IE54262B1 - Chemical compounds - Google Patents
Chemical compoundsInfo
- Publication number
- IE54262B1 IE54262B1 IE2266/82A IE226682A IE54262B1 IE 54262 B1 IE54262 B1 IE 54262B1 IE 2266/82 A IE2266/82 A IE 2266/82A IE 226682 A IE226682 A IE 226682A IE 54262 B1 IE54262 B1 IE 54262B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- product
- carbon atoms
- compounds
- compound
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 38
- -1 aminomethyl 1H-indol-4-methanol Chemical compound 0.000 claims abstract description 75
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 32
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 125000005843 halogen group Chemical group 0.000 claims abstract description 14
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 12
- 239000000460 chlorine Substances 0.000 claims abstract description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 11
- 239000011707 mineral Substances 0.000 claims abstract description 11
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 10
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 9
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 9
- 235000005985 organic acids Nutrition 0.000 claims abstract description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052740 iodine Chemical group 0.000 claims abstract description 8
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims abstract description 7
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 4
- DITHIFQMPPCBCU-UHFFFAOYSA-N propa-1,2-diene Chemical compound [CH]=C=C DITHIFQMPPCBCU-UHFFFAOYSA-N 0.000 claims abstract description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 19
- 150000007513 acids Chemical class 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 12
- 150000004820 halides Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- PEMZQGFPOMEHPI-UHFFFAOYSA-N [1-(aminomethyl)indol-4-yl]methanol Chemical class C1=CC=C2N(CN)C=CC2=C1CO PEMZQGFPOMEHPI-UHFFFAOYSA-N 0.000 claims description 5
- 150000002680 magnesium Chemical class 0.000 claims description 5
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 230000003276 anti-hypertensive effect Effects 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 150000002923 oximes Chemical class 0.000 claims description 4
- SVLZRCRXNHITBY-UHFFFAOYSA-N 4-chloro-1h-indole Chemical compound ClC1=CC=CC2=C1C=CN2 SVLZRCRXNHITBY-UHFFFAOYSA-N 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 claims description 3
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000002220 antihypertensive agent Substances 0.000 claims 2
- 150000001728 carbonyl compounds Chemical class 0.000 claims 2
- 229940125898 compound 5 Drugs 0.000 claims 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 claims 1
- 229940125758 compound 15 Drugs 0.000 claims 1
- 230000001035 methylating effect Effects 0.000 claims 1
- 150000002475 indoles Chemical class 0.000 abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 7
- 239000001257 hydrogen Substances 0.000 abstract description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 6
- 230000011987 methylation Effects 0.000 abstract description 3
- 238000007069 methylation reaction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 99
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- 239000000377 silicon dioxide Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000012280 lithium aluminium hydride Substances 0.000 description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000004872 arterial blood pressure Effects 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 208000025865 Ulcer Diseases 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000004678 hydrides Chemical class 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 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 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
- 229920002472 Starch Polymers 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BVSGXWCTWBZFEV-UHFFFAOYSA-N 1h-indol-4-ylmethanol Chemical compound OCC1=CC=CC2=C1C=CN2 BVSGXWCTWBZFEV-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 208000037849 arterial hypertension Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- WDJQAYUPVJEQJW-UHFFFAOYSA-N chloroform;n,n-diethylethanamine;methanol Chemical compound OC.ClC(Cl)Cl.CCN(CC)CC WDJQAYUPVJEQJW-UHFFFAOYSA-N 0.000 description 2
- ULGGPDHVFPOYQP-UHFFFAOYSA-N chloroform;n,n-diethylethanamine;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl.CCN(CC)CC ULGGPDHVFPOYQP-UHFFFAOYSA-N 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- JFDDFGLNZWNJTK-UHFFFAOYSA-N indole-4-carbaldehyde Chemical compound O=CC1=CC=CC2=C1C=CN2 JFDDFGLNZWNJTK-UHFFFAOYSA-N 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000001187 pylorus Anatomy 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 2
- 231100000397 ulcer Toxicity 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- KTOQRRDVVIDEAA-UHFFFAOYSA-N 2-methylpropane Chemical compound [CH2]C(C)C KTOQRRDVVIDEAA-UHFFFAOYSA-N 0.000 description 1
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 1
- KRTGJZMJJVEKRX-UHFFFAOYSA-N 2-phenylethan-1-yl Chemical compound [CH2]CC1=CC=CC=C1 KRTGJZMJJVEKRX-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JKLIMAKWIYEWTK-UHFFFAOYSA-N C(C)(=S)OC1=NC=CC=C1 Chemical compound C(C)(=S)OC1=NC=CC=C1 JKLIMAKWIYEWTK-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- NOTFZGFABLVTIG-UHFFFAOYSA-N Cyclohexylethyl acetate Chemical compound CC(=O)OCCC1CCCCC1 NOTFZGFABLVTIG-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 241000283986 Lepus Species 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FQYUMYWMJTYZTK-UHFFFAOYSA-N Phenyl glycidyl ether Chemical compound C1OC1COC1=CC=CC=C1 FQYUMYWMJTYZTK-UHFFFAOYSA-N 0.000 description 1
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- BQOWUDKEXDCGQS-UHFFFAOYSA-N [CH]1CCCC1 Chemical compound [CH]1CCCC1 BQOWUDKEXDCGQS-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- 231100000403 acute toxicity Toxicity 0.000 description 1
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- 235000019270 ammonium chloride Nutrition 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
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- 150000005840 aryl radicals Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- ZTZTWQPPCCBBML-UHFFFAOYSA-N azane;ethyl acetate;methanol Chemical compound N.OC.CCOC(C)=O ZTZTWQPPCCBBML-UHFFFAOYSA-N 0.000 description 1
- GKDUGYQHQFCXKM-UHFFFAOYSA-N azane;methanol;methyl acetate Chemical compound N.OC.COC(C)=O GKDUGYQHQFCXKM-UHFFFAOYSA-N 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- WVMHLYQJPRXKLC-UHFFFAOYSA-N borane;n,n-dimethylmethanamine Chemical compound B.CN(C)C WVMHLYQJPRXKLC-UHFFFAOYSA-N 0.000 description 1
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
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- USYYTAZBXJZVHZ-UHFFFAOYSA-N ethanesulfonic acid;methane Chemical class C.CCS(O)(=O)=O USYYTAZBXJZVHZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
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- 150000002431 hydrogen Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 230000003902 lesion Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
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- 230000009245 menopause Effects 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
- RMCDUNHIVVEEDD-UHFFFAOYSA-N methylcyclopropane Chemical compound [CH2]C1CC1 RMCDUNHIVVEEDD-UHFFFAOYSA-N 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N methylenecarboxanilide Natural products CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940105631 nembutal Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005270 trialkylamine group Chemical group 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Derivates of aminomethyl 1H-indol-4-methanol as well as their salts of addition with mineral or organic acids, characterized in that they answer to the general formula I : see diagramm : EP0076713,P28,F1 in which R represents a hydrogen atom, or an alkyl radical containing from 1 to 6 carbon atoms or a phenyl alkyl radical containing from 7 to 10 carbon atoms and R1 and R2 , being identical or different, each represents a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, possibly substituted, except in the case of the methyl radical, by one or more halogen atoms or by one or more hydroxy, phenyl or phenoxy radicals themselves possibly substituted by one or more halogen atoms or by one or more hydroxy, methyl, methoxy or acetamido radicals, R1 and R2 can also represent a cycloalkyl radical containing from 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms or an allyl or propargyl radical and the dotted line represents the possible presence of a carbon-carbon bond. 1. Claims for the Contracting State : AT Process for preparing derivatives of aminomethyl 1H-indol-4-methanol as well as their