NO843735L - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-BENZOIC ACID DERIVATIVES - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-BENZOIC ACID DERIVATIVESInfo
- Publication number
- NO843735L NO843735L NO843735A NO843735A NO843735L NO 843735 L NO843735 L NO 843735L NO 843735 A NO843735 A NO 843735A NO 843735 A NO843735 A NO 843735A NO 843735 L NO843735 L NO 843735L
- Authority
- NO
- Norway
- Prior art keywords
- group
- benzoic acid
- carbon atoms
- yield
- melting point
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- 238000000034 method Methods 0.000 title claims description 7
- RWZYAGGXGHYGMB-WGGUOBTBSA-N 2-aminobenzoic acid Chemical class NC1=CC=CC=C1[14C](O)=O RWZYAGGXGHYGMB-WGGUOBTBSA-N 0.000 title claims 4
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 piperazino group Chemical group 0.000 claims description 125
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- 239000005711 Benzoic acid Substances 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 239000012954 diazonium Substances 0.000 claims description 10
- 150000001989 diazonium salts Chemical class 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 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 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 8
- 235000005985 organic acids Nutrition 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 4
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000005059 halophenyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 150000002828 nitro derivatives Chemical class 0.000 claims description 2
- 230000000269 nucleophilic effect Effects 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 claims 1
- 238000002844 melting Methods 0.000 description 160
- 230000008018 melting Effects 0.000 description 160
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 235000010288 sodium nitrite Nutrition 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- AWUSNAPJSJWXMU-UHFFFAOYSA-N 2-(azepan-1-yl)-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCCCCC1 AWUSNAPJSJWXMU-UHFFFAOYSA-N 0.000 description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-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
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- QUEKGYQTRJVEQC-UHFFFAOYSA-N 2516-96-3 Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1Cl QUEKGYQTRJVEQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 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
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- YXBGPWYFIJPTPK-UHFFFAOYSA-N 2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-5-nitrobenzoic acid Chemical compound O1CCOC11CCN(CC1)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] YXBGPWYFIJPTPK-UHFFFAOYSA-N 0.000 description 2
- HNTSIQICPWAIER-UHFFFAOYSA-N 2-(3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinolin-2-yl)-5-nitrobenzoic acid Chemical compound C1N(CCC2CCCCC12)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] HNTSIQICPWAIER-UHFFFAOYSA-N 0.000 description 2
- DADPWHUJQRSREC-UHFFFAOYSA-N 2-(3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl)-5-aminobenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CC2CCCCC2CC1 DADPWHUJQRSREC-UHFFFAOYSA-N 0.000 description 2
- QOJMMCVSGRDNJA-UHFFFAOYSA-N 2-(azepan-1-yl)-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCCCCC1 QOJMMCVSGRDNJA-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- UNZIRKAVOTVSQE-UHFFFAOYSA-N 5-amino-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCC2(OCCO2)CC1 UNZIRKAVOTVSQE-UHFFFAOYSA-N 0.000 description 2
- MFVAUMXIVHUYOK-UHFFFAOYSA-N 5-amino-2-(azepan-1-yl)benzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCCCCC1 MFVAUMXIVHUYOK-UHFFFAOYSA-N 0.000 description 2
- MNKKPODCJXOTFM-UHFFFAOYSA-N 5-chloro-2-(4-methoxypiperidin-1-yl)benzoic acid Chemical compound C1CC(OC)CCN1C1=CC=C(Cl)C=C1C(O)=O MNKKPODCJXOTFM-UHFFFAOYSA-N 0.000 description 2
- HCXWVEFBJYGVAM-UHFFFAOYSA-N 5-chloro-2-morpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCOCC1 HCXWVEFBJYGVAM-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 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
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- ODSNARDHJFFSRH-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCCC2CNCC21 ODSNARDHJFFSRH-UHFFFAOYSA-N 0.000 description 1
- NCSLSNBZPNXIBP-UHFFFAOYSA-N 2-(1,2,4,5,5a,6,7,8,9,9a-decahydrobenzo[d]azepin-3-yl)-5-aminobenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCC2CCCCC2CC1 NCSLSNBZPNXIBP-UHFFFAOYSA-N 0.000 description 1
- JZGMTBXIAZMCBM-UHFFFAOYSA-N 2-(1,2,4,5,5a,6,7,8,9,9a-decahydrobenzo[d]azepin-3-yl)-5-bromobenzoic acid Chemical compound OC(=O)C1=CC(Br)=CC=C1N1CCC2CCCCC2CC1 JZGMTBXIAZMCBM-UHFFFAOYSA-N 0.000 description 1
- DRNZCKFDAGHCGO-UHFFFAOYSA-N 2-(1,2,4,5,5a,6,7,8,9,9a-decahydrobenzo[d]azepin-3-yl)-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCC2CCCCC2CC1 DRNZCKFDAGHCGO-UHFFFAOYSA-N 0.000 description 1
- XZDVFURWMBCIOX-UHFFFAOYSA-N 2-(1,2,4,5,5a,6,7,8,9,9a-decahydrobenzo[d]azepin-3-yl)-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCC2CCCCC2CC1 XZDVFURWMBCIOX-UHFFFAOYSA-N 0.000 description 1
- BUSXHOIFZKTAFN-UHFFFAOYSA-N 2-(1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl)-5-aminobenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CC2CCCCC2C1 BUSXHOIFZKTAFN-UHFFFAOYSA-N 0.000 description 1
- FZVHZMBTLAIRLJ-UHFFFAOYSA-N 2-(1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl)-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CC2CCCCC2C1 FZVHZMBTLAIRLJ-UHFFFAOYSA-N 0.000 description 1
- NXHPJMQPCZEENH-UHFFFAOYSA-N 2-(1,3,3a,4,5,6,7,7a-octahydroisoindol-2-yl)-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CC2CCCCC2C1 NXHPJMQPCZEENH-UHFFFAOYSA-N 0.000 description 1
- JDWVAQCMYYHYJY-UHFFFAOYSA-N 2-(1,4-dioxa-9-azaspiro[4.6]undecan-9-yl)-5-nitrobenzoic acid Chemical compound O1CCOC11CCN(CCC1)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] JDWVAQCMYYHYJY-UHFFFAOYSA-N 0.000 description 1
- ARCGWSIHHQVAJL-UHFFFAOYSA-N 2-(2-methylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound CC1CCCCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O ARCGWSIHHQVAJL-UHFFFAOYSA-N 0.000 description 1
- HCVFLTYSLOFRCI-UHFFFAOYSA-N 2-(3,4,4a,5,6,7,8,8a-octahydro-1h-isoquinolin-2-yl)-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CC2CCCCC2CC1 HCVFLTYSLOFRCI-UHFFFAOYSA-N 0.000 description 1
- AASLSVODTGLLBH-UHFFFAOYSA-N 2-(3,5-dimethylmorpholin-4-yl)-5-nitrobenzoic acid Chemical compound CC1COCC(C)N1C1=CC=C([N+]([O-])=O)C=C1C(O)=O AASLSVODTGLLBH-UHFFFAOYSA-N 0.000 description 1
- RBARJOPUOKMYJM-UHFFFAOYSA-N 2-(3,5-dimethylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1C(C)CC(C)CN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O RBARJOPUOKMYJM-UHFFFAOYSA-N 0.000 description 1
- DIQJRFDFQZDOTB-UHFFFAOYSA-N 2-(3,5-dimethylthiomorpholin-4-yl)-5-nitrobenzoic acid Chemical compound CC1CSCC(C)N1C1=CC=C([N+]([O-])=O)C=C1C(O)=O DIQJRFDFQZDOTB-UHFFFAOYSA-N 0.000 description 1
- IVCXWVWJQYYSHS-UHFFFAOYSA-N 2-(3-azabicyclo[3.2.2]nonan-3-yl)-5-chlorobenzoic acid Chemical compound C12CN(CC(CC1)CC2)C1=C(C(=O)O)C=C(C=C1)Cl IVCXWVWJQYYSHS-UHFFFAOYSA-N 0.000 description 1
- WRLGOKFPAURMRC-UHFFFAOYSA-N 2-(3-azabicyclo[3.2.2]nonan-3-yl)-5-nitrobenzoic acid Chemical compound C12CN(CC(CC1)CC2)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] WRLGOKFPAURMRC-UHFFFAOYSA-N 0.000 description 1
- QOEMYWHGIQIVQX-UHFFFAOYSA-N 2-(3-methylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1C(C)CCCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O QOEMYWHGIQIVQX-UHFFFAOYSA-N 0.000 description 1
- PDGGKKIWCLVVRV-UHFFFAOYSA-N 2-(4-benzylpiperazin-1-yl)-5-nitrobenzoic acid hydrochloride Chemical compound Cl.C(C1=CC=CC=C1)N1CCN(CC1)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] PDGGKKIWCLVVRV-UHFFFAOYSA-N 0.000 description 1
- ZLASGXOTUKQSAT-UHFFFAOYSA-N 2-(4-ethoxycarbonylpiperazin-1-yl)-5-nitrobenzoic acid Chemical compound C1CN(C(=O)OCC)CCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O ZLASGXOTUKQSAT-UHFFFAOYSA-N 0.000 description 1
- ZMRKWYMLWHYGLO-UHFFFAOYSA-N 2-(4-methoxypiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1CC(OC)CCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O ZMRKWYMLWHYGLO-UHFFFAOYSA-N 0.000 description 1
- ISYLQMMLDFSLPI-UHFFFAOYSA-N 2-(4-methylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1CC(C)CCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O ISYLQMMLDFSLPI-UHFFFAOYSA-N 0.000 description 1
- FDCUCRQWRNAOAT-UHFFFAOYSA-N 2-(5-ethyl-2-methylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1C(CC)CCC(C)N1C1=CC=C([N+]([O-])=O)C=C1C(O)=O FDCUCRQWRNAOAT-UHFFFAOYSA-N 0.000 description 1
- XCVVJJCXGYGILD-UHFFFAOYSA-N 2-(azepan-1-yl)-5-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1N1CCCCCC1 XCVVJJCXGYGILD-UHFFFAOYSA-N 0.000 description 1
- KWYLWYSUPXFVJH-UHFFFAOYSA-N 2-(azepan-1-yl)-5-methoxybenzoic acid Chemical compound COc1ccc(N2CCCCCC2)c(c1)C(O)=O KWYLWYSUPXFVJH-UHFFFAOYSA-N 0.000 description 1
- BUJFBAITAVQTIH-UHFFFAOYSA-N 2-(n-methylanilino)-5-nitrobenzoic acid Chemical compound C=1C=C([N+]([O-])=O)C=C(C(O)=O)C=1N(C)C1=CC=CC=C1 BUJFBAITAVQTIH-UHFFFAOYSA-N 0.000 description 1
- RBARJOPUOKMYJM-UWVGGRQHSA-N 2-[(3S,5S)-3,5-dimethylpiperidin-1-yl]-5-nitrobenzoic acid Chemical compound C[C@@H]1CN(C[C@H](C1)C)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] RBARJOPUOKMYJM-UWVGGRQHSA-N 0.000 description 1
- OFWGPDGSUXWDRC-AOOOYVTPSA-N 2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]-5-hydroxybenzoic acid Chemical compound C1[C@@H](C)C[C@@H](C)CN1C1=CC=C(O)C=C1C(O)=O OFWGPDGSUXWDRC-AOOOYVTPSA-N 0.000 description 1
- QOSWBJPYTNETKC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)piperazin-1-yl]-5-nitrobenzoic acid hydrochloride Chemical compound Cl.ClC1=CC=C(C=C1)N1CCN(CC1)C1=C(C(=O)O)C=C(C=C1)[N+](=O)[O-] QOSWBJPYTNETKC-UHFFFAOYSA-N 0.000 description 1
- KPVQAYNICSKZLI-UHFFFAOYSA-N 2-[4-(furan-2-carbonyl)piperazin-1-yl]-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCN(C(=O)C=2OC=CC=2)CC1 KPVQAYNICSKZLI-UHFFFAOYSA-N 0.000 description 1
- SLJIKKRTQUDACV-UHFFFAOYSA-N 2-[benzyl(methyl)amino]-5-chlorobenzoic acid Chemical compound C=1C=C(Cl)C=C(C(O)=O)C=1N(C)CC1=CC=CC=C1 SLJIKKRTQUDACV-UHFFFAOYSA-N 0.000 description 1
- HCZNADAWKQXMGG-UHFFFAOYSA-N 2-[benzyl(methyl)amino]-5-nitrobenzoic acid Chemical compound C=1C=C([N+]([O-])=O)C=C(C(O)=O)C=1N(C)CC1=CC=CC=C1 HCZNADAWKQXMGG-UHFFFAOYSA-N 0.000 description 1
- UMQNWTHSAFNNEA-UHFFFAOYSA-N 2-[butyl(cyclohexyl)amino]-5-chlorobenzoic acid Chemical compound C=1C=C(Cl)C=C(C(O)=O)C=1N(CCCC)C1CCCCC1 UMQNWTHSAFNNEA-UHFFFAOYSA-N 0.000 description 1
- GZSOVFNHSLRROK-UHFFFAOYSA-N 2-[butyl(cyclohexyl)amino]-5-nitrobenzoic acid Chemical compound C=1C=C([N+]([O-])=O)C=C(C(O)=O)C=1N(CCCC)C1CCCCC1 GZSOVFNHSLRROK-UHFFFAOYSA-N 0.000 description 1
- IGMFWKIEEYQDNZ-UHFFFAOYSA-N 2-[cyclohexyl(2-methylpropyl)amino]-5-nitrobenzoic acid Chemical compound C=1C=C([N+]([O-])=O)C=C(C(O)=O)C=1N(CC(C)C)C1CCCCC1 IGMFWKIEEYQDNZ-UHFFFAOYSA-N 0.000 description 1
- JUDOLFBMLDITFB-UHFFFAOYSA-N 2-[cyclohexyl(ethyl)amino]-5-nitrobenzoic acid Chemical compound C=1C=C([N+]([O-])=O)C=C(C(O)=O)C=1N(CC)C1CCCCC1 JUDOLFBMLDITFB-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 description 1
- MRCONLVSTRNJQT-UHFFFAOYSA-N 2-morpholino-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCOCC1 MRCONLVSTRNJQT-UHFFFAOYSA-N 0.000 description 1
- 125000005977 3-phenylpropyloxy group Chemical group 0.000 description 1
- LEJHUEWYEKQILF-UHFFFAOYSA-N 4-chloro-5-nitro-2-piperidin-1-ylbenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(Cl)C=C1N1CCCCC1 LEJHUEWYEKQILF-UHFFFAOYSA-N 0.000 description 1
- MRXKJRLANPTAOR-UHFFFAOYSA-N 5-amino-2-(1,4-dioxa-9-azaspiro[4.6]undecan-9-yl)benzoic acid Chemical compound NC=1C=CC(=C(C(=O)O)C=1)N1CCC2(OCCO2)CCC1 MRXKJRLANPTAOR-UHFFFAOYSA-N 0.000 description 1
- YILAZDUANQYWIV-UHFFFAOYSA-N 5-amino-2-(2-methylpiperidin-1-yl)benzoic acid Chemical compound CC1CCCCN1C1=CC=C(N)C=C1C(O)=O YILAZDUANQYWIV-UHFFFAOYSA-N 0.000 description 1
- YNMNQZPTYJZGID-UHFFFAOYSA-N 5-amino-2-(3,3,5,5-tetramethylpiperidin-1-yl)benzoic acid Chemical compound C1C(C)(C)CC(C)(C)CN1C1=CC=C(N)C=C1C(O)=O YNMNQZPTYJZGID-UHFFFAOYSA-N 0.000 description 1
- TYHRDGSAWMCTJR-UHFFFAOYSA-N 5-amino-2-(3,5-dimethylmorpholin-4-yl)benzoic acid Chemical compound CC1COCC(C)N1C1=CC=C(N)C=C1C(O)=O TYHRDGSAWMCTJR-UHFFFAOYSA-N 0.000 description 1
