IE47209B1 - Improvements in or relating to organic compounds - Google Patents
Improvements in or relating to organic compoundsInfo
- Publication number
- IE47209B1 IE47209B1 IE1382/78A IE138278A IE47209B1 IE 47209 B1 IE47209 B1 IE 47209B1 IE 1382/78 A IE1382/78 A IE 1382/78A IE 138278 A IE138278 A IE 138278A IE 47209 B1 IE47209 B1 IE 47209B1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- chg
- phenyl
- alkyl
- hydrogen
- Prior art date
Links
- 150000002894 organic compounds Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 105
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 48
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 36
- 239000001257 hydrogen Substances 0.000 claims abstract description 32
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 11
- 239000000460 chlorine Chemical group 0.000 claims abstract description 11
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 10
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- -1 4-piperidyl Chemical group 0.000 claims abstract description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 4
- 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 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229960005419 nitrogen Drugs 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 150000003839 salts Chemical group 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 125000001701 trimethoxybenzyl group Chemical group 0.000 claims 1
- 125000001680 trimethoxyphenyl group Chemical group 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 abstract 1
- 125000004663 dialkyl amino group Chemical group 0.000 abstract 1
- 150000002475 indoles Chemical class 0.000 abstract 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 description 1
- NTLAICDKHHQUGC-UHFFFAOYSA-N 3-(2-bromoethyl)-1h-indole Chemical compound C1=CC=C2C(CCBr)=CNC2=C1 NTLAICDKHHQUGC-UHFFFAOYSA-N 0.000 description 1
- YUBXEUBNYOBJMQ-UHFFFAOYSA-N 3-(3-bromopropyl)-1h-indole Chemical compound C1=CC=C2C(CCCBr)=CNC2=C1 YUBXEUBNYOBJMQ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000005277 alkyl imino group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- AOGPUGLWMPUQQZ-UHFFFAOYSA-N n-(3-aminopropyl)benzamide Chemical compound NCCCNC(=O)C1=CC=CC=C1 AOGPUGLWMPUQQZ-UHFFFAOYSA-N 0.000 description 1
- IHFFFHQIVOOONQ-UHFFFAOYSA-N naphthalene-2-sulfonic acid;dihydrate Chemical compound O.O.C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 IHFFFHQIVOOONQ-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-M oxalate(1-) Chemical compound OC(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-M 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical class NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- ZNZJJSYHZBXQSM-UHFFFAOYSA-N propane-2,2-diamine Chemical compound CC(C)(N)N ZNZJJSYHZBXQSM-UHFFFAOYSA-N 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000012262 resinous product Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- 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
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Indole compounds useful for the treatment of hypertension, of formula wherein n is 2 or 3, A is 1,4-cyclohexylidene or trimethylene and R1 is H or alkyl, or A together with NR1 is 4-piperidyl, R2 is hydrogen or alkyl, R3 is alkyl, cycloalkyl, amino, alkylamino, dialkylamino, phenylamino, unsubstituted or substituted phenyl or benzyl, pyridylmethyl or an heterocycle, R4 is hydrogen, chlorine, bromine or alkyl, R5 is hydrogen, alkyl, alkoxy or alkylthio, and X is -CO- or -CS, a process for their production which comprises a) acylating a compound of formula II wherein n, A and R1 to R5 are as defined above, or b) condensing a compound of formula III wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV wherein A, R1 to R3 and X are as defined above. n
Description
The present invention relates to new indole derivates, processes for their preparation, and pharmaceutical compositions containing them.
In accordance with the inventionthere are provided new compounds of formula I wherein n is 2 or 3, either A is trimethylene optionally substituted by (C^_4) alkyl or 1,4-cyclohexylidene and R^ is hydrogen or (C^_g) alkyl, or A together with R^ and the nitrogen atom to 10 which R-j· is bound, form a 4-piperidyl radical, R^ is hydrogen or (C^_g) alkyl, R3 is (C.j_4) alkyl; (C3_g)cycloalkyl; amino; (C.j_4) alkylamino; di (C^) alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1_4)alkyl, (C^ ^lalkoxy or di (C^_4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C^_4)alkyl, (C^_4)alkoxy or di-(C^_4>alkylamino; 2-,3- or 4-pyridyImethyl ;or an aromatic - or 6-membered heterocycle containing one 0 heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitro gen atoms, is hydrogen, chlorine, bromine or (C^ alkyl, R,. is hydrogen, (C^^) alkyl, (C^^) alkoxy or (Cj_4)alkylthio, and X is -CO- or -CS-.
Any alkyl, alkoxy or alkylthio radical contains preferably two carbon atoms, especially one carbon atom. Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
When A is 1,4-cyclohexylidene, this may be cis or trans-l,4-cyclohexylidene.
When A is optionally substituted trimethylene, this is preferably either unsubstituted or mono25 substituted, conveniently at the middle carbon atom.
When and Rj are chosen from hydrogen or alkyl, these are preferably alkyl.
Conveniently A is optionally substituted trimethy lene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.
When Rj is or contains a dialkylamino radical, the alkyl groups are preferably the same. When R3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical.
Conveniently these radicals are unsubstituted or monosubstituted preferably in the para position. When Rj is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
Rj is preferably unsubstituted phenyl.
R^ and Rj are conveniently hydrogen.
X is conveniently -CO-.
The present invention provides a process for the production of a compound of formula I as defined above, which comprises a) acylating a compound of formula II wherein n, A and R, to R_ are as defined above, 1 5 or b) condensing a compound of formula III (0Η2)η-ϊ ' (III) wherein n, R4 and Rg are as defined above, and Y is a leaving group, with a compound of formula IV wherein A, R^ to R^ and X are as defined above. Process a) may be effected in conventional manner for the production of amides or thio-amides from amines. For example there may be used, as acylating agent, a compound of formula V Z - X - Ri, (V) wherein X is as defined above,has the same signification as R^ but is other than amino, alkyl10 - 5 ' 47209 amino and optionally substituted phenylamino and Z is chlorine or bromine. The reaction may be effected conveniently in a solvent such as pyridine and at temperatures from 0 to 25°. Alternatively when R3 is amino, alkylamino or optionally substituted phenylamino, there may be used a compound of formula VI χ (VI) wherein X is as defined above and Rg is imino, alkylimino or optionally substituted phenylimino.
The reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25°. A compound of formula VI wherein Rg is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine. Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.
The reaction may be conveniently effected in acetone or dimethylformamide. Suitable reaction temperatures are from 20 to 150°.
The compounds of formula I may be isolated from the reaction mixture and purified in known manner. The free base forms may be converted ' into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are hydrochloric acid, oxalic acid, fumaric acidznaphthalene-25 sulphonic acid and naphthalene-1,5-disulphonic acid.
The starting material of formula II may be produced from a compound of formula III and a compound of formula VII Rn R, I2 I1 HN — A — NH (VII) wherein A, R^ and R^ are as defined above, in analogous manner to process b).
When the amine of formula VII is unsymmetrical, the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the substituent. For this purpose the amine may be used in protected form of formula VIII (VIII) HN - A - N - R? wherein R^ is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis. . 20 A starting material of formula Ila wherein A1 is -CH-CH_-CH_- or J 2 2 R8 -CHj-CH —CHj- and wherein Rg is alkyl and Rs n, Rj, R^ and Rg. are as defined above, may alternatively be produced by reducing a compound of formula IX wherein B is -CH(Rg)-CH2~ or -CH2~CH(Rg)and n, r R^, Rg and Rg are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.
Any starting material of formula II wherein R^ and/or Rj is hydrogen may be converted into a corresponding compound wherein R^ and R^ are both alkyl, or R^ is alkyl and Rj is hydrogen under appropriate selective alkylation conditions.
The starting material of formula IV may be produced by acylating an amine of formula VII in analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
A starting material of formula IVa HN (IVa) II wherein X, R2 and R3 are as defined above and A together with R^ and the nitrogen atom to which R^ is bound, form a 4-piperidyl radical, may alternatively be produced by acylating 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X (X) wherein X and R^ are as defined above, with a compound of formula XI R--NH (XI) wherein R2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst. Insofar as the production of any starting material is not particularly described, these are known or may be produced in conventional manner or in a manner analogous to that described above.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
EXAMPLE 1 N-benzoyl-N'-[3- (3-indolyl) propyl ]-N'~ methy1-1,3-diaminopropane A solution of 10.1 g benzoyl chloride in ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0 and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]N-methy1-1,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at 0°. The reaction mixture is divided between a 2N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title coumpound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73-74° after crystallization from methanol/water/ethyl acetate (1:1:1) .
The starting material may be obtained as follows : a) A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous acetonitrile are added dropwise to a stirred suspension of 95.1 g 3-(3-indolyl,propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15° for 30 minutes. - 10 Under good cooling 500 ml anhydrous pyridine are added between -20 and -15° and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring 5 at 0° for 15 minutes and maintained to 0° for 3 hours. 3-(3-indolyl)-N-methy1-propionamide (M.pt 97-98° after crystallization from methylene chloride/ethyl acetate) is obtained after working up. b) A solution of 60.6 g 3-(3-indolyl)-N-methy1-propiona10 mide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25° for 15 minutes under nitrogen atmosphere to a suspension of 34. 2 g lithium aluminium hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66° for 3 hours. N-methy1-3-(3-indolyl)15 propylamine (M.pt 81-82° after crystallization from methylene chloride/ethyl acetate) is obtained after working up. c) A mixture of 37.6 g N-methy1-3-(3-indolyl)-propylamine and 21,2 g acrylonitrile in 65 ml anhydrous 2o 1,2-dimethoxyethane are warmed with stirring at 60° for 2^2 hours. N- (2-cyanoethyl)-N-methy 1--3(3-indolyl)propylamine (M.pt 48-49° after crystallization from isopropyl ether) is obtained after working up. d) 36.2 g N-(2-cyanoethyl)-N-methy1-3-(3-indolyl)propyl amine are hydrogenated at normal pressure and at room temperature with 20 g Raney-nickel catalyst in 400 ml dioxan and 400 ml of a 10% ammonia solution. N-[3-(3-indolyl)propyl]-N-methyl-1,35 diaminopropane is obtained after working up.
M.pt of the neutral fumarate:180-181° (with decomposition) after crystallization from ethanol.
From the appropriate compounds of formula II the following compounds of formula I wherein X is 10 -CO- may be obtained in analogous manner to Example 1. Ρ CM σ> μ* Η CO rH ΙΛ X l m n 1 X ® ι a U I l in I X II II II II π 0$ II S X X II II Η - - π rH rH rH >< ΰ d β o 0 Λ Λ 0. Λ CM CM II X II co X Ο I ιη X CM Ο I I I ι co co co XXX -ΙΓ I « I _1L co co CO It X Ιΐ W I, -Ρ nJ fi Λ1 χί φ Φ 0 Φ CM •P -P •Ρ -Ρ ω nJ nJ -Ρ β 0 XJ P •Η Ρ Χί CM nJ Μ β Di rH ε θ § Φ fi 9 CM 3 fi •P Cfl Η Φ nJ ,_, ,—, 0 _ fcn P Φ Φ ϋ fi 0 nJ w w φ Φ P ΪΡ nJ ni Ό θ' nJ X5 Λ X3 0 >< 0 χ: ρ Λ fi 10 ω -Ρ nJ • o •H •H •Ρ >ί ε X3 Xi & χ: ID co σ» Ο rH rH rH nJ ϋ Q m rH a ω •rl I rH in Ο rH CM 1 X Φ fi CM Φ \ rH rH Φ β •Ρ χί Φ β 4J φ nJ ι-Η Χί nJ •Η β CM ♦Η Ρ X β ε 0 0 fi 0 rH Μ χ: fi Φ* Xi ο φ ϋ) 0 0 ζΡ β Ρ Ρ 0 Λ Ό nj Ρ >1 >1 Ό ω Χί Χί >1 •Η Ή ♦Η χ} XI Π3 Π3 CM co *3* ιη 472θβ - 16 EXAMPLE 2: N-ghenylcarbamoyl-Nj.yX2-^3yindolyl2 e_thy_l_]_=Nj.y ESiLyl^lj^diaminopropj-ne ml phenyl Isocyanate are added dropwise between and 10° and with stirring to a solution of 5.8 g N-[2-(3indolyl) ethyl ]-N-methyl-l,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10 and 15° and evaporated. The residue is dried in high vacuum and chromatographied on silicagel using methylene chloridewith 6 to 10% methanol,to yield the title compound (M.pt. of the hydrogen maleate 153-155° with decomposition after crystallization from alcohol/acetone) .
The starting material may be obtained as follows: a) Reaction of 3-[2-methylamino)ethyl]indole with acrylonitrile in dimethoxy-ethane yields the N-(2-cyanoethyl)-N-methy1-2-(3-indolyl)ethylamine which is worked up further directly. b) Reduction of N-(2-cyanoethyl)-N-methy1-2-(3-indolyl)ethylamine with Raney-Nickel catalyst yields the N- [2-(3-indolyl)ethyl]-N-methy1-1,3-diaminopropane (M.pt. of the fumarate 153-154°).
EXAMPLE 3 ; N-BenzoylytT y_[ 2-_(3yindolyl)ethyl_]_-lx^diaminoE£opane A solution of 8 g N-benzoyl-1,3-diaminopropane, 6,7 g 3-(2-bromoethyl) indole and 5 ml anhydrous triethylamine in 15 ml anhydrous dimethylformamide is maintained for 72 hours in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated.The residue is chromatographied on silicagel using as eluant methylene chloride+ 5% methanol + 0.3% ammonia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203-204° with decomposition after crystallization from ethanol).
The following compounds of formula may be obtained in analogous manner to Example 3 : 10 Table Ex. No.R2R3R4 M.Pt. a) -n-CgH? p-tolyl H 181-183° X) 1 2 3) b) -CHg p-methoxyphenyl H 133-135° 15 3) c) -CIi3 p-chlorophenyl H 161-163° -° a) -CH3 phenyl H 122-124° J) e) CHg 2-furyl H 95-96° f) -CH3 phenyl Br 148-150° 1) 3) 1) hydrogen oxalate 2) naphthalene-2-sulfonate 3) with decomposition - 18 EXEMPLE 4: From the appropriate 4-amino-piperidines and 2-(3-indolyDethyl bromide or 3- (3-indolyl)propyl bromide, the following compounds of formula H may be obtained in analogous manner to Example 3: T a b 1 e EX. NO. nR2R3 M.pt. a) 2 -ch3 phenyl 131-133° 3) b) 3 -CIIj phenyl 201-203° 3) c) 2 iso-C,H_ 4 9 phenyl 152-154 2) 3) d) 2 H phenyl 151-152 35 e) 2 -ch3 phenylamino ' 58-60" f) 2 H dimethylamino - 119-120° 1) naphthalene-2-sulfanate 2) hydrochloride 3) with decomposition The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds exhibit anti-hypertensive activity, as indicated by 72 0 9 standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 rng/kg animal body weight of the compounds,and in the awake renal hypertonic Goldblatt dog upon administration of 1 to 10 mg/kg animal body weight of the compounds.
The compounds are therefore indicated for use as anti-hypertensives. For this use an indicated daily dose is from about 10 to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 2,5 to about 1000 mg, or in sustained release form.
A particularly interesting compound is the Example 1 compound.
The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts exhibit the same order of activity as the free base forms.
The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule.
In one group of compounds n is 3, A is trimethylene, is hydrogen or (C1_5)alkyl, R2 is hydrogen or (C^g) alkyl, Rj is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by -20 halogen, hydroxy, (C^_4)alkyl, (C^_4)alkoxy or di(Cj_4)alkylamino; (C^_(,)oycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C^_4>alkyl, is hydrogen, (C1_4)alkyl, (C^ alkoxy, or (C^) alkylthio, and X is -CO-, In another group of compounds n is 2, either A is trimethylene and R^ is hydrogen or (C^ alkyl, or A together with R^ and the nitrogen atom to which is bound form a 4-p.iperidyl radical, and R^ is hydrogen or (C^_^)alkyl, is (C^_4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C4_4)alkyl or (C^_4)alkoxy; (C-j_g) cycloalkyl; or an aromatic 5- or G-membcred hetcrocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C^_4)alkyl, R^ is hydrogen, (C^_4)alky1 or (C^_4)alkoxy, and X is -CO- or -CS,
Claims (40)
1. C L A .I_M S 1) A process for tlie production of a compound of formula I wherein n is 2 or 3, either A is trimethylene optionally substituted by 5 (C^^) alkyl or 1,4-cyclohexylidene and is hydrogen or fC^_ 5 ) alkyl, or A together with R^ and the nitrogen atom to which R^ is bound, form a 4-piperidyl radical, R 2 is hydrogen or (C 1 _ g )alkyl, χθ r is (C^_ 4 ) alkyl; (C 3 _ g ) cycloalkyl; amino; (C )alkylamino; di(C^^) alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, alkyl, (C )alkoxy or di(C^_ 4 )alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C ^Jalkyl, (C^_ 4 )alkoxy or di-(C^_ 4 )alkyl2q amino; 2-,3- or 4-pyridyImethyl;or an aromatic 5- or G-mcinbered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sul4 7 2 0 9 phur and optionally additional one or two nitro gen atoms , R 4 is hydrogen, chlorine, bromine or (C 1 _ 4 )alkyl, Rj is hydrogen, (C^_ 4 )alkyl, (C^_ 4 )alkoxy or (C 1-4 )alkylthio, and X is -CO- or -CS-, which comprises a) acylating a compound of formula II wherein n, A and R to Rj are as defined above, or b) condensing a compound of formula III 5 < ri 1 H ' (III) 4 wherein n, R 4 and li 5 are as defined above, 5 and Y is a leaving group, with a compound of formula IV R , I 2 I 1 HN - Λ - N - X - R (IV wherein A, to Rj and X are as defined recte. 4720
2. ) A process for the production of a compound of formula I as defined in claim 1 substantially as hereinbefore des cribed with reference to any one of the examples.