salts of addition with mineral or organic acids, answering to the general formula I : see diagramm : EP0076713,P31,F2 in which R represents a hydrogen atom, or an alkyl radical containing from 1 to 6 carbon atoms or a phenyl alkyl radical containing from 7 to 10 carbon atoms and R1 and R2 , being identical or different, each represent a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, possibly substituted, except in the case of the methyl radical, by one or more halogen atoms or by one or more hydroxy, phenyl or phenoxy radicals themselves possibly substituted by one or more halogen atoms or by one or more hydroxy, methyl, methoxy or acetamido radicals, R1 and R2 can also represent a cycloalkyl radical containing from 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms or an allyl or propargyl radical and the dotted line represents the possible presence of a carbon-carbon bond, characterized in that a product with the formula II : see diagramm : EP0076713,P31,F4 in which R has the significance already indicated, is made to react with trimethyl silyl cyanide, so as to obtain a product with the formula III : see diagramm : EP0076713,P31,F5 in which R has the significance already indicated, which is reduced, so as to obtain a product with the formula IA : see diagramm : EP0076713,P32,F1 in which R has the significance already indicated which : either is isolated, and if desired, is salified, or the said product with the formula IA is made to react with a carbonyl derivative with the formula IV : see diagramm : EP0076713,P32,F3 in which R alpha and R beta are such that : see diagramm : EP0076713,P32,F5 has the significance of R1 already indicated with the exception of a hydrogen atom and a methyl radical, in the presence of a reducing agent, so as to obtain a product with the formula IB : see diagramm : EP0076713,P32,F7 or I'B see diagramm : EP0076713,P32,F9 in which R, R alpha and R beta have the significance already indicated, which product with the formula IB or I'B is isolated and if desired, salified or which product with the formula IB is submitted to the action of a halogenide with the formula V : X-R'2 in which X represents a chlorine, bromine or iodine atom, and R'2 has the significance of R2 already indicated with the exception of hydrogen, so as to obtain a product with the formula IC : see diagramm : EP0076713,P32,F2 in which R, R alpha, R beta and R'2 have the significance already indicated which is isolated and if desired, salified, or the said product with the formula IA is made to react with a carbonyl derivative with the formula IVa : see diagramm : EP0076713,P32,F4 in which Hal represents a chlorine, bromine or iodine atom, and see diagramm : EP0076713,P32,F6 is such that -CH2 -R'1 has the significance of R1 already indicated, with the exception of a hydrogen atom and of the methyl radical, then the derivative obtained is submitted to the action of a reducing agent, so as to obtain a product with the formula ID : see diagramm : EP0076713,P32,F8 in which R and R'1 have the significance already indicated, which product with the formula ID is either isolated and if desired, salified, or is submitted to the action of a halogenide with the formula V : X-R'2 in which X and R'2 have the significance already indicated, so as to obtain a product with the formula IE : see diagramm : EP0076713,P32,F10 in which R, R'1 and R'2 have the significance already indicated, which is isolated, and if desired, salified, or the said product with the formula IA is submitted to methylation, so as to obtain a product with the formula IF : see diagramm : EP0076713,P33,F2 in which R has the significance already indicated, which is either isolated, and if desired, salified, or is made to react with a halogenide with the formula V defined above, so as to obtain a product with the formula IG : see diagramm : EP0076713,P33,F4 in which R and R'2 have the significance already indicated, which is isolated and if desired, salified, and if desired, the said products with the formulae IA , IB , I'B , IC , ID , IE , IF and IG , are submitted to the action of a reducing agent of the indole nucleus, so as to obtain a product with the formula I' : see diagramm : EP0076713,P33,F7 in which R, R1 and R2 have the significance already indicated, which is isolated, and if desired, salified.
Description
The present invention is concerned with new derivatives of aminomethyl lH-indole-4—methanol as well as thair salts, the preparation process, the application as medicaments of the new derivatives, the compositions containing them and the intermediate^ for their preparation.
The subject of the invention is new derivatives of aminomethyl lH-indole-4-methanol, as well as their salts of addition with mineral or organic - acids characterised in that they have the general formula (I): H9 - 2 in which R represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms or a phenylalkyl radical containing from 7 to 10 carbon atoms; either R^ and R2, which may be identical or different, each represents a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted, except in the case of the methyl radical, by one or more halogen atoms, by one or more hydroxy radicals or by one or more phenyl or phenoxy radicals themselves optionally substituted, or R1 and R2 can also represent a eycloalkyl radical containing from 3 to 7 carbon atoms, a cycloalkyl-alkyl radical containing from 4 to 7 atoms or an allyl or propargyl radical; and the broken line represents the optional presence of a carbon-carbon bond.
In the general formula (I) and in what follows, the term alkyl radical containing from 1 to 6 carbon atoms, preferably designates a methyl, ethyl or n-propyl radical, the term phenylalkyl radical preferably designates a benzyl or a phenethyl radical, the term linear or branched alkyl radical containing from 1 to 8 carbon atoms designates for example a methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl or pentyl radical and preferably a methyl, ethyl, propyl, isopropyl or isobutyl radical; the alkyl radical when it is substituted preferably includes a single substituent; 542G2 the phenyl nucleus of the phenylalkyl or phenoxyalkyl radicals is optionally substituted by one or more halogen atoms, for example by fluorine or bromine and particularly by chlorine or by one or more hydroxy, methyl, methoxy or acetamido radicals; the term cycloalkyl radical containing from 3 to 7 carbon atoms signifies for example a cyclopropyl radical but it is preferred to be a cyclobutyl or cyclopentyl radical; the term cycloalkyl-alkyl radical containing from 4- to 7 carbon atoms signifies preferably a cyclopropylmethyl radical* The salts of addition with mineral or organic salts can for example be the salts formed with hydrochloric hydrobromic, hydriodic , nitric, sulphuric, phosphoric acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic or aspartic acid, alkanesulphonic acids such as methane- and ethanesulphonic acids, arylsulphonic acids such as benzene- and paratoluene-sulphonic acids and arylcarboxylic acids.
Among the products which are the subject of the invention there can in particular be cited the derivatives having the formula (I) above as well as their salts of addition with mineral or organic acids, - 4 characterised in that, in the said formula (I), R represents a hydrogen atom, an alkyl radical containing from 1 to 3 carbon atoms, or a benzyl radical and and Rg each represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted.
Among these, there can more particularily be cited the derivatives characterised in that in the said formula (I), R represents a hydrogen atom, R^ and Rg each represent a hydrogen atom or a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by a phenyl or phenoxy radical which themselves may optionally be substituted b.y a halogen atom, and the broken line represents a carbon-carbon bond, and quite particularily: -a - (aminomethyl)ΊΗ-indole-4—methanol, - β - // (1 methylethyl)-amino/methyl/-lH-indole-4-methanol, - a - (methylamino)methyl-lH-indole-4—methanol, - a -// (l-propyl)amino/methyl/-lH-indole-4-methanol, as well as their salts of addition with mineral or organic acids.
There can also be cited the other derivatives mentioned further on in the experimental part.
The invention equally has as its subject a process for the preparation of the derivatives, as I defined by the formula (I) above, as well as their »42(52 - 5 salts selected from the following: A product with the formula (III) (CH^SiO C=N (III ) in which R has the meanings already indicated may be 5 reduced, so as to obtain the product with the formula (1^, (lj in which R has the meanings already indicated. If desired the product of formula (III) may be obtained by reacting a product with the formula (II): Cl: in which R has the meanings already methyl silyl cyanide.
