ZA200603600B - 1-amino-2-oxy-substituted tetrahydronaphtalene derivatives, methods for the production thereof, and their use as antiphlogistics - Google Patents
1-amino-2-oxy-substituted tetrahydronaphtalene derivatives, methods for the production thereof, and their use as antiphlogistics Download PDFInfo
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- ZA200603600B ZA200603600B ZA200603600A ZA200603600A ZA200603600B ZA 200603600 B ZA200603600 B ZA 200603600B ZA 200603600 A ZA200603600 A ZA 200603600A ZA 200603600 A ZA200603600 A ZA 200603600A ZA 200603600 B ZA200603600 B ZA 200603600B
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- South Africa
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- alkyl
- optionally
- hydroxy
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 4
- 230000001741 anti-phlogistic effect Effects 0.000 title 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 179
- 125000005843 halogen group Chemical group 0.000 claims description 127
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 86
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 71
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 71
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 60
- 125000004432 carbon atom Chemical group C* 0.000 claims description 59
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 52
- 229910052799 carbon Inorganic materials 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- 125000000468 ketone group Chemical group 0.000 claims description 40
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 125000002619 bicyclic group Chemical group 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 125000002950 monocyclic group Chemical group 0.000 claims description 33
- 125000004434 sulfur atom Chemical group 0.000 claims description 32
- 150000001412 amines Chemical class 0.000 claims description 31
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000005024 alkenyl aryl group Chemical group 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000003107 substituted aryl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000005217 alkenylheteroaryl group Chemical group 0.000 claims description 7
- 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims 2
- 239000002841 Lewis acid Substances 0.000 claims 1
- 150000001450 anions Chemical class 0.000 claims 1
- 208000027866 inflammatory disease Diseases 0.000 claims 1
- 150000007517 lewis acids Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- -1 thiophthalidyl Chemical group 0.000 description 93
- 150000003254 radicals Chemical class 0.000 description 27
- 229910052736 halogen Inorganic materials 0.000 description 22
- 150000002367 halogens Chemical class 0.000 description 22
- 125000001424 substituent group Chemical group 0.000 description 16
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 13
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 12
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 12
- 125000005633 phthalidyl group Chemical group 0.000 description 12
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 12
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 11
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 11
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 11
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 11
- 125000001070 dihydroindolyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 10
- 125000004611 dihydroisoindolyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 9
- 125000005045 dihydroisoquinolinyl group Chemical group C1(NC=CC2=CC=CC=C12)* 0.000 description 9
- 125000001041 indolyl group Chemical group 0.000 description 9
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 9
- 125000001624 naphthyl group Chemical group 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 7
- 229910052740 iodine Inorganic materials 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 125000005427 anthranyl group Chemical group 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000005044 dihydroquinolinyl group Chemical group N1(CC=CC2=CC=CC=C12)* 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 125000006002 1,1-difluoroethyl group Chemical group 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- ZXMPSTMIJQZYLV-UHFFFAOYSA-N 2-methyl-1,2-dihydrophthalazin-1-one Chemical compound C1=CC=C2C(=O)N(C)N=CC2=C1 ZXMPSTMIJQZYLV-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000001331 3-methylbutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004715 3-methylbutylthio group Chemical group CC(CCS*)C 0.000 description 1
- FTGUQKOCZQPJDP-UHFFFAOYSA-N 7,8-difluoro-2-methylquinazoline Chemical compound C1=CC(F)=C(F)C2=NC(C)=NC=C21 FTGUQKOCZQPJDP-UHFFFAOYSA-N 0.000 description 1
- USHFEZVKIUMFEF-UHFFFAOYSA-N 7,8-difluoro-4-methylquinazoline Chemical compound FC1=CC=C2C(C)=NC=NC2=C1F USHFEZVKIUMFEF-UHFFFAOYSA-N 0.000 description 1
- IEPTWIQRBVELPL-UHFFFAOYSA-N 7-fluoro-2-methylquinazoline Chemical compound C1=CC(F)=CC2=NC(C)=NC=C21 IEPTWIQRBVELPL-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- FHYDPKAGEFSFQI-UHFFFAOYSA-N 8-fluoro-2-methylquinazoline Chemical compound C1=CC=C(F)C2=NC(C)=NC=C21 FHYDPKAGEFSFQI-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 206010013457 Dissociation Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 108010085012 Steroid Receptors Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000003808 silyl group Chemical class [H][Si]([H])([H])[*] 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006337 tetrafluoro ethyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
- C07D237/30—Phthalazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Rheumatology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
® ®
Tetrahydronaphthalene Derivatives, Process for their Production and their Use as
Anti-inflammatory Agents
The invention relates to tetrahydronaphthalene derivatives, process for their production and their use as anti-inflammatory agents.
Open-chain, non-steroidal anti-inflammatory agents are known from the prior art (DE 100 38 639 and WO 02/10143). In the experiment, these compounds show dissociations of action between anti-inflammatory and undesirable metabolic actions and are superior to the previously described nonsteroidal glucocorticoids or exhibit at least just as good an action.
The selectivity as well as the pharmacokinetic parameters of the compounds of the prior art still require improvement, however.
It was therefore the object of this invention to make available compounds whose selectivity relative to the other steroid receptors as well as their pharmacokinetic properties are at least just as good or better than that of the compounds of the prior art.
This object is achieved by the compounds of this invention, explained in the claims.
This invention therefore relates to stereoisomers of general formula (I),
Ry R°
R?
R®
RR? LN
R Mm in which
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy
® 2 pod 03600 ® group, a halogen atom, an optionally substituted (C,-Co)-alkyl group, an optionally substituted (C;-Co)-alkoxy group, a (C,-Cyo)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, a nitro group, or R! and R? together mean a group that is selected from the groups -0-(CH,),-0-, —0-(CHy),-CH;-, -O-CH=CH-, -(CHz)n:2-, -NH-(CH2)n+1, -N(C,-Cs-alkyl)-(CHz)n+1, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R’, independently of one another, mean hydrogen, C;-Cs- alkyl or (CO)-C,;-Cs-alkyl,
R'" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C,-Co)-alkyl group, a (C;-Cio)-alkoxy group, a (C1-Cio)-alkylthio group, or a (C,-Cs)-perfluoroalkyl group,
R'> means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, or a (C,-Co)-alkoxy group,
R’ means a C;-Cjo-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted (C;3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C,-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups), (C;-Cs)-alkoxy groups, halogen atoms, hydroxy groups, NR*R’
/ ® \ groups, exomethylene groups, or oxygen, and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1- 2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, a group OR’ or an O(CO)R'’ group, whereby
R'® means any hydroxy protective group or a C;-C q-alkyl group,
R’ means a (C;-Cjo)-alkyl group or an optionally partially or completely fluorinated (C;-C,o)-alkyl group, a (Cs-Cs)cycloalkyl group, a (C;-
Cy)alkyl(Cs-Cy)cycloalkyl group, a (C2-Cg)alkenyl(Cs-C7)cycloalkyl group, a heterocyclyl group, a (C;-Csg)alkylheterocyclyl group, a (C,-Cs)- alkenylheterocyclyl group, an aryl group, a (C;-Cg)alkylaryl group, a (C,-Csg)alkenylaryl group, (C;-Csg)alkinylaryl groups, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (Ci-Cs)alkylheteroaryl group or a (C,-Cg)alkenylheteroaryl group, or a (C,-Cyg)alkinylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Ce)-cycloalkyl ring.
Stereoisomers of general formula (I) according to claim 2, in which
) _
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-C;¢)-alkyl group, an optionally substituted (C;-Cj¢)-alkoxy group, a (C,-Cio)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R! and R? together mean a group that is selected from the groups -0-(CHy)s-O-, —O-(CH;),-CH;-, -O-CH=CH-, -(CH2)ni2-,-NH-(CH2)n+1, -N(C;-Cs-alkyl)-(CHz)n+1, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R®, independently of one another, can be hydrogen, C,-
Cs-alkyl or (CO)-C;-Cs-alkyl,
R!' means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-C,p)-alkyl group, a (C,;-C¢)-alkoxy group, a (C1-Cyp)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
R'? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cjp)-alkyl group, or a (C;-Cjo)-alkoxy group, rR’ means a C;-Cip-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-Cy)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C;-Cs)-alkyl groups : (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR"?
® ; ® groups), whereby R'> means hydrogen or (C-Cs)-alkyl), (C;-Cs)-alkoxy groups, halogen atoms, hydroxy groups, NR®R’ groups, exomethylene groups, or oxygen, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, a group OR? or an O(CO)R" group whereby R'® means any hydroxy protective group or a C;-Cjo-alky! group,
R’ means a (C;-Cj¢)-alkyl group or an optionally partially or completely fluorinated (C;-Cjo)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (Cz-Cs)-cycloalkyl ring, are another subject of this invention.
Stereoisomers of general formula (I), in which
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-C,¢)-alkyl group, a (C,-Cyo)-alkoxy group, a (Ci-Cyp)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -0-(CHy)n-0-, —O-(CH,)s-CH;-, -O-CH=CH-, -(CH2)n+2-, -NH-(CHy),+, -N(C,;-Cs-alkyl)-(CHy)y: 1, or -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms
® 6 ® and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R®, independently of one another, can be hydrogen, C1-
Cs-alkyl or (CO)-C,-Cs-alkyl,
R'" meansa hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-C,o)-alkyl group, a (C;-C;¢)-alkoxy group, a (Ci-Cyo)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
R'> means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Co)-alkyl group, or a (C,-Cio)-alkoxy group,
R’ means a C,-Cjg-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C;-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups), (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, a group OR'® or an O(CO)R'® group, whereby
R'? means any hydroxy protective group or a C;-Cjo-alkyl group,
R® means a (C;-Cs)-alkyl group or an optionally partially or completely
® fluorinated (C,-Cs)-alkyl group, a (Cs-C;)cycloalkyl group, a (C;-
Cs)alkyl(Cs-Cy)cycloalkyl group, a (C,-Cs)alkenyl(Cs-C7)cycloalkyl group, a heterocyclyl group, a (C;-Cs)alkylheterocyclyl group, a (C2-Cs)- alkenylheterocyclyl group, (C2-C8)alkinylaryl groups, an aryl group, a (Cy-Cg)alkylaryl group, a (C,-Csg)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (Ci-Cy)alkylheteroaryl group or a (C,-Cs)alkenylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (Cs-Cs)-cycloalkyl ring, are another subject of the invention.
Stereoisomers of general formula (1), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-C,o)-alkyl group, a (C,;-C,¢)-alkoxy group, a (C1-Cip)-alkylthio group, a (C,-Cs)-perfluoralkyl group, a cyano group, or a nitro group or R! and R? together mean a group that is selected from the groups -0-(CH)p-0-, “0-(CH2)s-CHz-, -O-CH=CH-, -(CH2)n+2-, -NH-(CH3),-, -N(C;-Cs-alkyl)-(CH2)n:1-, and -NH-N=CH-,
® : ® whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR°R’, whereby R® and R®, independently of one another, can be hydrogen, Ci-
Cs-alkyl or (CO)-C;-Cs-alkyl,
RY means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, a (C,-Cio)-alkoxy group, a (C;-Cp)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
R'? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C,-C,o)-alkyl group, or a (C;-C,¢)-alkoxy group,
R’ means a C,-Cyp-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C,-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups), (C;-Cs)-alkoxy groups, halogen atoms, exomethylene groups, or oxygen and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, rR means a hydroxy group, a group OR" or an O(CO)R" group, whereby
R'” means any hydroxy protective group or a C;-Cyo-alkyl group,
® ; ®
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl! or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C3-Cs)-cycloalkyl ring, are another subject of this invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C;-C¢)-alkyl group, a (C1-Co)-alkoxy group, a (C;-Cyo)-alkylthio group, a (C,-Cs)-perfluoralkyl group, a cyano group, Or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CHz),-O-, -O-(CH;),-CH2-, -
O-CH=CH-, -(CH2)n+2-, -NH-(CH2)n+1, -N(C;-Cs-alkyl)-(CH2)q-1-, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR®R®, whereby R® and R®, independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C,-Cs-alkyl,
R'"" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cjo)-alkyl group, a (C;-Cio)-alkoxy group, a (C,-Cip)-alkylthio group, or a (C;-Cs)-perfluoralkyl group,
R!2 means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, or a (C;-Co)-alkoxy group,
® " ®
R’ means a C,;-Cjo-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups that are selected from (C;-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups, whereby R'*> means hydrogen or (C;-Cs)-alkyl), (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, or that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, a group OR'’ or an O(CO)R' group, whereby
R' means any hydroxy protective group or a C;-Cj¢-alkyl group,
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, a (Cs-Cr)cycloalkyl group, a (C;-
Cy)alkyl(Cs-Cs)cycloalkyl group, a (C,-Cg)alkenyl(Cs-Cr)cycloalkyl group, a heterocyclyl group, a (C;-Cs)alkylheterocyclyl group, a (Cz-Cy)- alkenylheterocyclyl group, (C,-Cg)alkinylaryl groups, an aryl group, a (C:-Cy)alkylaryl group, a (C,-Cg)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C,;-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a
® 11 ® : (C1-Cy)alkylheteroaryl group or a (C,-Cg)alkenylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cg)-cycloalkyl ring, provided that at least three of radicals R', R*, R and R'? are not hydrogen, are another subject of this invention.
Stereoisomers of general formula (1), in which
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-C,o)-alkyl group, a (C1-Cyo)-alkoxy group, a (C,-Co)-alkylthio group, a (C-Cs)- perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CHz),-O-, -O- (CH3)n-CHz-, -O-CH=CH-, -(CH2)n+2-, -NH-(CHy)p+1, -N(C;-Cs-alkyl)- (CHy)y-1-, or -NH-N=CH-, whereby n= 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR'R’, whereby R® and R’, independently of one another, can be hydrogen, C,;-
Cs-alkyl or (CO)-C;-Cs-alkyl,
R'' means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group,
® a ® an optionally substituted (C;-Cjo)-alkyl group, a (C,-Cio)-alkoxy group, a (C,-C))-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
RZ means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cyo)-alkyl group, or a (C;-C,o)-alkoxy group,
R® means a C;-Cy-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C;)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C,-Cs)-alky! groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR"? groups), (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, a group OR" or an O(CO)R'® group, whereby
R'” means any hydroxy protective group or a C;-Cyp-alkyl group, rR’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, a (Cs-Cs)cycloalkyl group, a (Ci-
Cs)alkyl(Cs-Cr)cycloalkyl group, a (C,-Cg)alkenyl(Cs-Cr)cycloalkyl group, a heterocyclyl group, a (C;-Cg)alkylheterocyclyl group, a (C>-Cy)- alkenylheterocyclyl group, (C,-Cg)alkinylaryl groups, an aryl group, a (C1-Cg)alkylaryl group, a (Cz-Cg)alkenylaryl group,
® 13 ® a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C,-Cyg)alkylheteroaryl group or a (C;-Cs)alkenylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R! R? R'! and R'? are not hydrogen, are another subject of this invention.
