NZ202478A - Substituted amino-substituted benzene derivatives and pharmaceutical compositions - Google Patents
Substituted amino-substituted benzene derivatives and pharmaceutical compositionsInfo
- Publication number
- NZ202478A NZ202478A NZ20247880A NZ20247880A NZ202478A NZ 202478 A NZ202478 A NZ 202478A NZ 20247880 A NZ20247880 A NZ 20247880A NZ 20247880 A NZ20247880 A NZ 20247880A NZ 202478 A NZ202478 A NZ 202478A
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- theory
- benzoic acid
- compounds
- alkyl
- Prior art date
Links
- -1 amino-substituted benzene Chemical class 0.000 title claims description 90
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 84
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 11
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 11
- 239000012954 diazonium Substances 0.000 claims description 11
- 150000001989 diazonium salts Chemical class 0.000 claims description 11
- 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 11
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 239000010949 copper Substances 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 7
- 239000000725 suspension Substances 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000829 suppository Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical class NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 229910052751 metal Chemical class 0.000 claims description 4
- 239000002184 metal Chemical class 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 4
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical class [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical class [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 230000002152 alkylating effect Effects 0.000 claims description 3
- 125000005059 halophenyl group Chemical group 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 241001125671 Eretmochelys imbricata Species 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 239000003524 antilipemic agent Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 description 94
- 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 30
- 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 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229960001701 chloroform Drugs 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003054 catalyst Substances 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 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 5
- 150000002632 lipids Chemical class 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 235000010288 sodium nitrite Nutrition 0.000 description 5
- 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
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 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
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 3
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000001828 Gelatine Substances 0.000 description 2
- 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 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-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
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 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
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 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
- 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
- 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 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
- 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
- KKHPZMVOPGYMHD-UHFFFAOYSA-N 2-(4-benzylpiperazin-1-yl)-5-chlorobenzoic acid hydrochloride Chemical compound Cl.C(C1=CC=CC=C1)N1CCN(CC1)C1=C(C(=O)O)C=C(C=C1)Cl KKHPZMVOPGYMHD-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
- FQZBRAJJMZZXSV-UHFFFAOYSA-N 2-(4-ethoxycarbonylpiperidin-1-yl)-5-nitrobenzoic acid Chemical compound C1CC(C(=O)OCC)CCN1C1=CC=C([N+]([O-])=O)C=C1C(O)=O FQZBRAJJMZZXSV-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
- 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
- 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 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
- 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
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-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
- 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
- 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
- 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 1
- 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 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
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- BMTAFVWTTFSTOG-UHFFFAOYSA-N Butylate Chemical compound CCSC(=O)N(CC(C)C)CC(C)C BMTAFVWTTFSTOG-UHFFFAOYSA-N 0.000 description 1
- UTOOWGMWQNWYGF-UHFFFAOYSA-N C(=O)(OCC)N1CCN(CC1)C1=C(C(=O)O)C=CC=C1[N+](=O)[O-] Chemical compound C(=O)(OCC)N1CCN(CC1)C1=C(C(=O)O)C=CC=C1[N+](=O)[O-] UTOOWGMWQNWYGF-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- 241000699670 Mus sp. Species 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 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
- 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
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 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
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 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
- 239000004202 carbamide Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 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
- 235000012000 cholesterol Nutrition 0.000 description 1
- 235000019416 cholic acid Nutrition 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
- 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
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 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
- 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
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 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
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000023266 generation of precursor metabolites and energy Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000003516 hyperlipidaemic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 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
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000004060 metabolic process Effects 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
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- HVFSJXUIRWUHRG-UHFFFAOYSA-N oic acid Natural products C1CC2C3CC=C4CC(OC5C(C(O)C(O)C(CO)O5)O)CC(O)C4(C)C3CCC2(C)C1C(C)C(O)CC(C)=C(C)C(=O)OC1OC(COC(C)=O)C(O)C(O)C1OC(C(C1O)O)OC(COC(C)=O)C1OC1OC(CO)C(O)C(O)C1O HVFSJXUIRWUHRG-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000002071 phenylalkoxy group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 229940079827 sodium hydrogen sulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £02478
'2024
?8
Under the provisions of Regim lation 23 (I) the
sJh
Specification has been ante-dated-
to J.L- I *$8.gl+
Initials
Prioru1/ ■ c « • ■
^ " ... .. ji-1
PuiUsr HO^ 1984
P.O. Jo'.::r.:;, Ks . • fM.
O piRf! ppj f-
^ l~J L* LJ Ll3 u_j Lj Lj \ I
PATENTS FORM NO. 5
PATENTS ACT 1953
COMPLETE SPECIFICATION
&•
'jits
7JTC
lLu\\-
m
Nnr-rgrpv Date^XQ July 1980
■ft-fre-r- p-rovl-a-lmid3^
CHEMICAL COMPOUNDS
We,|KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG of Biberach an der Riss, Federal Republic of Germany a Body Corporate organised under the laws of Federal Republic of Germany, hereby declare this invention, for which we pray that a Patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
i
*0*478
This invention relates to new phenyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as pharmaceuticals and as intermediates in the preparation of other pharmaceutic ally active compounds.
In our New Zealand Patent Application No. 194317 we describe and claim, together with processes for their preparation, compounds of general formula I,
*4
o
(I)
wherein
R represents a hydrogen, chlorine or bromine atom or a cyclic C4_7 alkyleneimino group;
represents a hydrogen, fluorine, chlorine or bromine atom; a C^_galkyl or C^_galkoxy group; a phenyl-15 (Cj^alkoxy) group; a hydroxy, nitro, amino, cyano or carboxy group; or a C^^alkanoylamino> (C^_jalkoxy)-carbonyl or di (C^^alkyl)aminosulfonyl group;
R2 and R^ either may be the same or different and each represents a C^^alkyl, C3_7alkenyl, C3_7cycloalkyl, 20 phenyl (C^^alkyl) f phenyl or adamantyl group, or together with the nitrogen atom to which they are attached, they represent C4_6alkylenimino group optionally substituted by 1 or 2 C^_^alkyl groups or by a C^_3alkoxy, hydroxy, phenyl, carboxy or C2_4alkoxycarbonyl group and/or in which a 25 methylene group of the imino ring may optionally be replaced by a further imino group (which may itself optionally be substituted by a C-^_3alkyl, C2_^alkoxycarbonyl, phenyl, halo-phenyl, benzyl, pyridyl or furoyl group), by an oxygen or sulfur atom or by a carbonyl, sulfoxide or sulfonyl groups
202
47 Q
a saturated or partly unsaturated C7_10aza-bicycloalkyl group; a piperidino group substituted in the 3- and 5-
positiortsby a total of either 3 or 4 C1_3alkyl groups; a
C Ql,4-dioxa-8-aza-spiroalkyl group; or a trimethylenimino, 6-9
1-pyrrolyl, tetrahydropyridino, heptamethylenimino, octa-methylenimino, nonamethylenlmino, decamethylenimino, undecamethylenimino or dodecamethylenimino group;
represents a hydrogen atom or a C^_3alkyl group;
X represents a nitrogen atom or a group =CH-;
Y represents an oxygen atom; an imino group; or a methylene group optionally substituted by 1 or 2 C^_3alkyl groups; and
Z represents a hydrogen or halogen atom ; a 15 nitro, amino, cyano, formyl, hydroxymethyl or carboxy-ethylene group; an optionally esterified carboxy group; a methyl group (optionally substituted by 2 or 3 alkoxy groups or by a carboxy, (C^_3alkoxy)carbonyl or ethylenedioxy group); an acetyl group (optionally 20 substituted by a carboxy group or a C^_4alkoxycarbonyl group. ); an ethyl or ethylene group substituted by 1 or 2 C2_4 alkoxycarbonyl groups or by two carboxy groups); an aminocarbonyl group (substituted by one or two substituents selected from C1_?alkyl groups, 25 C3_7cycloalkyl groups and C3_7alkenyl groups);
a piperidinocarbonyl, morpholinocarbonyl, thiomorpholino-carbonyl or N-(C^_3alkyl)-piperazinocarbonyl group; or an ethyl group (substituted by a carboxy group);
and, where and together with the nitrogen 30 atom to which they are attached, represent a cyclic imino group as defined above, and/or where Z reipresents or contains a carboxy group/ the salts thereof.