The product with the formula with a carbonyl derivative with the indicated with tri(Ift) may be reacted formula (IV): 0=c R/, (IV) ia which He and Εβ are such that has the meanings of already indicated, with the exception of a hydrogen atom and of the methyl radical, in the presence of a reducing agent, so as to obtain a product of the formula (I-) :: V R* R in which R, Ra and R^ have the already indicated 1Ί meanings.
The product with the formula (Ιβ) may be reacted with a halide with the formula (V): X-R1 (V) in. which X represents a chlorine, bromine or iodine atom, and R’ 2 has the meanings of R2 indicated already, with the exception of a hydrogen atom, so as to obtain a product with the formula (Iq) already indicated.
The product with the formula (1A) may also be reacted with a carbonyl derivative with the formula (IVa): ί Hal-C (iva) in which Hal represents a chlorine, bromine or iodine atom and 0 -A - R'i is such that : lias the meanings of R^ already indicated, with the exception 15 of a hydrogen atom and of a methyl radical, then the product obtained is submitted to the action of a reducing agent, so as to obtain a product with the formula (Ιθ) 4 2 6 2 in which R and R'j have the meanings already indicated.
The product with the formula (Ιθ) may, if desired, be reacted with a halide with the formula (V) as herein5 before defined so as to obtain a product of formula (Ip) : in which R, R'j and R'g have the already indicated meanings. The product with the formula (I&) may alternatively be methylated so as to obtain a product with the formula (Ip) : R in which R has the already indicated meanings.
The product of formula dp) may also be reacted with a halide with the formula (V) defined above so as to obtain the product with the formula (1^) : '2 /CH3 HO (IG> in which R and R'^ have the already indicated meanings.
The above products with the formulae d&), (Ιβ), (I'B), (Ic), (ID), dE), dp) and (IQ) may, if desired, be treated with a reducing agent for the indole nucleus, so as to obtain a product with the formula (I') : in which R, R-j_ and R2 have the already indicated meanings.
The reaction of the product with the formula (II) with the trimethylsilyl cyanide is advantageously carried out in the presence of a catalytic quantity of a Lewis acid, such as aluminium chloride or preferably zinc iodide. 54263 - 10 The reduction of the product with the formula (III) ia preferably carried out by lithium aluminium hydride in a solvent such as tetrahydrofuran.
The reaction of the product with the formula(1^) with the carbonyl derivative of formula (TV) is advantageously carried out in a solvent such as acetonitrile or preferably an alkanol such as ethanol or particularly methanol.
The reaction can, if desired, be carried out in the presence of a hase such as triethylamine or pyridine.
The reduction agent leading: to the product with the formula (Ig) or (I'g) can be an alkaline borohydride or cyano borohydride, such as those of potassium or sodium; it is preferred to use gaseous hydrogen in the presence of a catalyst based: on palladium.
The halide with the formula (V) is preferably an iodide.' It is advantageous to make it react with the product with the formulae (Ig), (ID) or (Ip) in the presence of an acid binding agent such for example as an alkaline carbonate such as potassium carbonate, an alkaline, bicarbonate such as sodium bicarbonate, an alkaline hydroxide such as sodium or potassium hydroxide, a tertiary amine, such as', trialkylamine or pyridine, or even an alkaline alcoholate such as sodium ethylate.
The carbonyl derivative with the formula (IV ) is preferably a chloride. In particular the operation is carried out in tetrahydrofuran in the presence of a base. - 11 The reducing agent leading to the product with the formula (IR) is preferably a metallic hydride, for example lithium aluminium hydride.
The methylation of the product with the formula (1^) is preferably carried out by the reaction of the said product with the formula (1^) with an alkyl haloformate, preferably ethyl chloroformate, then reduction of the carbonate obtained, preferably by lithium aluminium hydride at reflux in tetrahydrofuran.
The reaction of the product of the formula (1^) with the alkyl haloformate is advantageously carried out in the presence of a base such as sodium carbonate or triethylamine. The methylation can also be carried out for example by the action of formal and methanol, followed by reduction with sodium borohydride.
The agent for reduction of the indole nucleus is preferably the complex borane-trimethylamine in a solvent such as dioxan in the presence of hydrochloric acid.
Also the subject of the invention, is a further preparation process to that described above, characterised in that a product with the formula (VII) (VII) Rz in which R' has the meanings already indicated, is converted into the oxime in a to the ketone which is then reduced, so as.to obtain a product with the formula (J'^) 1H- {i'a’ in which R' has the meanings of R with the exception of hydrogen.
The compound of formula (VII) may be obtained by conversion of a product with the formula Cl (VI) in which R' has the meanings already indicated into the corresponding magnesium derivative and subsequent reaction with an acetylation agent.
The compound of formula (VI) may be obtained from 4chloro-indole by reaction with a halide with the formula (V ) : a Hal-R* xn which Hal represents a chlorine, bromine or iodine atom and R* has the meanings already indicated. - 13 The halide with the formula (V) is preferably al a chloride. It is advantageous to make it react with 4-chloro-indole ia the presence of an acid binding agent such as an alkaline carbonate or hydroxide, sodium carbonate or potassium hydroxide for example and preferably sodium hydroxide.
The formation of the magnesium derivative, of the product with the formula (VI) is preferably carried out by making the product with the formula (VI) react with magnesium in an appropriate solvent such as tetrahydrofuran, in the presence of a small quantity of dibromoethane.
The acetylation agent can for example be an acetyl halide, a mixed anhydride such as the pivaloyl acetic mixed anhydride or 2-pyridyl thioacetate, but preferably acetic anhydride.
It is an advantage to operate at low temperatures, e.g. o between -20 and -40 C, and preferably the magnesium derivative is added to the acetylation reagent in a solvent such as tetrahydrofuran.' The oximation of the product with the formula VII is preferably carried out in a basic medium; it is an advantage to use a mixture of terbutyl nitrite, 4 2 6 3 - 14 potassium terbutylate, and. ter-butanol,in a solvent such as tetrahydrofuran. The operation is carried out at about 0°C, preferably between 0°C and 5°C· Because the oxime is not very stable it is 5 preferable for its reduction to take place in situ immediately after its formation. This reduction can be carried out in two operations, by reduction of the oxime function, for example by catalytic hydrogenation preferably using palladium as catalyst, then reduction of the ketone function preferably with sodium borohydride.
It is preferred to operate in a single operation, by reduction with lithium aluminium hydride for example.
Equally the subject of the invention is a further process for the preparation of the products with formula (I) in which R^ represents a linear or branched alkyl radical, containing from 2 to 8 carbon atoms, substituted by one or more hydroxy radicals of which at least one hydroxy is on the carbon in position 2 and furthermore optionally substituted by one or more halogen atoms or by one or more phenyl or phenoxy radicals themselves optionally substituted on the phenyl nucleus, and R2 represents a hydrogen atom or an alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by an aryl radical, which variant is characterised in that a product with the formuls (IR) 4 3 6 2 R in which. R is defined, as above and R'^ represents an alkyl radical containing from 1 to 8 carbon atoms, cpticnally substituted by a phenyl radical corresponding to a product with the formula (IQ) in which -CB^-R* has the meanings of R2 previously indicated, is treated witha reagent with the formula (VIII): H.C — CH-R, 1 (VIII) in which R^is such that -CH^CH—R^ has the meanings OH of Rj. indicated above, so as to obtain a product with the formula (Ij) (Ix) If desired the compound of formula (Ij) may be submitted to the action of a reducing agent, so as to obtain a compound with the formula (Ij) : S42G2 The compound of formula (Ij) may, as for the products with the formulae (Ιβ), (Ip) or (Ip) if desired be submitted to the action of a halide with the formula (V) as previously defined, so as to obtain a product with the formula (Ij,): (jIH-R! OH (IK) The products with the formulae (1^.), (Ij) or (IR) may also be submitted to the action of a reducing agent for the indole nucleus, so as to obtain the corresponding reduced pro10 duct.
