ZA200406447B - Tricyclic n-acyl compounds - Google Patents
Tricyclic n-acyl compounds Download PDFInfo
- Publication number
- ZA200406447B ZA200406447B ZA200406447A ZA200406447A ZA200406447B ZA 200406447 B ZA200406447 B ZA 200406447B ZA 200406447 A ZA200406447 A ZA 200406447A ZA 200406447 A ZA200406447 A ZA 200406447A ZA 200406447 B ZA200406447 B ZA 200406447B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- hydrogen
- alkoxy
- halogen
- hydroxy
- Prior art date
Links
- -1 cyanomethyl Chemical group 0.000 claims description 147
- 239000001257 hydrogen Substances 0.000 claims description 82
- 229910052739 hydrogen Inorganic materials 0.000 claims description 82
- 150000002431 hydrogen Chemical group 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 41
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- CPEONABTMRSIKA-UHFFFAOYSA-N 1,4$l^{2}-oxazinane Chemical compound C1COCC[N]1 CPEONABTMRSIKA-UHFFFAOYSA-N 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 239000011737 fluorine Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002950 monocyclic group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Chemical group 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 150000003254 radicals Chemical class 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- MXBVNILGVJVVMH-UHFFFAOYSA-N 1,7-naphthyridine Chemical compound C1=NC=CC2=CC=CN=C21 MXBVNILGVJVVMH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003638 chemical reducing agent Substances 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
- 238000001816 cooling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- BHNPNBRMSQEZAN-UHFFFAOYSA-N (10-acetyl-2,3-dimethyl-9-phenyl-9h-imidazo[1,2-h][1,7]naphthyridin-7-yl) acetate Chemical compound CC(=O)N1C(C2=NC(C)=C(C)N2C=C2)=C2C(OC(=O)C)=CC1C1=CC=CC=C1 BHNPNBRMSQEZAN-UHFFFAOYSA-N 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FCIWOTAANUDCRC-HNNXBMFYSA-N (9s)-2,3-dimethyl-9-phenyl-9,10-dihydro-8h-imidazo[1,2-h][1,7]naphthyridin-7-one Chemical compound C1([C@H]2NC=3C4=NC(=C(N4C=CC=3C(=O)C2)C)C)=CC=CC=C1 FCIWOTAANUDCRC-HNNXBMFYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- PIKFXKSSNMLKLP-UHFFFAOYSA-N 1,2,3,5-tetrahydroimidazo[1,2-h][1,7]naphthyridine Chemical class C1C=C2C=CC=NC2=C2N1CCN2 PIKFXKSSNMLKLP-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- DMTADULPJIAIEO-UHFFFAOYSA-N 2,3-dimethyl-6,7-dihydro-5h-imidazo[1,2-a]pyridin-8-one Chemical compound O=C1CCCN2C(C)=C(C)N=C21 DMTADULPJIAIEO-UHFFFAOYSA-N 0.000 description 1
- FCIWOTAANUDCRC-UHFFFAOYSA-N 2,3-dimethyl-9-phenyl-9,10-dihydro-8h-imidazo[1,2-h][1,7]naphthyridin-7-one Chemical compound C1C(=O)C=2C=CN3C(C)=C(C)N=C3C=2NC1C1=CC=CC=C1 FCIWOTAANUDCRC-UHFFFAOYSA-N 0.000 description 1
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 1
- YGTUPRIZNBMOFV-UHFFFAOYSA-N 2-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=C(O)C=C1 YGTUPRIZNBMOFV-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-N 3-Hydroxy-2-naphthoate Chemical compound C1=CC=C2C=C(O)C(C(=O)O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- YCPXWRQRBFJBPZ-UHFFFAOYSA-N 5-sulfosalicylic acid Chemical compound OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O YCPXWRQRBFJBPZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- WZKSXHQDXQKIQJ-UHFFFAOYSA-N F[C](F)F Chemical compound F[C](F)F WZKSXHQDXQKIQJ-UHFFFAOYSA-N 0.000 description 1
- 101001110286 Homo sapiens Ras-related C3 botulinum toxin substrate 1 Proteins 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 102100022122 Ras-related C3 botulinum toxin substrate 1 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- BHNPNBRMSQEZAN-IBGZPJMESA-N [(9s)-10-acetyl-2,3-dimethyl-9-phenyl-9h-imidazo[1,2-h][1,7]naphthyridin-7-yl] acetate Chemical compound C1([C@@H]2C=C(C3=C(C4=NC(C)=C(C)N4C=C3)N2C(C)=O)OC(=O)C)=CC=CC=C1 BHNPNBRMSQEZAN-IBGZPJMESA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- ZHDSCPNAZAJOKO-UHFFFAOYSA-N [O]C(F)F Chemical compound [O]C(F)F ZHDSCPNAZAJOKO-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 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
- 125000006627 ethoxycarbonylamino group Chemical group 0.000 description 1
- NUWRDXMXYDWUAN-JTQLQIEISA-N ethyl (3s)-3-amino-3-phenylpropanoate Chemical compound CCOC(=O)C[C@H](N)C1=CC=CC=C1 NUWRDXMXYDWUAN-JTQLQIEISA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 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
- 239000005457 ice water Substances 0.000 description 1
- JTXHKSJRKCFKLA-UHFFFAOYSA-N imidazo[1,2-h][1,7]naphthyridine Chemical compound C1=CN=C2C3=NC=CN3C=CC2=C1 JTXHKSJRKCFKLA-UHFFFAOYSA-N 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 125000000468 ketone group Chemical group 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
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 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
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000018556 stomach disease Diseases 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
TRICYCLIC N-ACYL COMPOUNDS
The invention relates to novel compounds which are used in the pharmaceutical industry as valuable . intermediates for preparing active ingredients. ] Prior art
The International Patent Applications WO 98/42707, WO 00/17200, WO 00/26217, WO 00/63211,
WO 01/72756, WO 01/72754, WO 01/72757 and WO 02/34749 disclose tricyclic imidazopyridine derivatives having very particular substitution patterns which are said to be suitable for treating gastric and intestinal diseases.