Stereoisomers of general formula (I), in which
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C;-Cio)-alkyl group, a (C,-Cjo)-alkoxy group, a (Ci-Cig)-alkylthio group, a (C,-Cs)- perfluoroalkyl group, a cyano group, or a nitro group, or R! and R? together mean a group that is selected from the groups -O-(CHa),-O-, -O- (CH2),-CH;-, -O-CH=CH-, -(CH2)5+2-, -NH-(CH2)y. 1, -N(C,-C;-alkyl)- (CH2)n+1-, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms,
® ’ _ or NR®R®, whereby R® and R®, independently of one another, can be hydrogen, Ci-
Cs-alkyl or (CO)-C,-Cs-alkyl,
R'' means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, a (C;-Cio)-alkoxy group, a (C,-Co)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
R means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cig)-alkyl group, or a (C,-Cyo)-alkoxy group,
R? means a C;-Cjo-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C;-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups), (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, rR? means a hydroxy group, a group OR" or an O(CO)R' group, whereby
R'® means any hydroxy protective group or a C,-Cj¢-alky! group,
R® means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
® ’ _
R® and R7, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or together with the carbon atom of the tetrahydronaphthalene system mean a (Cs-Cg)-cycloalkyl ring, provided that at least three of radicals R! R? R'' and R" are not hydrogen, are another subject of this invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-C)-alkyl group, a (C,-C,¢)-alkoxy group, a (C,-Cyg)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH)n-0-, “O-(CH,)a-CH;-, -O-CH=CH-, -(CH2)q+2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R’, independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C,;-Cs-alkyl,
R!"" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, a (C,-C,¢)-alkoxy group, a (C1-Cu)-alkylthio group, or a (C,-Cs)-perfluoralkyl group,
R’*> means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, or a (C;-Cjo)-alkoxy group,
R® means a C,-Cjg-alkyl group that optionally is substituted by 1-3 hydroxy
® o _ groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted phenyl group or a naphthyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (Ci-
Cs)-alkyl groups, 1-2-(C4-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,;-Cs)-alkyl group, an aryl group, a (C;-Cyg)alkylaryl group, a (C,-Cg)alkenylaryl group, a (Cs-Cy)cycloalkyl group, a (C;-Cs)alkyl(Cs-
Cy)cycloalkyl group, or a (C,-Cg)alkenyl(Cs-C7)cycloalkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R!, RZ R'' and R*? are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cjo)-alkyl group, a (C,-Cy¢)-alkoxy group, a (C-Cyp)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group,
Or a nitro group, or R! and R? together mean a group that is selected from
® 17 the groups -O-(CH;),-O-, —0-(CH;),-CH;-, -O-CH=CH-, or -(CH3)x-2-, whereby n= 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and rR’ independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C,-Cs-alkyl,
R'' means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Ci¢)-alkyl group, a (C;-C,)-alkoxy group, a (C,-Cjp)-alkylthio group, or a (C,-Cs)-perfluoroalkyl group,
R'? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Ciy)-alkyl group, a (C;-C,)-alkoxy group,
R’ means a C,-Cjp-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)-alkoxy groups, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C4-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’® means a (C;-Cs)-alkyl group or an optionally partially or completely
® ” ® fluorinated (C,-Cs)-alkyl group, an aryl group, a (C,-Cg)alkylaryl group, a (C;-Cg)alkenylaryl group, a (Cs-C;)cycloalkyl group, a (C;-Cs)alkyl(Cs-
Cr)cycloalkyl group, or a (C;-Cs)alkenyl(Cs-Cr)cycloalkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R!, rR? R'! and R'"? are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-Cs)-alkyl group, a (C,-Cs)-alkoxy group, a (C,-Cs)-perfluoroalkyl group, or a cyano group, or R' and R? together mean a group that is selected from the groups -O-(CH3),-O-, —O-(CHz),-
CHj;-, -O-CH=CH-, and -(CH2)pn+2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R'" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cjo)-alkyl group, a (C;-Cy¢)-alkoxy group, a (C1-Cyp)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
R"” means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C,-Cyo)-alkyl group, or a (C;-C,g)-alkoxy group,
R’ means a C;-Cjg-alkyl group that optionally is substituted by 1-3 hydroxy
® 0 groups or halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolony], dihydroisoindolonyl, benzimidazolyl or indoly! group that optionally is substituted with C;-Cs-alkyl, halogen, hydroxy, or C;-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C,-Cs)-alkyl groups, 1-2 (C;-Cs)- alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R® means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R RZ, R'" and R'? are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cs)-alkyl group, a (C;-Cs)-perfluoroalkyl group, a cyano group, a (C,-Cs)-alkoxy group, or together mean a (C;-
® 20 ®
C,)-alkylenedioxy group, whereby then R! and R? must be directly adjacent,
R' meansa hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cjo)-alkyl group, a (C,-Cjo)-alkoxy group, a (C1-Cyo)-alkylthio group, or a (C1-Cs)-perfluoroalkyl group,
R'> means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cy,)-alkyl group, or a (C,-Cjo)-alkoxy group,
R’ means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazoly! or indolyl group that optionally is substituted with C;-Cs- alkyl, halogen, hydroxy, or C,-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, or 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R® means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or
® : _ ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (C;-Cs)-cycloalkyl ring, provided that at least three of the radicals, R' RZ R'" and R'?, are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R? independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-C,¢)-alkyl group, a (C,-Ci¢)-alkoxy group, a (C1-Cyg)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R! and R? together mean a group that is selected from the groups -O-(CHy),-0-, —0-(CH3),-CHa-, -O-CH=CH-, and -(CH;)n:2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR*R®, whereby R* and R’, independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C;-Cs-alkyl,
R’ means a C;-Co-alkyl group, which optionally can be substituted by a group that is selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (Ci-Cs)-alkoxy groups, an optionally substituted phenyl group or a naphthyl group, a monocyclic or bicyclic heteroaryl group that optionally 1s substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the
® 22 ® tetrahydronaphthalene system and optionally can be hydrogenated at one
Or more sites,
R* means a hydroxy group,
R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, an aryl group, a (C;-Cs)alkylaryl group, a (C2-Cy)alkenylaryl group, a (C3-Cr)cycloalkyl group, a (C,-Cg)alkyl(Cs-
C7)cycloalkyl group, or a (C,-Cy)alkenyl(Cs-C7)cycloalkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R!, R?, R!! and R'? are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-C,o)-alkyl group, a (C,-C,)-alkoxy group, a (C1-Cyo)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH;),-0-, ~O-(CH,)n-CH;-, -O-CH=CH-, or -(CH)x:2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR'R’, whereby R* and R’, independently of one another, mean hydrogen, C,-C;- alkyl or (CO)-C,-Cs-alkyl,
R’ means a C;-C g-alkyl group, which optionally can be substituted by a
® 23 ® group selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)- alkoxy groups, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one
Or more sites,
R* means a hydroxy group,
R® means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group, an aryl group, a (C;-Cs)alkylaryl group, a (C2-Cy)alkenylaryl group, a (Cs-Cr)cycloalkyl group, a (C;-Cy)alkyl(Cs-
Cr)cycloalkyl group, or a (C;-Cg)alkenyl(Cs-Cr)cycloalkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring, provided that at least three of radicals R', R?, R' and R"? are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (1), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cs)-alkyl group, a (C,-Cs)-alkoxy group, a (C1-Cs)-perfluoroalkyl group, or a cyano group, or R' and R? together
® 24 ® mean a group that is selected from the groups -O-(CH;),-O-, “0-(CH;)»-
CH;-, -O-CH=CH-, and -(CH3)y+2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R® means a C;-Cyo-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolony], benzimidazolyl or indolyl group that optionally is substituted with C;-Cs- alkyl, halogen, hydroxy, or C,-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C,-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-Csg)-cycloalkyl ring,
® . ® provided that at least three of radicals R!, R? R! and R'?are not hydrogen, are another subject of the invention.
Stereoisomers of general formula (I), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cs)-alkyl group, a (C,-Cs)-perfluoroalkyl group, a cyano group, or a (C;-Cs)-alkoxy group, or together a (C;-Cy)- alkylenedioxy group, whereby then R! and R? must be directly adjacent,
R’ means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C;-Cs- alkyl, halogen, hydroxy, or C,-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R? means a hydroxy group,
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or
® ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-Cs)-cycloalkyl ring, provided that at least three of radicals R' rR’, R!! and R"* are not hydrogen, are another subject of the invention.
Another subject of this invention relates to stereoisomers of general formula (I),
Ry R°
R! rR?
RT R® ne
R (1) in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C;-C,o)-alkyl group, an optionally substituted (C,-Cig)-alkoxy group, a (C,;-Cy¢)-alkylthio group, a (Cy-Cs)-perfluoralkyl group, a cyano group, Or a nitro group, or R' and
R? together mean a group that is selected from the groups -0-(CH,),-O-, “O-(CH,),-CH,-, -O-CH=CH-, -(CH2)n:2-, -NH-(CH2)a+1,
N(C,-Cs-alkyl)-(CH2)n+1, and -NH-N=CH-, whereby n= 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR°R’, whereby R® and R®, independently of one another, can be hydrogen, C,-
Cs-alkyl or (CO)-C;-Cs-alkyl,
R'' means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, :
® . ® an optionally substituted (C;-Cyo)-alky! group, a (C;-Cio)-alkoxy group, a (C1-Cyp)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,
RZ means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cyo)-alkyl group, or a (C,-C,o)-alkoxy group,
R’ means a C;-Co-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C;-
Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups), (C;-Cs)-alkoxy groups, halogen atoms, exomethylene groups, or oxygen, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1- 2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R? means a hydroxy group, or a group OR" whereby R'® means a C,-C)o-alkyl group,
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R’, independently of one another, means a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (C3-Cs)-cycloalkyl ring.
® , ®
The stereoisomers of formula II are also covered by general formula I.
Another subject of this invention relates to stereoisomers of general formula (11), " Ry R°
R® rR’
R? HN
Ra in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-Co)-alkyl group, a (C;-C,o)-alkoxy group, a (C1-Cyo)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH2),-O-, —O-(CHz)n-CHa2-, -O-CH=CH-, -(CH2)s+2-, -NH-(CH2)a+1, N(C;-Cs-alkyl)-(CH2)n+1, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NRPR’, whereby R® and R’, independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C;-Cs-alkyl,
R’ means a C;-Cig-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C;-Cs)-alkyl groups (which optionally can be
® 29 substituted by 1-3 hydroxy or 1-3 COOR'? groups), (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group, or a group OR", whereby R'® means a C;-Co-alkyl group,
R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (Cs-Cs)-cycloalkyl ring.
Stereoisomers of general formula (II), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cy)-alkyl group, a (C;-C,0)-alkoxy group, a (C1-Cyo)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group,
Or a nitro group, or R! and R? together mean a group that is selected from the groups -O-(CHa),-O-, ~0-(CH2),-CHz-, -O-CH=CH-, and -(CH2)n-2-, whereby n= 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R®, independently of one another, can be hydrogen, C;-
Cs-alkyl or (CO)-C,-Cs-alkyl,
R’ means a C;-Cj¢-alkyl group, which optionally can be substituted by 1-3
® " ® hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, an aryl group, a (C;-Cg)alkylaryl group, a (C,-Cg)alkenylaryl group, a (C3-C7)cycloalkyl group, a (C;-Cg)alkyl(Cs-
C;)cycloalkyl group, or a (C;-Cg)alkenyl(Cs-Cr)cycloalkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Ce)-cycloalkyl ring, are another subject of the invention.
Stereoisomers of general formula (II), in which
R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-Cio)-alkyl group, a (C;-Cyo)-alkoxy group, a (C;-Co)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH;),-0-, —-0O-(CH3),-CH;-, -O-CH=CH-, and -(CH.),.,-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
® 31 ® or NRPR®, whereby R® and R®, independently of one another, can be hydrogen,
C;-Cs-alkyl or (CO)-C;-Cs-alkyl,
R’ means a C,-Cjo-alkyl group that optionally is substituted by 1-3 hydroxy groups or halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R® means a (C,;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the chain, a (C3-Ce)- cycloalkyl ring, are another subject of this invention.
Stereoisomers of general formula (II), in which
R! and R? independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C,-Cs)-alkyl group, or a (C;-Cs)-alkoxy group, or R! and R? together mean a group that is selected from the groups -O- (CH2),-0-, -O-(CHy),-CHs-, -O-CH=CH-, or -(CHz)n2-,
® 32 ® whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms,
R® means a C;-C)o-alkyl group that optionally is substituted by 1-3 hydroxy groups or halogen atoms, a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolony], dihydroisoindolonyl, benzimidazole or indoly! group that optionally is substituted with C;-Cs-alkyl, halogen, hydroxy, or C;-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C;-Cs)- alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring, are another subject of this invention.
Stereoisomers of general formula (II), in which
R! and R?, independently of one another, mean a hydrogen atom, a hydroxy
® 33 _ group, a halogen atom, a (C,-Cs)-alkyl group, or a (C,-Cs)-alkoxy group, or together a (C,-C;)-alkylenedioxy group, whereby then R! and R? must be directly adjacent,
R® means a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazoly], benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with C;-Cs- alkyl, halogen, hydroxy, or C;-Cs-alkoxy, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be substituted in one or more places with 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, or 1-2 exomethylene groups and optionally can be hydrogenated at one or more sites,
R* means a hydroxy group,
R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,
RS and R, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cg)-cycloalkyl ring are another subject of this invention.
Stereoisomers according to claim 1, which carry substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C;-Cs-alkyl, C-Cs-alkoxy,
COOR", NR*R’, C,-Cs-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O-(CH),-O-,
® 34 _ —~0-(CH;)4-CH;-, -O-CH=CH-, -(CHp)s+2-, -NH-(CH2)n+1-, - N(C;-Cs-alkyl)-(CH2)n41-, or -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, whereby then the divalent radicals can be counted as two substituents in terms of the invention, are a special subject of the invention.
R" means hydrogen or C;-C 4-alkyl or C;-Cs-alkyl. If R'/R? means COOR", then tert-butyl is preferred for R".
A special subject is if R® is formed by a radical, which contains COOR" as a substituent, and R'® means C;-Cyo-alkyl or C,-Cs-alkyl.
Stereoisomers according to claim 2, which carry three substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C,-Cs-alkyl,
C,-Cs-alkoxy, C;-Cs-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O-(CHz),-O-, -O- (CH,),-CHy-, -O-CH=CH-, -(CH2)n+2-, -NH-(CH2)n+1-, - N(C;-Cs-alkyl)-(CHz)n+1-, Or -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, and then the divalent radicals can be counted as two substituents in terms of the invention, are another subject of the invention.
The stereoisomers of formula I or II according to claim 2, in which R' and R? together mean the radicals —O-(CH,),-O-, —O-(CH2),-CH;-, -O-CH=CH-, -(CH;),-2-, -NH-(CH2)u+1-, -N(C;-Cs-alkyl)-(CHa)q+1, or -NH-N=CH- are a sub-group of these stereoisomers. The terminal atoms, in each case, of the divalent groups that are presented above are linked to directly adjacent carbon atoms of the tetrahydronaphthalene system.
® 35 _
The stereoisomers according to claim 2, in which R! R?, R''or R" is selected from the group that consists of C;-Cs-alkyl, C,-Cs-alkoxy, C;-Cs-perfluoroalkyl, halogen, hydroxy, cyano, or nitro, are a sub-group.
The stereoisomers according to claim 1 or 2, in which R', R?, R"or R"? is selected from the group that consists of optionally substituted C;-Cs-alkyl, optionally substituted C,-Cs-alkoxy, C,-Cs-perfluoroalkyl, halogen, hydroxy, or cyano, are another sub-group.
The stereoisomers of formula I or II according to claim 2 represent another sub- group, in which alkyl radicals R! and R? have the meaning -(CH;)n+2- and thus together with the carbon atom of the chain form a S- to 6-membered ring.
Stereoisomers of general formula I or II, which carry one or two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group
C,-Cs-alkyl, Ci-Cs-alkoxy, Ci-Cs-perfluoroalkyl, halogen, hydroxy, nitro, -O-(CHz).-O-, —0-(CHy)s-CHy-, -O-CH=CH-, -(CH2)s-2-, -NH-(CH3)5+1, N(Ci-Cs-alkyl)-(CHz)n+1, OF -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, are a special subject of the invention.
Stereoisomers of general formula I, which carry two substituents on the aromatic ring of the tetrahydronaphthalene system, selected from the group C;-Cs-alkyl, Cy-Cs- alkoxy, C;-Cs-perfluoroalkyl, halogen, hydroxy, cyano, nitro, -O-(CHz)»-O-, ~0-(CH,),-
CH,-, -O-CH=CH-, -(CH3)s-2-, -NH-(CH2)n+1-, - N(C;-Cs-alkyl)-(CH2)n+1-, Or -NH-N=CH-,
® y whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, whereby then the divalent radicals can be counted as two substituents in terms of the invention, are a sub-group.
Stereoisomers of general formula I or II according to claim 1 or 2, in which R’® means a C,-Cyo-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (C3-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C,-Cs)-alkyl groups, (C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby these groups can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are another subject of the invention.
Stereoisomers of formula I or II, in which R?> means a C;-Cjo-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups, and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the nitrogen atom and optionally can be hydrogenated at one or more sites, are another subject of the invention.
Stereoisomers of general formula I or II, in which R®> means a phenyl or naphthyl group that optionally is substituted with one or more radicals from the group C;-Cs- alkyl, C,-Cs-alkoxy, hydroxy, halogen, cyano, CF3, nitro, COOR™, or NR®*R®, are a subject of the invention.
® . ®
Compounds of general formula I or II according to claims 1-6, in which R® means a monocyclic or bicyclic hetereoaryl group that optionally is substituted by one or more groups, independently of one another, selected from (C,-Cs)-alkyl groups, which themselves optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups, whereby R'® means hydrogen or (C;-Cs)-alkyl, (C;-Cs)-alkoxy groups, halogen atoms, hydroxy groups, NR*R’ groups, exomethylene groups, or oxygen and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are a preferred subject of this invention.
Compounds of general formula I or II according to claims 1-6, in which R’ means a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups, independently of one another, selected from (C;-Cs)-alkyl groups, which themselves optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups, whereby R'? means hydrogen or (C,-Cs)-alkyl, (C;-Cs)-alkoxy groups, halogen atoms, hydroxy groups, NR*R’ groups, exomethylene groups, or oxygen, and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system, and optionally can be hydrogenated at one or more sites, and R’ means an optionally partially or completely fluorinated (C,-Cs)-alky! group, are another preferred subject of this invention.
Stereoisomers of general formula I, in which R’ means a C;-Co-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, a phenyl, naphthyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroquinolinyl, thiophthalidyl, benzoxazinonyl,
® 38 ® phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8- naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C;-Cs-alkyl, halogen, hydroxy, or C,-Cs-alkoxy, are a preferred subject of the invention.
Stereoisomers of general formula I or II, in which R’ means a C;-Cjg-alkyl group, which optionally can be substituted by 1-3 hydroxy groups, halogen atoms, or a phenyl, phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, dihydroisoquinolinyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazole or indolyl group that optionally is substituted with C;-Cs- alkyl, halogen, hydroxy, or C;-Cs-alkoxy, are a special subject of the invention.
Stereoisomers of formula (I), in which R® means a phthalidyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, thiophthalidyl, indazolyl, benzothiazolyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazoly! or indolyl group, are another subject of the invention.
Stereoisomers of formula (1), in which R? means dihydroisoquinolinyl, dihydroquinolinyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, are another subject of the invention.
Stereoisomers of general formula I, in which R* means an isoquinolonyl, quinolonyl, quinazolinyl or phthalaziny! group, are another subject of the invention.
Stereoisomers of general formula I or 11, in which R’ means an optionally substituted isoquinolonyl, quinolonyl, quinazolinyl, phthalazinyl, indazolyl, quinolinyl,
® 39 _ isoquinolinyl, isoquinolonyl, dihydroindolonyl, dihydroindolyl, dihydroindolonyl, naphthyl, pyridyl, or phthalidyl group, are another subject of the invention.
Stereoisomers of general formula I, in which R? means isoquinolin-1(2H)on-5yl, quinolin-2(1H)-on-5yl, 8- or 7-fluoro-2-methyl-quinazoline, 7,8-difluoro-4-methyl- quinazoline, 7,8-difluoro-2-methyl-quinazoline or 2-methyl-phthalazin-1-one are another subject of the invention.
Radical R® is bonded via the amine to the tetrahydronaphthalene system. If radical R* has several positions that are chemically possible to be bonded to the ring system, then this invention comprises all of these possibilities.
Radical R? is also encompassed by this invention, if it is hydrogenated at one or more sites.
As substituents of monocyclic or bicyclic heteroaryl groups (heterocyclic groups) R?, as they were previously defined, for example, hydroxy, halogen atoms, in particular fluorine and chlorine, (C;-Cs)-alkyl groups (which themselves optionally can be substituted by hydroxy groups, (C;-Cs)-alkoxy groups or COOR" groups, whereby
R'? means hydrogen or (C,-Cs)-alkyl), in particular methyl, (C,-Cs)-alkenyl groups, completely or partially fluorinated (C,-Cs)-alky! groups, in particular CF3, CFHy, or
C,Fs, (C,-Cs)-alkoxy groups, in particular methoxy and ethoxy, NR®R’ groups, in particular NH,, N(CHs); or NH(CHs), cyano groups as well as keto groups, which are formed with a carbon atom of a ring of the heteroaryl group and oxygen, which forms an
N-oxide with an optionally present nitrogen atom of the ring, are suitable at chemically suitable positions. From the above, as a preferred group of substituents for radical R3, as it is defined in Claim 1 and for all other claims, the group that consists of fluorine, chlorine, OH, CHs, CFs, CFHy, or CFs, OCHs, OC,Hs, NH;, N(CH3), and NH(CH3), cyano, keto, or oxygen follows.
@® 40 _
As substituents of the heterocyclic groups R®, as it was previously defined in the above-mentioned subjects of the invention, for example, halogen atoms, (C-Cs)-alkyl groups (which themselves are substituted by hydroxy groups or COOR"? groups), whereby R'* means hydrogen or (C,-Cs)-alkyl), (C,-Cs)-alkenyl groups, fluorinated (C-Cs)-alkyl groups, (C;-Cs)-alkoxy groups or cyano groups are suitable at suitable positions.
Stereoisomers of general formula I or II, in which R® means a phenyl or naphthyl, phthalidyl], thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with
C;-Cs-alkyl, halogen, hydroxy, or C;-Cs-alkoxy, are an also preferred subject.
Stereoisomers of general formula I, in which R? means a phenyl, phthalidyl, thiophthalidyl, benzoxazinonyl, phthalazinonyl, quinolinyl, isoquinolinyl, quinolonyl, isoquinolonyl, indazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, 1,7- or 1,8-naphthyridinyl, dihydroindolonyl, dihydroisoindolonyl, benzimidazolyl or indolyl group that optionally is substituted with C,-Cs-alkyl, halogen, hydroxy, or C;-Cs-alkoxy, are an especially preferred subject.
The heterocyclyl group R® is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine.
The hydroxy group in R* can be protected by one of the commonly used hydroxy protective groups known to one skilled in the art, such as, for example, silyl ether or ester of organic C,-Cig-acids or as C,-Cs-ether or benzyl ether, preferably as one or the commonly used hydroxy protective groups or as C;-Cs-ether. As radical RY, the hydroxy group is especially preferred.
® 41 ®
The commonly used hydroxy protective groups are described in detail in T. W.
Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis," 20d Edition, John
Wiley & Sons, 1991.
The protective groups are preferably alkyl, aryl or mixed alkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS), triethylsilyl (TES), tert.-butyldimethylsilyl (TBDMS), tert.-butyldiphenylsilyl (TBDPS) or triisopropylsilyl groups (TIPS) or another standard hydroxy protective group (methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl or tetrahydropyranyl groups).
Radical R® is bonded directly to the tetrahydronaphthalene system. If radical R’ has several positions, which are chemically possible, to be bonded to the ring system, then this invention comprises all of these possibilities.
Stereoisomers of general formula I, in which R’ means a (C,;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, a (Cs-
Cr)cycloalkyl group, a (C;-Cg)alkyl(Cs-Cr)cycloalkyl group, a (C,-Cy)alkenyl(C3-Cr)cycloalkyl group, a heterocyclyl group, a (Ci-Cs)alkylheterocyclyl group, a (C,-Cy)alkenylheterocyclyl group, an aryl group, a (C,-Cs)alkylaryl group, or a (C,-Cg)alkenylaryl group, are another subject of the invention.
Stereoisomers of general formula I according to claim 1, in which R’ means a (Cs-Cy)cycloalkyl group, a (C;-Cg)alkyl(Cs-Cr)cycloalkyl group, a (C,-Cy)alkenyl(Cs-Cr)eycloalkyl group, a heterocyclyl group, a (Ci-Cs)alkylheterocyclyl group, a (C;-Cs)alkenylheterocyclyl group, an aryl group, a (C;-Cs)alkylaryl group, a (C,-Cy)alkenylaryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C,-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (Ci-Cs)alkylheteroaryl group or a
® 42 (C2-Cy)alkenylheteroaryl group, or a (C,-Cs)alkinylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, are another sub-group of the invention.
Stereoisomers of general formula I, in which R® means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group, an aryl group, a (C1-Cg)alkylaryl group, a (C;-Cg)alkenylaryl group, a (Cs-Cr)cycloalkyl group, a (Cy-
Cr)alkyl(Cs-Cs)cycloalkyl group, or a (C,-Cg)alkenyl(Cs-C7)cycloalkyl group, are a subject of the invention.
Stereoisomers of general formula I or II according to claims 1 to 6, in which R’ represents a (C,-Cj¢)-alkyl group or an optionally partially or completely fluorinated (C,-Cio)-alkyl group, preferably a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group, especially preferably a (C;-Cs)-alky! group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, in particular an optionally partially or completely fluorinated (C;-Cs)-alkyl group, quite especially CF; or CFs, are another subject of the invention.
Stereoisomers of general formula I or II according to claims S and 6, in which R’ means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group, are another subject of the invention. R® preferably stands for the trifluoromethyl group or the pentafluoroethyl group.
Preferred are stereoisomers according to claims 1 to 6, whose radical R® means an optionally partially or completely fluorinated (C;-Cs)-alkyl group, in particular an optionally partially or completely fluorinated (C;-Cs)-alkyl group.
o 43 _
The radicals and all thier subcombinations, which are confirmed by the examples, represent an especially preferred sub-group, as they were disclosed for this invention.
The designation halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. A fluorine, chlorine or bromine atom is preferred.
The C;-Cio- or C;-Cs-alkyl groups R', R% R* R® R% R7 R', Rand R" can be straight-chain or branched and stand for, for example, a methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, tert.-butyl or n-pentyl, 2,2-dimethylpropyl, 2-methylbutyl or 3-methylbutyl group, as well as the hexyl, heptyl, nonyl, or decyl group and their arbitrarily branched derivatives. A methyl or ethyl group is preferred.
The above-mentioned alkyl groups optionally can be substituted by 1-5 groups, independently of one another, selected from hydroxy, cyano, nitro, COORD", C,-Cs- alkoxy groups, halogen, NR®R® a partially or completely fluorinated C,-Cs-alkyl group; the substituents 1-3 halogen atoms and/or 1-3 hydroxy- and/or 1-3 cyano- and/or 1-3
COOR" groups represent a sub-group. Fluorine atoms, or hydroxy, methoxy and/or cyano groups represent a preferred sub-group.
The alkyl groups optionally can only be substituted by 1-3 hydroxy groups and/or 1-3 COOR"® groups. Hydroxy groups are then preferred.
For a partially or completely fluorinated C;-Cs-alkyl group, for example, the following partially or completely fluorinated groups are considered: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1- trifluoroethyl, tetrafluoroethyl, and pentafluoroethyl. Of the latter, the trifluoromethyl group or the pentafluoroethyl group is preferred, whereby the completely fluorinated group is also referred to as the perfluoroalkyl group. The reagents that optionally are used during the synthesis are commercially available or the published syntheses of the
® 44 ERE u260D:
PS . corresponding reagents fall into the category of the prior art, or published syntheses can be used in a similar way.
The C;-Cyo- or C;-Cs-alkoxy groups can be straight-chain or branched and stand for, for example, a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert.-butoxy or n-pentoxy, 2,2-dimethylpropoxy, 2-methylbutoxy or 3-methylbutoxy group. C;-Cs-Alkoxy groups are preferred. A methoxy or ethoxy group is especially preferred.
The above-mentioned alkoxy groups optionally can be substituted with 1-3 groups that are selected from halogen, in particular fluorine, chlorine, hydroxy and cyano.
The C;-Cs-alkylthio groups can be straight-chain or branched and stand for, for example, a methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert.-butylthio or n-pentylthio, 2,2-dimethylpropylthio, 2-methylbutylthio or 3- methylbutylthio group. A methylthio or ethylthio group is preferred.
The substituent NR*R® means, for example, NH, NH(CHz), N(CHa)z,
NH(C;Hs), N(CzHs),, NH(CsHj7), N(C3Hy7)2, NH(CsHy), N(CsHo)2, NH(CsHi1),
N(CsHj1)2, NH(CO)CHs, NH(CO)C,Hs, NH(CO)C;H,, NH(CO)C4Hs, or
NH(CO)CsHi.
The cycloalkyl group means a saturated cyclic group with 3 to 7 ring-carbon atoms that optionally is substituted by one or more groups selected from hydroxy groups, halogen atoms, (C;-Cs)-alkyl groups, (C;-Cs)-alkoxy groups, NR!R’ groups,
COOR" groups, CHO, or cyano, such as, for example, cyclopropyl, methylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methylcyclopentyl, cyclohexyl, methylcyclohexyl, cycloheptyl, or methylcycloheptyl.
® 45 ®
A (C1-Cg)alky}(Cs-Cr)cycloalkyl group R’ is defined as a cycloalkyl group that is linked to the ring system via a straight-chain or branched (C;-Cg)-alkyl unit.
A (C2-Cy)alkenyl(Cs-Cr)cycloalkyl group R® is defined as a cycloalkyl group that is linked to the ring system via a straight-chain or branched (C,-Cs)-alkenyl unit.
The heterocyclyl group is not aromatic and can be, for example, pyrrolidine, imidazolidine, pyrazolidine, or piperidine. Perhydroquinoline and perhydroisoquinoline are also part of the included heterocyclyl groups.
As substituents for heterocyclyl and heteroaryl groups, for example, substituents from the group optionally substituted C;-Cs-alkyl group, hydroxy-, C,-Cs-alkoxy-,
NR®R’-, halogen, cyano-, COOR"-, and CHO- are considered. The substituents optionally can also be bonded to the nitrogen atom; N-oxides are then also included in the definition.
Aryl groups in terms of the invention are aromatic or partially aromatic carbocyclic groups with 6 to 14 carbon atoms that have a ring, such as, e.g., phenyl or phenylene or several condensed rings, such as, e.g., naphthyl or anthranyl. By way of example, phenyl, naphthyl, tetralinyl, anthranyl, indanyl, and indenyl can be mentioned.
The aryl groups can be substituted at any suitable site that results in a stable stereoisomer, by one or more radicals from the group hydroxy, halogen, or C;-Cs-alkyl,
C,-Cs-alkoxy, cyano, CFs, or nitro that optionally is substituted by 1-3 hydroxy groups, or COOR®® groups. The optionally substituted phenyl group and the naphthyl group are preferred.
A (C,-Cy)alkylaryl group is an aryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C,-Cs)-alkyl unit.
A (C,-Cg)alkenylaryl group is an aryl group, as it is already described above, which is linked to the ring system via a straight-chain or branched (C;-Cs)-alkenyl unit.
Claims (1)
- ® 380 ® Claims1. Compounds of general formula (I), R\ R° Ri rR? RR LN R M in which R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-Cio)-alkyl group, an optionally substituted (C;-Cj¢)-alkoxy group, a (C;-Cy)-alkylthio group, a (C,-Cs)-perfluoroalkyl group, a cyano group, a nitro group, or R! and R? together mean a group that is selected from the groups -0-(CH2)p-0-, “0-(CH3)n-CH;-, -O-CH=CH-, -(CH2)n+2-, -NH-(CH2)5+1, -N(C,-Cs-alkyl)-(CH2)n.1, and -NH-N=CH-, whereby n= 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR*R?, whereby R* and R®, independently of one another, mean hydrogen, C,-Cs- alkyl or (CO)-C,-Cs-alkyl, R'" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cio)-alkyl group, a (C,-C)-alkoxy group, a (C,-Cyg)-alkylthio group, or a (C,;-Cs)-perfluoroalkyl group, R'?> means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group,® 381 ® an optionally substituted (C,;-Co)-alkyl group, or a (C,-C¢)-alkoxy group,R’ means a C;-Cyy-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C;- Cs)-alkyl groups, which themselves optionally can be substituted by 1-3 hydroxy or 1-3 COOR"® groups, whereby R'*> means hydrogen or (C;-Cs)- alkyl, (C;-Cs)-alkoxy groups, halogen atoms, hydroxy groups, NR*R’ groups, exomethylene groups, or oxygen, and that optionally contains 1-4 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R* means a hydroxy group, a group OR'’ or an O(CO)R' group, whereby R'® means any hydroxy protective group or a C;-Cj¢-alkyl group,R’ means a (C;-Co)-alkyl group or an optionally partially or completely® 382 fluorinated (C,-Cig)-alkyl group, a (Cs-Cs)cycloalkyl group, a (C;- Cs)alkyl(Cs-C7)cycloalkyl group, a (C;-Cg)alkenyl(Cs-C7)cycloalkyl group, a heterocyclyl group, a (C;-Cs)alkylheterocyclyl group, a (C;-Cs)- alkenylheterocyclyl group, an aryl group, a (C;-Cs)alkylaryl group, a (C,-Cy)alkenylaryl group, (C,-Cg)alkinylaryl groups, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C,-Cs)-alkyl groups, 1-2 (C;-Cs)-alkoxy groups, 1-3 halogen atoms, or 1-2 exomethylene groups and that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C1-Cy)alkylheteroaryl group or a (C,-Cg)alkenylheteroaryl group, or a (C,-Cy)alkinylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites, R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring.2. Stereoisomers of general formula (I) Ry R° R! R]* RT RE ANS? in which R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-C;¢)-alkyl group, a (Ci-Cip)-alkoxy group, a (C;-Cyp)-alkylthio group, a (C,-Cs)-® 383 ® perfluoroalkyl group, a cyano group, or a nitro group, or R! and R? together mean a group that is selected from the groups -0-(CH2)s-0-, —O-(CH,),-CH;-, -O-CH=CH-, -(CH2)x-2-, -NH-(CH2)n+1, -N(C;-Cs-alkyl)-(CH2)n+1, or -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR'R’, whereby R* and R’, independently of one another, can be hydrogen, C;- Cs-alkyl or (CO)-C;-Cs-alkyl,R'"'" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-Cjg)-alkyl group, a (C;-Ci¢)-alkoxy group, a (C;-Cyp)-alkylthio group, or a (C,-Cs)-perfluoroalkyl! group,R'? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-C,p)-alkyl group, or a (C;-C,¢)-alkoxy group,R’ means a C;-Cjo-alkyl group that optionally can be substituted by a group that is selected from 1-3 hydroxy groups, halogen atoms, or 1-3 (C,;-Cs)- alkoxy groups, an optionally substituted (Cz-C;)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group,a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C;-Cs)-alkyl groups, which optionally themselves can be substituted by 1-3 hydroxy or 1-3 COOR"® groups, whereby R"? means hydrogen or (C;-Cs)-alkyl,® 384 ®(C;-Cs)-alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R* means a hydroxy group, a group OR" or an O(CO)R'’ group, whereby R'® means any hydroxy protective group or a C;-Ciy-alkyl group,R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, a (Cs-C7)cycloalkyl group, a (C;- Cy)alkyl(Cs-C7)cycloalkyl group, a (C,-Cg)alkenyl(Cs-C7)cycloalkyl group, a heterocyclyl group, a (C,-Cg)alkylheterocyclyl group, a (C,-Cs)- alkenyltheterocyclyl group, an aryl group, a (C;-Cg)alkylaryl group, a (C;-Cy)alkenylaryl group, a (C,-Cg)alkinylaryl group,a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C;-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3 halogen atoms, 1-2 exomethylene groups or that contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, a (C-Cg)alkylheteroaryl group or a (C,-Csg)alkenylheteroaryl group, whereby these groups can be linked via any position to the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R® and R’, independently of one another, mean a hydrogen atom, a methyl or® 385 ® ethyl group or together with the carbon atom of the tetrahydronaphthalene system mean a (Cs-Cg)-cycloalkyl ring, provided that at least three of radicals R!, R? R!! and R'? are not hydrogen.3. Compounds of general formula (I), Ry R° R rR? RIT RY HN. , R M in which R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C,-C,,)-alkyl group, an optiona}'y substituted (C;-Cjp)-alkoxy group, a (C;-Co)-alkylthio group, a (C,-Cs)-perfluoralkyl group, a cyano group, or a nitro group or R' and R? together mean a group that is selected from the groups -O-(CH3),-0O-, “O-(CH>),-CH;-, -O-CH=CH-, -(CH2)p:2-, -NH-(CH2)y:1, -N(C,-Cs-alkyl)-(CH2)n:1-, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR'R’, whereby R® and R’, independently of one another, can be hydrogen, C;- Cs-alkyl or (CO)-C,;-Cs-alkyl, R'" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group,® 386 ® an optionally substituted (C,-Cio)-alkyl group, a (C,-C,o)-alkoxy group, a (C,-Cyp)-alkylthio group, or a (C;-Cs)-perfluoroalkyl group,R? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C,-Co)-alkyl group, or a (C;-Cio)-alkoxy group,R’ means a C,-Cjg-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C,;-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group,a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups selected from (C;- Cs)-alkyl groups, which optionally can be substituted by 1-3 hydroxy or 1-3 COOR" groups, whereby R'’ means hydrogen or (C,-Cs)-alkyl, (C;-Cs)-alkoxy groups,halogen atoms,hydroxy group,NR*R’ groups,exomethylene groups, or oxygen and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R* means a hydroxy group, a group OR or an O(CO)R" group, whereby R'° means any hydroxy protective group or a C;-Cj¢-alkyl group,® 387 _ R’ means a (C;-Cyo)-alkyl group or an optionally partially or completely fluorinated (C,-C,0)-alkyl group, R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (Cs3-Cs)-cycloalkyl ring.4. Compounds of general formula (I), Ry R° R! R® RT RE HN R M in which R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, an optionally substituted (C;-C,)-alkyl group, an optionally substituted (C;-Co)-alkoxy group, a (C;-Cjo)-alkylthio group, a (C,-Cs)-perfluoralkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH,),-O-, —0-(CH,),-CH;-, -O-CH=CH-, -(CH2)s-2-, -NH-(CH2)4+1, -N(C-Cs- alkyl)-(CHz)n+1-, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms and/or nitrogen atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R* and R®, independently of one another, can be hydrogen, C;- Cs-alkyl or (CO)-C,-Cs-alkyl, R''" means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group,® 388 ® an optionally substituted (C;-Cj¢)-alky! group, a (C;-Cio)-alkoxy group, a (Cy-Cio)-alkylthio group, or a (C;-Cs)-perfluoralkyl group,R'? means a hydrogen atom, a hydroxy group, a halogen atom, a cyano group, an optionally substituted (C;-C,o)-alkyl group, or a (C,-Cjo)-alkoxy group,rR? means a C,-Cyy-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, or 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C;)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted, independently of one another, by one or more groups that are selected from (C,-Cs)-alkyl groups, which optionally themselves can be substituted by 1-3 hydroxy or 1-3 COOR" groups, whereby R"? means hydrogen or (C,-Cs)-alkyl),(C,-Cs)-alkoxy groups, halogen atoms, exomethylene groups or oxygen, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R* means a hydroxy group, or a group OR, whereby R' means a C,-Cy- alkyl group,R’ means a (C;-Cs)-alkyl group or an optionally partially or completely® 389 . ® fluorinated (C,-Cs)-alkyl group, R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cg)-cycloalkyl ring.5S. Stereoisomers of general formula (II), Ry R® R RS rR al HN. Ra in which R! and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-C,)-alkyl group, a (C-Cjo)-alkoxy group, a (C1-Cyp)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R! and R? together mean a group that is selected from the groups -O-(CH;),-O-, ~O-(CH;),-CH,-, -O-CH=CH-, or -(CHy)p+2-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR®R’, whereby R® and R®, independently of one another, can be hydrogen, C,- Cs-alkyl or (CO)-C,-Cs-alkyl, R’ means a C;-C,p-alkyl group that optionally can be substituted by 1-3 hydroxy groups, halogen atoms, an optionally substituted phenyl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by 1-2 keto groups, 1-2 (C,-Cs)-alkyl groups, 1-2 (C,-Cs)-alkoxy groups, 1-3@® 390 ® halogen atoms, or 1-2 exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1-2 sulfur atoms, whereby these groups can be linked via any position to the amine of the ’ tetrahydronaphthaiene system and optionally can be hydrogenated at one or more sites, R* means a hydroxy group, R’ means a (C;-Cs)-alkyl group or an optionally partially or completely fluorinated (C;-Cs)-alkyl group, an aryl group, a (C,-Cyg)alkylaryl group, a (C,-Cs)alkenylaryl group, a (Cs-Cy)cycloalkyl group, a (C;-Cs)alkyl(Cs- C7)cycloalkyl group, or a (C,-Cs)alkenyl(Cs-Cs)cycloalkyl group, R® and R’, independently of one another, mean a hydrogen atom, a methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, mean a (C;-Cg)-cycloalkyl ring.6. Compounds of general formula (II), Ry R° R! OE rR R? HN Rw in which R' and R?, independently of one another, mean a hydrogen atom, a hydroxy group, a halogen atom, a (C;-Cy¢)-alkyl group, a (C,-C0)-alkoxy group, a (C1-Cio)-alkylthio group, a (C;-Cs)-perfluoroalkyl group, a cyano group, or a nitro group, or R' and R? together mean a group that is selected from the groups -O-(CH;),-O-, -O-(CH;),-CH>-, -O-CH=CH-, -(CH,),.2-,® 391 ®-NH-(CH2)n+1, N(C;-Cs-alkyl)-(CH2)n+1, and -NH-N=CH-, whereby n = 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring-carbon atoms, or NR*R’, whereby R® and R’, independently of one another, can be hydrogen, C- Cs-alkyl or (CO)-C;-Cs-alkyl,R’ means a C;-C¢-alkyl group that optionally is substituted by 1-3 hydroxy groups, halogen atoms, 1-3 (C;-Cs)-alkoxy groups, an optionally substituted (Cs-C7)-cycloalkyl group, an optionally substituted heterocyclyl group, an optionally substituted aryl group, a monocyclic or bicyclic heteroaryl group that optionally is substituted by one or more groups selected from (C;-Cs)-alkyl groups (which optionally can be substituted by 1-3 hydroxy or 1-3 COOR' groups), (C;-Cs)- alkoxy groups, halogen atoms, or exomethylene groups, and that optionally contains 1-3 nitrogen atoms and/or 1-2 oxygen atoms and/or 1- 2 sulfur atoms and/or 1-2 keto groups, whereby this group can be linked via any position to the amine of the tetrahydronaphthalene system and optionally can be hydrogenated at one or more sites,R* means a hydroxy group, or a group OR, whereby R'® means a C-Cjo-alkyl group,R® means a (C,-Cs)-alkyl group or an optionally partially or completely fluorinated (C,-Cs)-alkyl group,RS and R’, independently of one another, mean a hydrogen atom, aLJ 392 ® methyl or ethyl group, or, together with the carbon atom of the tetrahydronaphthalene system, a (Cs-Cs)-cycloalkyl ring.7. Stereoisomers of general formula I, according to one of claims 1-6, whereby radical R® stands for the trifluoromethyl group or the pentafluoroethyl group.8. Stereoisomers of general formula I, according to one of claims 1-6, in the form of salts with physiologically compatible anions.9. Use of the stereoisomers according to one of the preceding claims for the production of a pharmaceutical agent.10. Use of the stereoisomers of claims 1-5 for the production of a pharmaceutical agent for the treatment of inflammatory diseases.11. Pharmaceutical preparations that contain at least one stereoisomer according to claims 1-5 or mixtures thereof as well as pharmaceutically compatible vehicles.12. Process for the production of stereoisomers of general formula I, characterized in that stereoisomers of general formula I1I rR' R® R’ x No 3 RR (In) in which radicals R', R", R"?, R?, R*, R®, R®, and R’ have the above-indicated meanings, optionally are cyclized to compounds of general formula I with the addition of organic or organic acids or Lewis acids.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10347386A DE10347386B4 (en) | 2003-10-08 | 2003-10-08 | Tetrahydronaphthalene derivatives, process for their preparation and their use as anti-inflammatory agents |
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| Publication Number | Publication Date |
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| ZA200603600B true ZA200603600B (en) | 2007-09-26 |
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| ZA200603600A ZA200603600B (en) | 2003-10-08 | 2006-05-05 | 1-amino-2-oxy-substituted tetrahydronaphtalene derivatives, methods for the production thereof, and their use as antiphlogistics |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100581543C (en) |
| DE (1) | DE10347386B4 (en) |
| ZA (1) | ZA200603600B (en) |
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| CN105523939B (en) * | 2015-12-30 | 2017-11-14 | 李函璞 | A kind of preparation method of lenalidomide intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1988008836A2 (en) * | 1987-05-15 | 1988-11-17 | Schering Corporation | Aryl substituted naphthalene, benzoxepine, benzazepine, benzocycloheptene derivatives |
| CA1327796C (en) * | 1987-07-16 | 1994-03-15 | Jorg Senn-Bilfinger | Diazoles |
| JPH0717589B2 (en) | 1990-01-22 | 1995-03-01 | ファイザー製薬株式会社 | Novel 1,3-dicarbonyl compound and composition thereof |
| US5489584A (en) * | 1994-12-29 | 1996-02-06 | Allergan, Inc. | Acetylenes disubstituted with a 5-amino or substituted 5-amino substituted tetrahydronaphthyl group and with an aryl or heteroaryl group having retinoid-like biological activity |
| EP1303483B1 (en) * | 2000-08-21 | 2008-04-23 | Pacific Corporation | Novel thiourea derivatives and the pharmaceutical compositions containing the same |
-
2003
- 2003-10-08 DE DE10347386A patent/DE10347386B4/en not_active Expired - Fee Related
-
2004
- 2004-10-06 CN CN200480036334A patent/CN100581543C/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
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| DE10347386B4 (en) | 2006-05-24 |
| CN1889947A (en) | 2007-01-03 |
| CN100581543C (en) | 2010-01-20 |
| DE10347386A1 (en) | 2005-05-19 |
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