The reaction of the product with the formula (I„) with the reagent with the formula (Vl) is preferablycarried out in an alcohol such as methanol or ethanol, or in an aromatic hydrocarbon. 542 62 - 17 The reducing agent for the product with the formula (1^) is preferably hydrogen in the presence of a catalyst based on palladium. In the product with the formula (1^) R2 particularly represents a benzyl radical.
The halide with the formula (V) and the reduction agent for the indole nucleus are preferably those already mentioned.
The derivatives with the formula (I) present a basic 10 character and may be converted into their corresponding salts. The salts of addition of these derivatives of formula (I) can advantageously be prepared by making a mineral or organic acid react, in substantially stoichiometric proportions with the said derivative with the formula (I). The salts can be prepared without isolating the corresponding bases.
The derivatives which are the subject of the present invention present very useful pharmacological properties; they are in particular endowed with remarkable antihypertensive and hypotensive properties, as well as for certain subjects antiulcer properties.
These properties are illustrated further on in the experimental part.
These properties justify the use of these derivatives 25 of aminomethyl lH-indole-4-methanol as well as of their pharmaceutically acceptable salts as medicaments. - 18 The present application thus also has as its subject the application as medicaments of the derivatives of aminomethyl lH-indole-4.~methanol, defined by formula (X), as well as of their salts of addition with pharmaceutically acceptable acids.
Among the medicaments which are subjects of the invention, preferred are the medicaments characterised in that they are constituted hy new derivatives of aminomethyl-IH- indole-a-methanol corresponding to the formula (I) in which R represents a hydrogen atom, an alkyl radical containing from 1 to 3 carbon atoms or a benzyl radical and R^ and Rg each represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted as well as their salts of addition with pharmaceutically acceptable acids.
Among these there are particularly held in preference those having the formula (1) in which R represents a hydrogen atom and R^ and R2 each represent a hydrogen atom or a linear or branched alkyl radical, containing from 1 to 8 carbon atoms, optionally substituted by a phenyl or a phenoxy radical, itself optionally substituted by a halogen atom, and the broken line represents a carbon-carbon bond, as well as their salts of addition with pharmaceutically acceptable acids - 19 Among these latter there are more particularly held, in preference those derivatives of which the names follow:: - a (aminomethyl)-lH-indole-4—methanol, - a [[(1-methylethyl)-aminolmethyl]-lH-indole-4-methanol 5 -a (methylamino)methyl-lH-indole-4-methanol - a [[(l-propyl)aminolmethyl]-lH-indolef-4-aethanol as well as their salts of addition with pharmaceutically acceptable acids.
The medicaments according to the invention find 10 use for example in the treatment o£ essential arterial hypertension, of hypertension of the fifties, of the menopause, of the diabetic, of the obese and of the plethoric as well as in the treatment of arterial hypertension of the aged or one suffering from arterial sclerosis, and in the treatment of hypertension of renal origin. They also find use in the treatment of ulcers of various origins.
The usual dose variable according to tbe product utilised, the subject treated and the disorder concerned, can be for example from 5 mg to 500 mg per day by oral route in man, of the product of example 1.
Also a subject of the invention are pharmaceutical compositions which contain at least one of the previously mentioned derivatives, or one of its salts of addition with pharmaceutically acceptable acids, as active principle As medicaments, the derivatives having the formula - 20 (I) and their salts of addition with pharmaceutically acceptable acids can be incorporated in pharmaceutical compositions intended for the digestive or the parenteral route.
These pharmaceutical compositions can for example be solid or liquid and can be presented ia the pharmaceutical forms currently used for human medicine, as for example, plain or sugar coated tablets, capsules, gelatin capsules, granules, suppositories or injectable preparations; they may be prepared according to the usual methods. The active principle or principles can be incorporated with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, the various wetting, dispersing or emulsifying agents and preservatives.
In addition the invention is extended to the new industrial products useful in particular for the preparation of the derivatives corresponding to the formula (I), that is to say the products with the formula (III); in which R has the meanings already indicated.
The products with the formula (II) can be prepared by making 4-formyl indole react with a halide with the formula (Va): Hal-R' (Va) in which Hal and R' have the meanings already indicated, for example, by phase transfer according to the technique described by Hosco et al in Synthesis 2, 124 (1976), In the presence of sodium hydroxide, benzene and a quaternary ammonium salt such as tetrabutylammonium chloride or tetrabutylammonium hydrogenosulphate.
There are now given in a non-limiting way, examples of putting the invention into operation: - 22 EXAMPLE 1 s a -(aminomethyl)-lH-lndole-4-methanol fumarate Under an inert atmosphere 1 al of trimethylsilyl cyanide is agitated for 30 minutes with 1 g of 4-formylindole and a catalytic quantity of zinc iodide, the excess cyanide is eliminated under reduced pressure, then 350 ml of lithium aluminium hydride in solution in tetrahydrofuran is added, agitation is continued for 16 hours at 0°0, the excess hydride is destroyed by addition of dilute aqueous sodium hydroxide, then after filtering, washing with tetrahydrofuran, drying on sodium sulphate, concentrating, and purifying by chromatography on silica (eluant : ethyl acetate - methanol - ammonia 92-5-3) O'. 8 g of an oily product is obtained.
Formation of the Fumarate .5 g of the base as obtained above is dissolved z in 200 enr of isopropanol and 3.6 g fumaric acid is added. After heating to reflux for 15 minutes·, concentrating to 100 cm^, chilling, filtering, drying at 60°C under reduced pressure and recrystallising from isopropanol 6 g of the expected product is obtained.
M.Pt. » 196° 0' Analysis C14H16H2°5 ’ 292*294 Calculated: C% 57.55 5.52 H% 9.56 Found: 57.8 5·’* 9 Λ - 25 EXAMPLE 2 : Neutral oxalate of tt-C[(l-methyleth;yl)aiiiino3methyl]-ΙΗ-indole-a-methanol.
Under hydrogen 2.8 g of a-aminomethyl-lH-indole-4-methanol in 50 cm^ of methanol and 20 cm^ of acetone is agitated at 50° C in the presence of 1 g of 10 % palladium-on-carbon, for 4 hours. After filtering, expelling the solvents from the filtrate under reduced pressure at 50° 0, and purifying the residue by chromatography on silica (Eluant ·. chloroform - acetone - trimethyl amine, 6-5-1-), 3 g of the base of the expected product is obtained.
Formation of the neutral oxalate The product obtained above is dissolved in 200 cm^ of isopropanol, 1.73 g of oxalic acid is added, and the oxalate formed crystallises. 200 cm^ of methanol is added, and the whole is heated to reflux until the crystals dissolve. Then after concentrating chilling filtering, drying under reduced pressure, and re-crystallising from ethanol, 2.3 g of the expected product is obtained.
M.Pt. - 275° C.
Analysis : Cp^^^O^ * 263.318 Calculated : C% 63.86 Ξ% 7·27 N %·10.64 Found : C % 63.7 Η % 7·4- N % 10.7 4 2 6 2 - 24 Example 3 ί: a-(methylamino)jmethyl-lH-lndole-4—methanol Stage A : Formation of the carbamate Under an inert atmosphere 4· cnr of ethyl chloroformate is added slowly to a solution of 5.4· g of o-aminomethyl5 1H-indole-4—methanol in 50 cm^ of. methanol and 5.9 cm3 of triethylaminej the whole is agitated for 30 minutes, concentrated, taken up with ethyl acetate, washed with water,dried over sodium sulphate, concentrated, recrystallised from ethyl acetate, and 4.10 g of the expected product is obtained.