The above compounds exhibit interesting pharmacological properties and in particular an effect on inter-35 mediary metabolism. Thus these compounds possess a blood-sugar lowering and/or lipid lowering activity.
f ,
2°2178
A number of the compounds useful in the processes described in New Zealand Patent Application No. 194317 for the preparation of compounds of general formula I and in particular a number of those of formula IV and XIV are novel 5 compounds which are not only useful as intermediates in the preparation of compounds of general formula I but also themselves exhibit interesting pharmacological properties and in particular a lipid lowering activity. These novel compounds constitute the subject of the present invention.
Thus according to the present invention there are provided compounds of general formula la,
(la)
wherein represents a fluorine, chlorine or bromine atom or an 15 amino, cyano, hydroxy, C^_g alkoxy or phenyl(C^_^ alkoxy) group;
Rg and R^, together with the nitrogen atom to which they are attached, represent an N-(C2_^ alkyl)-cyclohexylamino group; an N-(C^_3 alkyl)-phenylamino or N-(C^_3 alkyl)-20 benzylamino group; a Cg_l2 alkylenimino group; a piperidino group (substituted by alkyl, c^-3 alkoxy,
£■2-4 alkoxycarbonyl or phenyl group) ; a piperidino group (substituted by 2, 3 or 4 alkylgroups); a morpholino or thiomorpholino group (each optionally 25 substituted by 1 or 2 alkyl groups); a piperazino group (substituted in the 4-position by a alkyl,
C2_4 alkoxycarbonyl, phenyl, halophenyl, pyridyl,
benzyl or furoyl group); a saturated or partly unsaturated C1_lQ aza-bioycloalkyl group; or a C6_g 1,4-30 dioxa-8-aza-spiro-alkyl, pyrrolidino or tetrahydro-pyridino group; and
W represents a carboxy, aminocarbonyl, cyano or C2_^
*°2
478
alkoxycarbonyl group;
and their acid addition salts and, where W represents a carboxy group, their salts with bases.
As will be appreciated, for pharmaceutical use, the 5 salts of the compounds of general formula la will be physiologically compatible salts.
In formula la R,. may, for example, represent a fluorine, chlorine or bromine atom or an amino,cyano,
hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 10 isobutoxy, tert.butoxy, pentoxy, hexoxy, benzyloxy,
1-phenylethoxy, 2-phenylethoxy, 1-phenyl-propoxy or 3-phenyl-propoxy group.
Rg and R^ together with nitrogen atom to which they are attached, may for example represent an N-methyl-15 phenylamino, N-ethyl-phenylamino, N-isopropyl-
phenylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-propyl-benzylamino, N-ethyl-cyclohexylamino, N-propyl-cyclohexylamino, N-isopropyi-cyclohexylamino, N-butyl-cyclo-hexylamino, pyrrolidino, hexamethylamino, heptamethylenimino, 20 octamethylenimino, nonamethylenimino, decamethylenimino, undecamethylenimino, dodecamethylenimino, methyl-piperi-dino, ethyl-piperidino, propyl-piperidino, isopropyl-piperidino, butyl-piperidino, isobutyl-piperidino, tert.-butyl-piperidino, methoxy-piperidino, ethoxy-piperidino, 25 propoxy-piperidino, isopropoxy-piperidino, methoxycarbo-nyl-piperidino, ethoxycarbonyl-piperidino, propoxycar-bonyl-piperidino, isopropoxycarbony1-piperidino, dimethy1-piperidino, trimethyl-piperidino, tetramethy1-piperidino, diethyl-piperidino, dipropyl-piperidino, tetraethyl-pipe-30 ridino, methyl-ethy1-piperidino, ethyl-propy1-piperidino, morpholino, methyl-morpholino, ethyl-morpholino, propyl-morpholino, dimethyl-morpholino, diethyl-morpholino, thiomorpholino, methyl-thiomorpholino, propyl-thiomorpho-lino, dimethyl-thiomorpholino, N-methyl-piperazino, 35 N-ethyl-piperazino, N-propyl-piperazino, N-methoxycar-bonyl-piperazino, N-ethoxycarbonyl-piperazino, N-iso-propoxycarbonyl-piperazino, N-phenyl-piperazino, N-fluoro-phenyl-piperazino, N-chlorophenyl-piperazino, N-bromophenyl-
2°2478
piperazino, N-pyridyl-piperazino, N-benzyl-piperazino, N-furoyl-piperazino, octahydro-isoindol-2-yl, tetrahydro-isoquinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro-isoquinolin-2-yl, tetrahydro-3-benzazepin-3-yl, decahydro-5 3-benzazepir/-3-yl, 3-aza-bicyclo-nonan-3-yl, l,4-dioxa~ 8-aza-spiro[4,5]decan-3-yl, 1,4-dioxa-8-aza-spiro{4,6]un-decan-8-yl or tetrahydro-pyridino group.
W may represent a carboxy, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or cyano 10 group.
Preferred compounds of general formula la and their salts are those wherein
Rj- represents a chlorine or bromine atom or a hydroxy, amino, cyano, benzyloxy or C^_g alkoxy group; 15 and R^ together with the nitrogen atom to which they are attached, represent an N-(C^_^ alkyl)-cyclo-hexylamino group; a cg_^2 alkylen;i-m:i-no group, a piperidino group (substituted in the 4-position by a alkyl,
phenyl, methoxy or ethoxycarbonyl group); a piperidino 20 group (substituted both in the 3- and in the 5-positions by a methyl or ethyl group); a piperidino group (substituted both in tho 3- and in the 5-positions by a total of 4 methyl group.1;) ; a piperazino group (substituted in the 4-position by a methyl, benzyl, 25 phenyl, chlorophenyl, pyridyl-(2)-, ethoxycarbonyl or furoyl-(2)- group); a morpholino or thiomorpholino group (each optionally substituted by 1 or 2 methyl groups); or a pyrrolidino, tetrahydro-pyridino, N-methyl-benzylamino, 1,4-dioxa-8-aza-spiro[4,5]decan-8-yl, 30 1,4-dioxa-8-aza-spiro[4,6]undecan-8-y1, 3-aza-bicyclo-nonan-3-yl, 1,2,4,5-tetrahydro-3-benzazepin-3-y1, decahydro-3-benzazepin-3-ylf 1,2,3,4-tetrahydro-isoquinolin-2-yl, 1,2,3,4,5,6,7,8-octahydro-iso-quinolin-2-yl, decahydro-isoquinolin-2-yl, or octahydro-
47 q isoindol-2-yl group; and
W represents a carboxy, aminocarbonyl, methoxy-carbonyl or cyano group.
Of these preferred compounds especially preferred are those wherein R,. is present in the 5-position of the benzene ring and more especially those wherein
Rt- represents a alkoxy group or a chlorine or bromine atorn;
Rg and R^f together with the nitrogen atom to which they are attached, represent a Cg g alkylenimino group or a 1,4-dioxa-8-aza-spiro[4,5Jdecan-8-yl, l,4-dioxa-8-aza-spiro[4,6]undecan-8-yl, decahydro-3-benzazepino or 4-methoxy-piperidino group; and
A particularly preferred compound is 5-chloro-
2- (1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-benzoic acid and its acid addition salts.
The compounds of general formula la may, for example, be obtained according to the following processes, which processes are further features of the present invention:
a) for the preparation of compounds of general formula la wherein R^ represents an amino group:
(wherein R^, R_ and W are as hereinbefore defined).
D /
The reduction is conveniently carried out in the
W represents a carboxy group.
Reduction of a compound of formula II,
\
R.
7
202
presence of a solvent such as methanol, ethanol, water, water/ethanol, dioxan, methanol/dioxan, ethyl acetate, dimethylformamide or dioxan/dimethylformamide.)
Preferably reduction is effected with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal, platinum or. Raney nickel, for example at a hydrogen pressure of 1 to 10 bar; with hydrazine in the presence of Raney nickel; with nascent hydrogen, e.g. with zinc/acetic acid, tin/hydrochloric acid or iron/ hydrochloric acid; or with a metal salt, e.g. tin(II) chloride/hydrochloric acid or iron (I I) sulfate/sulfuric acid. Preferred temperatures are from 0 to 50°C, most preferably ambient temperature.
b) for the preparation of compounds of general formula la wherein R,. represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom:
Reaction of a compound of formula la as hereinbefore defined (wherein R^ represents an amino group) with a nitrite and subsequent heating of the diazonium salt thus obtained, if required in .the presence of copper or of a corresponding copper (I) sall^. u '
The reaction is conveniently carred out in the presence of a solvent such as e.g. water/hydrochloric acid, methanol/hydrochloric acid or dioxan/hydrochloric acid. As the nitrite for example sodium nitrite or an ester of nitrous acid m.iy be used, preferably at low
- >o 0
temperatures, e.g. at temperatures of from irtO to 5 C.