The invention provides compounds of the formula 1
R3a R2
R3b 7 oN \ R1
Rda —
R4b x N
Rba N-Prot (1)
R5b
Arom where
R1 is hydrogen, C,4-alkyl, Css-cycloalkyl, Csz-cycloalkyl-Ci4-alkyl, Ci4-alkoxy, Ci4-alkoxy-Cy.4- alkyl, C,4-alkoxycarbonyl, C,4-alkenyl, C,4-alkynyl, fluoro-C44-alkyl or hydroxy-C,4-alkyl,
R2 is hydrogen, C,4-alkyl, Cas-cycloalkyl, Cj.;-cycloalkyl-Cq4-alkyl, Ci4-alkoxycarbonyl, hydroxy-
C.<-alkyl, halogen, C,4-alkenyl, C,4-alkynyl, fluoro-C,.4-alkyl or cyanomethyl,
R3a is hydrogen, halogen, fluoro-C,4-alkyl, Ci4-alkyl, Co4-alkenyl, Ca4-alkynyl, C.4-alkoxy, carboxyl, . C.«-alkoxycarbonyl, hydroxy-C,s-alkyl, Ci4-alkoxy-Ci4-atkyl, C,4-alkoxy-C,4-alkoxy-C,4-alkyl, fluoro-C4-alkoxy-C,4-alkyl or the -CO-NR31R32 radical,
R3b is hydrogen, halogen, fluoro-C,4-alkyl, C,4-alkyl, C,4-alkenyl, C,4-alkynyl, C,_4-alkoxy, carboxyl,
C,4-alkoxycarbonyl, hydroxy-C,.4-alkyl, Cy4-alkoxy-Ci4-alkyl, C,4-alkoxy-Ci4-alkoxy-C;4-alkyl, fluoro-C;4-alkoxy-C4-alkyl or the -CO-NR31R32 radical, where
R31 is hydrogen, C,.;-alkyl, hydroxy-C,4-alkyl or C,4-alkoxy-C,4-alkyl and
R32 is hydrogen, Cy.;-alkyl, hydroxy-C,4-alkyl or C,4-alkoxy-C,4-alkyl, or where
R31 and R32 together, including the nitrogen atom to which they are both bonded, are a pyrrolidino, piperidino or morpholino radical,
R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where . R41 is a suitable oxygen protecting group, or where
R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen,
Arom is a mono- or bicyclic aromatic radical which is substituted by R6, R7, R8 and R9 and is selected ] from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indoly!, benzimidazolyt, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyl (benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinoliny! and isoquinolinyl, where
R6 is hydrogen, C,4-alkyl, hydroxy-C,4-alkyl, Ci4-alkoxy, C,4-alkenyloxy, C,4-alkyicarbonyl, carboxyl, Ci4-alkoxycarbonyl, carboxy-Ci4-alkyl, Ci4-alkoxycarbonyl-C,-alky!, halogen, hydroxyl, aryl, aryl-C,4-alkyl, aryloxy, aryl-C,4-alkoxy, trifluoromethyl, nitro, amino, mono- or di-C,4-alkylamino, C,4-alkylcarbonylamino, C,4-alkoxycarbonylamino, Ci4-alkoxy-C, 4- alkoxycarbonylamino or sulphonyl,
R7 is hydrogen, Cq4-alkyl, Cy4-alkoxy, C,4-alkoxycarbonyl, halogen, trifluoromethyl or hydroxyl,
R8 is hydrogen, C,4-alky! or halogen and
R9 is hydrogen, C.4-alkyl or halogen, where aryl is phenyl or substituted phenyl having one, two or three identical or different substituents from the group of Ci4-alkyl, C,4-alkoxy, carboxyl, C,4-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifftuoromethoxy, hydroxyl and cyano,
Prot is an amino protecting group, and their salts.
C14-Alkyl represents straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.
Ca.7-Cycloalky! represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which preference is given to cyclopropy!, cyclobutyl and cyclopentyl.
Cs7-Cycloalkyl-C,.4-alkyl represents one of the abovementioned C,-alkyl radicals which is substituted . by one of the abovementioned Cj;-cycloalkyt radicals. Examples include the cyclopropylmethyl, cyclo- hexylmethyl and cyclohexylethyl radicals.
Ci4-Alkoxy represents radicals which, in addition to the oxygen atom, contain a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples include the butoxy, iso-butoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxy and methoxy radicals.
C14-Alkoxy-C44-alkyl represents one of the abovementioned C,4-alkyl radicals which is substituted by one of the abovementioned C,-alkoxy radicals. Examples include the methoxymethyl!, methoxyethy! and butoxyethyl radicals.
C,.4-Alkoxycarbonyl (-CO-C,4-alkoxy) represents a carbonyl group to which one of the . abovementioned C,4-alkoxy radicals is bonded. Examples include the methoxycarbonyl (CH3;0-C(O)-) and ethoxycarbonyl (CH;CH,0-C(O)-) radicals.
C,4-Alkenyl represents straight-chain or branched alkenyl radicals having 2 to 4 carbon atoms.
Examples include the 2-butenyl, 3-butenyl, 1-propenyl and 2-propenyl (allyl) radicals.
C,4-Alkynyl represents straight-chain or branched alkynyl radicals having 2 to 4 carbon atoms.
Examples include the 2-butynyl, 3-butynyl and preferably the 2-propynyl (propargyl) radicals.
Fluoro-C,4-alkyl represents one of the abovementioned C,4-alkyl radicals which is substituted by one or more fluorine atoms. An example is the trifluoromethyl radical. )
Hydroxy-C4-alkyl represents the abovementioned C,4-alkyl radicals which are substituted by a hydroxyl group. Examples include the hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropy! radicals.
For the purposes of the invention, halogen is bromine, chlorine and fluorine.
C,4-Alkoxy-C4-alkoxy represents one of the abovementioned C.4-alkoxy radicals which is substituted by a further C,4-alkoxy radical. Examples include the 2-(methoxy)ethoxy (CH;-O-CH,-CH2-O-) and 2-(ethoxy)ethoxy (CH;-CH,-O-CH,-CH, -O-) radicals.
C14-Alkoxy-C44-alkoxy-C4-alkyl represents one of the abovementioned Ci4-alkoxy-Cy4-alkyl radicals which is substituted by one of the abovementioned C,.-alkoxy radicals. An example is the 2-(methoxy)ethoxymethyl (CH;3-O-CH,-CH;-O-CH,-) radical.
Fluoro-C,4-alkoxy-C, 4-alky! represents one of the abovementioned Ci4-alkyl radicals which is substituted by a fluoro-C,4-alkoxy radical. Fluoro-C.4-alkoxy represents one of the abovementioned
C,4-alkoxy radicals which is predominantly or fully substituted by fluorine. Examples of predominantly : or fully fluorine-substituted C,4-alkoxy include the 1,1,1 ,3,3,3-hexafluoro-2-propoxy, 2-trifluoromethyl-2- propoxy, 1,1,1-trifluoro-2-propoxy, perfluoro-tert-butoxy, 2,2,3,3,4,4,4-heptafluoro-1-butoxy, 444- . trifluoro-1-butoxy, 2,2,3,3,3-pentafluorpropoxy, perfluoroethoxy or 1,2,2-trifluoroethoxy radicals, in particular the 1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy or trifluoromethoxy radicals, and preferably the difluoromethoxy radical.
C..;-Alkyl represents straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples include the heptyl, isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), nechexy! (3,3-dimethyl-
butyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals. . C.4-Alkenyloxy represents a radical which, in addition to the oxygen atom, contains a C,4-alkenyl radical. An example is the allyloxy radical.
Ci4-Alkyicarbonyl represents a radical which, in addition to the carbonyl group, contains one of the : abovementioned C,4-alkyl radicals. An example is the acetyl radical.
An example of carboxy-C,4-alkyl is the carboxymethyl (-CH,COOH) or the carboxyethyl (-CH,CH,COOH) radical.
C.4-Alkoxycarbonyl-C,4-alkyl represents one of the abovementioned C,4-alkyl radicals which is substituted by one of the abovementioned C,,-alkoxycarbonyl radicals. An example is the ethoxy- carbonylmethy! radical (CH;CH,OC(O)CH_-).
Aryl-C,4-alkyl represents an aryl-substituted C,4-alkyl radical. An example is the benzyl radical.
Aryl-C,s-alkoxy represents an aryl-substituted C,.4-alkoxy radical. An example is the benzyloxy radical. in addition to the nitrogen atom, mono- or di-C4-alkylamino radicals contain one or two of the abovementioned C,j-alkyl radicals. Preference is given to di-C,4-alkylamino and in particular dimethyl-, diethyl- or diisopropylamino.
Ci4-Alkylcarbonylamino represents an amino group to which is bonded a C,4-alkylcarbonyl radical.
Examples include the propionylamino (C3H;C(O)NH-) and the acetylamino (acetamido) (CH;C(O)NH-) radicals.
C.4-Alkoxycarbonytamino represents an amino radical which is substituted by one of the above- mentioned C,4-atkoxycarbonyl radicals. Examples include the ethoxycarbonylamino and methoxycarbonylamino radicals.
C14-Alkoxy-C,4-alkoxycarbonyl represents a carbonyl group which is bonded to one of the above- . mentioned C,4-alkoxy-C,,-alkoxy radicals. Examples include the 2-(methoxy)ethoxycarbonyl (CH;3-O-CH,CH,-O-CO-) and the 2-(ethoxy)ethoxycarbonyl (CH;CH,-O-CH,CH,-O-CO-) radicals.
C14-Alkoxy-C, 4-alkoxycarbonylamino represents an amino radical which is substituted by one of the abovementioned C;4-alkoxy-C,_4-alkoxycarbonyl radicals. Examples include the 2-(methoxy)ethoxy- carbonylamino and 2-(ethoxy)ethoxycarbonylamino radicals.