Stage B ; Seduction of the carbamate 2 g of lithium aluminium hydride is added to .65 g of the above carbamate, in solution in 700 cur of tetrahydrofuran, under an inert atmosphere. This is taken to reflux for 20 hours, cooled, the excess hydride is destroyed, then by filtering, washing with tetrahydrofuran drying over sodium sulphate, concentrating, and crystallising from ethyl acetate, 2.09 g of the expected product is obtained M. Pt. - 120 °C Analysis CilH14li2° " ^-90. 24 Calculated s C % 69.44 H % 7.42 N % 14.73 Found : 69.4 7.4 14.’6 Example 4 : a-(aminomethyl)Ί-(phenylmethyl)-!H-indole -4-methanol a) !-[!-(phenylmethyl)lg-indol-4-yl]ethanone cm of acetic anhydride in 300 car of anhydrous tetrahydrofuran is cooled to -40°C, then without the temperature rising above -20°0, a magnesium derivative solution [prepared starting with 150 g of 4-ohloro1-phenylmethyl-lH-indole (described in the French Patent Application 2458 549)] is added and the whole is agitated 10 for 1 hour at -20°C to +10°C. After adding a saturated solution of ammonium chloride, the mixture is diluted with water and extracted with ethyl acetate. The organic phases are washed with salt water, drie.d, the solvents are eliminated at 50°C under reduced pressure and the 33 residue obtained is purified by chromatography on silica (Eluant cyclohexane-ethyl acetate (9-1). The crude product is recrystallised from diisopropyl ether and 70 g of the product sought is obtained.
If.’pt, 93°C b) a-(aminomethyl)1-(phenylmethyl)IH-indole-4-methanol A solution of 5.5 g of the above product in 60 cm3 of tetrahydrofuran and 66 cm3 of a IN solution of potassium tert-butylate in tertbutanol is cooled to 0° to +5°C, 13.1 cm3 of tert-butyl nitrite is added and the whole is maintained under agitation in an inert atmosphere for 1 hour. On diluting with water, 542G2 - 26 concentrated acetic acid is added to a pH of 4.5, with agitation for 15 minutes and then neutralisation is carried out with a saturated aqueous solution of sodium bicarbonate. By extracting with ethyl acetate 6.6 g of uz i me is ι .b ι j ined .
A suspension of 9 g of lithium aluminium hydride in 120 cm^ of tetrahydrofuran is cooled to 0 to 5 °C, z the above product in solution ia 120 cnr of tetrahydrofuran is added and the whole is left under agitation for 20 hours at 20 to 25°C. , then cooled to 0 to +5°C. After destroying the excess hydride, taking up with water and then with ethyl acetate, filtering, extracting with ethyl acetate, drying, concentrating to dryness, the residue obtained is purified by chromatograpby on silica (Eluant: chloroform-methanol 1-1), and recrystallised from benzene under reflux; 1,3 g of the expected product is obtained.
M.Pt. - 92°C.
Example 5 i- a-[C(l-methylethyl)amino]methTl]-2,3-dihydro 1H-indole-4—methanol A mixture of 4 g of the product obtained in example 2 (base), 60 cm^ of dioxan, 6.6 g of complex trimethylamine-borane and 9.2 cm^ of 12N hydrochloric acid is agitated for 20 hours at 20°C, then 600 cm^ of water is added. The mixture is then z concentrated under reduced pressure to about 400 cm and washed with ether. After alkalising with sodium - 27 hydroxide, extracting with methyl acetate, chromatographing the residue on silica, eluting with a mixture of ohloroform-acetone-triethylamine (6-3-1), 3 6 of the expected product is obtained. K.Pt » 88°C after recrystallisation from diisopropyl ether.
Analysis : 5^30^2° " 220.316 Calculated: C% 70.87 9.15 N% 12.¼ Found: 71.Ί 9.3 12.6 Example 6: g-(methTlamino)meth,yl-2.3-dihydro-lH-indole-410 methanol.
By operating in a manner analogous to that described in example 5 starting with 4.4 g of product obtained, at Example 3, 2.4 g of the expected product is obtained after chromatographing on silica, eluting with a mixture of methyl acetate-methanol-ammonia (92-5-3) M.Pt.' 132°0 after recrystallisation from benzene.
Analysis: GnHigR2® ’^927263 Calculated : σ % 68¼ H % 8.39 14.'57 Found : 68.6 8.'2 14.4 EXAMPLE 7 ϊ Neutral oxalate of u-[[(1-ethylpropyl)amino]~ methyl]-lH- indole- 4-methanol By operating in a manner analogous to that described in Example 2, starting with 3.45 g of the Ζ v indole derivative and with 10 cur of diethylketone, after chromatographing on silica, eluting with a mixture of chloroform-acetone triethylamine (8-1-1), 4.3 g of 5426 - 28 the base of the expected product is obtained.
The oxalate is formed in isopropanoi with 1 g of oxalic acid and 3.’8 g of the expected product is obtained. M.Pt.' « 212°C after recrystallisation from methanol.
Analysis: °52^46N4°6 " 582.74? Calculated : C % 65.'96 H % 7^96 N % 9 .’61 Pound : 66.2 8.0 9.5 Example 8 : Acid oxalate of a-[[(phenylmethyl)amino]-methyl] lH-indole-4-methanol Stage A : a-C[(phenylcarbonyl)amino]methyl3~lH-indole4-methanol 3.6 g of the product obtained in Example 1 (base), 60 cm3 of tetrahydrofuran and 5 cm3 of triethylamine are mixed together. After cooling to 0 to -5°C, a solution of 3.1 cm3 of benzoyl chloride in 25 cm3 of tetrahydrofuran is added,the mixture is agitated for 30 minutes at 0°C, diluted with water, and the solution is concentrated at o · C to about 50 cm .
Stage B : Acid oxalate of The solution obtained at Stage A is diluted with tetrahydrofuran then,at 0 to +5°C, 5 g of lithium aluminium hydride is introduced and the whole is taken to reflux for one hour, then* eooled·; after adding first tetrahydrofuran with 20 % water, then water, filtering, extracting with ethyl acetate, evaporating the solvent and chromatographing the residue on silica, eluting with 54252 - 29 10 ethyl acetate, 4 g of the expected product is obtained; The product is dissolved at reflux in isopropanol and 2 g of oxalic acid is added. After concentrating, cooling, separating and drying the crystals formed, 4.9 g of the expected product is obtained.' M.Pt. 25O°G (with decomposition) Analysis : ^9^20^2° 5 * 556.381 Calculated:: C & 64.04 H % 6.66 N % 7.86 Found : 63.’9 6.7 7.’δ Example 9 : Acid oxalate.of By operating in a manner analogous to that described in Stage A of Example 8, using 4 g of the indole derivative and 4.5 cm^ of phenylacetyl chloride, the expected product is obtained.
Stage B : Acid oxalate of By operating in a manner analogous to th&t described in Stage B of Example 8, 1.9 g of the expected product (base) is obtained, and then, after recrystallisation in. isopropanol, 2 g of salt. M.Pt. 200°C Analysis : C20H2^205 " 570.408 Calculated: C % 64.85 Found: 64.8 H % 5.99 6.0 N % 7.56 7.6 - 30 Example 10 : a-([(2-hydroxy-3-phenoxy propyl)-amino] methyl]' lffi-indole-4-methanol Stage A a-[((2-hydroxy-3-Phenoxypropyl)-(phenylmethyl)- amino]methylJ-lH-indole-4-methanol 5 A mixture of 3*7 g of the product obtained in Example (base), 50 om^ of methanol and 3.8 cm^ of 1,2-epoxy 3-phenoxypropane is agitated for 65 hours at 20°C.