The corresponding diazonium salt thus obtained, e.g. a fluoroborate, a hydronulfate in sulfuric acid or a hydrochloride is converted optionally in the presence of copper or of a corresponding copper(1) salt such as e.g. copper(I) chloride/hydrochloric acid, copper(I)
*°?478
bromide/hydrobromic acid or trisodium-copper(I) tetracyanide at pH 7, into the desired compound of formula la by heating for example to temperatures of from 15 to 90°C.
c) for the preparation of compounds of general formula la wherein R^_ represents a alkoxy or phenyl (C^ ^
alkoxy) group:
Alkylation of a compound of formula la as hereinbefore defined (wherein represents a hydroxy group) 10 with a compound of formula III»
D - R5' • (III)
(wherein R,_' represents a alkyl or phenyl (C^_^
alkyl) group and D represents a nucleophilically exchangeable group or, together with a hydrogen atom on the a carbon of R,-', a diazo group) followed where required by hydrolysis of the product thus obtained whereby the desired compound of formula la is obtained.
D in the compound of formula III may, for 20 example, be a chlorine, bromine or iodine atom or a sulfonyloxy group such as e.g. a methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group.
The reaction is conveniently carried out in the presence of a solvent such as ether, tetrahydrofuran , 25 ethanol, acetone, dimethylformamide or dimethyl sulfoxide and optionally in the presence of a base such as e.g. sodium carbonate, potassium carbonate,
barium hydroxide, sodium ethylate or potassium tert. butylate. The alkylating agent of formula III may, 30 for example, be diazomethane, diazoethane, methyl iodide, ethyl iodide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate or methyl p-toluene-sulfonate. Preferred temperatures are from 0 to 100°C,
- 10
202478
most preferably from 15 to 70°C.
If W in the compound of formula la represents a carboxy group, this group may simultaneously be esterified when alkylating with a diazoalkane^or when 5 alkylating in the presence of a strong base. The ester thus obtained may subsequently, if desired, be converted back into the corresponding carboxylic acid by means of hydrolysis in the presence of an acid or a base, d) for the preparation of compounds of general 10 formula la wherein W represents a carboxy group:
Hydrolysis of a compound of formula la (wherein W represents a cyano, am.inocarbonyl or C2-4 alkoxycarbonyl group).
The hydrolysis is preferably carried out in the 15 presence of a solvent miscible with water such as e.g. methanol, ethanol, dioxan, water/ethanol or water/ tetrahydrofuran and in the presence of an acid such as hydrochloric acid or sulfuric acid or of a base such as sodium or potassium hydroxide, preferably at elevated 20 temperatuies, e.g. at the boiling point of the reaction mixture. ^
The compounds of general formula la may be converted, if desired, into their acid addition salts by reaction with an acid.. Compounds of general formula la 25 where W represents a carboxy group may be converted into salts with bases by reaction with a base. Suitable acids and bases for the formation of such salts include hydrochloric, hydrobromic, sulfuric, phosphoric, lactic-, citric,
... tartaric, succinic, maleic and ' fumaric_acidssodium 30 potassium hydroxide and cyclohexylamine.
The compounds of formulae II and III are generally known from the literature or may be prepared by processes known from the literature. Thus, for example, compounds of general formula II can be obtained by reaction of 35 a 2-chloro- or 2-bromo-nitro-carboxylie acid or a
"> v»
4?q derivative thereof with a corresponding amine; subsequent reduction of the nitro group in the thus obtained 2-amino compound by means of catalytically activated hydrogen, nascent hydrogen or a metal or metal salt; 5 and by conversion of the thus obtained amino compound via a corresponding diazonium salt into the desired compound of formula II. For the preparation of a starting compound of general formula II, wherein represents an alkoxy or phenylalkoxy group, 10 preferably a hydroxy carboxylic acid is first obtained and subsequently alkylated followed, if necessary, by hydrolysis.
As mentioned above the compounds of general fonmula la are useful intermediates in the preparation of the new 15 compounds of general formula I described and claimed in our New Zealand Patent Application No. 194317. The new compounds of general formula la, however, also themselves show interesting pharmacological properties and especially, an effect on intermediary metabolism. Thus, the compounds of 20 general formula la possess a lipid lowering activity. For examples the compounds
A = 5-Chloro-2-(1,4-dioxa-8-aza-spiro/5,57decane-8-yl)-benzoic acid,
B s 2-(Decahydro-3-benzazepino)-5-chloro-benzoic acid,
C » 2-(Decahydro-3-benzazepino)-5-bromo-benzoic acid,
D s 5-Chloro-2-(4-methoxy-piperidino)-benzoic acid and
E =t 5-Methoxy-2-octamethylenimino benzoic acid were tested on their lipid lowering properties:
1 ,
12
4 T
2. Lipid lowering activity;
Literatures P. E. Schurr et al. in Atherosclerosis Drug Dis-
covery (1976), editor: C. E. Day; Plenum, New York, page 215.
Young male rats with an average weight of 100 g were made hyperlipemic by administration of a diet consisting of 10 % of coconut fat, 1.5 % of cholesterin, 0.5 % of cholic acid, 0.2 % of choline chloride and 15 % of sucrose for 4 days.
The test compounds were administered in methyl cellulose suspen-10 sion by stomach tubing on two successive days. Subsequently the animals were starved overnight and, 5 or 24 hours after the last test compound administration, a blood sample was taken and the serum isolated.
In the serum cholesterol (Boehringer Mannheim test combination 15 187.313) and-triglycerides (Boehringer Mannheim test combination 126.039) levels were determined enzymatically. The B-lipo-proteins were determined nephelometrically after precipitation with Ca++ and heparine using an auto analyzer.
The percentage lowering was calculated in comparison with a 20 control group.
The followina table contains the values obtained:
Lowering in % as compared with a control after two administrations
Test Dose com- (mg/kg) pound cholesterol
B-lipoproteins
A
E
D
C
B
100 100 100 100 100
- 54
- 39
- 32
- 31
- 29
- 54
- 43
- 32
- 29
- 30
-13 - •>
+ Decrease of serum 5 hours after last compound administration, all other values were found 24 hours after last compound administration.
3. Acute Toxicity:
The acute toxicity was determined in home-bred female and male mice with a body weight of 20 - 26 g after oral administration (suspension in 1% methyl cellulose) of a single dose. Observation time: at least 7 days.
The following table contains the values obtained:
Test peroral toxicity compound
>2000 mg/kg (0 out of 10 animals died)
Based on their pharmacological properties the compounds of general formula la are suitable for the treat-
ment of artherosclerosis and of hyperlipidemic conditions,
particularly of type IIA, IIB and IV.
According to a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of
formula la as hereinbefore defined or a physiologically compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient as well as a method of treating patient suffering from or susceptible to artherosclerosis and/or hyperlipidemic conditions which
comprises administering to the said patient an effective amount of at least one compound of formula la as hereinbefore defined or a physiologically compatible salt thereof.
For pharmaceutical administration the compounds of
*0
general formula la and their physiologically compatible salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for 5 example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, suppositories suspensions and solutions e.g. for injection.
The active ingredient may be incoporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic,
lactose, starch, magnesium stearate, cocoa butter,
aqueous or non-aqueous vehicles, fatty substances of 15 animal or vegetable, origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a 20 fixed dose of active ingredient. Suitc;hle dosage units for adults contain from 5 to 200 mg, preferably from 5 to 50 mg of active ingredient of formula la or a salt thereof. The oral daily dosage of the compound of formula la or salt thereof, whicli may be varied according to the 25 compound used, the subject treated and the complaint concerned, may, for example, be from 10 to 500 mg,
preferably from 15 to 150 mg per day in adults.
The following non-limiting examples serve to illustrate the present invention.
20y
<-65,
Preparation of the starting products:
4?8
Preparation 1
2-(Decahvdro-isoqulnolin —2-yl)-5-nltro-benzoic acid
19 g (0.136 mol) of decahydro-isoquinoline, 27.3 g (0.136 mol) 5 of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassium carbonate vere refluxed in 500 ml of ethanol for 18 hours whilst stirring. After distilling off the ethanol, the residue was dissolved in 800 ml of water and was adjusted to pH 4 by addition of 2N hydrochloric acid, whereby the reaction product 10 was obtained in crystalline form.
