CA2566821A1 - 7-substituted benzimidazoles and their use as inhibitors of gastric acid secretion - Google Patents
7-substituted benzimidazoles and their use as inhibitors of gastric acid secretion Download PDFInfo
- Publication number
- CA2566821A1 CA2566821A1 CA002566821A CA2566821A CA2566821A1 CA 2566821 A1 CA2566821 A1 CA 2566821A1 CA 002566821 A CA002566821 A CA 002566821A CA 2566821 A CA2566821 A CA 2566821A CA 2566821 A1 CA2566821 A1 CA 2566821A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- hydrogen
- hydroxy
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- -1 7-substituted benzimidazoles Chemical class 0.000 title claims description 285
- 230000027119 gastric acid secretion Effects 0.000 title description 5
- 239000003112 inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 131
- 239000001257 hydrogen Substances 0.000 claims description 271
- 229910052739 hydrogen Inorganic materials 0.000 claims description 271
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 191
- 229910052736 halogen Inorganic materials 0.000 claims description 137
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 136
- 150000002367 halogens Chemical group 0.000 claims description 135
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 132
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 91
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 69
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 150000003839 salts Chemical class 0.000 claims description 52
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 229910052760 oxygen Inorganic materials 0.000 claims description 30
- 125000004104 aryloxy group Chemical group 0.000 claims description 29
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 29
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 28
- 239000001301 oxygen Substances 0.000 claims description 28
- SCEVBRBKKQZTKM-UHFFFAOYSA-N 5-[[6-chloro-5-(1-methylindol-5-yl)-1H-benzimidazol-2-yl]oxy]-N-hydroxy-2-methylbenzamide Chemical compound ClC=1C(=CC2=C(NC(=N2)OC=2C=CC(=C(C(=O)NO)C=2)C)C=1)C=1C=C2C=CN(C2=CC=1)C SCEVBRBKKQZTKM-UHFFFAOYSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 24
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 23
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 20
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 19
- RBIIKVXVYVANCQ-CUWPLCDZSA-N (2s,4s,5s)-5-amino-n-(3-amino-2,2-dimethyl-3-oxopropyl)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-propan-2-ylhexanamide Chemical compound C1C(C)(C)N(C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)CC(=O)N1C1=CC=CC=C1Cl RBIIKVXVYVANCQ-CUWPLCDZSA-N 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 15
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 15
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 claims description 15
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 15
- AXLOCHLTNQDFFS-BESJYZOMSA-N azastene Chemical compound C([C@H]1[C@@H]2CC[C@@]([C@]2(CC[C@@H]1[C@@]1(C)C2)C)(O)C)C=C1C(C)(C)C1=C2C=NO1 AXLOCHLTNQDFFS-BESJYZOMSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 12
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 12
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 12
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000001041 indolyl group Chemical group 0.000 claims description 12
- 125000002950 monocyclic group Chemical group 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 12
- 125000001544 thienyl group Chemical group 0.000 claims description 12
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 11
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 11
- 125000000335 thiazolyl group Chemical group 0.000 claims description 11
- 238000011282 treatment Methods 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 229910052727 yttrium Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims 102
- 210000004211 gastric acid Anatomy 0.000 abstract description 3
- 230000028327 secretion Effects 0.000 abstract description 3
- 235000013350 formula milk Nutrition 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 150000001556 benzimidazoles Chemical class 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 235000011167 hydrochloric acid Nutrition 0.000 description 8
- 229960000443 hydrochloric acid Drugs 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 0.000 description 6
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 229940126409 proton pump inhibitor Drugs 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- 125000006017 1-propenyl group Chemical group 0.000 description 3
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 3
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 3
- CEJSJXWFXSXWCA-UHFFFAOYSA-N 4-(methylamino)-3,5-dinitrobenzoic acid Chemical compound CNC1=C([N+]([O-])=O)C=C(C(O)=O)C=C1[N+]([O-])=O CEJSJXWFXSXWCA-UHFFFAOYSA-N 0.000 description 3
- UKGCFMYYDATGNN-UHFFFAOYSA-N 6,6a-dihydro-1ah-indeno[1,2-b]oxirene Chemical class C12=CC=CC=C2CC2C1O2 UKGCFMYYDATGNN-UHFFFAOYSA-N 0.000 description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 108010079943 Pentagastrin Proteins 0.000 description 3
- 239000012317 TBTU Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 3
- 230000009858 acid secretion Effects 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- ALXRNCVIQSDJAO-KRCBVYEFSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCNC(=O)OCC(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ALXRNCVIQSDJAO-KRCBVYEFSA-N 0.000 description 3
- 229960000444 pentagastrin Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- KUCWUAFNGCMZDB-UHFFFAOYSA-N 2-amino-3-nitrophenol Chemical compound NC1=C(O)C=CC=C1[N+]([O-])=O KUCWUAFNGCMZDB-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- ONDQRDYJQDWXIJ-UHFFFAOYSA-N 6-bromo-2-methyl-4-phenylmethoxy-1h-benzimidazole Chemical compound C1=C(Br)C=C2NC(C)=NC2=C1OCC1=CC=CC=C1 ONDQRDYJQDWXIJ-UHFFFAOYSA-N 0.000 description 2
- NYFXEFQRMJATQT-UHFFFAOYSA-N 7-[(2,6-dimethylphenyl)methylideneamino]-n,n,1,2-tetramethylbenzimidazole-5-carboxamide Chemical compound C=12N(C)C(C)=NC2=CC(C(=O)N(C)C)=CC=1N=CC1=C(C)C=CC=C1C NYFXEFQRMJATQT-UHFFFAOYSA-N 0.000 description 2
- LQCALNAMPJBSPZ-UHFFFAOYSA-N 7-hydroxy-n,n,1,2-tetramethylbenzimidazole-5-carboxamide Chemical compound CN(C)C(=O)C1=CC(O)=C2N(C)C(C)=NC2=C1 LQCALNAMPJBSPZ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 description 2
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- 238000005893 bromination reaction Methods 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- UQHKFADEQIVWID-UHFFFAOYSA-N cytokinin Natural products C1=NC=2C(NCC=C(CO)C)=NC=NC=2N1C1CC(O)C(CO)O1 UQHKFADEQIVWID-UHFFFAOYSA-N 0.000 description 2
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- 238000001212 derivatisation Methods 0.000 description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 2
- 125000005594 diketone group Chemical group 0.000 description 2
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- 150000004677 hydrates Chemical class 0.000 description 2
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- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
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- 229960003529 diazepam Drugs 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
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- 238000006735 epoxidation reaction Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
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- 239000000796 flavoring agent Substances 0.000 description 1
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- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
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- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 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
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- GSOSVVULSKVSLQ-JJVRHELESA-N imipenem hydrate Chemical compound O.C1C(SCCNC=N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 GSOSVVULSKVSLQ-JJVRHELESA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
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- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- QANMHLXAZMSUEX-UHFFFAOYSA-N kinetin Chemical compound N=1C=NC=2N=CNC=2C=1NCC1=CC=CO1 QANMHLXAZMSUEX-UHFFFAOYSA-N 0.000 description 1
- 229960001669 kinetin Drugs 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
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- 239000007788 liquid Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 238000002844 melting Methods 0.000 description 1
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- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000006626 methoxycarbonylamino group Chemical group 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000004957 nitroimidazoles Chemical class 0.000 description 1
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960002369 oxyphencyclimine Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004986 phenylenediamines Chemical class 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- 150000007519 polyprotic acids Polymers 0.000 description 1
- 239000005077 polysulfide Substances 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- 150000008117 polysulfides Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- BZGIPVGCJGXQTA-UHFFFAOYSA-N s-[2-(diethylamino)ethyl] n,n-diphenylcarbamothioate Chemical compound C=1C=CC=CC=1N(C(=O)SCCN(CC)CC)C1=CC=CC=C1 BZGIPVGCJGXQTA-UHFFFAOYSA-N 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002311 subsequent effect Effects 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229950004351 telenzepine Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001562 ulcerogenic effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides compounds of the formula (1), in which the substituents and symbols are as defined in the description. The compounds inhibit the secretion of gastric acid.
Description
Description Title GASTRIC ACID SECRETION
Technical field The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
Background Art In the European patent application EP 0266326 (which corresponds to US Patent 5,106,862), ben-zimidazole derivatives having a broad variety of substituents are disclosed which are said to be ac-tive as anti-ulcer agents. In the intemational patent application WO 97/47603 (which corresponds to the US Patent 6,465,505), benzimidazole derivatives having a very specific substitution pattem are disclosed, which are said to be suitable for inhibition of gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.
Torigoe et al. describe in Phytochemistry, 1972, 11, 1623 the cytokinin activity of azaindene, azanaphtalene, naphtalene and indole derivatives in the tobacco pith callus bioassay.
Dincer et aI. describe in Indian Joumal of Chemistry, Section B, 1995, 34 (11), 982 the synthesis of 4-(substituted benzylamino)benzimidazole derivatives which compounds are expected to give an insight into the relationship between their structures and cytokinin activity.
The US Patent 6,083,961 describes benzimidazole oompounds which have activities as bradykinin antagonists and are said to be useful for treating several diseases such as allergy, inflammation, autoimmune disease, shock, pain or the like.
Brauninger et aI. describe in Archiv der Pharmazie, 1966, 299 (3), the synthesis of some benzimi-dazole derivatives and their kinetin activity.
In the Intemational patent application WO 04/054984, 4-substituted benzimidazole derivatives hav-ing a broad variety of substituents are disclosed, which compounds are useful in the prevention and treatment of gastrointestinal disorders.
In the intemational patent application WO 94/18199 (which corresponds to US
Patent 5,665730), imidazopyridine derivatives and their use in treating gastrointestinal diseases is disclosed.
Technical field The invention relates to novel compounds which are used in the pharmaceutical industry as active compounds for the production of medicaments.
Background Art In the European patent application EP 0266326 (which corresponds to US Patent 5,106,862), ben-zimidazole derivatives having a broad variety of substituents are disclosed which are said to be ac-tive as anti-ulcer agents. In the intemational patent application WO 97/47603 (which corresponds to the US Patent 6,465,505), benzimidazole derivatives having a very specific substitution pattem are disclosed, which are said to be suitable for inhibition of gastric acid secretion and thus can be used in the prevention and treatment of gastrointestinal inflammatory diseases.
Torigoe et al. describe in Phytochemistry, 1972, 11, 1623 the cytokinin activity of azaindene, azanaphtalene, naphtalene and indole derivatives in the tobacco pith callus bioassay.
Dincer et aI. describe in Indian Joumal of Chemistry, Section B, 1995, 34 (11), 982 the synthesis of 4-(substituted benzylamino)benzimidazole derivatives which compounds are expected to give an insight into the relationship between their structures and cytokinin activity.
The US Patent 6,083,961 describes benzimidazole oompounds which have activities as bradykinin antagonists and are said to be useful for treating several diseases such as allergy, inflammation, autoimmune disease, shock, pain or the like.
Brauninger et aI. describe in Archiv der Pharmazie, 1966, 299 (3), the synthesis of some benzimi-dazole derivatives and their kinetin activity.
In the Intemational patent application WO 04/054984, 4-substituted benzimidazole derivatives hav-ing a broad variety of substituents are disclosed, which compounds are useful in the prevention and treatment of gastrointestinal disorders.
In the intemational patent application WO 94/18199 (which corresponds to US
Patent 5,665730), imidazopyridine derivatives and their use in treating gastrointestinal diseases is disclosed.
Disclosure of Invention Technical problem A whole series of compounds are known from the prior art which inhibit gastric acid secretion by blockade of the H+/K+-ATPase. The compounds designated as proton pump inhibitors (PPI's), for example omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, bind irreversibly to the H+/K+-ATPase. PPI's are available as therapeutics for a long time al-ready. A new class of compounds designated as reversible proton pump inhibitors (rPPI's) or as acid pump antagonists (APA's) bind reversibly to the H+/K+-ATPase. Although rPPI's or APA's are known for more than 20 years and many companies are engaged in their develop-ment, no rPPI or APA is at present available for therapy. The technical problem underlying the present invention is therefore to provide acid pump antagonists which can be used in therapy.
Technical solution The invention relates to compounds of the formula 1 \>R1 (1) ~ N
'X R2 in yrhich R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1 -4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyi, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5~(gp) z wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-l-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-l-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Ex-amples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups.
Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.
1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having I to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is sub-stituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.
Technical solution The invention relates to compounds of the formula 1 \>R1 (1) ~ N
'X R2 in yrhich R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1 -4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyi, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5~(gp) z wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-l-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-l-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Ex-amples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
3-7C-Cycloalkyl represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkyl-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups.
Examples which may be mentioned are the cyclopropylmethyl, the cyclohexylmethyl and the cyclohexylethyl group.
1-4C-Alkoxy represents groups, which in addition to the oxygen atom contain a straight-chain or branched alkyl group having I to 4 carbon atoms. Examples which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy group.
1-4C-Alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is sub-stituted by one of the aforementioned 1-4C-alkoxy groups. Examples which may be mentioned are the methoxymethyl, the methoxyethyl group and the butoxyethyl group.
1-4C-Alkoxycarbonyl (-CO-1-4C-alkoxy) represents a carbonyl group, to which one of the aforementioned 1-4C-alkoxy groups is bonded. Examples which may be mentioned are the methoxycarbonyl (CH3O-C(O)-) and the ethoxycarbonyl group (CH3CH2O-C(O)-) .
2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).
2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to 4 carbon atoms.
Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).
Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substi-tuted by one or more fluorine atoms. An example which may be mentioned is the trifluoro-methyl group.
Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group.
1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 1-4C-alkyl groups. An example which may be mentioned is the acetyl group.
Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups.
Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.
Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned is the 2,2,2-trifluoroethyl group.
Aryl-1-4C-alkoxy denotes an aryl-subsfituted 1-4C-alkoxy radical. An example which may be mentioned is the benzyloxy radical.
2-4C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 4 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl and the 2-propenyl group (allyl group).
2-4C-Alkynyl represents straight-chain or branched alkynyl groups having 2 to 4 carbon atoms.
Examples which may be mentioned are the 2-butynyl, 3-butynyl, and preferably the 2-propynyl, group (propargyl group).
Fluoro-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substi-tuted by one or more fluorine atoms. An example which may be mentioned is the trifluoro-methyl group.
Hydroxy-1-4C-alkyl represents aforementioned 1-4C-alkyl groups, which are substituted by a hydroxy group. Examples which may be mentioned are the hydroxymethyl, the 2-hydroxyethyl and the 3-hydroxypropyl group.
1-4C-Alkylcarbonyl represents a group, which in addition to the carbonyl group contains one of the aforementioned 1-4C-alkyl groups. An example which may be mentioned is the acetyl group.
Mono- or di-1-4C-alkylamino represents an amino group, which is substituted by one or by two - identical or different - groups from the aforementioned 1-4C-alkyl groups.
Examples which may be mentioned are the dimethylamino, the diethylamino and the diisopropylamino group.
Mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl represents a 1-4C-alkylcarbonyl group, which is substituted by a mono- or di-1-4C-alkylamino groups. Examples, which may be mentioned, are the dimethylamino-methylcarbonyl and the dimethylamino-ethylcarbonyl group.
Fluoro-2-4C-alkyl represents a 2-4C-alkyl groups, which is substituted by one or more fluorine atoms. An example which may be mentioned is the 2,2,2-trifluoroethyl group.
Aryl-1-4C-alkoxy denotes an aryl-subsfituted 1-4C-alkoxy radical. An example which may be mentioned is the benzyloxy radical.
Aryl-1-4C-alkoxy-1-4C-alkyl denotes one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned aryl-1-4C-alkoxy radicals. An example which may be mentioned is the benzyloxymethyl radical.
Halogen within the meaning of the invention is bromo, chloro and fluoro.
1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH3-O-CH2-CH2-O-) and 2-(ethoxy)ethoxy (CH3-CH2-O-CHa-CH2-O-).
1-4C-Alkoxy-1-4C-alkoxy-1-4C-aIkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH3-O-CH2-CH2-O-CH2-).
Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C-alkoxy groups, which is completely or mainly substituted by fluorine.
Examples of completely or mainly fluoro-substituted 1-4C-alkoxy groups which may be men-tioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroeth-oxy, in particular:the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. Examples of fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are 1,1,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, the 1,1,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluorometh-oxyethyl radicals.
1-7C-Alkyl represents straight-chain or branched alkyl groups having I to 7 carbon atoms. Ex-amples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the abovementioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the butenyloxy, 3-butenyloxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy group).
Halogen within the meaning of the invention is bromo, chloro and fluoro.
1-4C-Alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by a further 1-4C-alkoxy group. Examples which may be mentioned are the groups 2-(methoxy)ethoxy (CH3-O-CH2-CH2-O-) and 2-(ethoxy)ethoxy (CH3-CH2-O-CHa-CH2-O-).
1-4C-Alkoxy-1-4C-alkoxy-1-4C-aIkyl represents one of the aforementioned 1-4C-alkoxy-1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example which may be mentioned is the group 2-(methoxy)ethoxymethyl (CH3-O-CH2-CH2-O-CH2-).
Fluoro-1-4C-alkoxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by a fluoro-1-4C-alkoxy group. Fluoro-1-4C-alkoxy in this case represents one of the aforementioned 1-4C-alkoxy groups, which is completely or mainly substituted by fluorine.
Examples of completely or mainly fluoro-substituted 1-4C-alkoxy groups which may be men-tioned are the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-1-butoxy, the 4,4,4-trifluoro-1-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the 1,2,2-trifluoroeth-oxy, in particular:the 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group. Examples of fluoro-1-4C-alkoxy-1-4C-alkyl radicals which may be mentioned are 1,1,2,2-tetrafluoroethoxymethyl, the 2,2,2-trifluoroethoxymethyl, the trifluoromethoxymethyl, the 1,1,2,2-tetrafluoroethoxyethyl, the 2,2,2-trifluoroethoxyethyl, the trifluoromethoxyethyl and preferably the difluoromethoxymethyl and the difluorometh-oxyethyl radicals.
1-7C-Alkyl represents straight-chain or branched alkyl groups having I to 7 carbon atoms. Ex-amples which may be mentioned are the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl (3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl group.
2-4C-Alkenyloxy represents groups, which in addition to the oxygen atom contain one of the abovementioned 2-4C-alkenyl groups. Examples, which may be mentioned, are the butenyloxy, 3-butenyloxy, 1-propenyloxy and the 2-propenyloxy group (allyloxy group).
Carboxy-1-4C-alkyl represents 1-4C-alkyl groups which are substituted by a carboxyl group.
Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group.
1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alkyl groups, which are substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxycarbonylmethyl and the ethoxycarbonylmethyl group.
Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be men-tioned is the benzyl radical.
1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C3H7C(O)NH-) and the acetylamino group (acetamido group) (CH3C(O)NH-).
1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.
1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforemen-tioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl (CH3-O-CH2CHa-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH3CH2-O-CH2CH2-O-CO-).
1-4C-Alkoxy-l-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred.
Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a methylene group contains a carbonyl group. An example which may be mentioned is the 2-oxopropoxy group.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the cyclohexylethoxy group.
Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are substituted by a hydroxy group. A preferred example which may be mentioned is the 2-hydroxyethoxy group.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups. A
preferred example which may be mentioned is the methoxyethoxyethoxy group.
3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups.
Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexy-loxyethoxy group.
3-7C-Cycloalkyl-1-4C-alkoxy-1 -4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobu-tylmethoxyethoxy and the cyclohexylethoxyethoxy group.
1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy group (CH3CO-O-).
1-4C-Alkylcarbonyloxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy groups. An example which may be mentioned is the acetoxymethyl group (CH3C0-O-CH2).
Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly" in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups are primarily chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups. Examples of halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-butoxy, the 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-l-butoxy, the 4,4,4-trifluoro-l-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the per-fluoroethoxy, the 1,2,2-trifluoroethoxy, in par6cularthe 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group.
Mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Ex-amples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group.
1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C-alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy group.
Suitable salts of compounds of the formula 1 are - depending on the substitution - in particular all acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are wa-ter-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochlo-ric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, em-bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation in an equimolar ratio or in a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt is desired.
Pharmacologically unacceptable salts, which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts can, for example when they are isolated in crystalline form, comprise varying amounts of solvents. The invention therefore also embraces all solvates and, in particular, all hydrates of the compounds of the formula 1, and all solvates and, in particular, all hydrates of the salts of the compounds of the formula 1.
One embodiment (embodiment 1) of the invention relates to compounds of the formula 1, in which X is 0 (oxygen) R1, R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
Another embodiment (embodiment 2) of the invention relates to compounds of the formula 1, in which XisNH, R1, R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
Another embodiment (embodiment 3) of the invention relates to compounds of the formula 1, in which R3 is hydrogen, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
Still another embodiment (embodiment 4) of the invention relates to compounds of the for-mula 1, in which R3 does not have the meaning hydrogen, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
Still another embodiment (embodiment 5) of the invention relates to compounds of the for-mula 1, in which R3 is halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-l-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds The invention also relates to compounds of the formula 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 14C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl or 3-7C-cycloalkyl, amino and .w R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5 (gp) 7z wherein Z has the meaning -CHR8- or-CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-aikyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-l-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-l-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Y denotes CH2-phenyl or a CH2-phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
The invention also relates to compounds of the formula 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5 (gp) '?~7z wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1 -4C-alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl, R2 denotes hydrogen, 1-4C-atkyl or 3-7C-cycloalkyl-1-4C-alkyl and Y denotes CH2-Ar, and the salts of these compounds.
In one aspect, the invention relates to compounds of the formula 1a C
>R1 I
~ N
x R2 ~ (1 a) Ar in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C=cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1a, in which RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is Q(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyn=olyl,: pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyi, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1 a, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-N R31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 14C-alkoxy-1-4C-alkyl, or where R31 and R32 together, induding the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloal kyl-1-4C-alkyl, and the salts of these compounds.
In another aspect, the invention relates to compounds of the formula 1 b \>-R1 R5 / x R2 (1 b) z in which R1 is hydrogen, 14C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-l-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-l-4C-alkyl, or where R31 and R32 together, induding the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihy-droisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9-where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alk6xy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
The compounds of the formula 1 b have up to three chiral centers in the parent structure. The invention thus relates to all conceivable stereoisomers in any desired mixing ration to one an-other, including the pure enantiomers, which are a preferred subject of the invention.
Among the compounds of the formula I a, preferred compounds are those of the formula 1 a-1 C
I
~>-R1 \ N
(1 a-1) in which RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,l-4C-alkyl, hydroxy, 1-4C-alkoxy or aryi-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl, cyano, the group -CO-N R31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-tolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoro-methyl, fluoro-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O(oxygen) or NH, and the salts of these compounds.
Among the compounds of the formula 1 a, particularly preferred compounds are those of the formula 1 a-1 where R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoro-methyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or.1-4C-alkoxy and X is O(oxygen) or NH, and the salts of these compounds.
Emphasis is given to those compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O(oxygen) or NH, and their salts.
Emphasis is also given to those compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is 0 (oxygen) or NH, and their salts.
Particular emphasis also given to compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino group, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and their salts.
Particular emphasis is also given to compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and their salts.
Among the compounds of the formula I b, preferred compounds are those of the formula 1 b-1 I ~-R1 R3 ':; N
R5 X (1b-1) in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1 -4C-alkoxy-1 -4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpipera;dno, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-l-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cyctoalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O(oxygen) or NH, and their salts.
Particularly preferred compounds of the formula 1 b-1 are those, in which R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l-4C-alkoxy, 3-7C-cycloalkyl-l-4C-alkoxy-l-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-a(koxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy X is O (oxygen) or NH, and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O(oxygen) or NH, and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in which RI is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl or 1-4C-alkoxy X is O(oxygen) or NH, and their salts.
Emphasis is given to compounds of the 1 b-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is the group -CO-NR31 R32, where R31 is 1-4C-alkyl, R32 is 1-4C-alkyl R4 is hydrogen R5 is hydrogen, R8 is hydroxyl X is 0 (oxygen) and their salts.
The compounds of the general formula I a can be obtained as depicted in scheme I by react-ing substituted benzimidazole compounds of formula 2 with compounds of formula 3, wherein L is a suitable leaving group like for example a suitable halogen atom, like for example chlo-rine.
Scheme 1:
~>--R1 + >---R1 N Ar N
2, X= O, N H 3 qr 1a,X=0,NH
Another method for the preparation of compounds of the formula I a where X =
NH consists of reacting substituted benzimidazole compounds of the general formula 2 where X=
NH with substituted ketones of the formula 4 and subsequent reduction of the resulting imine interme-diate by suitable reducing agents, like for example sodium borohydride (reductive amination, scheme 2).
Scheme 2:
R3 I ~ N~R1 + /O R3 ~> -R1 ~ N Arr/ N
2,X=NH 4 ,qr 1a,X=NH
Analogously, compounds of the general formula 1 b are obtained by reacting substituted ben-zimidazoles of formula 2 with 1,2-epoxyindanes of the formula 5, carrying any desired sub-stituent R4 and R5 (cf. scheme 3 for a compound 1 b-1). 1,2-Epoxyindan is described for ex-ample in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912. In general, substi-tuted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the corresponding sub-stituted indenes by methods known from literature (e.g. epoxidation).
Scheme 3:
\ I ~>-R1 + I / -~ R4 ( N~
XH R2 R5 rac. R5 ~ ..X R2 N
2,X=0,NH 5 OH
1b-1, X = O, NH
The starting compounds of the formula 2 where X 0 can be obtained for example according to the reaction sequence as shown in scheme 4. Compounds of the formula 6 can be deprotonated using a suitable base, like for example n-butyllithium, followed by reaction with a suitable R2 precursor R2-Lg, whereby that precursor R2-Lg is a R2 group substituted with a suitable leaving group Lg, like a halogen atom, for example an iodine atom.
This reaction leads to compounds of the formula 7 which can be converted by methods known to the expert to the desired compounds of the formula 2 with X= (oxygen).
Scheme 4:
R3 / N 1. base / N R3 N
\ I ~ -R1 2. R2-Lg \ ~ \R1 \R1 N N N
O ~
r O ~ OH ~
Ph 6 ~ 2,X=O
Compounds of the formula 6 can be prepared from compounds of the formula 8 for example following the reaction sequence shown in scheme 5.
Scheme 5:
NOz NOZ R3 / NOz I
\
NHz NHz NHz OH O O
g ~ 9 10 Ph Ph O-R3 / NHz O- 12 R3 / CN
I R1 ~ ~R1 -~ \ NHz \ N
O O
~ 11 ~ 6 Ph Ph 3-Nitro-2-aminophenol can be reacted in a first step with a suitable benzyl derivative, for ex-ample benzylchloride, to form the reaction product of the formula 9 which is known for exam-ple from J. Heterocyclic Chem. (1983), 20, 1525). Into the compound of the formula 9 a sub-stituent R3 can be introduced, for example a bromine substituent can be introduced by a bro-mination reaction using a suitable bromination reagent, like for example N-bromosuccinimide.
Subsequent reduction of the compound of the formula 10 under standard conditions, for ex-ample using hydrazine N2H4 in the presence of FeC13, leads to the formation of compounds of the formula 11 which can be transformed to the benzimidazole derivatives of the formula 6 by methods known to the expert, for example by a cyclization reaction with a diketone of the for-mula 12.
The starting compounds of the formula 2 where X = NH can be obtained for example accord-ing to the reaction sequence as shown in scheme 6. Starting from substituted dinitrochlorben-zenes of the formula 13, reaction with primary amines of the formula 14 leads to compounds of the formula 15 (L. A. Summers, Austr. J. Chem. 1965, 18, 1695-1698) that are reduced to phenylenediamines of the formula 16 by methods known to the expert. The benzimidazoles of the formula 2 are then obtained by a cyclization reaction of compounds of the formula 16, for example with a diketone of the formula 12 to give compounds of the formula 17, and subse-quent reduction of the N02-group by catalytic hydrogenation or any other method known from literature (scheme 6).
Scheme 6:
14 ~
\ Ci -y ~ yLNR2 - ~ I NR2 O
R1 ~ I N~R1 ~ ~ N>--R1 17 2,X=NH
The reaction steps outlined above are carried out in a manner known per se, e.
g. as de-scribed in more detail in the examples. The derivatization, if any, of the compounds obtained according to the above Scheme 1, 2 and 3 (e.g. conversion of a group R3 into another group R3, or of R2 = H into another group R2, or conversion of a hydroxyl group into an alkoxy or ester group) is likewise carried out in a manner known per se. If compounds where R3 =
-CO-1-4C-alkoxy or R3 =-CO-NR31 R32 are desired, an appropriate derivatization can be per-formed in a manner known per se (e. g. metal catalysed carbonylation of the corresponding bromo compound or conversion of an ester into an amide) at the stage of the benzimidazoles of the formula 2 (scheme 1, 2 and 3), or at a later point in time.
Advantageous effects The excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal ex-perimental models. The compounds of the formula 1 according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the num-bers of these compounds in the examples.
Testing of the secretion-inhibiting action on the perfused rat stomach In Table A which follows, the influence of the compounds of the formula I
according to the in-vention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after in-traduodenal administration in vivo is shown.
Table A
Dose Inhibition of No. ( mol/kg) acid secretion i.d. (%) 1 1 > 50 2 1 > 50 3 1 > 50 Methodologv The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m.
urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC
catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.
After thorough rinsing (about 50-100 ml), warm (37 C) physiological NaCl solution was con-tinuously passed through the stomach (0.5 mi/min, pH 6.8-6.9; Braun-Unita I).
The pH (pH
meter 632, glass electrode EA 147; ~= 5 mm, Metrohm) and, by titration with a freshly pre-pared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI
were deter-mined in the effluent in each case collected at an interval of 15 minutes.
The gastric secretion was stimulated by continuous infusion of 1 g/kg (= 1.65 ml/h) of i.v.
pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determi-nation of 2 preliminary fractions). The substances to be tested were administered intraduode-nally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
The body temperature of the animals was kept at a constant 37.8-38 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
Mode(s) for Carrying Out the Invention The examples below serve to illustrate the invention in more detail without limiting it. Further com-pounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary proc-ess techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.
1. Final Compounds of the formula 1 1. 7-(trans-2,3-Dihydro-2-hydroxy-l-indenyloxy)-5-(N, N-dimethylaminocarbonyl)-1,2-d imethyl-1H-benzimidazole To a suspension of 0.38 g (1.63 mmol) 7-hydroxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid dimethylamide and 0.8 g (6.1 mmol) 1,2-epoxyindane in 4 ml methanol and 1 ml water were added 0.45 ml triethylamine and the mixture was heated to 70 C for I h. The cooled solution was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magne-sium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) and crystallization from ethyl acetate yielded 0.45 g (76 %) of the title compound as a colourless solid (m.p. 230 C).
2. 6-(N, N-d imethylam inocarbonyl)-4-(2,6-d imethyl-benzylam ino)-2,3-d imethyl-3H-benzimidazole To a solution of 0.54 g (1.56 mmol) 6-(N,N-dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylidene-amino)-2,3-dimethyl-3H-benzimidazole in 10 ml methanol were slowly added 0.09 g (2.38 mmol) so-dium borohydride. After 10 min, the reaction mixture was partitioned between saturated aqueous am-monium chloride and dichloromethane. The organic layer was separated, dried over anhydrous mag-nesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/n-heptane yielded 0.52 g (95 %) of the title compound as a colourless solid (m.p. 187-188 C).
3. 4-(2,6-Dimethyl-benzylam ino)-2,3-d imethyl-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole To a solution of 0.5 g (1.94 mmol) 4-amino-2,3-dimethyl-6-(N-pyn-olidinocarbonyl)-3H-benzimidazole and 0.39 g (2.9 mmol) 2,6-dimethylbenzaldehyd in 15 ml dichloromethane and 5 ml acetic acid were added 0.82 mg (3.9 mmol) sodium triacetoxyborohydride. After 2 h, TLC
indicated incomplete reaction and the mixture was evaporated to dryness. The residue was diisolved in 20 ml methanol and treated with excess sodium borohydride. After complete reaction, mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried over an-hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.41 g (56 %) of the title compound as a colourless solid (m.p. 188-189 C).
II. Starting Compounds A. 2-Be nzyl oxy-4-b romo-6-n itro-a n i l i n e To a suspension of 50 g (325 mmol) 2-amino-3-nitrophenol, 45 g (325 mmol) potassium carbonate and 2 g (13 mmol) sodium iodide in 400 ml ethanol were added 47 ml (408 mmol) benzyl chloride and the mixture was heated to 80 C. After 2 h, the reaction mixture was cooled down and the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Coevaporation with dichloromethane led to a dark brown oily residue which was dissolved in 400 ml acetonitriie.
After addition of 63.4 g (356 mmol) N-bromosuccinimide, the reaction mixture was refluxed for I h.
After cooling down, 400 g silica gel were added and the mixture was evaporated to dryness. The resulting solid was put on a column and the product was eluted with ethyl acetateaight petroleum ether (4:1). Evaporation::of the eluent left a solid which was recrystallized from ethyl acetateln-heptane to give 62 g (59 %) of the title compound as a red solid (m.p. 90 C).
B. 2-Ami no-3-benzyloxy-5-bromo-an i l i ne To a suspension of 3.23 g (10 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 60 ml methanol and 15 ml concentrated hydrochloric acid were added 2.23 g (40 mmol) iron filings in small portions at 60 C.
After 10 min, the mixture was cooled down and neutralized with 6N aqueous sodium hydroxide. Acti-vated charcoal was added and the suspension was filtered. The filtrate was partitioned between di-chloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Crystallization of the residue from ethyl acetate/n-heptane yielded 2.05 g (70 %) of the title compound as a colourless solid (m.p. 108 C).
C. 4-Benzyloxy-6-bromo-2-methyl-1 H-benzimidazole To a suspension of 2.0 g (6.82 mol) 2-amino-3-benzyloxy-5-bromo-aniline in 20 ml ethanol were added 5 ml 5N hydrochloric acid. The reaction mixture was hetaed to 60 C and 1.41 ml (13.6 mol) 2,4-pentanedione were added in one portion. After refluxing 1 h, the mixture was cooled down and neutralized with 6N aqueous sodium hydroxide. The mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Crystal-lization of the residue from ethyl acetateln-heptane yielded 2.12 g (98 %) of the title compound as a colourless solid (m.p. 174 C).
D. 7-Benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide To a suspension of 2.0 g (6.3 mmol) 4-benzyloxy-6-bromo-2-methyl-IH-benzimidazole in 30 ml di-methylamine (3.2M solution in tetrahydrofuran) were added 210 mg (0.95 mmol) palladium(II) acetate and 495 mg (1.9 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbon-ylated (5 bar carbon monoxide pressure, 120 C) for 16 h. The reaction mixture was cooled down and evaporated. Purification of the residue by column chromatography on silica gel using dichloro-methane/methanol (13:1) yielded 1.53 g(79 %) of the title compound as a a light brown oil, which was used without further purification in the next step.
E. 7-Benzyloxy-1,2-dimethyl-1 H-benzimidazole-5-carboxylic acid dimethylamide To a solution of 1.53 g (4.7 mmol) 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid di-methylamide in 25 ml dried tetrahydrofuran were slowly added 3.1 ml (5 mmol) n-butyllithium (1.6M in hexanes) at -78 C. After adding 0.32 ml (5.1 mmol) methyl iodide, the reaction mixture was allowed to warm to room temperature. After 16 h, the mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated.
Purification of the residue by column chromatography on silica gel using dichloromethane/methanol (13:1) and crystallization of the residue from ethyl acetate/n-heptane yielded 0.79 g (52 %) of the title compound as a colourless solid (m.p. 117-118 C).
F. 7-Hydroxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid dimethylamide A solution of 0.7 g (2.2 mmol) 7-benzyloxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid di-methylamide in 25 ml methanol and 0.1 ml acetic acid was hydrogenated over 0.25 g 10% Pd/C (25 C, 1 bar Hz) for 16 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate to give 0.44 g (87 %) of the title compound as a colourless solid (m.p.
209 C).
G. 4-Methylamino-3,5-dinitrobenzene-carboxylic acid 25.0 g(101 mmol) 4-chloro-3,5-dinitrobenzene-carboxylic acid were slowly added to 120 ml aqueous methylamine (40 %) and the mixture was heated to reflux. After I h, the mixture was cooled down and evaporated to dryness. The residue was dissolved in water and the pH was adjusted to pH w 5 by add-ing 6N hydrochloric acid. The precipitate was collected, washed with water and dried to yield 21.6 g (90 %) of the title compound as a yellow solid (m.p. 184-188 C).
H. 1,2-Dimethyl-7-nitro-1 H-benzimidazole-5-carboxylic acid To a suspension of 4.0 g (16.6 mmol) 4-methylamino-3,5-dinitrobenzene-carboxylic acid in 50 ml ethanol were added 40 ml 2N aqueous ammonium polysulfide. After 1 h, excess ethanol was evapo-rated and the residue was neutralized with 6N hydrochloric acid. The solids were filtered off and the filtrate was evaporated to dryness. The residue was suspended in 100 ml ethanol and 20 ml 5N hydro-chloric acid. To the boiling mixture were added 4.1 ml (40 mmol) 2,5-pentanedione. After 4 h, the sol-vent was removed and the residue was diluted with water and neutralized with 40% aqueous sodium hydroxide. The precipitate was collected and suspended in 30 ml methanol and 10 ml water. To the mixture were added 0.96 g (40 mmol) lithium hydroxide and the suspension was heated to 70 C. After 30 min, the pH of the reaction mixture was adjusted to pH - 6 by adding 4N
hydrochloric acid. Excess methanol was removed and the precipitate was collected and washed with water to yield 0.8 g (21 %) of the title compound as a colourless solid (m.p. 303-305 C).
1. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylidene-amino)-2,3-dimethyl-3H-benzimidazole A suspension of 0.8 g (3.4 mmol)1,2-dimethyl-7-nitro-1 H-benzimidazole-5-carboxylic acid in 10 ml methanol and I ml acetic acid was hydrogenated over palladium on charcoal (3 h, 80 C). The reac-tion mixture was neutralized with 40% aqueous sodium hydroxide and the catalyst was filtered off. The filtrate was evaporated and the residue was redissolved in 15 ml methanol and 10 ml acetic acid and treated with 2,6-dimethylbenzaidehyd to yield the corresponding imine, which was dissolved in 10 ml dimethylformamide and 10 ml dichloromethane. To this solution were added 1.5 g (4.7 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 50 C. After 20 min, 5 ml (10 mmol) dimethylamine (2M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (10:1) and crystallization from ethyl acetate/n-heptane yielded 0.6 g (51 %) of the title compound as a light yellow solid (m.p. 165-166 C).
J. 4-Methylam ino-3,5-d initro-N-pyrrolidinyl-benzamide To a suspension of 2.0 g (8.3 mmol) 4-methylamino-3,5-dinitrobenzene-carboxylic acid and 4.0 g (12.4 mmol) O-(1F!-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) in 25 ml chloroform were added 2.5 ml (30 mmol) pyrrolidine at 45 C. After 30 min, a further amount of 4.0 g TBTU and 2.5 ml pyrrolidine were added and stirring was continued for 45 min.
The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from ethyl acetate/n-heptane yielded 1.72 g (70 %) of the title compound as an orange solid (m.p. 148-150 C).
K. 2,3-Dimethyl-4-n itro-6-(N-pyrrol id inocarbonyl)-3H-benzi m idazole To a mixture of 1.65 g (5.6 mmol) 4-methylamino-3,5-dinitro-N-pyrrolidinyl-benzamide and 330 mg ruthenium on charcoal (5 %) in 30 ml ethanol were slowly added 0.55 ml (11.2 mmol) hydrazine hy-drate at 75 C. After 1.5 h, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (20:1).
The intermediate product was suspended in 25 ml methanol and 5 ml 5N
hydrochloric acid. To this suspension were added 1.15 ml (11.2 mmol) 2,4-pentanedione at 80 C. After 30 min, the reaction mixture was cooled down, neutralized with 40% aqueous sodium hydroxide and extracted with di-chloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro-methane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.91 g (56 %) of the title compound as an orange solid (m.p. 114-117 C).
L. 4-Amino-2,3-dimethyl-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole ~t.
A solution of 0.82 g (2.84 mmol) 2,3-dimethyl-4-nitro-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole in 20 ml methanol and I ml acetic acid was hydrogenated over 300 mg palladium on charcoal (10 %, 2.5 h, 50 C). The catalyst was filtered off and the reaction mixture was evaporated to dryness. The residue was crystallized with ethyl acetate/n-heptane to give 0.61 g (83 %) of a beige solid (m.p. 250-251 C).
Industrial applicability The compounds of the formula I and their salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid se-cretion and an excellent gastric and intestinal protective action in warm-blooded animals, in par-ticular humans. In this connection, the compounds according to the invention are distinguished by a high selectivity of action, an advantageous duration of action, a par6cularly good enteral activity, the absence of significant side effects and a large therapeutic range.
"Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. etha-nol), gastric acid or stress situations. "Gastric and intestinal protection"
is understood to include, according to general knowledge, gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartbum and/or acid regurgitation.
In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiul-cerogenic and the antisecretory properties are determined. On account of these properties, the compounds of the formula 1 and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, where they are used, in par6cular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.
A further subject of the invention are therefore the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
The invention likewise includes the use of the compounds according to the invention for the pro-duction of medicaments which are employed for the treatment and/or prophylaxis of the above-mentioned diseases.
The invention furthermore includes the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
A further subject of the invention are medicaments which comprise one or more compounds of the formula 1 and/or their pharmacologically acceptable salts.
The medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the in-vention (= active compounds) are either employed as such, or preferably in combination with suit-able pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, sup-positories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound con-tent advantageously being between 0.1 and 95% and it being possible to obtain a pharmaceutical administration form exactly adapted to the active compound and/or to the desired onset and/or du-ration of action (e.g. a sustained-release form or an enteric form) by means of the appropriate se-lection of the auxiliaries and excipients.
The auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge. In addition to sol-vents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipi-ents, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor cor-rigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex-ing agents (e.g. cyclodextrins).
The active compounds can be administered orally, parenterally or percutaneously.
In general, it has proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, prefera-bly 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably I to 4, individual doses to achieve the de,sired result. In the case of a parenteral treat-ment, similar or (in particular in the case of the intravenous administration of the active com-pounds), as a rule, lower doses can be used. The establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for ex-ample, bietamiverine or camylofine), anticholinergics (for example, oxyphencyclimine or phencar-bamide), local anesthetics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins or amino acids.
To be emphasized in this connection is in particular the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H2 block-ers (e.g. cimetidine, ranitidine), H+/K' ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antago-nists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimi-dazoles or altematively bismuth salts) for the control of Helicobacter pylori.
Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefa-lothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, met-ronidazole, clarithromycin, azithromycin and combinations thereof (for example clarithromycin +
metronidazole).
In view of their excellent gastric and intestinal protection action, the compounds of formula 1 are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic potency. In addi-tion, the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.
Examples, which may be mentioned, are the carboxymethyl and the 2-carboxyethyl group.
1-4C-Alkoxycarbonyl-1-4C-alkyl represents 1-4C-alkyl groups, which are substituted by one of the abovementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the Methoxycarbonylmethyl and the ethoxycarbonylmethyl group.
Aryl-1-4C-alkyl denotes an aryl-substituted 1-4C-alkyl radical. An example which may be men-tioned is the benzyl radical.
1-4C-Alkylcarbonylamino represents an amino group to which a 1-4C-alkylcarbonyl group is bonded. Examples which may be mentioned are the propionylamino (C3H7C(O)NH-) and the acetylamino group (acetamido group) (CH3C(O)NH-).
1-4C-Alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxycarbonyl groups. Examples, which may be mentioned, are the ethoxycarbonylamino and the methoxycarbonylamino group.
1-4C-Alkoxy-1-4C-alkoxycarbonyl represents a carbonyl group, to which one of the aforemen-tioned 1-4C-alkoxy-1-4C-alkoxy groups is bonded. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonyl (CH3-O-CH2CHa-O-CO-) and the 2-(ethoxy)ethoxycarbonyl group (CH3CH2-O-CH2CH2-O-CO-).
1-4C-Alkoxy-l-4C-alkoxycarbonylamino represents an amino group, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxycarbonyl groups. Examples which may be mentioned are the 2-(methoxy)ethoxycarbonylamino and the 2-(ethoxy)ethoxycarbonylamino group.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred.
2-7C-Alkenyl represents straight-chain or branched alkenyl groups having 2 to 7 carbon at-oms. Examples which may be mentioned are the 2-butenyl, 3-butenyl, 1-propenyl, the 2-propenyl (allyl) and the vinyl group. The aforementioned 2-4C-alkenyl groups are preferred.
Oxo-substituted 1-4C-alkoxy represents a 1-4C-alkoxy group, which instead of a methylene group contains a carbonyl group. An example which may be mentioned is the 2-oxopropoxy group.
3-7C-Cycloalkoxy represents cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkyl-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl groups. Examples which may be mentioned are the cyclopropylmethoxy, the cyclobutylmethoxy and the cyclohexylethoxy group.
Hydroxy-1-4C-alkoxy represents aforementioned 1-4C-alkoxy groups, which are substituted by a hydroxy group. A preferred example which may be mentioned is the 2-hydroxyethoxy group.
1-4C-Alkoxy-1-4C-alkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 1-4C-alkoxy-1-4C-alkoxy groups. A
preferred example which may be mentioned is the methoxyethoxyethoxy group.
3-7C-Cycloalkoxy-1-4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkoxy groups.
Examples which may be mentioned are the cyclopropoxymethoxy, the cyclobutoxymethoxy and the cyclohexy-loxyethoxy group.
3-7C-Cycloalkyl-1-4C-alkoxy-1 -4C-alkoxy represents one of the aforementioned 1-4C-alkoxy groups, which is substituted by one of the aforementioned 3-7C-cycloalkyl-1-4C-alkoxy groups. Examples which may be mentioned are the cyclopropylmethoxyethoxy, the cyclobu-tylmethoxyethoxy and the cyclohexylethoxyethoxy group.
1-4C-Alkylcarbonyloxy represents a 1-4C-alkylcarbonyl group which is bonded to an oxygen atom. An example which may be mentioned is the acetoxy group (CH3CO-O-).
1-4C-Alkylcarbonyloxy-1-4C-alkyl represents one of the aforementioned 1-4C-alkyl groups, which is substituted by one of the aforementioned 1-4C-alkylcarbonyloxy groups. An example which may be mentioned is the acetoxymethyl group (CH3C0-O-CH2).
Halo-1-4C-alkoxy represents 1-4C-alkoxy groups which are completely or mainly substituted by halogen. "Mainly" in this connection means that more than half of the hydrogen atoms in the 1-4C-alkoxy groups are replaced by halogen atoms. Halo-1-4C-alkoxy groups are primarily chloro- and/or in particular fluoro-substituted 1-4C-alkoxy groups. Examples of halogen-substituted 1-4C-alkoxy groups which may be mentioned are the 2,2,2-trichloroethoxy, the hexachloroisopropoxy, the pentachloroisopropoxy, the 1,1,1-trichloro-3,3,3-trifluoro-2-propoxy, the 1,1,1-trichloro-2-methyl-2-propoxy, the 1,1,1-trichloro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-propoxy, the 3-bromo-1,1,1-trifluoro-2-butoxy, the 4-bromo-3,3,4,4-tetrafluoro-1-butoxy, the chlorodifluoromethoxy, the 1,1,1,3,3,3-hexafluoro-2-propoxy, the 2-trifluoromethyl-2-propoxy, the 1,1,1-trifluoro-2-propoxy, the perfluoro-tert-butoxy, the 2,2,3,3,4,4,4-heptafluoro-l-butoxy, the 4,4,4-trifluoro-l-butoxy, the 2,2,3,3,3-pentafluoropropoxy, the per-fluoroethoxy, the 1,2,2-trifluoroethoxy, in par6cularthe 1,1,2,2-tetrafluoroethoxy, the 2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably the difluoromethoxy group.
Mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy represents a 1-4C-alkylcarbonyloxy group, which is substituted by one of the aforementioned mono- or di-1-4C-alkylamino groups. Ex-amples, which may be mentioned, are the dimethylamino-methylcarbonyloxy and the dimethylamino-ethylcarbonyloxy group.
1-4C-Alkoxy-1-4C-alkylcarbonyloxy represents one of the aforementioned 1-4C-alkylcarbonyloxy radicals which is substituted by one of the aforementioned 1-4C-alkoxy groups. An example, which may be mentioned, is the methoxymethylcarbonyloxy group.
Suitable salts of compounds of the formula 1 are - depending on the substitution - in particular all acid addition salts. Particular mention may be made of the pharmacologically acceptable salts of the inorganic and organic acids customarily used in pharmacy. Those suitable are wa-ter-soluble and water-insoluble acid addition salts with acids such as, for example, hydrochlo-ric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, em-bonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, where the acids are employed in the salt preparation in an equimolar ratio or in a ratio differing therefrom, depending on whether the acid is a mono- or polybasic acid and on which salt is desired.
Pharmacologically unacceptable salts, which can be initially obtained, for example, as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that the compounds according to the invention and their salts can, for example when they are isolated in crystalline form, comprise varying amounts of solvents. The invention therefore also embraces all solvates and, in particular, all hydrates of the compounds of the formula 1, and all solvates and, in particular, all hydrates of the salts of the compounds of the formula 1.
One embodiment (embodiment 1) of the invention relates to compounds of the formula 1, in which X is 0 (oxygen) R1, R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
Another embodiment (embodiment 2) of the invention relates to compounds of the formula 1, in which XisNH, R1, R2, R3 and Y have the meanings as indicated in the outset, and the salts of these compounds.
Another embodiment (embodiment 3) of the invention relates to compounds of the formula 1, in which R3 is hydrogen, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
Still another embodiment (embodiment 4) of the invention relates to compounds of the for-mula 1, in which R3 does not have the meaning hydrogen, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds.
Still another embodiment (embodiment 5) of the invention relates to compounds of the for-mula 1, in which R3 is halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-l-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R1, R2, X and Y have the meanings as indicated in the outset, and the salts of these compounds The invention also relates to compounds of the formula 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 14C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1 -4C-alkyl or 3-7C-cycloalkyl, amino and .w R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5 (gp) 7z wherein Z has the meaning -CHR8- or-CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-aikyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-l-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-l-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Y denotes CH2-phenyl or a CH2-phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
The invention also relates to compounds of the formula 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp R5 (gp) '?~7z wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1 -4C-alkylamino-1 -4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl, R2 denotes hydrogen, 1-4C-atkyl or 3-7C-cycloalkyl-1-4C-alkyl and Y denotes CH2-Ar, and the salts of these compounds.
In one aspect, the invention relates to compounds of the formula 1a C
>R1 I
~ N
x R2 ~ (1 a) Ar in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C=cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1a, in which RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-l-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is Q(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyn=olyl,: pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyi, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
In a further aspect, the invention relates to compounds of the formula 1 a, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-N R31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 14C-alkoxy-1-4C-alkyl, or where R31 and R32 together, induding the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloal kyl-1-4C-alkyl, and the salts of these compounds.
In another aspect, the invention relates to compounds of the formula 1 b \>-R1 R5 / x R2 (1 b) z in which R1 is hydrogen, 14C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-l-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-l-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group S02-NR31 R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-l-4C-alkyl, or where R31 and R32 together, induding the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group consisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihy-droisoxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9-where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alk6xy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and the salts of these compounds.
The compounds of the formula 1 b have up to three chiral centers in the parent structure. The invention thus relates to all conceivable stereoisomers in any desired mixing ration to one an-other, including the pure enantiomers, which are a preferred subject of the invention.
Among the compounds of the formula I a, preferred compounds are those of the formula 1 a-1 C
I
~>-R1 \ N
(1 a-1) in which RI is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-l-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,l-4C-alkyl, hydroxy, 1-4C-alkoxy or aryi-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-l-4C-alkyl, cyano, the group -CO-N R31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-tolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoro-methyl, fluoro-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O(oxygen) or NH, and the salts of these compounds.
Among the compounds of the formula 1 a, particularly preferred compounds are those of the formula 1 a-1 where R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoro-methyl, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or.1-4C-alkoxy and X is O(oxygen) or NH, and the salts of these compounds.
Emphasis is given to those compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is O(oxygen) or NH, and their salts.
Emphasis is also given to those compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is 1-4C-alkyl or 1-4C-alkylcarbonylamino, R5 is 1-4C-alkyl, X is 0 (oxygen) or NH, and their salts.
Particular emphasis also given to compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino group, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and their salts.
Particular emphasis is also given to compounds of the formula 1a-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and their salts.
Among the compounds of the formula I b, preferred compounds are those of the formula 1 b-1 I ~-R1 R3 ':; N
R5 X (1b-1) in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1 -4C-alkoxy-1 -4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31 R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpipera;dno, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-l-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cyctoalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-alkoxy-l-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O(oxygen) or NH, and their salts.
Particularly preferred compounds of the formula 1 b-1 are those, in which R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl, R2 is hydrogen or 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, or the group -CO-NR31 R32, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-l-4C-alkoxy, 3-7C-cycloalkyl-l-4C-alkoxy-l-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-a(koxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-l-4C-alkylcarbonyloxy X is O (oxygen) or NH, and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O(oxygen) or NH, and their salts.
Still particularly preferred compounds of the formula 1 b-1 are those, in which RI is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is carboxyl, -CO-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl or the group -CO-NR31 R32, where R31 is hydrogen, 1-4C-alkyl, hydroxy-1 -4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl and R32 is hydrogen or 1-4C-alkyl, R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen, R8 is hydroxyl or 1-4C-alkoxy X is O(oxygen) or NH, and their salts.
Emphasis is given to compounds of the 1 b-1, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is the group -CO-NR31 R32, where R31 is 1-4C-alkyl, R32 is 1-4C-alkyl R4 is hydrogen R5 is hydrogen, R8 is hydroxyl X is 0 (oxygen) and their salts.
The compounds of the general formula I a can be obtained as depicted in scheme I by react-ing substituted benzimidazole compounds of formula 2 with compounds of formula 3, wherein L is a suitable leaving group like for example a suitable halogen atom, like for example chlo-rine.
Scheme 1:
~>--R1 + >---R1 N Ar N
2, X= O, N H 3 qr 1a,X=0,NH
Another method for the preparation of compounds of the formula I a where X =
NH consists of reacting substituted benzimidazole compounds of the general formula 2 where X=
NH with substituted ketones of the formula 4 and subsequent reduction of the resulting imine interme-diate by suitable reducing agents, like for example sodium borohydride (reductive amination, scheme 2).
Scheme 2:
R3 I ~ N~R1 + /O R3 ~> -R1 ~ N Arr/ N
2,X=NH 4 ,qr 1a,X=NH
Analogously, compounds of the general formula 1 b are obtained by reacting substituted ben-zimidazoles of formula 2 with 1,2-epoxyindanes of the formula 5, carrying any desired sub-stituent R4 and R5 (cf. scheme 3 for a compound 1 b-1). 1,2-Epoxyindan is described for ex-ample in W. F. Whitmore; A. I. Gebhart, J. Am. Chem. Soc. 1942, 64, 912. In general, substi-tuted alkyl-, alkoxy- or halogeno-epoxyindanes can be prepared from the corresponding sub-stituted indenes by methods known from literature (e.g. epoxidation).
Scheme 3:
\ I ~>-R1 + I / -~ R4 ( N~
XH R2 R5 rac. R5 ~ ..X R2 N
2,X=0,NH 5 OH
1b-1, X = O, NH
The starting compounds of the formula 2 where X 0 can be obtained for example according to the reaction sequence as shown in scheme 4. Compounds of the formula 6 can be deprotonated using a suitable base, like for example n-butyllithium, followed by reaction with a suitable R2 precursor R2-Lg, whereby that precursor R2-Lg is a R2 group substituted with a suitable leaving group Lg, like a halogen atom, for example an iodine atom.
This reaction leads to compounds of the formula 7 which can be converted by methods known to the expert to the desired compounds of the formula 2 with X= (oxygen).
Scheme 4:
R3 / N 1. base / N R3 N
\ I ~ -R1 2. R2-Lg \ ~ \R1 \R1 N N N
O ~
r O ~ OH ~
Ph 6 ~ 2,X=O
Compounds of the formula 6 can be prepared from compounds of the formula 8 for example following the reaction sequence shown in scheme 5.
Scheme 5:
NOz NOZ R3 / NOz I
\
NHz NHz NHz OH O O
g ~ 9 10 Ph Ph O-R3 / NHz O- 12 R3 / CN
I R1 ~ ~R1 -~ \ NHz \ N
O O
~ 11 ~ 6 Ph Ph 3-Nitro-2-aminophenol can be reacted in a first step with a suitable benzyl derivative, for ex-ample benzylchloride, to form the reaction product of the formula 9 which is known for exam-ple from J. Heterocyclic Chem. (1983), 20, 1525). Into the compound of the formula 9 a sub-stituent R3 can be introduced, for example a bromine substituent can be introduced by a bro-mination reaction using a suitable bromination reagent, like for example N-bromosuccinimide.
Subsequent reduction of the compound of the formula 10 under standard conditions, for ex-ample using hydrazine N2H4 in the presence of FeC13, leads to the formation of compounds of the formula 11 which can be transformed to the benzimidazole derivatives of the formula 6 by methods known to the expert, for example by a cyclization reaction with a diketone of the for-mula 12.
The starting compounds of the formula 2 where X = NH can be obtained for example accord-ing to the reaction sequence as shown in scheme 6. Starting from substituted dinitrochlorben-zenes of the formula 13, reaction with primary amines of the formula 14 leads to compounds of the formula 15 (L. A. Summers, Austr. J. Chem. 1965, 18, 1695-1698) that are reduced to phenylenediamines of the formula 16 by methods known to the expert. The benzimidazoles of the formula 2 are then obtained by a cyclization reaction of compounds of the formula 16, for example with a diketone of the formula 12 to give compounds of the formula 17, and subse-quent reduction of the N02-group by catalytic hydrogenation or any other method known from literature (scheme 6).
Scheme 6:
14 ~
\ Ci -y ~ yLNR2 - ~ I NR2 O
R1 ~ I N~R1 ~ ~ N>--R1 17 2,X=NH
The reaction steps outlined above are carried out in a manner known per se, e.
g. as de-scribed in more detail in the examples. The derivatization, if any, of the compounds obtained according to the above Scheme 1, 2 and 3 (e.g. conversion of a group R3 into another group R3, or of R2 = H into another group R2, or conversion of a hydroxyl group into an alkoxy or ester group) is likewise carried out in a manner known per se. If compounds where R3 =
-CO-1-4C-alkoxy or R3 =-CO-NR31 R32 are desired, an appropriate derivatization can be per-formed in a manner known per se (e. g. metal catalysed carbonylation of the corresponding bromo compound or conversion of an ester into an amide) at the stage of the benzimidazoles of the formula 2 (scheme 1, 2 and 3), or at a later point in time.
Advantageous effects The excellent gastric protective action and the gastric acid secretion-inhibiting action of the compounds according to the invention can be demonstrated in investigations on animal ex-perimental models. The compounds of the formula 1 according to the invention investigated in the model mentioned below have been provided with numbers which correspond to the num-bers of these compounds in the examples.
Testing of the secretion-inhibiting action on the perfused rat stomach In Table A which follows, the influence of the compounds of the formula I
according to the in-vention on the pentagastrin-stimulated acid secretion of the perfused rat stomach after in-traduodenal administration in vivo is shown.
Table A
Dose Inhibition of No. ( mol/kg) acid secretion i.d. (%) 1 1 > 50 2 1 > 50 3 1 > 50 Methodologv The abdomen of anesthetized rats (CD rat, female, 200-250 g; 1.5 g/kg i.m.
urethane) was opened after tracheotomy by a median upper abdominal incision and a PVC
catheter was fixed transorally in the esophagus and another via the pylorus such that the ends of the tubes just projected into the gastric lumen. The catheter leading from the pylorus led outward into the right abdominal wall through a side opening.
After thorough rinsing (about 50-100 ml), warm (37 C) physiological NaCl solution was con-tinuously passed through the stomach (0.5 mi/min, pH 6.8-6.9; Braun-Unita I).
The pH (pH
meter 632, glass electrode EA 147; ~= 5 mm, Metrohm) and, by titration with a freshly pre-pared 0.01 N NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCI
were deter-mined in the effluent in each case collected at an interval of 15 minutes.
The gastric secretion was stimulated by continuous infusion of 1 g/kg (= 1.65 ml/h) of i.v.
pentagastrin (left femoral vein) about 30 min after the end of the operation (i.e. after determi-nation of 2 preliminary fractions). The substances to be tested were administered intraduode-nally in a 2.5 ml/kg liquid volume 60 min after the start of the continuous pentagastrin infusion.
The body temperature of the animals was kept at a constant 37.8-38 C by infrared irradiation and heat pads (automatic, stepless control by means of a rectal temperature sensor).
Mode(s) for Carrying Out the Invention The examples below serve to illustrate the invention in more detail without limiting it. Further com-pounds of the formula 1 whose preparation is not described explicitly can likewise be prepared in an analogous manner or in a manner known per se to the person skilled in the art, using customary proc-ess techniques. The compounds named expressly as examples, and the salts of these compounds, are preferred subject matter of the invention. The abbreviation min stands for minute(s), h stands for hour(s), m.p. stands for melting point and ee for enantiomeric excess.
1. Final Compounds of the formula 1 1. 7-(trans-2,3-Dihydro-2-hydroxy-l-indenyloxy)-5-(N, N-dimethylaminocarbonyl)-1,2-d imethyl-1H-benzimidazole To a suspension of 0.38 g (1.63 mmol) 7-hydroxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid dimethylamide and 0.8 g (6.1 mmol) 1,2-epoxyindane in 4 ml methanol and 1 ml water were added 0.45 ml triethylamine and the mixture was heated to 70 C for I h. The cooled solution was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magne-sium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (13:1) and crystallization from ethyl acetate yielded 0.45 g (76 %) of the title compound as a colourless solid (m.p. 230 C).
2. 6-(N, N-d imethylam inocarbonyl)-4-(2,6-d imethyl-benzylam ino)-2,3-d imethyl-3H-benzimidazole To a solution of 0.54 g (1.56 mmol) 6-(N,N-dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylidene-amino)-2,3-dimethyl-3H-benzimidazole in 10 ml methanol were slowly added 0.09 g (2.38 mmol) so-dium borohydride. After 10 min, the reaction mixture was partitioned between saturated aqueous am-monium chloride and dichloromethane. The organic layer was separated, dried over anhydrous mag-nesium sulphate and evaporated. Purification of the residue by crystallization from ethyl acetate/n-heptane yielded 0.52 g (95 %) of the title compound as a colourless solid (m.p. 187-188 C).
3. 4-(2,6-Dimethyl-benzylam ino)-2,3-d imethyl-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole To a solution of 0.5 g (1.94 mmol) 4-amino-2,3-dimethyl-6-(N-pyn-olidinocarbonyl)-3H-benzimidazole and 0.39 g (2.9 mmol) 2,6-dimethylbenzaldehyd in 15 ml dichloromethane and 5 ml acetic acid were added 0.82 mg (3.9 mmol) sodium triacetoxyborohydride. After 2 h, TLC
indicated incomplete reaction and the mixture was evaporated to dryness. The residue was diisolved in 20 ml methanol and treated with excess sodium borohydride. After complete reaction, mixture was partitioned between saturated aqueous ammonium chloride and dichloromethane. The organic layer was separated, dried over an-hydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.41 g (56 %) of the title compound as a colourless solid (m.p. 188-189 C).
II. Starting Compounds A. 2-Be nzyl oxy-4-b romo-6-n itro-a n i l i n e To a suspension of 50 g (325 mmol) 2-amino-3-nitrophenol, 45 g (325 mmol) potassium carbonate and 2 g (13 mmol) sodium iodide in 400 ml ethanol were added 47 ml (408 mmol) benzyl chloride and the mixture was heated to 80 C. After 2 h, the reaction mixture was cooled down and the solvent was evaporated. The residue was dissolved in ethyl acetate and extracted with water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Coevaporation with dichloromethane led to a dark brown oily residue which was dissolved in 400 ml acetonitriie.
After addition of 63.4 g (356 mmol) N-bromosuccinimide, the reaction mixture was refluxed for I h.
After cooling down, 400 g silica gel were added and the mixture was evaporated to dryness. The resulting solid was put on a column and the product was eluted with ethyl acetateaight petroleum ether (4:1). Evaporation::of the eluent left a solid which was recrystallized from ethyl acetateln-heptane to give 62 g (59 %) of the title compound as a red solid (m.p. 90 C).
B. 2-Ami no-3-benzyloxy-5-bromo-an i l i ne To a suspension of 3.23 g (10 mmol) 2-benzyloxy-4-bromo-6-nitro-aniline in 60 ml methanol and 15 ml concentrated hydrochloric acid were added 2.23 g (40 mmol) iron filings in small portions at 60 C.
After 10 min, the mixture was cooled down and neutralized with 6N aqueous sodium hydroxide. Acti-vated charcoal was added and the suspension was filtered. The filtrate was partitioned between di-chloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Crystallization of the residue from ethyl acetate/n-heptane yielded 2.05 g (70 %) of the title compound as a colourless solid (m.p. 108 C).
C. 4-Benzyloxy-6-bromo-2-methyl-1 H-benzimidazole To a suspension of 2.0 g (6.82 mol) 2-amino-3-benzyloxy-5-bromo-aniline in 20 ml ethanol were added 5 ml 5N hydrochloric acid. The reaction mixture was hetaed to 60 C and 1.41 ml (13.6 mol) 2,4-pentanedione were added in one portion. After refluxing 1 h, the mixture was cooled down and neutralized with 6N aqueous sodium hydroxide. The mixture was partitioned between dichloromethane and water. The organic layer was dried over anhydrous magnesium sulphate and evaporated. Crystal-lization of the residue from ethyl acetateln-heptane yielded 2.12 g (98 %) of the title compound as a colourless solid (m.p. 174 C).
D. 7-Benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide To a suspension of 2.0 g (6.3 mmol) 4-benzyloxy-6-bromo-2-methyl-IH-benzimidazole in 30 ml di-methylamine (3.2M solution in tetrahydrofuran) were added 210 mg (0.95 mmol) palladium(II) acetate and 495 mg (1.9 mmol) triphenylphosphine. The mixture was transferred to an autoclave and carbon-ylated (5 bar carbon monoxide pressure, 120 C) for 16 h. The reaction mixture was cooled down and evaporated. Purification of the residue by column chromatography on silica gel using dichloro-methane/methanol (13:1) yielded 1.53 g(79 %) of the title compound as a a light brown oil, which was used without further purification in the next step.
E. 7-Benzyloxy-1,2-dimethyl-1 H-benzimidazole-5-carboxylic acid dimethylamide To a solution of 1.53 g (4.7 mmol) 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid di-methylamide in 25 ml dried tetrahydrofuran were slowly added 3.1 ml (5 mmol) n-butyllithium (1.6M in hexanes) at -78 C. After adding 0.32 ml (5.1 mmol) methyl iodide, the reaction mixture was allowed to warm to room temperature. After 16 h, the mixture was partitioned between dichloromethane and water. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated.
Purification of the residue by column chromatography on silica gel using dichloromethane/methanol (13:1) and crystallization of the residue from ethyl acetate/n-heptane yielded 0.79 g (52 %) of the title compound as a colourless solid (m.p. 117-118 C).
F. 7-Hydroxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid dimethylamide A solution of 0.7 g (2.2 mmol) 7-benzyloxy-1,2-dimethyl-lH-benzimidazole-5-carboxylic acid di-methylamide in 25 ml methanol and 0.1 ml acetic acid was hydrogenated over 0.25 g 10% Pd/C (25 C, 1 bar Hz) for 16 h. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from ethyl acetate to give 0.44 g (87 %) of the title compound as a colourless solid (m.p.
209 C).
G. 4-Methylamino-3,5-dinitrobenzene-carboxylic acid 25.0 g(101 mmol) 4-chloro-3,5-dinitrobenzene-carboxylic acid were slowly added to 120 ml aqueous methylamine (40 %) and the mixture was heated to reflux. After I h, the mixture was cooled down and evaporated to dryness. The residue was dissolved in water and the pH was adjusted to pH w 5 by add-ing 6N hydrochloric acid. The precipitate was collected, washed with water and dried to yield 21.6 g (90 %) of the title compound as a yellow solid (m.p. 184-188 C).
H. 1,2-Dimethyl-7-nitro-1 H-benzimidazole-5-carboxylic acid To a suspension of 4.0 g (16.6 mmol) 4-methylamino-3,5-dinitrobenzene-carboxylic acid in 50 ml ethanol were added 40 ml 2N aqueous ammonium polysulfide. After 1 h, excess ethanol was evapo-rated and the residue was neutralized with 6N hydrochloric acid. The solids were filtered off and the filtrate was evaporated to dryness. The residue was suspended in 100 ml ethanol and 20 ml 5N hydro-chloric acid. To the boiling mixture were added 4.1 ml (40 mmol) 2,5-pentanedione. After 4 h, the sol-vent was removed and the residue was diluted with water and neutralized with 40% aqueous sodium hydroxide. The precipitate was collected and suspended in 30 ml methanol and 10 ml water. To the mixture were added 0.96 g (40 mmol) lithium hydroxide and the suspension was heated to 70 C. After 30 min, the pH of the reaction mixture was adjusted to pH - 6 by adding 4N
hydrochloric acid. Excess methanol was removed and the precipitate was collected and washed with water to yield 0.8 g (21 %) of the title compound as a colourless solid (m.p. 303-305 C).
1. 6-(N,N-Dimethylaminocarbonyl)-4-(2,6-dimethyl-benzylidene-amino)-2,3-dimethyl-3H-benzimidazole A suspension of 0.8 g (3.4 mmol)1,2-dimethyl-7-nitro-1 H-benzimidazole-5-carboxylic acid in 10 ml methanol and I ml acetic acid was hydrogenated over palladium on charcoal (3 h, 80 C). The reac-tion mixture was neutralized with 40% aqueous sodium hydroxide and the catalyst was filtered off. The filtrate was evaporated and the residue was redissolved in 15 ml methanol and 10 ml acetic acid and treated with 2,6-dimethylbenzaidehyd to yield the corresponding imine, which was dissolved in 10 ml dimethylformamide and 10 ml dichloromethane. To this solution were added 1.5 g (4.7 mmol) O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) and the mixture was heated to 50 C. After 20 min, 5 ml (10 mmol) dimethylamine (2M in tetrahydrofuran) were added at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (10:1) and crystallization from ethyl acetate/n-heptane yielded 0.6 g (51 %) of the title compound as a light yellow solid (m.p. 165-166 C).
J. 4-Methylam ino-3,5-d initro-N-pyrrolidinyl-benzamide To a suspension of 2.0 g (8.3 mmol) 4-methylamino-3,5-dinitrobenzene-carboxylic acid and 4.0 g (12.4 mmol) O-(1F!-benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium tetrafluoroborate (TBTU) in 25 ml chloroform were added 2.5 ml (30 mmol) pyrrolidine at 45 C. After 30 min, a further amount of 4.0 g TBTU and 2.5 ml pyrrolidine were added and stirring was continued for 45 min.
The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (100:1) and crystallization from ethyl acetate/n-heptane yielded 1.72 g (70 %) of the title compound as an orange solid (m.p. 148-150 C).
K. 2,3-Dimethyl-4-n itro-6-(N-pyrrol id inocarbonyl)-3H-benzi m idazole To a mixture of 1.65 g (5.6 mmol) 4-methylamino-3,5-dinitro-N-pyrrolidinyl-benzamide and 330 mg ruthenium on charcoal (5 %) in 30 ml ethanol were slowly added 0.55 ml (11.2 mmol) hydrazine hy-drate at 75 C. After 1.5 h, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel using dichloromethane:methanol (20:1).
The intermediate product was suspended in 25 ml methanol and 5 ml 5N
hydrochloric acid. To this suspension were added 1.15 ml (11.2 mmol) 2,4-pentanedione at 80 C. After 30 min, the reaction mixture was cooled down, neutralized with 40% aqueous sodium hydroxide and extracted with di-chloromethane. The organic layer was separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloro-methane:methanol (20:1) and crystallization from ethyl acetate/n-heptane yielded 0.91 g (56 %) of the title compound as an orange solid (m.p. 114-117 C).
L. 4-Amino-2,3-dimethyl-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole ~t.
A solution of 0.82 g (2.84 mmol) 2,3-dimethyl-4-nitro-6-(N-pyrrolidinocarbonyl)-3H-benzimidazole in 20 ml methanol and I ml acetic acid was hydrogenated over 300 mg palladium on charcoal (10 %, 2.5 h, 50 C). The catalyst was filtered off and the reaction mixture was evaporated to dryness. The residue was crystallized with ethyl acetate/n-heptane to give 0.61 g (83 %) of a beige solid (m.p. 250-251 C).
Industrial applicability The compounds of the formula I and their salts have valuable pharmacological properties which make them commercially utilizable. In particular, they exhibit marked inhibition of gastric acid se-cretion and an excellent gastric and intestinal protective action in warm-blooded animals, in par-ticular humans. In this connection, the compounds according to the invention are distinguished by a high selectivity of action, an advantageous duration of action, a par6cularly good enteral activity, the absence of significant side effects and a large therapeutic range.
"Gastric and intestinal protection" in this connection is understood as meaning the prevention and treatment of gastrointestinal diseases, in particular of gastrointestinal inflammatory diseases and lesions (such as, for example, gastric ulcer, peptic ulcer, including peptic ulcer bleeding, duodenal ulcer, gastritis, hyperacidic or medicament-related functional dyspepsia), which can be caused, for example, by microorganisms (e.g. Helicobacter pylori), bacterial toxins, medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs and COX-inhibitors), chemicals (e.g. etha-nol), gastric acid or stress situations. "Gastric and intestinal protection"
is understood to include, according to general knowledge, gastroesophageal reflux disease (GERD), the symptoms of which include, but are not limited to, heartbum and/or acid regurgitation.
In their excellent properties, the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art in various models in which the antiul-cerogenic and the antisecretory properties are determined. On account of these properties, the compounds of the formula 1 and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, where they are used, in par6cular, for the treatment and/or prophylaxis of disorders of the stomach and/or intestine.
A further subject of the invention are therefore the compounds according to the invention for use in the treatment and/or prophylaxis of the abovementioned diseases.
The invention likewise includes the use of the compounds according to the invention for the pro-duction of medicaments which are employed for the treatment and/or prophylaxis of the above-mentioned diseases.
The invention furthermore includes the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
A further subject of the invention are medicaments which comprise one or more compounds of the formula 1 and/or their pharmacologically acceptable salts.
The medicaments are prepared by processes which are known per se and familiar to the person skilled in the art. As medicaments, the pharmacologically active compounds according to the in-vention (= active compounds) are either employed as such, or preferably in combination with suit-able pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, sup-positories, patches (e.g. as TTS), emulsions, suspensions or solutions, the active compound con-tent advantageously being between 0.1 and 95% and it being possible to obtain a pharmaceutical administration form exactly adapted to the active compound and/or to the desired onset and/or du-ration of action (e.g. a sustained-release form or an enteric form) by means of the appropriate se-lection of the auxiliaries and excipients.
The auxiliaries and excipients which are suitable for the desired pharmaceutical formulations are known to the person skilled in the art on the basis of his/her expert knowledge. In addition to sol-vents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound excipi-ents, it is possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor cor-rigents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex-ing agents (e.g. cyclodextrins).
The active compounds can be administered orally, parenterally or percutaneously.
In general, it has proven advantageous in human medicine to administer the active compound(s) in the case of oral administration in a daily dose of approximately 0.01 to approximately 20, prefera-bly 0.05 to 5, in particular 0.1 to 1.5, mg/kg of body weight, if appropriate in the form of several, preferably I to 4, individual doses to achieve the de,sired result. In the case of a parenteral treat-ment, similar or (in particular in the case of the intravenous administration of the active com-pounds), as a rule, lower doses can be used. The establishment of the optimal dose and manner of administration of the active compounds necessary in each case can easily be carried out by any person skilled in the art on the basis of his/her expert knowledge.
If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned diseases, the pharmaceutical preparations can also contain one or more pharmacologically active constituents of other groups of medicaments, for example: tranquillizers (for example from the group of the benzodiazepines, for example diazepam), spasmolytics (for ex-ample, bietamiverine or camylofine), anticholinergics (for example, oxyphencyclimine or phencar-bamide), local anesthetics, (for example, tetracaine or procaine), and, if appropriate, also enzymes, vitamins or amino acids.
To be emphasized in this connection is in particular the combination of the compounds according to the invention with pharmaceuticals which inhibit acid secretion, such as, for example, H2 block-ers (e.g. cimetidine, ranitidine), H+/K' ATPase inhibitors (e.g. omeprazole, pantoprazole), or further with so-called peripheral anticholinergics (e.g. pirenzepine, telenzepine) and with gastrin antago-nists with the aim of increasing the principal action in an additive or super-additive sense and/or of eliminating or of decreasing the side effects, or further the combination with antibacterially active substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimi-dazoles or altematively bismuth salts) for the control of Helicobacter pylori.
Suitable antibacterial co-components which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefa-lothin, cefoxitin, cefotaxime, imipenem, gentamycin, amikacin, erythromycin, ciprofloxacin, met-ronidazole, clarithromycin, azithromycin and combinations thereof (for example clarithromycin +
metronidazole).
In view of their excellent gastric and intestinal protection action, the compounds of formula 1 are suited for a free or fixed combination with those medicaments (e.g. certain antiinflammatories and antirheumatics, such as NSAIDs), which are known to have a certain ulcerogenic potency. In addi-tion, the compounds of formula 1 are suited for a free or fixed combination with motility-modifying drugs.
Claims (14)
1 A compound of the formula 1 in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and its salts.
2. A compound of the formula 1 as claimed in claim 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp wherein Z has the meaning -CHR8- or-CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Y denotes CH2-phenyl or a CH2-phenyl substituted by a 1-4C-alkoxy radical, and its salts.
3. A compound of the formula 1 as claimed in claim 1, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH and Y has either the meaning -CH2-Ar wherein Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, or Y denotes the group gp wherein Z has the meaning -CHR8- or -CHR8-CHR9-where in, Ar and/or in the group gp R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, alkylcarbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when R1 denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl, R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl and Y denotes CH2-Ar, and its salts.
4. A compound of the formula 1 as claimed in claim 1, characterized by the formula 1 a in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy- 1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, flu-oro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and its salts.
5. A compound of the formula 1 a as claimed in claim 4, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31 R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-l-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen when R1 and R2 have the meanings hydrogen or 1-4C-alkyl and Ar is phenyl or a phenyl substituted by a 1-4C-alkoxy radical, and the salts of these compounds.
6. A compound of the formula 1 a as claimed in claim 4, in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-1-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl; aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O (oxygen) or NH, Ar is a mono- or bicyclic aromatic residue, substituted by R4, R5, R6 and R7, which is se-lected from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyl, benzimidazolyl, furyl, benzofuryl, thienyl, benzothienyl, thiazolyl, isoxa-zolyl, pyridinyl, pyrimidinyl, chinolinyl and isochinolinyl, R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R6 is hydrogen, 1-4C-alkyl or halogen and R7 is hydrogen, 1-4C-alkyl or halogen, Aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, with the proviso that R3 does not have the meaning hydrogen or halogen when RI
denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, and its salts
denotes hydrogen, 1-4C-alkyl, or hydroxy-1-4C-alkyl and R2 denotes hydrogen, 1-4C-alkyl or 3-7C-cycloalkyl-1-4C-alkyl, and its salts
7. A compound of the formula 1 as claimed in claim 1, characterized by the formula 1b in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-14C-alkyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxycarbonyl, 2-4C-alkenyl, 2-4C-alkynyl, fluoro-1-4C-alkyl, hydroxy-1-4C-alkyl, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonyloxy-1-4C-alkyl R2 is hydrogen, 1-4C-alkyl, aryl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, alkoxycarbonyl, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyl, hydroxy-l-4C-alkyl, fluoro-2-4C-alkyl, aryl-1-4C-alkoxy-1-4C-alkyl, hydroxy or 1-4C-alkoxy R3 is hydrogen, halogen, fluoro-1-4C-alkyl, carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, hydroxyl, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl or 3-7C-cycloalkyl, amino and R32 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol, dihydroimidazol, oxazol, imidazol, isoxazol, dihydroi-soxazol, pyrazol and tetrazol where R33 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R34 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, R35 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, halogen, trifluoromethyl or hydroxy, X is O(oxygen) or NH and Z has the meaning -CHR8- or-CHR8-CHR9-where R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 2-4C-alkenyloxy, 1-4C-alkyl-carbonyl, carboxy, 1-4C-alkoxycarbonyl, carboxy-1-4C-alkyl, 1-4C-alkoxycarbonyl-1-4C-alkyl, halogen, hydroxy, aryl, aryl-1-4C-alkyl, aryl-oxy, aryl-1-4C-alkoxy, trifluoromethyl, fluoro-1-4C-alkoxy, nitro, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or sulfonyl, R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbomyl, halogen, trifluoromethyl or hydroxy, R8 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy R9 is hydrogen, 1-7C-alkyl, 2-7C-alkenyl, hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-l-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy, and wherein aryl is phenyl or substituted phenyl with one, two or three same or different substituents from the group of 1-4C-alkyl, 1-4C-alkoxy, carboxy, 1-4C-alkoxycarbonyl, halogen, trifluoro-methyl, nitro, trifluoromethoxy, hydroxy and cyano, and its salts.
8. A compound of the formula 1a as claimed in claim 4, characterized by the formula 1a-1 in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, trifluoro-methyl, fluoro-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkoxycarbonylamino, R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and X is O (oxygen) or NH, and its salts.
9. A compound of the formula 1a-1 as claimed in claim 8, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyrrolidino group, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and their salts.
10. A compound of the formula 1a-1 as claimed in claim 8, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 the group -CO-NR31R32, where R31 is 1-4C-alkyl and R32 is 1-4C-alkyl, R4 is 1-4C-alkyl R5 is 1-4C-alkyl, X is NH, and its salts.
11. A compound of the formula 1b as claimed in claim 7, characterized by the formula 1b-1 in which R1 is hydrogen, 1-4C-alkyl, 3-7C-cycloalkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl, R2 is hydrogen,1-4C-alkyl, hydroxy, 1-4C-alkoxy or aryl-1-4C-alkoxy-1-4C-alkyl R3 is carboxyl, -CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, cyano, the group -CO-NR31R32, the group SO2-NR31R32 or the group Het, where R31 is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, 3-7C-cycloalkyl or amino and R32 is hydrogen or 1-7C-alkyl, or where R31 and R32 together, including the nitrogen atom to which both are bonded, are a pyr-rolidino, piperidino, piperazino, N-1-4C-alkylpiperazino, morpholino, aziridino or azetidino group and Het is a heterocyclic residue, substituted by R33, R34 and R35, selected from the group con-sisting of oxadiazol, dihydrooxazol and dihydroimidazol, where R33 is hydrogen or 1-4C-alkyl, R34 is hydrogen or 1-4C-alkyl R35 is hydrogen or 1-4C-alkyl R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen, R5 is hydrogen or 1-4C-alkyl, R8 is hydroxyl, 1-4C-alkoxy, oxo-substituted 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkyl-1-4C-alkoxy, hydroxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy-1-4C-alkoxy, 3-7C-cycloalkoxy-1-4C-alkoxy, 3-7C-cycloalkyl-l-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, halo-1-4C-alkoxy, amino, mono- or di-1-4C-alkylamino, 1-alkylcarbonylamino, 1-4C-alkoxycarbonylamino, mono- or di-1-4C-alkylamino-1-4C-alkylcarbonyloxy, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or 1-4C-alkoxy-1-4C-alkylcarbonyloxy X is O (oxygen) or NH, and its salts.
12. A compound of the formula 1b-1 as claimed in claim 11, in which R1 is 1-4C-alkyl, R2 is 1-4C-alkyl, R3 is the group -CO-NR31R32, where R31 is 1-4C-alkyl, R32 is 1-4C-alkyl R4 is hydrogen R5 is hydrogen, R8 is hydroxyl X is O (oxygen) and its salts.
13. A medicament comprising a compound as claimed in claim 1 and/or a pharmacologically ac-ceptable salt thereof together with customary pharmaceutical auxiliaries and/or excipients.
14. The use of a compound as claimed in claim 1 and its pharmacologically acceptable salts for the prevention and treatment of gastrointestinal disorders.
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EP04102191 | 2004-05-18 | ||
EP04102191.6 | 2004-05-18 | ||
PCT/EP2005/052196 WO2005111000A1 (en) | 2004-05-18 | 2005-05-13 | 7-substituted benzimidazoles and their use as inhibitors of gastric acid secretion |
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EP (1) | EP1756067A1 (en) |
JP (1) | JP2007538047A (en) |
AR (1) | AR049168A1 (en) |
AU (1) | AU2005243434A1 (en) |
CA (1) | CA2566821A1 (en) |
TW (1) | TW200600502A (en) |
WO (1) | WO2005111000A1 (en) |
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JP2009504798A (en) * | 2005-08-22 | 2009-02-05 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | Isotopically substituted benzimidazole derivatives |
WO2007031860A1 (en) * | 2005-09-15 | 2007-03-22 | Pfizer Japan Inc. | Indane substituted benzimidazoles and their use as acid pump inhibitors |
WO2007072142A2 (en) * | 2005-12-19 | 2007-06-28 | Pfizer Japan Inc. | Benzimidazole-5-carboxamide derivatives |
ES2345726T3 (en) * | 2005-12-19 | 2010-09-30 | Raqualia Pharma Inc | BENCIMIDAZOLS REPLACED WITH CHROMAN AND ITS USE AS INHIBITORS OF THE ACID PUMP. |
KR20190057569A (en) * | 2017-11-20 | 2019-05-29 | 제일약품주식회사 | 7-amino-1H-indole-5-carboxamide derivatives, and use thereof |
WO2024087155A1 (en) * | 2022-10-28 | 2024-05-02 | 深圳市华先医药科技有限公司 | Method for synthesizing 4-hydroxy-n,n,2-trimethylbenzimidazole-6-carboxamide |
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SE8604566D0 (en) * | 1986-10-27 | 1986-10-27 | Haessle Ab | NOVEL COMPUNDS |
IL108520A (en) * | 1993-02-15 | 1997-09-30 | Byk Gulden Lomberg Chem Fab | 2, 3, 8-TRISUBSTITUTED IMIDAZO £1, 2-a| PYRIDINE DERIVATIVES, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
WO1996004251A1 (en) * | 1994-08-03 | 1996-02-15 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic compound |
SE9602286D0 (en) * | 1996-06-10 | 1996-06-10 | Astra Ab | New compounds |
AR043063A1 (en) * | 2002-12-13 | 2005-07-13 | Altana Pharma Ag | 6-SUBSTITUTED BENCIMIDAZOLS AND THEIR USE AS INHIBITORS OF GASTRIC SECRETIONS |
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- 2005-05-10 AR ARP050101885A patent/AR049168A1/en unknown
- 2005-05-13 EP EP05747188A patent/EP1756067A1/en not_active Withdrawn
- 2005-05-13 JP JP2007517241A patent/JP2007538047A/en not_active Withdrawn
- 2005-05-13 WO PCT/EP2005/052196 patent/WO2005111000A1/en active Application Filing
- 2005-05-13 AU AU2005243434A patent/AU2005243434A1/en not_active Abandoned
- 2005-05-13 CA CA002566821A patent/CA2566821A1/en not_active Abandoned
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WO2005111000A1 (en) | 2005-11-24 |
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AR049168A1 (en) | 2006-07-05 |
TW200600502A (en) | 2006-01-01 |
AU2005243434A1 (en) | 2005-11-24 |
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