After dilution with water, saturation with potassium carbonate, extraction with ethyl acetate, drying and evaporating the solvent, the residue is chromatographed on silica, eluting with a mixture of ethyl acetate and benzene (7:3)» and 5.25 g of the expected product is obtained.
Stage B : g-[[(2-hydroxy-3-phenoxypropyl)-amino]15 methyl]- lH-indole-4-methanol The product obtained in Stage A is mixed with a 100 cm^ of methanol and 2.5 g of palladium (10 % on carbon)and maintained under agitation under hydrogen at 4O°C until absorbtion is finished. After filtering, expelling the solvent under reduced pressure and chromatographing the residue on silica, eluting with a chloroform-methanol-triethylamine (9-5-5) mixture, 3.1 g of the expected product is obtained.
Analysis:C19H22N205» 326.398 Calculated : C % 69.92 H % 6.79 N % 8.58 Found: 69.7 6.9 8.5 54202 Example 11: Oxalate of a-[C(l-propyl)amino]methyl]-lH-indole -4-methanol Stage A a-[[(l-oxo-l-propyl)-ainino]methyl]-15-indole4-methanol. g of the product obtained in Example 1, 250 cm^ of tetrahydrofuran and 3 equivalents of triethylamine are mixed together. At 0.5°G, 4.9 cm^ of propionyl chloride in 100 om^ of tetrahydrofuran is added and the whole is then maintained at 0 to +5°C for one hour after' adding water, extracting with ether and chromatographing on silica, eluting with se mixture of chloroform-acetone-triethylamine (6-3-1), 8g of the expected product is obtained.
Stage B : Oxalate of a-CC(l-propyl)'amino]methyl]15 lH-indole-4-methanol The product obtained in Stage A is dissolved x in 300 cur of tetrahydrofuran, 1 equivalent of lithium aluminium hydride is added, and the whole is taken to reflux for 1 hour 30 minutes, then cooled. Tetrahydrofuran with 20 & water and then water are added and after filtering, extracting with ethyl acetate and evaporating the solvent, the product is chromatographed on silica, eluting with a chloroform methanol mixture (7:3).
The product is dissolved in isopropanol at reflux, an equivalent of oxalic acid is added, then by concentrating, cooling, separating the crystals formed and recrystallising - 52 them from an ethanol/methanol mixture (1-1), 6 g of. the expected product is obtained M.Pt. - 202°C.
Example 12 : Neutral fumarate of a-[[di-(l-propyl)-amino]~ methyl)~lH-indole-4-methanol .6 g of the product obtained in Example 1 (base), 200 cm^ of methanol, 8.8 cm^ of propionaldehyde andi 5 g of palladium (10 % on carbon) are mixed together and kept under agitation and under hydrogen at 4O°C. until absorption is finished. After filtering,the solvent is expelled under reduced pressure and the residue is chromatographed on silica, eluting with a cyclohexane-chloroformtriethylamine mixture (6-3-1), and after recystallisation from diisopropyl ether 9.1 g of the expected product (base) is obtained. M.Pt. 78°0. 4.3 g of the above product is dissolved in 100 car of isopropanol and at reflux 1.9 g of fumaric acid is added.
By cooling, separating the salt, drying it and recrystallising it from an isopropanol-methanol mixture (2-1), 3.8 g of the expected salt is obtained.
M.Pt. > 174°C Analysis ; ciaH26N2°3 " 518.419 Calculated .· C % 67.90 H % 8.23 N % 8.80 Found : 67.9 8.3 8.6 - 55 Example 13 :»(-///2-hydroxy-3-(4-acetylaminophenoxy) propyl/,- . amino/ methyl/-ΙΗ-indole -4-methanol.
Stage A jt><-///2-hydroxy 3-(4-acetylaminophenoxy)-propyl/· /phenylmethyl·/-amino/-methyl/lH-indole -4-methanol. By operating in a manner analogous to that described. in Example 10 using 5.5 g of the indole derivative and 8.7 g of 1,2-epoxy propoxy acetanilide (described in J. Pharm. et Pharmacol. £ 559, 1953), after purification by chromatography on silica, eluting with a chloroform-methanol (9-1) mixture, 7.5 g of the expected product is obtained.
Stage B : o/-///2-hydroxy-3-(4-acetylaminophenoxy)-propyl/amino/-methyl/-lH-indole-4-methanol.
By operating in a manner analogous to that described In Example 10, starting with 7.5 g of the product from Stage A, after chromatographing on silica,eluting with a chloroform-methanol-triethylamine (8-1-1) mixture, 3.'9 g of the expected product is obtained.’ Analysis: ^21^25^3^4·" 383.4-51 Calculated: C % 65.78 H % S.57 N % 10.96 Found 65.3 6.8 10.8 Example 14- : Tablets have been prepared corresponding to the formulation: -Neutral oxalate of a-[[(1-methylethyl)amino]methyl](Detail of the excipient : lactose, starch, tale, magnesium sLcarate) IH-indol-4-methanol .......................... 10 mg -Excipient q.s. for a tablet finishing at .....100 mg - 34 Example 15 ! Tablets have been prepared corresponding to the formulation; - a-(methylamino)methyl-lH-indole-4-methanol ..... 20 mg - excipient q.s. for a tablet finishing at .......100 mg (Detail of excipient ; lactose, starch, talc, magnesium stearate) - 35 PHARMACOLOGICAL STUDY A) Determination, of hypotensive activity The hypotensive activity was studied on male rats of WISTAR strain weighing about 300 g and anaesthetized with nembutal (50 mg/kg by intravenous route) The product tested was administered by intravenous route in the jugular vein.
The arterial pressure in the carotids was measured before and after administration of the product tested.
The following table indicates the variations of the arterial pressure after administration of the product tested, as a percentage of the initial control arterial pressure.
Product of Example Dose in mg/kg % VARIATION OF THE ARTERIAL' PRESSURE 1 minute after adminis- tration 5 minutes after adminis- tration 10 minutes after adminis- tration 30 minutes after adminis- tration 2 1 -41 -38 -29 -20 O.’l -36 -28 -30 -27 3 0.1 +19 - 4 - 5 - 9 5 1 -20 -19 -17 -14 0.1 -24 . -28 -26 -22 7 10 -59 -56 -50 -35 8 10 -38 -21 -21 -15 1 - 9 - 8 - 6 -10 9 10 -48 -44 -37 -33 1 -13 -11 . - 4 - 5 10 1 -32 -14 -15 -13 11 1 -22 -33 -33 -30 1 O.’l -11 -12 -12 -13 - 36 B) Determination of antihypertensive activity The antihypertensive action has been studied on male rats spontaneously hypertensive (OKAMOTO strain) aged 20 weeks, weighing 300 to 320 g.
The product was administered by oral route 48 hours after the insertion of an intracarotid catheter.
The arterial pressure was measured on the tail of the rat by means of a pneumatic sleeve and with piezoelectric pressure transducer. The pressure was measured before and 1 hour, 4 hours and 24 hours after the administration of the product.
The following table indicates the variations of the arterial pressure after administration of the product expressed as a percentage of the initial control pressure Product of Example Dose in mg/kg % VARIATION OF THE ABTERIAL PRESSURE 1 hour after administration 4 hours after administration 24 hours after administration 2 1 -22 -21 - 5 5 1 -27 -24 -17 4 2 6a . 37 .