d
Useful oxygen protecting groups R41 are in principle any groups which behave in the desired manner on further conversion of the compounds of the formula 1, i.e., for example, can be converted by oxidation with suitable oxidizing agents to a keto group and by reduction with suitable reducing agents . to a hydroxyl group. Examples of protecting groups include the C,4-alkoxycarbonyl, Ci4-alkoxy-C,4- alkoxycarbonyl and C,4-alkylcarbonyl radicals. In a preferred embodiment of the invention, the R41 . and Prot groups are identical. - Examples of Arom radicals include the following substituents: 4-acetoxyphenyl, 4-acetamidophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 3-benzyloxy-4-methoxyphenyl, 4-benzyloxy-3-methoxyphenyl, 3,5-bis(trifluoromethyl)phenyl, 4-butoxy- phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-chloro-6-fluorophenyl, 3-chioro-4-fluoro- phenyl, 2-chloro-5-nitrophenyl, 4-chloro-3-nitrophenyl, 3-(4-chlorophenoxy)phenyl, 2,4-dichlorophenyt, 3.4-difluorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxy-5-hydroxyphenyi, 2,5-dimethylphenyl, 3-ethoxy-4-hydroxyphenyl, 2-fluorophenyl, 4-flucrophenyl, 4-hydroxyphenyl, 2-hydroxy-5-nitrophenyl, 3-methoxy-2-nitrophenyl, 3-nitrophenyl, 2,3,5-trichlorophenyl, 2,4,6-trinydroxy- phenyl, 2,3,4-trimethoxyphenyl, 2-hydroxy-1-naphthyl, 2-methoxy-1-naphthyl, 4-methoxy-1-naphthyf, 1-methyi-2-pyrrolyl, 2-pyrrolyl, 3-methyl-2-pyrrolyl, 3,4-dimethyl-2-pyrrolyl, 4-(2-methoxycarbonylethyl)- 3-methyl-2-pyrrolyl, 5-ethoxycarbonyl-2,4-dimethyl-3-pyrrolyl, 3,4-dibromo-5-methyl-2-pyrrolyl, 2,5-dimethyl-1-phenyl-3-pyrrolyl, 5-carboxy-3-ethyl-4-methyl-2-pyrrolyl, 3,5-dimethyl-2-pyrrolyl, 2,5-dimethyi-1-(4-trifluoromethylphenyl)-3-pyrrolyl, 1-(2,6-dichloro-4-trifluoromethylphenyl)-2-pyrrolyl, 1-(2-nitrobenzyl)-2-pyrrolyl, 1-(2-fluorophenyl)-2-pyrrolyl, 1-(4-trifluoromethoxyphenyl)-2-pyrrolyl, 1-(2-nitrobenzyt)-2-pyrrolyl, 1-(4-ethoxycarbonyl)-2,5-dimethyl-3-pyrrolyi, 5-chloro-1,3-dimethyl- 4-pyrazolyl, 5-chloro-1-methyl-3-trifluormethyl-4-pyrazolyl, 1-(4-chlorobenzyl)-5-pyrazolyl, 1,3-dimethyl- 5-(4-chlorophenoxy)-4-pyrazolyl, 1-methyl-3-trifluoromethyl-5-(3-triflioromethylphenoxy)-4-pyrazolyl, 4-methoxycarbonyl-1-(2,6-dichlorophenyl)-5-pyrazolyl, 5-allyloxy-1-methyi-3-trifluoromethyl-4-pyrazolyl, 5-chloro-1-phenyl-3-trifluoromethyl-4-pyrazolyl, 3,5-dimethyl-1-phenyl-4-imidazolyl, 4-bromo-1-methyl- 5-imidazolyt, 2-butylimidazolyl, 1-phenyl-1,2,3-triazol-4-yl, 3-indolyl, 4-indolyl, 7-indolyl, - 5-methoxy- 3-indolyl, 5-benzyloxy-3-indolyl, 1-benzyl-3-indolyl, 2-(4-chlorophenyl)-3-indolyl, 7-benzyloxy-3-indolyl, 6-benzyloxy-3-indolyl, 2-methyl-5-nitro-3-indolyl, 4,5,6,7-tetrafluoro-3-indoly!, 1-(3,5-difluorobenzyl)- 3-indolyi, 1-methyl-2-(4-trifluorophenoxy)-3-indolyl, 1-methyl-2-benzimidazolyl, S-nitro-2-furyl, 5-hydroxymethyl-2-furyl, 2-furyl, 3-furyl, 5-(2-nitro-4-trifluoromethylphenyl)-2-furyl, 4-ethoxycarbonyl-5- methyl-2-furyl, 5-(2-trifluoromethoxyphenyl}-2-furyl, 5-(4-methoxy-2-nitrophenyt)-2-furyl, 4-bromo-2- furyl, 5-dimethylamino-2-furyl, 5-bromo-2-furyl, 5-sulpho-2-furyl, 2-benzofuryl, 2-thienyl, 3-thienyi, 3- . methyl-2-thienyl, 4-bromo-2-thienyl, 5-bromo-2-thienyl, 5-nitro-2-thienyl, ~~ 5-methyl-2-thienyl, 5-(4-methoxyphenyl)-2-thienyl, 4-methyl-2-thienyl, 3-phenoxy-2-thienyl, 5-carboxy-2-thienyl, 2,5- . dichloro-3-thienyt, 3-methoxy-2-thienyl, 2-benzothienyl, 3-methyl-2-benzothienyl, 2-bromo-5-chloro-3- benzothienyl, 2-thiazolyl, 2-amino-4-chloro-5-thiazolyl, 2,4-dichloro-5-thiazolyl, 2-diethylamino-5- thiazolyl, 3-methyl-4-nitro-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 6-methyl-2-pyridyl, 3-hydroxy-5- hydroxymethyl-2-methyl-4-pyridyt, 2,6-dichloro-4-pyridyl, 3-chloro-5-trifuoromethyl-2-pyridyl, 4,6- dimethyl-2-pyridyl, 4-(4-chlorophenyl)-3-pyridyl, 2-chloro-5-methoxycarbonyl-6-methyl-4-phenyl-3- pyridyl, 2-chloro-3-pyridyl, 6-(3-trifluoromethylphenoxy)-3-pyridyl, 2-(4-chiorophenoxy)-3-pyridyl, 2,4-
dimethoxy-5-pyrimidine, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 2-chloro-3-quinolinyl, 2-chloro-6- methoxy-3-quinolinyl, 8-hydroxy-2-quinolinyl and 4-isoquinolinyi. . Useful amino protecting groups are in principle any protecting groups used for protecting amino acids in peptide and protein syntheses or for protecting other amines, for example in alkaloid or nucleotide syntheses (on this subject, see, for example, T. W. Greene and P. G. M. Wuts, Protective groups in organic synthesis, 2nd edition, 1991, John Wiley & Sons, Inc., pages 309-385). Examples of useful protecting groups include the C,-alkylcarbonyt (for example acetyl), C,.4-alkoxycarbony! (for example butoxycarbonyl), C,4-alkoxy-C4-alkoxycarbonyl, benzyloxycarbonyl or nitrobenzenesulphenyi radicals.
Preference is given to the acetyl radical.
Useful salts for compounds of the formula 1, depending on the substitution, are in particular all acid addition salts. Particular mention is made of the salts of the customarily used inorganic and organic acids. Useful salts are the water-soluble and water-insoluble acid addition salts with the acids, for example hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyric acid, sulphosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulphonic acid, methanesulphonic acid or 3-hydroxy- 2-naphthoic acid, and, depending on whether the acid is mono- or polybasic and depending on which salt is desired, the acids in the sait preparation are used in an equimolar ratio or a ratio deviating therefrom.
It is known to those skilled in the art that both the compounds according to the invention and their salts, when, for example, they are isolated in crystalline form, may contain different amounts of solvents. The invention therefore also encompasses all solvates and in particular all hydrates of the compounds of the formula 1, and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
There are in principle three chiral centres in the basic skeleton of the compounds of the formula 1. The invention therefore provides all conceivable stereoisomers in any desired mixing ratio to one another, including the pure enantiomers which are provided with preference by the invention.
Compounds to be emphasized are those of the formula 1 where : R1 is hydrogen, C,4-alkyl, Cs.;-cycloalkyl, C,4-alkoxy-C,4-alkyl, C,4-alkynyl or fluoro-C,4-alkyt,
R2 is hydrogen, C,4-alkyl, halogen, C,4-alkenyl, C,4-alkynyl or fluoro-C,4-alkyl, ) R3a is hydrogen,
R3b is hydrogen, halogen, C,.s-alkyl or the -CO-NR31R32 radical, where
R31 is hydrogen, C,;-alkyl, hydroxy-C4-alkyl or C,4-alkoxy-C,4-alkyl and
R32 is hydrogen, C,_;-alkyl, hydroxy-C4-alkyl or Cy 4-alkoxy-C4-alkyl, or where
R31 and R32 together, including the nitrogen atom to which they are both bonded, are a pyrrolidino, piperidino or morpholino radical,
R4a is hydrogen or R41-O, Rba is hydrogen, and R4b and R5b together are a bond, where - R41 is a suitable oxygen protecting group, or where : R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen,
Arom is a mono- or bicyclic aromatic radical which is substituted by R6, R7, R8 and RS and is selected from the group consisting of phenyl, furanyl (furyl) and thiophenyl (thienyl), where
R6 is hydrogen, C,4-alkyl, hydroxy-C,.4-alkyl, Cy4-alkoxy, Ci4-alkylcarbonyl, carboxyl, Cq4-alkoxy- carbonyl, halogen, hydroxyl, trifluoromethyl, Ci4-alkylcarbonylamino, C4-alkoxycarbonyl- amino, C,.4-alkoxy-C, s-alkoxycarbonylamino or sulphonyil,
R7 is hydrogen, C,4-alkyl, C44-alkoxy, C,4-alkoxycarbonyl, halogen, trifluoromethyl or hydroxyl,
R8 is hydrogen and
R9 is hydrogen,
Prot is an amino protecting group, and their salts.
Among the compounds according to the invention, emphasis is given to the optically pure compounds of the formula 1*
R3a Ro ess ~~
R4b = N
R5a N-Prot (19)
R5b “,
H Arom and their salts.
Particular emphasis is given to compounds of the formula 1* where
R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or trifluoromethyl, ) R2 is hydrogen, methyl, chlorine, bromine, ethynyl or trifluoromethyl,
R3a is hydrogen, ’ R3b is hydrogen, fluorine, methyl or the -CO-N(CHj3), radical,
R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where
R41 is a suitable oxygen protecting group, or where
R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen,
Arom is a phenyl radical and
Prot is an amino protecting group, and their salts. . Preference is given to compounds of the formula 1* where
R1 is methyl, } R2 is methyl,
R3a is hydrogen,
R3b is hydrogen,
R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where
R41 is a suitable oxygen protecting group, or where
R4a is hydroxyl and R5a, R4b and R5b are each hydrogen,
Arom is a phenyl radical and
Prot is an amino protecting group, and their salts.
The compounds of the formula 1 according to the invention where R1, R2, R3a, R3b, Arom and Prot are each as defined above, and R4a is R41-O, R5a is hydrogen and R4b and R5b together are a bond may be prepared from the compounds of the formula 2
R3a R2
R3b. -
R1 0] x =
NH
(2)
Arom by introducing the protecting groups R41 and Prot in a suitable manner. The way in which the protecting groups are introduced depends on their type and is familiar to those skilled in the art on the basis of their knowledge. In a preferred embodiment of the invention, the R41 and Prot groups are identical, so that these groups can be introduced at the same time in one reaction step. When R41 and ] Prot are each an acetyl group, the reaction of compounds of the formula 2 may be carried out, for example, with acetyl chloride, or preferably with acetic anhydride under suitable conditions. ) The compounds of the formula 1 according to the invention where R1, R2, R3a, R3b, Arom and Prot are each as defined above, and R4a is hydroxyl and R5a, R4b and R5b are each hydrogen may be prepared from the compounds of the formula 1 in which R4a is R41-O, R5a is hydrogen, and R4b and
R5b together are a bond, where R41 is a suitable oxygen protecting group, by reduction with a suitable reducing agent. An example of a suitable reducing agent is sodium borohydride.
The compounds of the formula 1 according to the invention where R1, R2, R3a, R3b, Arom and Prot are each as defined above, and R4a and R5a are each hydrogen, and R4b and R5b together are a bond may be prepared from the compounds of the formula 1 in which R4a is hydroxyl, and R5a, R4b . and R5b are each hydrogen, by elimination (dehydration) in a manner known per se, preferably under acid catalysis and/or using a suitable dehydrating agent (see, for example, Patai-Rappaport, The : Chemistry of the Hydroxyl Group, Vol. 2, pp. 641-718, New York, Wiley 1971).
The compounds of the formula 1 accerding to the invention are valuable precursors and intermediates for preparing tetrahydroimidazo[1,2-h][1,7]naphthyridines, as described, for example, in the
International Patent Applications WO 98/42707, WO 00/17200, WO 00/26217, WO 00/63211,
WO 01/72756, WO 01/72754, WO 01/72757 and WO 02/34749. Exemplary conversions of compounds of the formula 1 to the abovementioned tetrahydroimidazo[1,2-h}[1,7]naphthyridines are described in the examples.
The compounds of the formula 2 are known or may be prepared starting from appropriate starting compounds using similar process steps (see, for example, WO 01/72756, scheme 2 where G = hydrogen) as described exemplarily in the examples which follow herein below.
The examples which follow serve to illustrate the invention without limiting it. Equally, further compounds of the formula 1 whose preparation is not explicitly described may be prepared in a similar manner or a manner familiar to those skilled in the art using customary process techniques. The abbreviation min represents minute(s), h represents hour(s) and m.p. represents melting point.
End products of the formula 1 } 1. rac-7-Acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naphthyridine _ 90.0 g (0.31 mol) of rac-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 250 mi of acetic anhydride and admixed with 20 m! of methanesulphonic acid. The mixture is then heated to reflux for 3 h. After cooling, the acetic anhydride is distilled off under reduced pressure and the oily residue is added to 200 ml of water. The pH of the mixture is adjusted to pH 9 by adding concentrated ammonia solution with stirring. After adding 200 ml of water, extraction is effected using methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether, and the precipitate is filtered off with suction and washed with diethyl ether. 85.4 g (74%) of the title compound are isolated as a yellow solid (m.p. 237-239°C). 2. (9S)-7-Acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]naphthyridine 8.7 g (0.03 mol) of (95)-2,3-dimethyi-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7}naphthyridin-7-one are suspended in 49 ml of acetic anhydride, admixed with 2 m! of methanesulphonic acid and heated to reflux. After 30 min, another 2 ml of methanesulphonic acid are added. After 1 h, the reaction mixture is added to 250 mi of ice-water and neutralized by adding concentrated ammonia solution. Extraction is effected using methylene chioride, and the organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether, and the precipitate is filtered off with suction and washed with diethyl ether. 7.2 g (65%) of the title compound are isolated as a yellow solid (m.p. 237-239°C). 3. rel-(7S,9S)-10-Acetyl-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2h][1,7]- naphthyridine (racemic) . 12.2 g (32.5 mmol) of rac-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h][1,7]- naphthyridine are dissolved in 50 mi of methanol and 10 mi of dichloromethane. 5.0 g (132 mmol) of } sodium borohydride are then introduced at 0°C over a period of 2 h. After 3 h, 30 ml of saturated ammonium chloride solution are added. The reaction mixture is extracted using dichloromethane, and the organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether. 8.2 g (75%) of the title compound are isolated as a colorless solid (m.p. 217°C).
4. rac-1 0-Acetyl-2,3-dimethyl-9-phenyi-9,10-dihydroimidazo[1 ,2-h][1,7]naphthyridine (racemic) 60g (17.9 mmol) of rel-(7S,95)-1 0-acetyi-7-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydro- : imidazo[1,2-h]{1,7]naphthyridine (racemic) are dissolved in 100 ml of dichloromethane and 20 ml of triethylamine. A solution of 2.9 g (25 mmol) of methanesulphonyl chloride in 5 ml of dichloromethane is . then added dropwise with ice cooling within 30 min. After 2 h, hydrolysis is effected using water and extraction using dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyl ether. 4.8 g (85%) of the title compound are isolated as a pale brown solid (m.p. 170°C).
Use of compounds of the formula 1 according to the invention for preparing active ingredients having a tetrahydroimidazof1,2-hl[1,7]naphthyridine structure
A. (8R,9R)-1 0-Acetyl-8-hydroxy-2,3-dimethyl-9-phenyl-7,8,9,1 O-tetrahydroimidazo([1,2-h][1,7]- naphthyridin-7-one 20g (5.4 mmol) of (95)-7-acetoxy-10-acetyl-2,3-dimethyl-9-phenyl-9,10-dihydroimidazo[1,2-h]{1,7]- naphthyridine are dissolved in 30 ml of acetone and 6 ml of water. 1.0 g (6.4 mmol) of potassium permanganate is then introduced in portions at 0°C. After 30 min, the brown suspension is admixed with 1 mi of saturated sodium hydrogensulphite solution, filtered through Celite and washed with methanol and dichloromethane. The filtrate is concentrated and the residue crystallized using ethanol. 0.3 g (16%) of the title compound is isolated as a yellow solid (m.p. 192°C).
B. (7R,8R,9R)-10-Acetyl-7,8-dihydroxy-2,3-dimethyl-3-phenyl-7,8,9,10-tetrahydroimidazo(1,2- h][1,7}naphthyridine 0.2 g (0.6 mmol) of (8R.9R)-10-acetyl-8-hydroxy-2,3-dimethyl-9-pheny!-7,8,9,10-tetrahydroimidazo(1 2- h][1,7]naphthyridin-7-one is dissolved in 15 ml of methanol and admixed with 40 mg (1.1 mmol) of sodium borohydride in portions with ice cooling. After 10 min, hydrolysis is effected using saturated sodium hydrogencarbonate solution and extraction using dichloromethane. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized using diethyt ether. 0.16 g (80%) : of the title compound is isolated as a colourless solid (m.p. 260-261°C).
C. (7R,8R,9R)-7,8-Dihydroxy-2,3-dimethyl-3-phenyi-7,8,9,1 0-tetrahydroimidazo[1,2-h}[1,7]}- naphthyridine
The N-acetyl protecting group is detached from the compound (7R.8R,9R)-10-acetyl-7,8-dihydroxy-2,3- dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo(1 ,2-h][1,7]naphthyridine by heating with potassium carbonate in 2-aminoethano! (temp. 70-100°C). After extractive workup and crystallization, the title compound is obtained as a colourless solid of m.p. 206-209°C.
Starting compounds
AA. (95)-2,3-Dimethy!-9-phenyl-5,6,7,8,9,10-hexahydroimidazo[1,2-h][1,7]naphthyridin-7-one 9.7 g (51.6 mmol) of ethyl (S)-3-amino-3-phenylpropionate, 8.5 g (51.6 mmol) of 2,3-dimethyl-6,7- dihydro-5H-imidazo{1,2-a]pyridin-8-one and 0.26 g (1.3 mmol) of p-toluenesulphonic acid monohydrate are heated to reflux in 50 ml of toluene using a water separator. After no more water separates, the reaction mixture is cooled to 0°C and diluted with 100 mi of tetrahydrofuran. 7.24 g (64.5 mmol) of potassium tert-butoxide are then introduced and the mixture is stirred at room temperature for 16 h. 150 m! of saturated ammonium chloride are added to the reaction mixture, the organic phase is removed and the aqueous phase is extracted with 300 ml of ethyl acetate. The combined organic phases are washed with 250 ml of water, dried over sodium sulphate and evaporated. 13.27 g (88%) of the title compound are isolated as a red-brown oil. An analytical sample is obtained by crystallizing with diethyl ether (red solid, m.p. 134°C).
BB. (9S)-2,3-Dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one 63.5 g (0.22 mol) of (95)-2,3-dimethyl-9-phenyl-5,6,7,8,9,10-hexahydroimidazo(1,2-h][1,7]naphthyridin- 7-one are dissolved in 250 ml of toluene and 250 mi of tetrahydrofuran, and cooled to 0°C. 59g (0.26 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are introduced in portions of 10g over a period of 1 h with mechanical stirring. The reaction mixture is stirred at room temperature for 16 h. 1.21 of 0.5N sodium hydroxide solution and 11 of ethyl! acetate are then added dropwise. The organic phase is removed and washed with water. The aqueous phase is reextracted with ethyl acetate, and the combined organic phases are dried over sodium sulphate and evaporated. The residue is crystallized at 0°C in 300 ml of methanol. The solid is filtered off with suction, washed with cold methanol and dried. 20 g (32%) of the title compound are isolated as a pale yellow solid (m.p. 103- 105°C).
Commercial applicability
The compounds of the formula 1 and their salts are valuable intermediates for preparing active . ingredients, as disclosed, for example, in the International Patent Applications WO 98/42707,
WO 00/17200, WO 00/26217, WO 00/63211, WO 01/72756, WO 01/72754, WO 01/72757 and WO i 02/34749.
Claims (5)
1. Compounds of the formula 1 R3a R2
R3b._, a Rda — R1 R4b xy” N R5a N-Prot (1) R5b Arom where R1 is hydrogen, Cis-alkyl, Css-cycloalkyl, Ca 7-cycloaikyl-C44-alkyl, Ciy4-alkoxy, Ci4-alkoxy-Ci4- alkyl, C,.4-alkoxycarbonyl, C,4-alkenyl, C,4-alkynyl, fluoro-C;-alkyl or hydroxy-C4-alkyl, R2 is hydrogen, Ci4-alkyl, Csz-cycloalkyl, Csz-cycloalkyl-Cy4-alkyl, C,4-alkoxycarbonyl, hydroxy- Ci4-alkyl, halogen, C4-alkenyl, C,4-alkynyl, fluoro-C,4-alkyl or cyanomethyl, R3a is hydrogen, halogen, fluoro-C,4-alkyl, C,4-alkyl, Co4-alkenyl, Co4-alkynyl, C,4-alkoxy, carboxyl, Ci4-alkoxycarbonyl, hydroxy-C,.s-alkyl, C,4-alkoxy-Cq4-alkyl, C4-alkoxy-C,.4-alkoxy-C4.4-alkyl, fluoro-C,-alkoxy-Cy4-alkyt or the -CO-NR31R32 radical, R3b is hydrogen, halogen, fluoro-Ci4-alkyl, Ci4-alkyl, Ca4-alkenyl, Co4-alkynyl, C,4-alkoxy, carboxyl, C,4-alkoxycarbonyl, hydroxy-Ci4-alkyl, Ci4-alkoxy-Ci4-alkyl, C4-alkoxy-C,4-alkoxy-C,.4-alkyl, fluoro-C,4-alkoxy-C,4-alkyl or the -CO-NR31R32 radical, where R31 is hydrogen, C,.-alkyl, hydroxy-C,4-alkyl or C;4-alkoxy-C,4-alkyl and R32 is hydrogen, C,.;-alkyl, hydroxy-C4-alkyl or Cy4-alkoxy-C,4-alkyl, or where R31 and R32 together, including the nitrogen atom to which they are both bonded, are a pyrrolidino, piperidino or morpholino radical, Rda is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where R41 is a suitable oxygen protecting group, or where 3 R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen, Arom is a mono- or bicyclic aromatic radical which is substituted by R6, R7, R8 and R9 and is selected ] from the group consisting of phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, indolyt, benzimidazolyl, furanyl (furyl), benzofuranyl (benzofuryl), thiophenyl (thienyl), benzothiophenyi (benzothienyl), thiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, quinoliny! and isoquinolinyl, where R6 is hydrogen, C,s-alkyl, hydroxy-C4-alkyl, Ci4-alkoxy, Ci4-alkenyloxy, C«-alkylcarbonyl, carboxyl, C,.-alkoxycarbonyl, carboxy-Ci4-alkyl, Ci4-alkoxycarbonyl-Cy4-alkyl, halogen, hydroxyl, aryl, aryl-C,4-alkyl, aryloxy, aryl-C,4-alkoxy, trifluoromethyl, nitro, amino, mono- or di-C,4-alkylamino, Ci4-alkylcarbonylamino, Ci4-alkoxycarbonylamino, Ci4-alkoxy-C4- alkoxycarbonylamino or sulphonyl, R7 is hydrogen, C,4-alkyl, Ci4-alkoxy, C,4-alkoxycarbonyl, halogen, trifluoromethyl or hydroxyl, + R8 is hydrogen, Cy4-alkyl or halogen and RS is hydrogen, C,4-alkyl or halogen, . where aryl is phenyl or substituted phenyl having one, two or three identical or different substituents from the group of C,4-alkyl, Cis-alkoxy, carboxyl, Ci4-alkoxycarbonyl, halogen, trifluoromethyl, nitro, trifluoromethoxy, hydroxyl and cyano, Prot is an amino protecting group, and their saits.
2. Compounds of the formula 1 according to Claim 1, where R1 is hydrogen, C,4-alkyl, Csz-cycloalkyl, Cy4-alkoxy-C4-alkyl, Ca4-alkynyl or fluoro-C,4-alkyl, R2 is hydrogen, C,4-alkyl, halogen, C,4-alkenyl, C4-alkynyl or fluoro-C,4-alkyl, R3a is hydrogen, R3b is hydrogen, halogen, Cy4-alkyl or the -CO-NR31R32 radical, where R31 is hydrogen, Cy.7-alkyl, hydroxy-C,4-alkyl or C,_4-alkoxy-C,.4-alkyl and R32 is hydrogen, C,.;-alkyl, hydroxy-C,4-alkyl or Cy_4-alkoxy-C4-alkyl, or where R31 and R32 together, including the nitrogen atom to which they are both bonded, are a pyrrolidino, piperidino or morpholino radical, R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where R41 is a suitable oxygen protecting group, or where R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen, Arom is a mono- or bicyclic aromatic radical which is substituted by R6, R7, R8 and R9 and is selected from the group consisting of phenyl, furany! (furyl) and thiopheny! (thienyl), where R6 is hydrogen, C,4-alkyl, hydroxy-C,4-alkyl, Cy.4-alkoxy, Cy.4-alkylcarbonyl, carboxyl, C4-alkoxy- carbonyl, halogen, hydroxyl, trifluoromethyl, C,4-alkylcarbonylamino, Ci4-alkoxycarbonyl- amino, C,4-alkoxy-C,4-alkoxycarbonylamino or sulphonyt, : R7 is hydrogen, C,4-alkyl, Ci4-alkoxy, C4-alkoxycarbonyl, halogen, trifluoromethyl or hydroxyl, R8 is hydrogen and - R9 is hydrogen, Prot is an amino protecting group, and their salts.
3. Optically pure compounds according to Claim 1, characterized by the formula 1* R3a R2 rn ~ An a Rab—Y N ] R5a N-Prot 1%) R5b , H Arom where R1, R2, R3a, R3b, R4a, R4b, R5a, R5b, Arom and Prot are each as defined in Claim 1, and their salts.
4. Compounds of the formula 1* according to Claim 3, where R1 is hydrogen, methyl, cyclopropyl, methoxymethyl or trifluoromethyl, R2 is hydrogen, methyl, chlorine, bromine, ethynyt or trifluoromethyl, R3a is hydrogen, R3b is hydrogen, fluorine, methyl or the -CO-N(CHj3), radical, R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where R41 is a suitable oxygen protecting group, or where R4a is hydroxyl, and R5a, R4b and R5b are each hydrogen, Arom is a phenyl radical and Prot is an amino protecting group, and their salts.
5. Compounds of the formula 1* according to Claim 3, where R1 is methyl, R2 is methyl, R3a is hydrogen, R3b is hydrogen, R4a is hydrogen or R41-O, R5a is hydrogen, and R4b and R5b together are a bond, where R41 is a suitable oxygen protecting group, ) or where R4a is hydroxyl and R5a, R4b and R5b are each hydrogen, ) Arom is a phenyl radical and Prot is an amino protecting group, and their salts.
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