- MXCSFLXGBVGXGX-UHFFFAOYSA-N 5-amino-2-(3,5-dimethylthiomorpholin-4-yl)benzoic acid Chemical compound CC1CSCC(C)N1C1=CC=C(N)C=C1C(O)=O MXCSFLXGBVGXGX-UHFFFAOYSA-N 0.000 description 1
- NMKAXQCMKPCYAC-UHFFFAOYSA-N 5-amino-2-(3-azabicyclo[3.2.2]nonan-3-yl)benzoic acid Chemical compound NC=1C=CC(=C(C(=O)O)C=1)N1CC2CCC(C1)CC2 NMKAXQCMKPCYAC-UHFFFAOYSA-N 0.000 description 1
- HLHXVRSOPLAEAC-UHFFFAOYSA-N 5-amino-2-(3-methylpiperidin-1-ium-1-yl)benzoate Chemical compound C1C(C)CCCN1C1=CC=C(N)C=C1C(O)=O HLHXVRSOPLAEAC-UHFFFAOYSA-N 0.000 description 1
- WQUUUKBKWCVGSK-UHFFFAOYSA-N 5-amino-2-(4-benzylpiperazin-1-yl)benzoic acid hydrochloride Chemical compound Cl.NC=1C=CC(=C(C(=O)O)C1)N1CCN(CC1)CC1=CC=CC=C1 WQUUUKBKWCVGSK-UHFFFAOYSA-N 0.000 description 1
- FXOZKPCRGKAQAF-UHFFFAOYSA-N 5-amino-2-(4-ethoxycarbonylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C(=O)OCC)CCN1C1=CC=C(N)C=C1C(O)=O FXOZKPCRGKAQAF-UHFFFAOYSA-N 0.000 description 1
- MLQUXRUGIUNMMH-UHFFFAOYSA-N 5-amino-2-(4-ethoxycarbonylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C(=O)OCC)CCN1C1=CC=C(N)C=C1C(O)=O MLQUXRUGIUNMMH-UHFFFAOYSA-N 0.000 description 1
- QXZDFBVHQZWOJU-UHFFFAOYSA-N 5-amino-2-(4-methoxypiperidin-1-yl)benzoic acid Chemical compound C1CC(OC)CCN1C1=CC=C(N)C=C1C(O)=O QXZDFBVHQZWOJU-UHFFFAOYSA-N 0.000 description 1
- QECCLZCMMWNHHS-UHFFFAOYSA-N 5-amino-2-(4-methylpiperazin-1-yl)benzoic acid;hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=CC=C(N)C=C1C(O)=O QECCLZCMMWNHHS-UHFFFAOYSA-N 0.000 description 1
- WLIBXILRXKJRAY-UHFFFAOYSA-N 5-amino-2-(4-methylpiperidin-1-ium-1-yl)benzoate Chemical compound C1CC(C)CCN1C1=CC=C(N)C=C1C(O)=O WLIBXILRXKJRAY-UHFFFAOYSA-N 0.000 description 1
- YHQOIAWXAVZVEQ-UHFFFAOYSA-N 5-amino-2-(4-phenylpiperazin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCN(C=2C=CC=CC=2)CC1 YHQOIAWXAVZVEQ-UHFFFAOYSA-N 0.000 description 1
- ZYLJRULCPWPINV-UHFFFAOYSA-N 5-amino-2-(4-phenylpiperidin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCC(C=2C=CC=CC=2)CC1 ZYLJRULCPWPINV-UHFFFAOYSA-N 0.000 description 1
- LMYWMYGRWGMFEA-UHFFFAOYSA-N 5-amino-2-(4-propan-2-ylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C(C)C)CCN1C1=CC=C(N)C=C1C(O)=O LMYWMYGRWGMFEA-UHFFFAOYSA-N 0.000 description 1
- UZISGXPDDOVJGK-UHFFFAOYSA-N 5-amino-2-(5-ethyl-2-methylpiperidin-1-yl)benzoic acid Chemical compound C1C(CC)CCC(C)N1C1=CC=C(N)C=C1C(O)=O UZISGXPDDOVJGK-UHFFFAOYSA-N 0.000 description 1
- QSXVNKWWRYKSDG-UHFFFAOYSA-N 5-amino-2-(n-methylanilino)benzoic acid Chemical compound C=1C=C(N)C=C(C(O)=O)C=1N(C)C1=CC=CC=C1 QSXVNKWWRYKSDG-UHFFFAOYSA-N 0.000 description 1
- PEPUMPQTKIHPMR-AOOOYVTPSA-N 5-amino-2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]benzoic acid Chemical compound C1[C@@H](C)C[C@@H](C)CN1C1=CC=C(N)C=C1C(O)=O PEPUMPQTKIHPMR-AOOOYVTPSA-N 0.000 description 1
- PEPUMPQTKIHPMR-UWVGGRQHSA-N 5-amino-2-[(3s,5s)-3,5-dimethylpiperidin-1-yl]benzoic acid Chemical compound C1[C@@H](C)C[C@H](C)CN1C1=CC=C(N)C=C1C(O)=O PEPUMPQTKIHPMR-UWVGGRQHSA-N 0.000 description 1
- QMZTYNRPSCTBLK-UHFFFAOYSA-N 5-amino-2-[4-(4-chlorophenyl)piperazin-1-yl]benzoic acid hydrochloride Chemical compound Cl.NC=1C=CC(=C(C(=O)O)C1)N1CCN(CC1)C1=CC=C(C=C1)Cl QMZTYNRPSCTBLK-UHFFFAOYSA-N 0.000 description 1
- UXCYIXFTBMSQHX-UHFFFAOYSA-N 5-amino-2-[4-(furan-2-carbonyl)piperazin-1-yl]benzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCN(C(=O)C=2OC=CC=2)CC1 UXCYIXFTBMSQHX-UHFFFAOYSA-N 0.000 description 1
- KSYAFXYGXVBRIG-UHFFFAOYSA-N 5-amino-2-[benzyl(methyl)amino]benzoic acid Chemical compound C=1C=C(N)C=C(C(O)=O)C=1N(C)CC1=CC=CC=C1 KSYAFXYGXVBRIG-UHFFFAOYSA-N 0.000 description 1
- AMBYEYBIHLSTKG-UHFFFAOYSA-N 5-amino-2-[butyl(cyclohexyl)amino]benzoic acid Chemical compound C=1C=C(N)C=C(C(O)=O)C=1N(CCCC)C1CCCCC1 AMBYEYBIHLSTKG-UHFFFAOYSA-N 0.000 description 1
- WRBVVDFSVHXIKG-UHFFFAOYSA-N 5-amino-2-[cyclohexyl(2-methylpropyl)amino]benzoic acid Chemical compound C=1C=C(N)C=C(C(O)=O)C=1N(CC(C)C)C1CCCCC1 WRBVVDFSVHXIKG-UHFFFAOYSA-N 0.000 description 1
- YRLMNDKLBAGNJP-UHFFFAOYSA-N 5-amino-2-[cyclohexyl(ethyl)amino]benzoic acid Chemical compound C=1C=C(N)C=C(C(O)=O)C=1N(CC)C1CCCCC1 YRLMNDKLBAGNJP-UHFFFAOYSA-N 0.000 description 1
- XHGJRPHMWRRIDE-UHFFFAOYSA-N 5-amino-2-morpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCOCC1 XHGJRPHMWRRIDE-UHFFFAOYSA-N 0.000 description 1
- TVZSCEWHFAKJOE-UHFFFAOYSA-N 5-amino-2-pyrrolidin-1-ylbenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCCC1 TVZSCEWHFAKJOE-UHFFFAOYSA-N 0.000 description 1
- HTDMMZILJVIOAE-UHFFFAOYSA-N 5-amino-2-thiomorpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC(N)=CC=C1N1CCSCC1 HTDMMZILJVIOAE-UHFFFAOYSA-N 0.000 description 1
- QBZVDIRFIDFVQA-UHFFFAOYSA-N 5-bromo-2-(2-methylpiperidin-1-yl)benzoic acid Chemical compound CC1CCCCN1C1=CC=C(Br)C=C1C(O)=O QBZVDIRFIDFVQA-UHFFFAOYSA-N 0.000 description 1
- JGJCZZGVSPAUQF-UHFFFAOYSA-N 5-bromo-2-(4-methoxypiperidin-1-yl)benzoic acid Chemical compound C1CC(OC)CCN1C1=CC=C(Br)C=C1C(O)=O JGJCZZGVSPAUQF-UHFFFAOYSA-N 0.000 description 1
- SENIBCRWPOSZED-UHFFFAOYSA-N 5-chloro-2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCC2(OCCO2)CC1 SENIBCRWPOSZED-UHFFFAOYSA-N 0.000 description 1
- YICVYUJJEFQXJV-UHFFFAOYSA-N 5-chloro-2-(1,4-dioxa-9-azaspiro[4.6]undecan-9-yl)benzoic acid Chemical compound OC(=O)C1=C(C=CC(Cl)=C1)N1CCCC2(CC1)OCCO2 YICVYUJJEFQXJV-UHFFFAOYSA-N 0.000 description 1
- ZPUQGJHIGUYDTP-UHFFFAOYSA-N 5-chloro-2-(2-methylpiperidin-1-yl)benzoic acid Chemical compound CC1CCCCN1C1=CC=C(Cl)C=C1C(O)=O ZPUQGJHIGUYDTP-UHFFFAOYSA-N 0.000 description 1
- OVZVMGBCOKCLBR-UHFFFAOYSA-N 5-chloro-2-(3,3,5,5-tetramethylpiperidin-1-yl)benzoic acid Chemical compound C1C(C)(C)CC(C)(C)CN1C1=CC=C(Cl)C=C1C(O)=O OVZVMGBCOKCLBR-UHFFFAOYSA-N 0.000 description 1
- YJDAJXYFNXRAFL-UHFFFAOYSA-N 5-chloro-2-(3,5-dimethylmorpholin-4-yl)benzoic acid Chemical compound CC1COCC(C)N1C1=CC=C(Cl)C=C1C(O)=O YJDAJXYFNXRAFL-UHFFFAOYSA-N 0.000 description 1
- GSFBMSHQWXSKGP-UHFFFAOYSA-N 5-chloro-2-(3,5-dimethylthiomorpholin-4-yl)benzoic acid Chemical compound CC1CSCC(C)N1C1=CC=C(Cl)C=C1C(O)=O GSFBMSHQWXSKGP-UHFFFAOYSA-N 0.000 description 1
- VYUIBEZXJBXHKB-UHFFFAOYSA-N 5-chloro-2-(3-methylpiperidin-1-yl)benzoic acid Chemical compound C1C(C)CCCN1C1=CC=C(Cl)C=C1C(O)=O VYUIBEZXJBXHKB-UHFFFAOYSA-N 0.000 description 1
- AVJODSRLMMOBFK-UHFFFAOYSA-N 5-chloro-2-(4-ethoxycarbonylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C(=O)OCC)CCN1C1=CC=C(Cl)C=C1C(O)=O AVJODSRLMMOBFK-UHFFFAOYSA-N 0.000 description 1
- UZVFXYNDMSDNBT-UHFFFAOYSA-N 5-chloro-2-(4-ethoxycarbonylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C(=O)OCC)CCN1C1=CC=C(Cl)C=C1C(O)=O UZVFXYNDMSDNBT-UHFFFAOYSA-N 0.000 description 1
- XINDWSVEMLWQDS-UHFFFAOYSA-N 5-chloro-2-(4-methylpiperazin-1-yl)benzoic acid hydrochloride Chemical compound Cl.ClC=1C=CC(=C(C(=O)O)C1)N1CCN(CC1)C XINDWSVEMLWQDS-UHFFFAOYSA-N 0.000 description 1
- KVGVZWDWWULCOZ-UHFFFAOYSA-N 5-chloro-2-(4-methylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C)CCN1C1=CC=C(Cl)C=C1C(O)=O KVGVZWDWWULCOZ-UHFFFAOYSA-N 0.000 description 1
- BAZIZDFWLLCYMR-UHFFFAOYSA-N 5-chloro-2-(4-phenylpiperazin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCN(C=2C=CC=CC=2)CC1 BAZIZDFWLLCYMR-UHFFFAOYSA-N 0.000 description 1
- OSJSLLRQIYEWKN-UHFFFAOYSA-N 5-chloro-2-(4-phenylpiperidin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCC(C=2C=CC=CC=2)CC1 OSJSLLRQIYEWKN-UHFFFAOYSA-N 0.000 description 1
- KTGQRSBFFISBHO-UHFFFAOYSA-N 5-chloro-2-(4-propan-2-ylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C(C)C)CCN1C1=CC=C(Cl)C=C1C(O)=O KTGQRSBFFISBHO-UHFFFAOYSA-N 0.000 description 1
- BUGQENBPTWBGAJ-UHFFFAOYSA-N 5-chloro-2-(5-ethyl-2-methylpiperidin-1-yl)benzoic acid Chemical compound C1C(CC)CCC(C)N1C1=CC=C(Cl)C=C1C(O)=O BUGQENBPTWBGAJ-UHFFFAOYSA-N 0.000 description 1
- OCHGCLDQVKXWFT-UHFFFAOYSA-N 5-chloro-2-(n-methylanilino)benzoic acid Chemical compound C=1C=C(Cl)C=C(C(O)=O)C=1N(C)C1=CC=CC=C1 OCHGCLDQVKXWFT-UHFFFAOYSA-N 0.000 description 1
- ITNCLVAQRUEBAM-UWVGGRQHSA-N 5-chloro-2-[(3S,5S)-3,5-dimethylpiperidin-1-yl]benzoic acid Chemical compound ClC=1C=CC(=C(C(=O)O)C=1)N1C[C@H](C[C@@H](C1)C)C ITNCLVAQRUEBAM-UWVGGRQHSA-N 0.000 description 1
- ITNCLVAQRUEBAM-AOOOYVTPSA-N 5-chloro-2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]benzoic acid Chemical compound C1[C@@H](C)C[C@@H](C)CN1C1=CC=C(Cl)C=C1C(O)=O ITNCLVAQRUEBAM-AOOOYVTPSA-N 0.000 description 1
- REOJABRWMFBZPQ-UHFFFAOYSA-N 5-chloro-2-[4-(4-chlorophenyl)piperazin-1-yl]benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCN(C=2C=CC(Cl)=CC=2)CC1 REOJABRWMFBZPQ-UHFFFAOYSA-N 0.000 description 1
- DCDJBUPTNBXDFF-UHFFFAOYSA-N 5-chloro-2-[4-(furan-2-carbonyl)piperazin-1-yl]benzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCN(C(=O)C=2OC=CC=2)CC1 DCDJBUPTNBXDFF-UHFFFAOYSA-N 0.000 description 1
- RLUBLRQPRBPJGQ-UHFFFAOYSA-N 5-chloro-2-[cyclohexyl(2-methylpropyl)amino]benzoic acid Chemical compound C=1C=C(Cl)C=C(C(O)=O)C=1N(CC(C)C)C1CCCCC1 RLUBLRQPRBPJGQ-UHFFFAOYSA-N 0.000 description 1
- YPIWHNJUZNQZCD-UHFFFAOYSA-N 5-chloro-2-[cyclohexyl(ethyl)amino]benzoic acid Chemical compound C=1C=C(Cl)C=C(C(O)=O)C=1N(CC)C1CCCCC1 YPIWHNJUZNQZCD-UHFFFAOYSA-N 0.000 description 1
- XRSRSDLVOFVSFT-UHFFFAOYSA-N 5-chloro-2-morpholin-4-ylbenzamide Chemical compound NC(=O)C1=CC(Cl)=CC=C1N1CCOCC1 XRSRSDLVOFVSFT-UHFFFAOYSA-N 0.000 description 1
- LEMIJOINGPOVQV-UHFFFAOYSA-N 5-chloro-2-pyrrolidin-1-ylbenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCCC1 LEMIJOINGPOVQV-UHFFFAOYSA-N 0.000 description 1
- YLTYULRTQLHZNV-UHFFFAOYSA-N 5-chloro-2-thiomorpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC=C1N1CCSCC1 YLTYULRTQLHZNV-UHFFFAOYSA-N 0.000 description 1
- RQRBLTZTXJRFDD-UHFFFAOYSA-N 5-hexoxy-2-piperidin-1-ylbenzoic acid Chemical compound OC(=O)C1=CC(OCCCCCC)=CC=C1N1CCCCC1 RQRBLTZTXJRFDD-UHFFFAOYSA-N 0.000 description 1
- CYPOVTAFMRLRCW-UHFFFAOYSA-N 5-nitro-2,4-di(piperidin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(N2CCCCC2)C=C1N1CCCCC1 CYPOVTAFMRLRCW-UHFFFAOYSA-N 0.000 description 1
- UNEAUOPNMFUVEC-UHFFFAOYSA-N 5-nitro-2-(3,3,5,5-tetramethylpiperidin-1-yl)benzoic acid Chemical compound C1C(C)(C)CC(C)(C)CN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O UNEAUOPNMFUVEC-UHFFFAOYSA-N 0.000 description 1
- PFHJMRRYUIYQTH-UHFFFAOYSA-N 5-nitro-2-(4-phenylpiperazin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCN(C=2C=CC=CC=2)CC1 PFHJMRRYUIYQTH-UHFFFAOYSA-N 0.000 description 1
- TUIBWENOIVPIAT-UHFFFAOYSA-N 5-nitro-2-(4-phenylpiperidin-1-yl)benzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCC(C=2C=CC=CC=2)CC1 TUIBWENOIVPIAT-UHFFFAOYSA-N 0.000 description 1
- CHSOARKRVYSVQB-UHFFFAOYSA-N 5-nitro-2-(4-propan-2-ylpiperidin-1-yl)benzoic acid Chemical compound C1CC(C(C)C)CCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O CHSOARKRVYSVQB-UHFFFAOYSA-N 0.000 description 1
- BFGCALKAENBFBV-UHFFFAOYSA-N 5-nitro-2-thiomorpholin-4-ylbenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=CC=C1N1CCSCC1 BFGCALKAENBFBV-UHFFFAOYSA-N 0.000 description 1
- BJOSCVBMMPNMLK-UHFFFAOYSA-N 5-phenylmethoxy-2-piperidin-1-ylbenzoic acid Chemical compound C=1C=C(N2CCCCC2)C(C(=O)O)=CC=1OCC1=CC=CC=C1 BJOSCVBMMPNMLK-UHFFFAOYSA-N 0.000 description 1
- MTNNQFXOHFKDAR-UHFFFAOYSA-N 6-bromo-6-nitrocyclohexa-2,4-diene-1-carboxylic acid Chemical class OC(=O)C1C=CC=CC1(Br)[N+]([O-])=O MTNNQFXOHFKDAR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 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
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical class NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 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
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-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
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 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
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 description 1
- 229960003178 choline chloride Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 230000003516 hyperlipidaemic effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 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
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/205—Radicals derived from carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
I DE-A1-2.655.144 er beskrevet substituerte nikotinsyre-amider som representerer verdifulle koblingskomponenter. DE-A1-2,655,144 describes substituted nicotinic acid amides which represent valuable coupling components.