C) Determination of the antiulcer activity The technique utilised, is described by SHAY et al in Gastroenterology, 5, 43 (1945).
The SHAY technique consists o£ inducing ulcers at the level of the stomach,ia rats, by ligature from the pylorus.
The animals are anaesthetized with ether. A longitudinal incision is made about 1 cm below the sternum, the glandular part of the stomach and the duodenum is opened up and a ligature is placed; a few millimeters, below the pylorus.' The muscular plan is left as it is and the skin is sutured with two clips? Immediately afterwards the animals receive dispersive or the substance under study, by oral route, at a volume of 0.5 ml/100 g and they are kept without food or drink until they are killed by carotidian bleeding which takes place about 16 hours after the treatment.
Before the stomach is removed, a ligature is placed above the cardia.
The gastric liquid is collected in order to measure its pH.
The stomach is then opened along the large curvature, rinsed in physiological serum and stretched out on millimetric paper so as to be examined under a binocular magnifier. 542G2 - 38 The extent of the lesions is evaluated macroscopically and rated at 0 to 4 for each stomach.
For each group of rats, the mean intensity of the ulcerations are determined and the protection is calculated as a ratio of the means index of the group to the mean index of the control group.
The value of pH of the gastric liquid is also determined for the animals treated and the control animals.
The following results were obtained; Product of the Example Hose (mg/kg) pH of the gastric liquid % Protection of 1 ulceration in relation to the controls animals treated control animals 5 2 2.6 2 90% 0.4 2.5 2.2 60% 0.08 2.6 2.2 66% 11 5 2.9 3.0 63% 1 3.2 3..3 48% D) Study of the acute toxicity The lethal doses LDq of the different compounds tested was evaluated after administration by oral route to mice. LDq is the maximum dose which does not cause any death in 8 days.
The following results were obtained:’ 54202 Product of the Example EDq in mg/kg 1 >1000 2 200 3 600 5 200 6 >•400 7 80 8 100 9 80 10 > 400 11 100
Claims (25)
1. Aminomethyl-lH-indol-4-methanol compounds as well as their salts of addition with mineral or organic acids, characterised in that they have the general formula (I): R 2X k / R 1 in which B represents a hydrogen atom or an alkyl radical containing from 1 to 6 carbon atoms or a phenylalkyl radical containing from 7 Vo 10 c»bon atoms; R^ and Rj, which may be identical or different, each 10 represents a hydrogen atom, a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted, except in the case of the methyl radical, by one or more halogen atoms, by one or more hydroxy radicals or by one or more phenyl or phenoxy radicals, themselves 15 optionally substituted by one or more halogen atoms or by one or more hydroxy, methyl, methoxy or acetamido radicals, or R, and Rj can also represent a cycloalkyl radical containing from 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms or an 2 θ allyl or propargyl radical; and the broken line represents the optional presence of a carbon-carbon bond.
2. Aminomethyl-1H-indol-4-methanol compounds 41 as defined, by formula (I) of Claim 1 as well as their salts of addition with mineral or organic acids, characterised in that. E represents a hydrogen atom, an alkyl radical containing from 1 to 3 carbon atoms or a benzyl radical and R^ and Rg each represents a hydrogen atom or a linear or branched alkyl radical, containing from 1 to 8 carbon atoms, optionally substituted.
3. Aminomethyl-ΙΗ-indol-4-methanol compounds according to Claim 2 as well as their salts of addition with mineral or organic acids, characterised in that E represents a hydrogen atom, E^ and Eg each represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 8 carbon atoms, optionally substituted by a phenyl or phenoxy radical, which themselves may be substituted by a halogen atom, and the broken line represents a carbon-carbon bond.
4. Any one of the following compounds as well as their salts of addition with mineral or organic acids: - a-(aminomethyl)lH-indol-4~methanol - «χ-C C(1-methylethyl)amino]methyl]lH-indol-4-methanol - - a-C[(1-propyl)amino]methyl]-lH-indol-4-methanol
5. Process for the preparation of compounds of formula I R - 42 (wherein R is as defined ing a product of formula in claim 1) (III) , which comprises reductCHjiy (wherein R is as defined in claim 1) whereby the desired 5 product is obtained.
6. Process as claimed in claim 5 wherein the product of formula (III) is obtained by reaction of a product of formula (XI) CHO (XI) 10 (wherein R is as defined in claim 1) with trimethyl silyl cyanide.
7. Process for the preparation of compounds of formula d B ) or (I- B ) I R 54282 - 43 (wherein R is as defined in claim 1 and the group -CH' has the meanings of R^ other than a hydrogen atom or a methyl radical) which comprises reacting a compound of formula (1^) as defined in claim 5 with a carbonyl compound 5 of formula (IV) (IV) (wherein R a and R^ are as defined above) in the presence of a reducing agent.
8. Process for the preparation of compounds of formula (I D ) (wherein R is as defined in claim 1 and R’^ is such that the group -CI^R'j is as defined for R^ in claim 1 other than a hydrogen atom or a methyl radical) which comprises 15 reacting a compound of formula (I ft ) as defined in claim 5 with a carbonyl compound of formula (IV ) d II Hal-C-S' (wherein Hal represents a chlorine, bromine or iodine atom and R'j is as defined above) and submitting the product thus - 44 obtained to the action of a reducing agent.
9. Process for the preparation of compounds of formula (I F ) > 5 (wherein R is as defined in claim 1) which comprises methylating a compound of formula (I A ) as defined in claim 5.
10. Process for the preparation of compounds of formula (i c ), (I E ) or (X G ) - 45 (wherein R is as defined in claim 1, R'^ is as defined in claim 8, R and R_ are as defined in claim 7 and R' is as (X p i defined for R^ in claim 1 other than a hydrogen atom) which comprises reacting a compound of formula (I„) as defined in D 5 claim 7, a compound of formula (1^) as defined in claim 8 or a compound of formula (1^,) as defined in claim 9 with a halide of formula (V) X-R' 2 (V) (wherein X represents a chlorine, bromine or iodine atom 10 and R'2 is as defined above).
11. Process for the preparation of compounds of formula (I 1 ) I R (wherein R, R^ and R 2 are as defined in claim 1) which com15 prises reducing a compound of formula: (wherein R, R^ and R 2 are as defined in claim 1) whereby the 54362 - 46 desired product is obtained.
12. Process for the preparation of salts of compounds of formula (1) as defined in claim 1 which comprises salifying a compound of formula (I) as defined in claim 1.
13. Process for the preparation of compounds of formula (I ' A > (I ’ A ’ (wherein R' is as defined for R in claim 1 other than a hydrogen atom) which comprises preparing an oxime in * to 10 the ketone of a compound of formula (VII), 0^ H 3 w (VII) (VI) (wherein R’ is as defined above) and reducing the product thus formed whereby the desired compound is obtained.
14. Process as claimed in claim 13 wherein the compound 15. Of formula (VII) is obtained by conversion of a compound of formula (VI), 5 4 262 - 47 (wherein R' is as defined in claim 13) into the corresponding magnesium derivative and subsequent reaction with an acetylation agent.