Yield: 38 g (92 % of theory),
M.p.: 132 - 134°C (lsopropanol)
Calc.: C 63.14 H 6.62 N 9.20 Found: 63.02 6.48 9.38
Preparation 2
2-(1.4-Dloxa-8-aza-spiro/5.57decan —8-yl)-5-nitro-benzoic acid
A mixture of 20.1 g (0.1 mol) of 2-chloro-5-nitro-benzoic acid and of 42.9 g (0.3 mol) of 1,4-dioxa-8-aza-spiro/5,]>7decane was heated for 8 hours in 200 ml of ethanol up to the reflux tempe-
rature. After distilling off the solvent, the evaporation re sidue was taken up in water and adjusted to pH 5.2 by addition of 2N hydrochloric acid, whereby the product was precipitated.
Subsequently, the reaction product was extracted with chloro form and dried over sodium sulfate and after distilling off
the solvent, the compound was crystallized.
Yield: 12 g (39 % of theory),
M.p.: 155°C (ethanol).
Calc.: C 54.54 H 5.24 N 9.09 Found: 54.20 5.13 8.97
2°2<>7S
Analogously to the Preparations I and 2 Ihe following compiincfc were prepared:
2-(2-Methyl-piperidino)-5-nitro-benzoic acid Yield: 99 % of theory, m.p.: 164°C.
2-(3-Methyl-piperidino)-5-nitro-benzoic acid Yield: 85 % of theory, m.p.: 161°C.
2-(4-Methyl-piperidino)-5-nitro-benzoic acid Yield: 85 % of theory, m.p.: 155°C.
2-(3-Ethyl-6-methyl-piperidino)-5-nitro-benzoic acid 10 Yield: 76 % of theory, m.p.: <20°C.
2-(3,5-Dimethyl-piperidino)-5-nitro-benzoic acid Yield: 65 % of theory, m.p.: 172°C.
2-(4-Methoxy-piperidino)-5-nitro-benzoic acid Yield: 68 % of theory, m.p.: 140°C.
5-Nitro-2-(4-phenyl-piperidino)-benzoic acid Yield: 88 # of theory, m.p.: 196°C.
2-(4-Ethoxycarbonyl-piperidino)-5-nitro-benzoic acid Yield: 82 % of theory, m.p.: 160°C.
-Nitro-2-thiomorpholino-benzoic acid 20 Yield: 80 % of theory, m.p.: 235°C.
-Nitro-2-(1,2,4,5-tetrahydro-3 benzazepino)-benzoic acid Yield: 68 % of theory, m.p.: 222°C.
-Nitro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid Yield: 70 % of theory, m.p.: 195°C.
-Nitro-2-(4-phenyl-piperazino)-benzoic acid Tield: 88 % of theory, m.p.: 196°C.
-Nitro-2-(4-pyridyl-(2)-piperazino)-benzoic acid Tield: 66 # of theory, m.p.: 192°C.
2-(trana-3,5-Dimethylpiperidino)-5-nitro-benzoic acid Yield: 63 % of theory, m.p.: 132°C.
2-(3,3 $ 5,5-Tetramethyl-piperidino)-5-nitro-benzoic acid Yield: 98 % of theory, m.p.: 138°C.
2-(3,5-Dimethyl-morpholino)-5-nitro-benzoic acid 10 Yieldj 75 % of theory, m.p.: 164°C.
2-(3»5-Dimethyl-thiomorpholino)-5-nitro-benzoic acid Yield: 70 % of theory, m.p.: 118°C.
2-(3-Aza-bicyclo/5,2,27nonane-3-yl)-5-nitro-benzoic acid Yield: 72 % .of theory, m.p.: 221°C.
5-Nitro-2-nonamethylenimino-benzoic acid Yield: 80 % of theory, m.p.: 127°C.
-Nitro-2-decamethylenimino-benzoic acid Yield: 92 % of theory, m.p.: 128°C.
-Nitro-2-imdecamethylenimino-benzoic acid 20 Yield: 91 % of theory, m.p.: 120°C.
-Nitro-2-dodecamethylenimino-benzoic acid Yield: 95 % of theory, m.p.: 115°C.
2-(N-Methyl-N-phenylamino)-5-nitro-benzoic acid Yield: 10 % of theory, m.p.: 115°C.
• " 2o*4ys
2-(N-Ethyl-N-cyclohexylamino)-5-nitrO-benzoic acid Yield: 78 % of theory, m.p.: 74°C.
2-(N-Butyl-N-cyclohexylamino)-5-nitro-benzoic acid Yield: 84 % of theory, m.p.: 56°C.
2-(N-Cyclohexyl-N-isobutylamino)-5-nitro-benzoic acid Yield: 63 % of theory, m.p.: < 20°C.
2-(Decahydro-3-benzazepin -3-yl)-5-nitro-benzoic acid Yield: 98 % of theory, m.p.: < 20°C.
2-(0ctahydro-isoindol —2-yl)-5-nitro-benzoic acid 10 Yield: 80 % of theory, m.p.: 128°C.
2-(4-Isopropyl-piperidino)-5-nitro-benzoic acid Yield: 79 % of theory, m.p.: 142°C.
2-(4-tert.Butyl-piperidino)-5-nitro-benzoic acid Yield: 57 % of theory, m.p.: 136°C.
2—(1,4-Dioxa-8-aza-spiro^f,67undecan-8-yl)-5-nitro-benzoic acid Yield: 75 % of theory, m.p.: 135°C.
2,4-Dipiperidino-5-nitro-ben;?oic acid Yield: 31 % of theory, m.p.: 152°C.
4-Chloro-2-piperidino-5-nitro-benzoic acid 20 Yield: 18 % of theory, m.p.: 133°C.
-Nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 58 % of theory, m.p.: 215°C.
2-(N-Methyl-N-benzylamino)-5-nitro-benzoic acid Yield: 93 % of theory, m.p.: 123 - 126°C.
*°24?fl
2-/5-(4-Chlorophenyl)-piperazino7-5-nitro-benzoic acid O hydrochloride
Yield: 71.5 % of theory, m.p,: 225 - 227°C (decomp.).
2-(4-Carbethoxy-piperazino)-3-nitro-benzoic acid 5 Yield: 23.1 # of theory, m.p.: 155 - 156°C.
2-( 2-Furoyl)-piperazino7-5-nitro-benzoic acid Yield: 64.8 % of theory, m.p.: 200 - 205°C.
2-(4-Benzyl-piperazino)-5-nitro-benzoic acid hydrochloride Yield: 86.6 % of theory, m.p.: 142 - 145°C.
Preparation 3
2-Hexamethylenlmlno-5-nitro-benzolc acid nitrile
A mixture of 18.4 g (0.11 mol) of 2-chloro-5-nitro-benzoic acid nitrile and of 22.4 g (0.21 mol) of hexamethylenimine was refluxed for 4 hours in 250 ml of ethanol. After cooling
the product was oily precipitated by addition of 500 ml of water. The precipitate was taken up in chloroform and after drying with sodium sulfate and distilling off the chloroform,
the evaporation residue was recrystallized from ethanol.
Yield: 19.7 g (73 % of theory),
M.p.s 70°C.
Calc.: C 63.65 H 6.16 H 17.13 Found: 63.80 6.07 17.05
r . n
Preparation of the products of general formula la: Example a
-Amlno-2-(decahydro-isoqulnolln —2-vl)-benzoic acid
36 g (0.118 mol) of 2-(decahydro-isoquinolin—2-yl)-5-nitro-5 benzoic acid were dissolved in 250 ml of dimethyl formamide and the solution was hydrogenated at room temperature with a hydrogen pressure of 5 bar by addition of 10 % palladium charcoal as catalyst. After hydrogen absorption finished, the catalyst was filtered off, the solvent was distilled off in 10 vacuo and the residue was recrystallized from ethanol.
Yield: 31.2 g (96 % of theory),
M.p.: 252°C.
Calc.: C 70.04 H 8.08 N 10.20 Found: 70.09 7.85 10.12
Example B
-Amino-2-(1.4-dloxa-8-aza-spiro/?.57decan~8-vl)-benzolc acid
12 g (0.039 mol) of 2-(1,4-dioxa-8-aza-spiro/ZT,5.7decan —8-yl)-5-nitro-benzoic acid were hydrogenated at room temperature in 100 ml of dimethyl formamide at a hydrogen pressure of 5 bar 20 by addition of 10 # palladium charcoal as catalyst. After finished hydrogen absorption the catalyst was filtered off, the solvent was distilled off and recrystallized from ethanol.
Yield: 9 g (83 % of theory),
M.p.: 209°C.
Calc.: C 60.42 H 6.56 N 10.07 Found: 60.18 6.58 10.12
Analogously to the Example A and B the following compounds were prepared:
-Amino-2-pyrrolidino-benzoic acid Yield: 79 % of theory, m.p.: 208°C.
5-Amino-2-(2-methyl-piperidino)-benzoic acid Yield: 84 96 of theory, m.p.: 240°C.
-Amino-2-(3-nethy -piperidino)-benzoic acid Yield: 75 J6 of theory, m.p.: 192°C.
-Amino-2-(4-methyl-piperidino)-benzoic acid 10 Yield: 88 % of theory, m.p.: 215°C.
-Amino-2-(3-ethyl-6-methyl-piperidino)-benzoic acid Yield: 59 % of theory* m.p.: 219°C.
-Amino-2-(cis-3,5-dimethyl-piperidino)-benzoic acid Yield: 87 % of theory, m.p.: 234°C.
5-Amino-2-(4-methoxy-piperidino)-benzoic acid Yield: 80 % of theory, m.p.: 228°C.
-Amino-2-heptamethylenimino-benzoic acid Yield: 64 96 of theory, m.p.: 214°C.
-Amino-2-(4-phenyl-piperidino)-benzoic acid 20 Yield: 76 96 of theory, m.p.: 275°C.
-Amino-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Yield: 85 96 of theory, m.p.: 203°C.
-Amino-2-thiomorpholino-benzoic acid Yield: 76 96 of theory, m.p.: 193°C.
-Amino-2-(1,2,4,5-tetrahydro-3 benzazeplno)-benzoic acid Yield: 86 96 of theory, m.p.: 258°C.
-Amino-2-(1,2,3»4-tetrahydro-isoquinolino)-benzoic acid Yield: 66 % of theory, m.p.: 220°C.
-Amino-2-(4-phenyl-piperazino)-benzoic acid Yield: 83 % of theory, m.p.: 255°C.
-Amino-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield: 80 % of theory, m.p.: 248°C.
-Amino-2-(trans-3,5-dimethyl-piperidino)-benzoic acid Yield: 89 % of theory, m.p. : 156°C.
-Amino-2-(3»3,5,5-tetramethyl-piperidino)-benzoic acid Yield: 98 96 of theory, m.p.: <20°C.
-Amino-2-(3 >5-dimethyl-morpholino)-benzoic acid Yield: 83 % of theory, m.p.: 255°C.
-Amino-2-(3,5-dimethyl-thiomorpholino)-benzoic acid Yield: 50 % of theory, m.p.: 233°C.
-Amino-2-(3-aza-bicyclo/5» 2,27nonan —3-yl)-benzoic acid Yield: 86 % of theory, m.p.: 288°C.
-Amino-2-octamethylenimino-benzoic acid Yield: 88 % of theory, m.p.: 191°C.
-Amino-2-nonamethylenimino-benzoic acid Yield: 80 96 of theory, m.p.: 212°C.
-Amino-2-decamethylenimino-benzoic acid Yield: 52 % of theory, m.p.: 202°C.
-Amino-2-undecamethylenimino-benzoic acid Yields 93 % of theory, m.p.s 242°C.
-Amino-2-dodecamethylenimino-benzoic acid Yield: 59 % of theory, m.p.s 224°C.
-Amino-5-(N-methyl-N-phenylamino)-benzoic acid Yield: 47 % of theory, m.p.s 184°C.
-Amino-2-(N-ethyl-N-cyclohexylamino)-benzoic acid Yields 66 % of theory, m.p.: 160°C.
-Amino-2-(N-butyl-N-cyclohexylamino)-benzoic acid Yield: 48 % of theory, m.p.: 140°C.
-Amino-2-(N-cyclohexyl-N-isobutylamirio)-benzoic acid Yield: 62 % of theory, m.p.: < 20°C.
-Amino-2-(decahydro-3-benzazepin —3-yl)-benzoic acid Yield: 54 # of theory, m.p.: 204°C.
-Amino-2-(octahydro-isoindol—2-yl)-benzoic acid Yield: 43 % of theory, m.p.: 228°C.
-Amino-2-(4-isopropyl-piperidino)-benzoic acid Yield: 50 % of theory, m.p.: 231°C.
-Amino-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 81 % of theory, m.p.: 276°C.
-Amino-2-(1,4-dioxa-8-aza-spiro/^,67undecan —8-yl)-benzoic acid Yield: 49 % of theory, m.p.: 235°C.
-Amino-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 51 % of theory, m.p.: 232°C.
*°2478
-Amino-2-(4-methyl-piperazino)-benzoic acid hydrochloride Yield: 90 % of theory, m.p.j <C20°C.
-Amino-2-(N-methyl-N-benzylamino)-benzoic acid Yield: 95 % of theory, m.p.: <20°C
-Amino-2-/5-(4-chloro-phenyl)-piperazino7benzoic acid hydrochloride
Yield: 80.5 % of theory, m.p.: 305°C (decomp.).
-Amino-2- (4-carbethoxy-piperazino)-benzoic acid Yield: 87.5 56 of theory, m.p.: 195 - 197°C.
-Amino-2-jfc- (2-furoyl)-piperazino/benzoic acid Yield: 97 % of theory, m.p.: £20°C..v
-Amino-2-(4-benzyl-piperazino)-benzoic acid hydrochloride Yield: 80 % of theory, m.p.: 200 - 210°C.
Example C
-Chloro-2-(decahYdro-l3oqulnolin —2-yl)-benzolc acid
g (0.0365 mol) of 5-amino-2-(decahydro-isoquinolin —2-yl)-benzoic acid were dissolved in 55 ml of semi-conc. hydrochloric acid and the solution was diazotized at 0°C by dropwise addition of a solution of 2.7 g (0.039 mol) of sodium nitrate in 10 ml of water. After the addition was finished the reaction mixture was stirred for 15 minutes and subsequently, the diazonium salt solution was dropped into a suspension of 4 g of copper powder in 40 ml of conc. hydrochloric acid. After stirring over night a deep green homogeneous solution was obtained, which was diluted with 100 ml of water and subsequently was completely extracted with chloroform. After drying over sodium sulfate the chloroform evaporation residue was purified by chromatography over a silica gel column with an eluant of ethyl acetate/ methanol « 9.5 : 0.5.
Yield: 4.8 g (45 96 of theory),
M.p.: 138°C.
Calc.: C 65.41 H 6.85 N 4.76 Found: 65.51 7.07 4.89
Example p
-Chloro-2-(1t4-dloxa-8-aza-splro/5.57decan —8-yl)-benzoic acid
8.5 g (0.031 mol) of 5-amlno-2-(1,4-dioxa-8-aza-spiro/5,£7-decan—8-yl)-benzoic acid were dissolved in 28 ml of semi-conc. hydrochloric acid and diazotized at 0°C with a solu-10 tion of 2.4 g (0.034 mol) of sodium nitrite in 10 ml of water.
The diazonium salt solution was added dropwise whilst stirring to a suspension of 3 g of copper powder in 3 ml of conc. hydrochloric acid. After nitrogen formation finished the reaction mixture was stirred for 2 hours, diluted with water and ex-15 tracted with chloroform. After drying over sodium sulfate the solvent was distilled off and after digesting the evaporation residue with petroleum ether, 6.1 g (66 % of theory) of the compound were obtained.
M.p.: 180°C.
Calc.: C 56.47 H 5.42 N 4.71 Found: 56.11 5.37 4.83
Analogously to the Examples C and D the following compounds were prepared:
-Chloro-2-pyrrolidino-benzoic acid 25 Yield: 30 % of theory, m.p.: 164°C.
-Chloro-2-(2-methyl-piperidino)-benzoic acid Yield: 74 % of theory, m.p.: 124°C.
-Chloro-2-(3-methyl-piperidino)-benzoic acid Yield: 47 96 of theory, m.p. : 165°C.
Cl 12.06 12.32
-Chloro-2-(4-methyl-piperidino)-benzoic acid Yield: 52 % of theory, m.p.: 107°C.
2-(3-Ethyl-6-methyl-piperidino)-3-chloro-benzoic acid Yield: 73 96 of theory, m.p.: <20°C.
-Chloro-2-(cis-3»5-dimethyl-piperidino)-benzoic acid Yield: 46 % of theory, m.p.: 167°C.
-Chloro-2-(trans-3»5-dimethyl-piperidino)-benzoic acid Yield: 63 96 of theory, m.p.: 132°C.
-Chloro-2-(4-methoxy-piperidino)-benzoic acid Yield: 63 % of theory, m.p.: 136°C.
-Chloro-2-heptamethylenimino-benzoic acid Yield: 58 % of theory, m.p.: < 20°C.
-Chloro-2-(4-phenyl-piperidino)-benzoic acid Yield: 51 % of theory, m.p.: 217°C.
-Chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Yield: 97 96 of theory, m.p.:< 20°C.
-Chloro-2-hexamethylenimino-benzoic acid Yield: 34 % of theory, m.p.: 113°C.
-Chloro-2-thiomorpholino-benzoic acid Yield: 16 % of theory, m.p.: 160°C.
-Chloro-2-(1,2,4,5-tetrahydro-3 benzazeplno)-benzoic acid Yield: 59 96 of theory, m.p.: 174°C.
-Chloro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid Yield: 50 96 of theory, m.p.: 182°C.
-Chloro-2-(4-phenyl-piperazino)-benzoic acid Yield: 42 % of theory, m.p.: 154°C.
-Chloro-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield: 45 # of theory, m.p.: 168°C.
-Bromo-2-(2-methyl-piperidino)-benzoic acid Yield: 31 % of theory, m.p.: 168°C.
-Chloro-2-(3»3»5,5-tetramethyl-piperidino)-benzoic acid Yield: 62 % of theory, m.p.: <20°C.
-Bromo-2-(4-methoxy-piperidino)-benzoic acid Yield: 48 % of theory, m.p.: 138°C.
-Chloro-2-(3»5-dimethylmorpholino)-benzoic acid Yield: 50 % of theory,, m.p.: 174°C.
-Chloro-2-(3»5-dimethyl-thiomorpholino)-benzoic acid Yield: 18 % of theory, m.p.: 134°C.
-Bromo-2-heptamethylenimino-benzoic acid Yield: 15 % of theory, m.p.: 104°C.
-Chloro-2-(3-aza-bicyclo/5,2,27nonan —3-yl)-benzoic acid Yield: 16 % of theory, m.p.: 199°C.
-Chloro-2-octamethylenimino-benzoic acid Yield: 70 % of theory, m.p.: 84°C.
-Chloro-2-nonamethylenimino-benzoic acid Yield: 30 % of theory, m.p.: 78°C.
-Chloro-2-decamethylenimino-benzoic acid Yield: 65 56 of theory, m.p.: 70°C.
-Chloro-2-undecamethylenimino-benzoic acid Yield: 41 9* of theory, m.p.: 41°C.
-Chloro-2-dodecamethylenimino-benzoic acid Yield: 36 % of theory, m.p.: 40°C.
-Chloro-2-(N-phenyl-N-methylamino)-benzoic acid Yield: 27 % of theory, m.p.: 164°C.
2-(N-Ethyl-N-cyclohexylamino)-5-chloro-benzoic acid Yield: 24 % of theory, m.p.: 152°C.
2-(N-Butyl-N-cyclohexylamino)-5-chloro-benzoic acid Yield: 16 % of theory, m.p.: 145°C.
-Chloro-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid Yield: 22 % of theory, m.p.: 131°C.
-Chloro-2-(decahydro-3_benzazepin —3-yl)-benzoic acid Yield: 70 % Of theory, m.p.: 153°C.
-Bromo-2-(decahydro-3'benzazepin -3-yl)-benzoic acid Yield: 54 % of theory, m.p.: 154°C.
-Chloro-2-(octahydro-isoindol—2-yl)-benzoic acid Yield: 33 # of theory, m.p.: 164°C.
-Bromo-2-octamethylenimino-benzoic acid Yield: 48 of theory, m.p. : 94°C.
-Chloro-2-(4-isopropyl-pipe ridino)-benzoic acid Yield: 43 96 of theory, m.p.: 172°C.
-Chloro-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 35 96 of theory, m.p.: 161°C.
-Chloro-2-(1,4-dioxa-8-aza-spiro/5,67undecan —8-yl)-benzoics"* acid
Yield: 42 96 of theory, m.p.: 163°C.
-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 73 % of theory, m.p.: 173°C.
-Chloro-2-(4-methyl-piperazino)-benzoic acid hydrochloride Yield: 75 96 of theory, m.p.: 132°C (decomp.).
-Chloro-2-(N-methyl-N-benzylamino)-benzoic acid Yield: 18.2 96 of theory, m.p.: 156 - 157°C.
-Chloro-2-^f-(4-chloro-phenyl)-piperazino7benzoic acid Yield: 30.5 96 of theory, m.p.: 228 - 230°C.
-Chloro-2-/£-(2-furoyl)-piperazino7benzoic acid Yield: 33.1 96 of theory, m.p.: 200 - 202°C.
2-(4-Benzyl-piperazino)-5-chloro-benzoic acid hydrochloride Yield: 42.8 96 of theory, m.p.: 230 - 232°C (decomp.).
Example E
-Amlno-hexamethylenlmlno-benzolc acid nitrile
21.4 g (0.087 mol) of 2-hexamethylenimino-5-nitro-benzoic acid nitrile were dissolved in 200 ml of dioxane and 500 ml of methanol and the solution was hydrogenated at room temperature with a hydrogen pressure of 5 bar in the presence of 10 96 palladium charcoal as catalyst. After filtering off the catalyst and distilling off the solvent, 20 g (100 96 of theory) of the compound were obtained.
M.p.: C 20°C.
Example F
-Chloro-2-hexamethylenimlno-benzolc acid nitrile
g (0.092 mol) of 5-amino-2-hexamethylenimino-benzoic acid nitrile were dissolved in 90 ml of semi-conc. hydrochloric acid and at 0°C the solution was diazotized by dropwisely adding a solution of 6.5 g (0.094 mol) of sodium nitrite in
ml of water. After addition was finished the reaction mixture was stirred for 15 minutes. The diazonium salt solution was added dropwise whilst stirring to a solution of copper-(I) chloride in conc. hydrochloric acid, which was warmed up to 70°C. After the nitrogen formation was finished, the reaction solution was extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation residue was purified by chromatography over a silica gel column (eluant: toluene).
Yield: 5 g (23 % of theory),
M.p.: <20°C.
Example G
-Chloro-2-hexamethylenlmino-benzolc acid
g (0.021 mol) of 5-chloro-2-hexamethyleniroino-benzoic acid nitrile were heated in 32 g of potassium hydroxide solution and 20 ml of water for 8 hours up to 170°C. The cold melt was dissolved in water and the amide was precipitated quantitatively by acidifying to a pH value of 5. By hydrolysis with semi-conc. hydrochloric acid 3.6 g (67.4 96 of theory) of the compound were obtained.
M.p.: 113°C.
Analogously to the Example ],to G the following compounds were prepared:
2-Morpholino-5-nitro-benzoic acid nitrile Yield: 78 % of theory, m.p.: 138°C.
_ 31 -
-Amino-2-morpholino-benzoic acid nitrile Yield: 68 % of theory, m.p.: 142°C.
-Chloro-2-morpholino-benzoic acid nitrile YieLd: 20 % of theory, m.p.: 57°C.
-Chloro-2-morpholino-benzamide Yield: 98 J6 of theory, m.p.: 280°C.
-Chloro-2-morpholino-benzoic acid Yield: 60 % of theory, m.p.: 157°C.
Example H
-Cyano-2-octamethylenlmino--benzoic acid
26.2 g (0.1 mol) of 5-amino-2-octamethylenimino-benzoic acid were dissolved in 38 ml of conc. hydrochloric acid, 280 ml of water were added and the solution was diazotized at 0°C by dropwise addition of a solution of 7.6 g (0.11 mol) of sodium nitrite in 30 ml of water. After stirring for 30 minutes the solution was adjusted to pH 7 by means of sodium carbonate. Subsequently, a solution of trisodium-tetracyano-copper-(I) complex was dropwisely added at 0°C to the diazonium salt solution.
This copper-(l) complex solution was obtained in the following way: 32 g (0.128 mol) of copper sulfate x 5 1^0 and 8.7 g of sodium chloride in 100 ml of water were reduced to the copper-(1) chloride by means of a sodium hydrogene sulfite solution, consisting of 6.6 g (0.063f mol) of sodium hydrogen sulfite and 4.4 g of sodium hydroxide in 50 ml of water. The precipitated copper-(I) chloride was suction filtered, 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 the nitrogen formation was finished, the reaction mixture was heated for 1 hour up to 70°C. After cooling the reaction mixture was adjusted to pH 5.5 by means of 2N hydrochloric acid and extracted with chloroform. The chloroform phases were dried over sodium sulfate and after distilling off the chlor
*°2
4?
8
form, the obtained crude product was purified over a silica gel column with ethyl acetate as eluant.
Yield: 9 g (30 % of theory),
M.p.: 20°C.
Calc.: C 70.56 H 7.40 N 10.28 Found: 70.38 7.20 10.10
Example J
2-Heptamethylenlmlno-5-hydroxy-benzoic acid
26.7 g (0.107 mol) of 5-amino-2-heptamethylenimino-benzoic acid were dissolved in 190 ml of 3N sulfuric acid and the solution was diazotized at 0°C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water, which was added dropwisely. After stirring for 30 minutes, 2 g of finely pulverized urea were added. The diazonium salt solution was added dropwise whilst stirring to 320 ml of 50 % sulfuric acid, which was warmed up to 90°C. After nitrogen formation finished, the reaction mixture was adjusted at room temperature to pH 4 by means of ammonia and extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the obtained dry residue was purified over a silica gel column by means of chloroform as eluant.
After recrystallization from isopropanol, 8 g (30 % of theory) of the compound were obtained.
M.p.: 199°C
Calc.: C 67.45 H 7.68 N 5.61 Found: 66.87 7.71 5.65
Analogously to the Example J the following compounds were prepared:
2-Hexamethylenimino-5-hydroxy-b6nzoic acid Yield: 24 96 of theory, m.p. : 214°C.
-Hydroxy-2-oxtamethylenimino-benzoic acid Yield: 27 % of theory, m.p.: 208°C.
2 0^
-Hydroxy-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 33 % of theory, m.p.: 240°C
-Hydroxy-2-(cis-3,5-dimethyl-piperidino)-benzoic acid Yield: 67.4 % of theory, m.p.: 248 - 250°C.
Example K
-Methoxv-2-ootamethvlenlmino-benzolc acid
0.6 g (25 mmol) of sodium hydroxide were mixed with 3.2 g (12.2 mmol) of 5-hydroxy-2-octamethylenimino-benzoic acid in 20 ml of absolute dimethyl formamide and the reaction mixture was warmed up to 50°C, whereby the the sodium salt partly precipitated. After addition of 5.2 g (36.6 mmol) of methyl iodide in 3 ml of absolute dimethyl formamide the mixture was stirred for 5 hours at room temperature. After distilling off the dimethyl formamide the crude 5-methoxy-2-octamethylenimino-benzoic acid-methyl ester was purified over a silica gel column by means of chloroform as eluant.
Yield: 90 % of theory, m.p.: 20°C.
This ester was hydrolyzed at 80°C by means of sodium hydroxide solution. After acidifying to a pH value of 5.2, the ester was extracted with chloroform, dried over sodium sulfate and the evaporation residue was digested with petroleum ether.
Yield: 85 % of theory,
M.p.: 84°C.
Calc.: C 69.28 H 8.35 N 5.04 Found: 69.12 8.29 4.95
Analogously to Example K the following compounds were prepared:
2-Hexamethylenimino-5-methoxy-benzoic acid Yield: 88 96 of theory, m.p.: 141°C.
< 4?
2-Heptametbylenimino-5-methylenimino-5-methoxy-benzoic acid Yield: 30 % of theory, m.p.: 120°C.
2-Heptamethylenimino-5-isopropyloxy-benzoic acid Yield: 78 % of theory, m-p.: 120°C.
-Ethoxy-2-octamethylenimino-benzoic acid Yield: 87 # of theory, m.p.: <20°C.
-Isopropyloxy-2-octamethylenimino-benzoic acid Yield: 60 % of theory, m.p.: 78°C.
-Butyl-(2)-oxy-2-octamethylenimino-benzoic acid Yield: 48 96 of theory, m.p.: < 20°C.
-Methoxy-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 22 % of theory, m.p.: 156°C.
-Methoxy-2-(2,5-cis-dimethyl-piperidino)-benzoic acid Yield: 90 % of theory, m.p.: 124°C.
-Hexyloxy-2-piperidino-benzoic acid Yield: 73 % of theory, m.p.: 72°C.
-Benzyloxy-2-piperidino-benzoic acid Yield: 41 % of theory, m.p.: 188°C.
I
202478
- 35 •-
Example I
Suppositories containing 30 mg of 5-chloro-2-(1,4-dioxa 8-aza-splro/5, 57<jtecan ,-8-yl)-benzolc acid t
Composition:
1 suppository contains:
Active ingredient 0.030 g Suppository mass .
(e.g. Witepsol ¥ 45 1.336 g
Witepsol E 75) 0.334 g
1.700 g
Method of preparation:
The pulverized active ingredient was added, with stirring, to the molten mixture of the Witepsol masses tempered to 40°C. The melt was then poured into cooled moulds. After complete solidification the suppositories were removed from the moulds and packed in a suitable manner.
Example II
Gelatine capsules containing 5 mg of 5-chloro-2-(1,4-dioxa-
8-aza-splro/5.s7 decan -8-yl)-benzoic acid ;
.0 mg 100.0 mg 93.0 mg 2.0 mg
200.0 mg
1 capsule contains:
Active ingredient Com starch, dried Corn starch, pulverized Magnesium stearate
20247
Method of preparation:
The active ingredient and the auxiliary products were mixed. The mixture was passed through a screen of 0.75 jam mesh size and homogeneously dispersed in a suitable mixer. The powder obtained was filled into gelatine capsules of size 3 (Parke Davis) by a capsule filling and closing machine.
Example III
Tablets containing 25 mg of 5-chloro-2-(1,4-dioxa-8-aza-spiro/5.5 7-decan -8-vl )-benzolc acid
1 tablet contains:
Active ingredient 25.0 mg
Lactose 35.0 mg
Corn starch 15.0 mg
Polyvinyl pyrrolidone 4.5 mg
Magnesium stearate 0.5 mg
80.0 mg
Method of preparation:
The active ingredient was,mixed with the lactose and starch and the mixture obtained was then homogeneously moistened with the aqueous solution of the polyvinyl pyrrolidone.
Moist screening: 1.5 mm mesh size Dryings in a circulating air drier at 45°C
Dry screening: 1.0 mm mesh size
The dry granulate was pressed into tablets- after addition of the magnesium stearate.
Tablets: 6 mm 0, faceted on both sides, dividing slot on one aide, biplanar
202478
Example iv !
Coated tablets containing 25 mg of 5-chloro-2-(1.A-dioxa-S-aza-spiro/?. dp<-An-8-vl)-benzoic acid
The tablet cores were prepared analogously to Example H.
Pressing was to biconvex coated tablet cores of 80.0 mg weight, 6 mm 0 and radius of curvature 5 mm.
The cores were coated with a conventional sugar suspension to a weight of 110 mg in a coating pan and subsequently polished with a polish suspension.
202478
Claims (35)
1. Compounds of general formula la, S JZ. JL ^R6 ^ 2 n wherein represents a fluorine, chlorine or bromine atom or an amino, cyano, hydroxy, ^ alkoxy or phenyl-(C^ ^ alkoxy) group; R^ and R^, together with the nitrogen atom to which they are attached, represent an N-CC^ ^ alkyl)-cyclo-hexylamino group; an N-(C^ ^ alkyl)-phenylamino or N-(C^ ^ alkyl)-benzylamino group; a ^ alkylenimino group; a piperidino group (substituted by a alkyl, ^ alkoxy, ^ alkoxycarbonyl or phenyl group); a piperidino group (substituted by 2, 3 or 4 alkyl groups); a morpholino or thiomorpholino group (each optionally substituted by 1 or 2 alkyl groups); a piperazino group (substituted in the 4-position by a Cj ^ alkyl, C^ ^ alkoxycarbonyl, phenyl, halophenyl, pyridyl, benzyl or furoyl group); a saturated or partly unsaturated aza-bicycloalkyl group; or a g 1f4-dioxa-8-aza-spiro-alkyl^pyrrolidine or tetrahydro-pyridino group; and W represents a carboxy, aminocarbonyl, cyano or C2alkoxycarbonyl group; and their acid addition salts and, where W represents a carboxy group, their salts with bases.
2. Compounds as claimed in claim 1 wher 202478 - 39 - Rj. represents a chlorine or bromine atom or a hydroxy, amino, cyano, benzyloxy or ^ alkoxy group; and R^ together with the nitrogen atom to which they are attached, represent an N-Cc^ ^ alkyl)-cyclo-hexylamino group; a ^ alkylenimino group; a piperidino group (substituted in the 4-position by a alkyl, phenyl, methoxy or ethoxycarbonyl group); a piperidino group (substituted both in the 3- and in the 5-positions by a methyl or ethyl group); a piperidino group (substituted in the 3- and 5-positions by a total of 4 methyl groups); a piperazino group (substituted in the 4-position by a methyl, benzyl, phenyl, chlorophenyl, pyridyl-(2), ethoxycarbonyl or furoyl-(2) group); a morpholino or thiomorpholino group (each optionally substituted by 1 or 2 methyl groups); or a pyrrolidino, tetrahydro-pyridino, N-methyl-phenylamino, N-methyl-benzylamino, 1,4-dioxa-8-aza-spiro[4,5]decan-S-yl, 1>4-dioxa-8-aza-spiro[4,6]undecan-3-yl, 3-aza-bicyclo-nonan-3-yl, tetrahydro-3-benzazepin-3-yi, decahydro-3-benzazepin-3-yl, tetrahydro-isoquinolin-2-yl, octahydro-isoquinolin-2-yl, decahydro-isoquinolin_2-yl or octahydro-isoindol-2-yl group; and W represents a carboxy, aminocarbonyl, methoxy-carbonyl or cyano group.
3.. Compounds as claimed in claim 2 wherein R^ is present in the 5-position of the benzene ring.
4# Compounds as claimed in claim 3 wherein . R,. represents a ^ alkoxy group or a chlorine or bromine atom; R^ and R^ together with the nitrogen atom to which they are attached, represent a g alkylenimino group - 40 - 202478 or a l,4-dioxa-8-aza-spiro[4,5]decan-8-yl, l,4-dioxa-8-aza-spiro[4,6]undecan-8-yl, decahydro-3-benzazepino or 4-methoxy-piperidino group; and W represents a carboxy group.
5. 5-Chloro-2-(1,4-dioxa-8-aza-spiro[4,5]decan-8-yl)-benzoic acid and its acid addition salts.
6. Physiologically compatible salts of compounds of general formula la as defined in claim 1-
7. Compounds as claimed in claim 1 other than that claimed in claim 5 as herein specifically disclosed in any one of Examples A to K.
8. A process for the preparation of compounds of general formula la as defined in claim 1 wherein R<. represents an amino group which comprises reducing a compound of formula II, °2H-CX-r6 ui) V (wherein R,, R_. and W are as defined in claim 1). b /
9. A process as claimed in claim 8 wherein reduction is effected by means of catalytically activated hydrogen, hydrazine in the presence of Raney nickel, nascent hydrogen or a metal salt.
10. A process as claimed in claim 8 or claim 9 wherein the reduction is effected at ambient temperature.
11. A process for the preparation of compounds of general formula la as defined in claim 1 wherein T - 41 - O ■"! ,( -I A U- U £14/3 represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom which comprises reacting a compound of formula la as defined in claim 1 (wherein R,. represents an amino group) with a nitrite and subsequently heating the diazonium salt thus obtained if required in the presence of copper or of an V V rc d - appropriate copper (3T) saltj. 0
12. A process as claimed in claim 11 wherein the diazonium salt is prepared at temperatures of from -10 to +5°C.
13. A process as claimed in claim 11 or claim 12 wherein a fluoroborate, a hydrosulfate in the presence of sulfuric acid or a hydrochloride in the presence of copper, copper(l) chloride/hydrochloric acid, copper(l) bromide/ hydrobromic acid or trisodium-copper(I) tetracyanide at pH 7 is heated to give the desired compound of formula la.
14. A process as claimed in any one of claims 11 to 13 wherein the diazonium salt is heated to from 15 to 90°C.
15. A process for the preparation of compounds of general formula la as defined in claim 1 wherein R<- represents a C^-6 alkoxy or phenyl(C^, ^ alkoxy) group which comprises alkylating a compound of formula la as defined in claim 1 (wherein R represents a hydroxy group) with a compound of formula III, f D - R5 (III) (wherein R^ represents a ^ alkyl or phenyl(C^ alkyl) group and D represents a nucleophilically exchangeable group or, together with a hydrogen atom on the a carbon of 1* IIIKI. *16JUN|984 * - 42 - 202478 R^, a diazo group) followed where required by hydrolysis of the product thus obtained whereby the desired compound of formula la is obtained.
16. A process as claimed in claim 15 wherein the alkylation is effected at temperatures of from 15 to 70°C.
17. A process as claimed in claim 15 or claim 16 wherein alkylation is effected by means of a diazoalkane.
18. A process as claimed in claim 15 or claim 16 wherein alkylation is effected by means of an alkyl halide or alkyl sulfonic acid ester in the presence of a base.
19. A process for the preparation of compounds of general formula la as defined in claim 1 wherein W represents a carboxy group which comprises hydrolysing a compound of formula la as defined in claim 1 (wherein W represents a cyano, aminocarbonyl or ^ alkoxycarbonyl group).
20. A process as claimed in claim 19 wherein the hydrolysis is effected in the presence of hydrochloric acid, sulfuric acid, sodium hydroxide or potassium hydroxide.
21.. A process for the preparation of acid addition salts of compounds of general formula la as defined in claim :1 which comprises reacting a compound of formula la as defined in claim 1 with an acid.
22. A process for the preparation of salts of compounds of general formula la as defined in claim 1 wherein W represents a carboxy group with bases which comprises reacting a compound of formula la as defined in claim l (wherein W represents a carboxy group) with a base. - 43 ~ 202478
23. A process as claimed in claim 2-1 or claim 22 for the preparation of physiologically compatible salts.
24. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.
25. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples A to K.
26. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 3 to 25.
27. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula la as defined in claim 1 or a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipiento
28. Compositions as claimed in claim 27 in a form suitable-for oral, rectal or parenteral administration.
29. Compositions as claimed in claim 27 or claim 28 in the form of plain tablets, coated tablets, capsules, suppositories, suspensions and solutions.
30. Compositions as claimed in any one of claims 27 to 29 in the form of dosage units.
31. Compositions as claimed in claim 30 wherein each dosage unit contains from 5 to 200 mg of active ingredient.
32. Compositions as claimed in claim 31 wherein each dosage unit contains from 5 to 50 mg of active ingredient.
33. Compositions as claimed in any one of claims 27 to 32 wherein the active ingredient comprises a compound of formula la as claimed in claim 5 or a physiologically compatible salt thereof.
34. Pharmaceutical compositions substantially as herein described in any one of Examples I to IV. - 44 -
35. Compounds of general formula Ia-as defined in claim 1 and their physiologically compatible salts suitable for use as lipid lowering agents. BALDWIN, SON & CAREY ATTORNEYS FOR THE APPLICANTS
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19792928352 DE2928352A1 (en) | 1979-07-13 | 1979-07-13 | Hypoglycaemic 2-amino-benzamido-ethyl-benzoic acid derivs. - prepd. e.g. by reaction of 2-amino-benzoic acid derivs. with 4-aminoethyl-benzoic acid derivs. |
| DE19792949259 DE2949259A1 (en) | 1979-07-13 | 1979-12-07 | Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity |
| DE19803016651 DE3016651A1 (en) | 1980-04-30 | 1980-04-30 | Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity |
| DE19803016650 DE3016650A1 (en) | 1979-07-13 | 1980-04-30 | Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity |
| NZ194317A NZ194317A (en) | 1979-07-13 | 1980-07-11 | Benzoic acid derivatives and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ202478A true NZ202478A (en) | 1984-11-09 |
Family
ID=27510576
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ20247880A NZ202478A (en) | 1979-07-13 | 1980-07-11 | Substituted amino-substituted benzene derivatives and pharmaceutical compositions |
Country Status (1)
| Country | Link |
|---|---|
| NZ (1) | NZ202478A (en) |
-
1980
- 1980-07-11 NZ NZ20247880A patent/NZ202478A/en unknown
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