Det er nu funnet at de nye 2-amino-benzoesyrederivater med den generelle formel It has now been found that the new 2-amino-benzoic acid derivatives with the general formula
og deres salter med uorganiske eller organiske syrer og også and their salts with inorganic or organic acids and also
baser når W betyr en karboksylgruppe, oppviser verdifulle farmakologiske egenskaper, nemlig en virkning på stoffskiftet, særlig en lipidsenkende virkning. bases when W means a carboxyl group exhibit valuable pharmacological properties, namely an effect on the metabolism, in particular a lipid-lowering effect.
Denne oppfinnelse angår således fremstilling av nye 2-amino-benzoesyrederivater med den generelle formel I og deres salter med uorganiske eller organiske syrer og også baser når W betyr eller inneholder en karboksylgruppe. This invention thus relates to the preparation of new 2-amino-benzoic acid derivatives of the general formula I and their salts with inorganic or organic acids and also bases when W means or contains a carboxyl group.
I den ovenstående generelle formel I betyrIn the above general formula I means
et fluor, klor- eller bromatom, en amino-, cyano- eller hydroksygruppe, en eventuelt med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer, eller en alkoksy- a fluorine, chlorine or bromine atom, an amino, cyano or hydroxy group, an optionally substituted by a phenyl group alkoxy group with 1 to 3 carbon atoms, or an alkoxy-
gruppe med 4 til 6 karbonatomer.group with 4 to 6 carbon atoms.
1*2 og Ry sammen med det mellomliggende nitrogenatom, en N-alkyl-cykloheksylaminogruppe hvor alkyldelen kan inneholde 1*2 and Ry together with the intervening nitrogen atom, an N-alkyl-cyclohexylamino group where the alkyl part may contain
2 til 4 karbonatomer, en N-alkyl-fenylamino- eller N-alkyl-benzylaminogruppe hvor alkyldelen i hvert tilfelle kan inne- 2 to 4 carbon atoms, an N-alkyl-phenylamino- or N-alkyl-benzylamino group where the alkyl part in each case can contain
holde 1 til 3 karbonatomer, en cyklisk alkyleniminogruppe med 6 til 12 karbonatomer, en med en alkylgruppe med 1 til 4 karbonatomer, en alkoksygruppe med 1 til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer eller en fenylgruppe substituert piperidinogruppe, en med to, tre eller fire alkylgrupper med hver 1 til 3 karbonatomer substituert piperidinogruppe, en eventuelt med én eller to alkylgrupper med hver 1 til 3 karbonatomer substituert morfolino- eller tiomorfolinogruppe, en i 4-stilling med en alkylgruppe med 1 containing 1 to 3 carbon atoms, a cyclic alkyleneimino group with 6 to 12 carbon atoms, one with an alkyl group with 1 to 4 carbon atoms, an alkoxy group with 1 to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms or a phenyl group substituted piperidino group, one with two , three or four alkyl groups with each 1 to 3 carbon atoms substituted piperidino group, one optionally with one or two alkyl groups with each 1 to 3 carbon atoms substituted morpholino or thiomorpholino group, one in the 4-position with an alkyl group with 1
til 3 karbonatomer, en alkoksykarbonylgruppe med ialt 2 til 4 karbonatomer, en fenyl-, halogenfenyl-, pyridyl-, benzyl- to 3 carbon atoms, an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, a phenyl-, halophenyl-, pyridyl-, benzyl-
eller furoylgruppe substituert piperazinogruppe, en mettetor furoyl group substituted piperazino group, a saturated
eller delvis umettet azabicykloalkylgruppe med 8 til 10 karbonatomer, en 1,4-dioksa-8-aza-spiroalkangruppe med ialt 6 til 8 karbonatomer, en pyrrolidino- eller tetrahydro-pyridinogruppe, or partially unsaturated azabicycloalkyl group with 8 to 10 carbon atoms, a 1,4-dioxa-8-aza-spiroalkane group with a total of 6 to 8 carbon atoms, a pyrrolidino or tetrahydro-pyridino group,
og and
W en karboksy-, aminokarbonyl-, cyano- eller karbalkoksygruppe med ialt 2 til 4 karbonatomer. W a carboxy-, aminocarbonyl-, cyano- or car- alkoxy group with a total of 2 to 4 carbon atoms.
For de ved definisjonen av restene R^, og R^angitte betydninger kommer således i betrakning for For the meanings given in the definition of the residues R^, and R^ thus come into consideration for
R^betydningen et fluor-, klor- eller bromatom, en amino-, R^meaning a fluorine, chlorine or bromine atom, an amino,
cyano-, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, butoksy-, isobutoksy-, tert.butoksy-, pentoksy-, heksoksy-, benzyloksy-, 1-fenyletoksy-, 2-fenyletoksy-, 1-fenyl-propoksy-eller 3-fenyl-propoksygruppe, og for cyano-, hydroxy-, methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, tert.butoxy-, pentoxy-, hexoxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 1- phenyl-propoxy or 3-phenyl-propoxy group, and for
R2og R^sammen med det mellomliggende nitrogenatom, betydningen en N-metyl-fenylamino-, N-etylfenylamino-, N-metyl-benzylamino-, N-etyl-benzylamino-, N-propyl-benzylamino-, N-etyl-cykloheksylamino-, N-propyl-cykloheksylamino-, N-isopropyl-cykloheksylamino-, N-butyl-cykloheksylamino-, pyrrolidino-, heksametylenimino-, R2 and R^ together with the intervening nitrogen atom, meaning a N-methyl-phenylamino-, N-ethylphenylamino-, N-methyl-benzylamino-, N-ethyl-benzylamino-, N-propyl-benzylamino-, N-ethyl-cyclohexylamino- , N-propyl-cyclohexylamino-, N-isopropyl-cyclohexylamino-, N-butyl-cyclohexylamino-, pyrrolidino-, hexamethyleneimino-,
heptametylenimino-, oktametylenimino-, nonametylenimino-, dekam-etylenimino-, undekametylenimino-, dodekametylenimino-, metyl-piperidino-, ety1-piperidino-, propyl-piperidino-, isopropyl-piperidino-, butyl-piperidino-, isobutyl-piperidino-, tert.-butyl-piperidino-, metoksy-piperidino-, etoksy-piperidino-, propoksy-piperidino-, isopropoksy-piperidino-, metoksykarbonyl-piperidino-, etoksykarbonyl-piperidino-, propoksy-karbonyl-piperidino-, isopropoksykarbony1-piperidino-, dimetyl-piperidino-, trimetyl-piperidino-, tetrametyl-piperidino-, dietyl-piperidino-, dipropy1-piperidino-, tetraetylpiperidino-, metyletyl-piperidino-, etylpropy1-piperidino-, morfolino-, metyl-morfolino-, etyl-morfolino-, propylmorfolino-, dimetyl-morfolino-, dietylmorfolino-, tiomorfolino-, metyltio-morfolino-, propyl-tiomorfolino-, dimetyl-tiomorfolino-, N-metyl-piperazino-, N-ety1-piperazino-, N-propyl-piperazino-, N-metoksykarbonyl-piperazino-, N-etoksykarbony1-piperazino-, N-isopropoksykarbony1-piperazino-, N-fenylpiperazino-, N-fluorfenyl-piperazino-, N-klorfenyl-piperazino-, N-brom-feny1-piperazino-, N-pyridyl-piperazino-, N-benzyl-piperazino-, N-furoyl-piperazino-, oktahydro-isoindol-2-yl-, tetrahydro- heptamethyleneimino-, octamethyleneimino-, nonamethyleneimino-, decamethyleneimino-, undecamethyleneimino-, dodecamethyleneimino-, methyl-piperidino-, ethyl1-piperidino-, propyl-piperidino-, isopropyl-piperidino-, butyl-piperidino-, isobutyl-piperidino-, tert-butyl-piperidino-, methoxy-piperidino-, ethoxy-piperidino-, propoxy-piperidino-, isopropoxy-piperidino-, methoxycarbonyl-piperidino-, ethoxycarbonyl-piperidino-, propoxy-carbonyl-piperidino-, isopropoxycarbonyl-piperidino-, dimethyl-piperidino-, trimethyl-piperidino-, tetramethyl-piperidino-, diethyl-piperidino-, dipropyl-piperidino-, tetraethylpiperidino-, methylethyl-piperidino-, ethylpropyl-piperidino-, morpholino-, methyl-morpholino-, ethyl-morpholino- , propylmorpholino-, dimethyl-morpholino-, diethylmorpholino-, thiomorpholino-, methylthio-morpholino-, propyl-thiomorpholino-, dimethyl-thiomorpholino-, N-methyl-piperazino-, N-ethyl1-piperazino-, N-propyl-piperazino- , N-methoxycarbonyl-piperazino-, N-ethoxycarbonyl-1-piperazino-, N-isopropoxycarbonyl-piperazino-, N-fe nylpiperazino-, N-fluorophenyl-piperazino-, N-chlorophenyl-piperazino-, N-bromo-phenyl-piperazino-, N-pyridyl-piperazino-, N-benzyl-piperazino-, N-furoyl-piperazino-, octahydro-isoindole -2-yl-, tetrahydro-
isokinolin-2-yl-, oktahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl-, tetrahydro-3-benzazepin-3-yl-, dekahydro-3-benzazepin-3-yl-, 3-aza-bicyklo-nonan-3-yl-, 1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]-undekan-8-yl- eller tetrahydro-pyridinogruppe. isoquinolin-2-yl-, octahydro-isoquinolin-2-yl-, decahydro-isoquinolin-2-yl-, tetrahydro-3-benzazepin-3-yl-, decahydro-3-benzazepin-3-yl-, 3-aza -bicyclo-nonan-3-yl-, 1,4-dioxa-8-aza-spiro[4,5]decan-8-yl-, 1,4-dioxa-8-aza-spiro[4,6]- undecan-8-yl or tetrahydro-pyridino group.
Foretrukne forbindelser med den generelle formel I er imidlertid de hvor However, preferred compounds of the general formula I are those where
er et klor- eller bromatom, en hydroksy-, amino-, cyano-eller benzyloksygruppe eller en alkoksygruppe med 1 til 6 is a chlorine or bromine atom, a hydroxy, amino, cyano or benzyloxy group or a 1 to 6 alkoxy group
karbonatomer,carbon atoms,
R2og R^sammen med det mellomliggende nitrogenatom er en N-alkyl-cykloheksylaminogruppe hvor alkyldelen kan inneholde 2 til 4 karbonatomer, en cyklisk alkyleniminogruppe med 6 til 12 karbonatomer, en i 4-stilling med en alkylgruppe med 1 til 4 karbonatomer, en fenyl-, metoksy- eller karbetoksygruppe substituert piperidinogruppe, en i 3- og 5-stilling med hver en metyl- eller etylgruppe disubstituert piperidinogruppe, en i 3- og 5 stilling med ialt 4 metylgrupper substituert piperidinogruppe, en i 4-stilling med en metyl-, benzyl-, fenyl-, klorfenyl-, pyridyl-(2)-, karbetoksy- eller furoyl-(2)-gruppe substituert piperazinogruppe, en eventuelt med én R2 and R^ together with the intervening nitrogen atom is an N-alkyl-cyclohexylamino group where the alkyl part may contain 2 to 4 carbon atoms, a cyclic alkyleneimino group with 6 to 12 carbon atoms, one in the 4-position with an alkyl group with 1 to 4 carbon atoms, a phenyl- , methoxy or carbethoxy group substituted piperidino group, one in the 3- and 5-position with each a methyl or ethyl group disubstituted piperidino group, one in the 3- and 5-position with a total of 4 methyl groups substituted piperidino group, one in the 4-position with a methyl-, benzyl, phenyl, chlorophenyl, pyridyl-(2)-, carbethoxy or furoyl-(2) group substituted piperazino group, an optionally with one
eller to metylgrupper substituert morfolino- eller tiomorfolinogruppe, en pyrrolidino-, tetrahydro-pyridino-, N-metyl-fenylamino-, N-metyl-benzylamino-, 1,4-dioksa-8-aza-spiro-[4,5]dekan-8-yl-, 1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl-, 3-aza-bicyklo-nonan-3-yl-, tetrahydro-benzazepin-3-yl-, dekahydro-benzazepin-3-yl-, tetrahydro-isokinolin-2-yl-, dekahydro-isokinolin-2-yl- eller oktahydro-isoindol-2-yl-gruppe, og or two methyl substituted morpholino or thiomorpholino groups, a pyrrolidino-, tetrahydro-pyridino-, N-methyl-phenylamino-, N-methyl-benzylamino-, 1,4-dioxa-8-aza-spiro-[4,5]decane -8-yl-, 1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl-, 3-aza-bicyclo-nonan-3-yl-, tetrahydro-benzazepin-3-yl- , decahydro-benzazepin-3-yl, tetrahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl or octahydro-isoindol-2-yl group, and
W er en karboksy-, aminokarbonyl- eller cyangruppe,W is a carboxy, aminocarbonyl or cyano group,
og salter derav.and salts thereof.
Ifølge oppfinnelsen fremstilles de nye forbindelser som følger: a) For fremstilling av forbindelser med den generelle formel I hvor R^betyr en aminogruppe: Reduksjon av en nitroforbindelse med den generelle formel II According to the invention, the new compounds are prepared as follows: a) For the preparation of compounds of the general formula I where R^ denotes an amino group: Reduction of a nitro compound of the general formula II
hvor / Rj og W er som innledningsvis angitt. where / Rj and W are as indicated at the outset.
Reduksjonen foretas hensiktsmessig i et oppløsningsmiddelThe reduction is conveniently carried out in a solvent
så som metanol/etanol, vann, vann/etanol, dioksan, metanol/ dioksan, etylacetat, dimetylformamid eller dioksan/dimetylformamid med katalytisk aktivert hydrogen, f.eks. med hydrogen i nærvær av en hydrogeneringskatalysator så som palladium/kull, platina eller Raney-nikkel ved et hydrogentrykk på 1 til 10 bar, med nascerende hydrogen, f.eks. med sink/eddiksyre, tinn/saltsyre eller jern/saltsyre, eller med et metallsalt, f.eks. tinn(II)klorid/ saltsyre eller jern(II)sulfat/svovelsyre, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. such as methanol/ethanol, water, water/ethanol, dioxane, methanol/dioxane, ethyl acetate, dimethylformamide or dioxane/dimethylformamide with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal, platinum or Raney nickel at a hydrogen pressure of 1 to 10 bar, with nascent hydrogen, e.g. with zinc/acetic acid, tin/hydrochloric acid or iron/hydrochloric acid, or with a metal salt, e.g. stannous chloride/hydrochloric acid or iron(II)sulphate/sulfuric acid, at temperatures between 0 and 50°C, preferably at room temperature.
b) For fremstilling av forbindelser med den generelleb) For making connections with the general
formel I, hvor R^betyr en hydroksygruppe, en cyangruppe, et formula I, where R₂ means a hydroxy group, a cyano group, et
fluor-, klor- eller bromatom:fluorine, chlorine or bromine atom:
Omsetning av en forbindelse med den generelle formel Ia Reaction of a compound of the general formula Ia
hvor R2f R-j og W er som innledningsvis angitt, med et nitritt og derefter oppvarmning av det således erholdte diazoniumsalt, og eventuelt i nærvær av kobber eller et passende kobber(I)salt. where R2f R-j and W are as indicated at the outset, with a nitrite and then heating of the diazonium salt thus obtained, and optionally in the presence of copper or a suitable copper (I) salt.
Omsetningen utføres hensiktsmessig ved at en forbindelse med den generelle formel Ia i et egnet oppløsningsmiddel, f.eks. i vann/saltsyre, metanol/saltsyre eller dioksan/saltsyre, over-føres med et nitritt, f.eks. natriumnitritt eller en ester av salpetersyrling, til et diazoniumsalt ved lavere temperaturer, f.eks. ved temperaturer mellom -10 og 5°C. The reaction is conveniently carried out by a compound of the general formula Ia in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid or dioxane/hydrochloric acid, transferred with a nitrite, e.g. sodium nitrite or an ester of nitric acid, to a diazonium salt at lower temperatures, e.g. at temperatures between -10 and 5°C.
Det således erholdte tilsvarende diazoniumsalt overføres derefter, f.eks. som fluorborat, som hydrosulfat i svovelsyre, som hydroklorid i nærvær av kobber eller i nærvær av et passende kobber(I)salt så som kobber(I)klorid/saltsyre, kobber(I)bromid/ bromhydrogensyre eller trinatrium-kobber(I)tetracyanid ved pH 7, ved oppvarmning, f.eks. til temperaturer mellom 15 og 90°C, The corresponding diazonium salt thus obtained is then transferred, e.g. as fluoroborate, as hydrosulphate in sulfuric acid, as hydrochloride in the presence of copper or in the presence of a suitable copper(I) salt such as copper(I) chloride/hydrochloric acid, copper(I) bromide/hydrobromic acid or trisodium copper(I) tetracyanide at pH 7, by heating, e.g. to temperatures between 15 and 90°C,
til den tilsvarende forbindelse.to the corresponding connection.
c) For fremstilling av forbindelser med den generelle formel I hvor betyr en eventuelt med en fenylgruppe substituert alkoksygruppe med 1 til 3 karbonatomer eller en alkoksygruppe med 1 til 6 karbonatomer: Alkylering av en hydroksyforbindelse med den generelle formel Ib c) For the preparation of compounds with the general formula I where an optionally substituted by a phenyl group means an alkoxy group with 1 to 3 carbon atoms or an alkoxy group with 1 to 6 carbon atoms: Alkylation of a hydroxy compound with the general formula Ib
hvor R2fR3og W er som innledningsvis angitt, med en forbindelse med den generelle formel where R 2 f R 3 and W are as indicated at the outset, with a compound of the general formula
hvor R^' er en eventuelt med en fenylgruppe substituert alkylgruppe med 1 til 3 karbonatomer eller en alkylgruppe med 4 til 6 karbonatomer, og Z er en nukleofii utgående gruppe eller sammen med det nabostilte H-atom i resten R^' en diazogruppe, og om nødvendig, påfølgende hydrolyse. where R^' is an alkyl group with 1 to 3 carbon atoms optionally substituted with a phenyl group or an alkyl group with 4 to 6 carbon atoms, and Z is a nucleophilic leaving group or together with the adjacent H atom in the residue R^' a diazo group, and if necessary, subsequent hydrolysis.
Som utgående gruppe kan man f.eks. anvende et klor-, brom-eller jodatom eller en sulfonyloksygruppe så som en metan-sulfonyloksy-, p-toluensulfonyloksy- eller metoksysulfonyloksy-gruppe . As an outgoing group, you can e.g. use a chlorine, bromine or iodine atom or a sulfonyloxy group such as a methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group.
Omsetningen foretas hensiktsmessig i et oppløsningsmiddel så som eter, tetrahydrofuran, etanol, aceton, dimetylformamid, eller dimetylsulfoksyd, eventuelt i nærvær av en base så som natriumkarbonat, kaliumkarbonat, bariumhydroksyd, natrium-etylat eller kalium-tert.butylat, med et alkyleringsmiddel så som diazometan, diazoetan, metyljodid, etyljodid, isopropyl-bromid, butylbromid, dimetylsulfat, dietylsulfat eller p-toluen-sulfonsyremetylester, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 15 og 70°C. The reaction is suitably carried out in a solvent such as ether, tetrahydrofuran, ethanol, acetone, dimethylformamide or dimethylsulfoxide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, barium hydroxide, sodium ethylate or potassium tert-butylate, with an alkylating agent such as diazomethane, diazoethane, methyl iodide, ethyl iodide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate or p-toluene sulfonic acid methyl ester, at temperatures between 0 and 100°C, preferably at temperatures between 15 and 70°C.
Hvis W betyr en karboksygruppe, vil denne ved alkyleringen med et diazoalkan eller ved alkyleringen i nærvær av en sterk base samtidig forestres. Den således erholdte ester overføres eventuelt derefter til den tilsvarende karboksylsyre ved hydrolyse i nærvær av en syre eller base. If W means a carboxy group, this will be simultaneously esterified during the alkylation with a diazoalkane or during the alkylation in the presence of a strong base. The ester thus obtained is optionally then transferred to the corresponding carboxylic acid by hydrolysis in the presence of an acid or base.
En fremstilt forbindelse med den generelle formel I hvorA prepared compound of the general formula I wherein
W er en cyano- eller aminokarbonylgruppe, kan derefter overføres ved hydrolyse til en tilsvarende forbindelse med den generelle formel I hvor W betyr en karboksygruppe. W is a cyano or aminocarbonyl group, can then be transferred by hydrolysis to a corresponding compound of the general formula I where W means a carboxy group.
Den påfølgende hydrolyse foretas fortrinnsvis i et med vann blandbart oppløsningsmiddel så som metanol, etanol, dioksan, vann/etanol eller vann/tetrahydrofuran i nærvær av en syre så The subsequent hydrolysis is preferably carried out in a water-miscible solvent such as methanol, ethanol, dioxane, water/ethanol or water/tetrahydrofuran in the presence of an acid such
som saltsyre eller svovelsyre eller en base så som natrium-such as hydrochloric or sulfuric acid or a base such as sodium
eller kaliumhydroksyd ved forhøyet temperatur, f.eks. ved reaksjonsblandingens koketemperatur. or potassium hydroxide at an elevated temperature, e.g. at the boiling temperature of the reaction mixture.
De således oppnådde 2-amino-benzoesyrederivater kan over-føres videre til sine salter med uorganiske eller organiske syrer eller også baser når W betyr en karboksylgruppe. Som syrer kan f.eks. anvendes saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, melkesyre, sitronsyre, vinsyre, ravsyre, maleinsyre eller fumar-syre, og som baser natriumhydroksyd eller kaliumhydroksyd. The 2-amino-benzoic acid derivatives thus obtained can be further transferred to their salts with inorganic or organic acids or also bases when W means a carboxyl group. As acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid are used, and as bases sodium hydroxide or potassium hydroxide.
De som utgangsstoffer anvendte forbindelser med de generelle formler II og III er kjent fra litteraturen, resp. The compounds with the general formulas II and III used as starting materials are known from the literature, resp.
man får dem ved i og for seg kjente fremgangsmåter. Således får man f.eks. en forbindelse med den generelle formel II ved omsetning av et passende 2-klor- eller 2-brom-nitro-benzoesyre-derivat, med et tilsvarende amin. they are obtained by methods known per se. Thus, you get e.g. a compound of the general formula II by reaction of a suitable 2-chloro- or 2-bromo-nitro-benzoic acid derivative, with a corresponding amine.
Som nevnt innledningsvis oppviser de nye forbindelser med den generelle formel I verdifulle farmakologiske egenskaper, særlig lipid-senkende virkning. As mentioned at the outset, the new compounds with the general formula I exhibit valuable pharmacological properties, in particular lipid-lowering action.
Som eksempler ble forbindelseneAs examples were the compounds
A= 5-klor-2-(1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl)benzoe-A= 5-chloro-2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)benzoe-
syre,acid,
B= 2-(dekahydro-3-benzazepino)-5-klor-benzoesyre,B= 2-(decahydro-3-benzazepino)-5-chloro-benzoic acid,
C= 2-(dekahydro-3-benzazepino)-5-brom-benzoesyre,C= 2-(decahydro-3-benzazepino)-5-bromo-benzoic acid,
D= 5-klor-2-(4-metoksy-piperidino)-benzoesyre ogD= 5-chloro-2-(4-methoxy-piperidino)-benzoic acid and
E= 5-metoksy-2-oktametylenimino-benzoesyreE= 5-methoxy-2-octamethyleneimino-benzoic acid
undersøkt med hensyn til biologiske egenskaper som følger:examined for biological properties as follows:
1. Lipidsenkende virkning:1. Lipid-lowering effect:
Litteratur: P.E. Schurr et al. i Atherosclerosis DrugLiterature: P.E. Schurr et al. in Atherosclerosis Drug
Discovery (1976), utgiver: CE. Day; Plenum, New York, side 215. Discovery (1976), Publisher: CE. Day; Plenum, New York, page 215.
Unge hannrotter med en gjennomsnittsvekt på 100 g bleYoung male rats with an average weight of 100 g were
gjort hyperlipemiske ved 4 dagers tilførsel av en diett (bestående av 10% kokosfett, 1,5% sholesterol, 0,5% cholsyre, 0,2% cholinklorid og 15% sukrose). Under bibeholdelse av dietten tilførte man i to påhverandre følgende dager, prøve-forbindelsen i metylce-lulosesuspensjon via svelgsonde. Derefter ble dyrene holdt fastende natten over, og 5 resp. 2 4 timer efter siste administrering av prøveforbindelse ble blodprøve tatt for serumutvinning. rendered hyperlipemic by 4 days of feeding a diet (consisting of 10% coconut fat, 1.5% cholesterol, 0.5% cholic acid, 0.2% choline chloride and 15% sucrose). While maintaining the diet, the test compound in methyl cellulose suspension was administered via throat tube on two consecutive days. The animals were then kept fasting overnight, and 5 resp. 2 4 hours after the last administration of the test compound, a blood sample was taken for serum extraction.
I serumet ble det samlede innhold av cholesterol (Boehringer Mannheim test-kombinasjon 187.313) og triglycerider (Boehringer Mannheim test-kombinasjon 126.039) bestemt enzymatisk. 3-lipoproteinene ble bestemt nefelometrisk efter felling med Ca<++>og heparin i autoanalysator. In the serum, the total content of cholesterol (Boehringer Mannheim test combination 187,313) and triglycerides (Boehringer Mannheim test combination 126,039) was determined enzymatically. The 3-lipoproteins were determined nephelometrically after precipitation with Ca<++> and heparin in an autoanalyzer.
Beregning av den prosentvise senkning ble foretatt motCalculation of the percentage lowering was made against
en kontrollgruppe.a control group.
Den følgende tabell inneholder de fundne verdier:The following table contains the values found:
2. Akutt toksistet 2. Acutely poisoned
Den akutte toksisitet ble bestemt på grupper på 10 mus (5 han- og 5 hun-mus; observasjonstid: 14 dager) efter administrering av en dose på 2000 mg/kg pr. dyr i metylcellulosesuspensjon via svelgsonde. The acute toxicity was determined on groups of 10 mice (5 male and 5 female mice; observation time: 14 days) after administration of a dose of 2000 mg/kg per animals in methylcellulose suspension via pharyngeal tube.
På grunn av sine farmakologiske egenskaper er forbindelsene med den generelle formel I egnet til behandling av hyperlipidemier, særlig av typene Ila, Ilb og IV, og derav betingede arterosklero-tiske forandringer i karsystemet, og kan anvendes for farmasøytiske formål, eventuelt i kombinasjon med andre aktive stoffer, i de vanlige farmasøytiske tilberedninger så som dragéer, tabletter, kapsler, suppositorier, suspensjoner eller oppløsninger, idet enkeltdosen er 5 til 200 mg, fortrinnsvis 5 til 50 mg, og den daglige dose er 10 til 500 mg, fortrinnsvis 15-150 mg. Due to their pharmacological properties, the compounds of the general formula I are suitable for the treatment of hyperlipidaemias, particularly of types Ila, Ilb and IV, and the resulting arteriosclerotic changes in the vascular system, and can be used for pharmaceutical purposes, possibly in combination with other active substances, in the usual pharmaceutical preparations such as dragees, tablets, capsules, suppositories, suspensions or solutions, the single dose being 5 to 200 mg, preferably 5 to 50 mg, and the daily dose being 10 to 500 mg, preferably 15-150 mg.
Fremstilling av utgangsforbindelsene:Preparation of the output compounds:
Eksempel AExample A
2-( dekahydro- isokinolin- 2- yl)- 5- nitro- benzoesyre2-(decahydro-isoquinolin-2-yl)-5-nitro-benzoic acid
I 500 ml etanol oppvarmes 19 g (0,136 mol) dekahydro-isokinolin, 27,3 g (0,136 mol) 2-klor-5-nitro-benzoesyre og 38,6 g kaliumkarbonat under omrøring i 18 timer under tilbake-løpskjøling. Efter avdestillering av etanolen oppløses residuet i 800 ml vann og innstilles på pH 4 ved tilsetning av 2N saltsyre, hvorved produktet utkrystalliserer. In 500 ml of ethanol, 19 g (0.136 mol) of decahydro-isoquinoline, 27.3 g (0.136 mol) of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassium carbonate are heated with stirring for 18 hours under reflux. After distilling off the ethanol, the residue is dissolved in 800 ml of water and adjusted to pH 4 by adding 2N hydrochloric acid, whereby the product crystallizes out.
Utbytte: 38 g (92% av det teoretiske),Yield: 38 g (92% of the theoretical),
Smeltepunkt: 132-134°C (isopropanol).Melting point: 132-134°C (isopropanol).
Beregnet: C 63,14, H 6,62, N 9,20Calculated: C 63.14, H 6.62, N 9.20
Funnet: 63,02 6,48 9,38. Found: 63.02 6.48 9.38.
Eksempel B Example B
2-( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- 8- yl)- 5- nitro- benzoesyre 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decan- 8- yl)- 5- nitro- benzoic acid
20,1 g (0,1 mol) 2-klor-5-nitro-benzoesyre oppvarmes i 200 ml etanol med 42,9 g (0,3 mol) 1,4-dioksa-8-aza-spiro-[4.5]dekan i 8 timer til tilbakeløpstemperatur. Efter avdestillering av oppløsningsmidlet opptas inndampningsresiduet i vann og innstilles på pH 5,2 med 2N saltsyre, hvorved produktet utfelles. Efter ekstraksjon med kloroform og tørring over natriumsulfat utkrystalliserer forbindelsen efter avdestillering av oppløsningsmidlet. 20.1 g (0.1 mol) of 2-chloro-5-nitro-benzoic acid is heated in 200 ml of ethanol with 42.9 g (0.3 mol) of 1,4-dioxa-8-aza-spiro-[4.5] decan for 8 hours to reflux temperature. After distilling off the solvent, the evaporation residue is taken up in water and adjusted to pH 5.2 with 2N hydrochloric acid, whereby the product is precipitated. After extraction with chloroform and drying over sodium sulfate, the compound crystallizes after distilling off the solvent.
Utbytte: 12 g (39% av det teoretiske),Yield: 12 g (39% of the theoretical),
Smeltepunkt: 155°C (etanol).Melting point: 155°C (ethanol).
Beregnet: C 54,54, H 5,23, N 9,09Calculated: C 54.54, H 5.23, N 9.09
Funnet: 54,20 5,13 8,97. Found: 54.20 5.13 8.97.
Analogt med eksemplene A og B ble følgende forbindelser fremstilt: Analogous to examples A and B, the following compounds were prepared:
2-(2-metyl-piperidino)-5-nitro-benzoesyre,2-(2-methyl-piperidino)-5-nitro-benzoic acid,
Utbytte: 99% av det teoretiske, smeltepunkt: 164°C, Yield: 99% of the theoretical, melting point: 164°C,
2-(3-metyl-piperidino)-5-nitro-benzoesyre,2-(3-methyl-piperidino)-5-nitro-benzoic acid,
utbytte: 85% av "det teoretiske, smeltepunkt: 161°C, yield: 85% of "theoretical, melting point: 161°C,
2-(4-mety1-piperidino)-5-nitro-benzoesyre,2-(4-methyl-piperidino)-5-nitro-benzoic acid,
utbytte: 85% av det teoretiske, smeltepunkt: 155°C, yield: 85% of the theoretical, melting point: 155°C,
2-(3-etyl-6-mety1-piperidino)-5-nitro-benzoesyre, utbytte: 76% av det teoretiske, smeltepunkt: <20°C, 2-(3-ethyl-6-methyl-piperidino)-5-nitro-benzoic acid, yield: 76% of theory, melting point: <20°C,
2-(3,5-dimety1-piperidino)-5-nitro-benzoesyre,2-(3,5-dimethyl-piperidino)-5-nitro-benzoic acid,
utbytte: 65% av det teoretiske, smeltepunkt: 172°C, yield: 65% of the theoretical, melting point: 172°C,
2-(4-metoksy-piperidino)-5-nitro-benzoesyre,2-(4-Methoxy-piperidino)-5-nitro-benzoic acid,
utbytte: 68% av det teoretiske, smeltepunkt: 140°C, yield: 68% of the theoretical, melting point: 140°C,
5-nitro-2-(4-fenyl-piperidino)-benzoesyre,5-nitro-2-(4-phenyl-piperidino)-benzoic acid,
utbytte: 88% av det teoretiske, smeltepunkt: 196°C, yield: 88% of the theoretical, melting point: 196°C,
2- (4-etoksykarbonyl'-piperidino)-5-nitro-benzoesyre, utbytte: 82% av det teoretiske, smeltepunkt: 160°C, 2-(4-ethoxycarbonyl'-piperidino)-5-nitro-benzoic acid, yield: 82% of the theoretical, melting point: 160°C,
5-nitro-2-tiomorfolino-benzoesyre,5-nitro-2-thiomorpholino-benzoic acid,
utbytte: 80% av det teoretiske, smeltepunkt: 235°C, yield: 80% of the theoretical, melting point: 235°C,
5-nitro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 68% av det teoretiske, smeltepunkt: 222°C, 5-nitro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 68% of the theoretical, melting point: 222°C,
5-nitro-2-(1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 70% av det teoretiske, smeltepunkt: 195°C, 5-nitro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 70% of the theoretical, melting point: 195°C,
5-nitro-2-(4-fenyl-piperazino)-benzoesyre,5-nitro-2-(4-phenyl-piperazino)-benzoic acid,
utbytte: 88% av det teoretiske, smeltepunkt: 196°C, yield: 88% of the theoretical, melting point: 196°C,
5-nitro-2-(4-pyridyl-(2)-piperazino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 192°C, 5-nitro-2-(4-pyridyl-(2)-piperazino)-benzoic acid, yield: 66% of theory, melting point: 192°C,
2-(trans-3,5-dimetylpiperidino)-5-nitro-benzoesyre, utbytte: 63% av det teoretiske, smeltepunkt: 132°C, 2-(trans-3,5-dimethylpiperidino)-5-nitro-benzoic acid, yield: 63% of theory, melting point: 132°C,
2-(3,3,5,5-tetrametyl-piperidino)-5-nitro-benzoesyre, utbytte: 98% av det teoretiske, smeltepunkt: 138°C, 2-(3,3,5,5-tetramethyl-piperidino)-5-nitro-benzoic acid, yield: 98% of theory, melting point: 138°C,
2-(3,5-dimetyl-morfolino)-5-nitro-benzoesyre,2-(3,5-dimethyl-morpholino)-5-nitro-benzoic acid,
utbytte: 75% av det teoretiske, smeltepunkt: 164°C, yield: 75% of the theoretical, melting point: 164°C,
2-(3,5-dimetyl-tiomorfolino)-5-nitro-benzoesyre, utbytte: 70% av det teoretiske, smeltepunkt: 118°C, 2-(3,5-dimethyl-thiomorpholino)-5-nitro-benzoic acid, yield: 70% of the theoretical, melting point: 118°C,
2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-5-nitro-benzoesyre, utbytte: 72% av det teoretiske, smeltepunkt: 221°C, 2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-5-nitro-benzoic acid, yield: 72% of the theoretical, melting point: 221°C,
5-nitro-2-nonametylenimino-benzoesyre,5-nitro-2-nonamethyleneimino-benzoic acid,
utbytte: 80% av det teoretiske, smeltepunkt: 12 7°C, yield: 80% of the theoretical, melting point: 12 7°C,
5-nitro-2-dekametylenimino-benzoesyre,5-nitro-2-decamethyleneimino-benzoic acid,
utbytte: 92% av det teoretiske, smeltepunkt: 128°C, yield: 92% of the theoretical, melting point: 128°C,
5-nitro-2-undekametylenimino-benzoesyre,5-nitro-2-undecamethyleneimino-benzoic acid,
utbytte: 91% av det teoretiske, smeltepunkt: 120°C, yield: 91% of the theoretical, melting point: 120°C,
5-nitro-2-dodekametylenimino-benzoesyre,5-nitro-2-dodecamethyleneimino-benzoic acid,
utbytte: 95% av det teoretiske, smeltepunkt: 115°C, yield: 95% of the theoretical, melting point: 115°C,
2-(N-metyl-N-fenylamino)-5-nitro-benzoesyre,2-(N-methyl-N-phenylamino)-5-nitro-benzoic acid,
utbytte: 10% av det teoretiske, smeltepunkt: 115°C, yield: 10% of the theoretical, melting point: 115°C,
2-(N-etyl-N-cykloheksylamino)-5-nitro-benzoesyre,2-(N-ethyl-N-cyclohexylamino)-5-nitro-benzoic acid,
utbytte: 78% av det teoretiske, smeltepunkt: 74°C, yield: 78% of the theoretical, melting point: 74°C,
2-(N-butyl-N-cykloheksylamino)-5-nitro-benzoesyre,2-(N-butyl-N-cyclohexylamino)-5-nitro-benzoic acid,
utbytte: 84% av det teoretiske, smeltepunkt: 56°C, yield: 84% of the theoretical, melting point: 56°C,
2- (N-cykloheksyl-N-isobutylamino)-5-nitro-benzoesyre,2-(N-cyclohexyl-N-isobutylamino)-5-nitro-benzoic acid,
utbytte: 63% av det teoretiske, smeltepunkt: < 20°C, yield: 63% of the theoretical, melting point: < 20°C,
2-(dekahydro-3-benzazepin-3-yl)-5-nitro-benzoesyre,2-(decahydro-3-benzazepin-3-yl)-5-nitro-benzoic acid,
utbytte: 98% av det teoretiske, smeltepunkt: < 20°C, yield: 98% of the theoretical, melting point: < 20°C,
2-(oktahydro-isoindol-2-yl)-5-nitro-benzoesyre,2-(octahydro-isoindol-2-yl)-5-nitro-benzoic acid,
utbytte: 80% av det teoretiske, smeltepunkt: 12 8°C, yield: 80% of the theoretical, melting point: 12 8°C,
2-(4-isopropy1-piperidino)-5-nitro-benzoesyre,2-(4-isopropyl-piperidino)-5-nitro-benzoic acid,
utbytte: 79% av det teoretiske, smeltepunkt: 142°C, yield: 79% of the theoretical, melting point: 142°C,
2- (4-tert.buty1-piperidino)-5-nitro-benzoesyre,2-(4-tert.buty1-piperidino)-5-nitro-benzoic acid,
utbytte: 57% av det teoretiske, smeltepunkt: 136°C, yield: 57% of the theoretical, melting point: 136°C,
2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-5-nitro-benzoesyre, utbytte: 75% av det teoretiske, smeltepunkt: 135°C, 2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-5-nitro-benzoic acid, yield: 75% of theory, melting point: 135°C,
2,4-dipiperidino-5-nitro-benzoesyre,2,4-dipiperidino-5-nitro-benzoic acid,
utbytte: 31% av det teoretiske, smeltepunkt: 152°C, yield: 31% of the theoretical, melting point: 152°C,
4- klor-2-piperidino-5-nitro-benzoesyre,4-chloro-2-piperidino-5-nitro-benzoic acid,
utbytte: 18% av det teoretiske, smeltepunkt: 133°C, yield: 18% of the theoretical, melting point: 133°C,
5- nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre,5-nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,
utbytte: 5 8% av det teoretiske, smeltepunkt: 215°C, yield: 5 8% of the theoretical, melting point: 215°C,
2-(N-metyl-N-benzylamino)-5-nitro-benzoesyre,2-(N-methyl-N-benzylamino)-5-nitro-benzoic acid,
utbytte: 93% av det teoretiske, smeltepunkt: 123-126°C, yield: 93% of the theoretical, melting point: 123-126°C,
2- [4-(4-klorfenyl)-piperazino]-5-nitro-benzoesyre-hydroklorid, utbytte: 71,5% av det teoretiske, smeltepunkt: 225-227 C (spaltn.). 2-[4-(4-chlorophenyl)-piperazino]-5-nitro-benzoic acid hydrochloride, yield: 71.5% of the theoretical, melting point: 225-227 C (dec.).
2-(4-karbetoksy-piperazino)-5-nitro-benzoesyre,2-(4-carbethoxy-piperazino)-5-nitro-benzoic acid,
utbytte: 23,1% av det teoretiske, smeltepunkt: 155-156°C, yield: 23.1% of the theoretical, melting point: 155-156°C,
2-[4-(2-furoyl)-piperazino]-5-nitro-benzoesyre,2-[4-(2-furoyl)-piperazino]-5-nitro-benzoic acid,
utbytte: 64,8% av det teoretiske, smeltepunkt: 200-205°C, yield: 64.8% of the theoretical, melting point: 200-205°C,
2-(4-benzyl-piperazino)-5-nitro-benzoesyre-hydroklorid,2-(4-benzyl-piperazino)-5-nitro-benzoic acid hydrochloride,
utbytte: 86,6% av det teoretiske, smeltepunkt: 142-145°C. yield: 86.6% of the theoretical, melting point: 142-145°C.
Eksempel CExample C
2- heksametylenimino- 5- nitro- benzoesyrenitril2- hexamethyleneimino- 5- nitro- benzoic acid nitrile
18,4 g (0,11 mol) 2-klor-5-nitro-benzoesyrenitril oppvarmes i 250 ml etanol med 22,4 g (0,21 mol) heksametylenirain i 4 timer til tilbakeløpstemperatur. Efter avkjøling utfelles det olje-aktige produkt ved tilsetning av 500 ml vann. Felningen opptas i kloroform. Efter tørring med natriumsulfat og avdestillering av kloroformen omkrystalliseres inndampningsresiduet fra etanol. Utbytte: 19,7 g (73% av det teoretiske), 18.4 g (0.11 mol) of 2-chloro-5-nitro-benzoic acid nitrile are heated in 250 ml of ethanol with 22.4 g (0.21 mol) of hexamethylene amine for 4 hours to reflux temperature. After cooling, the oily product is precipitated by adding 500 ml of water. The precipitate is recorded in chloroform. After drying with sodium sulfate and distilling off the chloroform, the evaporation residue is recrystallized from ethanol. Yield: 19.7 g (73% of the theoretical),
Smeltepunkt: 70°C.Melting point: 70°C.
Beregnet: C 63,65, H 6,16, H 17,13Calculated: C 63.65, H 6.16, H 17.13
Funnet: 6 3,80 6,07 17,05. Found: 6 3.80 6.07 17.05.
Fremstilling av forbindelsene med den generelle formel I : Preparation of the compounds of the general formula I:
Eksempel 1Example 1
5- amino- 2-( dekahydro- isokinolin- 2- yl)- benzoesyre5-amino-2-(decahydro-isoquinolin-2-yl)-benzoic acid
I 250 ml dimetylformamid oppløses 36 g (0,118 mol) 2-(dekahydro-isokinolin-2-yl)-5-nitro-benzosyre og hydrogeneres ved et hydrogentrykk på 5 bar med 10%ig palladium-kull som katalysator ved romtemperatur. Efter avsluttet hydrogenopptagelse frafiltreres katalysatoren, oppløsningsmidlet avdestilleres i vakuum, og residuet omkrystalliseres fra etanol. Utbytte: 31,2 g (96% av det teoretiske), In 250 ml of dimethylformamide, 36 g (0.118 mol) of 2-(decahydro-isoquinolin-2-yl)-5-nitro-benzoic acid are dissolved and hydrogenated at a hydrogen pressure of 5 bar with 10% palladium charcoal as catalyst at room temperature. After completion of hydrogen uptake, the catalyst is filtered off, the solvent is distilled off in a vacuum, and the residue is recrystallized from ethanol. Yield: 31.2 g (96% of the theoretical),
Smeltepunkt: 252°C.Melting point: 252°C.
Beregnet: C 70,04, H 8,08, N 10,20Calculated: C 70.04, H 8.08, N 10.20
Funnet: 70,09, 7,85 10,12. Found: 70.09, 7.85 10.12.
Eksempel 2 Example 2
5-amino-2-( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- 8- yl)- benzoesyre5-amino-2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-benzoic acid
12 g (0,039 mol) 2-(1,4-dioksa-8-aza-spiro[4,5]dekan-8-yl)-5-nitro-benzoesyre hydrogeneres i 100 ml dimetylformamid ved et hydrogentrykk på 5 bar ved romtemperatur med 10%ig palladium-kull som katalysator. Efter avsluttet hydrogenopptagelse fra filtreres katalysatoren, oppløsningsmidlet avdestilleres, og residuet omkrystalliseres fra etanol. 12 g (0.039 mol) of 2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-5-nitro-benzoic acid are hydrogenated in 100 ml of dimethylformamide at a hydrogen pressure of 5 bar at room temperature with 10% palladium charcoal as catalyst. After completion of hydrogen absorption from the catalyst, the catalyst is filtered, the solvent is distilled off, and the residue is recrystallized from ethanol.
Utbytte: 9 g (83% av det teoretiske),Yield: 9 g (83% of the theoretical),
Smeltepunkt: 209°C.Melting point: 209°C.
Beregnet: C 60,42, H 6,52, N 10,07Calculated: C 60.42, H 6.52, N 10.07
Funnet: 60,18 6,58 10,12 Found: 60.18 6.58 10.12
Analogt med eksemplene l.og 2 ble følgende forbindelser fremstilt: Analogous to examples 1. and 2, the following compounds were prepared:
5-amino-2-pyrrolidino-benzoesyre,5-amino-2-pyrrolidino-benzoic acid,
utbytte: 79% av det teoretiske, smeltepunkt: 208°C, yield: 79% of the theoretical, melting point: 208°C,
5-amino-2-(2-mety1-piperidino)-benzoesyre,5-amino-2-(2-methyl-piperidino)-benzoic acid,
utbytte: 84% av det teoretiske, smeltepunkt: 240°C, yield: 84% of the theoretical, melting point: 240°C,
5-amino-2-(3-mety1-piperidino)-benzoesyre,5-amino-2-(3-methyl-piperidino)-benzoic acid,
utbytte: 75% av det teoretiske, smeltepunkt: 192°C, yield: 75% of the theoretical, melting point: 192°C,
5-amino-2-(4-metyl-piperidino)-benzoesyre,5-amino-2-(4-methyl-piperidino)-benzoic acid,
utbytte: 88% av det teoretiske, smeltepunkt: 215°C, yield: 88% of the theoretical, melting point: 215°C,
5-amino-2-(3-ety1-6-mety1-piperidino)-benzoesyre,5-amino-2-(3-ethyl-6-methyl-piperidino)-benzoic acid,
utbytte: 59% av det teoretiske, smeltepunkt: 219°C, yield: 59% of the theoretical, melting point: 219°C,
5-amino-2-(cis-3,5-dimety1-piperidino)-benzoesyre,5-amino-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,
utbytte: 87% av det teoretiske, smeltepunkt: 234°C, yield: 87% of the theoretical, melting point: 234°C,
5-amino-2-(4-metoksy-piperidino)-benzoesyre,5-amino-2-(4-methoxy-piperidino)-benzoic acid,
utbytte: 80% av det teoretiske, smeltepunkt: 228°C, yield: 80% of the theoretical, melting point: 228°C,
5-amino-2-heptametylenimino-benzoesyre,5-amino-2-heptamethyleneimino-benzoic acid,
utbytte: 64% av det teoretiske, smeltepunkt: 214°C, yield: 64% of the theoretical, melting point: 214°C,
5-amino-2-(4-fenyl-piperidino)-benzoesyre,5-amino-2-(4-phenyl-piperidino)-benzoic acid,
utbytte: 76% av det teoretiske, smeltepunkt: 275°C, yield: 76% of the theoretical, melting point: 275°C,
5-amino-2-(4-etoksykarbonyl-piperidino)-benzoesyre, utbytte: 85% av det teoretiske, smeltepunkt: 203°C, 5-amino-2-(4-ethoxycarbonyl-piperidino)-benzoic acid, yield: 85% of the theoretical, melting point: 203°C,
5-amino-2-tiomorfolino-benzoesyre,5-amino-2-thiomorpholino-benzoic acid,
utbytte: 76% av det teoretiske, smeltepunkt: 193°C, yield: 76% of the theoretical, melting point: 193°C,
5-amino-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 86% av det teoretiske, smeltepunkt: 258°C, 5-amino-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 86% of the theoretical, melting point: 258°C,
5-amino-2-(1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 220°C, 5-amino-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 66% of the theoretical, melting point: 220°C,
5-amino-2-(4-fenyl-piperazino)-benzoesyre,5-amino-2-(4-phenyl-piperazino)-benzoic acid,
utbytte: 83% av det teoretiske, smeltepunkt: 255°C, yield: 83% of the theoretical, melting point: 255°C,
5-amino-2-(4-pyridy1-(2)-piperazino)-benzoesyre, utbytte: 80% av det teoretiske, smeltepunkt: 248°C, 5-amino-2-(4-pyridy1-(2)-piperazino)-benzoic acid, yield: 80% of theoretical, melting point: 248°C,
5-amino-2-(trans-3,5-dimety1-piperidino)-benzoesyre, utbytte: 89% av det teoretiske, smeltepunkt: 156°C, 5-amino-2-(trans-3,5-dimethyl-piperidino)-benzoic acid, yield: 89% of theory, melting point: 156°C,
5-amino-2-(3,3,5,5-tetrametyl-piperidino)-benzoesyre, utbytte: 9 8% av det teoretiske, smeltepunkt: < 20°C, 5-amino-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid, yield: 9 8% of theory, melting point: < 20°C,
5-amino-2-(3,5-dimety1-morfolino)-benzoesyre, utbytte: 83% av det teoretiske, smeltepunkt: 255°C, 5-amino-2-(3,5-dimethyl-morpholino)-benzoic acid, yield: 83% of the theoretical, melting point: 255°C,
5-amino-2-(3,5-dimety1-tiomorfolino)-benzoesyre, utbytte: 50% av det teoretiske, smeltepunkt: 233°C, 5-amino-2-(3,5-dimethyl-thiomorpholino)-benzoic acid, yield: 50% of the theoretical, melting point: 233°C,
5-amino-2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-benzoesyre, utbytte: 86% av det teoretiske, smeltepunkt: 2 8 8°C, 5-amino-2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-benzoic acid, yield: 86% of the theoretical, melting point: 2 8 8°C,
5-amino-2-oktametylenimino-benzoesyre,5-amino-2-octamethyleneimino-benzoic acid,
utbytte: 88% av det teoretiske, smeltepunkt: 191°C, yield: 88% of the theoretical, melting point: 191°C,
5-amino-2-nonametylenimino-benzoesyre,5-amino-2-nonamethyleneimino-benzoic acid,
utbytte: 80% av det teoretiske, smeltepunkt: 212°C, yield: 80% of the theoretical, melting point: 212°C,
5-amino-2-dekametylenimino-benzoesyre,5-amino-2-decamethyleneimino-benzoic acid,
utbytte: 52% av det teoretiske, smeltepunkt: 202°C, yield: 52% of the theoretical, melting point: 202°C,
5-amino-2-undekametylenimino-benzoesyre,5-amino-2-undecamethyleneimino-benzoic acid,
utbytte: 93% av det teoretiske, smeltepunkt: 242°C, yield: 93% of the theoretical, melting point: 242°C,
5-amino-2-dodekametylenimino-benzoesyre,5-amino-2-dodecamethyleneimino-benzoic acid,
utbytte: 59% av det teoretiske, smeltepunkt: 224°C, yield: 59% of the theoretical, melting point: 224°C,
5-amino-2-(N-metyl-N-fenylamino)-benzoesyre,5-amino-2-(N-methyl-N-phenylamino)-benzoic acid,
utbytte: 47% av det teoretiske, smeltepunkt: 184°C, yield: 47% of the theoretical, melting point: 184°C,
5-amino-2-(N-etyl-N-cykloheksylamino)-benzoesyre, utbytte: 66% av det teoretiske, smeltepunkt: 160°C, 5-amino-2-(N-ethyl-N-cyclohexylamino)-benzoic acid, yield: 66% of the theoretical, melting point: 160°C,
5-amino-2-(N-butyl-N-cykloheksylamino)-benzoesyre, utbytte: 48% av det teoretiske, smeltepunkt: 140 C, 5-amino-2-(N-butyl-N-cyclohexylamino)-benzoic acid, yield: 48% of the theoretical, melting point: 140 C,
5-amino-2-(N-cykloheksyl-N-isobutylamino)-benzoesyre, utbytte: 62% av det teoretiske, smeltepunkt: < 20°C, 5-amino-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid, yield: 62% of the theoretical, melting point: < 20°C,
5-amino-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre, utbytte: 54% av det teoretiske, smeltepunkt: 204°C, 5-amino-2-(decahydro-3-benzazepin-3-yl)-benzoic acid, yield: 54% of theory, melting point: 204°C,
5-amino-2-(oktahydro-isoindol-2-yl)-benzoesyre,5-amino-2-(octahydro-isoindol-2-yl)-benzoic acid,
utbytte: 43% av det teoretiske, smeltepunkt: 228°C, yield: 43% of the theoretical, melting point: 228°C,
5-amino-2-(4-isopropy1-piperidino)-benzoesyre,5-amino-2-(4-isopropyl-piperidino)-benzoic acid,
utbytte: 50% av det teoretiske, smeltepunkt: 231°C, yield: 50% of the theoretical, melting point: 231°C,
5-amino- 2- (4-tert.buty1-piperidino)-benzoesyre,5-amino-2-(4-tert.buty1-piperidino)-benzoic acid,
utbytte: 81% av det teoretiske, smeltepunkt: 276°C, yield: 81% of the theoretical, melting point: 276°C,
5-amino-2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-benzoesyre, utbytte: 49% av det teoretiske, smeltepunkt: 235°C, 5-amino-2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-benzoic acid, yield: 49% of theory, melting point: 235°C,
5-amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre,5-amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,
utbytte: 51% av det teoretiske, smeltepunkt: 232°C, yield: 51% of the theoretical, melting point: 232°C,
5-amino-2-(4-mety1-piperazino)-benzoesyre-hydroklorid,5-amino-2-(4-methyl-piperazino)-benzoic acid hydrochloride,
utbytte: 90% av det teoretiske, smeltepunkt: < 20°C, yield: 90% of the theoretical, melting point: < 20°C,
5-amino-2-(N-metyl-N-benzylamino)-benzoesyre,5-amino-2-(N-methyl-N-benzylamino)-benzoic acid,
utbytte: 95% av det teoretiske, smeltepunkt: < 20°C, yield: 95% of the theoretical, melting point: < 20°C,
5-amino-2-[4-(4-klorfenyl)-piperazino]-benzoesyre-hydroklorid, utbytte: 80,5% av det teoretiske, smeltepunkt: 305°C (spaltn.), 5-amino-2-[4-(4-chlorophenyl)-piperazino]-benzoic acid hydrochloride, yield: 80.5% of the theoretical, melting point: 305°C (dec.),
5-amino-2-(4-karbetoksy-piperazino)-benzoesyre,5-amino-2-(4-carbethoxy-piperazino)-benzoic acid,
utbytte: 87,5% av det teoretiske, smeltepunkt: 195-197°C, yield: 87.5% of the theoretical, melting point: 195-197°C,
5-amino-2-[4-(2-furoyl)-piperazino]-benzoesyre,5-amino-2-[4-(2-furoyl)-piperazino]-benzoic acid,
utbytte: 97% av det teoretiske, smeltepunkt: < 20°C, yield: 97% of the theoretical, melting point: < 20°C,
5-amino-2-(4-benzyl-piperazino)-benzoesyre-hydroklorid,5-amino-2-(4-benzyl-piperazino)-benzoic acid hydrochloride,
utbytte: 80% av det teoretiske, smeltepunkt: 200-210°C.yield: 80% of the theoretical, melting point: 200-210°C.
Eksempel 3Example 3
5- klor- 2-( dekahydro- isokinolin- 2- yl)- benzoesyre5-chloro-2-(decahydro-isoquinolin-2-yl)-benzoic acid
I 55 ml halvkonsentrert saltsyre oppløses 10 g (0,0365 mol) 5-amino-2-(dekahydro-isokinolin-2-yl)-benzoesyre og diazoteres ved 0°C med en oppløsning av 2,7 g (0,039 mol) natriumnitritt i 10 ml vann ved dråpevis tilsetning. Efter avsluttet tilsetning omrøres videre i 15 minutter, og derefter settes diazoniumsaltoppløsningen dråpevis til en suspensjon av 4 g kobberpulver i 40 ml konsentrert saltsyre. Efter omrøring natten over dannes en dypgrønn, homogen oppløsning, som efter fortynning med 100 ml vann ekstraheres uttømmende med kloroform. Efter tørring over natriumsulfat renses residuet efter kloroform-avdampningen kromatografisk over en silikagelkolonne med en In 55 ml of semi-concentrated hydrochloric acid, 10 g (0.0365 mol) of 5-amino-2-(decahydro-isoquinolin-2-yl)-benzoic acid are dissolved and diazotized at 0°C with a solution of 2.7 g (0.039 mol) of sodium nitrite in 10 ml of water by dropwise addition. After the addition has been completed, stirring continues for 15 minutes, and then the diazonium salt solution is added dropwise to a suspension of 4 g of copper powder in 40 ml of concentrated hydrochloric acid. After stirring overnight, a deep green, homogeneous solution is formed, which after dilution with 100 ml of water is extracted exhaustively with chloroform. After drying over sodium sulfate, the residue after the chloroform evaporation is purified chromatographically over a silica gel column with a
blanding av eddiksyreetylester/metanol = 9,5 : 0,5.mixture of acetic acid ethyl ester/methanol = 9.5 : 0.5.
Utbytte: 4,8 g (45% av det teoretiske),Yield: 4.8 g (45% of the theoretical),
Smeltepunkt: 138°C.Melting point: 138°C.
Beregnet: C 65,41, H 6,85, N 4,76, Cl 12,06 Calculated: C 65.41, H 6.85, N 4.76, Cl 12.06
Funnet: 65,51 7,07 4,89 12,32 Found: 65.51 7.07 4.89 12.32
E ksempel 4 Example 4
5- klor- 2- ( 1, 4- dioksa- 8- aza- spiro[ 4, 5] dekan- 8- yl)- benzoesyre5- chloro- 2-( 1, 4- dioxa- 8- aza- spiro[ 4, 5] decan- 8- yl)- benzoic acid
8,5 g (0,031 mol) 5-amino-2-(1,4-dioksa-8-aza-spiro[4,5]-dekan-8-yl)-benzoesyre oppløses i 28 ml halvkonsentrert saltsyre og diazoteres ved 0°C med en oppløsning av 2,4 g (0,034 mol) natriumnitritt i 10 ml vann. Diazoniumsaltoppløsningen settes under omrøring dråpevis til en suspensjon av 3 g kobberpulver i 3 ml konsentrert saltsyre. Efter avsluttet nitrogenutvikling omrøres videre i 2 timer, reaksjonsblandingen fortynnes med vann og utristes med kloroform. Efter tørring over natriumsulfat avdestilleres oppløsningsmidlet. Ved oppslutning av inndampningsresiduet med petroleter får man 6,1 g (66% utbytte). 8.5 g (0.031 mol) of 5-amino-2-(1,4-dioxa-8-aza-spiro[4,5]-decan-8-yl)-benzoic acid are dissolved in 28 ml of semi-concentrated hydrochloric acid and diazotized at 0 °C with a solution of 2.4 g (0.034 mol) of sodium nitrite in 10 ml of water. The diazonium salt solution is added dropwise with stirring to a suspension of 3 g of copper powder in 3 ml of concentrated hydrochloric acid. After completion of nitrogen evolution, stirring continues for 2 hours, the reaction mixture is diluted with water and shaken out with chloroform. After drying over sodium sulphate, the solvent is distilled off. Digesting the evaporation residue with petroleum ether gives 6.1 g (66% yield).
Smeltepunkt: 180°C.Melting point: 180°C.
Beregnet: C 56,47, H 5,42, N 4,71Calculated: C 56.47, H 5.42, N 4.71
Funnet: 56,11 5,37 4,83 Found: 56.11 5.37 4.83
Analogt med eksemplene 3 og 4 ble følgende forbindelser fremstilt: Analogous to examples 3 and 4, the following compounds were prepared:
5-klor-2-pyrrolidino-benzoesyre,5-chloro-2-pyrrolidino-benzoic acid,
utbytte: 30% av det teoretiske, smeltepunkt: 164°C, yield: 30% of the theoretical, melting point: 164°C,
5-klor-2-(2-metyl-piperidino)-benzoesyre,5-chloro-2-(2-methyl-piperidino)-benzoic acid,
utbytte: 74% av det teoretiske, smeltepunkt: 12 4°C, yield: 74% of the theoretical, melting point: 12 4°C,
5-klor-2-(3-mety1-piperidino)-benzoesyre,5-chloro-2-(3-methyl-piperidino)-benzoic acid,
utbytte: 47% av det teoretiske, smeltepunkt: 165°C, yield: 47% of the theoretical, melting point: 165°C,
5-klor-2-(4-mety1-piperidino)-benzoesyre,5-chloro-2-(4-methyl-piperidino)-benzoic acid,
utbytte: 52% av det teoretiske, smeltepunkt: 107°C, yield: 52% of the theoretical, melting point: 107°C,
2-(3-ety1-6-mety1-piperidino)-5-klor-benzoesyre,2-(3-ethyl-6-methyl-piperidino)-5-chloro-benzoic acid,
utbytte: 73% av det teoretiske, smeltepunkt: < 20°C, yield: 73% of the theoretical, melting point: < 20°C,
5-klor-2-(cis-3,5-dimetyl-piperidino)-benzoesyre,5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,
utbytte: 46% av det teoretiske, smeltepunkt: 16 7°C, yield: 46% of the theoretical, melting point: 16 7°C,
5-klor-2-(trans-3,5-dimetyl-piperidino)-benzoesyre,5-chloro-2-(trans-3,5-dimethyl-piperidino)-benzoic acid,
utbytte: 63% av det teoretiske, smeltepunkt: 132°C, yield: 63% of the theoretical, melting point: 132°C,
5-klor-2-(4-metoksy-piperidino)-benzoesyre,5-chloro-2-(4-methoxy-piperidino)-benzoic acid,
utbytte: 63% av det teoretiske, smeltepunkt: 136°C, yield: 63% of the theoretical, melting point: 136°C,
5-klor-2-heptametylenimino-benzoesyre,5-chloro-2-heptamethyleneimino-benzoic acid,
utbytte: 58% av det teoretiske, smeltepunkt: < 20°C, yield: 58% of the theoretical, melting point: < 20°C,
5-klor-2-(4-fenyl-piperidino)-benzoesyre,5-chloro-2-(4-phenyl-piperidino)-benzoic acid,
utbytte: 51% av det teoretiske, smeltepunkt: 217°C, yield: 51% of the theoretical, melting point: 217°C,
5-klor-2-(4-etoksykarbonyl-piperidino)-benzoesyre, utbytte: 97% av det teoretiske, smeltepunkt: < 20°C, 5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid, yield: 97% of theory, melting point: < 20°C,
5-klor-2-heksametylenimino-benzoesyre,5-chloro-2-hexamethyleneimino-benzoic acid,
utbytte: 34% av det teoretiske, smeltepunkt: 113°C, yield: 34% of the theoretical, melting point: 113°C,
5-klor-2-tiomorfolino-benzoesyre,5-chloro-2-thiomorpholino-benzoic acid,
utbytte: 16% av det teoretiske, smeltepunkt: 160°C, yield: 16% of the theoretical, melting point: 160°C,
5-klor-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoesyre, utbytte: 59% av det teoretiske, smeltepunkt: 174°C, 5-chloro-2-(1,2,4,5-tetrahydro-3-benzazepino)-benzoic acid, yield: 59% of theory, melting point: 174°C,
5-klor-2-(1,2,3,4-tetrahydro-isokinolino)-benzoesyre, utbytte: 50% av det teoretiske, smeltepunkt: 182°C, 5-chloro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid, yield: 50% of the theoretical, melting point: 182°C,
5-klor-2- (4-feny1-piperazino)-benzoesyre,5-chloro-2-(4-phenyl-piperazino)-benzoic acid,
utbytte: 42% av det teoretiske, smeltepunkt: 154°C, yield: 42% of the theoretical, melting point: 154°C,
5-klor-2-(4-pyridyl-(2)-piperazino)-benzoesyre, utbytte: 45% av det teoretiske, smeltepunkt: 168°C, 5-chloro-2-(4-pyridyl-(2)-piperazino)-benzoic acid, yield: 45% of theory, melting point: 168°C,
5-brom-2-(2-metyl-piperidino)-benzoesyre,5-bromo-2-(2-methyl-piperidino)-benzoic acid,
utbytte: 31% av det teoretiske, smeltepunkt: 168°C, yield: 31% of the theoretical, melting point: 168°C,
5-klor-2-(3,3,5,5-tetramety1-piperidino)-benzoesyre, utbytte: 62% av det teoretiske, smeltepunkt: < 20°C, 5-chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid, yield: 62% of theory, melting point: < 20°C,
5-brom-2-(4-metoksy-piperidino)-benzoesyre,5-bromo-2-(4-methoxy-piperidino)-benzoic acid,
utbytte: 48% av det teoretiske, smeltepunkt: 138°C, yield: 48% of the theoretical, melting point: 138°C,
5-klor-2-(3,5-dimetylmorfolino)-benzoesyre,5-chloro-2-(3,5-dimethylmorpholino)-benzoic acid,
utbytte: 50% av det teoretiske, smeltepunkt: 174°C, yield: 50% of the theoretical, melting point: 174°C,
5-klor-2-(3,5-dimety1-tiomorfolino)-benzoesyre, utbytte: 18% av det teoretiske, smeltepunkt: 134°C, 5-chloro-2-(3,5-dimethyl-thiomorpholino)-benzoic acid, yield: 18% of the theoretical, melting point: 134°C,
5-brom-2-heptametylenimino-benzoesyre,5-bromo-2-heptamethyleneimino-benzoic acid,
utbytte: 15% av det teoretiske, smeltepunkt: 104°C, yield: 15% of the theoretical, melting point: 104°C,
5-klor-2-(3-aza-bicyklo[3,2,2]nonan-3-yl)-benzoesyre, utbytte: 16% av det teoretiske, smeltepunkt: 199°C, 5-chloro-2-(3-aza-bicyclo[3,2,2]nonan-3-yl)-benzoic acid, yield: 16% of the theoretical, melting point: 199°C,
5-klor-2-oktametylenimino-benzoesyre,5-chloro-2-octamethyleneimino-benzoic acid,
utbytte: 70% av det teoretiske, smeltepunkt: 84°C, yield: 70% of the theoretical, melting point: 84°C,
5-klor-2-nonametylenimino-benzoesyre,5-chloro-2-nonamethyleneimino-benzoic acid,
utbytte: 30% av det teoretiske, smeltepunkt: 78°C, yield: 30% of the theoretical, melting point: 78°C,
5-klor-2-dekametylenimino-benzoesyre,5-chloro-2-decamethyleneimino-benzoic acid,
utbytte: 65% av det teoretiske, smeltepunkt: 70°C, yield: 65% of the theoretical, melting point: 70°C,
5-klor-2-undekametylenimino-benzoesyre,5-chloro-2-undecamethyleneimino-benzoic acid,
utbytte: 41% av det teoretiske, smeltepunkt: 41°C, yield: 41% of the theoretical, melting point: 41°C,
5-klor-2-dodekametylenimino-benzoesyre,5-chloro-2-dodecamethyleneimino-benzoic acid,
utbytte: 36% av det teoretiske, smeltepunkt: 40°C, yield: 36% of the theoretical, melting point: 40°C,
5-klor-2-(N-feny1-N-metylamino)-benzoesyre,5-chloro-2-(N-phenyl-N-methylamino)-benzoic acid,
utbytte: 27% av det teoretiske, smeltepunkt: 164°C, yield: 27% of the theoretical, melting point: 164°C,
2-(N-etyl-N-cykloheksylamino)-5-klor-benzoesyre,2-(N-ethyl-N-cyclohexylamino)-5-chloro-benzoic acid,
utbytte: 24% av det teoretiske, smeltepunkt: 152°C, yield: 24% of the theoretical, melting point: 152°C,
2-(N-butyl-N-cykloheksylamino)-5-klor-benzoesyre,2-(N-butyl-N-cyclohexylamino)-5-chloro-benzoic acid,
utbytte: 16% av det teoretiske, smeltepunkt: 145°C, yield: 16% of the theoretical, melting point: 145°C,
5-klor-2-(N-cykloheksyl-N-isobutylamino)-benzoesyre,5-chloro-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid,
utbytte: 22% av det teoretiske, smeltepunkt: 131°C, yield: 22% of the theoretical, melting point: 131°C,
5-klor-2-(dekahydro-3-benzazepin-3-y1)-benzoesyre,5-chloro-2-(decahydro-3-benzazepin-3-yl)-benzoic acid,
utbytte: 70% av det teoretiske, smeltepunkt: 153°C, yield: 70% of the theoretical, melting point: 153°C,
5-brom-2-(dekahydro-3-benzazepin-3-yl)-benzoesyre,5-bromo-2-(decahydro-3-benzazepin-3-yl)-benzoic acid,
utbytte: 54% av det teoretiske, smeltepunkt: 154°C, yield: 54% of the theoretical, melting point: 154°C,
5-klor-2-(oktahydro-isoindol-2-yl)-benzoesyre,5-chloro-2-(octahydro-isoindol-2-yl)-benzoic acid,
utbytte: 33% av det teoretiske, smeltepunkt: 164°C, yield: 33% of the theoretical, melting point: 164°C,
5-brom-2-oktametylenimino-benzoesyre,5-bromo-2-octamethyleneimino-benzoic acid,
utbytte: 48% av det teoretiske, smeltepunkt: 94°C, yield: 48% of the theoretical, melting point: 94°C,
5-klor-2- (4-isopropy1-piperidino)-benzoesyre,5-chloro-2-(4-isopropyl-piperidino)-benzoic acid,
utbytte: 43% av det teoretiske, smeltepunkt: 172 C, yield: 43% of the theoretical, melting point: 172 C,
5-klor-2-(4-tert.butyl-piperidino)-benzoesyre,5-chloro-2-(4-tert.butyl-piperidino)-benzoic acid,
utbytte: 35% av det teoretiske, smeltepunkt: 161°C, yield: 35% of the theoretical, melting point: 161°C,
5-klor-2-(1,4-dioksa-8-aza-spiro[4,6]undekan-8-yl)-benzoesyre, utbytte: 42% av det teoretiske, smeltepunkt: 16 3°C, 5-chloro-2-(1,4-dioxa-8-aza-spiro[4,6]undecan-8-yl)-benzoic acid, yield: 42% of theory, melting point: 16 3°C,
5-klor-2-(1,2,3,6-tetrahydro-pyridino)-benzoesyre,5-chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid,
utbytte: 73% av det teoretiske, smeltepunkt: 173 C, yield: 73% of the theoretical, melting point: 173 C,
5-klor-2-(4-mety1-piperazino)-benzoesyre-hydroklorid,5-chloro-2-(4-methyl-piperazino)-benzoic acid hydrochloride,
utbytte: 75% av det teoretiske, smeltepunkt: 132°C (spaltn.), yield: 75% of the theoretical, melting point: 132°C (dec.),
5-klor-2-(N-metyl-N-benzylamino)-benzoesyre,5-chloro-2-(N-methyl-N-benzylamino)-benzoic acid,
utbytte: 18,2% av det teoretiske, smeltepunkt: 156-157°C, yield: 18.2% of the theoretical, melting point: 156-157°C,
5-klor-2-[4-(4-klorfenyl)-piperazino]-benzoesyre,5-chloro-2-[4-(4-chlorophenyl)-piperazino]-benzoic acid,
utbytte: 30,5% av det teoretiske, smeltepunkt: 228-230°C, yield: 30.5% of the theoretical, melting point: 228-230°C,
2-(4-karbetoksy-piperazino)-5-klor-benzoesyre,2-(4-carbethoxy-piperazino)-5-chloro-benzoic acid,
utbytte: 52% av det teoretiske, smeltepunkt: 129-130°C, yield: 52% of the theoretical, melting point: 129-130°C,
5-klor-2-[4-(2-furoyl)-piperazino]-benzoesyre,5-chloro-2-[4-(2-furoyl)-piperazino]-benzoic acid,
utbytte: 33,1% av det teoretiske, smeltepunkt: 200-202°C, yield: 33.1% of the theoretical, melting point: 200-202°C,
2-(4-benzy1-piperazino)-5-klor-benzoesyre-hydroklorid,2-(4-Benzy1-piperazino)-5-chloro-benzoic acid hydrochloride,
utbytte: 42,8% av det teoretiske, smeltepunkt: 230-232°C (spaltn.). yield: 42.8% of the theoretical, melting point: 230-232°C (dec.).
Eksempel 5Example 5
5- amino- 2- heksametylenimino- benzoesyrenitril5- amino- 2- hexamethyleneimino- benzoic acid nitrile
21,4 g (0,087 mol) 2-heksametylenimino-5-nitro-benzoesyrenitril oppløses i 200 ml dioksan og 500 ml metanol og hydrogeneres ved romtemperatur og et hydrogentrykk på 5 bar i nærvær av 10%ig palladium-kull som katalysator. Efter frafiltrering av katalysatoren og avdestillering av oppløsningsmidlet får man 20 g (100% av det teoretiske). 21.4 g (0.087 mol) of 2-hexamethyleneimino-5-nitro-benzoic acid nitrile is dissolved in 200 ml of dioxane and 500 ml of methanol and hydrogenated at room temperature and a hydrogen pressure of 5 bar in the presence of 10% palladium charcoal as a catalyst. After filtering off the catalyst and distilling off the solvent, you get 20 g (100% of the theoretical).
Smeltepunkt: < 20°C.Melting point: < 20°C.
Eksempel 6Example 6
5- klor- 2- heksametylenimino- benzoesyrenitril5-chloro-2-hexamethyleneimino-benzoic acid nitrile
20 g (0,092 mol) 5-amino-2-heksametylenimino-benzoesyrenitril oppløses i 90 ml halvkonsentrert saltsyre og diazoteres ved 0°C med en oppløsning av 6,5 g (0,09 4 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter avsluttet tilsetning omrøres videre i 15 minutter. Diazoniumsaltoppløsningen settes dråpevis under omrøring til en oppløsning av kobber(I)-klorrd i konsentrert saltsyre, som er oppvarmet til 70°C. Efter avsluttet nitrogenutvikling ekstraheres med kloroform. Efter tørring over natriumsulfat og avdestillering av kloroformen renses inndampningsresiduet kromatografisk over en silikagelkolonne. Som elueringsmiddel anvendes toluen. 20 g (0.092 mol) of 5-amino-2-hexamethyleneimino-benzoic acid nitrile are dissolved in 90 ml of semi-concentrated hydrochloric acid and diazotized at 0°C with a solution of 6.5 g (0.09 4 mol) of sodium nitrite in 30 ml of water by dropwise addition . After the addition is finished, continue stirring for 15 minutes. The diazonium salt solution is added dropwise with stirring to a solution of copper (I) chloride in concentrated hydrochloric acid, which has been heated to 70°C. After completion of nitrogen evolution, extract with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation residue is purified chromatographically over a silica gel column. Toluene is used as an eluent.
Utbytte: 5 g (23% av det teoretiske),Yield: 5 g (23% of the theoretical),
Smeltepunkt: < 20°C.Melting point: < 20°C.
Eksempel 7Example 7
5- klor- 2- heksametylenimino- benzoesyre5- chloro- 2- hexamethyleneimino- benzoic acid
5 g (0,021 mol) 5-klor-2-heksametylenimino-benzoesyrenitril oppvarmes i 32 g kalilut og 20 ml vann i 8 timer til 170°C. Den avkjølte smelte oppløses i vann. Ved surgjøring til pH 5 utfelles amidet kvantitativt og hydrolyseres derefter med halvkonsentrert saltsyre. 5 g (0.021 mol) of 5-chloro-2-hexamethyleneimino-benzoic acid nitrile are heated in 32 g of potassium hydroxide and 20 ml of water for 8 hours at 170°C. The cooled melt is dissolved in water. When acidified to pH 5, the amide precipitates quantitatively and is then hydrolysed with semi-concentrated hydrochloric acid.
Utbytte: 3,6 g (67,4% av det teoretiske),Yield: 3.6 g (67.4% of the theoretical),
Smeltepunkt: 113°C.Melting point: 113°C.
Analogt med eksemplene 5 til 7 ble følgende forbindelser fremstilt: Analogous to examples 5 to 7, the following compounds were prepared:
2-morfolino-5-nitro-benzoesyrenitril,2-morpholino-5-nitro-benzoic acid nitrile,
utbytte: 78% av det teoretiske, smeltepunkt: 138°C, yield: 78% of the theoretical, melting point: 138°C,
5-amino-2-morfolino-benzoesyrenitril,5-amino-2-morpholino-benzoic acid nitrile,
utbytte: 68% av det teoretiske, smeltepunkt: 142°C, yield: 68% of the theoretical, melting point: 142°C,
5-klor-2-morfolino-benzoesyrenitril,5-chloro-2-morpholino-benzoic acid nitrile,
utbytte: 20% av det teoretiske, smeltepunkt: 57°C, yield: 20% of the theoretical, melting point: 57°C,
5-klor-2-morfolino-benzamid,5-chloro-2-morpholino-benzamide,
utbytte: 98% av det teoretiske, smeltepunkt: 280°C, yield: 98% of the theoretical, melting point: 280°C,
5-klor-2-morfolino-benzoesyre,5-chloro-2-morpholino-benzoic acid,
utbytte: 60% av det teoretiske, smeltepunkt: 157°C.yield: 60% of the theoretical, melting point: 157°C.
Eksempel 8Example 8
5- cyano- 2- oktametylenimino- benzoesyre5- cyano- 2- octamethyleneimino- benzoic acid
2 6,2 g (0,1 mol) 5-amino-2-oktametylenimino-benzoesyre oppløses i 38 ml konsentrert saltsyre, fortynnes med 280 ml vann og diazoteres ved 0°C med en oppløsning av 7,6 g 2 Dissolve 6.2 g (0.1 mol) of 5-amino-2-octamethyleneimino-benzoic acid in 38 ml of concentrated hydrochloric acid, dilute with 280 ml of water and diazotize at 0°C with a solution of 7.6 g
(0,11 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter 1/2 times efterrøring innstilles oppløsningen på pH 7 (0.11 mol) of sodium nitrite in 30 ml of water by dropwise addition. After 1/2 hour of stirring, the solution is adjusted to pH 7
med natriumkarbonat. Til diazoniumsaltoppløsningen settes derefter dråpevis en oppløsning av trinatrium-tetracyano-kobber(I)-kompleks ved 0°C. with sodium carbonate. A solution of trisodium-tetracyano-copper(I) complex at 0°C is then added dropwise to the diazonium salt solution.
Denne kobber(I)kompleks-oppløsning fremstilles som følger:This copper (I) complex solution is prepared as follows:
32 g (0,128 mol) kobbersulfat x 5H20 og 8,7 g natriumklorid32 g (0.128 mol) copper sulfate x 5H2O and 8.7 g sodium chloride
i lOO ml vann reduseres med en natriumhydrogensulfittoppløsning bestående av 6,6 g (0,06 35 mol) natriumhydrogensulfitt og 4,4 g natriumhydroksyd i 50 ml vann, til kobber (I)klorid. Det utfelte in lOO ml water is reduced with a sodium hydrogen sulphite solution consisting of 6.6 g (0.06 35 mol) sodium hydrogen sulphite and 4.4 g sodium hydroxide in 50 ml water, to copper (I) chloride. It precipitated
kobber(I)klorid avsuges, suspenderes i 50 ml vann og oppløses i en oppløsning av 17 g (0,346 mol) natriumcyanid i 30 ml vann. Efter avsluttet nitrogenutvikling oppvarmes reaksjonsblandingen 1 1 time til 70°C. Efter avkjøling innstilles pH-verdien på 5,5 med 2N saltsyre, og reaksjonsblandingen ekstraheres med kloroform. Kloroformfåsene tørres over natriumsulfat, og efter avdestillering av kloroformen renses det erholdte råprodukt over en silikagelkolonne med eddiksyreetylester som elueringsmiddel. Utbytte: 9 g (30% av det teoretiske), copper (I) chloride is filtered off, suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water. After completion of nitrogen evolution, the reaction mixture is heated to 70°C for 1 hour. After cooling, the pH value is adjusted to 5.5 with 2N hydrochloric acid, and the reaction mixture is extracted with chloroform. The chloroform phases are dried over sodium sulfate, and after distilling off the chloroform, the crude product obtained is purified over a silica gel column with acetic acid ethyl ester as eluent. Yield: 9 g (30% of the theoretical),
Smeltepunkt: < 20°C.Melting point: < 20°C.
Beregnet: C 70,56, H 7,40, N 10,28Calculated: C 70.56, H 7.40, N 10.28
Funnet: 70,38 7,20 10,10 Found: 70.38 7.20 10.10
Eksempel 9Example 9
2- heptametylenimino- 5- hydroksy- benzoesyre2- heptamethyleneimino- 5- hydroxy-benzoic acid
26,7 g (0,107 mol) 5-amino-2-heptametylenimino-benzoesyre oppløses i 190 ml 3N svovelsyre og diazoteres ved 0°C med en oppløsning av 8,3 g (0,12 mol) natriumnitritt i 30 ml vann ved dråpevis tilsetning. Efter 1/2 times efterrøring tilsettes 2 g finpulverisert urinstoff. Under god omrøring settes diazoniumsaltoppløsningen dråpevis til 320 ml 50%ig svovelsyre oppvarmet til 90°C. Efter avsluttet nitrogenutvikling innstilles pH-verdien ved romtemperatur på 4 med ammoniakk, og reaksjonsblandingen ekstraheres med kloroform. Det tørre residuum som oppnås efter tørring over natriumsulfat og avdestillering av kloroformen, renses over en silikagelkolonne med kloroform som elueringsmiddel. Efter omkrystallisering fra isopropanol får man 8 g (30% av det teoretiske). Smeltepunkt: 199°C. 26.7 g (0.107 mol) of 5-amino-2-heptamethyleneimino-benzoic acid are dissolved in 190 ml of 3N sulfuric acid and diazotized at 0°C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water dropwise addition. After stirring for 1/2 hour, add 2 g of finely powdered urea. With good stirring, the diazonium salt solution is added dropwise to 320 ml of 50% sulfuric acid heated to 90°C. After completion of nitrogen evolution, the pH value at room temperature is adjusted to 4 with ammonia, and the reaction mixture is extracted with chloroform. The dry residue obtained after drying over sodium sulfate and distilling off the chloroform is purified over a silica gel column with chloroform as eluent. After recrystallization from isopropanol, 8 g are obtained (30% of the theoretical). Melting point: 199°C.
Beregnet: C 67,45, H 7,68, N 5,61Calculated: C 67.45, H 7.68, N 5.61
Funnet: 66,87 7,71 5,65 Found: 66.87 7.71 5.65
Analogt med eksempel 9 ble følgende forbindelser fremstilt: Analogous to example 9, the following compounds were prepared:
2-hekametylenimino-5-hydroksy-benzoeysre,2-hexamethyleneimino-5-hydroxybenzoic acid,
utbytte: 24% av det teoretiske, smeltepunkt: 214°C, yield: 24% of the theoretical, melting point: 214°C,
5-hydroksy-2-oktametylenimino-benzoesyre,5-hydroxy-2-octamethyleneimino-benzoic acid,
utbytte: 2 7% av det teoretiske, smeltepunkt: 208°C, yield: 2 7% of the theoretical, melting point: 208°C,
5-hydroksy-2-(4-tert.butyl-piperidino)-benzoesyre,5-hydroxy-2-(4-tert.butyl-piperidino)-benzoic acid,
utbytte: 33% av det teoretiske, smeltepunkt: 240°C, yield: 33% of the theoretical, melting point: 240°C,
5-hydroksy-2-(cis-3,5-dimetyl-piperidino)-benzoesyre,5-hydroxy-2-(cis-3,5-dimethyl-piperidino)-benzoic acid,
utbytte: 67,4% av det teoretiske, smeltepunkt: 248-250°C. yield: 67.4% of the theoretical, melting point: 248-250°C.
Eksempel 10Example 10
5- metoksy- 2- oktametylenimino- benzoesyre5- methoxy- 2- octamethyleneimino- benzoic acid
3,2 g (12,2 mmol) 5-hydroksy-2-oktametylenimino-benzoesyre i 20 ml absolutt dimetylformamid tilsettes 0,6 g (25 mmol) natriumhydroksyd og oppvarmes til 50°C, hvorved natriumsaltet delvis utfelles. Efter tilsetning av 5,2 g (36,6 mmol) metyljodid i 3 ml absolutt dimetylformamid omrøres i 5 timer ved romtemperatur. Efter avdestillering av dimetylformamidet renses den rå 5-metoksy-2-oktametylenimino-benzoesyre-metylester over en silikagelkolonne med kloroform som elueringsmiddel. 3.2 g (12.2 mmol) of 5-hydroxy-2-octamethyleneimino-benzoic acid in 20 ml of absolute dimethylformamide is added to 0.6 g (25 mmol) of sodium hydroxide and heated to 50°C, whereby the sodium salt is partially precipitated. After adding 5.2 g (36.6 mmol) of methyl iodide in 3 ml of absolute dimethylformamide, the mixture is stirred for 5 hours at room temperature. After distilling off the dimethylformamide, the crude 5-methoxy-2-octamethyleneimino-benzoic acid methyl ester is purified over a silica gel column with chloroform as eluent.
Utbytte: 90% av det teoretiske, smeltepunkt: < 20°C. • Yield: 90% of the theoretical, melting point: < 20°C. •
Denne ester hydrolyseres med natronlut ved 80°C. Efter sur-gjøring til pH 5,2 foretas ekstraksjon med kloroform, tørring over natriumsulfat og oppslutning av inndampningsresiduet med petroleter. This ester is hydrolysed with caustic soda at 80°C. After acidification to pH 5.2, extraction is carried out with chloroform, drying over sodium sulphate and digestion of the evaporation residue with petroleum ether.
Utbytte: 85% av det teoretiske,Yield: 85% of the theoretical,
Smeltepunkt: 84°C.Melting point: 84°C.
Beregnet: C 69,28, H 8,35, N 5,04Calculated: C 69.28, H 8.35, N 5.04
Funnet: 69,12 8,29 4,95. Found: 69.12 8.29 4.95.
Analogt med eksempel 10 ble følgende forbindelser fremstilt: Analogous to example 10, the following compounds were prepared:
2-heksametylenimino-5-metoksy-benzoesyre,2-hexamethyleneimino-5-methoxy-benzoic acid,
utbytte: 88% av det teoretiske, smeltepunkt: 141°C, yield: 88% of the theoretical, melting point: 141°C,
2-heptametylenimino-5-metoksy-benzoesyre,2-heptamethyleneimino-5-methoxy-benzoic acid,
utbytte: 30% av det teoretiske, smeltepunkt: 120°C, yield: 30% of the theoretical, melting point: 120°C,
2-heptametylenimino-5-isopropyloksy-benzoesyre,2-heptamethyleneimino-5-isopropyloxy-benzoic acid,
utbytte: 78% av det teoretiske, smeltepunkt: 120°C, yield: 78% of the theoretical, melting point: 120°C,
5-etoksy-2-oktametylenimino-benzoesyre,5-ethoxy-2-octamethyleneimino-benzoic acid,
utbytte: 87% av det teoretiske, smeltepunkt: < 20°C, yield: 87% of the theoretical, melting point: < 20°C,
5-isopropyloksy-2-oktametylenimino-benzoesyre,5-isopropyloxy-2-octamethyleneimino-benzoic acid,
utbytte: 60% av det teoretiske, smeltepunkt: 78°C, yield: 60% of the theoretical, melting point: 78°C,
5-butyl-(2)-oksy-2-oktametylenimino-benzoesyre,5-butyl-(2)-oxy-2-octamethyleneimino-benzoic acid,
utbytte: 48% av det teoretiske, smeltepunkt: < 20°C, yield: 48% of the theoretical, melting point: < 20°C,
5-metoksy-2-(4-tert.buty1-piperidino)-benzoesyre,5-Methoxy-2-(4-tert.butyl1-piperidino)-benzoic acid,
utbytte: 22% av det teoretiske, smeltepunkt: 156°C, yield: 22% of the theoretical, melting point: 156°C,
5-metoksy-2-(3,5^cis-dimetyl-piperidino)-benzoesyre, utbytte: 90% av det teoretiske, smeltepunkt: 124°C, 5-Methoxy-2-(3,5^cis-dimethyl-piperidino)-benzoic acid, yield: 90% of theoretical, melting point: 124°C,
5-heksyloksy-2-piperidino-benzoesyre,5-hexyloxy-2-piperidino-benzoic acid,
utbytte: 73% av det teoretiske, smeltepunkt: 72°C, yield: 73% of the theoretical, melting point: 72°C,
5-benzyloksy-2-piperidino-benzoesyre,5-benzyloxy-2-piperidino-benzoic acid,
utbytte: 41% av det teoretiske, smeltepunkt: 188°C. yield: 41% of the theoretical, melting point: 188°C.
Claims (5)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19803016650 DE3016650A1 (en) | 1979-07-13 | 1980-04-30 | Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity |
Publications (1)
Publication Number | Publication Date |
---|---|
NO843735L true NO843735L (en) | 1981-01-14 |
Family
ID=6101342
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO843735A NO843735L (en) | 1980-04-30 | 1984-09-19 | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-BENZOIC ACID DERIVATIVES |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0063826B1 (en) |
DE (1) | DE3069781D1 (en) |
ES (3) | ES501882A0 (en) |
HU (1) | HU186675B (en) |
NO (1) | NO843735L (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9326373D0 (en) * | 1993-12-23 | 1994-02-23 | Zeneca Ltd | Chemical compounds |
GB9326232D0 (en) * | 1993-12-23 | 1994-02-23 | Zeneca Ltd | Chemical compounds |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3936467A (en) * | 1968-03-27 | 1976-02-03 | Ciba-Geigy Corporation | Hydroxyalkylenimino-phenyl-acetic acids |
-
1980
- 1980-06-28 DE DE8282104991T patent/DE3069781D1/en not_active Expired
- 1980-06-28 EP EP82104991A patent/EP0063826B1/en not_active Expired
- 1980-07-11 HU HU801085A patent/HU186675B/en unknown
-
1981
- 1981-05-05 ES ES501882A patent/ES501882A0/en active Granted
- 1981-05-05 ES ES501884A patent/ES8202804A1/en not_active Expired
- 1981-05-05 ES ES501883A patent/ES8202803A1/en not_active Expired
-
1984
- 1984-09-19 NO NO843735A patent/NO843735L/en unknown
Also Published As
Publication number | Publication date |
---|---|
ES501884A0 (en) | 1982-03-01 |
ES8202802A1 (en) | 1982-03-01 |
EP0063826A2 (en) | 1982-11-03 |
ES501883A0 (en) | 1982-03-01 |
HU186675B (en) | 1985-09-30 |
DE3069781D1 (en) | 1985-01-17 |
EP0063826A3 (en) | 1982-12-29 |
ES501882A0 (en) | 1982-03-01 |
EP0063826B1 (en) | 1984-12-05 |
ES8202804A1 (en) | 1982-03-01 |
ES8202803A1 (en) | 1982-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US4507303A (en) | Succinimide derivatives, compositions and method of use | |
US4746667A (en) | Pharmaceutical composition containing 2-(2-benzimidazolyl thiomethyl) pyridine | |
US4430343A (en) | Benzimidazole derivatives, process for the preparation thereof and pharmaceutical composition containing the same | |
EP0109562A1 (en) | Succinimide derivatives and their production | |
JPS6056973A (en) | Antihistamic with weak sedative activity | |
NO310070B1 (en) | Benzo [g] quinoline derivatives, their preparation, pharmaceuticals and preparations containing them and the use of derivatives for the manufacture of medicinal products | |
DD200152A5 (en) | PROCESS FOR THE PREPARATION OF NEW 2-AMINOBENZOESAEURE DERIVATIVES | |
NO820047L (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE CARBOXYLIC ACIDAMIDS | |
CH636099A5 (en) | METHOD FOR PRODUCING PIPERIDINOPROPANOL DERIVATIVES. | |
DD149804A5 (en) | PROCESS FOR THE PREPARATION OF NEW INDOOR DERIVATIVES | |
CS236668B2 (en) | Manufacturing process of aralkylamides 2-substituted aminophenylalkancarboxyle and amino-3-pyridylalkancarboxyl acides | |
EP0250361B1 (en) | Disubstituted piperazines | |
US4110455A (en) | 6-aryl-s-triazolo-(4,3-a)-pyrido-(2,3-f)-1,4-diazepines | |
DD254201A5 (en) | METHOD FOR PRODUCING PHENOXY-SUBSTITUTED BETA-CARBOLINE DERIVATIVES | |
US4515944A (en) | 1,5-Diphenyl-2-haloalkylpyrazolin-3-one intermediates | |
NO843735L (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2-AMINO-BENZOIC ACID DERIVATIVES | |
NO138660B (en) | ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NEW 3- (PIPERAZINALKYL) -2,4-CHINAZOLINE INDIATIONS | |
US4654349A (en) | Anti-allergic methods using pyrazolo(1,5-A)pyridines | |
JPS6130588A (en) | Benzo(c)(1,8)naphthylidine, manufacture, use and medicine | |
US3822267A (en) | 1 substituted 4 piperazino cycloalkylthiazoles | |
DK159850B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF PHENYLOIC ACETIC ACID DERIVATIVES | |
NO881899L (en) | NEW 2-AMINOALKYL-4-BENZYL-1- (2H) -PHTHALAZINO DERIVATIVES. | |
KR840002235B1 (en) | Process for preparing carboxylic acid derivatives | |
US3998955A (en) | Antihypertensive compositions | |
WO2007044491A1 (en) | N-substituted pyridinone or pyrimidinone compounds useful as soluble epoxide hydrolase inhibitors |