15. Process as claimed in claim 14 wherein the compound 5 of formula (VI) is obtained by reaction of 4-chloro-indole with a halide of formula (V a ) Hal-R· (V ) α (wherein Hal represents a chlorine, bromine or iodine atom and R' is as defined in claim 13. 10
16. Process for the preparation of compounds of formula (Ij·) , (wherein R is as defined in claim 1, R 2 represents an alkyl radical containing from 1 to 8 carbon atoms optionally 15 substituted by a phenyl radical and R^ represents a hydrogen atom or a linear or branched alkyl radical containing from 1 to 6 carbon atoms optionally substituted by one or more hydroxy radicals, by one or more halogen atoms or by one or more phenyl or phenoxy radicals, themselves optionally 20 substituted by one or more halogen atoms or by one or more hydroxy, methyl, methoxy or acetamido radicals) which comprises reacting a compound of formula (I H ), (wherein R is as defined in claim 1 and R'^ is as defined above) with a reagent of formula (VIII) H^-CH-R'^ (VIII) 5 (wherein R^ is as defined above!·
17. Process for the preparation of compounds of formula (Ij), (wherein R is as defined in claim 1 and R 1 is as defined 10 in claim 16) which comprises reducing a compound of formula (Ij) as defined in claim 16 whereby the desired compound is obtained.
18. Process for the preparation of compounds of formula (I„) Λ 5 4 2 6-2 (wherein R is as defined in claim 1, R' 2 is as defined in claim 10 and R^ is as defined in claim 16) which comprises reacting a compound of formula (lj) as defined in claim 17 with a halide of formula (V) as defined in claim 10.
19. Process for the preparation of compounds as claimed in claim 1 substantially as herein described.
20. Process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 13.
21. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 5 to 20.
22. Medicaments, characterised in that they are constituted by the new derivatives of arainomethyl-lH-indole-4methanol as defined by formula (I) of claim 1 as well as by their salts of addition with pharmaceutically acceptable acids.
23. Medicaments, characterised in that they are constituted by the new derivatives of aminomethyl-lH-indole-4methanol, as defined in one of the claims 2 and 3 as well as by their salts of addition with pharmaceutically acceptable acids. - 50
24. Medicaments, characterised in that they are constituted by the derivatives of aminomethyl-lH-indole-4-methanol as defined in claim 4, as well as by their salts of addition with pharmaceutically acceptable acids. 5 25. Pharmaceutical compositions, characterised in that they contain as active principle at least one of the medicaments, as defined in one of the claims 22, 23 and 24. 26. Pharmaceutical compositions as claimed in claim 25 substantially as herein described. 10 27. Pharmaceutical compositions as claimed in claim 25 substantially as herein described in Example 14 or Example 15. 28. Compounds as claimed in claim 1 for use as antihypertensive or hypotensive agents. 15 29 . As new industrial products, the products with the formula (III) s (III) in which R has the meanings already indicated. 30. A process for the preparation of products as claimed in claim 29 substantially as herein described.
25. 31. Products as claimed in Claim 29 whenever prepared by a process as Claimed in Claim 30.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8117560A FR2512817A1 (en) | 1981-09-17 | 1981-09-17 | NOVEL AMINOMETHYL 1H-INDOLE-4-METHANOL DERIVATIVES AND THEIR SALTS, PROCESS FOR PREPARING THEM, THEIR APPLICATION AS MEDICAMENTS, THE COMPOSITIONS COMPRISING THEM AND THEIR PREPARATION INTERMEDIATES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE822266L IE822266L (en) | 1983-03-17 |
| IE54262B1 true IE54262B1 (en) | 1989-08-02 |
Family
ID=9262232
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2266/82A IE54262B1 (en) | 1981-09-17 | 1982-09-16 | Chemical compounds |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0076713B1 (en) |
| JP (1) | JPS5862161A (en) |
| AT (1) | ATE17347T1 (en) |
| AU (1) | AU550238B2 (en) |
| CA (1) | CA1200554A (en) |
| DE (1) | DE3268423D1 (en) |
| DK (1) | DK413482A (en) |
| ES (2) | ES8401463A1 (en) |
| FI (1) | FI77444C (en) |
| FR (1) | FR2512817A1 (en) |
| HU (1) | HU189177B (en) |
| IE (1) | IE54262B1 (en) |
| PT (1) | PT75565B (en) |
| ZA (1) | ZA826497B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2591595B1 (en) * | 1985-12-13 | 1988-09-09 | Roussel Uclaf | NOVEL 4-MORPHOLINYL 1H-INDOLE DERIVATIVES, SALTS THEREOF, PROCESS FOR THEIR PREPARATION, APPLICATION AS MEDICAMENTS, COMPOSITIONS CONTAINING THEM, AND INTERMEDIATES |
| EP0600675B1 (en) * | 1992-12-02 | 1998-07-08 | Kissei Pharmaceutical Co., Ltd. | Indoline compounds for the treatment of dysuria |
| FR2792313A1 (en) * | 1999-04-13 | 2000-10-20 | Synthelabo | 2-AMINOETHYL-INDOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1532210A (en) * | 1963-06-21 | 1968-07-12 | Ici Ltd | Heterocyclic compounds and their preparation process |
| FR2332010A1 (en) * | 1975-11-18 | 1977-06-17 | Continental Pharma | HETEROCYCLIC AMINO-ALCOHOL, ITS SALT AND ITS PREPARATION PROCESS |
-
1981
- 1981-09-17 FR FR8117560A patent/FR2512817A1/en active Granted
-
1982
- 1982-09-06 ZA ZA826497A patent/ZA826497B/en unknown
- 1982-09-13 EP EP82401660A patent/EP0076713B1/en not_active Expired
- 1982-09-13 DE DE8282401660T patent/DE3268423D1/en not_active Expired
- 1982-09-13 AT AT82401660T patent/ATE17347T1/en not_active IP Right Cessation
- 1982-09-15 PT PT75565A patent/PT75565B/en not_active IP Right Cessation
- 1982-09-16 HU HU822951A patent/HU189177B/en not_active IP Right Cessation
- 1982-09-16 FI FI823209A patent/FI77444C/en not_active IP Right Cessation
- 1982-09-16 DK DK413482A patent/DK413482A/en not_active Application Discontinuation
- 1982-09-16 AU AU88452/82A patent/AU550238B2/en not_active Ceased
- 1982-09-16 ES ES515755A patent/ES8401463A1/en not_active Expired
- 1982-09-16 IE IE2266/82A patent/IE54262B1/en not_active IP Right Cessation
- 1982-09-17 CA CA000411657A patent/CA1200554A/en not_active Expired
- 1982-09-17 JP JP57161090A patent/JPS5862161A/en active Pending
-
1983
- 1983-06-30 ES ES523718A patent/ES523718A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| PT75565A (en) | 1982-10-01 |
| JPS5862161A (en) | 1983-04-13 |
| ZA826497B (en) | 1983-07-27 |
| EP0076713B1 (en) | 1986-01-08 |
| FI77444C (en) | 1989-03-10 |
| ES8403869A1 (en) | 1984-04-01 |
| ES523718A0 (en) | 1984-04-01 |
| DE3268423D1 (en) | 1986-02-20 |
| DK413482A (en) | 1983-03-18 |
| CA1200554A (en) | 1986-02-11 |
| FI77444B (en) | 1988-11-30 |
| AU8845282A (en) | 1983-03-24 |
| AU550238B2 (en) | 1986-03-13 |
| FR2512817B1 (en) | 1983-12-30 |
| PT75565B (en) | 1985-12-09 |
| ES515755A0 (en) | 1983-12-16 |
| HU189177B (en) | 1986-06-30 |
| ES8401463A1 (en) | 1983-12-16 |
| FR2512817A1 (en) | 1983-03-18 |
| FI823209L (en) | 1983-03-18 |
| FI823209A0 (en) | 1982-09-16 |
| EP0076713A1 (en) | 1983-04-13 |
| ATE17347T1 (en) | 1986-01-15 |
| IE822266L (en) | 1983-03-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |