiomers, both the levorotatory and
the dextrorotatory antipode, in enantiomerically pure form and essentially
enantiomerically pure form, for example with a molar ratio of the two enantiomers of
98:2, or 99:1, or greater, and in the form of their racemate, i.e. a mixture of the two
enantiomers in molar ratio of 1:1, and in the form of mixtures of the two enantiomers
in all ratios. The invention likewise relates to diastereomers in the form of pure and
essentially pure diastereomers and in the form of mixtures of two or more
diastereomers in all ratios. The invention also comprises all cis/trans isomers of the
compounds of the formula I in pure form and essentially pure form, for example with
a molar ratio of the cis/trans isomers of 98:2, or 99:1, or greater, and in the form of
mixtures of the cis isomer and the trans isomer in all ratios. Cis/trans isomerism can
occur in substituted rings. The preparation of individual stereoisomers, if desired, can
be carried out by resolution of a mixture according to customary methods, for
example, by chromatography or crystallization, or by use of stereochemically uniform
starting compounds in the synthesis, or by stereoselective reactions. Optionally,
before a separation of stereoisomers a derivatization can be carried out. The
separation of a mixture of stereoisomers can be carried out at the stage of the
compound of the formula I or at the stage of an intermediate in the course of the
synthesis. For example, in the case of a compound of the formula I containing an
asymmetric center the individual enantiomers can be prepared by preparing the
racemate of the compound of the formula I and resolving it into the enantiomers by
high pressure liquid chromatography on a chiral phase according to standard
procedures, or resolving the racemate of any intermediate in the course of its
synthesis by such chromatography or by crystallization of a salt thereof with an
optically active amine or acid and converting the enantiomers of the intermediate into
the enantiomeric forms of the final compound of the formula I, or by performing an
enantioselective reaction in the course of the synthesis. The invention also comprises
all tautomeric forms of the compounds of the formula I.
If the compounds of the formula I comprise one or more acidic or basic groups, for
example basic heterocyclic groups, the corresponding physiologically or
toxicologically acceptable salts are also included in the invention, especially the
pharmaceutically acceptable salts. The compounds of the formula I may thus be
deprotonated on an acidic group and be used for example as alkali metal salts, for
example sodium or potassium salts, or as ammonium salts, for example as salts with
ammonia or organic amines or amino acids. Compounds of the formula I comprising
at least one basic group may also be prepared and used in the form of their acid
addition salts, for example in the form of pharmaceutically acceptable salts with
inorganic acids and organic acids, such as salts with hydrochloric acid and thus be
present in the form of the hydrochlorides, for example. Salts can in general be
prepared from acidic and basic compounds of the formula I by reaction with an acid
or base in a solvent or diluent according to customary procedures. If the compounds
of the formula I simultaneously contain an acidic and a basic group in the molecule,
the invention also includes internal salts (betaines, zwitterions) in addition to the salt
forms mentioned. The present invention also comprises all salts of the compounds of
the formula I which, because of low physiological tolerability, are not directly suitable
for use as a pharmaceutical, but are suitable as intermediates for chemical reactions
or for the preparation of physiologically acceptable salts, for example by means of
anion exchange or cation exchange.
In one embodiment of the invention, an aromatic heterocycle representing the group
Ar comprises 1 or 2 identical or different ring heteroatoms which are selected from
the series consisting of nitrogen and sulfur. In another embodiment, an aromatic
heterocycle representing Ar is a 5-membered heterocycle which comprises 1 or 2
identical or different ring heteroatoms which are selected from the series consisting
of nitrogen and sulfur, in another embodiment 1 ring heteroatom which is a sulfur
atom, or it is a 6-membered heterocycle which comprises 1 or 2 ring heteroatoms
which are nitrogen atoms. In another embodiment, an aromatic heterocycle
representing Ar is selected from the series consisting of thiophene, thiazole, pyridine,
pyridazine, pyrimidine and pyrazine, in another embodiment from the series
consisting of thiophene, pyridine, pyridazine, pyrimidine and pyrazine, in another
embodiment from the series consisting of thiophene, pyridine, pyrimidine and
pyrazine, in another embodiment from the series consisting of thiophene, pyridine
and pyrazine, in another embodiment from the series consisting of pyridine and
pyrazine, in another embodiment from the series consisting of thiophene and pyridine,
in another embodiment it is thiophene, and in another embodiment is pyridine, which
heterocycles are all unsubstituted or substituted as indicated. In one embodiment of
the invention, Ar is phenyl which is unsubstituted or substituted by one or more
identical or different substituents R1, in another embodiment Ar is a 5-membered or
6-membered aromatic heterocycle which is unsubstituted or substituted by one or
more identical or different substituents R1. In one embodiment of the invention, the
number of substituents R1 which can be present in the group Ar is 1, 2 or 3, in
another embodiment it is 1 or 2, in another embodiment it is 1.
The double bond which is present in the mono-unsaturated ring which can be formed
by two substituents R1 bonded to adjacent ring carbon atoms in Ar together with the
carbon atoms carrying them, is present between the said two adjacent ring carbon in
the aromatic ring Ar which are common to the ring Ar and the ring formed by the two
groups R1, and because of the rules of nomenclature for fused rings is regarded as a
double bond present in both rings. The case that two groups R1 bonded to adjacent
carbon atoms in Ar together with the carbon atoms carrying them form a 5-
membered to 7-membered mono-unsaturated ring, which is a monocyclic ring, can in
other terms be regarded as two groups R1 together forming a divalent residue
comprising a chain of 3 to 5 atoms of which 0, 1 or 2 are identical or different
heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, the
terminal atoms of which, which are bonded to the two adjacent ring carbon atoms in
Ar, are separated from each other by 1 to 3 atoms. Examples of such divalent
residues, from any one or more of which two groups R1 bonded to adjacent ring
carbon atoms in Ar are selected in one embodiment of the invention, are the residues
-CH -CH -CH -, -CH -CH -CH -CH -,
2 2 2 2 2 2 2
-CH -CH -CH -CH -CH -, -O-CH -CH -,-CH -CH -O-, -O-CH -O-, -O-CH -CH -O-,
2 2 2 2 2 2 2 2 2 2 2 2
-O-CH -CH -CH -O-, -NH-CH -CH -O-, -O-CH -CH -NH-, -S-CH -CH -NH- and -NH-
2 2 2 2 2 2 2 2 2
CH -CH -S-, which can all be substituted on carbon atoms and nitrogen atoms by
substituents selected from the series consisting of fluorine and (C -C )-alkyl, for
example fluorine and methyl, and can thus also be present, for example, as the
divalent residues -O-CF -O-, -O-C(CH ) -O-, -N(CH )-CH -CH -O-, -O-CH -CH -
2 3 2 3 2 2 2 2
N(CH )-, -S-CH -CH -N(CH )- and -N(CH )-CH -CH -S-. In one embodiment of the
3 2 2 3 3 2 2
invention, the ring which can be formed by two groups R1 bonded to adjacent ring
carbon atoms in Ar together with the carbon atoms carrying them, is a 5-membered
or 6-membered, in another embodiment a 5-membered, in another embodiment a 6-
membered ring. In one embodiment of the invention, the number of substituents
selected from the series consisting of fluorine and (C -C )-alkyl, which can be present
in a ring formed by two groups R1 bonded to adjacent ring carbon atoms in Ar
together with the carbon atoms carrying them, is 1, 2 or 3, in another embodiment 1
or 2, in another embodiment 1. In one embodiment of the invention, substituents
which can be present in a ring formed by two groups R1 bonded to adjacent ring
carbon atoms in Ar together with the carbon atoms carrying them, are fluorine
substituents, and in another embodiment they are (C -C )-alkyl substituents, for
example methyl substituents, and in another embodiment are substituents in such a
ring bonded to a ring nitrogen atom selected from the series consisting of (C -C )-
alkyl.
In one embodiment of the invention, R1 is selected from the series consisting of
halogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, HO-, (C -
1 6 3 7 3 7 1 4 1
C )-alkyl-O-, (C -C )-cycloalkyl-O- and (C -C )-cycloalkyl-(C -C )-alkyl-O-, in another
6 3 7 3 7 1 4
embodiment from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-
1 6 1 6
alkyl-O-, in another embodiment from the series consisting of halogen, (C -C )-alkyl
and (C -C )-alkyl-O-, in another embodiment from the series consisting of halogen
and (C -C )-alkyl, in another embodiment from the series consisting of halogen, in
another embodiment from the series consisting of (C -C )-alkyl, in another
embodiment from the series consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl,
1 6 3 7
(C -C )-cycloalkyl-(C -C )-alkyl-, HO-, (C -C )-alkyl-O-, (C -C )-cycloalkyl-O-, (C -C )-
3 7 1 4 1 6 3 7 3 7
cycloalkyl-(C -C )-alkyl-O- and (C -C )-alkyl-S(O) -, in another embodiment from the
1 4 1 6 n
series consisting of halogen, (C -C )-alkyl, HO-, (C -C )-alkyl-O- and (C -C )-alkyl-
1 6 1 6 1 6
S(O) -, in another embodiment from the series consisting of halogen, (C -C )-alkyl,
n 1 6
(C -C )-alkyl-O- and (C -C )-alkyl-S(O) -, and in all these embodiment two groups R1
1 6 1 6 n
bonded to adjacent carbon atoms in Ar, together with the carbon atoms carrying
them, can form a 5-membered to 7-membered mono-unsaturated ring which
comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series
consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted
by one or more identical or different substituents selected from the series consisting
of fluorine and (C -C )-alkyl. In another embodiment, R1 is selected from the series
consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-
1 6 3 7 3 7 1 4
alkyl-, phenyl, Het1, HO-, (C -C )-alkyl-O-, (C -C )-cycloalkyl-O-, (C -C )-cycloalkyl-
1 6 3 7 3 7
(C -C )-alkyl-O-, phenyl-O-, Het1-O- and (C -C )-alkyl-S(O) -, in another embodiment
1 4 1 6 n
from the series consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-
1 6 3 7 3 7
cycloalkyl-(C -C )-alkyl-, HO-, (C -C )-alkyl-O-, (C -C )-cycloalkyl-O- and (C -C )-
1 4 1 6 3 7 3 7
cycloalkyl-(C -C )-alkyl-O-, in another embodiment from the series consisting of
halogen, (C -C )-alkyl, HO- and (C -C )-alkyl-O-, in another embodiment from the
1 6 1 6
series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O-, in another
1 6 1 6
embodiment from the series consisting of halogen and (C -C )-alkyl, in another
embodiment from the series consisting of halogen, in another embodiment from the
series consisting of (C -C )-alkyl, in another embodiment from the series consisting
of halogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, HO-,
1 6 3 7 3 7 1 4
(C -C )-alkyl-O-, (C -C )-cycloalkyl-O-, (C -C )-cycloalkyl-(C -C )-alkyl-O- and (C -
1 6 3 7 3 7 1 4 1
C )-alkyl-S(O) -, in another embodiment from the series consisting of halogen, (C -
6 n 1
C )-alkyl, HO-, (C -C )-alkyl-O- and (C -C )-alkyl-S(O) -, in another embodiment from
6 1 6 1 6 n
the series consisting of halogen, (C -C )-alkyl, (C -C )-alkyl-O- and (C -C )-alkyl-
1 6 1 6 1 6
S(O) -. In one embodiment, substituents R1 which are bonded to a ring nitrogen
atom in Ar, such as in the case of a pyrrole, pyrazole or imidazole ring representing
Ar, are selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl, (C -
1 6 3 7 3
C )-cycloalkyl-(C -C )-alkyl-, phenyl and Het1, in another embodiment from the series
7 1 4
consisting of (C -C )-alkyl.
In one embodiment of the invention, a (C -C )-alkyl group which represents R1 or is
present in the groups (C -C )-alkyl-O- and (C -C )-alkyl-S(O) - representing R1, is a
1 6 1 6 n
(C -C )-alkyl group, in another embodiment a (C -C )-alkyl group, in another
1 4 1 3
embodiment a (C -C )-alkyl group, in another embodiment a methyl group. In one
embodiment of the invention, a (C -C )-cycloalkyl group which represents R1 or is
present in R1, is a (C -C )-cycloalkyl group, in another embodiment a (C -C )-
3 6 3 4
cycloalkyl group, in another embodiment a cyclopropyl group.
Examples of groups Ar including the optional substituents R1, from any one or more
of which Ar is selected in one embodiment of the invention, are phenyl, i.e.
unsubstituted phenyl, thiophenyl, thiophenyl, pyridinyl, pyridinyl, pyridin
yl, pyrazinyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-
chloro-phenyl, 4-chloro-phenyl, 2-methyl-phenyl (o-tolyl), 3-methyl-phenyl (m-tolyl), 4-
methyl-phenyl (p-tolyl), 2-ethyl-phenyl, 3-ethyl-phenyl, 4-ethyl-phenyl, 2-methoxy-
phenyl, 3-methoxy-phenyl, 4-methoxy-phenyl, 2-ethoxy-phenyl, 3-ethoxy-phenyl, 4-
ethoxy-phenyl, 2-propoxy-phenyl, 3-propoxy-phenyl, 4-propoxy-phenyl, 2-isopropoxy-
phenyl, 3-isopropoxy-phenyl, 4-isopropoxy-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-
phenyl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-
phenyl, 2,3-dichloro-phenyl, 2,4-dichloro-phenyl, 2,5-dichloro-phenyl, 2,6-dichloro-
phenyl, 3,4-dichloro-phenyl, 3,5-dichloro-phenyl, 2-chlorofluoro-phenyl, 2-chloro
fluoro-phenyl, 2-chlorofluoro-phenyl, 2-chlorofluoro-phenyl, 3-chlorofluoro-
phenyl, 3-chlorofluoro-phenyl, 3-chlorofluoro-phenyl, 4-chlorofluoro-phenyl,
4-chlorofluoro-phenyl, 5-chlorofluoro-phenyl, 2,3-dimethyl-phenyl, 2,4-dimethyl-
phenyl, 2,5-dimethyl-phenyl, 2,6-dimethyl-phenyl, 3,4-dimethyl-phenyl, 3,5-dimethyl-
phenyl, 2-fluoromethyl-phenyl, 2-fluoromethyl-phenyl, 2-fluoromethyl-phenyl,
2-fluoromethyl-phenyl, 3-fluoromethyl-phenyl, 3-fluoromethyl-phenyl, 3-
fluoromethyl-phenyl, 4-fluoromethyl-phenyl, 4-fluoromethyl-phenyl, 5-fluoro-
2-methyl-phenyl, 2-chloromethyl-phenyl, 2-chloromethyl-phenyl, 2-chloro
methyl-phenyl, 2-chloromethyl-phenyl, 3-chloromethyl-phenyl, 3-chloro
methyl-phenyl, 3-chloromethyl-phenyl, 4-chloromethyl-phenyl, 4-chloro
methyl-phenyl, 5-chloromethyl-phenyl, 2-fluoromethoxy-phenyl, 2-fluoro
methoxy-phenyl, 2-fluoromethoxy-phenyl, 2-fluoromethoxy-phenyl, 3-fluoro
methoxy-phenyl, 3-fluoromethoxy-phenyl, 3-fluoromethoxy-phenyl, 4-fluoro
methoxy-phenyl, 4-fluoromethoxy-phenyl, 5-fluoromethoxy-phenyl, 2-methoxy-
3-methyl-phenyl, 2-methoxymethyl-phenyl, 2-methoxymethyl-phenyl, 2-
methoxymethyl-phenyl, 3-methoxymethyl-phenyl, 3-methoxymethyl-phenyl,
3-methoxymethyl-phenyl, 4-methoxymethyl-phenyl, 4-methoxymethyl-phenyl,
5-methoxymethyl-phenyl, 3-fluoro-thiophenyl, 4-fluoro-thiophenyl, 5-fluoro-
thiophenyl, 2-fluoro-thiophenyl, 4-fluoro-thiophenyl, 5-fluoro-thiophenyl, 3-
chloro-thiophenyl, 4-chloro-thiophenyl, 5-chloro-thiophenyl, 2-chloro-
thiophenyl, 4-chloro-thiophenyl, 5-chloro-thiophenyl, 3-methyl-thiophenyl,
4-methyl-thiophenyl, 5-methyl-thiophenyl, 2-methyl-thiophenyl, 4-methyl-
thiophenyl, 5-methyl-thiophenyl, 3-fluoro-pyridinyl, 4-fluoro-pyridinyl, 5-
fluoro-pyridinyl, 6-fluoro-pyridinyl, 2-fluoro-pyridinyl, 4-fluoro-pyridinyl, 5-
fluoro-pyridinyl, 6-fluoro-pyridinyl, 2-fluoro-pyridinyl, 3-fluoro-pyridinyl, 3-
chloro-pyridinyl, 4-chloro-pyridinyl, 5-chloro-pyridinyl, 6-chloro-pyridinyl, 2-
chloro-pyridinyl, 4-chloro-pyridinyl, 5-chloro-pyridinyl, 6-chloro-pyridinyl, 2-
chloro-pyridinyl, 3-chloro-pyridinyl, 3-methyl-pyridinyl, 4-methyl-pyridinyl,
-methyl-pyridinyl, 6-methyl-pyridinyl, 2-methyl-pyridinyl, 4-methyl-pyridin
yl, 5-methyl-pyridinyl, 6-methyl-pyridinyl, 2-methyl-pyridinyl, 3-methyl-pyridin-
4-yl, 3-methoxy-pyridinyl, 4-methoxy-pyridinyl, 5-methoxy-pyridinyl, 6-
methoxy-pyridinyl, 2-methoxy-pyridinyl, 4-methoxy-pyridinyl, 5-methoxy-
pyridinyl, 6-methoxy-pyridinyl, 2-methoxy-pyridinyl, 3-methoxy-pyridinyl.
In one embodiment of the invention, the group R2 is selected from the series
consisting of R5-N(R6)-C(O)- and R5-N(R6)-CH -, and in another embodiment from
the series consisting of R7-C(O)-NH-CH - and R7-S(O) -NH-CH -. In another
2 2 2
embodiment of the invention, the group R2 is the group R5-N(R6)-C(O)-, and
respective compounds are designated as compounds of the formula Ia. In another
embodiment of the invention, the group R2 is the group R5-N(R6)-CH -, and
respective compounds are designated as compounds of the formula Ib. In another
embodiment of the invention, the group R2 is the group R7-C(O)-NH-CH -, and
respective compounds are designated as compounds of the formula Ic. In another
embodiment of the invention, the group R2 is the group R7-S(O) -NH-CH -, and
respective compounds are designated as compounds of the formula Id.
C(O)-N(R6)-R(5)
R3 Ia
Ar O
CH -N(R6)-R(5)
CH -NH-C(O)-R7
R3 Ic
Ar O
CH -NH-S(O) -R7
R3 Id
Ar O
The groups Ar, R3, R4, R5, R6 and R7 in the compounds of the formulae Ia, Ib, Ic
and Id are defined as in the compounds of the formula I.
In one embodiment of the invention, the group R2 is bonded in ring position 5 of the
thiazole ring system and the group R3 is bonded in position 4 of the thiazole ring
system, and respective compounds are designated as compounds of the formula Ie.
In another embodiment of the invention, the group R3 is bonded in ring position 5 of
the thiazole ring system and the group R2 is bonded in position 4 of the thiazole ring
system, and respective compounds are designated as compounds of the formula If.
Ar O
The groups Ar, R2, R3 and R4 in the compounds of the formulae Ie and If are
defined as in the compounds of the formula I.
In one embodiment of the invention, the group R2 is bonded in ring position 5 of the
thiazole ring system and the group R3 is bonded in position 4 of the thiazole ring
system, and the group R2 is selected from the series consisting of
R5-N(R6)-C(O)- and R5-N(R6)-CH -, and in another embodiment from the series
consisting of R7-C(O)-NH-CH - and R7-S(O) -NH-CH -. In another embodiment of
2 2 2
the invention, the group R2 is bonded in ring position 4 of the thiazole ring system
and the group R3 is bonded in position 5 of the thiazole ring system, and the group
R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)-CH -, and
in another embodiment from the series consisting of R7-C(O)-NH-CH - and R7-
S(O) -NH-CH -. In another embodiment of the invention, the group R2 is bonded in
ring position 5 of the thiazole ring system and is the group R5-N(R6)-C(O)-, and the
group R3 is bonded in ring position 4 of the thiazole ring system, and respective
compounds are designated as compounds of the formula Ig. In another embodiment
of the invention, the group R2 is bonded in ring position 5 of the thiazole ring system
and is the group R5-N(R6)-CH -, and the group R3 is bonded in ring position 4 of the
thiazole ring system, and respective compounds are designated as compounds of
the formula Ih. In another embodiment of the invention, the group R2 is bonded in
ring position 5 of the thiazole ring system and is the group R7-C(O)-NH-CH -, and the
group R3 is bonded in ring position 4 of the thiazole ring system, and respective
compounds are designated as compounds of the formula Ij. In another embodiment
of the invention, the group R2 is bonded in ring position 5 of the thiazole ring system
and is the group R7-S(O) -NH-CH -, and the group R3 is bonded in ring position 4 of
the thiazole ring system, and respective compounds are designated as compounds
of the formula Ik. In another embodiment of the invention, the group R2 is bonded in
ring position 4 of the thiazole ring system and is the group R5-N(R6)-C(O)-, and the
group R3 is bonded in ring position 5 of the thiazole ring system, and respective
compounds are designated as compounds of the formula Im. In another embodiment
of the invention, the group R2 is bonded in ring position 4 of the thiazole ring system
and is the group R5-N(R6)-CH -, and the group R3 is bonded in ring position 5 of the
thiazole ring system, and respective compounds are designated as compounds of
the formula In. In another embodiment of the invention, the group R2 is bonded in
ring position 4 of the thiazole ring system and is the group R7-C(O)-NH-CH -, and the
group R3 is bonded in ring position 5 of the thiazole ring system, and respective
compounds are designated as compounds of the formula Io. In another embodiment
of the invention, the group R2 is bonded in ring position 4 of the thiazole ring system
and is the group R7-S(O) -NH-CH -, and the group R3 is bonded in ring position 5 of
the thiazole ring system, and respective compounds are designated as compounds
of the formula Ip.
C(O)-N(R6)-R(5)
Ar O
CH -N(R6)-R(5)
Ar O
CH -NH-C(O)-R7
Ar O
CH -NH-S(O) -R7
Ar O
C(O)-N(R6)-R(5)
Ar O
CH -N(R6)-R(5)
Ar O
CH -NH-C(O)-R7
Ar O
CH -NH-S(O) -R7
The groups Ar, R3, R4, R5, R6 and R7 in the compounds of the formulae Ig, Ih, Ij, Ik,
Im, In, Io and Ip are defined as in the compounds of the formula I.
In one embodiment of the invention, the group R3 is selected from the series
consisting of hydrogen, halogen and (C -C )-alkyl, in another embodiment from the
series consisting of hydrogen and halogen, in another embodiment from the series
consisting of hydrogen, fluorine and chlorine, in another embodiment from the series
consisting of hydrogen and (C -C )-alkyl, and in another embodiment R3 is hydrogen.
In one embodiment of the invention, a (C -C )-alkyl group representing R3 or present
in R3 is (C -C )-alkyl, in another embodiment it is methyl, wherein alkyl groups
including methyl groups can also be substituted by one or more fluorine substituents
and, for example, trifluoromethyl groups be present, as applies to alkyl groups in
general.
As indicated above, in the free binding sites of the chroman ring, i.e. binding sites in
positions 2, 3, 4, 5, 7 and 8 of the chroman ring system which are not occupied by
bonds within the ring or the bond to the group Ar, hydrogen atoms or substituents
selected from the series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O- can
1 4 1 4
be present which represent groups R4. In one embodiment of the invention, in the
free binding site in position 2 of the chroman ring system, i.e. the free binding site of
the ring carbon atom which carries the group Ar, a hydrogen atom is present, and in
the free binding sites in positions 3, 4, 5, 7 and 8 of the chroman ring system
hydrogen atoms or substituents selected from the series consisting of halogen, (C -
C )-alkyl and (C -C )-alkyl-O- are present. In another embodiment of the invention, in
4 1 4
the free binding sites in positions 2, 3 and 4 of the chroman ring system hydrogen
atoms are present, and in the free binding sites in positions 5, 7 and 8 of the
chroman ring system hydrogen atoms or substituents selected from the series
consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O- are present. In another
1 4 1 4
embodiment of the invention, in the free binding sites in positions 2 and 5 of the
chroman ring system hydrogen atoms are present, and in the free binding sites in
positions 3, 4, 7 and 8 of the chroman ring system hydrogen atoms or substituents
selected from the series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O- are
1 4 1 4
present. In another embodiment of the invention, in the free binding sites in positions
2, 5, 7 and 8 of the chroman ring system hydrogen atoms are present, and in the free
binding sites in positions 3 and 4 of the chroman ring system hydrogen atoms or
substituents selected from the series consisting of halogen, (C -C )-alkyl and (C -C )-
1 4 1 4
alkyl-O- are present. In one embodiment, the number of groups R4 which are
different from hydrogen, i.e. the number of substituents R4 which are selected from
halogen, (C -C )-alkyl and (C -C )-alkyl-O-, is 3, in another embodiment it is 2, in
1 4 1 4
another embodiment it is 1, and in another embodiment it is 0, and in the latter
embodiment thus no groups R4 which are different from hydrogen are present in the
chroman ring system, and hydrogen atoms are present in all its free binding sites. In
one embodiment, R4 is hydrogen or one or more identical or different substituents
selected from the series consisting of halogen and (C -C )-alkyl, in another
embodiment R4 is hydrogen or one or more identical or different substituents
selected from the series consisting of fluorine, chlorine and (C -C )-alkyl. In one
embodiment, R4 in the free binding sites in positions 2, 3 and 4 of the chroman ring
system is hydrogen or one or more identical or different substituents selected from
the series consisting of fluorine and (C -C )-alkyl, in another embodiment R4 in the
free binding sites in positions 2, 3 and 4 of the chroman ring system is hydrogen or
one or more identical or different substituents selected from the series consisting of
(C -C )-alkyl, and R4 in the free binding sites in positions 5, 7 and 8 of the chroman
ring system is hydrogen or one or more identical or different substituents selected
from the series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O-, in another
1 4 1 4
embodiment R4 in the free binding sites in positions 5, 7 and 8 of the chroman ring
system is hydrogen or one or more identical or different substituents selected from
the series consisting of halogen and (C -C )-alkyl, in another embodiment R4 in the
free binding sites in positions 5, 7 and 8 of the chroman ring system is hydrogen or
one or more identical or different substituents selected from the series consisting of
halogen. In one embodiment of the invention, a (C -C )-alkyl group representing R4
or present in R4 is (C -C )-alkyl, in another embodiment it is methyl.
In one embodiment of the invention, R5 and R6 are independently of one another
selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -
1 6 3 7 6
C )-bicycloalkyl and Het2, in another embodiment from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-bicycloalkyl, in another
1 6 3 7 6 10
embodiment from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl
1 6 3 7
and Het2, in another embodiment from the series consisting of hydrogen, (C -C )-
alkyl and (C -C )-cycloalkyl, in another embodiment from the series consisting of
hydrogen and (C -C )-alkyl, wherein in all these embodiment (C -C )-alkyl is
1 6 1 6
unsubstituted or substituted by one or more identical or different substituents R10,
and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all are unsubstituted or
3 7 6 10
substituted by one or more identical or different substituents R11, or the groups R5
and R6, together with the nitrogen atom carrying them, form a 4-membered to 10-
membered, monocyclic or bicyclic, saturated or partially unsaturated heterocycle
which, in addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further
ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur,
and which is unsubstituted or substituted by one ore more identical or different
substituents R12. In another embodiment of the invention, R5 and R6 are
independently of one another selected from the series consisting of hydrogen, (C -
C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2, in another embodiment
6 3 7 6 10
from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-
1 6 3 7 6 10
bicycloalkyl, in another embodiment from the series consisting of hydrogen, (C -C )-
alkyl, (C -C )-cycloalkyl and Het2, in another embodiment from the series consisting
of hydrogen, (C -C )-alkyl and (C -C )-cycloalkyl, in another embodiment from the
1 6 3 7
series consisting of hydrogen and (C -C )-alkyl, wherein in all these embodiment (C -
1 6 1
C )-alkyl is unsubstituted or substituted by one or more identical or different
substituents R10, and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all are
3 7 6 10
unsubstituted or substituted by one or more identical or different substituents R11.
In one embodiment of the invention, one of the groups R5 and R6 is selected from
the series consisting of hydrogen and (C -C )-alkyl, in another embodiment from the
series consisting of hydrogen and (C -C )-alkyl, in another embodiment from the
series consisting of hydrogen and methyl, and in another embodiment is hydrogen,
and the other of the groups R5 and R6 is selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2, in another
1 6 3 7 6 10
embodiment from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl
1 6 3 7
and (C -C )-bicycloalkyl, in another embodiment from the series consisting of
6 10
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and Het2, in another embodiment from the
1 6 3 7
series consisting of hydrogen, (C -C )-alkyl and (C -C )-cycloalkyl, in another
1 6 3 7
embodiment from the series consisting of hydrogen and (C -C )-alkyl, wherein in all
these embodiment (C -C )-alkyl, (C -C )-alkyl and methyl representing R5 or R6 is
1 6 1 4
unsubstituted or substituted by one or more identical or different substituents R10,
and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all are unsubstituted or
3 7 6 10
substituted by one or more identical or different substituents R11, or the groups R5
and R6, together with the nitrogen atom carrying them, form a 4-membered to 10-
membered, monocyclic or bicyclic, saturated or partially unsaturated heterocycle
which, in addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further
ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur,
and which is unsubstituted or substituted by one ore more identical or different
substituents R12. In another embodiment of the invention, one of the groups R5 and
R6 is selected from the series consisting of hydrogen and (C -C )-alkyl, in another
embodiment from the series consisting of hydrogen and (C -C )-alkyl, in another
embodiment from the series consisting of hydrogen and methyl, and in another
embodiment is hydrogen, and the other of the groups R5 and R6 is selected from the
series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl
1 6 3 7 6 10
and Het2, in another embodiment from the series consisting of hydrogen, (C -C )-
alkyl, (C -C )-cycloalkyl and (C -C )-bicycloalkyl, in another embodiment from the
3 7 6 10
series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and Het2, in another
1 6 3 7
embodiment from the series consisting of hydrogen, (C -C )-alkyl and (C -C )-
1 6 3 7
cycloalkyl, in another embodiment from the series consisting of hydrogen and (C -
C )-alkyl, wherein in all these embodiment (C -C )-alkyl, (C -C )-alkyl and methyl
6 1 6 1 4
representing R5 or R6 is unsubstituted or substituted by one or more identical or
different substituents R10, and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all
3 7 6 10
are unsubstituted or substituted by one or more identical or different substituents R11.
In one embodiment of the invention, one of the groups R5 and R6 is selected from
the series consisting of hydrogen and (C -C )-alkyl, in another embodiment from the
series consisting of hydrogen and (C -C )-alkyl, in another embodiment from the
series consisting of hydrogen and methyl, and in another embodiment is hydrogen,
and the other of the groups R5 and R6 is selected from the series consisting of (C -
C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2, in another embodiment
6 3 7 6 10
from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-bicycloalkyl,
1 6 3 7 6 10
in another embodiment from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl
1 6 3 7
and Het2, in another embodiment from the series consisting of (C -C )-alkyl and (C -
1 6 3
C )-cycloalkyl, in another embodiment from the series consisting of (C -C )-alkyl,
7 1 6
wherein in all these embodiment (C -C )-alkyl, (C -C )-alkyl and methyl representing
1 6 1 4
R5 or R6 is unsubstituted or substituted by one or more identical or different
substituents R10, and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all are
3 7 6 10
unsubstituted or substituted by one or more identical or different substituents R11, or
the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-
membered to 10-membered, monocyclic or bicyclic, saturated or partially unsaturated
heterocycle which, in addition to the nitrogen atom carrying R5 and R6, comprises 0
or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen
and sulfur, and which is unsubstituted or substituted by one ore more identical or
different substituents R12. In another embodiment of the invention, one of the groups
R5 and R6 is selected from the series consisting of hydrogen and (C -C )-alkyl, in
another embodiment from the series consisting of hydrogen and (C -C )-alkyl, in
another embodiment from the series consisting of hydrogen and methyl, and in
another embodiment is hydrogen, and the other of the groups R5 and R6 is selected
from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl
1 6 3 7 6 10
and Het2, in another embodiment from the series consisting of (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and (C -C )-bicycloalkyl, in another embodiment from the series
6 10
consisting of (C -C )-alkyl, (C -C )-cycloalkyl and Het2, in another embodiment from
1 6 3 7
the series consisting of (C -C )-alkyl and (C -C )-cycloalkyl, in another embodiment
1 6 3 7
from the series consisting of (C -C )-alkyl, wherein in all these embodiment (C -C )-
1 6 1 6
alkyl, (C -C )-alkyl and methyl representing R5 or R6 is unsubstituted or substituted
by one or more identical or different substituents R10, and (C -C )-cycloalkyl, (C -
3 7 6
C )-bicycloalkyl and Het2 all are unsubstituted or substituted by one or more
identical or different substituents R11.
In one embodiment of the invention, a (C -C )-alkyl group representing R5 or R6 is a
(C -C )-alkyl group, in another embodiment a (C -C )-alkyl group, in another
1 4 1 3
embodiment a (C -C )-alkyl group, in another embodiment any one or more groups
selected from the series consisting of butyl, propyl, isopropyl, ethyl and methyl, for
example selected from the series consisting of methyl, ethyl and propyl, which are all
unsubstituted or substituted by one or more, for example 1, 2 or 3, or 1 or 2, or 1,
identical or different substituents R10, which substituents can be present in any
positions, for example in position 1 and/or in position 2 of an ethyl group representing
R5 or R6, or in position 1 and/or in position 2 and/or in position 3 of a propyl group
representing R5 or R6.
In one embodiment of the invention, the number of identical or different substituents
R10 which are optionally present in a (C -C )-alkyl group representing R5 or R6, is 1,
2, 3 or 4, in another embodiment it is 1, 2 or 3, in another embodiment it is 1 or 2, in
another embodiment it is 1. In one embodiment, the number of groups R14
representing substituents R10, which are optionally present in an (C -C )-alkyl group
representing R5 or R6 besides any other substituents R10, is 1 or 2, in another
embodiment it is 1, in another embodiment it is 0 (zero), i.e., in the latter embodiment
R10 is as defined, but is not R14. In one embodiment, the number of oxo groups
representing substituents R10, which are optionally present in an (C -C )-alkyl group
representing R5 or R6 besides any other substituents R10, is 1 or 2, in another
embodiment it is 1. In one embodiment, the number of groups selected from the
series consisting of R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -
representing substituents R10, which are optionally present in an (C -C )-alkyl group
representing R5 or R6 besides any other substituents R10, is 1 or 2, in another
embodiment it is 1.
In one embodiment of the invention, the number of identical or different substituents
R11 which are optionally present in (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2
3 7 6 10
groups representing R5 or R6, is independently of each other 1, 2, 3 or 4, in another
embodiment it is 1, 2 or 3, in another embodiment it is 1 or 2, in another embodiment
it is 1. In one embodiment, the number of groups R14 representing substituents R11,
which are optionally present in (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2
3 7 6 10
groups representing R5 or R6 besides any other substituents R11, is 1 or 2, in
another embodiment it is 1, in another embodiment it is 0. In one embodiment, the
number of oxo groups representing substituents R11, which are optionally present in
(C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 groups representing R5 or R6
3 7 6 10
besides any other substituents R11, is 1 or 2, in another embodiment it is 1. In one
embodiment, the number of groups selected from the series consisting of R19-O-
C(O)-(C -C )-alkyl-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -
1 4 2
representing substituents R11, which are optionally present in (C -C )-cycloalkyl, (C -
3 7 6
C )-bicycloalkyl and Het2 groups representing R5 or R6 besides any other
substituents R11, is 1 or 2, in another embodiment it is 1.
The monocyclic or bicyclic heterocycle which can be formed by the groups R5 and
R6 together with the nitrogen atom carrying them, which heterocycle is thus bonded
via a ring nitrogen atom, can be 4-membered, 5-membered, 6-membered, 7-
membered, 8-membered, 9-membered or 10-membered. In one embodiment of the
invention, this heterocycle is 5-membered to 10-membered, in another embodiment it
is 5-membered to 8-membered, in another embodiment it is 5-membered or 6-
membered. In one embodiment of the invention, a monocyclic heterocycle formed by
the groups R5 and R6 together with the nitrogen atom carrying them, is 4-membered,
-membered, 6-membered or 7-membered, and a bicyclic heterocycle formed by the
groups R5 and R6 together with the nitrogen atom carrying them, is 6-membered, 7-
membered, 8-membered, 9-membered or 10-membered. In one embodiment, a
heterocycle formed by the groups R5 and R6 together with the nitrogen atom
carrying them, is monocyclic, in another embodiment it is bicyclic. The two cycles in a
bicyclic heterocyclic group formed by the groups R5 and R6 together with the
nitrogen atom carrying them, can be fused or form a bridged bicycle or a spirocycle.
In one embodiment, a heterocycle formed by the groups R5 and R6 together with the
nitrogen atom carrying them, is saturated or contains one double bond within the ring,
in another embodiment it is saturated. In one embodiment, the further ring
heteroatom which is optionally present in a heterocycle formed by the groups R5 and
R6 together with the nitrogen atom carrying them, is selected from the series
consisting of nitrogen and oxygen, in another embodiment it is a nitrogen atom, and
in another embodiment it is an oxygen atom. Examples of heterocyclic groups, from
any one or more of which the heterocyclic groups formed by the groups R5 and R6
together with the nitrogen atom carrying them is selected in one embodiment of the
invention, are the groups of the following formulae,
R12 R12
in which the line crossed with the symbol represents the free bond via which
the group is bonded. The bond originating at the substituent R12 which is depicted in
these formulae, which is not directed to a specific atom, indicates that these
heterocyclic groups are optionally substituted by one or more identical or different
substituents R12 which can be present in any positions.
In one embodiment of the invention, the number of identical or different substituents
R12 which are optionally present in a heterocycle formed by R5 and R6 together with
the nitrogen atom carrying them, is 1, 2, 3 or 4, in another embodiment it is 1, 2 or 3,
in another embodiment it is 1 or 2, in another embodiment it is 1. In one embodiment,
the number of groups R14 representing substituents R12, which are optionally
present in a heterocycle formed by R5 and R6 together with the nitrogen atom
carrying them besides any other substituents R12, is 1 or 2, in another embodiment it
is 1, in another embodiment it is 0. In one embodiment, the number of oxo groups
representing substituents R12, which are optionally present in a heterocycle formed
by R5 and R6 together with the nitrogen atom carrying them besides any other
substituents R12, is 1 or 2, in another embodiment it is 1. In one embodiment, the
number of groups selected from the series consisting of R19-O-C(O)-(C -C )-alkyl-,
R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) - representing substituents
R12, which are optionally present in a heterocycle formed by R5 and R6 together
with the nitrogen atom carrying them besides any other substituents R12, is 1 or 2, in
another embodiment it is 1.
In one embodiment of the invention, R7 is in any of its occurrences, independently of
other occurrences, selected from the series consisting of (C -C )-alkyl, phenyl, Het2
and Het3, in another embodiment from the series consisting of (C -C )-alkyl, Het2
and Het3, in another embodiment from the series consisting of (C -C )-alkyl and
Het2, in another embodiment from the series consisting of (C -C )-alkyl and Het3, in
another embodiment from the series consisting of phenyl and Het3, and in another
embodiment is (C -C )-alkyl, and in another embodiment is phenyl, and in another
embodiment is Het2, and in another embodiment is Het3, wherein all groups (C -C )-
alkyl and Het2 are unsubstituted or substituted by one or more identical or different
substituents R10, and all groups phenyl and Het3 are unsubstituted or substituted by
one or more identical or different substituents R13.
In one embodiment of the invention, the number of identical or different substituents
R10 which are optionally present in (C -C )-alkyl, (C -C )-cycloalkyl and Het2 groups
1 6 3 7
representing R7, is independently of each other 1, 2 or 3, in another embodiment it is
1 or 2, in another embodiment it is 1. In one embodiment, the number of groups R14
representing substituents R10, which are optionally present in (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and Het2 groups representing R7 besides any other substituents R10, is 1
or 2, in another embodiment it is 1, in another embodiment it is 0. In one
embodiment, the number of oxo groups representing substituents R10, which are
optionally present in (C -C )-alkyl, (C -C )-cycloalkyl and Het2 groups representing
1 6 3 7
R7 besides any other substituents R10, is 1 or 2, in another embodiment it is 1. In
one embodiment, the number of groups selected from the series consisting of R16-
N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) - representing substituents R10,
which are optionally present in (C -C )-alkyl, (C -C )-cycloalkyl and Het2 groups
1 6 3 7
representing R7 besides any other substituents R10, is 1 or 2, in another
embodiment it is 1. In one embodiment of the invention, the number of identical or
different substituents R13 which are optionally present in phenyl and Het3 groups
representing R7, is independently of each other 1, 2 or 3, in another embodiment it is
1 or 2, in another embodiment it is 1, in another embodiment it is 0.
In one embodiment of the invention, R10 is selected from the series consisting of
R14, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -
1 6 2
O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-,
2 2 2
R16-N(R17)-C(O)- and R19-O-C(O)-, in another embodiment from the series
consisting of fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-,
HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, (C -C )-alkyl-S(O) -,
2 2 2 2 1 6 n
R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-
S(O) -, in another embodiment from the series consisting of R14, fluorine, HO-, oxo,
(C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-,
1 6 2 2
(HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-, in another
embodiment from the series consisting of R14, fluorine, HO-, (C -C )-alkyl-O-, R15-
C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-
2 2 2 2
O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-, in
another embodiment from the series consisting of fluorine, HO-, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-, in
another embodiment from the series consisting of R14, fluorine, HO-, (C -C )-alkyl-O-
, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)-, R18-
C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-, in another embodiment from the
series consisting of fluorine, HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-,
HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)-
and R19-O-C(O)-, in another embodiment from the series consisting of R14, fluorine,
HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-,
1 6 2 2
(HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-, in another
embodiment from the series consisting of fluorine, HO-, (C -C )-alkyl-O-, R15-C(O)-
O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-,
2 2 2 2
R16-N(R17)- and R18-C(O)-N(R17)-, in another embodiment from the series
consisting of R14, HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -
1 6 2
O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)- and R18-C(O)-
2 2 2
N(R17)-, in another embodiment from the series consisting of HO-, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-, in another embodiment from the
series consisting of R14, HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-
S(O) -O-, (HO) P(O)-O- and (HO) P(O)-O-CH -O-C(O)-O-, in another embodiment
2 2 2 2
from the series consisting of HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-,
HO-S(O) -O-, (HO) P(O)-O- and (HO) P(O)-O-CH -O-C(O)-O-, in another
2 2 2 2
embodiment from the series consisting of R14, HO-, (C -C )-alkyl-O-, R15-C(O)-O-,
R15-NH-C(O)-O-, HO-S(O) -O- and (HO) P(O)-O-, in another embodiment from the
series consisting of HO-, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -
1 6 2
O- and (HO) P(O)-O-, in another embodiment from the series consisting of HO-, R15-
C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O- and (HO) P(O)-O-, in another embodiment
from the series consisting of HO-, HO-S(O) -O- and (HO) P(O)-O-, in another
embodiment from the series consisting of HO- and (HO) P(O)-O-, in another
embodiment from the series consisting of R14, HO- and (HO) P(O)-O-, in another
embodiment from the series consisting of R14 and HO-, and in another embodiment
R10 is HO-, and in another embodiment R10 is R14, wherein in case that more than
one substituent R10 is present, the substituents R10 are independently of one
another defined as in any of these embodiments.
In one embodiment of the invention, R11 and R12 are independently of one another
selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-
1 4 1 4
(C -C )-alkyl-, R19-O-C(O)-(C -C )-alkyl-, R14, fluorine, HO-, oxo, (C -C )-alkyl-O-,
1 4 1 4 1 6
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-, in
another embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-alkyl-, R14, fluorine, HO-, oxo, (C -
1 4 1 4 1
C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-,
6 2 2
(HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)- and R19-O-C(O)-, in
another embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-
1 4 1 4 1 6
alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-
2 2 2
CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)- and R19-O-C(O)-, in another
embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-
1 4 1 6
C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-
2 2 2 2
and R18-C(O)-N(R17)-, in another embodiment from the series consisting of (C -C )-
alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-alkyl-,
1 4 1 4 1 4
fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-,
1 6 2
(HO) P(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)- and R19-O-C(O)-, in another
embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-
1 4 1 6
C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-, in
another embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O-, HO-S(O) -O-,
1 4 1 6 2
(HO) P(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-, in another embodiment from the
series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-,
1 4 1 4 1 4
fluorine, HO-, (C -C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and R18-
1 6 2 2
C(O)-N(R17)-, in another embodiment from the series consisting of (C -C )-alkyl, HO-
(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O- and
1 4 1 4 1 6
R16-N(R17)-, in another embodiment from the series consisting of (C -C )-alkyl, HO-
(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, (C -C )-alkyl-O- and R16-
1 4 1 4 1 6
N(R17)-, in another embodiment from the series consisting of (C -C )-alkyl, HO-(C -
1 4 1
C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo and R16-N(R17)-, in another
4 1 4
embodiment from the series consisting of (C -C )-alkyl, fluorine and oxo, in another
embodiment from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl-, fluorine, HO- and R16-N(R17)-, in another embodiment from
the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-,
1 4 1 4 1 4
HO- and R16-N(R17)-, in another embodiment from the series consisting of (C -C )-
alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-alkyl-, HO-,
1 4 1 4 1 4
R16-N(R17)- and R19-O-C(O)-, in another embodiment from the series consisting of
(C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, HO-, R16-N(R17)- and
1 4 1 4 1 4
R19-O-C(O)-, wherein in case that more than one substituent R11 or R12 is present,
the substituents R11 and R12 are independently of one another defined as in any of
these embodiments. In one embodiment, substituents R11 and R12 which are
bonded to a ring nitrogen atom, as can occur in the case of the group Het2 or the ring
which can be formed by R5 and R6 together with the nitrogen atom carrying them,
are selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl- and R14, wherein R14 is bonded via a ring carbon atom, in
another embodiment from the series consisting of (C -C )-alkyl.
The explanations given above with respect to the ring which can be formed by two
substituents R1 bonded to adjacent ring carbon atoms in Ar together with the carbon
atoms carrying them, apply correspondingly to the ring which can be formed by two
substituents R13 bonded to adjacent ring carbon atoms in R7, which is a monocyclic
ring. I.e., the ring which can be formed by two substituents R13 bonded to adjacent
ring carbon atoms in R7, is mono-unsaturated because it is fused to an aromatic ring,
i.e. a phenyl group or a group Het3 representing R7, and two such groups R13
forming a ring together with the carbon atoms carrying them can in other terms be
regarded as together forming a divalent residue comprising a chain of 3 to 5 atoms of
which 0, 1 or 2 are identical or different heteroatoms selected from the series
consisting of nitrogen, oxygen and sulfur. The examples of such divalent residues
given above with respect to the ring which can be formed by two groups R1 together
with the ring carbon atoms carrying them, apply likewise to the ring which can be
formed by two substituents R13 together with the ring carbon atoms carrying them. In
one embodiment of the invention, the ring which can be formed by two groups R13
bonded to adjacent ring carbon atoms in R7 together with the carbon atoms carrying
them, is a 5-membered or 6-membered, in another embodiment a 5-membered, in
another embodiment a 6-membered ring. In one embodiment of the invention, the
number of substituents selected from the series consisting of fluorine and (C -C )-
alkyl, which can be present in a ring formed by two groups R13 bonded to adjacent
ring carbon atoms in R7 together with the carbon atoms carrying them, is 1, 2 or 3, in
another embodiment 1 or 2, in another embodiment 1. In one embodiment of the
invention, substituents which can be present in a ring formed by two groups R13
bonded to adjacent ring carbon atoms in R7 together with the carbon atoms carrying
them, are fluorine substituents, and in another embodiment they are (C -C )-alkyl
substituents, for example methyl substituents, and in another embodiment are
substituents in such a ring bonded to a ring nitrogen atom selected from the series
consisting of (C -C )-alkyl. In one embodiment, a ring formed by two substituents
R13 bonded to adjacent ring carbon atoms in R7 together with the carbon atoms
carrying them, comprises 1 or 2, in another embodiment 2, identical or different ring
heteroatoms, wherein in one embodiment the ring heteroatoms are selected from the
series consisting of nitrogen and sulfur, and in another embodiment 1 ring nitrogen
atom and 1 ring sulfur atom is present in such a ring.
In one embodiment of the invention, R13 is selected from the series consisting of
halogen, (C -C )-alkyl, (C -C )-alkyl-O- and R16-N(R17)-, in another embodiment
1 4 1 4
from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-alkyl-O-, in
1 4 1 4
another embodiment from the series consisting of halogen, (C -C )-alkyl and (C -C )-
1 4 1 4
alkyl-O-, in another embodiment from the series consisting of halogen, (C -C )-alkyl
and R16-N(R17)-, in another embodiment from the series consisting of halogen and
(C -C )-alkyl, and two substituents R13 bonded to adjacent ring carbon atoms in R7,
together with the carbon atoms carrying them, can form a 5-membered to 7-
membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring
heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and
which is unsubstituted or substituted by one or more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl. In another
embodiment, R13 is selected from the series consisting of halogen, (C -C )-alkyl,
HO-, (C -C )-alkyl-O- and R16-N(R17)-, in another embodiment from the series
consisting of halogen, (C -C )-alkyl, (C -C )-alkyl-O- and R16-N(R17)-, in another
1 4 1 4
embodiment from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-
1 4 1 4
alkyl-O-, in another embodiment from the series consisting of halogen, (C -C )-alkyl
and (C -C )-alkyl-O-, in another embodiment from the series consisting of halogen,
(C -C )-alkyl and R16-N(R17)-, in another embodiment from the series consisting of
halogen and (C -C )-alkyl.
The monocyclic or bicyclic group R14 can be 3-membered, 4-membered, 5-
membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered.
In one embodiment of the invention, a monocyclic group R14 is 3-membered, 4-
membered, 5-membered, 6-membered or 7-membered, and a bicyclic group R14 is
6-membered, 7-membered, 8-membered, 9-membered or 10-membered. In one
embodiment of the invention, R14 is monocyclic, in another embodiment it is bicyclic.
The two cycles in a bicyclic group R14 can be fused or form a bridged bicycle or a
spirocycle. The monocyclic or bicyclic ring R14 can be saturated, i.e. not contain any
double bonds within the ring system, or be partially unsaturated, i.e. contain one or
more double bonds within the ring system, for example, one two, three or four double
bonds, or one, two or three double bonds, or one or two double bonds, or one double
bond, but is not fully aromatic, i.e. it does not contain a cyclic system of six
delocalized pi electrons in the case of a monocycle or of ten delocalized pi electrons
in the case of a bicycle, or it can be aromatic. The number of double bonds which
can be present in ring, depends on the type of the ring system and the ring size.
Partially unsaturated rings R14 include also bicyclic ring systems in which one of the
two cycles is aromatic and the other is not aromatic. The ring R14 can be carbocyclic,
i.e. contain 0 (zero) ring heteroatoms, or heterocyclic, i.e. contain 1, 2, 3 or 4 identical
or different ring heteroatoms. In one embodiment, the number of ring heteroatoms
which are present in R14 is 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another
embodiment 0 or 1. In one embodiment of the invention, R14 is in any of its
occurrences, independently of its other occurrences, a carbocyclic ring, and in
another embodiment it is a heterocyclic ring. In a bicyclic ring R14, ring heteroatoms
can be present in one of the two rings or in both rings in any suitable positions. In
bridged and fused bicyclic rings, ring nitrogen atoms can also be present in
bridgehead positions and fusion positions. In one embodiment of the invention, a 3-
membered ring R14 is carbocyclic ring, in particular a cyclopropane ring, i.e., in this
case the group R14 is a cyclopropyl group. In one embodiment, ring heteroatoms
which are present in R14, are selected from the series consisting of nitrogen and
oxygen, in another embodiment from the series consisting of nitrogen and sulfur, and
in another embodiment they are nitrogen atoms. In another embodiment, R14 is as
defined, but is not a pyrazolyl group which is unsubstituted or substituted by one or
more identical or different (C -C )-alkyl substituents. R14 can be bonded via any ring
carbon atom and any ring nitrogen atom which has a free binding position. In a
bicyclic group R14, the ring atom via which R14 is bonded, can be present in a
saturated ring, a partially unsaturated ring or in an aromatic ring. In one embodiment
of the invention, R14 is bonded in any of its occurrences, independently of its other
occurrences, via a ring carbon atom, in another embodiment via a ring nitrogen atom.
Types of cyclic groups which are comprised by the definition of R14, are cycloalkyl
groups, bicycloalkyl groups, phenyl groups, naphthyl groups including naphthalen
yl groups and naphthalenyl groups, partially hydrogenated naphthyl groups such
as 1,2,3,4-tetrahydronaphthalenyl groups, monocyclic and bicyclic aromatic
heterocyclic groups such as the groups Het1 and Het3, and saturated and partially
unsaturated monocyclic and bicyclic heterocyclic groups such as the group Het2. The
explanations given above and below with respect to such groups apply
correspondingly to such groups representing R14, as do the explanations given
above with respect to heterocyclic groups in general. Examples of groups, from any
one or more of which the group R14 is selected in one embodiment of the invention,
are the groups of the following formulae,
R20 R20
R20 H
S R20
R20 R20
R20 R20
HN HN
in which the line crossed with the symbol represents the free bond via which
the group is bonded. The bond originating at the substituent R20 which is depicted in
these formulae, which is not directed to a specific atom, indicates that these groups
are optionally substituted by one or more identical or different substituents R20,
which can be present in any positions.
In one embodiment of the invention, the number of identical or different substituents
R20 which are optionally present in the group R14, is 1, 2, 3 or 4, in another
embodiment it is 1, 2 or 3, in another embodiment it is 1 or 2, in another embodiment
it is 1. In one embodiment, the number of oxo groups representing substituents R20,
which are optionally present in R14 besides any other substituents R20, is 1 or 2, in
another embodiment it is 1. In one embodiment, the number of groups selected from
the series consisting of R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -
representing substituents R20, which are optionally present in R14 besides any other
substituents R20, is 1 or 2, in another embodiment it is 1.
In one embodiment of the invention, R15 is in any of its occurrences, independently
of its other occurrences, selected from the series consisting of (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-, in another embodiment from the
3 7 1 4
series consisting of (C -C )-alkyl, in another embodiment from the series consisting
of (C -C )-alkyl, and in another embodiment R15 is methyl.
In one embodiment of the invention, R16 and R17 are in any of their occurrences,
independently of other occurrences, and independently of one another, selected from
the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-
1 6 3 7 3 7
cycloalkyl-(C -C )-alkyl-, in another embodiment from the series consisting of
hydrogen and (C -C )-alkyl, in another embodiment from the series consisting of
hydrogen and (C -C )-alkyl, in another embodiment from the series consisting of
hydrogen and methyl, or the groups R16 and R17, together with the nitrogen atom
carrying them, form a 4-membered to 7-membered, monocyclic saturated
heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises
0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen
and sulfur, and which is unsubstituted or substituted by one ore more identical or
different substituents selected from the series consisting of fluorine and (C -C )-alkyl.
In another embodiment, R16 and R17 are in any of their occurrences, independently
of other occurrences, and independently of one another, selected from the series
consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -
1 6 3 7 3 7 1
C )-alkyl-, in another embodiment from the series consisting of hydrogen and (C -
C )-alkyl, in another embodiment from the series consisting of hydrogen and (C -C )-
6 1 4
alkyl, in another embodiment from the series consisting of hydrogen and methyl.
The monocyclic heterocycle which can be formed by the groups R16 and R17
together with the nitrogen atom carrying them, which heterocycle is thus bonded via
a ring nitrogen atom, can be 4-membered, 5-membered, 6-membered or 7-
membered. In one embodiment of the invention, the heterocycle formed by the
groups R16 and R17 together with the nitrogen atom carrying them, is 5-membered
or 6-membered, in another embodiment it is 6-membered. In one embodiment, the
further ring heteroatom which is optionally present in a heterocycle formed by the
groups R16 and R17 together with the nitrogen atom carrying them, is selected from
the series consisting of nitrogen and oxygen, in another embodiment it is a nitrogen
atom, and in another embodiment it is an oxygen atom. In one embodiment of the
invention, the number of substituents selected from the series consisting of fluorine
and (C -C )-alkyl, which can be present in a ring formed by the groups R16 and R17
together with the nitrogen atom carrying them, is 1, 2 or 3, in another embodiment 1
or 2, in another embodiment 1. In one embodiment of the invention, substituents
which can be present in a ring formed by the groups R16 and R17 together with the
nitrogen atom carrying them, are fluorine substituents, and in another embodiment
they are (C -C )-alkyl substituents, for example methyl substituents, and in another
embodiment are substituents in such a ring bonded to a ring nitrogen atom selected
from the series consisting of (C -C )-alkyl. Examples of heterocyclic groups, from any
one or more of which the heterocyclic groups formed by the groups R16 and R17
together with the nitrogen atom carrying them is selected in one embodiment of the
invention, are azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, and 4-methylpiperazinyl.
In one embodiment of the invention, R18 is in any of its occurrences, independently
of its other occurrences, selected from the series consisting of (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-, in another embodiment from the
3 7 1 4
series consisting of (C -C )-alkyl, in another embodiment from the series consisting
of (C -C )-alkyl, and in another embodiment R18 is methyl.
In one embodiment of the invention, R19 is in any of its occurrences, independently
of its other occurrences, selected from the series consisting of hydrogen, (C -C )-
alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-, in another embodiment
3 7 3 7 1 4
from the series consisting of hydrogen and (C -C )-alkyl, in another embodiment from
the series consisting of hydrogen and (C -C )-alkyl, in another embodiment from the
series consisting of (C -C )-alkyl, and in another embodiment R19 is hydrogen.
In one embodiment of the invention, R20 is selected from the series consisting of
halogen, (C -C )-alkyl, HO-(C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-
1 4 1 4 3 7 1 6
O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -
2 2 2 2
O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R18-O-C(O)-N(R17)-, NC-, R18-C(O)-,
R16-N(R17)-C(O)- and R19-O-C(O)-, in another embodiment from the series
consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo,
1 4 1 4 3 7
(C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-,
1 6 2 2
(HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R18-O-C(O)-
N(R17)- and NC-, in another embodiment from the series consisting of halogen, (C -
C )-alkyl, HO-(C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-
4 1 4 3 7 1 6
O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-, in another
embodiment from the series consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
(C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-
3 7 1 6 2 2
N(R17)- and NC-, in another embodiment from the series consisting of halogen, (C -
C )-alkyl, HO-(C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-,
4 1 4 3 7 1 6
(HO) P(O)-O-, R16-N(R17)- and NC-, in another embodiment from the series
consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo,
1 4 1 4 3 7
(C -C )-alkyl-O-, R16-N(R17)- and NC-, in another embodiment from the series
consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-,
1 4 3 7 1 6
R16-N(R17)- and NC-, in another embodiment from the series consisting of halogen,
(C -C )-alkyl, oxo, (C -C )-alkyl-O- and R16-N(R17)-, in another embodiment from
1 4 1 6
the series consisting of halogen, (C -C )-alkyl, (C -C )-alkyl-O- and R16-N(R17)-, in
1 4 1 6
another embodiment from the series consisting of (C -C )-alkyl and oxo, wherein in
case that more than one substituent R20 is present, the substituents R20 are
independently of one another defined as in any of these embodiments.
In one embodiment of the invention, the aromatic group Het1 is in any of its
occurrences, independently of other occurrences, a 5-membered heterocycle which
comprises one ring heteroatom which is selected from the series consisting of
nitrogen, oxygen and sulfur, and a further ring heteroatom which is a ring nitrogen
atom, or it is 6-membered heterocycle which comprises one or two ring nitrogen
atoms, in another embodiment Het1 is selected from the series consisting of the
aromatic heterocycles pyrazole, imidazole, isoxazole, oxazole, thiazole, pyridine,
pyrimidine and pyrazine, in another embodiment from the series consisting of
pyrazole, isoxazole, oxazole, thiazole, pyridine and pyrimidine, in another
embodiment from the series consisting of pyrazole, isoxazole, oxazole, thiazole and
pyridine, which are all unsubstituted or substituted as indicated. In one embodiment,
the group Het1 is bonded via a ring carbon atom. In one embodiment, the number of
substituents which are optionally present in a group Het1, is 1, 2 or 3, in another
embodiment 1 or 2, in another embodiment 1. In one embodiment, the substituents
which are optionally present in Het 1 are selected from the series consisting of
halogen and (C -C )-alkyl. In one embodiment, a substituent which is bonded to a
ring nitrogen atom, such as in a pyrrole, pyrazole or imidazole ring, is selected from
the series consisting of (C -C )-alkyl.
The heterocyclic group Het2 can be 4-membered, 5-membered, 6-membered, 7-
membered, 8-membered, 9-membered or 10-membered. In one embodiment of the
invention, a monocyclic group Het2 is 4-membered, 5-membered, 6-membered or 7-
membered, and a bicyclic group Het2 is 6-membered, 7-membered, 8-membered, 9-
membered or 10-membered. In one embodiment of the invention, Het2 is in any of its
occurrences, independently of other occurrences, monocyclic, and in another
embodiment it is bicyclic. The two cycles in a bicyclic group Het2, can be fused or
form a bridged bicycle or a spirocycle. In one embodiment, the group Het2 is
saturated or contains one double bond within the ring, in another embodiment it is
saturated. In one embodiment, the further ring heteroatom which is optionally present
in a group Het2, is selected from the series consisting of nitrogen and oxygen, in
another embodiment it is a nitrogen atom, and in another embodiment it is an oxygen
atom. Het2 can be bonded via any ring carbon atom and any ring nitrogen atom
which has a free binding position. In one embodiment of the invention, Het2 is
bonded in any of its occurrences, independently of its other occurrences, via a ring
carbon atom, in another embodiment via a ring nitrogen atom. Examples of
heterocyclic groups, from any one or more of which Het2 is selected in one
embodiment of the invention, are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,
morpholinyl, thiomorpholinyl, piperazinyl and 3-azabicyclo[3.1.0]hexyl, which in one
embodiment are bonded via ring carbon atom and, for example, are the residues
azetidinyl, azetidinyl, pyrrolidinyl, pyrrolidinyl, piperidinyl, piperidinyl,
piperidinyl and 3-azabicyclo[3.1.0]hexyl.
In one embodiment of the invention, the aromatic group Het3 is a 5-membered or 6-
membered monocyclic heterocycle or an 8-membered, 9-membered or 10-
membered bicyclic heterocycle, in another embodiment a 5-membered or 6-
membered monocyclic heterocycle or a 9-membered or 10-membered bicyclic
heterocycle. In a bicyclic heterocycle representing Het3, the ring heteroatoms can be
present in one of the rings or both of the rings. In one embodiment, one of the ring
heteroatoms in Het3 is a ring nitrogen atom and no further ring heteroatom is present,
or a second ring heteroatom is present which is selected from the series consisting of
nitrogen, oxygen and sulfur. In one embodiment, Het3 is selected from the series
consisting of the aromatic heterocycles pyrazole, imidazole, isoxazole, oxazole,
thiazole, pyridine, pyrimidine, pyrazine, benzimidazole, benzoxazole, benzthiazole,
quinoline and isoquinoline, in another embodiment from the series consisting of
pyrazole, imidazole, isoxazole, oxazole, thiazole, pyridine, benzimidazole,
benzoxazole and benzthiazole, in another embodiment from the series consisting of
pyrazole, imidazole, isoxazole, thiazole, pyridine, benzimidazole and benzthiazole, in
another embodiment from the series consisting of pyrazole, imidazole, isoxazole,
thiazole, pyridine and benzthiazole.
In one embodiment of the invention, the substituents in a phenyl group in any
occurrence in a compound of the formula I, independently of any other occurrences,
are selected from the series consisting of halogen and (C -C )-alkyl, unless specified
otherwise. In one embodiment, the number of substituents in a phenyl group is 1, 2
or 3, in another embodiment 1 or 2, in another embodiment 1, unless specified
otherwise.
In one embodiment of the invention, the chiral carbon atom in position 2 of the
chroman ring system in a compound of the formula I is present, or is essentially
present, for example with a molar ratio of the two stereoisomers of 98:2, or 99:1, or
greater, in uniform configuration, either in R configuration or in S configuration, as is
indicated by the wavy wedge in the compound of the formula Iq. In another
embodiment of the invention, the chiral carbon atom in position 2 of the chroman ring
system in a compound of the formula I is present, or is essentially present, for
example with a molar ratio of the two stereoisomers of 98:2, or 99:1, or greater, in the
configuration depicted in formula Ir, i.e. in the respective compound of the formula I
the group Ar is located above the plane which may be assumed to be formed by the
chroman ring system arranged as depicted in formulae Ir and Is, which configuration
is R configuration in case all groups R4 are hydrogen. In another embodiment of the
invention, the chiral carbon atom in position 2 of the chroman ring system in a
compound of the formula I is present, or is essentially present, for example with a
molar ratio of the two stereoisomers of 98:2, or 99:1, or greater, in the configuration
depicted in formula Is, i.e. in the respective compound of the formula I the group Ar is
located below the plane which may be assumed to be formed by the chroman ring
system arranged as depicted in formulae Ir and Is, which configuration is S
configuration in case all groups R4 are hydrogen.
N Iq
Ar O
Ar O
Ar O
The groups Ar, R2, R3 and R4 in the compounds of the formulae Iq, Ir and Is are
defined as in the compounds of the formula I.
A subject of the invention are all compounds of the formula I wherein any one or
more structural elements such as groups, residues, substituents and numbers are
defined as in any of the specified embodiments or definitions of the elements, or
have one or more of the specific meanings which are mentioned herein as examples
of elements, wherein all combinations of one or more definitions of compounds or
elements and/or specified embodiments and/or specific meanings of elements are a
subject of the present invention. Also with respect to all such compounds of the
formula I, all their stereoisomeric forms and mixtures of stereoisomeric forms in any
ratio, and their pharmaceutically acceptable salts are a subject of the present
invention.
As an example of compounds of the invention which with respect to any structural
elements are defined as in specified embodiments of the invention or definitions of
such elements, compounds of the formula I may be mentioned wherein
Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl,
which are all unsubstituted or substituted by one or more identical or different
substituents R1;
R1 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )-cycloalkyl,
1 6 3 7
(C -C )-cycloalkyl-(C -C )-alkyl-, HO-, (C -C )-alkyl-O-, (C -C )-cycloalkyl-O-, (C -C )-
3 7 1 4 1 6 3 7 3 7
cycloalkyl-(C -C )-alkyl-O- and (C -C )-alkyl-S(O) -;
1 4 1 6 n
R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)-CH -, R7-
C(O)-NH-CH - and R7-S(O) -NH-CH -;
2 2 2
R3 is selected from the series consisting of hydrogen, halogen and (C -C )-alkyl;
R4 is hydrogen or one or more identical or different substituents selected from the
series consisting of halogen and (C -C )-alkyl;
R5 and R6 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2, wherein
1 6 3 7 6 10
(C -C )-alkyl is unsubstituted or substituted by one or more identical or different
substituents R10, and (C -C )-cycloalkyl, (C -C )-bicycloalkyl and Het2 all are
3 7 6 10
unsubstituted or substituted by one or more identical or different substituents R11,
or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-
membered to 10-membered, monocyclic or bicyclic, saturated heterocycle which, in
addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring
heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and
which is unsubstituted or substituted by one ore more identical or different
substituents R12;
R7 is selected from the series consisting of (C -C )-alkyl, Het2 and Het3, wherein
(C -C )-alkyl and Het2 all are unsubstituted or substituted by one or more identical or
different substituents R10, and Het3 is unsubstituted or substituted by one or more
identical or different substituents R13;
R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-;
R11 and R12 are independently of one another selected from the series consisting of
(C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O-C(O)-(C -C )-
1 4 1 4 1 4 1 4
alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-,
HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-
2 2 2 2
N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-;
R13 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )-alkyl-O-
1 4 1 4
and R16-N(R17)-;
R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated,
partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring
heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and
which is unsubstituted or substituted by one or more identical or different substituents
R20;
R15 and R18 are independently of one another selected from the series consisting of
(C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
1 6 3 7 3 7 1 4
R16 and R17 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-,
1 6 3 7 3 7 1 4
or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-
membered to 6-membered, monocyclic saturated heterocycle which, in addition to
the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one ore more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
3 7 1 4
R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
(C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-
3 7 1 6
S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-;
Het2 is a 4-membered to 10-membered monocyclic or bicyclic, saturated or partially
unsaturated heterocycle comprising 1 or 2 identical or different ring heteroatoms
selected from the series consisting of nitrogen, oxygen and sulfur;
Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle
comprising 1 or 2 identical or different ring heteroatoms selected from the series
consisting of nitrogen, oxygen and sulfur;
n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are
independent of one another;
wherein all cycloalkyl and bicycloalkyl groups, independently of any other
substituents which can be present on a cycloalkyl or bicycloalkyl group, can be
substituted by one or more identical substituents selected from the series consisting
of fluorine and (C -C )-alkyl;
wherein all alkyl groups, independently of any other substituents which can be
present on an alkyl group, can be substituted by one ore more fluorine substituents;
in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio,
and the pharmaceutically acceptable salt thereof.
As another such example, compounds of the formula I may be mentioned, wherein
Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl,
which are all unsubstituted or substituted by one or more identical or different
substituents R1;
R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-
1 6 1 6
alkyl-O-;
R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)-CH -, R7-
C(O)-NH-CH - and R7-S(O) -NH-CH -;
2 2 2
R3 is selected from the series consisting of hydrogen, halogen and (C -C )-alkyl;
R4 is hydrogen or one or more identical or different substituents selected from the
series consisting of halogen and (C -C )-alkyl;
R5 and R6 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl and (C -C )-cycloalkyl, wherein (C -C )-alkyl is unsubstituted
1 6 3 7 1 6
or substituted by one or more identical or different substituents R10, and (C -C )-
cycloalkyl is unsubstituted or substituted by one or more identical or different
substituents R11,
or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-
membered to 10-membered, monocyclic or bicyclic, saturated heterocycle which, in
addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring
heteroatom selected from the series consisting of nitrogen and oxygen, and which is
unsubstituted or substituted by one ore more identical or different substituents R12;
R7 is selected from the series consisting of (C -C )-alkyl and Het3, wherein (C -C )-
1 6 1 6
alkyl is unsubstituted or substituted by one or more identical or different substituents
R10, and Het3 is unsubstituted or substituted by one or more identical or different
substituents R13;
R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-;
R11 and R12 are independently of one another selected from the series consisting of
(C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -
1 4 1 4 1 4 1
C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-;
6 2 2
R13 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )-alkyl-O-
1 4 1 4
and R16-N(R17)-;
R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated,
partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring
heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and
which is unsubstituted or substituted by one or more identical or different substituents
R20;
R15 and R18 are independently of one another selected from the series consisting of
(C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
1 6 3 7 3 7 1 4
R16 and R17 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-,
1 6 3 7 3 7 1 4
or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-
membered to 6-membered, monocyclic saturated heterocycle which, in addition to
the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one ore more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-
1 6 3 7
cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
3 7 1 4
R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
(C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-
3 7 1 6
S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-;
Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle
comprising 1 or 2 identical or different ring heteroatoms selected from the series
consisting of nitrogen, oxygen and sulfur;
wherein all cycloalkyl groups, independently of any other substituents which can be
present on a cycloalkyl group, can be substituted by one or more identical
substituents selected from the series consisting of fluorine and (C -C )-alkyl;
wherein all alkyl groups, independently of any other substituents which can be
present on an alkyl group, can be substituted by one ore more fluorine substituents;
in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio,
and the pharmaceutically acceptable salt thereof.
As another such example, compounds of the formula I may be mentioned, which are
compounds of the formula Ie,
Ar O
wherein
Ar is phenyl which is unsubstituted or substituted by one or more identical or different
substituents R1;
R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-
1 6 1 6
alkyl-O-;
R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)-CH -;
R3 is selected from the series consisting of hydrogen, halogen and (C -C )-alkyl;
R4 is hydrogen or one or more identical or different substituents selected from the
series consisting of halogen and (C -C )-alkyl;
one of the groups R5 and R6 is hydrogen and the other of the groups R5 and R6 is
selected from the series consisting of (C -C )-alkyl and (C -C )-cycloalkyl, wherein
1 6 3 7
(C -C )-alkyl is unsubstituted or substituted by one or more identical or different
substituents R10, and (C -C )-cycloalkyl is unsubstituted or substituted by one or
more identical or different substituents R11;
R10 is selected from the series consisting of R14, fluorine, HO-, (C -C )-alkyl-O-,
R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-
2 2 2 2
C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-;
R11 is selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl-, fluorine, HO-, (C -C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-,
1 4 1 6 2 2
R16-N(R17)- and R18-C(O)-N(R17)-;
R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated,
partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring
heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and
which is unsubstituted or substituted by one or more identical or different substituents
R20;
R15 and R18 are independently of one another selected from the series consisting of
(C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
1 6 3 7 3 7 1 4
R16 and R17 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-,
1 6 3 7 3 7 1 4
or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-
membered to 6-membered, monocyclic saturated heterocycle which, in addition to
the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one ore more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO-(C -C )-alkyl-,
1 4 1 4
(C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-
3 7 1 6
S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-;
wherein all cycloalkyl groups, independently of any other substituents which can be
present on a cycloalkyl group, can be substituted by one or more identical
substituents selected from the series consisting of fluorine and (C -C )-alkyl;
wherein all alkyl groups, independently of any other substituents which can be
present on an alkyl group, can be substituted by one ore more fluorine substituents;
in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio,
and the pharmaceutically acceptable salt thereof.
As another such example, compounds of the formula I may be mentioned, which are
compounds of the formula Ie,
Ar O
wherein
Ar is phenyl which is unsubstituted or substituted by one or more identical or different
substituents R1;
R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-
1 6 1 6
alkyl-O-;
R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)-CH -;
R3 is selected from the series consisting of hydrogen, halogen and (C -C )-alkyl;
R4 is hydrogen or one or more identical or different substituents selected from the
series consisting of halogen and (C -C )-alkyl;
one of the groups R5 and R6 is hydrogen and the other of the groups R5 and R6 is
selected from the series consisting of (C -C )-alkyl and (C -C )-cycloalkyl, wherein
1 6 3 7
(C -C )-alkyl is unsubstituted or substituted by one or more identical or different
substituents R10, and (C -C )-cycloalkyl is unsubstituted or substituted by one or
more identical or different substituents R11;
R10 is selected from the series consisting of fluorine, HO-, (C -C )-alkyl-O-, R15-
C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-
2 2 2 2
O-, R16-N(R17)- and R18-C(O)-N(R17)-;
R11 is selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-
1 4 1 4
N(R17)-(C -C )-alkyl-, fluorine, HO-, (C -C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-,
1 4 1 6 2 2
R16-N(R17)- and R18-C(O)-N(R17)-;
R15 and R18 are independently of one another selected from the series consisting of
(C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-;
1 6 3 7 3 7 1 4
R16 and R17 are independently of one another selected from the series consisting of
hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-,
1 6 3 7 3 7 1 4
or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-
membered to 6-membered, monocyclic saturated heterocycle which, in addition to
the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom
selected from the series consisting of nitrogen, oxygen and sulfur, and which is
unsubstituted or substituted by one ore more identical or different substituents
selected from the series consisting of fluorine and (C -C )-alkyl;
wherein all cycloalkyl groups, independently of any other substituents which can be
present on a cycloalkyl group, can be substituted by one or more identical
substituents selected from the series consisting of fluorine and (C -C )-alkyl;
wherein all alkyl groups, independently of any other substituents which can be
present on an alkyl group, can be substituted by one ore more fluorine substituents;
in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio,
and the pharmaceutically acceptable salt thereof.
A subject of the invention also is a compound of the formula I which is selected from
any of the specific compounds of the formula I which are disclosed herein, or is any
one of the specific compounds of the formula I which are disclosed herein,
irrespective thereof whether they are disclosed as a free compound and/or as a
specific salt, or a pharmaceutically acceptable salt thereof, wherein the compound of
the formula I is a subject of the invention in any of its stereoisomeric forms or a
mixture of stereoisomeric forms in any ratio. For example, a subject of the invention
is a compound of the formula I which is selected from the series consisting of:
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid [2-(2-oxo-imidazolidinyl)-
ethyl]-amide,
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid cyclopropylamide,
2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
2-(2-Oxo-pyrrolidinyl)-N-[2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-
acetamide,
Isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-amide,
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid propylamide,
4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid (isoxazol
ylmethyl)-amide,
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid (2-
hydroxy-ethyl)-amide,
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
propylamide,
Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-
amino}-ethyl) ester,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazolylmethyl)-amide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid propylamide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (2-chloro-pyridin
ylmethyl)-amide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (1,5-dimethyl-1H-pyrazol
ylmethyl)-amide,
1,3,5-Trimethyl-1H-pyrazolesulfonic acid [2-(2-phenyl-chromanyloxy)-thiazol
ylmethyl]-amide,
2-((R)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
[2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl-amine,
or which is any one of these compounds, and its pharmaceutically acceptable salts,
wherein the compound of the formula I is a subject of the invention in any of its
stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, unless a
specific stereoisomeric form is specified with respect to any carbon atoms in the
respective compound.
Another subject of the invention is a compound of the formula I which is selected
from the series consisting of:
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid [2-(2-oxo-imidazolidinyl)-
ethyl]-amide,
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid cyclopropylamide,
2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
2-(2-Oxo-pyrrolidinyl)-N-[2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-
acetamide,
Isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-amide,
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid propylamide,
4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid (isoxazol
ylmethyl)-amide,
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid (2-
hydroxy-ethyl)-amide,
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
propylamide,
Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-
amino}-ethyl) ester,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazolylmethyl)-amide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid propylamide,
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (2-chloro-pyridin
ylmethyl)-amide,
2-((R)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide,
[2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl-amine,
or which is any one of these compounds, and its pharmaceutically acceptable salts,
wherein the compound of the formula I is a subject of the invention in any of its
stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, unless a
specific stereoisomeric form is specified with respect to any carbon atoms in the
respective compound.
In one embodiment of the invention, the compounds of the formula I are defined as
above in their generic definition or in any more specific definition or embodiment, with
the proviso that the compound of the formula I is not one of the following compounds,
which are named according to the Chemical Abstracts system of nomenclature:
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[1-
(1,5-dimethyl-1H-pyrazolyl)ethyl]-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-
[(1,3-dimethyl-1H-pyrazolyl)methyl]-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]-1,3,5-trimethyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]-1,5-dimethyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]-1,3,5-trimethyl-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[2-
(3,5-dimethyl-1H-pyrazolyl)ethyl]-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[(1-
ethylmethyl-1H-pyrazolyl)methyl]-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[(1-
methyl-1H-pyrazolyl)methyl]-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-,
5-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-
[(1,3-dimethyl-1H-pyrazolyl)methyl]-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]-1,5-dimethyl-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]methyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]ethyl-,
1H-Pyrazoleacetamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]
thiazolyl]methyl]-,
1H-Pyrazoleacetamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]
thiazolyl]methyl]methyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]ethyl-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[3-
(1H-pyrazolyl)propyl]-,
5-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[2-
(3-methyl-1H-pyrazolyl)ethyl]-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]ethyl-,
-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[2-(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
-Thiazolecarboxamide, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[(1-
ethyl-1H-pyrazolyl)methyl]-,
1H-Pyrazolepropanamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyran
yl)oxy]thiazolyl]methyl]-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]methyl(1-methylethyl)-,
-Thiazolecarboxamide, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[(1,5-
dimethyl-1H-pyrazolyl)methyl]-,
-Thiazolecarboxamide, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[1-
(1,5-dimethyl-1H-pyrazolyl)ethyl]-,
-Thiazolecarboxamide, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[1-
(1,3-dimethyl-1H-pyrazolyl)ethyl]-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]ethyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]-1,3-dimethyl-,
-Thiazolemethanamine, 2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-N-[2-
(1H-pyrazolyl)ethyl]-,
1H-Pyrazolesulfonamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
5-thiazolyl]methyl]methyl-,
1H-Pyrazolecarboxamide, N-[[2-[(3,4-dihydrophenyl-2Hbenzopyranyl)oxy]-
-thiazolyl]methyl]methyl-,
-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[(2R)(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
5-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[(2S)(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
-Thiazolecarboxamide, 2-[[(2R)-3,4-dihydrophenyl-2Hbenzopyranyl]oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-, and
-Thiazolecarboxamide, 2-[[(2S)-3,4-dihydrophenyl-2Hbenzopyranyl]oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-,
wherein in the excluded compounds the carbon atom in position 2 of the chroman
ring, which carries a phenyl group or 3-fluorophenyl group, is present in racemic form,
unless specified otherwise, and in another embodiment the excluded compounds are
excluded as the free compounds, i.e. not in the form of an addition salt with an acid,
and in the form of their 2,2,2-trifluoroacetates, i.e. their acid addition salts with
trifluoroacetic acid.
In another embodiment of the invention, the compounds of the formula I are defined
as above in their generic definition or in any of the more specific definitions or
embodiments, with the proviso that the compound of the formula I is not a compound
in which simultaneously the group Ar is an unsubstituted phenyl group, the groups
R3 and R4 are hydrogen, one of the groups R5 and R6 is hydrogen, the other of the
groups R5 and R6 is R40-(C -C )-alkyl-, and R7 is R40 or R40-(C -C )-alkyl-,
1 4 1 4
wherein R40 is pyrazolyl which is unsubstituted or substituted by one or more
identical or different (C -C )-alkyl substituents, and the carbon atom in position 2 of
the chroman ring which carries the group Ar is present in racemic form, and the
proviso that the compound of the formula I is not one of the following compounds,
which are named according to the Chemical Abstracts system of nomenclature:
-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[2-(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[(2R)(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
-Thiazolecarboxamide, N-[(1,5-dimethyl-1H-pyrazolyl)methyl][[(2S)(3-
fluorophenyl)-3,4-dihydro-2Hbenzopyranyl]oxy]-,
-Thiazolecarboxamide, 2-[[(2R)-3,4-dihydrophenyl-2Hbenzopyranyl]oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-, and
5-Thiazolecarboxamide, 2-[[(2S)-3,4-dihydrophenyl-2Hbenzopyranyl]oxy]-N-
[(1,5-dimethyl-1H-pyrazolyl)methyl]-,
and in another embodiment the excluded compounds are excluded as the free
compounds, i.e. not in the form of an addition salt with an acid, and in the form of
their 2,2,2-trifluoroacetates, i.e. their acid addition salts with trifluoroacetic acid.
In another embodiment of the invention, the compounds of the formula I are defined
as above in their generic definition or in any of the more specific definitions or
embodiments, provided that the compound of the formula I is not a compound in
which simultaneously the group Ar is unsubstituted phenyl or 3-fluorophenyl, the
groups R3 and R4 are hydrogen, one of the groups R5 and R6 is hydrogen, the other
of the groups R5 and R6 is R40-(C -C )-alkyl-, and R7 is R40 or R40-(C -C )-alkyl-,
1 4 1 4
wherein R40 is pyrazolyl which is unsubstituted or substituted by one or more
identical or different (C -C )-alkyl substituents, and in another embodiment the
excluded compounds are excluded as the free compounds, i.e. not in the form of an
addition salt with an acid, and in the form of their 2,2,2-trifluoroacetates, i.e. their acid
addition salts with trifluoroacetic acid.
Another subject of the present invention are processes for the preparation of the
compounds of the formula I which are outlined below and by which the compounds of
the formula I and intermediates occurring in the course of their synthesis are
obtainable. For example, one such process relates to the formation of compounds of
the formula I from chromanols of the formula II and 2-chloro-thiazoles of the
formula III, and includes the linkage of the thiazole ring to the chroman ring to give
compounds of the formula IV, and the subsequent conversion of the group Y into the
group R2 that is attached to the thiazole ring in the final compounds of the formula I.
Ar O
II S
Ar O
The groups Ar, R3 and R4 in the compounds of the formulae II, III and IV are defined
as in the compounds of the formula I, and additionally can functional groups be
present in protected form or in the form of a precursor group which is subsequently
converted into the final group. The group Y in the compounds of the formulae III and
IV, which group is subsequently transformed into the group R2 in the compound of
the formula I, is selected from the series consisting of R50-O-C(O)-, H-C(O)- and NC-,
wherein R50 is (C -C )-alkyl. The reaction of the compounds of the formulae II and III
is generally performed in an inert solvent, in particular an aprotic solvent, for example
an ether such as tetrahydrofuran (THF), dioxane or 1,2-dimethoxyethane (DME) or
an amide such as dimethylformamide (DMF), dimethylacetamide or N-
methylpyrrolidinone (NMP) in the presence of a base, for example a basic alkali
metal salt like an alkali metal carbonate such as sodium carbonate, potassium
carbonate or cesium carbonate, at temperatures from about 20°C to about 100°C, in
particular from about 40°C to about 60°C. In one embodiment of the invention, R50 is
(C -C )-alkyl, for example methyl or ethyl, in another embodiment it is tert-butyl.
Compounds of the formula IV in which the group Y is the group R50-O-C(O)-, which
are designated as compounds of the formula IVa, in particular compounds of the
formula IVa in which R50 is (C -C )-alkyl, can be reacted with amines of the formula
V under standard conditions for the aminolysis of esters, for example in a solvent
such as a hydrocarbon like toluene, a chlorinated hydrocarbon like dichloromethane,
1,2-dichloroethane or chlorobenzene or an ether like THF, dioxane or DME at
temperatures from about 20°C to about 120°C, to give compounds of the formula I in
which R2 is the group R5-N(R6)-C(O)-, i.e. compounds of the formula Ia.
C(O)-O-R50
Ar O V
C(O)-OH
Ar O
Compounds of the formula IV can also be transformed into compounds of the formula
Ia in a convenient manner by first converting the compound of the formula IVa into
the respective carboxylic acid of the formula VI, or a salt thereof, and reacting the
compound of the formula VI or its salt with an amine of the formula V under standard
conditions for the formation of amides from carboxylic acids. The groups Ar, R3, R4,
R5 and R6 in the compounds of the formulae IVa, V and VI are defined as in the
compounds of the formula I, and additionally can functional groups be present in
protected form or in the form of a precursor group which is subsequently converted
into the final group.
Compounds of the formula IVa can be converted into compounds of the formula VI
by treatment with an acid or base, for example by treatment with an alkali metal
hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a
solvent such as an ether like THF, dioxane or DME or an alcohol such as methanol
or ethanol, or a mixture of solvents, in particular an aqueous solvent or mixture of
solvents, or by treatment with hydrochloric acid or trifluoroacetic acid in a solvent
such as a chlorinated hydrocarbon like dichloromethane, an ether or an alcohol, in
particular in the case of a tert-butyl ester, at temperatures from about 20°C to about
100°C, followed by standard work-up procedures such as an acidification in case the
ester of the formula IVa is hydrolyzed in the presence of a base and a free carboxylic
acid of the formula VI is to be prepared, wherein the detailed conditions depend on
the particulars of the specific case, as usual, and are readily chosen by a person
skilled in the art. For the reaction with the compound of the formula V, the carboxylic
acid group HO-C(O)- in the compound of the formula VI is generally activated in situ
by means of a customary amide coupling reagent or converted into a reactive
carboxylic acid derivative which can be prepared in situ or isolated. For example, the
compound of the formula VI can be converted into an acid halide, e. g. by treatment
with thionyl chloride, phosphorus pentachloride or oxalyl chloride, or treated with an
alkyl chloroformate like ethyl chloroformate or isobutyl chloroformate to give a mixed
anhydride. Customary coupling reagents which can be employed, are
propanephosphonic anhydride, N,N'-carbonyldiazoles like N,N'-carbonyldiimidazole
(CDI), carbodiimides like 1,3-diisopropylcarbodiimide (DIC), 1,3-
dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)ethylcarbodiimide
hydrochloride (EDC), carbodiimides together with additives like 1-hydroxy-
benzotriazole (HOBT) or 1-hydroxyazabenzotriazole (HOAT), uronium-based
coupling reagents like O-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), O-(benzotriazolyl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU) or O-(cyano(ethoxycarbonyl)methyleneamino)-
N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), and phosphonium-based
coupling reagents like (benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate (BOP), (benzotriazolyloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyBOP) or bromotripyrrolidinophosphonium
hexafluorophosphate (PyBroP). The reaction of the activated compound of the
formula VI or a reactive derivative of the compound of the formula VI is generally
carried out in an inert solvent, for example a hydrocarbon like toluene, a chlorinated
hydrocarbon like dichloromethane, an ether like THF, dioxane or DME, an ester like
ethyl acetate or butyl acetate, a nitrile like acetonitrile, an amide like DMF or NMP, or
water, or a mixture of solvents, at temperatures from about -10°C to about 100°C, in
particular at temperatures from about 0°C to about 60°C. Favorably, the reaction is
carried out in the presence of a base such as a tertiary amine, like triethylamine,
ethyldiisopropylamine, N-methylmorpholine or pyridine, or an inorganic base such as
an alkali metal hydroxide, carbonate or hydrogencarbonate, like sodium hydroxide,
potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.
Compounds of the formula IV in which the group Y is the group H-C(O)-, i.e. an
aldehyde group or formyl group, which are designated as compounds of the formula
IVb, can be reacted with amines of the formula V, in particular amines in which at
least one of the groups R5 and R6 is different from hydrogen, in a reductive
amination reaction to give compounds of the formula I in which R2 is the group R5-
N(R6)-CH -, i.e. compounds of the formula Ib.
C(O)-H
N Ib
Ar O V
The groups Ar, R3 and R4 in the compounds of the formula IVb are defined as in the
compounds of the formula I, and additionally can functional groups be present in
protected form or in the form of a precursor group which is subsequently converted
into the final group. The reductive amination can be carried out with a complex
borohydride as reducing agent such as sodium cyanoborohydride or sodium
triacetoxyborohydride, which can favorably be used also in polymer-bound form, in a
solvent such an ether like THF, dioxane or DME, an alcohol like methanol or ethanol,
or an acid like acetic acid, or a mixture of solvents, at temperatures from about 0°C to
about 70°C.
Compounds of the formula IV in which the group Y is the group NC-, i.e. a nitrile
group or cyano group, which are designated as compounds of the formula IVc, can
be reduced to aminomethyl compounds of the formula It, which can then be acylated
with compounds of the formula VII and sulfonylated with compounds of the formula
VIII to give further compounds of the formula I in which R2 is the group R7-C(O)-NH-
CH - and the group R7-S(O) -NH-CH -, respectively, i.e. compounds of the formulae
2 2 2
Ic and Id.
CN CH -NH
Ar O Ar O
R7-S(O) -X2
R7-C(O)-X1
VII VIII
The groups Ar, R3, R4 and R7 in the compounds of the formulae It, IVc, VII and VIII
are defined as in the compounds of the formula I, and additionally can functional
groups be present in protected form or in the form of a precursor group which is
subsequently converted into the final group. The groups X1 and X2 in the
compounds of the formulae VII and VIII are nucleophilically substitutable leaving
groups, in particular chlorine, in which latter case the compounds of the formulae VII
and VIII are carboxylic acid chlorides and sulfonic acid chlorides. The groups X1 and
X2 can also be a hydroxy group, in which case the compounds of the formulae VII
and VIII are carboxylic acids and sulfonic acids which are generally activated in situ
by means of a customary amide coupling reagent or converted into a reactive
carboxylic acid derivative, such as the compound in which X1 or X2 is chlorine, for
the reaction with the compound of the formula It. The explanations on activating
agents and reaction conditions given above with respect to the reaction of the
compounds of the formula VI with the compounds of the formula V to give
carboxamides apply correspondingly to the reaction of the compounds of the
formulae VII and VIII with the compounds of the formula It to give carboxamides and
sulfonamides. The reduction of the nitrile group in the compounds of the formula IVc
to the aminomethyl group in the compounds of the formula It can be performed with
various reducing agents known to a person skilled in the art, such as complex metal
hydrides or boranes, or by catalytic hydrogenation in the presence of a
hydrogenation catalyst, for example Raney nickel, in a solvent such as an ether like
THF, dioxane or DME, an alcohol like methanol or ethanol, or water or a mixture of
solvents, at temperatures from about 0°C to about 80°C, the detailed conditions
being dependent on the chosen reducing agent and the particulars of the specific
case.
Compounds of the formula IV and It can be transformed into further compounds of
the formula I also according to other synthetic strategies. For example, in case
compounds of the formula Ib are to be prepared in which one of the groups R5 and
R6 is hydrogen and the other is a substituted methyl group, such as a group of the
type R14-CH -, a reductive amination reaction with a compound of the formula It and
an aldehyde of the formula R14-C(O)-H can be performed in a manner as described
above for the reaction of the compounds of the formulae IVb and V. Compounds of
the formulae Ib, Ic and Id can also be obtained by reducing a compound of the
formula IVa or a compound of the formula IVb to the respective compound in which
the group Y is a hydroxymethyl group HO-CH -, converting the hydroxy group into a
nucleophilically substitutable leaving group such as chlorine or bromine or a
sulfonyloxy group like methanesulfonyloxy, and reacting the obtained alkylating agent
with an amine of the formula V, an amide of the formula R7-C(O)-NH or a salt
thereof, or a sulfonamide of the formula R7-S(O) -NH or a salt thereof, respectively,
wherein in the compounds of the formulae R7-C(O)-NH and R7-S(O) -NH the
2 2 2
groups R7 are defined as in the compounds of the formula I and additionally
functional groups can be present in protected form or in the form of a precursor group
which is subsequently converted into the final group. Further, compounds of the
formulae IVa, IVb, IVc and VI can be converted into one another. If it is more
convenient in a specific case to react a compound of the formula II with a compound
of the formula III in which Y is either R50-O-C(O)- or H-C(O)- or NC-, the obtained
compound of the formula IV or a subsequently obtained compound of the formula VI
can be converted by standard procedures into compounds of the formula IV in which
Y has another meaning. For example, a carboxylic acid ester of the formula IVa or a
nitrile of the formula IVc can be reduced to the aldehyde of the formula IVb, or a
compound of the formula IVa or the formula VI can be converted into the
carboxamide and the latter dehydrated to the nitrile of the formula IVc, or an
aldehyde of the formula IVb can be oxidized to a carboxylic acid of the formula VI, or
a nitrile of the formula IVc can be hydrolyzed to the carboxylic acid of the formula VI.
For obtaining further compounds of the formula I, various transformations of
functional groups can be carried out under standard conditions in compounds of the
formula I obtained as described above, or in intermediates or starting compounds in
the synthesis of the compounds of the formula I. For example, a hydroxy group can
be reacted with a carboxylic acid or a reactive derivative thereof in a similar manner
as described above for the reaction of a carboxylic acid with an amine to give a
carboxylic acid ester. Etherifications of hydroxy groups can be performed by
alkylation with the respective halogen compound, for example a bromide or iodide, in
the presence of a base such an alkali metal carbonate like potassium carbonate or
cesium carbonate in an inert solvent such as an amide like DMF or NMP or a ketone
like acetone or butanone, or with the respective alcohol under the conditions of the
Mitsunobu reaction in the presence of a phosphine like triphenylphosphine or
tributylphosphine and an azodicarboxylic acid derivative like diethyl azodicarboxylate
or diisopropyl azodicarboxylate. By reaction with an isocyanate, a hydroxy group can
be converted into an N-substituted carbamic acid ester. By treatment with a suitable
halogenating agent, a hydroxy group can be converted into a halide. By treatment
with sulfur trioxide in the presence of pyridine, a hydroxy group can be converted into
the sulfuric acid mono ester. By treatment with a suitable phosphoramidite, such as
dibenzyl N,N-diisopropyl-phosphoramidite, diallyl N,N-diisopropylphosphoramidite or
di-tert-butyl N,N-diisopropyl-phosphoramidite of the formula (isopropyl) N-P(O-R55) ,
in which R55 is benzyl, allyl or tert-butyl, for example, in the presence of tetrazole
and subsequent oxidation, for example with a peracid like 3-chloro-perbenzoic acid, a
hydroxy group can be converted into its phosphoric acid ester dibenzyl ester,
phosphoric acid ester diallyl ester and phosphoric acid ester di-tert-butyl ester,
respectively, which can be cleaved to the phosphoric acid mono ester of the hydroxy
group, i.e. the compound which contains the group (HO) P(O)- attached to the
oxygen atom of the hydroxy group, by catalytic hydrogenation in the presence of a
palladium catalyst in the case of the dibenzyl ester, by a palladium-catalyzed
nucleophilic substitution in the case of the diallyl ester, and by treatment with an acid
such as trifluoroacetic acid in the case of the di-tert-butyl ester. By treatment with
chloromethyl chloroformate and subsequently with silver dibenzylphosphate, a
hydroxy group can be converted into the carbonic acid ester
dibenzyloxyphosphoryloxymethyl ester, which can be cleaved to the carbonic acid
ester phosphonooxymethyl ester of the hydroxy group. i.e. the compound which
contains the group (HO) P(O)-O-CH -O-C(O)- attached to the oxygen atom of the
hydroxy group, by catalytic hydrogenation in the presence of a palladium catalyst (cf.
). A halogen atom can be replaced with a variety of groups in a
substitution reaction which may also be a transition-metal catalyzed reaction. An
amino group can be modified under standard conditions for alkylation, for example by
reaction with a halogen compound or by reductive amination of a carbonyl compound,
or for acylation or sulfonylation, for example by reaction with an activated carboxylic
acid or a carboxylic acid derivative like an acid chloride or anhydride. A carboxylic
acid ester group can be hydrolyzed under acidic or basic conditions to give a
carboxylic acid. A carboxylic acid group can be activated or converted into a reactive
derivative as outlined above and reacted with an alcohol or an amine or ammonia to
give an ester or amide. A primary amide can be dehydrated to give a nitrile. A sulfur
atom in an alkyl-S- group or in a heterocyclic ring can be oxidized with a peroxide like
hydrogen peroxide or a peracid to give a sulfoxide moiety (S(O)) or a sulfone moiety
(S(O) ). A carboxylic acid group, carboxylic acid ester group and a ketone group can
be reduced to an alcohol, for example with a complex hydride such al lithium
aluminium hydride, lithium borohydride or sodium borohydride. A hydroxy group can
be oxidized to an oxo group by means of pyridinium chlorochromate or the Dess-
Martin periodinane reagent, for example. All such reactions in the preparation of the
compounds of the formula I are known per se and can be carried out in a manner
familiar to a person skilled in the art according to, or analogously, to procedures
which are described in the standard literature, for example in Houben-Weyl, Methods
of Organic Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or R. C.
Larock, Comprehensive Organic Transformations: A Guide to Functional Group
Preparations, 2. ed. (1999), John Wiley & Sons, and the references quoted therein.
The chromanols of the formula II which are employed in the synthesis of the
compounds of the formula IV described above, can be obtained by different
processes. In one of them, an acetophenone of the formula IX, which is substituted in
the benzene ring by a hydroxy group and a group G1 and can additionally be
substituted in the benzene ring and the acetyl group by substituents R4, is
condensed with an aldehyde of the formula X in the presence of a base to give a
chromanone of the formula XII and/or a chalcone of the formula XI, and an
obtained chalcone of the formula XI subsequently cyclized to the chromanone of
the formula XII.
Ar O
The groups Ar and R4 in the compounds of the formulae IX, X, XI and XII are defined
as in the compounds of the formula I, and additionally can functional groups be
present in protected form or in the form of a precursor group which is subsequently
converted into the final group. The group G1 in the compounds of the formulae IX, XI
and XII is a hydroxy group or bromine. When performing the reaction of the
compounds of the formulae IX and X in the presence of an alkali metal hydroxide
such as potassium hydroxide as the base in a solvent such as an alcohol like
methanol or ethanol at temperatures from about 30°C to about 70°C, the obtained
product is the chalcone of the formula XI. When performing the reaction of the
compounds of the formulae IX and X in the presence of a salt of a weak acid such as
ammonium acetate, for example, in a solvent such as acetic acid at temperatures
from about 100°C to about 120°C, the obtained product is a mixture of the chalcone
of the formula XI and chromanone of the formula XII. The compound of the
formula XI, as well as a mixture of the compounds of the formulae XI and XII, can be
employed in the cyclization reaction to give the compound of the formula XII, which
can be carried out by treating the starting material with an acid like hydrochloric acid
or with an amine like ethyldiisopropylamine and potassium fluoride, in a solvent such
as an alcohol like methanol or ethanol at temperatures from about 60°C to about
100°C.
The oxo group in the ring position 4 of the compounds of the formula XII is then
reduced to a CH group to give the compounds of the formula XIV, favorably
stepwise via the 4-hydroxy-chroman derivatives of the formula XIII.
Ar O
XIII
The groups Ar and R4 in the compounds of the formulae XIII and XIV are defined as
in the compounds of the formula I, and additionally can functional groups be present
in protected form or in the form of a precursor group which is subsequently converted
into the final group. The group G1 in the compounds of the formulae XIII and XIV is a
hydroxy group or bromine. The reduction of the compounds of the formula XII to the
compounds of the formula XIII can be carried out under standard conditions for the
reduction of a ketone to an alcohol, for example by means of a complex hydride as
reducing agent, or a borane derivative, such as the borane-tetrahydrofuran complex
in a solvent such as an ether like THF or dioxane, at temperatures from about 30°C
to about 80°C. The reduction of the compounds of the formula XIII to the compounds
of the formula XIV can be performed, for example, by treatment with a silane
reducing such as a trialkylsilane like triethylsilane and an acid such as trifluoroacetic
acid in a solvent such as a chlorinated hydrocarbon like dichloromethane at
temperatures from about 0°C to about 40°C. In case the group G1 in the compound
of the formula XIII and its precursor compounds is a hydroxy group, the obtained
compound of the formula XIV already is a compound of the formula II. In case the
group G1 in the obtained compound of the formula XIV is bromine, it can be
converted into a hydroxy group by metalation of the compound of the formula XIV
with a organolithium compound such as butyllithium and treatment with a trialkyl
borate such as triisopropyl borate in a solvent such as a hydrocarbon like heptane or
cyclohexane or an ether like THF or dioxane at temperatures from about -80°C to
about 0°C, followed by oxidative cleavage, for example by means of hydrogen
peroxide in the presence of a base such as sodium hydroxide.
Further processes for the preparation of chromanols of the formula II involve a
cyclization of a 3-hydroxypropyl-substituted benzene derivative of the formula XV,
which is substituted in the benzene ring by two suitable groups G2 and G3 and can
additionally be substituted in the benzene ring and the propyl group by substituents
R4, to give a chroman derivative of the formula XVI, in which the group G3 is then
converted into the hydroxy group present in the compounds of the formula II.
Ar O
G2 R4
XV XVI
The groups Ar and R4 in the compounds of the formulae XV and XVI are defined as
in the compounds of the formula I, and additionally can functional groups be present
in protected form or in the form of a precursor group which is subsequently converted
into the final group. The group G2 in the compounds of the formula XV can be a
hydroxy group or a nucleophilically substitutable leaving group, for example fluorine.
The group G3 in the compounds of the formulae XV and XVI can be bromine or (C -
C )-alkyl-O- such as methoxy, for example. In case G3 is bromine, the conversion of
the group G3 in the compound of the formula XVI into the hydroxy group in the
compound of the formula II can be performed as described above for the conversion
of the compounds of the formula XIV into the compounds of the formula II. In case
G3 is (C -C )-alkyl-O-, the conversion into the hydroxy group can be performed
according to standard procedures for ether cleavage, for example by treatment with
boron tribromide in a chlorinated hydrocarbon such as dichloromethane at
temperatures from about -20°C to about 10°C in the case of a methoxy group. In
case the group G2 is a hydroxy group, the cyclization of the compound of the formula
XV to the compound of the formula XVI can conveniently be performed under the
conditions of the Mitsunobu reaction by treatment with a phosphine such as
triphenylphosphine or tributylphosphine and an azodicarboxylic acid derivative such
as diethyl azodicarboxylate or diisopropyl azodicarboxylate in a solvent such as an
ether like THF or dioxane at temperatures from about 0° to about 30°C. In case the
benzene ring carrying G2 in the compound of the formula XV is susceptible to a
nucleophilic aromatic substitution and G2 is a leaving group such as fluorine, the
cyclization can be performed by treatment of the compound of the formula XV with a
base which enhances the nucleophilicity of the hydroxy group in position 3 of the
propyl group, for example an alkali metal amide or an alkali metal hydride like sodium
hydride, in an inert solvent such as an ether like THF or dioxane or an amide like
DMF or NMP at temperatures from about -20°C to about 100°C.
By cyclization of compounds of the formula XV also individual stereoisomeric forms
of the compounds of the formula XVI and II, and finally of compounds of the formula I,
can be conveniently be prepared in which the chiral carbon atom in position 2 of the
chroman ring system is present either in R configuration or in S configuration. For the
synthesis of such individual stereoisomers, which can otherwise be obtained, for
example, by chromatographic resolution on a chiral phase of a mixture of the
stereoisomers of the final compounds of the formula I or at any stage of the synthesis,
the individual stereoisomeric forms of the 3-hydroxypropyl-substituted benzene of the
formula XV are employed, i.e. the compounds of the formula XVa. Depending on the
cyclization reaction and the conditions chosen, the cyclization can proceed with
retention or inversion of the configuration of the chiral carbon atom to give the
individual stereoisomeric forms of the compounds of the formula XVI, i.e. the
compounds of the formula XVIa, which can be reacted further to the individual
stereoisomeric forms compounds of the formulae II and I. In the compounds of the
formulae XVa and XVIa are the groups Ar, R4, G2 and G3 defined as in the
compounds of the formula XV and XVI, respectively, and the depicted chiral carbon
atom is present, or is essentially present, either in R configuration or in S
configuration, as is indicated by the wavy wedge.
Ar O
XVIa
One embodiment of the present invention thus relates to a process for the
preparation of a compound of the formula I,
Ar O O
G2 R4
S R3
Ar O
which comprises cyclizing a compound of the formula XV to a compound of the
formula XVI, converting the compound of the formula XVI into a compound of the
formula II, reacting the compound of the formula II with a compound of the formula III
to give a compound of the formula IV, and converting the compound of the formula IV
into a compound of the formula I, wherein the groups Ar, R3 and R4 in the
compounds of the formulae II, III, IV, XV and XVI are defined as in the compounds of
the formula I, and additionally can functional groups be present in protected form or
in the form of a precursor group which is subsequently converted into the final group,
the group G2 in the compound of the formula XV is a hydroxy group or a
nucleophilically substitutable leaving group, for example fluorine, the group G3 in the
compounds of the formulae XV and XVI is bromine or (C -C )-alkyl-O-, and the group
Y in the compounds of the formulae III and IV is R50-O-C(O)-, H-C(O)- or NC-,
wherein R50 is (C -C )-alkyl.
Another embodiment of the present invention relates to the process described afore,
in which the chiral carbon atom carrying the group Ar in the compounds of the
formulae II, IV, XV and XVI is present, or is essentially present, in uniform
configuration, either in R configuration or in S configuration, i.e. to a process for the
preparation of a compound of the formula Iq,
Ar O Ar O
G2 R4
XVIa
S R2
Ar O
Ar O
Iq IVd
which comprises cyclizing a compound of the formula XVa to a compound of the
formula XVIa, converting the compound of the formula XVIVa into a compound of the
formula IIa, reacting the compound of the formula IIa with a compound of the formula
III to give a compound of the formula IVd, and converting the compound of the
formula IVd into a compound of the formula Iq, wherein the groups Ar, R2, R3 and
R4 in the compounds of the formulae Iq, IIa, III, IVd, XVa and XVIa are defined as in
the compounds of the formula I, and additionally can functional groups be present in
protected form or in the form of a precursor group which is subsequently converted
into the final group, the group G2 in the compound of the formula XVa is a hydroxy
group or a nucleophilically substitutable leaving group, for example fluorine, the
group G3 in the compounds of the formulae XVa and XVIa is bromine or (C -C )-
alkyl-O-, and the group Y in the compounds of the formulae III and IVd is R50-O-
C(O)-, H-C(O)- or NC-, wherein R50 is (C -C )-alkyl, wherein the chiral carbon atom
carrying the group Ar in the compounds of the formulae Iq, IIa, IVd, XVa and XVIa is
present, or is essentially present, in uniform configuration, either in R configuration or
in S configuration.
The compounds of the formula XV, including the stereoisomeric forms of the formula
XVa, which are employed in the cyclization reaction to the compounds of the
formulae XVI and XVIa described above, can be obtained according to, or
analogously to, various processes which are described in the literature. For example,
a 3-oxo-propionic acid ester of the formula XVII can be alkylated with a benzyl halide
of the formula XVIII to give a 3-oxo-propyl-substituted benzene derivative of the
formula XIX, in which the ketone group is then reduced to the alcohol group to give a
compound of the formula XV.
C(O)-O-R51
Ar O
XVII
G2 R4
XVIII
The groups Ar and R4 in the compounds of the formulae XVII, XVIII and XIX are
defined as in the compounds of the formula I, and additionally can functional groups
be present in protected form or in the form of a precursor group which is
subsequently converted into the final group. In the preparation of compounds of the
formula XV according to this process, the group G2 in the compounds of the
formulae XVIII and XIX is in particular a nucleophilically substitutable leaving group,
for example fluorine, and the group G3 in the compounds of the formulae XVIII and
XIX in particular is bromine. The group R51 in the compounds of the formula XVII is
(C -C )-alkyl, for example methyl or ethyl. The group X3 in the compounds of the
formula XVIII is a nucleophilically substitutable leaving group, for example chlorine or
bromine. The reaction of the compounds of the formulae XVII and XVIII to give the
compounds of the formula XIX is performed in an inert solvent such as an ether like
THF, dioxane or DME in the presence of base such as an alkali metal alkoxide or an
alkali metal hydride, for example sodium hydride, at temperatures from about 0°C to
about 50°C. By treatment of the obtained benzylated 3-oxo-propionic acid ester with
an acid, for example hydrochloric acid in an aqueous solvent such as an ether like
dioxane or an acid like acetic acid or a mixture of solvents at temperatures from
about 60°C to about 120°C the ester moiety is then saponified and decarboxylated to
give the ketone of the formula XIX. For the reduction of the ketone moiety in the
compounds of the formula XIX to the compounds of the formula XV, various reducing
agents can be employed, for example complex metal hydride such as sodium
borohydride or lithium borohydride in a solvent such as an ether or an alcohol. In an
asymmetric reduction reaction, by employing a chiral reducing agent, for example an
enantiomeric form of a chiral complex metal hydride or a chiral borane, such as an
alpha-pinene-based organoborane like B-chloro-diisopinocampheylborane, which is
commonly abbreviated as (-)-Ipc BCl or (-)-DipCl, and (+)-Ipc BCl or (+)-DipCl,
respectively, in an inert solvent such as an ether like THF or dioxane at temperatures
from about -40°C to about 30°C, conveniently the individual stereoisomeric forms of
the compounds of the formula XV can be obtained, i.e. compounds of the formula
XVa, which can be cyclized to the enantiomeric forms of the compounds of the
formula XVI, i.e. the compounds of the formula XVIa, as described above.
In another process for the preparation of compounds of the formula XV, an indan
one of the formula XX is subjected to a ring enlargement to give a chromanone of
the formula XXI, in which the lactone moiety can be reduced to an aldehyde moiety
which is present in the form of the cyclic hemiacetal of the formula XXII and which
can be reacted with a suitable organometal compound of the formula XXIII.
Ar-M
HO O
XXIII
XXII
The groups Ar and R4 in the compounds of the formulae XX, XXI, XXII and XXIII are
defined as in the compounds of the formula I, and additionally can functional groups
be present in protected form or in the form of a precursor group which is
subsequently converted into the final group. In the preparation of compounds of the
formula XV according to this process, the group G3 in the compounds of the
formulae XX, XXI and XXII is in particular a (C -C )-alkyl-O- group. The group M in
the compounds of the formula XXIII is a metal or a metal equivalent, for example
lithium. The conversion of the compound of the formula XX into the compound of the
formula XXI can be performed by treatment with a peracid such as 3-chloro-
perbenzoic acid in a solvent such as a chlorinated hydrocarbon like dichloromethane
at temperatures from about -10°C to about 30°C. For the reduction of the lactone
moiety in the compound of the formula XXI to the masked aldehyde moiety in the
compound of the formula XXII, a complex metal reducing agent can be used, such as
diisobutylaluminum hydride, in a solvent such as a hydrocarbon like cyclohexane or
toluene or a chlorinated hydrocarbon like dichloromethane or an ether like THF or
dioxane, or a mixture of solvents, at temperatures from about -80°C to about 30°C.
For the subsequent step, the compound of the formula XXIII is generally prepared in
situ from a suitable respective benzene or aromatic heterocycle or halogen-
substituted benzene or halogen-substituted aromatic heterocycle by metalation, for
example with an organolithium compound like butyllithium or a lithium amide like
lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide, and reacted with the
compound of the formula XXII in an inert solvent such as a hydrocarbon like heptane
or cyclohexane or an ether like THF or a mixture of solvents at temperatures from
about -80°C to about 30°C.
As already indicated, it can be advantageous or necessary in all reactions which are
carried out in the course of the preparation of the compounds of the formula I to
temporarily protect functional groups or have them initially present in the form of
precursor groups, and later deprotect them or convert them into the desired groups.
Appropriate synthesis strategies and protective groups and precursor groups which
are suitable for the respective case, are known to the person skilled in the art and
can be found in P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in
Organic Synthesis, 4. ed. (2007), John Wiley & Sons, for example. Examples of
protective groups which may be mentioned, are benzyl protective groups, for
example benzyl ethers of hydroxy compounds and benzyl esters of carboxylic acids,
from which the benzyl group can be removed by catalytic hydrogenation in the
presence of a palladium catalyst, tert-butyl protective groups, for example tert-butyl
esters of carboxylic acids, from which the tert-butyl group can be removed by
treatment with trifluoroacetic acid, acyl protective groups, for example ester and
amides of hydroxy compounds and amino compounds, which can be cleaved again
by acidic or basic hydrolysis, or alkoxycarbonyl protective groups, for example tert-
butoxycarbonyl derivatives of amino compounds, which can be cleaved again by
treatment with trifluoroacetic acid. Examples of precursors which may be mentioned
are halogen atoms which can be replaced by many other groups, or nitro groups
which can be converted, for example by catalytic hydrogenation, into amino groups
which can be diazotized and converted into a large number of groups.
The starting materials employed in the procedures outlined above are commercially
available or can be prepared according to procedures, or in analogy to procedures,
described in the literature. Procedures for the preparation of 2-chloro-thiazole
derivatives of the formula III, for example, are described in US 4168380, WO
01/17995 or I. Sawhney et al., J. Chem. Soc. Perkin Trans. 1 (1990), 329-331, for
example.
As is usual and applies to all reactions performed in the course of the synthesis of a
compound of the formula l, appropriate details of the conditions applied in a specific
preparation process, including the solvent, a base or acid, the temperature, the order
of addition, the molar ratios and other parameters, are routinely chosen by the skilled
person in view of the characteristics of the starting compounds and the target
compound and the other particularities of the specific case. As is also known by the
skilled person, not all processes described herein will in the same way be suitable for
the preparation of all compounds of the formula I and their intermediates, and
adaptations have to be made. In all processes for the preparation of the compounds
of the formula I, workup of the reaction mixture and the purification of the product is
performed according to customary methods known to the skilled person which
include, for example, quenching of a reaction mixture with water, adjustment of a
certain pH, precipitation, extraction, drying, concentration, crystallization, distillation
and chromatography. Also for the characterization of the product, customary
methods are used such as NMR, IR and mass spectroscopy.
Another subject of the present invention are the novel starting compounds and
intermediates occurring in the synthesis of the compounds of the formula I, including
the compounds of the formulae II, III, IV, IVa, IVb, IVc, IVd, V, VI, VII, VIII, IX, X, XI,
XII, XIII, XIV, XV, XVa, XVI, XVIa, XVII, XVIII, XIX, XX, XXI, XXII and XXIII, wherein
the groups Ar, R2, R3, R4, R5, R6, R7, R50, R51, G1, G2, G3, M, X1, X2, X3 and Y
are defined as above, in any of their stereoisomeric forms or a mixture of
stereoisomeric forms in any ratio, and their salts, and their use as synthetic
intermediates or starting compounds. All general explanations, specifications of
embodiments and definitions of numbers and groups given above with respect to the
compounds of the formula I apply correspondingly to the said intermediates and
starting compounds. A subject of the invention are in particular the novel specific
starting compounds and intermediates described herein. Independently thereof
whether they are described as a free compound and/or as a specific salt, they are a
subject of the invention both in the form of the free compounds and in the form of
their salts, and if a specific salt is described, additionally in the form of this specific
salt.
The compounds of the formula I inhibit the sodium-calcium exchanger (NCX),
especially the sodium-calcium exchanger of subtype 1 (NCX1), as can be
demonstrated in the pharmacological tests described below and in other
pharmacological tests which are known to a person skilled in the art, for example in
animal models in which the effect on heart function can be determined ex vivo or
in vivo. The compounds of the formula I and their pharmaceutically acceptable salts
therefore are valuable pharmaceutical active compounds. The compounds of the
formula I and their pharmaceutically acceptable salts can be used for the treatment of
heart failure, including acute and chronic congestive heart failure (CHF), systolic
heart failure, diastolic heart failure, heart failure with preserved ejection fraction,
diabetic heart failure and decompensated heart failure and the management of heart
failure in combination with a device, cardiac arrhythmias including atrial arrhythmias,
atrial fibrillation, atrial fibrillation in CHF patients, ventricular arrhythmias, ventricular
tachycardia, monomorphic ventricular tachycardia, polymorphic ventricular
tachycardia, Torsade-de-pointes tachycardia and ventricular arrhythmias in CHF
patients, stroke, dementia including Alzheimer's Disease, hypertension, cardiac
ischemia, renal failure, shock including hemodynamic shock, cardiogenic shock and
septic shock, age-related disorders, and diseases which are caused secondarily by
an NCX-related damage, for example. The treatment of diseases is to be understood
as meaning both the therapy of existing pathological changes or malfunctions of the
organism or of existing symptoms with the aim of relief, alleviation or cure, and the
prophylaxis or prevention of pathological changes or malfunctions of the organism or
of symptoms in humans or animals which are susceptible thereto and are in need of
such a prophylaxis or prevention, with the aim of a prevention or suppression of their
occurrence or of an attenuation in the case of their occurrence. For example, in
patients who on account of their disease history are susceptible to cardiac
arrhythmias or cardiac decompensation, by means of the prophylactic or preventive
medicinal treatment the occurrence or re-occurrence of arrhythmias or
decompensation can be prevented or their extent and sequelae decreased. The
treatment of diseases can occur both in acute cases and in chronic cases. The
compounds of the formula I and their pharmaceutically acceptable salts can further
be used in various disorders in order to achieve an improvement of the perfusion of
heart, brain and kidney, and in general in disorders in which intracellular calcium
homeostasis is disturbed, or the NCX is activated in an undesired manner, or an
inhibition of the NCX is intended by the physician for improving the patient's condition,
where the compounds of the formula I and their pharmaceutically acceptable salts
can also be employed in cases where only a certain partial inhibition of the NCX is
intended, for example by use of a low dosage.
The compounds of the formula I and their pharmaceutically acceptable salts can
therefore be used in animals, in particular in mammals and specifically in humans, as
a pharmaceutical or medicament on their own, in mixtures with one another, or in the
form of pharmaceutical compositions. A subject of the present invention also are the
compounds of the formula I and their pharmaceutically acceptable salts for use as a
pharmaceutical. A subject of the present invention also are pharmaceutical
compositions and medicaments which comprise at least one compound of the
formula I and/or a pharmaceutically acceptable salt thereof as an active ingredient, in
an effective dose for the desired use, and a pharmaceutically acceptable carrier, i.e.
one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or
excipients, and optionally one or more other pharmaceutical active compounds. A
subject of the present invention also are the compounds of the formula I and their
pharmaceutically acceptable salts for use as an anti-arrhythmic. A subject of the
present invention also are the compounds of the formula I and their pharmaceutically
acceptable salts for use in the treatment of the diseases mentioned above or below,
including the treatment of any one of the mentioned diseases, for example heart
failure, cardiac arrhythmias, stroke, dementia, hypertension, cardiac ischemia, renal
failure, shock, age-related disorders or diseases which are caused secondarily by an
NCX-related damage, wherein treatment of diseases comprises their therapy and
prophylaxis as mentioned above, or for use an inhibitor of the NCX. A subject of the
present invention also are the use of the compounds of the formula I and their
pharmaceutically acceptable salts for the manufacture of a medicament for the
treatment of the diseases mentioned above or below, including the treatment of any
one of the mentioned diseases, for example heart failure, cardiac arrhythmias, stroke,
dementia, hypertension, cardiac ischemia, renal failure, shock, age-related disorders
or diseases which are caused secondarily by an NCX-related damages, wherein
treatment of diseases comprises their therapy and prophylaxis as mentioned above,
or a medicament for inhibition of the NCX. A subject of the present invention also are
methods for the treatment of the diseases mentioned above or below, including the
treatment of any one of the mentioned diseases, for example heart failure, cardiac
arrhythmias, stroke, dementia, hypertension, cardiac ischemia, renal failure, shock,
age-related disorders or diseases which are caused secondarily by an NCX-related
damage, wherein treatment of diseases comprises their therapy and prophylaxis as
mentioned above, and a method for inhibiting the NCX, which comprise administering
an efficacious amount of at least one compound of the formula I and/or a
pharmaceutically acceptable salt thereof to a human or an animal which is in need
thereof. The compounds of the formula I and their pharmaceutically acceptable salts,
and pharmaceutical compositions and medicaments comprising them, can be
administered enterally, for example by oral or rectal administration, parenterally, for
example by intravenous, intramuscular or subcutaneous injection or infusion, or by
another type of administration such as topical, percutaneous, transcutaneous, nasal,
pharyngeal or inhalative administration, the preferred form of administration
depending on the particulars of the specific case. The compounds of the formula I
and their pharmaceutically acceptable salts can also be used in combination with
other pharmaceutical active compounds.
The pharmaceutical compositions and medicaments according to the invention
normally contain from about 0.5 to about 90 percent by weight of a compound or
compounds of the formula I or pharmaceutically acceptable salts thereof, and an
amount of active ingredient of the formula I and/or its pharmaceutically acceptable
salt which in general is from about 0.1 mg to about 1 g, in particular from about 0.2
mg to about 500 mg, for example from about 1 mg to about 300 mg, per dose unit.
Depending on the kind of the pharmaceutical composition and other particulars of the
specific case, the amount may deviate from the indicated ones. The production of the
pharmaceutical compositions and medicaments can be carried out in a manner
known per se and familiar to the person skilled in the art. For this, the compounds of
the formula I and/or their pharmaceutically acceptable salts are mixed together with
one or more solid or liquid vehicles and/or excipients, if desired also in combination
with one or more other pharmaceutical active compounds, and brought into a suitable
form for dosage and administration, which can then be used in human medicine or
veterinary medicine.
As vehicles, which may also be looked upon as diluents or solvents or bulking agents,
and excipients suitable organic and inorganic substances can be used which do not
react in an undesired manner with the compounds of the formula I. As examples of
types of excipients, or additives, which can be contained in the pharmaceutical
compositions and medicaments, lubricants, preservatives, gel formers, thickeners,
stabilizers, disintegrants, wetting agents, emulsifiers, dispersants, antifoaming agents,
salts, buffer substances, colorants, flavorings and antioxidants may be mentioned.
Examples of vehicles and excipients are water, physiological saline, vegetable oils
such as sunflower oil, animal oils such as fish liver oil, waxes, alcohols such as
ethanol, isopropanol, 1,2-propanediol, glycerol, polyols, polyethylene glycols,
polyvinylpyrrolidone, gelatin, gum arabic, cellulose, carbohydrates such as glucose,
lactose or starch like corn starch, magnesium carbonate, potassium phosphate,
sodium chloride, stearic acid and its salts such as magnesium stearate, talc, lanolin,
petroleum jelly, or mixtures thereof, for example mixtures of water or saline with one
or more organic solvents such as mixtures of water with alcohols.
For oral and rectal use, pharmaceutical forms such as, for example, tablets, coated
tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories,
solutions, including oily, alcoholic or aqueous solutions, or drops, furthermore
suspensions or emulsions, can be used. For parenteral use, for example by injection
or infusion, pharmaceutical forms such as solutions, for example aqueous solutions,
can be used. For topical use, pharmaceutical forms such as ointments, creams,
pastes, lotions, gels, sprays, foams, aerosols, solutions or powders can be used.
Pharmaceutical formulations such as, for example, aerosols and sprays may
comprise solutions, suspensions or emulsions of the active ingredient in a
pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such
solvents. The formulation may also comprise other pharmaceutical excipients such
as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a
pharmaceutical form normally comprises the active ingredient in a concentration of
about 0.1 to about 10%, in particular of about 0.3 to about 3% by weight.
As usual, the dosage of the compounds of the formula I and the frequency of
administration depend on the circumstances of the specific case and is adjusted by
the physician according to the customary rules and procedures. It depends, for
example, on the compound of the formula I administered and its potency and
duration of action, on the nature and severity of the individual syndrome, on the
gender, age, weight and the individual responsiveness of the human or animal to be
treated, on whether the treatment is acute or chronic or prophylactic, or on whether
further pharmaceutical active compounds are administered in addition to a compound
of the formula I. Normally, in the case of administration to an adult weighing about 75
kg, a dose from about 0.1 mg to about 100 mg per kg per day, in particular from
about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight),
is sufficient. The daily dose can be administered in the form of a single dose or
divided into a number of individual doses, for example two, three or four individual
doses. The administration can also be carried out continuously, for example by
continuous injection or infusion. Depending on the individual behavior in a specific
case, it may be necessary to deviate upward or downward from the indicated
dosages.
Besides as a pharmaceutical active compound in human medicine and veterinary
medicine, the compounds of the formula I can also be employed as an aid in
biochemical investigations or as a scientific tool or for diagnostic purposes, for
example in in vitro diagnoses of biological samples, if an inhibition of the NCX is
intended. The compounds of the formula I and their salts can also be used as
intermediates for the preparation of further pharmaceutical active substances.
The following examples illustrate the invention.
When example compounds containing a basic group were purified by preparative
high pressure liquid chromatography (HPLC) on reversed phase (RP) column
material and, as customary, the eluent was a gradient mixture of water and
acetonitrile containing trifluoroacetic acid, they were in part obtained in the form of
their acid addition salts with trifluoroacetic acid, depending on the details of the
workup such as evaporation or lyophilization conditions. In the names of the example
compounds and the structural formulae such contained trifluoroacetic acid is not
specified.
The prepared compounds were in general characterized by spectroscopic data and
chromatographic data, in particular mass spectra (MS) and HPLC retention times (Rt;
in min) which were obtained by combined analytical HPLC/MS characterization
(LC/MS), and/or nuclear magnetic resonance (NMR) spectra. Unless specified
otherwise, H-NMR spectra were recorded at 500 MHz in D -DMSO as solvent at 298
K. In the NMR characterization, the chemical shift (in ppm), the number of hydrogen
atoms (H) and the multiplicity (s: singlet, d: doublet, dd: double doublet, t: triplet, m:
multiplet; br: broad) of the peaks as determined on printouts are given. In the MS
characterization, in general the mass number (m/z) of the peak of the molecular ion
[M], e.g. [M ], or of a related ion such as the ion [M+1], e.g. [(M+1) ], i.e. the
protonated molecular ion [(M+H) ] ([MH ]), or the ion [M-1], e.g. [(M-1)‾], i.e. the
deprotonated molecular ion [(M-H)‾], which was formed depending on the ionization
method used, is given. Generally, the ionization method was electrospray ionization
(ESI ). The UV wavelength for HPLC detection generally was 220 nm. The
particulars of the LC/MS methods used are as follows. "ACN" means acetonitrile,
"TFA" means trifluoroacetic acid, and "FA" means "formic acid.
Method A
Column: Waters XBridge C18, 3.5 µm, 3x100 mm; temperature: 55°C; eluent A:
water + 0.05% TFA (trifluoroacetic acid); eluent B: ACN (acetonitrile) + 0.05% TFA;
flow rate: 1 ml/min; gradient: from 5% of B to 95% of B in 5 min.
Method B
Column: WatersXBridge C18, 2.5 µm, 4.6x50 mm ; temperature: 50°C; eluent A:
water + 0.05% TFA; eluent B: ACN + 0.05% TFA; flow rate: 1.7 ml/min; gradient: 5%
B for 0.2 min, then to 95% of B in 2.2 min, then 95% of B for 1.1 min, then to 5% of B
in 0.1 min, then 5% of B for 0.9 min.
Method C
Column: Atlantis T3 C18, 3 µm, 3x100 mm; temperature: 55°C; eluent A: water +
0.05% TFA; eluent B: ACN + 0.05% TFA; flow rate: 1 ml/min; gradient: from 5 of B to
95% of B in 5 min.
Method D
Column: Acquity BEH C18, 1.7 µm, 2.1x50 mm; temperature: 40°C; eluent A: water +
0.05% TFA; eluent B: ACN + 0.035% TFA; flow rate: 1.0 ml/min; gradient: from 2% of
B to 100% of B in 1.6 min, then 100% of B for 0.5 min, then to 2% of B in 0.4 min,
then 2% of B for 0.5 min.
Method E
Column: Merck Chromolith FastGrad RP-18e, 1.6 µm, 2x50 mm; temperature: 50°C;
eluent A: water + 0.05% TFA; eluent B: ACN+ 0.05% TFA; flow rate: 2.0 ml/min;
gradient: 2% of B for 0.2 min, then to 98% of B in 2.2 min, then 98% of B for 0.8 min,
then to 2% of B in 0.1 min, then 2% of B for 0.7 min.
Method F
Column: Kromasil C18, 3.5 µm, 2x50 mm; temperature: 40°C; eluent A; 5 mM
aqueous ammonium acetate solution + 3% of ACN; eluent B: ACN; flow rate: 0.8
ml/min; gradient: from 0% of B to 100% of B in 5.5. min, 100% of B for 1.5 min, then
to 0% of B in 0.1 min, then 0% of B for 2.9 min.
Method G
Column: YMC-Pack Jsphere H80, 4 µM, 2.1x33 mm; temperature: room temperature;
eluent A: water + 0.05% TFA; eluent B: ACN + 0.05% TFA; flow rate: 1 ml/min;
gradient: 2% of B for 1.0 min, then to 95% of B in 4 min, then 95% of B for 1.25 min.
Method H
Column: Waters UPLC BEH C18, 1.7 µm, 2.1x50 mm; temperature: 55°C; eluent A:
water + 0.1% FA; eluent B: ACN + 0.08% FA; flow rate: 0.9 ml/min; gradient: from
5% of B to 95% of B in 1.1 min, then 95% of B for 0.6 min, then to 5% of B in 0.1 min,
then 5% of B for 0.2 min.
Method I
Column: Waters BEH C18, 1.7 µm, 2.1x50 mm; temperature: 50°C; eluent A: water +
0.1% FA; eluent B: ACN + 0.1% FA; flow rate: 0.8 ml/min; gradient: from 5% of B to
6% of B in 0.05 min, then to 100% of B in 2.45 min.
Method J
Column:Waters XBridge C18, 2.5 µm, 4.6x50 mm; temperature: 45°C; eluent A:
water + 0.1% FA; eluent B: ACN + 0.1% FA; flow rate: 1.3 ml/min; gradient: from 3%
of B to 60% of B in 3.5 min, then to 98% of B in 0.5 min, then 98% of B for 1 min,
then to 3% of B in 0.2 min, then 3% of B for 1.3 min.
Method K
Column: Waters UPLC BEH C18 2, 1.7 µm, 1x50 mm; temperature: 55°C; eluent A:
water + 0.05% FA; eluent B: ACN + 0.035% FA; flow rate: 0.9 ml/min; gradient: from
% of B to 95% of B in 1.1 min, then 95% of B for 0.6 min, then to 5% of B in 0.1 min,
then 5% of B for 0.2 min.
Method L
Column: YMC-Pack Jsphere H80, 4µm, 2.1x33 mm; temperature: room temperature;
eluent A: water + 0.05% TFA; flow rate: 1 ml/min; eluent B: methanol + 0.05% TFA ;
gradient: 2% of B for 1 min, then to 95% of B in 4 min, then 95% of B for 1.25 min.
Method M
Column: Acquity BEH C18, 1.7 µm, 2.1x50 mm; temperature: 40°C; eluent A: water +
0.05% FA; eluent B: ACN + 0.035% FA; flow rate: 1.0 ml/min; gradient: from 2% of B
to 100% of B in 1.6 min, then 100% of B for 0.5 min, then to 2% of B in 0.4 min, then
2% of B for 0.5 min.
Method N
Column: Waters UPLC BEH C18, 1.7 µm, 2.1x50 mm; temperature: 55°C; eluent A:
water + 0.05% FA; eluent B: ACN + 0.035% FA; flow rate: 0.9 ml/min; gradient: from
% of B to 95% of B in 1.1 min, then 95% of B for 0.6 min, then to 5% of B in 0.2 min;
then 5% of B for 0.1 min.
Method O
Column: Waters BEH Shield RP18, 1.7. µm, 2.1x50 mm; temperature: 50°C; eluent
A: water + 0.1% of FA; eluent B: ACN + 0.1% of FA; flow rate: 0.8 ml/min; gradient:
from 5% of B to 6% of B in 0.05 min, then to 100% of B in 2.45 min.
Exemplary synthesis examples
Example A
(E)(2,5-Dihydroxy-phenyl)(5-fluoro-pyridinyl)-propenone and 2-(5-fluoro-
pyridinyl)hydroxy-chromanone
F OH
N HO
2,5-Dihydroxy-acetophenone (3.4 g, 22.4 mmol), 5-fluoro-pyridinecarbaldehyde
(3.1 g, 24.6 mmol, 1.1 eq) and ammonium acetate (2.2 g, 29.1 mmol, 1.3 eq) were
suspended in acetic acid (100%, 70 ml) and heated to reflux for 8 h. The solution was
allowed to reach room temperature. The volume of the resulting suspension was
reduced to half of the volume under reduced pressure. The mixture was poured on
ice water and neutralized with caution using sodium carbonate. The aqueous layer
was washed with ethyl acetate and the remaining precipitate filtered. Solid (E)(2,5-
dihydroxy-phenyl)(5-fluoro-pyridinyl)-propenone (2.4 g, 42%) was obtained as a
brownish solid and used in the cyclization reaction without further purification. The
remaining aqueous solution was extracted with ethyl acetate and the combined
organic layers dried with sodium sulfate, filtered, the solvent removed under reduced
pressure and the resulting solid digested with few dichloromethane. 2-(5-Fluoro-
pyridinyl)hydroxy-chromanone was obtained as a brown solid (2.3 g, 39%)
and used in the next step without further purification.
(E)(2,5-Dihydroxy-phenyl)(5-fluoro-pyridinyl)-propenone (2.4 g, 9.3 mmol)
was suspended in methanol (55 ml) and potassium fluoride (2.7 g, 46.3 mmol, 5 eq)
and diisopropylethylamine (1.2 g, 9.3 mmol, 1 eq) were added. The mixture was
heated to reflux for 8 h and afterwards allowed to reach room temperature. The
solvent was removed under reduced pressure. The resulting residue was suspended
in water and washed with ethyl acetate. The mixture was filtered and the layers
separated. The organic layer was washed with water, dried with sodium sulfate,
filtered, the solvent removed under reduced pressure and the resulting solid digested
with few dichloromethane. 2-(5-Fluoro-pyridinyl)hydroxy-chromanone was
obtained as a brown solid (2.1 g, 88%) and used in the next step without further
purification.
According to the described procedure, also the following chromanones were
synthesized:
2-(6-Chloro-pyridinyl)hydroxy-chromanone
6-Hydroxy(6-methyl-pyridinyl)-chromanone
6-Hydroxymethylphenyl-chromanone
2-(2-Fluoromethoxy-phenyl)hydroxy-chromanone
6-Hydroxymethylphenyl-chromanone
Example B
(E)(5-Bromohydroxy-phenyl)o-tolyl-propenone and 6-bromoo-tolyl-
chromanone
O Br
To a solution of o-tolylaldehyde (4.1 g, 33.7 mmol, 1.1 eq) and 5-bromohydroxy-
acetophenone (6.9 g, 32.1 mmol) at room temperature in ethanol (100 ml) powdered
potassium hydroxide (5.2 g, 93 mmol, 5 eq) was added and the suspension was
stirred at 50°C for 3 h while a red solution formed. The solution was allowed to reach
room temperature and poured on ice. The aqueous mixture was adjusted to pH < 7
using aqueous hydrochloric acid. The resulting yellow suspension was stirred till a
yellow solid formed, and the precipitate filtered, washed with water and dried. The
yellow (E)(5-bromohydroxy-phenyl)o-tolyl-propenone (9.6 g, 94%) was used
in the cyclization reaction without further purification.
To a solution of (E)(5-bromohydroxy-phenyl)o-tolyl-propenone (9.6 g, 30.3
mmol) in ethanol (130 ml) concentrated aqueous hydrochloric acid was added (1.5
ml). The solution was heated to reflux for 5 h. Afterwards the solution was cooled to
room temperature and the solvents was removed under reduced pressure. The
resulting red 6-bromoo-tolyl-chromanone (9.5 g, 100%) was used in the next
step without further purification.
According to the described procedure, also the following chromanones were
synthesized:
2-(3-Fluoro-phenyl)hydroxy-chromanone
6-Bromo(3-isopropoxy-phenyl)-chromanone
6-Bromo(2-ethyl-phenyl)-chromanone
6-Hydroxythiophenyl-chromanone
2-(2,5-Difluoro-phenyl)hydroxy-chromanone
6-Bromo(2,6-dimethyl-phenyl)-chromanone
6-Hydroxy(4-methanesulfonyl-phenyl)-chromanone
6-Bromo(5-fluoromethyl-phenyl)-chromanone
6-Hydroxypyridinyl-chromanone
Example C
6-Bromoo-tolyl-chromanol and 6-bromoo-tolyl-chroman
To a solution of 6-bromoo-tolyl-chromanone (11.0 g, 34.7 mmol) in
tetrahydrofuran (100 ml) at room temperature a solution of borane tetrahydrofuran
adduct (1M in tetrahydrofuran, 86.7 ml, 2.5 eq) was added dropwise. The solution
was heated to reflux for 1 h, cooled to room temperature and added with caution to a
mixture of ice water and 1N aqueous hydrochloric acid. The aqueous layer was
extracted with dichloromethane, and the combined organic layers washed with water,
dried with sodium sulfate and filtered and the solvent removed under reduced
pressure. 6-Bromoo-tolyl-chromanol was obtained as a yellow oil (11.1 g,
100%) and used in the reduction to the chroman without further purification.
To a solution of 6-bromoo-tolyl-chromanol (11.9 g, 37.3 mmol) in
dichloromethane (130 ml) at 0°C triethylsilane (29.6 g, 255 mmol, 6.8 eq) and
trifluoroacetic acid (75 ml, 27 eq) were added. The solution was stirred at room
temperature for 2.5 h. The solvent was removed under reduced pressure and the
residue separated between water and ethyl acetate. The aqueous layer was
extracted with ethyl acetate and the combined organic layers washed with water and
saturated aqueous solution of sodium hydrogencarbonate, dried with sodium sulfate
and filtered, and the solvent removed under reduced pressure. The crude product
was purified by column chromatography (silica gel; ethyl acetate/heptane gradient).
6-Bromoo-tolyl-chroman was obtained as a pale yellow oil (7.10 g, 63%).
According to the described procedure, also the following chroman derivatives were
synthesized:
2-(3-Fluoro-phenyl)-chromanol
6-Bromo(3-isopropoxy-phenyl)-chroman
6-Bromo(2-ethyl-phenyl)-chroman
2-(6-Methyl-pyridinyl)-chromanol
2-(2,5-Difluoro-phenyl)-chromanol
6-Bromo(2,6-dimethyl-phenyl)-chroman
6-Bromo(4-methanesulfonyl-phenyl)-chroman
6-Bromo(5-fluoromethyl-phenyl)-chroman
2-(6-Chloro-pyridinyl)-chromanol
2-Pyridinyl-chromanol
2-Thiophenyl-chromanol
2-(5-Fluoro-pyridinyl)-chromanol
7-Methylo-tolyl-chromanol
2-(2-Fluoromethoxy-phenyl)-chromanol
3-Methylphenyl-chromanol
Example D
(S)Bromoo-tolyl-chroman
a) 3-(5-Bromofluoro-phenyl)o-tolyl-propanone
Sodium hydride (60% in oil, 2.1 g, 52 mmol) and methyl 3-oxoo-tolylpropanoate
(10 g, 52 mmol) were suspended in tetrahydrofuran and 4-bromo(bromomethyl)
fluoro-benzene (15.3 g, 57 mmol) was added. After complete conversion, the mixture
was quenched with ice and a saturated solution of ammonium chloride and extracted
with n-heptane. The combined organic layers were washed once with a saturated
solution of ammonium chloride, water and brine. The organic layer was dried over
magnesium sulfate and evaporated to dryness. The obtained yellow oil was dissolved
in 25 ml of acetic acid, 25 ml of concentrated hydrochloric acid and 20 ml of 1,4-
dioxane and heated under reflux for 4 h until LC/MS showed consumption of the
starting material. 50 ml of water and 100 ml of tert-butyl methyl ether were added and
the product was extracted. The combined organic layers were washed once with
saturated solution of ammonium chloride, water and brine. The organic layer was
dried over magnesium sulfate and evaporated to dryness. The residue was purified
by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 11.2 g
of 3-(5-bromofluoro-phenyl)o-tolyl-propanone as a colorless oil.
b) (S)(5-Bromofluoro-phenyl)o-tolyl-propanol
1 3-(5-Bromofluoro-phenyl)o-tolyl-propanone (14 g, 43.6 mmol) was diluted
with 20 ml of dry tetrahydrofuran and added dropwise to a solution of (−)-B-chloro-
diisopinocampheyl-borane ((-)-DipCl, 27.96 g, 87.2 mmol) in 100 ml of dry
tetrahydrofuran while maintaining the temperature between -30°C and -25°C. After 6
h, LC/MS showed complete conversion of the starting material. The cold mixture was
quenched with 10 ml of methanol and 10 g of sodium hydrogencarbonate and
allowed to come to room temperature. The solvents were removed in vacuum and
the obtained yellow oil was dissolved in 200 ml of ethyl acetate and a saturated
solution of ammonium chloride. The phases were separated and the organic layer
was washed once with 50 ml of brine, dried over magnesium sulfate and evaporates
to give 45 g of a yellow oil. This oil was purified by column chromatography (silica gel,
heptane/ethyl acetate gradient) to give 11.2 g of (S)(5-bromofluoro-phenyl)o-
tolyl-propanol as a colorless oil.
Ratio of enantiomers (HPLC; column: Chiralcel OJ-H, 250 x 4.6 mm; eluent heptane/
ethyl acetate/methanol 20:1:1): (S):(R) = 99.4:0.6
c) (S)Bromoo-tolyl-chroman
3-(5-Bromofluoro-phenyl)o-tolyl-propanol (10.5 g) was dissolved in 10 ml of
dry N-methylpyrrolidinone, and the solution was added dropwise to a suspension
of sodium hydride (60% in oil, 1.56 g, 39 mmol) in 20 ml of dry N-methylpyrrolidin
one at 60°C. After complete addition the mixture was stirred at 60°C to reach
complete consumption of the starting material after 12 h. Then the mixture was
quenched on ice and a saturated solution of ammonium chloride and extracted with
n-heptane. The combined organic layers were washed once with a saturated solution
of ammonium chloride, water and brine. The organic layer was dried over
magnesium sulfate and evaporated to give 12 g of a clear oil. This oil was purified by
column chromatography (silica gel, heptane/ethyl acetate gradient) to give 7.7 g of
(S)bromoo-tolyl-chroman as a colorless oil.
Example E
2-o-Tolyl-chromanol
To a solution of 6-bromoo-tolyl-chroman (1 g, 3.3 mmol) in tetrahydrofuran (3 ml)
at -78°C n-butyllithium (2.2 M in cyclohexane, 1.8 ml, 1.2 eq) was slowly added and
the mixture kept at -78°C for 30 min. Triisopropyl borate (1.9 g, 2.3 ml, 9.9 mmol, 3
eq) was added and stirring was continued at the same temperature for 1 h. The cold
solution was poured in a solution of ethanol (1.1 ml), water (3.0 ml) and aqueous
sodium hydroxide (8 M, 1.6 ml). To this solution hydrogen peroxide (aqueous 35%,
0.9 ml, 3.1 eq) was slowly added while the temperature was kept < 30°C. Stirring at
room temperature was continued for 15 min, the suspension was cooled to 0°C and
adjusted to pH < 7 using aqueous hydrochloric acid. To the resulting solution a
saturated aqueous solution of sodium sulfite (4 ml) was added and the aqueous layer
extracted with ethyl acetate. The combined organic layers were dried with sodium
sulfate and filtered, and the solvent removed under reduced pressure. The crude
product was purified by column chromatography (silica gel; ethyl acetate/heptane
gradient). 2-o-Tolyl-chromanol was obtained as a pale yellow solid (480 mg, 60%).
According to the described procedure, also the following chromanols were
synthesized:
2-(3-Isopropoxy-phenyl)-chromanol
2-(2-Ethyl-phenyl)-chromanol
(S)o-Tolyl-chromanol
2-(4-Methanesulfonyl-phenyl)-chromanol
2-(5-Fluoromethyl-phenyl)-chromanol
2-(2,6-Dimethyl-phenyl)-chromanol
Example F
2-Pyrazinyl-chromanol
a) 6-Methoxy-chromanone
To a solution of 5-methoxy-indanone (4.2 g, 25.9 mmol) in 240 ml of
dichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g,
51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) was added portionwise,
and the reaction mixture was stirred at 0°C for 2 h and at room temperature overnight.
The precipitate was filtered off and washed with dichloromethane. The filtrate was
washed with saturated solution of sodium hydrogencarbonate and dried with sodium
sulfate. After evaporation of the solvent, 6-methoxy-chromanone (3.68 g, 80%)
was obtained as an orange oil which was used without further purification.
b) 6-Methoxy-chromanol
A solution of 6-methoxy-chromanone (3.66 g, 20.53 mmol) in 300 ml of
dichloromethane was cooled to -70°C, and a solution of diisobutylaluminium hydride
(40 ml of a 1M solution in toluene, 40 mmol) was added dropwise. The solution was
stirred at -70°C for 2 h, and then ethyl acetate (10 ml) was added. After stirring for 15
min, 200 ml of a saturated solution of Rochelle salt was added dropwise, and the
mixture was warmed to room temperature. 200 ml of ethyl acetate were added, and
the mixture was stirred vigorously for 2 h and then decanted. The organic layer was
washed with water and brine and dried with sodium sulfate, and the solvent removed
under reduced pressure. The crude product was purified by chromatography on silica
gel (ethyl acetate in cyclohexane) to afford 2.90 g of white crystals (78%).
c) 2-(3-Hydroxypyrazinyl-propyl)methoxy-phenol
A solution of 2,2,6,6-tetramethyl-piperidine (8.5 ml, 50.4 mmol) in 200 ml of
anhydrous tetrahydrofuran was cooled to -30°C, n-butyllithium (20 ml of a 2.5 M
solution in hexane, 50 mmol) was added dropwise, and the mixture stirred for 30 min
at 0°C. After cooling at -70°C, a solution of pyrazine (4.0 g, 49.9 mmol) in 50 ml of
anhydrous tetrahydrofuran was added dropwise. After 10 min at -70°C, 6-methoxy-
chromanol (1.8 g, 10.0 mmol) was added and stirring was continued at -70°C for
1.5 h. The reaction mixture was quenched with 20 ml of water and hydrochloric acid
added until pH 5-6 was reached. After extraction with ethyl acetate, the organic layer
was washed with water and brine, dried with sodium sulfate and concentrated. The
obtained crude orange oil (960 mg) was used without further purification.
d) 2-(6-Methoxy-chromanyl)-pyrazine
Diethyl azodicarboxylate (0.87 ml, 5.53 mmol) was added dropwise at room
temperature to a mixture of 2-(3-hydroxypyrazinyl-propyl)methoxy-phenol
(960 mg, 3.69 mmol) and triphenylphosphine (1.45 g, 5.53 mmol) in 20 ml of
tetrahydrofuran. After stirring at 20°C for 1 h, the reaction mixture was concentrated
and purified by chromatography on silica gel (ethyl acetate in cyclohexane). 2-(6-
Methoxy-chromanyl)-pyrazine was obtained as white crystals (665 mg, 74%).
e) 2-Pyrazinyl-chromanol
A solution of 2-(6-methoxy-chromanyl)-pyrazine (663 mg, 2.74 mmol) in 50 ml of
anhydrous dichloromethane was cooled to -10°C, and a solution of boron tribromide
(9.6 ml of 1M solution in dichloromethane, 9.6 mmol) was added dropwise. After
stirring at 0°C for 1 h, 1 ml of boron tribromide solution was added and the reaction
mixture was stirred at 0°C for 1.5 h. The reaction mixture was quenched by slow
addition of water, and after 10 min neutralized by addition of a sodium
hydrogencarbonate solution. After decantation and extraction with dichloromethane,
the organic layer was dried over sodium sulfate and concentrated in vacuo. After
chromatography on silica gel (methanol in dichloromethane), 2-pyrazinyl-chroman-
6-ol was obtained as a yellow powder (625 mg, 100%).
Example G
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
A suspension of 2-o-Tolyl-chromanol (2.5 g, 10.4 mmol), methyl 2-chloro-thiazole-
5-carboxylate (1.9 g, 10.6 mmol, 1.02 eq) and potassium carbonate (1.9 g, 1.3 eq) in
dimethylformamide (30 ml) was stirred at 50°C for 10 h. The suspension was cooled
to room temperature and diluted with water. The aqueous layer was extracted with
ethyl acetate and the combined organic layers washed with water, dried with sodium
sulfate and filtered, and the solvent was removed under reduced pressure. The crude
product was purified by column chromatography (silica gel; ethyl acetate/heptane
gradient). The product was obtained as a pale yellow solid (3.87 g, 98%).
According to the described procedure, also the following 2-(chromanyloxy)-
thiazole derivatives were synthesized:
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
4-Chloro(2-phenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-(2-Phenyl-chromanyloxy)-thiazolecarbonitrile
4-Methyl(2-phenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-(2-Phenyl-chromanyloxy)-thiazolecarbaldehyde
2-(2-Phenyl-chromanyloxy)trifluoromethyl-thiazolecarboxylic acid methyl
ester
2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazolecarbonitrile
2-[2-(4-Methanesulfonyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl
ester
4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-(2-Pyridinyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl
ester
2-[2-(2,5-Difluoro-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-[2-(5-Fluoro-pyridinyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-[2-(2-Ethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-(2-Thiophenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-[2-(6-Chloro-pyridinyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-(2-Pyrazinyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-[2-(6-Methyl-pyridinyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-(2-o-Tolyl-chromanyloxy)-thiazolecarbonitrile
2-[2-(3-Isopropoxy-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl ester
2-((S)Phenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-[2-(2-Fluoromethoxy-phenyl)-chromanyloxy]-thiazolecarboxylic acid methyl
ester
2-(7-Methylo-tolyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
2-(3-Methylphenyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
Example H
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid
To a solution of 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid methyl ester
(300 mg, 0.8 mmol) in tetrahydrofuran (5.5 ml) and methanol (1.0 ml) at room
temperature a solution of lithium hydroxide (18.9 mg, 1.0 eq) in water (1.0 ml) was
added and the mixture stirred for 3 h. The solvent was removed under reduced
pressure and the resulting residue dissolved in water and lyophilized. The obtained
white 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid lithium salt (100%
yield) was used in the formation of 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic
acid amides without further purification. For the preparation of the free acid, the crude
lithium salt was dissolved in water and the resulting solution acidified with aqueous
hydrochloric acid. The resulting suspension was filtered and the precipitate washed
with water. The obtained 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid was
dried under reduced pressure. It can be used in the next step without further
purification as described for the lithium salt.
According to the described procedure, also the following 2-(chromanyloxy)-
thiazolecarboxylic acids in the form of the free acid or its lithium salt were
synthesized:
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid
4-Chloro(2-phenyl-chromanyloxy)-thiazolecarboxylic acid
4-Methyl(2-phenyl-chromanyloxy)-thiazolecarboxylic acid
2-(2-Phenyl-chromanyloxy)trifluoromethyl-thiazolecarboxylic acid
2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-[2-(4-Methanesulfonyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid
2-(2-Pyridinyl-chromanyloxy)-thiazolecarboxylic acid
2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-[2-(2,5-Difluoro-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-[2-(5-Fluoro-pyridinyl)-chromanyloxy]-thiazolecarboxylic acid
2-[2-(2-Ethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-(2-Thiophenyl-chromanyloxy)-thiazolecarboxylic acid
2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-[2-(6-Chloro-pyridinyl)-chromanyloxy]-thiazolecarboxylic acid
2-(2-Pyrazinyl-chromanyloxy)-thiazolecarboxylic acid
2-[2-(3-Isopropoxy-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-((S)Phenyl-chromanyloxy)-thiazolecarboxylic acid
2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid
2-[2-(2-Fluoromethoxy-phenyl)-chromanyloxy]-thiazolecarboxylic acid
2-(7-Methylo-tolyl-chromanyloxy)-thiazolecarboxylic acid
2-(3-Methylphenyl-chromanyloxy)-thiazolecarboxylic acid
Example J
2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide
To a solution of 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid lithium salt
(100 mg, 0.27 mmol) in dimethylformamide (2 ml) 1-(3-dimethylaminopropyl)
ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol, 1.4 eq), 1-hydroxy-benzotriazole
(51 mg, 0.38 mmol, 1.4 eq) and N-methylmorpholine (68 mg, 0.67 mmol, 2.5 eq)
were added and the mixture was stirred at room temperature for 15 min.
Ethanolamine (25 mg, 0.40 mmol, 1.5 eq) was added and stirring was continued for
16 h. The mixture was diluted with water and the aqueous layer extracted with ethyl
acetate. The combined organic layers were washed with a diluted aqueous solution
of sodium carbonate and brine, dried over sodium sulfate and filtered, and the
solvent was removed under reduced pressure. The crude product was purified by
column chromatography (silica gel, ethyl acetate/methanol gradient). The desired
compound was obtained as a white powder (43 mg, 39%).
Example K
[2-(2-o-Tolyl-chromanyloxy)-thiazolylmethyl]amine
To a solution of 2-(2-o-tolyl-chromanyloxy)-thiazolecarbonitrile (2.3 g, 6.6 mmol)
in tetrahydrofuran (100 ml) an aqueous suspension of Raney nickel (approximately
500 mg) was added and the resulting suspension was vigorously stirred under an
hydrogen atmosphere (atmospheric pressure) for 1 h (TLC control) at 45°C. The
suspension was filtered through a celite plug and the filter cake washed with ethyl
acetate. The organic layer was dried over sodium sulfate and filtered, and the solvent
was removed under reduced pressure. The crude product was purified by column
chromatography (silica gel, ethyl acetate/methanol gradient). [2-(2-o-Tolyl-chroman-
6-yloxy)-thiazolylmethyl]amine was obtained as pale yellow oil (834 mg, 36%).
Example L
Isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-amide
To a solution of [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]amine (150 mg,
0.43 mmol) in DMF (2 ml), 1-(3-dimethylaminopropyl)ethylcarbodiimide
hydrochloride (114 mg, 0.60 mmol, 1.4 eq), 1-hydroxy-benzotriazole (81 mg, 0.60
mmol, 1.4 eq) and N-methylmorpholine (107 mg, 1.07 mmol, 2.5 eq) and isoxazole
carboxylic acid (72 mg, 0.64 mmol, 1.5 eq) were added. The mixture was stirred for
16 h, then diluted with water, and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with a diluted aqueous solution of sodium
carbonate and brine, dried over sodium sulfate and filtered, and the solvent was
removed under reduced pressure. The crude product was purified by column
chromatography (silica gel, ethyl acetate/methanol gradient). Isoxazolecarboxylic
acid [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]-amide (112 mg, 59%) was
obtained as a white solid.
Example M
[2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl-amine
To a suspension of 2-(2-phenyl-chromanyloxy)-thiazolecarbaldehyde (54 mg,
0.13 mmol) and pyridinyl-methylamine (17 mg, 0.16 mmol, 1.2 eq) in
tetrahydrofuran (3 ml) and acetic acid (0.5 ml) at 0°C sodium cyanoborohydride
(polymer bond, 2.19 mM/g, 137 mg, 0.30 mmol, 2.3 eq) was added and the mixture
stirred at 40°C for 16 h. The reaction mixture was filtered, the volatile components
removed under reduced pressure and the remaining residue purified by reversed
phase HPLC (water/acetonitrile gradient (+ 0.1% trifluoroacetic acid)) to give 30 mg
(42%) of [2-(2-phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl-amine
in the form of its salt with trifluoroacetic acid.
Example N
1,3,5-Trimethyl-1H-pyrazolesulfonic acid [2-(2-phenyl-chromanyloxy)-thiazol
ylmethyl]-amide
33 mg of 1,3,5-trimethyl-1H-pyrazolesulfonic acid chloride (0.16 mmol, 1.2 eq)
were weighted into a reaction tube and dissolved in dry tetrahydrofuran (1 ml). 44 mg
of [2-(2-phenyl-chromanyloxy)-thiazolylmethyl]amine (0.13 mmol) in dry
tetrahydrofuran (3 ml) and 30 mg triethylamine (0.3 mmol, 2.3 eq) were added, the
tube was flushed with argon, closed with a screw cap, and shaken over night at 40°C.
0.008 ml of tris-(2-aminoethyl)amine in 0.5 ml tetrahydrofuran were added, the
mixture was shaken for 2 h at room temperature and then evaporated. The residue
was dissolved in 2 ml of a mixture of dimethylformamide/trifluoroacetic acid (19:1),
filtered, and submitted to preparative reversed phase HPLC purification
(water/acetonitrile gradient (+ 0.1% trifluoroacetic acid)). 1,3,5-Trimethyl-1H-
pyrazolesulfonic acid [2-(2-phenyl-chromanyloxy)-thiazolylmethyl]-amide was
obtained as a white solid (42 mg, 63%).
Example O
Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-
amino}-ethyl) ester disodium salt
a) Phosphoric acid dibenzyl ester 2-{[2-((S)o-tolyl-chromanyloxy)-thiazole
carbonyl]-amino}-ethyl ester
To a suspension of 2-((S)o-tolyl-chromanyloxy)-thiazolecarboxylic acid (2-
hydroxy-ethyl)-amide (1 g, 2.44 mmol) and tetrazole (222 mg, 3.17 mmol, 1.3 eq) in
dichloromethane (14 ml) and acetonitrile (14 ml) at 0°C, dibenzyl-N,N-
diisopropylphophoramidite (1.01 g, 2.92 mmol, 1.2 eq) was added and the mixture
stirred at 0°C for 70 min. To the resulting solution 3-chloro-perbenzoic acid (65%,
776 mg, 2.92 mmol, 1.2 eq) was added in one portion and vigorous stirring at 0°C
was continued for 10 min. The mixture was diluted with dichloromethane and the
organic layer washed with a saturated aqueous solution of sodium
hydrogencarbonate and subsequently with a saturated aqueous solution of
ammonium chloride. The combined organic layers were dried over sodium sulfate
and filtered, and the solvent removed under reduced pressure. The crude product
was purified by column chromatography (silica gel, ethyl acetate). Phosphoric acid
dibenzyl ester 2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-amino}-ethyl
ester was obtained as a colorless oil (1.30 g, 80%).
b) Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-
amino}-ethyl) ester disodium salt
Phosphoric acid dibenzyl ester 2-{[2-((S)o-tolyl-chromanyloxy)-thiazole
carbonyl]-amino}-ethyl ester (1.3 g, 1.95 mmol) was dissolved in methanol (40 ml)
and palladium on charcoal was added (10% Pd, 54% water, 1.3 g). The suspension
was vigorously stirred under a hydrogen atmosphere. The mixture was filtered and
the filter cake rinsed with methanol. The filtrate was evaporated under reduced
pressure and the resulting crude product submitted to preparative reversed phase
HPLC purification (water/acetonitrile gradient (+ 0.1% trifluoroacetic acid)). The
obtained phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazole
carbonyl]-amino}-ethyl) ester was suspended in water and converted into the
disodium salt by addition of 2 equivalents of an aqueous 0.5 N sodium hydroxide
solution. The obtained aqueous solution was lyophilized to yield phosphoric acid
mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]-amino}-ethyl) ester
disodium salt as a white solid (460 mg, 44%).
In analogy to the procedures described above in the synthesis examples, the
example compounds of the formula I listed in Table 1 were prepared. In Table 1, "Ex.
no." means the number of the example compound; "LC/MS" means the LC/MS
method described above which was used in the HPLC and MS characterization of
the example compound; "MS" means the mass number (in amu) of the peak of the
molecular ion or a related ion such as M+1 in the mass spectrum, in the case of a
salt of the parent compound, i.e. the free acid or base; "Rt" means the HPLC
retention time (in minutes); and "NCX1rv IC " means the IC value for inhibition of
50 50
NCX1 in reverse mode determined in the assay for inhibition of Ca influx into cells
(reverse mode) described below (in µM (micromol/liter)).
Table 1. Example compounds of the formula I
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
1 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic A 461 4.97 0.3
acid (1-ethyl-1H-pyrazolylmethyl)-amide
2 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 474.21 2.15 0.3
acid (6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol
ylmethyl)-amide
3 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic C 461.29 5.02 0.4
acid (2-ethyl-2H-pyrazolylmethyl)-amide
4 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 444.17 2.11 0.3
acid (pyridinylmethyl)-amide
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 447.17 2.4 0.4
acid (2-methyl-2H-pyrazolylmethyl)-amide
6 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic C 458.27 4.02 0.4
acid (1-pyridinyl-ethyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
7 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 478.14 2.29 0.3
acid [2-(4-methyl-thiazolyl)-ethyl]-amide
8 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic C 475.23 4.9 0.8
acid [1-(1,5-dimethyl-1H-pyrazolyl)-ethyl]-amide
9 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 458.18 2.13 0.8
acid (2-methyl-pyridinylmethyl)-amide
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic B 474.14 2.38 0.6
acid (2-methoxy-pyridinylmethyl)-amide
11 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic D 459 1.13 0.4
acid (2-amino-pyridinylmethyl)-amide
12 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 477 1.14 0.2
carboxylic acid (2-amino-pyridinylmethyl)-amide
13 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 476 1.14 0.3
carboxylic acid (1-pyridinyl-ethyl)-amide
hydrochloride
14 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic C 461.33 4.75 0.3
acid (1,5-dimethyl-1H-pyrazolylmethyl)-amide
N-[2-(2-Phenyl-chromanyloxy)-thiazol D 444 1.16 0.1
ylmethyl]-nicotinamide hydrochloride
16 N-[2-(2-Phenyl-chromanyloxy)-thiazol D 458 1.08 0.1
ylmethyl]pyridinyl-acetamide hydrochloride
17 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 502 1.2 0.2
carboxylic acid ([1,2,4]triazolo[4,3-a]pyridin
ylmethyl)-amide hydrochloride
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
18 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 462 1.13 0.2
carboxylic acid (pyridinylmethyl)-amide
hydrochloride
19 N-[2-(2-Phenyl-chromanyloxy)-thiazol D 458 1.09 0.1
ylmethyl]pyridinyl-acetamide hydrochloride
2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 492 1.15 0.2
carboxylic acid (6,7-dihydro-5H-pyrrolo[2,1-
c][1,2,4]triazolylmethyl)-amide hydrochloride
21 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic C 459.69 4.64 0.1
acid (2-methyl-pyrimidinylmethyl)-amide
22 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 502.15 1.86 0.4
acid [(S)(6-methoxy-pyridinyl)-propyl]-amide
23 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 475.17 1.73 0.8
acid [1-(1,3-dimethyl-1H-pyrazolyl)-ethyl]-amide
24 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 434.12 1.77 0.1
acid (isoxazolylmethyl)-amide
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 513.17 1.6 0.4
acid (2-pyrrolidinyl-pyridinylmethyl)-amide
26 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 527.21 1.61 0.3
acid methyl-(2-pyrrolidinyl-pyridinylmethyl)-
amide
27 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 502.17 1.86 0.3
acid [(R)(6-methoxy-pyridinyl)-propyl]-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
28 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 529.19 1.57 0.2
acid (2-morpholinyl-pyridinylmethyl)-amide
29 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic E 487.17 1.57 0.1
acid (2-dimethylamino-pyridinylmethyl)-amide
2-(2-Phenyl-chromanyloxy)trifluoromethyl- F 512 1.21 0.3
thiazolecarboxylic acid (pyridinylmethyl)-
amide hydrochloride
31 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 475.31 3.15 1.0
acid [1-(3,5-dimethyl-1H-pyrazolyl)-ethyl]-amide
32 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 445.27 3.4 0.6
acid (pyrimidinylmethyl)-amide
33 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 473.26 3.54 0.2
acid (4,6-dimethyl-pyrimidinylmethyl)-amide
34 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 476.27 3.82 0.2
acid [2-(3,5-dimethyl-isoxazolyl)-ethyl]-amide
2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 484.27 3.27 0.6
acid ([1,2,4]triazolo[4,3-a]pyridinylmethyl)-amide
36 2-((S)Phenyl-chromanyloxy)-thiazole D 444 1.12 0.1
carboxylic acid (pyridinylmethyl)-amide
37 2-((R)Phenyl-chromanyloxy)-thiazole C 444.35 3.89 0.2
carboxylic acid (pyridinylmethyl)-amide
38 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 490.26 3.95 0.3
acid [3-(3,5-dimethyl-isoxazolyl)-propyl]-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
39 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 478.21 3.89 0.3
acid (2-chloro-pyridinylmethyl)-amide
40 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 478.2 1.29 0.4
acid (3-chloro-pyridinylmethyl)-amide
41 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic G 483.25 3.05 5.0
acid (imidazo[1,2-a]pyridinylmethyl)-amide
42 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 460.19 1.18 0.2
acid (2-hydroxy-pyridinylmethyl)-amide
43 N-[2-(2-Phenyl-chromanyloxy)-thiazol D 458 1.08 0.3
ylmethyl]pyridinyl-acetamide hydrochloride
44 N-{2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazol- D 462 1.17 0.2
-ylmethyl}-nicotinamide hydrochloride
45 N-{2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazol- D 476 1.1 0.1
-ylmethyl}pyridinyl-acetamide hydrochloride
46 N-{2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazol- D 476 1.1 0.2
-ylmethyl}pyridinyl-acetamide hydrochloride
47 Pyridinesulfonic acid [2-(2-phenyl-chroman D 480 1.31 0.1
yloxy)-thiazolylmethyl]-amide hydrochloride
48 Isoxazolecarboxylic acid [2-(2-phenyl-chroman- C 434.67 5 0.1
6-yloxy)-thiazolylmethyl]-amide
49 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole F 452 4.62 0.1
carboxylic acid (isoxazolylmethyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
50 1-Methyl-1H-imidazolesulfonic acid [2-(2-phenyl- D 1.3 483 0.2
chromanyloxy)-thiazolylmethyl]-amide
hydrochloride
51 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 479 1.28 0.2
carboxylic acid (1,5-dimethyl-1H-pyrazol
ylmethyl)-amide
52 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic L 504.13 4.75 0.4
acid [(S)(4-cyclopropyl-thiazolyl)-ethyl]-amide
53 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic L 506.13 4.77 0.7
acid [(S)(4-isopropyl-thiazolyl)-ethyl]-amide
54 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic L 464.1 4.47 0.2
acid ((S)thiazolyl-ethyl)-amide
55 2-(5-Chlorophenyl-chromanyloxy)-thiazole I 478 1.31 1.2
carboxylic acid (pyridinylmethyl)-amide
hydrochloride
56 2-[2-(3-Fluoro-phenyl)-chromanyloxy]-thiazole D 477 1.28 0.2
carboxylic acid (2-methyl-pyrimidinylmethyl)-
amide hydrochloride
57 C-[2-(2-Phenyl-chromanyloxy)-thiazolyl]- C 0.1
methylamine
58 2-(2-Pyridinyl-chromanyloxy)-thiazole I 435 0.97 0.6
carboxylic acid (isoxazolylmethyl)-amide
hydrochloride
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
59 4-Methyl(2-phenyl-chromanyloxy)-thiazole C 458.31 3.99 0.1
carboxylic acid (pyridinylmethyl)-amide
hydrochloride
60 2-(2-Thiophenyl-chromanyloxy)-thiazole I 450 1.15 0.1
carboxylic acid (pyridinylmethyl)-amide
hydrochloride
61 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic D 458 1.11 0.2
acid (2-pyridinyl-ethyl)-amide hydrochloride
62 2-((S)Phenyl-chromanyloxy)-thiazole D 461 1.29 0.3
carboxylic acid (1,5-dimethyl-1H-pyrazol
ylmethyl)-amide
63 2-((R)Phenyl-chromanyloxy)-thiazole D 461 1.29 0.6
carboxylic acid (1,5-dimethyl-1H-pyrazol
ylmethyl)-amide
64 6-Methyl-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 458.42 1.27 1.3
-ylmethyl]-nicotinamide
65 3,5-Dimethyl-isoxazolecarboxylic acid [2-(2- H 462.41 1.33 0.2
phenyl-chromanyloxy)-thiazolylmethyl]-amide
66 2,5-Dimethyl-2H-pyrazolecarboxylic acid [2-(2- H 461.44 1.33 0.6
phenyl-chromanyloxy)-thiazolylmethyl]-amide
67 1,3,5-Trimethyl-1H-pyrazolecarboxylic acid [2-(2- H 475.45 1.29 0.3
phenyl-chromanyloxy)-thiazolylmethyl]-amide
68 2-Chloro-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 478.36 1.36 0.8
-ylmethyl]-isonicotinamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
69 4-Methyl-oxazolecarboxylic acid [2-(2-phenyl- H 448.38 1.31 0.5
chromanyloxy)-thiazolylmethyl]-amide
70 2-Ethyl-2H-pyrazolecarboxylic acid [2-(2-phenyl- H 461.43 1.34 0.3
chromanyloxy)-thiazolylmethyl]-amide
71 1,5-Dimethyl-1H-pyrazolecarboxylic acid [2-(2- H 461.43 1.28 0.7
phenyl-chromanyloxy)-thiazolylmethyl]-amide
72 1-Ethyl-1H-pyrazolecarboxylic acid [2-(2-phenyl- H 461.42 1.29 0.3
chromanyloxy)-thiazolylmethyl]-amide
73 2-Methyl-thiazolecarboxylic acid [2-(2-phenyl- H 464.35 1.35 0.3
chromanyloxy)-thiazolylmethyl]-amide
74 2-(3-Methyl-pyrazolyl)-N-[2-(2-phenyl-chroman- H 461.45 1.3 0.3
6-yloxy)-thiazolylmethyl]-acetamide
75 3,4,5,6-Tetrahydro-2H-[1,2']bipyridinyl-4'-carboxylic H 527.12 1.3 9.8
acid [2-(2-phenyl-chromanyloxy)-thiazol
ylmethyl]-amide
76 2-Methoxy-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 474.41 1.35 5.6
-ylmethyl]-isonicotinamide
77 2-(3,5-Dimethyl-isoxazolyl)-N-[2-(2-phenyl- H 476.42 1.31 0.4
chromanyloxy)-thiazolylmethyl]-acetamide
78 2,4-Dimethyl-oxazolecarboxylic acid [2-(2- H 462.38 1.31 0.3
phenyl-chromanyloxy)-thiazolylmethyl]-amide
79 N-[2-(2-Phenyl-chromanyloxy)-thiazol H 444.38 1.27 0.2
ylmethyl]-isonicotinamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
80 3-Chloro-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 478.34 1.32 0.2
-ylmethyl]-isonicotinamide
81 3-Fluoro-N-[2-(2-phenyl-chromanyloxy)-thiazol H 462.37 1.32 1.1
ylmethyl]-isonicotinamide
82 2-Methyl-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 458.43 1.26 0.4
-ylmethyl]-isonicotinamide
83 2-Morpholinyl-N-[2-(2-phenyl-chromanyloxy)- H 529.47 1.31 2.1
thiazolylmethyl]-isonicotinamide
84 3-Methyl-isoxazolecarboxylic acid [2-(2-phenyl- H 448.36 1.33 0.3
chromanyloxy)-thiazolylmethyl]-amide
85 2-Amino-N-[2-(2-phenyl-chromanyloxy)-thiazol H 459.4 1.12 10.9
ylmethyl]-isonicotinamide
86 2-Methyl-2H-pyrazolecarboxylic acid [2-(2- H 447.39 1.32 0.3
phenyl-chromanyloxy)-thiazolylmethyl]-amide
87 Pyrimidinecarboxylic acid [2-(2-phenyl-chroman- H 445.39 1.27 0.4
6-yloxy)-thiazolylmethyl]-amide
88 2-Hydroxy-N-[2-(2-phenyl-chromanyloxy)-thiazol- H 460.32 1.23 5.0
-ylmethyl]-isonicotinamide
89 Pyrimidinecarboxylic acid [2-(2-phenyl-chroman- H 445.4 1.31 0.2
6-yloxy)-thiazolylmethyl]-amide
90 N-[2-(2-Phenyl-chromanyloxy)-thiazol H 461.44 1.28 0.6
ylmethyl]pyrazolyl-propionamide
91 2,6-Dimethyl-pyrimidinecarboxylic acid [2-(2- H 473.44 1.36 5.3
phenyl-chromanyloxy)-thiazolylmethyl]-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
92 N-[2-(2-Phenyl-chromanyloxy)-thiazol H 447.42 1.28 1.1
ylmethyl]pyrazolyl-acetamide
93 1-Ethyl-1H-pyrazolecarboxylic acid [2-(2-phenyl- H 461.44 1.33 0.5
chromanyloxy)-thiazolylmethyl]-amide
94 3-(3,5-Dimethyl-isoxazolyl)-N-[2-(2-phenyl- H 490.46 1.31 0.9
chromanyloxy)-thiazolylmethyl]-propionamide
95 2-(2,5-Dioxo-imidazolidinyl)-N-[2-(2-phenyl- H 479.3 1.19 0.6
chromanyloxy)-thiazolylmethyl]-acetamide
96 2-[2-(3-Isopropoxy-phenyl)-chromanyloxy]- H 502.48 1.12 0.8
thiazolecarboxylic acid (pyridinylmethyl)-
amide
97 2-[2-(3-Isopropoxy-phenyl)-chromanyloxy]- H 534.35 1.39 1.2
thiazolecarboxylic acid [2-(3,5-dimethyl-isoxazol-
4-yl)-ethyl]-amide
98 4-Methyl((S)phenyl-chromanyloxy)- D 458 1.13 0.3
thiazolecarboxylic acid (pyridinylmethyl)-
amide hydrochloride
99 Butyl-methyl-[2-(2-phenyl-chromanyloxy)-thiazol- J 409.34 4.99 0.7
-ylmethyl]-amine
100 (2R,6S)-2,6-Dimethyl[2-(2-phenyl-chroman H 437.34 1.19 1.0
yloxy)-thiazolylmethyl]-morpholine
101 Isobutyl-[2-(2-phenyl-chromanyloxy)-thiazol H 395.29 1.16 0.4
ylmethyl]-amine
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
102 1-Methyl[2-(2-phenyl-chromanyloxy)-thiazol H 436.3 1.26 0.4
ylmethyl]-piperazinone
103 Cyclopropyl-[2-(2-phenyl-chromanyloxy)-thiazol- H 379.26 1.13 0.2
-ylmethyl]-amine
104 2-(2-Phenyl-chromanyloxy)pyrrolidin H 393.29 1.13 0.4
ylmethyl-thiazole
105 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 423.33 1.19 0.8
(1,2,2-trimethyl-propyl)-amine
106 (1-Ethyl-propyl)-[2-(2-phenyl-chromanyloxy)- H 409.3 1.17 0.5
thiazolylmethyl]-amine
107 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 421.24 1.39 0.2
(2,2,2-trifluoro-ethyl)-amine
108 3-[2-(2-Phenyl-chromanyloxy)-thiazol H 447.37 1.19 1.4
ylmethyl]aza-bicyclo[3.2.2]nonane
109 4,4-Difluoro[2-(2-phenyl-chromanyloxy)- H 443.28 1.28 0.7
thiazolylmethyl]-piperidine
110 Cyclobutyl-[2-(2-phenyl-chromanyloxy)-thiazol H 393.28 1.14 0.2
ylmethyl]-amine
111 (3-Methyl-isoxazolyl)-[2-(2-phenyl-chroman H 420.26 1.28 0.8
yloxy)-thiazolylmethyl]-amine
112 (1,1-Dimethyl-propyl)-[2-(2-phenyl-chroman H 409.31 1.15 0.3
yloxy)-thiazolylmethyl]-amine
113 Isopropyl-[2-(2-phenyl-chromanyloxy)-thiazol H 381.27 1.13 0.3
ylmethyl]-amine
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
114 (2-Methoxy-ethyl)-[2-(2-phenyl-chromanyloxy)- H 397.28 1.13 0.2
thiazolylmethyl]-amine
115 (3-Methyl-butyl)-[2-(2-phenyl-chromanyloxy)- H 409.29 1.4 0.6
thiazolylmethyl]-amine
116 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 381.25 1.13 0.2
propyl-amine
117 4-[2-(2-Phenyl-chromanyloxy)-thiazol H 409.26 1.14 0.3
ylmethyl]-morpholine
118 tert-Butyl-[2-(2-phenyl-chromanyloxy)-thiazol H 395.26 1.13 0.4
ylmethyl]-amine
119 Dimethyl-[2-(2-phenyl-chromanyloxy)-thiazol H 367.23 1.11 0.4
ylmethyl]-amine
120 Cyclopropylmethyl-[2-(2-phenyl-chromanyloxy)- H 393.1 1.02 0.3
thiazolylmethyl]-amine
121 7-[2-(2-Phenyl-chromanyloxy)-thiazol J 419.34 3.76 0.6
ylmethyl]aza-bicyclo[2.2.1]heptane
122 1-Methyl[2-(2-phenyl-chromanyloxy)-thiazol H 422.33 1.14 0.8
ylmethyl]-piperazine
123 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine H 550.3 1.36 1.1
sulfonic acid [2-(2-phenyl-chromanyloxy)-thiazol-
-ylmethyl]-amide
124 2-Methyl-benzothiazolesulfonic acid [2-(2-phenyl- H 550.24 1.35 0.9
chromanyloxy)-thiazolylmethyl]-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
125 1,3,5-Trimethyl-1H-pyrazolesulfonic acid [2-(2- H 511.29 1.31 9.2
phenyl-chromanyloxy)-thiazolylmethyl]-amide
126 2,4-Dimethyl-thiazolesulfonic acid [2-(2-phenyl- H 514.25 1.34 0.6
chromanyloxy)-thiazolylmethyl]-amide
127 2,3-Dimethyl-3H-imidazolesulfonic acid [2-(2- H 497.3 1.22 1.1
phenyl-chromanyloxy)-thiazolylmethyl]-amide
128 2-Methyl-2H-pyrazolesulfonic acid [2-(2-phenyl- H 483.26 1.32 0.3
chromanyloxy)-thiazolylmethyl]-amide
129 1-Methyl-1H-pyrazolesulfonic acid [2-(2-phenyl- H 483.24 1.29 0.9
chromanyloxy)-thiazolylmethyl]-amide
130 1-Isopropylmethyl-1H-pyrazolesulfonic acid [2- H 525.31 1.35 0.7
(2-phenyl-chromanyloxy)-thiazolylmethyl]-
amide
131 3,5-Dimethyl-1H-pyrazolesulfonic acid [2-(2- H 497.24 1.27 23.8
phenyl-chromanyloxy)-thiazolylmethyl]-amide
132 1-Ethyl-1H-pyrazolesulfonic acid [2-(2-phenyl- H 497.27 1.31 0.3
chromanyloxy)-thiazolylmethyl]-amide
133 1,5-Dimethyl-1H-pyrazolesulfonic acid [2-(2- H 497.26 1.3 0.4
phenyl-chromanyloxy)-thiazolylmethyl]-amide
134 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 430.29 1.1 0.2
pyridinylmethyl-amine
135 (5-Methyl-pyrazinylmethyl)-[2-(2-phenyl- H 445.32 1.13 0.5
chromanyloxy)-thiazolylmethyl]-amine
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
136 [2-(3-Methyl-pyrazolyl)-ethyl]-[2-(2-phenyl- H 447.33 1.16 0.5
chromanyloxy)-thiazolylmethyl]-amine
137 (1,3-Dimethyl-1H-pyrazolylmethyl)-[2-(2-phenyl- H 447.33 1.12 0.4
chromanyloxy)-thiazolylmethyl]-amine
138 (1,5-Dimethyl-1H-pyrazolylmethyl)-[2-(2-phenyl- H 447.33 1.12 0.3
chromanyloxy)-thiazolylmethyl]-amine
139 (1-Ethylmethyl-1H-pyrazolylmethyl)-[2-(2- H 461.36 1.13 0.5
phenyl-chromanyloxy)-thiazolylmethyl]-amine
140 (5-Methyl-isoxazolylmethyl)-[2-(2-phenyl- H 434.3 1.15 0.2
chromanyloxy)-thiazolylmethyl]-amine
141 (2,5-Dimethyl-2H-pyrazolylmethyl)-[2-(2-phenyl- H 447.33 1.13 0.4
chromanyloxy)-thiazolylmethyl]-amine
142 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 447.36 1.13 0.3
(3-pyrazolyl-propyl)-amine
143 (4,6-Dimethyl-pyrimidinylmethyl)-[2-(2-phenyl- H 459.35 1.15 0.5
chromanyloxy)-thiazolylmethyl]-amine
144 (6,7-Dihydro-5H-thiazolo[3,2-a]pyrimidin H 491.33 1.11 0.8
ylmethyl)-[2-(2-phenyl-chromanyloxy)-thiazol
ylmethyl]-amine
145 (2-Morpholinyl-pyridinylmethyl)-[2-(2-phenyl- J 515.32 3.7 0.9
chromanyloxy)-thiazolylmethyl]-amine
146 (2-Methyl-2H-pyrazolylmethyl)-[2-(2-phenyl- H 433.32 1.12 0.2
chromanyloxy)-thiazolylmethyl]-amine
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
147 (1,5-Dimethyl-1H-pyrazolylmethyl)-[2-(2-phenyl- H 447.35 1.14 0.3
chromanyloxy)-thiazolylmethyl]-amine
148 [1-(1,5-Dimethyl-1H-pyrazolyl)-ethyl]-[2-(2- H 461.36 1.12 0.4
phenyl-chromanyloxy)-thiazolylmethyl]-amine
149 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 433.32 1.14 0.3
(2-pyrazolyl-ethyl)-amine
150 [2-(3,5-Dimethyl-pyrazolyl)-ethyl]-[2-(2-phenyl- H 461.37 1.17 0.8
chromanyloxy)-thiazolylmethyl]-amine
151 [2-(4-Methyl-thiazolyl)-ethyl]-[2-(2-phenyl- H 464.32 1.16 0.4
chromanyloxy)-thiazolylmethyl]-amine
152 (3,5-Dimethyl-isoxazolylmethyl)-[2-(2-phenyl- H 448.31 1.14 0.3
chromanyloxy)-thiazolylmethyl]-amine
153 [3-(3,5-Dimethyl-isoxazolyl)-propyl]-[2-(2-phenyl- H 476.36 1.15 0.5
chromanyloxy)-thiazolylmethyl]-amine
154 4-({[2-(2-Phenyl-chromanyloxy)-thiazol H 446.3 1.08 0.3
ylmethyl]-amino}-methyl)-pyridinol
155 4-({[2-(2-Phenyl-chromanyloxy)-thiazol H 445.31 1.04 0.4
ylmethyl]-amino}-methyl)-pyridinylamine
156 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 470.34 1.15 0.4
[1,2,4]triazolo[4,3-a]pyridinylmethyl-amine
157 5-({[2-(2-Phenyl-chromanyloxy)-thiazol H 455.3 1.16 0.2
ylmethyl]-amino}-methyl)-pyridinecarbonitrile
158 Imidazo[2,1-b]thiazolylmethyl-[2-(2-phenyl- H 475.29 1.14 0.3
chromanyloxy)-thiazolylmethyl]-amine
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
159 Isoxazolylmethyl-[2-(2-phenyl-chromanyloxy)- H 420.28 1.15 0.1
thiazolylmethyl]-amine
160 (3-Methyl-isoxazolylmethyl)-[2-(2-phenyl- H 434.3 1.16 0.2
chromanyloxy)-thiazolylmethyl]-amine
161 [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]- H 431.29 1.12 0.3
pyrimidinylmethyl-amine
162 (2-Morpholinyl-pyridinylmethyl)-[2-(2-phenyl- H 515.4 1.13 0.4
chromanyloxy)-thiazolylmethyl]-amine
163 1,2-Dimethyl-1H-imidazolesulfonic acid [2-(2- H 497.3 1.26 0.4
phenyl-chromanyloxy)-thiazolylmethyl]-amide
164 2-(3-Methyl-2,5-dioxo-imidazolidinyl)-N-[2-(2- H 493.26 1.25 0.7
phenyl-chromanyloxy)-thiazolylmethyl]-
acetamide
165 2-(2-Oxo-pyrrolidinyl)-N-[2-(2-phenyl-chroman H 464.26 1.25 0.5
yloxy)-thiazolylmethyl]-acetamide
166 4-Methyl(2-phenyl-chromanyloxy)-thiazole M 448 1.31 0.3
carboxylic acid (isoxazolylmethyl)-amide
167 4-Methyl(2-phenyl-chromanyloxy)-thiazole M 492 1.39 0.5
carboxylic acid (2-chloro-pyridinylmethyl)-amide
hydrochloride
168 4-Methyl((S)phenyl-chromanyloxy)- C 448.29 5.14 0.2
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
169 4-Methyl((S)phenyl-chromanyloxy)- M 472 1.01 0.3
thiazolecarboxylic acid (2-pyridinyl-ethyl)-
amide hydrochloride
170 4-Methyl(2-phenyl-chromanyloxy)-thiazole M 472 1.02 0.3
carboxylic acid (2-pyridinyl-ethyl)-amide
hydrochloride
171 2-((S)Phenyl-chromanyloxy)-thiazole C 434.27 5.05 0.1
carboxylic acid (isoxazolylmethyl)-amide
172 2-((R)Phenyl-chromanyloxy)-thiazole M 434 1.28 0.4
carboxylic acid (isoxazolylmethyl)-amide
173 2-[2-(3-Hydroxy-phenyl)-chromanyloxy]-thiazole- H 492.32 1.22 2.3
-carboxylic acid [2-(3,5-dimethyl-isoxazolyl)-
ethyl]-amide
174 2-[2-(3-Hydroxy-phenyl)-chromanyloxy]-thiazole- H 460.24 1.07 0.8
-carboxylic acid (pyridinylmethyl)-amide
hydrochloride
175 2-((R)Hydroxy-pyrrolidinyl)-N-[2-(2-phenyl- H 466.16 0.99 0.4
chromanyloxy)-thiazolylmethyl]-acetamide
176 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic H 490.16 1.26 0.4
acid [2-(3,5-dimethyl-isoxazolyl)-ethyl]-amide
177 4-Chloro(2-phenyl-chromanyloxy)-thiazole D 0.3
carboxylic acid (pyridinylmethyl)-amide
hydrochloride
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
178 4-Methyl((S)phenyl-chromanyloxy)- D 0.4
thiazolecarboxylic acid (2-chloro-pyridin
ylmethyl)-amide hydrochloride
179 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic H 458.07 1.08 0.5
acid (pyridinylmethyl)-amide
180 (S){[2-((S)Phenyl-chromanyloxy)-thiazole- H 453.26 1.36 0.2
-carbonyl]-amino}-propionic acid ethyl ester
181 {[2-((S)Phenyl-chromanyloxy)-thiazole H 425.22 1.31 0.2
carbonyl]-amino}-acetic acid methyl ester
182 2-Methyl{[2-((S)phenyl-chromanyloxy)- H 453.25 1.35 0.6
thiazolecarbonyl]-amino}-propionic acid methyl
ester
183 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 481.34 1.41 1.2
thiazolecarbonyl]-amino}-pentanoic acid methyl
ester
184 (R){[2-((S)Phenyl-chromanyloxy)-thiazole- H 439.25 1.34 0.4
-carbonyl]-amino}-propionic acid methyl ester
185 (S)[2-((S)Phenyl-chromanyloxy)-thiazole H 465.11 1.24 0.5
carbonyl]-pyrrolidinecarboxylic acid methyl ester
186 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 481.35 1.42 0.7
thiazolecarbonyl]-amino}-butyric acid ethyl ester
187 1-{[2-((S)Phenyl-chromanyloxy)-thiazole H 479.31 1.38 0.6
carbonyl]-amino}-cyclopentanecarboxylic acid
methyl ester
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
188 1-{[2-((S)Phenyl-chromanyloxy)-thiazole H 465.31 1.35 0.6
carbonyl]-amino}-cyclopropanecarboxylic acid ethyl
ester
189 (1R,2S){[2-((S)Phenyl-chromanyloxy)- H 507.38 1.43 0.6
thiazolecarbonyl]-amino}-cyclohexanecarboxylic
acid ethyl ester
190 {Methyl-[2-((S)phenyl-chromanyloxy)-thiazole- H 425.26 1.27 0.9
-carbonyl]-amino}-acetic acid
191 (S){[2-((S)Phenyl-chromanyloxy)-thiazole- H 425.26 1.28 0.6
-carbonyl]-amino}-propionic acid
192 {[2-((S)Phenyl-chromanyloxy)-thiazole H 411.25 1.25 0.5
carbonyl]-amino}-acetic acid
193 2-Methyl{[2-((S)phenyl-chromanyloxy)- H 439.12 1.18 0.6
thiazolecarbonyl]-amino}-propionic acid
194 (R){[2-((S)Phenyl-chromanyloxy)-thiazole- H 425.12 1.16 0.7
-carbonyl]-amino}-propionic acid
195 1-{[2-((S)Phenyl-chromanyloxy)-thiazole H 465.12 1.21 0.7
carbonyl]-amino}-cyclopentanecarboxylic acid
196 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 467.17 1.24 0.5
thiazolecarbonyl]-amino}-pentanoic acid
197 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 453.14 1.21 0.6
thiazolecarbonyl]-amino}-butyric acid
198 {4-[2-((S)Phenyl-chromanyloxy)-thiazole H 480.16 1.05 1.3
carbonyl]-piperazinyl}-acetic acid
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
199 1-{[2-((S)Phenyl-chromanyloxy)-thiazole H 437.1 1.16 1.0
carbonyl]-amino}-cyclopropanecarboxylic acid
200 (1R,2S){[2-((S)Phenyl-chromanyloxy)- H 479.16 1.23 0.4
thiazolecarbonyl]-amino}-cyclohexanecarboxylic
acid
201 2-((S)Phenyl-chromanyloxy)-thiazole H 473.26 1.33 0.3
carboxylic acid ((S)hydroxyphenyl-ethyl)-
amide
202 2-((S)Phenyl-chromanyloxy)-thiazole H 439.13 1.12 0.2
carboxylic acid ((1S,2S)hydroxy
hydroxymethyl-propyl)-amide
203 2-((S)Phenyl-chromanyloxy)-thiazole H 439.28 1.32 0.4
carboxylic acid ((S)hydroxymethylmethyl-
propyl)-amide
204 2-((S)Phenyl-chromanyloxy)-thiazole H 397.03 1.14 0.1
carboxylic acid (2-hydroxy-ethyl)-amide
205 ((S)Hydroxymethyl-pyrrolidinyl)-[2-((S) H 437.27 1.3 0.3
phenyl-chromanyloxy)-thiazolyl]-methanone
206 2-((S)Phenyl-chromanyloxy)-thiazole H 451.29 1.32 0.3
carboxylic acid (1-cyclopropylhydroxy-propyl)-
amide
207 2-((S)Phenyl-chromanyloxy)-thiazole H 465.14 1.25 0.5
carboxylic acid ((1R,2R)hydroxy-
cyclohexylmethyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
208 2-((S)Phenyl-chromanyloxy)-thiazole H 453.15 1.24 0.4
carboxylic acid ((1S,2S)hydroxymethylmethyl-
butyl)-amide
209 2-((S)Phenyl-chromanyloxy)-thiazole H 453.29 1.35 0.3
carboxylic acid ((1R,2R)hydroxymethylmethyl-
butyl)-amide
210 Isoxazolylmethyl-[2-((S)phenyl-chroman O 420 1.17 0.1
yloxy)-thiazolylmethyl]-amine
211 2-(2-Thiophenyl-chromanyloxy)-thiazole F 484 4.7 0.4
carboxylic acid (2-chloro-pyridinylmethyl)-amide
hydrochloride
212 2-(2-Thiophenyl-chromanyloxy)-thiazole F 440 4.45 0.3
carboxylic acid (isoxazolylmethyl)-amide
213 (4-Methyl-piperazinyl)-[2-((S)phenyl-chroman- F 436 4.4 0.8
6-yloxy)-thiazolyl]-methanone hydrochloride
214 Morpholinyl-[2-((S)phenyl-chromanyloxy)- F 423 4.57 0.5
thiazolyl]-methanone
215 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic L 492.2 4.7 1.0
acid (2-chloro-pyridinylmethyl)-amide
216 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic L 479.29 4.35 0.3
acid [2-(2-oxo-imidazolidinyl)-ethyl]-amide
217 2-[2-(2,5-Difluoro-phenyl)-chromanyloxy]- O 470 1.83 0.2
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
218 2-Methylphenyl{[2-((S)phenyl-chroman H 529.09 1.31 2.5
yloxy)-thiazolecarbonyl]-amino}-propionic acid
methyl ester
219 (S)Phenyl{[2-((S)phenyl-chromanyloxy)- H 529.08 1.31 4.8
thiazolecarbonyl]-amino}-propionic acid ethyl
ester
220 (S)-3,3-Dimethyl{[2-((S)phenyl-chroman H 481.13 1.3 0.6
yloxy)-thiazolecarbonyl]-amino}-butyric acid
methyl ester
221 1-[2-((S)Phenyl-chromanyloxy)-thiazole H 533.04 1.27 0.3
carbonyl]trifluoromethyl-pyrrolidinecarboxylic
acid methyl ester
222 (1R,2S,5S)[2-((S)Phenyl-chromanyloxy)- H 477.09 1.25 0.9
thiazolecarbonyl]aza-bicyclo[3.1.0]hexane
carboxylic acid methyl ester
223 (S)-4,4-Dimethyl[2-((S)phenyl-chroman H 493.25 1.41 1.3
yloxy)-thiazolecarbonyl]-pyrrolidinecarboxylic
acid methyl ester
224 4-Methyl[2-((S)phenyl-chromanyloxy)- H 479.22 1.37 0.3
thiazolecarbonyl]-pyrrolidinecarboxylic acid
methyl ester
225 3-Methyl[2-((S)phenyl-chromanyloxy)- H 479.25 1.37 0.5
thiazolecarbonyl]-pyrrolidinecarboxylic acid
methyl ester
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
226 (2R,3S)Hydroxymethyl{[2-((S)phenyl- H 511.29 1.38 0.7
chromanyloxy)-thiazolecarbonyl]-amino}-
hexanoic acid methyl ester
227 (3S,4S)Cyclohexylhydroxy{[2-((S) H 579.33 1.46 30%
phenyl-chromanyloxy)-thiazolecarbonyl]- (1)
amino}-pentanoic acid ethyl ester
228 (R)Methyl{[2-((S)phenyl-chromanyloxy)- H 523.32 1.48 46%
thiazolecarbonyl]-amino}-pentanoic acid tert- (1)
butyl ester
229 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 523.33 1.48 44%
thiazolecarbonyl]-amino}-pentanoic acid tert- (1)
butyl ester
230 4-Methyl({[2-((S)phenyl-chromanyloxy)- H 509.28 1.44 1.5
thiazolecarbonyl]-amino}-methyl)-pentanoic acid
ethyl ester
231 2,4-Dimethyl{[2-((S)phenyl-chromanyloxy)- H 495.27 1.44 1.5
thiazolecarbonyl]-amino}-pentanoic acid methyl
ester
232 2-[2-(6-Methyl-pyridinyl)-chromanyloxy]- H 449.21 0.88 1.5
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
233 2-Methylphenyl{[2-((S)phenyl-chroman H 515.24 1.25 0.8
yloxy)-thiazolecarbonyl]-amino}-propionic acid
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
234 (S)-4,4-Dimethyl[2-((S)phenyl-chroman H 479.21 1.22 1.0
yloxy)-thiazolecarbonyl]-pyrrolidinecarboxylic
acid
235 4-Methyl[2-((S)phenyl-chromanyloxy)- H 465.21 1.18 0.5
thiazolecarbonyl]-pyrrolidinecarboxylic acid
236 (2R,3S)Hydroxymethyl{[2-((S)phenyl- H 497.25 1.21 1.6
chromanyloxy)-thiazolecarbonyl]-amino}-
hexanoic acid
237 (R)Methyl{[2-((S)phenyl-chromanyloxy)- H 467.24 1.24 0.8
thiazolecarbonyl]-amino}-pentanoic acid
238 4-Methyl({[2-((S)phenyl-chromanyloxy)- H 481.26 1.24 0.3
thiazolecarbonyl]-amino}-methyl)-pentanoic acid
239 3-Methyl[2-((S)phenyl-chromanyloxy)- H 465.21 1.18 2.4
thiazolecarbonyl]-pyrrolidinecarboxylic acid
240 (3S,4S)Cyclohexylhydroxy{[2-((S) H 551.28 1.27 1.1
phenyl-chromanyloxy)-thiazolecarbonyl]-
amino}-pentanoic acid
241 (S)Methyl{[2-((S)phenyl-chromanyloxy)- H 467.24 1.24 0.6
thiazolecarbonyl]-amino}-pentanoic acid
242 2,4-Dimethyl{[2-((S)phenyl-chromanyloxy)- H 481.25 1.26 0.7
thiazolecarbonyl]-amino}-pentanoic acid
243 1-[2-((S)Phenyl-chromanyloxy)-thiazole H 519.19 1.22 0.7
carbonyl]trifluoromethyl-pyrrolidinecarboxylic
acid
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
244 (S)Phenyl{[2-((S)phenyl-chromanyloxy)- H 501.23 1.23 0.6
thiazolecarbonyl]-amino}-propionic acid
245 {[2-((S)Phenyl-chromanyloxy)-thiazol H 411.28 1.01 0.1
ylmethyl]-amino}-acetic acid methyl ester
246 {[2-((S)Phenyl-chromanyloxy)-thiazol H 397.19 1.13 0.6
ylmethyl]-amino}-acetic acid
247 2-[2-(5-Fluoro-pyridinyl)-chromanyloxy]- H 497.16 1.26 0.7
thiazolecarboxylic acid (2-chloro-pyridin
ylmethyl)-amide
248 2-[2-(5-Fluoro-pyridinyl)-chromanyloxy]- H 453.17 1.21 0.8
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
249 2-(2-Pyridinyl-chromanyloxy)-thiazole H 398.2 0.95 1.4
carboxylic acid (2-hydroxy-ethyl)-amide
250 {[2-(2-Pyridinyl-chromanyloxy)-thiazole H 426.19 1.03 1.2
carbonyl]-amino}-acetic acid methyl ester
251 2-(2-Pyridinyl-chromanyloxy)-thiazole H 474.25 1.1 1.1
carboxylic acid ((S)hydroxyphenyl-ethyl)-
amide
252 2-(2-Pyridinyl-chromanyloxy)-thiazole J 452.22 2.95 3.2
carboxylic acid (1-cyclopropylhydroxy-propyl)-
amide
253 2-[2-(5-Fluoro-pyridinyl)-chromanyloxy]- H 416.18 1.14 0.6
thiazolecarboxylic acid (2-hydroxy-ethyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
254 2-((S)Phenyl-chromanyloxy)-thiazole H 450.39 1.14 0.4
carboxylic acid ((3S,4S)methoxy-pyrrolidinyl)-
amide
255 2-((S)Phenyl-chromanyloxy)-thiazole H 434.21 1.14 0.3
carboxylic acid (3-aza-bicyclo[3.1.0]hexyl)-amide
256 2-((S)Phenyl-chromanyloxy)-thiazole H 408.2 1.12 0.3
carboxylic acid ((1S,2S)amino-cyclopropyl)-
amide
257 2-((S)Phenyl-chromanyloxy)-thiazole H 422.22 1.13 0.4
carboxylic acid (3-amino-cyclobutyl)-amide
258 2-{(2-Hydroxy-ethyl)-[2-((S)phenyl-chroman H 427.25 1.08 0.2
yloxy)-thiazolylmethyl]-amino}-ethanol
259 ((S)Hydroxymethyl-pyrrolidinyl)-[2-(2-pyridin- J 438.25 2.79 1.8
3-yl-chromanyloxy)-thiazolyl]-methanone
260 {[2-(2-Pyridinyl-chromanyloxy)-thiazole H 412.17 0.95 38%
carbonyl]-amino}-acetic acid (1)
261 (2S,3S)Methyl{[2-(2-pyridinyl-chroman H 482.26 1.22 3.1
yloxy)-thiazolecarbonyl]-amino}-pentanoic acid
methyl ester
262 (S)Phenyl{[2-(2-pyridinyl-chromanyloxy)- H 530.27 1.24 0.8
thiazolecarbonyl]-amino}-propionic acid ethyl
ester
263 (S)Methyl{[2-(2-pyridinyl-chromanyloxy)- H 482.26 1.22 25.2
thiazolecarbonyl]-amino}-butyric acid ethyl ester
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
264 (S)-3,3-Dimethyl{[2-(2-pyridinyl-chroman J 482.25 3.84 3.1
yloxy)-thiazolecarbonyl]-amino}-butyric acid
methyl ester
265 2-(2-Pyridinyl-chromanyloxy)-thiazole H 423.2 0.87 7.3
carboxylic acid (3-amino-cyclobutyl)-amide
hydrochloride
266 2-{[2-((S)Phenyl-chromanyloxy)-thiazol H 383.2 1.08 0.1
ylmethyl]-amino}-ethanol
267 2-(2-Pyridinyl-chromanyloxy)-thiazole H 409.17 0.86 0.6
carboxylic acid ((1S,2S)amino-cyclopropyl)-
amide hydrochloride
268 2-(2-Pyridinyl-chromanyloxy)-thiazole H 435.18 0.88 2.5
carboxylic acid (3-aza-bicyclo[3.1.0]hexyl)-amide
269 2-(2-Pyridinyl-chromanyloxy)-thiazole H 453.19 0.9 2.6
carboxylic acid ((3S,4S)methoxy-pyrrolidinyl)-
amide hydrochloride
270 (2S,3S)Methyl{[2-(2-pyridinyl-chroman H 468.23 1.12 12.5
yloxy)-thiazolecarbonyl]-amino}-pentanoic acid
271 (S)Phenyl{[2-(2-pyridinyl-chromanyloxy)- H 502.22 1.13 12.1
thiazolecarbonyl]-amino}-propionic acid
272 (S)Methyl{[2-(2-pyridinyl-chromanyloxy)- H 454.21 1.08 15.6
thiazolecarbonyl]-amino}-butyric acid
273 (S)-3,3-Dimethyl{[2-(2-pyridinyl-chroman H 467.89 1.13 10.1
yloxy)-thiazolecarbonyl]-amino}-butyric acid
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
274 2-((S)Phenyl-chromanyloxy)-thiazole O 458 96 0.4
carboxylic acid (2-methyl-pyridinylmethyl)-amide
hydrochloride
275 (R){[2-(2-Pyridinyl-chromanyloxy)-thiazole- H 440.22 1.08 3.1
-carbonyl]-amino}-propionic acid methyl ester
276 (S){[2-(2-Pyridinyl-chromanyloxy)-thiazole- H 454.24 1.13 0.4
-carbonyl]-amino}-propionic acid ethyl ester
277 2-[2-(6-Chloro-pyridinyl)-chromanyloxy]- H 469.13 1.26 2.0
thiazolecarboxylic acid (isoxazolylmethyl)-
amide hydrochloride
278 2-[2-(6-Chloro-pyridinyl)-chromanyloxy]- H 513.12 1.3 1.3
thiazolecarboxylic acid (2-chloro-pyridin
ylmethyl)-amide hydrochloride
279 2-((S)Phenyl-chromanyloxy)-thiazole H 468.39 1.13 0.5
carboxylic acid (2-dimethylamino-ethyl)-amide
280 2-((S)Phenyl-chromanyloxy)-thiazole H 471.19 1.47 38%
carboxylic acid (4-isopropyl-phenyl)-amide (1)
281 2-((S)Phenyl-chromanyloxy)-thiazole H 395.16 1.36 0.6
carboxylic acid propylamide
282 (3,3-Dimethyl-piperazinyl)-[2-((S)phenyl- H 450.2 1.13 1.2
chromanyloxy)-thiazolyl]-methanone
283 (3aS,6aS)-Hexahydro-pyrrolo[3,4-b]pyrrolyl-[2- H 448.22 1.01 0.6
((S)phenyl-chromanyloxy)-thiazolyl]-
methanone hydrochloride
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
284 2-((S)Phenyl-chromanyloxy)-thiazole H 408.2 1 0.2
carboxylic acid ((S)amino-cyclopropyl)-amide
hydrochloride
285 ((3R,4R)Methylmethylamino-piperidinyl)-[2- H 464.26 1.02 0.9
((S)phenyl-chromanyloxy)-thiazolyl]-
methanone hydrochloride
286 (2-Dimethylaminomethyl-morpholinyl)-[2-((S) J 480.2 3.53 1.5
phenyl-chromanyloxy)-thiazolyl]-methanone
287 2-((S)Phenyl-chromanyloxy)-thiazole H 450.22 1.14 0.5
carboxylic acid (piperidinylmethyl)-amide
288 [2-((S)Phenyl-chromanyloxy)-thiazolyl]- H 421.23 1.27 0.4
piperidinyl-methanone
289 2-((S)Phenyl-chromanyloxy)-thiazole H 454.14 0.98 0.3
carboxylic acid (3-amino-propyl)-amide
290 (2,7-Diaza-spiro[4.5]decyl)-[2-((S)phenyl- H 475.85 1 0.6
chromanyloxy)-thiazolyl]-methanone
291 (2-Aminomethyl-pyrrolidinyl)-[2-((S)phenyl- H 436.21 1.14 0.4
chromanyloxy)-thiazolyl]-methanone
292 (3-Amino-pyrrolidinyl)-[2-((S)phenyl-chroman- H 422.18 1.11 0.3
6-yloxy)-thiazolyl]-methanone
293 2-((S)Phenyl-chromanyloxy)-thiazole H 476.25 1.17 1.0
carboxylic acid ((1R,2R,3S,4S)aminomethyl-
bicyclo[2.2.1]heptyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
294 {[2-(2-Phenyl-chromanyloxy)-thiazole H 425.1 1.31 0.2
carbonyl]-amino}-acetic acid methyl ester
295 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 397.08 1.25 0.4
acid (2-hydroxy-ethyl)-amide
296 3-(3,5-Dimethyl-isoxazolyl)-N-[2-((S)phenyl- H 490.18 1.32 0.4
chromanyloxy)-thiazolylmethyl]-propionamide
297 N-[2-((S)Phenyl-chromanyloxy)-thiazol H 503.21 1.26 1.1
ylmethyl](1,3,5-trimethyl-1H-pyrazolyl)-
propionamide
298 ((R)Hydroxy-pyrrolidinyl)-[2-(2-phenyl- H 423.12 1.26 0.6
chromanyloxy)-thiazolyl]-methanone
299 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic H 411.27 1.28 0.4
acid (2-hydroxy-ethyl)-amide
300 ((R)Hydroxy-pyrrolidinyl)-[2-(2-o-tolyl- H 437.17 1.3 0.2
chromanyloxy)-thiazolyl]-methanone
301 2-[2-(4-Methanesulfonyl-phenyl)-chromanyloxy]- H 512.15 1.19 6.9
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
302 2-Amino-N-[2-((S)phenyl-chromanyloxy)- H 396.13 1.12 0.4
thiazolylmethyl]-acetamide
303 (S)Amino-N-[2-((S)phenyl-chromanyloxy)- H 410.15 1.14 0.3
thiazolylmethyl]-propionamide
304 (S)Aminophenyl-N-[2-((S)phenyl-chroman- H 486.2 1.18 1.9
6-yloxy)-thiazolylmethyl]-propionamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
305 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 427.13 1.23 0.3
acid (2,3-dihydroxy-propyl)-amide
306 {[2-(2-Phenyl-chromanyloxy)-thiazole H 467.15 1.39 0.5
carbonyl]-amino}-acetic acid tert-butyl ester
307 {[2-(2-Phenyl-chromanyloxy)-thiazole H 453.16 1.37 0.2
carbonyl]-amino}-acetic acid isopropyl ester
308 {[2-(2-Phenyl-chromanyloxy)-thiazole H 439.13 1.34 0.2
carbonyl]-amino}-acetic acid ethyl ester
309 2-(2-Pyrazinyl-chromanyloxy)-thiazole O 436 1.32 4.7
carboxylic acid (isoxazolylmethyl)-amide
310 2-(2-Pyrazinyl-chromanyloxy)-thiazole O 480 1.49 2.6
carboxylic acid (2-chloro-pyridinylmethyl)-amide
311 2-{[2-(2-Phenyl-chromanyloxy)-thiazol J 383.2 3.33 0.1
ylmethyl]-amino}-ethanol
312 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 441.21 1.1 0.1
acid bis-(2-hydroxy-ethyl)-amide
313 (4-Methyl-piperazinyl)-[2-(2-phenyl-chroman H 436.2 1.13 0.4
yloxy)-thiazolyl]-methanone
314 Morpholinyl-[2-(2-phenyl-chromanyloxy)- H 423.16 1.33 0.1
thiazolyl]-methanone
315 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic K 393.3 1.2 0.0
acid cyclopropylamide
316 [2-(2-Phenyl-chromanyloxy)-thiazolyl]- H 421.18 1.4 0.5
piperidinyl-methanone
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
317 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 409.18 1.4 0.1
acid butylamide
318 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic K 409.34 1.25 0.1
acid isobutyl-amide
319 2-{(2-Hydroxy-ethyl)-[2-(2-phenyl-chromanyloxy)- H 427.2 1.12 0.8
thiazolylmethyl]-amino}-ethanol
320 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 395.15 1.37 0.3
acid isopropylamide
321 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 395.22 1.36 0.4
acid propylamide
322 2-[2-(2-Ethyl-phenyl)-chromanyloxy]-thiazole H 493.23 1.31 1.1
carboxylic acid [2-(2-oxo-imidazolidinyl)-ethyl]-
amide
323 2-[2-(2-Ethyl-phenyl)-chromanyloxy]-thiazole H 504.24 1.4 0.9
carboxylic acid [2-(3,5-dimethyl-isoxazolyl)-
ethyl]-amide
324 2-[2-(2-Ethyl-phenyl)-chromanyloxy]-thiazole H 462.2 1.38 0.5
carboxylic acid (isoxazolylmethyl)-amide
325 2-((R)o-Tolyl-chromanyloxy)-thiazole N 411.16 1.15 0.2
carboxylic acid (2-hydroxy-ethyl)-amide
326 2-((S)o-Tolyl-chromanyloxy)-thiazole N 411.16 1.15 0.1
carboxylic acid (2-hydroxy-ethyl)-amide
327 2-(2-Oxo-pyrrolidinyl)-N-[2-(2-o-tolyl-chroman K 478.21 1.16 0.5
yloxy)-thiazolylmethyl]-acetamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
328 2-(2,5-Dioxo-imidazolidinyl)-N-[2-(2-o-tolyl- K 493.26 1.13 0.9
chromanyloxy)-thiazolylmethyl]-acetamide
329 Isoxazolecarboxylic acid [2-(2-o-tolyl-chroman K 448.2 1.21 0.6
yloxy)-thiazolylmethyl]-amide
330 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic K 409.27 1.25 0.3
acid propylamide
331 2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]- K 462.2 1.24 5.5
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
332 4-Methyl(2-o-tolyl-chromanyloxy)-thiazole K 423.27 1.27 10.0
carboxylic acid propylamide
333 4-Methyl(2-o-tolyl-chromanyloxy)-thiazole H 493.2 1.28 0.6
carboxylic acid [2-(2-oxo-imidazolidinyl)-ethyl]-
amide
334 4-Methyl(2-o-tolyl-chromanyloxy)-thiazole H 462.18 1.36 0.5
carboxylic acid (isoxazolylmethyl)-amide
335 4-Methyl(2-o-tolyl-chromanyloxy)-thiazole H 425.17 1.3 0.3
carboxylic acid (2-hydroxy-ethyl)-amide
336 ((R)Hydroxy-pyrrolidinyl)-[4-methyl(2-o- H 451.21 1.27 0.6
tolyl-chromanyloxy)-thiazolyl]-methanone
337 2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]- H 425.15 1.29 7.6
thiazolecarboxylic acid (2-hydroxy-ethyl)-amide
338 2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]- K 409.21 1.26 8.7
thiazolecarboxylic acid dimethylamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
339 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic H 353.15 1.25 0.4
acid amide
340 (S)Aminohydroxy-N-[2-(2-phenyl-chroman H 426.16 1.09 0.9
yloxy)-thiazolylmethyl]-propionamide
hydrochloride
341 (S)-Pyrrolidinecarboxylic acid [2-(2-phenyl- H 436.19 1.11 0.9
chromanyloxy)-thiazolylmethyl]-amide
hydrochloride
342 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- H 429.16 1.27 0.4
thiazolecarboxylic acid (2-hydroxy-ethyl)-amide
343 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- H 427.2 1.38 0.5
thiazolecarboxylic acid propylamide
344 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- H 466.17 1.34 0.8
thiazolecarboxylic acid (isoxazolylmethyl)-
amide
345 Phosphoric acid mono-(2-{[2-((S)o-tolyl- J 491.19 4.36 0.07
chromanyloxy)-thiazolecarbonyl]-amino}-ethyl)
ester disodium salt
346 N-[2-(2-Phenyl-chromanyloxy)-thiazol K 450.24 1 0.17
ylmethyl]pyrrolidinyl-acetamide hydrochloride
347 2-[2-(2,6-Dimethyl-phenyl)-chromanyloxy]- H 488.29 1.07 1.5
thiazolecarboxylic acid [2-(2-oxo-imidazolidin
yl)-ethyl]-amide
348 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- H 413.15 1.35 0.64
thiazolecarboxylic acid dimethylamide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
349 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- H 497.18 1.27 0.20
thiazolecarboxylic acid [2-(2-oxo-imidazolidin
yl)-ethyl]-amide
350 2-((S)Phenyl-chromanyloxy)-thiazole H 397.06 1.26 0.12
carboxylic acid (2-hydroxy-ethyl)-amide
351 2-((S)Phenyl-chromanyloxy)-thiazole H 395.07 1.38 0.11
carboxylic acid propylamide
352 2-((S)Phenyl-chromanyloxy)-thiazole K 465.08 1.26 0.21
carboxylic acid [2-(2-oxo-imidazolidinyl)-ethyl]-
amide
353 2-((S)Phenyl-chromanyloxy)-thiazole J 434.17 4.77 0.092
carboxylic acid (isoxazolylmethyl)-amide
354 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic K 411.22 1.14 0.16
acid (2-hydroxy-propyl)-amide
355 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic K 437.29 1.17 0.25
acid (2-hydroxy-cyclopentyl)-amide
356 {2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]- K 455.08 1.29 0.54
thiazolyl}-((R)hydroxy-pyrrolidinyl)-
methanone
357 2-(7-Methylo-tolyl-chromanyloxy)-thiazole K 425.05 1.33 0.60
carboxylic acid (2-hydroxy-ethyl)-amide
358 2-(7-Methylo-tolyl-chromanyloxy)-thiazole K 462.15 1.24 0.83
carboxylic acid (isoxazolylmethyl)-amide
Ex. Compound name LC/ MS Rt NCX1rv
no. MS IC
359 2-(7-Methylo-tolyl-chromanyloxy)-thiazole K 487.24 1.25 1.5
carboxylic acid (2-ethyl-2H-pyrazolylmethyl)-
amide
360 2-[2-(2-Fluoromethoxy-phenyl)-chroman K 445.05 1.25 1.8
yloxy]-thiazolecarboxylic acid (2-hydroxy-ethyl)-
amide
361 2-[2-(2-Fluoromethoxy-phenyl)-chroman K 482.06 1.31 9.6
yloxy]-thiazolecarboxylic acid (isoxazol
ylmethyl)-amide
362 2-[2-(2-Fluoromethoxy-phenyl)-chroman K 509.09 1.32 1.5
yloxy]-thiazolecarboxylic acid (2-ethyl-2H-
pyrazolylmethyl)-amide
363 2-(3-Methylphenyl-chromanyloxy)-thiazole K 448.06 1.36 1.9
carboxylic acid (isoxazolylmethyl)-amide
364 2-(3-Methylphenyl-chromanyloxy)-thiazole K 411.06 1.3 0.96
carboxylic acid (2-hydroxy-ethyl)-amide
365 2-[2-(3-Fluoromethoxy-phenyl)-chroman K 509.07 1.35 0.55
yloxy]-thiazolecarboxylic acid (2-ethyl-2H-
pyrazolylmethyl)-amide
366 2-[2-(3-Fluoromethoxy-phenyl)-chroman J 482.11 4.84 0.18
yloxy]-thiazolecarboxylic acid (isoxazol
ylmethyl)-amide
367 2-[2-(3-Fluoromethoxy-phenyl)-chroman K 445.04 1.28 0.27
yloxy]-thiazolecarboxylic acid (2-hydroxy-ethyl)-
amide
(1) Inhibition in % at 30 µM; IC value not determined
Exemplary NMR data of example compounds.
Example 2
H-NMR (400 MHz): (ppm) = 9.29 (t, 1H), 7.95 (s, 1H), 7.30-7.50 (m, 5H), 7.20 (m,
1H), 7.15 (dd, 1H), 6.95 (d, 1H), 5.18 (dd, 1H), 4.60 (d, 2H), 4.05 (t, 2H), 2.90-3.07
(m, 3H), 2.71-2.81 (m, 1H), 2.62-2.70 (m, 2H), 2.15-2.25 (m, 1H), 1.95-2.07 (m, 1H).
Example 14
H-NMR: (ppm) = 8.72 (t, 1H), 7.89 (s, 1H), 7.30-7.48 (m, 5H), 7.27 (s, 1H), 7.20 (m,
1H), 7.14 (dd, 1H), 6.93 (d, 1H), 5.17 (dd, 1H), 4.19 (d, 2H), 3.69 (s, 3H), 2.95-3.07
(m, 1H), 2.72-2.80 (m, 1H), 2.20 (s, 3H), 2.15-2.22 (m, 1H), 1.95-2.07 (m, 1H).
Example 39
H-NMR: (ppm) = 9.20 (t, 1H), 8.86 (d, 1H), 7.98 (s, 1H), 7.39-7.50 (m, 5H), 7.30-
7.38 (m, 2H), 7.20 (m, 1H), 7.15 (dd, 1H), 6.93 (d, 1H), 5.15 (dd, 1H), 4.48 (d, 2H),
2.95-3.07 (m, 1H), 2.72-2.82 (m, 1H), 2.15-2.22 (m, 1H), 1.95-2.07 (m, 1H).
Example 125
H-NMR: (ppm) = 7.90 (t, 1H), 7.30-7.50 (m, 5H), 7.10 (s, 1H), 7.07-7.00 (m, 2H),
6.93 (d, 1H), 5.15 (dd, 1H), 4.05 (m, 2H), 3.65 (s, 3H), 2.95-3.07 (m, 1H), 2.73-2.82
(m, 1H), 2.33 (s, 3H), 2.20 (s, 3H), 2.15-2.25 (m, 1H), 1.95-2.08 (m, 1H).
Example 134
H-NMR: (ppm) = 9.60-9.25 (br s, 2H), 8.70-8.60 (m, 2H), 7.52-7.30 (m, 8H), 7.15
(s, 1H), 7.15-7.08 (m, 1H), 6.93 (d, 1H), 5.15 (dd, 1H), 4.38 (s, 2H), 4.22 (s, 2H),
3.05-2.95 (m, 1H), 2.80-2.70 (m, 1H), 2.23-2.15 (m, 1H), 2.05-1.95 (m, 1H).
Example 321
H-NMR: (ppm) = 8.49 (t, 1H), 7.87 (s, 1H), 7.30-7.50 (m, 5H), 7.18 (m, 1H), 7.13
(dd, 1H), 6.93 (d, 1H), 5.18 (dd, 1H), 3.10-3.20 (m, 2H), 2.95-3.07 (m, 1H), 2.72-2.80
(m, 1H), 2.15-2.22 (m, 1H), 1.97-2.07 (m, 1H), 1.45-1.55 (m, 2H), 0.87 (t, 3H).
Example 326
H-NMR: (ppm) = 8.52 (t, 1H), 7.90 (s, 1H), 7.43 (m, 1H), 7.19-7.28 (m, 4H), 7.13
(m, 1H), 6.91 (d, 1H), 5.29 (d, 1H), 4.75 (t, 1H), 3.45-3.50 (m, 2H), 3.22-3.30 (m, 2H),
3.03-3.10 (m, 1H), 2.80-2.86 (m, 1H), 2.36 (s, 3H), 2.12-2.20 (m, 1H), 1.89-1.99 (m,
1H).
Example 329
H-NMR: (ppm) = 9.6 (s, 1H), 8.74 (s, 1H), 7.35-7.48 (m, 1H), 7.00-7.30 (m, 7H),
6.82-6.95 (m, 1H), 5.20-5.33 (m, 1H), 4.40-4.55 (m, 2H), 2.95-3.10 (m, 1H), 2.70-
2.86 (m, 1H), 2.35 (s, 3H), 2.10-2.20 (m, 1H), 1.85-2.00 (m, 1H).
Example 345
H-NMR (400 MHz, D O): (ppm) = 7.73 (s, 1H), 7.41-7.49 (m, 1H), 7.20-7.30 (m,
3H), 7.10-7.13 (m, 1H), 7.02-7.08 (m, 1H), 6.87 (d, 1H), 5.33 (dd, 1H), 3.77-3.85 (m,
2H), 3.40-3.48 (m, 2H), 2.95-3.07 (m, 1H), 2.75-2.85 (m, 1H), 2.30 (s, 3H), 2.10-2.20
(m, 1H), 1.97-2.10 (m, 1H).
Pharmacological examples
A) Assay method for determining the NCX1 inhibitory activity
The sodium/calcium exchanger NCX1 can transport calcium ions and sodium ions
2+ +
through the cell membrane. The transport is an exchange of Ca and Na in two
directions depending on membrane potential and ion gradients. At the first direction,
named “forward mode” or “calcium export mode”, Ca is transported out of the cell
and Na is transported into the cell. At the other direction, named "reverse mode” or
“calcium import mode”, the transport directions are vice versa. The effect of the
compounds of the invention on NCX1 was determined in CHO cells stably expressing
human NCX1 (gene symbol SLC8A1; cf. ). The assay is based on
the monitoring of intracellular Ca concentrations using a calcium-sensitive
fluorescence dye which is detected by means of a FLIPR device (Fluorimetric
Imaging Plate Reader, Molecular Devices).
Assay technology - reverse mode
The assay is based on the monitoring of intracellular Ca concentrations using the
calcium-sensitive dye Fluo-4. CHO cells expressing NCX1 were loaded with the dye
by means of the acetoxymethyl ester Fluo-4 AM (Invitrogen, F14202), which is
cleaved intracellularly by esterase activity to yield the charged species of free Fluo-4.
After an preincubation period with the test compound, Gramicidine (Sigma, G5002)
was added. Gramicidine is an ionophor for Na ions mediating an increase of
intracellular Na ions. Consequently, intracellular Na ions are exchanged against
2+ 2+ 2+
extracellular Ca ions (Ca influx, reverse mode). The intracellular elevation of Ca
ions was detected by measuring the fluorescence of Fluo-4 at a wavelength of 520
nm by a FLIPR device.
Briefly, for the reverse mode transport assay 18000 cells per well were seeded into a
96 well microplate (Corning COSTAR 3904) and incubated overnight in culture
medium (1X Nut Mix F12 (Ham) (Gibco, 21765-029); 10% (v/v) fetal calf serum (PAA
Gold, A15-649); 450 µg/ml Geneticin (Gibco, 10131-027)). A total volume of 100 µl
medium per well was used. For the preparation of the FLIPR assay, the culture
medium was removed from the plates and 100 µl of dye solution (2 µM Fluo-4 AM;
0.02% (v/v) Pluronic F-127 (20%, Invitrogen, P3000MP); 0.1% (v/v) bovine albumin
solution (30% (v/v), Sigma, A9205) in assay buffer (133.8 mM NaCl (Sigma, S5886);
4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl (Merck, 1.05833.0250); 3.5 mM CaCl
(Merck, 1.02083.0250); 5 mM glucose (Sigma, G7021); 10 mM Hepes (Sigma,
H4034); 0.01% (v/v) Pluronic F-127 (5%, Sigma, P2443); 2.5 mM Probenecid
(Maybridge, SB00915EB); pH 7.4)) were added into each well. The plates were
incubated in the dark at room temperature for 80 min. After the incubation period, the
dye solution was removed and the wells were washed with 100 µl of assay buffer.
Then 80 µl of a solution of the test compound in assay buffer in different
concentrations were added into the wells. The plates were incubated at 16°C for 45
min. Meanwhile a 60 µM solution of Gramicidine in assay buffer (4°C) was prepared
and stored in the wells of a 96 well microplate (96 well microplate, polypropylene, U-
shape (Greiner Bio-One, 650201)) at 4°C until measurement was started. The
fluorescence monitoring was performed at 240 measuring points with measurement
intervals of 2 sec. After the fifth measuring point, 40 µl of the Gramicidine solution
were added to each well of the assay plates to give a final Gramicidine concentration
of 20 µM. For the determination of the IC values the minimal fluorescence value
was subtracted from the maximal fluorescence value for all measuring points. The
calculation of the IC values via the percentage inhibitions of Ca influx into cells
(reverse mode) effected by the test compound was performed in Biost@t Speed 2.0.
Results obtained with compounds of the invention are given in Table 1.
Assay technology - forward mode
The assay is based on the monitoring of intracellular Ca concentrations using the
PBX Calcium Assay Kit from BD (Becton, Dickinson and Company) with calcium
indicator dye 51-9000177BKa (BD, 640177). CHO cells expressing NCX1 were
loaded with the dye, and after a preincubation period with the test compound,
Ionomycin (Calbiochem, 407950) was added. Ionomycin is an ionophor for Ca ions
2+ 2+
mediating an increase of intracellular Ca ions. Consequently, intracellular Ca ions
+ 2+
are exchanged against extracellular Na ions (Ca efflux, forward mode). The
decrease of intracellular Ca ions was detected by measuring the fluorescence of
the calcium indicator dye at a wavelength of 520 nm by a FLIPR device.
Briefly, similarly as for the reverse mode, for the forward mode transport assay 18000
cells per well were seeded into a 96 well microplate (Corning COSTAR 3904) and
incubated overnight in culture medium (cf. above). A total volume of 100 µl medium
per well was used. For the preparation of the FLIPR assay, the culture medium was
removed from the plates and 100 µl of assay buffer (133.8 mM NaCl (Sigma, S5886);
4.7 mM KCl (Sigma, P3911); 1.25 mM MgCl (Merck, 1.05833.0250); 3.5 mM CaCl
(Merck, 1.02083.0250); 5 mM glucose (Sigma, G7021); 10 mM Hepes (Sigma,
H4034); pH 7.4)) were added to each well in a washing step. Assay buffer was
removed, and 100 µl of a solution of the test compound in assay buffer in different
concentrations were added into the wells. Further, 100 µl of dye solution (0.09% (v/v)
calcium indicator dye, 9.1% (v/v) signal enhancer (from PBX Calcium Assay Kit); in
assay buffer) were added into each well. The plates were incubated in the dark at
room temperature for 60 min. Meanwhile a 10 µM solution of Ionomycin in assay
buffer (additionally containing 0.05% fetal calf serum (cf. above); 4°C) was prepared
and stored in the wells of a 96 well microplate (96 well microplate, polypropylene, U-
shape (Greiner Bio-One, 650201)). The fluorescence monitoring was performed at 60
measuring points with measurement intervals of 2 sec. After the fifth measuring point,
50 µl of the Ionomycin solution were added to each well of the assay plate to give a
final Ionomycin concentration of 2 µM. For the determination of the IC values the
minimal fluorescence value was subtracted from the maximal fluorescence value for
the fifteenth to fifty-fifth measuring points. The calculation of the IC values via the
percentage inhibitions of Ca efflux out of cells (forward mode) effected by the test
compound was performed in Biost@t Speed 2.0. Results obtained with compounds
of the invention are given in Table 2. "NCX1fw IC " in Table 2 means the IC value
50 50
for inhibition of NCX1 in forward mode (in µM (micromol/liter)).
Table 2. IC values for inhibition of the NCX1 in forward mode by example
compounds
Example NCX1fw Example NCX1fw
number IC number IC
50 50
2 1.9 243 19% (1)
13 0.9 255 0.6
14 2.2 275 9.9
18 0.6 299 0.6
1.2 315 3.3
Example NCX1fw Example NCX1fw
number IC number IC
50 50
32 27% (1) 321 1.5
39 1.2 325 26% (1)
58 8.3 326 0.2
59 0.2 327 3.0
103 3.1 329 2.5
125 20% (1) 330 0.35
134 2.6 334 2.1
158 46% (1) 335 0.9
177 0.8 342 0.7
182 8% (1) 343 0.8
189 17% (1) 348 0.8
206 1.6 352 31% (1)
214 4.5 345 3
216 1.9
(1) Inhibition in % at 10 µM; IC value not determined
B) In vivo method for determining the effect on heart contractility
Adult male Sprague-Dawley rats (Harlan Winkelmann, Borchen, Germany) weighing
340 to 370 g were anesthetized with pentobarbital (100 mg/kg i.p.) and ventilated
with a mixture of oxygen (40%) and room air (60%) at a tidal volume of 1 ml/100 g at
60 breaths/min. Body temperature was maintained at 36.5 ± 0.3 °C with a heating
lamp and was monitored with a rectal thermo sensor. Systemic blood pressure was
measured in the left carotid artery using a pressure transducer (Combitrans; B. Braun
Melsungen AG, Melsungen, Germany) connected to a DC-bridge-amplifier
(PLUGSYS/ADC Type 663; Harvard Apparatus GmbH, March-Hugstetten, Germany).
The electrocardiogram was measured as lead II via subcutaneously placed
electrodes connected to a Heart-Rate-Module (PLUGSYS/HRM Type 669; Harvard
Apparatus GmbH, March-Hugstetten, Germany). A micro-tip catheter (2 French,
SPR-320; Millar Instruments, Houston, TX, USA) was placed via the right carotid
artery into the left ventricle, and the left ventricular pressure (LVP) and the
enddiastolic pressure (EDP) were continuously measured. Registration of the
hemodynamic data was performed via an analog digital converter by a personal
computer using Notocord software (HEM version 3.5). Left ventricular contractility
(dp/dt ) and relaxation (dp/dt ) were calculated from the LVP signal. For
max min
intravenous administration of the test compounds, the left jugular vein was prepared
and a PP-50 catheter was inserted. Test compounds were administered either by
intravenous bolus injection or by intravenous infusion by means of an infusion pump
(Unita; B. Braun Melsungen AG, Melsungen, Germany). Test compounds were
dissolved in a mixture of Glycofurol (75%) and Cremophor (25%), and the solution
was further diluted with distilled water (1:4). In a typical experiment, several dosages
of the test compound were administered subsequently at increasing doses. Statistical
significance of the data obtained with drug vs control experiments, in which solvent
was administered, was evaluated with the 2-sided ANOVA test (program Everstat).
Increases in left ventricular contractility (percent increase) by example compounds
are given in Table 3 in comparison to control experiments in which solvent was
administered.
Table 3. Increase in left ventricular contractility by example compounds
Example Administration Dose Contractility
number mode (mg per kg of increase (%)
body weight)
299 Bolus injection 0.1 mg/kg 36%
0.3 mg/kg 62%
1.0 mg/kg 95%
315 Bolus injection 0.1 mg/kg 28%
0.3 mg/kg 41%
1.0 mg/kg 64%
326 Bolus injection 0.1 mg/kg 67%
0.3 mg/kg 105%
1.0 mg/kg 138%
327 Bolus injection 0.1 mg/kg 9%
0.3 mg/kg 27%
1.0 mg/kg 55%
329 Bolus injection 0.1 mg/kg 24%
0.3 mg/kg 53%
1.0 mg/kg 101%
330 Bolus injection 0.1 mg/kg 50%
0.3 mg/kg 86%
1.0 mg/kg 161%
334 Bolus injection 0.1 mg/kg 19%
0.3 mg/kg 41%
1.0 mg/kg 59%
Example Administration Dose Contractility
number mode (mg per kg of increase (%)
body weight)
342 Bolus injection 0.1 mg/kg 38%
0.3 mg/kg 73%
1.0 mg/kg 146%
343 Bolus injection 0.1 mg/kg 20%
0.3 mg/kg 25%
1.0 mg/kg 39%
345 Infusion 0.03 mg/kg/min 32%
0.1 mg/kg/min 85%
Comprises/comprising and grammatical variations thereof when used in this
specification are to be taken to specify the presence of stated features, integers,
steps or components or groups thereof, but do not preclude the presence or
addition of one or more other features, integers, steps, components or groups
thereof.
Claims (25)
1. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, Ar O wherein Ar is selected from the series consisting of phenyl and a 5-membered or 6- membered monocyclic aromatic heterocycle, which are all unsubstituted or substituted by one or more identical or different substituents R1, wherein the heterocycle comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom; R1 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )- 1 6 3 7 cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, phenyl, Het1, HO-, (C -C )-alkyl-O-, 3 7 1 4 1 6 (C -C )-cycloalkyl-O-, (C -C )-cycloalkyl-(C -C )-alkyl-O-, phenyl-O-, Het1-O- and 3 7 3 7 1 4 (C -C )-alkyl-S(O) -, and two groups R1 bonded to adjacent ring carbon atoms in 1 6 n Ar, together with the carbon atoms carrying them, can form a 5-membered to 7- membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C -C )- alkyl; R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)- CH -, R7-C(O)-NH-CH - and R7-S(O) -NH-CH -; 2 2 2 2 R3 is selected from the series consisting of hydrogen, halogen, (C -C )- alkyl and (C -C )-alkyl-O-; R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O-; 1 4 1 4 R5 and R6 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl, 1 6 3 7 6 10 phenyl, Het1 and Het2, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or different substituents R10, and (C -C )-cycloalkyl, (C - 3 7 6 C )-bicycloalkyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R11, or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated or partially unsaturated heterocycle which, in addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents R12; R7 is selected from the series consisting of (C -C )-alkyl, (C -C )- 1 6 3 7 cycloalkyl, phenyl, Het2 and Het3, wherein (C -C )-alkyl, (C -C )-cycloalkyl and 1 6 3 7 Het2 all are unsubstituted or substituted by one or more identical or different substituents R10, and phenyl and Het3 all are unsubstituted or substituted by one or more identical or different substituents R13; R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C - C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, 6 2 2 (HO) P(O)-O-CH -O-C(O)-O-, (C -C )-alkyl-S(O) -, R16-N(R17)-, R18-C(O)- 2 2 1 6 n N(R17)-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -; R11 and R12 are independently of one another selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O- 1 4 1 4 1 4 C(O)-(C -C )-alkyl-, R14, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15- 1 4 1 6 NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, (C -C )- 2 2 2 2 1 6 alkyl-S(O) -, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -; R13 is selected from the series consisting of halogen, (C -C )-alkyl, HO-, (C -C )-alkyl-O- and R16-N(R17)-, and two substituents R13 bonded to adjacent ring carbon atoms in R7, together with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated, partially unsaturated or aromatic and comprises 0, 1, 2, 3 or 4 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R20; R15 and R18 are independently of one another selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, 1 6 3 7 3 7 1 4 phenyl-(C -C )-alkyl- and Het1-(C -C )-alkyl-; 1 4 1 4 R16 and R17 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-cycloalkyl-(C - 1 6 3 7 3 7 1 C )-alkyl-, phenyl-(C -C )-alkyl- and Het1-(C -C )-alkyl-, 4 1 4 1 4 or the groups R16 and R17, together with the nitrogen atom carrying them, form a 4-membered to 7-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C - 1 6 3 C )-cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, phenyl-(C -C )-alkyl- and Het1- 7 3 7 1 4 1 4 (C -C )-alkyl-; R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO- (C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15- 1 4 3 7 1 6 NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, (C -C )- 2 2 2 2 1 6 alkyl-S(O) -, R16-N(R17)-, R18-C(O)-N(R17)-, R18-O-C(O)-N(R17)-, NC-, R18- C(O)-, R16-N(R17)-C(O)-, R19-O-C(O)- and R16-N(R17)-S(O) -; Het1 is a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C -C )-alkyl and (C -C )-alkyl-O-; 1 4 1 4 Het2 is a 4-membered to 10-membered monocyclic or bicyclic, saturated or partially unsaturated heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are independent of one another; wherein all phenyl groups, unless specified otherwise, are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C -C )-alkyl and -O-(C -C )-alkyl; 1 4 1 4 wherein all cycloalkyl and bicycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl or bicycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C -C )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
2. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1; R1 is selected from the series consisting of halogen, (C -C )-alkyl, (C -C )- 1 6 3 7 cycloalkyl, (C -C )-cycloalkyl-(C -C )-alkyl-, HO-, (C -C )-alkyl-O-, (C -C )- 3 7 1 4 1 6 3 7 cycloalkyl-O-, (C -C )-cycloalkyl-(C -C )-alkyl-O- and (C -C )-alkyl-S(O) -; 3 7 1 4 1 6 n R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)- CH -, R7-C(O)-NH-CH - and R7-S(O) -NH-CH -; 2 2 2 2 R3 is selected from the series consisting of hydrogen, halogen and (C - C )-alkyl; R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C -C )-alkyl; R5 and R6 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl, (C -C )-bicycloalkyl and 1 6 3 7 6 10 Het2, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or different substituents R10, and (C -C )-cycloalkyl, (C -C )- 3 7 6 10 bicycloalkyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R11, or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated heterocycle which, in addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents R12; R7 is selected from the series consisting of (C -C )-alkyl, Het2 and Het3, wherein (C -C )-alkyl and Het2 all are unsubstituted or substituted by one or more identical or different substituents R10, and Het3 is unsubstituted or substituted by one or more identical or different substituents R13; R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C - C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, 6 2 2 (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)- C(O)- and R19-O-C(O)-; R11 and R12 are independently of one another selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, R19-O- 1 4 1 4 1 4 C(O)-(C -C )-alkyl-, fluorine, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15-NH- 1 4 1 6 C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16- 2 2 2 2 N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)-C(O)- and R19-O-C(O)-; R13 is selected from the series consisting of halogen, (C -C )-alkyl, (C - 1 4 1 C )-alkyl-O- and R16-N(R17)-; R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated, partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R20; R15 and R18 are independently of one another selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 1 6 3 7 3 7 1 4 R16 and R17 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl- 1 6 3 7 3 7 (C -C )-alkyl-, or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-membered to 6-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C - 1 6 3 C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 7 3 7 1 4 R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO- (C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15- 1 4 3 7 1 6 NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-; Het2 is a 4-membered to 10-membered monocyclic or bicyclic, saturated or partially unsaturated heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are independent of one another; wherein all cycloalkyl and bicycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl or bicycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C -C )-alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
3. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1; R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-alkyl-O-; R2 is selected from the series consisting of R5-N(R6)-C(O)-, R5-N(R6)- CH -, R7-C(O)-NH-CH - and R7-S(O) -NH-CH -; 2 2 2 2 R3 is selected from the series consisting of hydrogen, halogen and (C - C )-alkyl; R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C -C )-alkyl; R5 and R6 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl and (C -C )-cycloalkyl, wherein (C -C )-alkyl 1 6 3 7 1 6 is unsubstituted or substituted by one or more identical or different substituents R10, and (C -C )-cycloalkyl is unsubstituted or substituted by one or more identical or different substituents R11, or the groups R5 and R6, together with the nitrogen atom carrying them, form a 4-membered to 10-membered, monocyclic or bicyclic, saturated heterocycle which, in addition to the nitrogen atom carrying R5 and R6, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen and oxygen, and which is unsubstituted or substituted by one ore more identical or different substituents R12; R7 is selected from the series consisting of (C -C )-alkyl and Het3, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or different substituents R10, and Het3 is unsubstituted or substituted by one or more identical or different substituents R13; R10 is selected from the series consisting of R14, fluorine, HO-, oxo, (C - C )-alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, 6 2 2 (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)-, R18-C(O)-N(R17)-, R16-N(R17)- C(O)- and R19-O-C(O)-; R11 and R12 are independently of one another selected from the series consisting of (C -C )-alkyl, HO-(C -C )-alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, 1 4 1 4 1 4 HO-, oxo, (C -C )-alkyl-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and R18- 1 6 2 2 C(O)-N(R17)-; R13 is selected from the series consisting of halogen, (C -C )-alkyl, (C - 1 4 1 C )-alkyl-O- and R16-N(R17)-; R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated, partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R20; R15 and R18 are independently of one another selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 1 6 3 7 3 7 1 4 R16 and R17 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl- 1 6 3 7 3 7 (C -C )-alkyl-, or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-membered to 6-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; R19 is selected from the series consisting of hydrogen, (C -C )-alkyl, (C - 1 6 3 C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 7 3 7 1 4 R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO- (C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15- 1 4 3 7 1 6 NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-; Het3 is a 5-membered to 10-membered monocyclic or bicyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C -C )- alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
4. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, which is a compound of the formula Ie. Ar O
5. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)-CH -.
6. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein R2 is selected from the series consisting of R7-C(O)-NH-CH - and R7-S(O) -NH-CH -. 2 2 2
7. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, which is a compound of the formula Ie, Ar O wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R1; R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-alkyl-O-; R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)- CH -; R3 is selected from the series consisting of hydrogen, halogen and (C - C )-alkyl; R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C -C )-alkyl; one of the groups R5 and R6 is hydrogen and the other of the groups R5 and R6 is selected from the series consisting of (C -C )-alkyl and (C -C )- 1 6 3 7 cycloalkyl, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or different substituents R10, and (C -C )-cycloalkyl is unsubstituted or substituted by one or more identical or different substituents R11; R10 is selected from the series consisting of R14, fluorine, HO-, (C -C )- alkyl-O-, R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH -O-C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-; R11 is selected from the series consisting of (C -C )-alkyl, HO-(C -C )- 1 4 1 4 alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, (C -C )-alkyl-O-, HO-S(O) -O-, 1 4 1 6 2 (HO) P(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-; R14 is a 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated, partially unsaturated or aromatic and comprises 0, 1, 2 or 3 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents R20; R15 and R18 are independently of one another selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 1 6 3 7 3 7 1 4 R16 and R17 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl- 1 6 3 7 3 7 (C -C )-alkyl-, or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-membered to 6-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; R20 is selected from the series consisting of halogen, (C -C )-alkyl, HO- (C -C )-alkyl-, (C -C )-cycloalkyl, HO-, oxo, (C -C )-alkyl-O-, R15-C(O)-O-, R15- 1 4 3 7 1 6 NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, R16-N(R17)- and NC-; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C -C )- alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
8. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 5 and 7, which is a compound of the formula Ie, Ar O wherein Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R1; R1 is selected from the series consisting of halogen, (C -C )-alkyl, HO- and (C -C )-alkyl-O-; R2 is selected from the series consisting of R5-N(R6)-C(O)- and R5-N(R6)- CH -; R3 is selected from the series consisting of hydrogen, halogen and (C - C )-alkyl; R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C -C )-alkyl; one of the groups R5 and R6 is hydrogen and the other of the groups R5 and R6 is selected from the series consisting of (C -C )-alkyl and (C -C )- 1 6 3 7 cycloalkyl, wherein (C -C )-alkyl is unsubstituted or substituted by one or more identical or different substituents R10, and (C -C )-cycloalkyl is unsubstituted or substituted by one or more identical or different substituents R11; R10 is selected from the series consisting of fluorine, HO-, (C -C )-alkyl-O- , R15-C(O)-O-, R15-NH-C(O)-O-, HO-S(O) -O-, (HO) P(O)-O-, (HO) P(O)-O-CH - 2 2 2 2 O-C(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-; R11 is selected from the series consisting of (C -C )-alkyl, HO-(C -C )- 1 4 1 4 alkyl-, R16-N(R17)-(C -C )-alkyl-, fluorine, HO-, (C -C )-alkyl-O-, HO-S(O) -O-, 1 4 1 6 2 (HO) P(O)-O-, R16-N(R17)- and R18-C(O)-N(R17)-; R15 and R18 are independently of one another selected from the series consisting of (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl-(C -C )-alkyl-; 1 6 3 7 3 7 1 4 R16 and R17 are independently of one another selected from the series consisting of hydrogen, (C -C )-alkyl, (C -C )-cycloalkyl and (C -C )-cycloalkyl- 1 6 3 7 3 7 (C -C )-alkyl-, or the groups R16 and R17, together with the nitrogen atom carrying them, form a 5-membered to 6-membered, monocyclic saturated heterocycle which, in addition to the nitrogen atom carrying R16 and R17, comprises 0 or 1 further ring heteroatom selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one ore more identical or different substituents selected from the series consisting of fluorine and (C -C )-alkyl; wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C -C )- alkyl; wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one ore more fluorine substituents.
9. A compound of the formula I according to any of claims 1 to 8, which is selected from the series consisting of: 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid [2-(2-oxo- imidazolidinyl)-ethyl]-amide, 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)- amide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid cyclopropylamide, 2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy- ethyl)-amide, 2-(2-Oxo-pyrrolidinyl)-N-[2-(2-o-tolyl-chromanyloxy)-thiazol ylmethyl]-acetamide, Isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazol ylmethyl]-amide, 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid propylamide, 4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid (isoxazol- 5-ylmethyl)-amide, 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide, 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid propylamide, Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazole carbonyl]-amino}-ethyl) ester, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (6,7-dihydro-5H- pyrrolo[2,1-c][1,2,4]triazolylmethyl)-amide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid propylamide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (2-chloro-pyridin- 4-ylmethyl)-amide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (1,5-dimethyl-1H- pyrazolylmethyl)-amide, 1,3,5-Trimethyl-1H-pyrazolesulfonic acid [2-(2-phenyl-chromanyloxy)- thiazolylmethyl]-amide, 2-((R)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy- ethyl)-amide, and [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl- amine, or a pharmaceutically acceptable salt thereof.
10. A compound of the formula I according to any of claims 1 to 9, which is selected from the series consisting of: 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid [2-(2-oxo- imidazolidinyl)-ethyl]-amide, 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)- amide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid cyclopropylamide, 2-((S)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy- ethyl)-amide, 2-(2-Oxo-pyrrolidinyl)-N-[2-(2-o-tolyl-chromanyloxy)-thiazol ylmethyl]-acetamide, Isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazol ylmethyl]-amide, 2-(2-o-Tolyl-chromanyloxy)-thiazolecarboxylic acid propylamide, 4-Methyl(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid (isoxazol- 5-ylmethyl)-amide, 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide, 2-[2-(5-Fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid propylamide, Phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazole carbonyl]-amino}-ethyl) ester, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (6,7-dihydro-5H- pyrrolo[2,1-c][1,2,4]triazolylmethyl)-amide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid propylamide, 2-(2-Phenyl-chromanyloxy)-thiazolecarboxylic acid (2-chloro-pyridin- 4-ylmethyl)-amide, 2-((R)o-Tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy- ethyl)-amide, and [2-(2-Phenyl-chromanyloxy)-thiazolylmethyl]-pyridinylmethyl- amine, or a pharmaceutically acceptable salt thereof.
11. A compound of the formula I according to any of claims 1 to 10, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)-amide.
12. A compound of the formula I according to any of claims 1 to 10, which is 2-((S)o-tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)- amide.
13. A compound of the formula I according to any of claims 1 to 10, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is isoxazolecarboxylic acid [2-(2-o-tolyl-chromanyloxy)-thiazolylmethyl]- amide.
14. A compound of the formula I according to any of claims 1 to 10, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-o-tolyl-chromanyloxy)-thiazolecarboxylic acid propylamide.
15. A compound of the formula I according to any of claims 1 to 10, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-[2-(5-fluoromethyl-phenyl)-chromanyloxy]-thiazolecarboxylic acid (2- hydroxy-ethyl)-amide.
16. A compound of the formula I according to any of claims 1 to 10, which is phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]- amino}-ethyl) ester, or a pharmaceutically acceptable salt thereof.
17. A compound of the formula I according to any of claims 1 to 10, which is 2-((R)o-tolyl-chromanyloxy)-thiazolecarboxylic acid (2-hydroxy-ethyl)- amide.
18. A compound of the formula I according to any of claims 1 to 10, which is phosphoric acid mono-(2-{[2-((S)o-tolyl-chromanyloxy)-thiazolecarbonyl]- amino}-ethyl) ester disodium salt.
19. A process for the preparation of a compound of the formula I as claimed in any of claims 1 to 18, Ar O Ar O G2 R4 R4 S R3 Ar O which comprises cyclizing a compound of the formula XV to a compound of the formula XVI, converting the compound of the formula XVI into a compound of the formula II, reacting the compound of the formula II with a compound of the formula III to give a compound of the formula IV, and converting the compound of the formula IV into a compound of the formula I, wherein the groups Ar, R3 and R4 in the compounds of the formulae II, III, IV, XV and XVI are defined as in the compounds of the formula I, the group G2 in the compounds of the formula XV is a hydroxy group or a nucleophilically substitutable leaving group, the group G3 in the compounds of the formulae XV and XVI is bromine or (C -C )-alkyl-O-, and the group Y in the compounds of the formulae III and IV is R50-O-C(O)-, H-C(O)- or NC-, wherein R50 is (C -C )-alkyl.
20. The process according to claim 19, wherein a compound of the formula Iq is prepared in which the chiral carbon atom carrying the group Ar is present in uniform configuration, Ar O Ar O G2 R4 XVIa S R2 R3 Ar O Ar O Iq IVd which comprises cyclizing a compound of the formula XVa, in which the chiral carbon atom carrying the group Ar is present in uniform configuration, to a compound of the formula XVIa, converting the compound of the formula XVIa into a compound of the formula IIa, reacting the compound of the formula IIa with a compound of the formula III to give a compound of the formula IVd, and converting the compound of the formula IVd into a compound of the formula Iq, wherein the groups Ar, R2, R3 and R4 in the compounds of the formulae Iq, IIa, III, IVd, XVa and XVIa are defined as in the compounds of the formula I, the group G2 in the compounds of the formula XVa, the group G3 in the compounds of the formulae XVa and XVIa and the group Y in the compounds of the formulae III and IVd are defined as in compounds of the formulae XV, XVI, III and IV in claim 19.
21. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, or a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, made according to the process according to claim 19 or 20, for use as a pharmaceutical.
22. A pharmaceutical composition, comprising a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to or a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, made according to the process according to claim 19 or 20, and a pharmaceutically acceptable carrier.
23. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, or a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, made according to the process according to claim 19 or 20, for use as an inhibitor of the sodium-calcium-exchanger (NCX) or in the treatment of heart failure, cardiac arrhythmias, stroke, dementia, hypertension, cardiac ischemia, renal failure, shock or age-related disorders.
24. Use of a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 18, or a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, made according to the process according to claim 19 or 20, in the manufacture of a medicament for the inhibition of the sodium- calcium-exchanger (NCX) or for the treatment of heart failure, cardiac arrhythmias, stroke, dementia, hypertension, cardiac ischemia, renal failure, shock or age-related disorders.
25. A compound according to any one of claims 1 to 8, 21 or 23, a pharmaceutical composition according to claim 22, or the use according to claim 24, substantially as hereinbefore described. SANOFI WATERMARK PATENT AND TRADE MARKS ATTORNEYS P38659NZ00
Applications Claiming Priority (3)
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EP11306128.7 | 2011-09-12 | ||
EP11306128.7A EP2567958B1 (en) | 2011-09-12 | 2011-09-12 | Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals |
PCT/EP2012/067622 WO2013037724A1 (en) | 2011-09-12 | 2012-09-10 | Substituted 2-(chroman-6-yloxy)-thiazoles and their use as pharmaceuticals |
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NZ622127A NZ622127A (en) | 2016-03-31 |
NZ622127B2 true NZ622127B2 (en) | 2016-07-01 |
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