3. ) A compound of formula I as defined in claim 1 whenever produced by a process as claimed in claim. 1 or 2.
4. ) A compound of formula I as defined in claim 1. 47309
5. ) A compound of claim 4 which is N-benzoyl-N'-[3(3-indolyl)propyl]-N’-methy1-1,3-diaminopropane.
6. ) A compound of claim 4 wherein X is CO.
7. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, 5 R^ and Rg are respectively 2, IJ, -(CHg)g~, dig, phenyl, Η, H.
8. ) A compound of claim 6 wherein n, Rj , A, Rg, Rg, R^ and Rg are respectively 2, H, - (Cllg)g-, ~CIIg, phenyl, H, 4-OCglIg. 30
9. ) A compound of claim 6 wherein n, R , A, Rg, Rg, R^ and Rg are respectively 3, H, -(CHg)g-, --CHg, phenyl, -CHg, Ii.
10. ) A compound of claim C wherein n, Rg, A, Rg, Rg, R^ and Rg are respectively 3, H, -(CHg)g-, -CHg, phenyl, 15 II, 6-SCIIg.
11. ) Λ compound of claim 6 wherein n, Rg, A, Rg, Rg, R^ and Rg are respectively 3, II, -(CHg)g-, -CHg, phenyl, H, 5-OCH,. 3 '
12. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, 2o R4 and Rg are respectively 3, Η, -(CHg)g-, “CHg, phenyl, II, 4-OCHg.
13. ) A compound of claim 6 wherein n, Rg, A, Rg, Rg, IL and R are respectively 3, H, —(CII O ) _—, C,H , phenyl, 4 j 2 ’ 2 □ II, II. 25
14. ) A compound of claim 6 wherein n, Rg, A, Rg , Rg, R and R r are respectively 3, -CHg, -(CHg)g-, dig, phenyl, II, II. -25
15. ) Λ compound of claim R. and R_ are respectively 3, 4 o phenyl, Η. H.
16. ) Λ compound of claim R^ and Rg are respectively 3, Η, H.
17. ) Λ compound of claim R^ and Rg are respectively 2, Η, H.
18. ) Λ conii>ound of claim R^ and (Rg are respectively 2, II, H.
19. ) Λ compound of claim and Rg are respectively 3, trimethoxybenzyl. Η, II.
20. ) A compound of claim R, and R_ are respectively 3, 4 b phenyl, Η, H.
21. ) A compound of claim R^ and Rg are respectively 2, Η, H.
22. ) A compound of claim R^ and R r are respectively 2, amino, II, II.
23. ) A compound of claim R^ and Rg are respectively 2, phenyl, II, II. 6 wherein n, Rg, A, R 2 , Rg, -n-C 3 H 7 , -(CHg) -, -CHg, 6 wherein n, Rg , A, Rg , Rg, II, -(CII 2 )g-, -CHg, benzyl, 6 wherein n, Rg, A, Rg , Rg, Η, , -dig, phenyl, H' ''H 6 wherein n, 1^, A, It,, Rg , Η, /“λ.-- , ” cn 3, phenyl, H- ’ Cwherein n, Rg, A, Rg , Rg, II, -(CII 2 )g-, -CHg, 3,4,56 wherein n, Rg , A , P.g , Rg , II, -(CH 2 )g-, CHg, o-chloro6 wherein n, Rg, A, Rg , Rg, H, -(CHgJg-, H, diethylamino, 6 wherein n, P.g, A, Rg , Rg, H, “(CH 2 )g-, -CHg, dimethyl6 wherein n, Rg, A, Rg, Rg, H, -( CH 2^3 - ' ~ CII 3' P-rcefch°xy47209 -26
24. ) A compound of claimθ and Rj are respectively 3, H, aminophenyl, Η, H.
25. ) A compound of claim 6 R^ and Rj are respectively 3, II, Η, H.
26. ) A compound of claims R^ and Rj are respectively 2, II, p-tolyl, II, H.
27. ) A compound of claim 6 I’ 4 and R,. are respectively 3, H, phenyl, II, H.
28. ) A compound of claim 6 I< 4 and Rj are respectively 2, II, phenyl, II, II.
29. ) A compound of claim θ and Rj are respectively 3, H, methoxyphenyl·. Η, II.
30. ) Λ compound of claim 6 I? 4 and Rj are respectively 3, II, trimethoxyphenyl, Η, H.
31. ) A compound of claim 6 R^ and Rj are respectively 3,H, phenyl, [I, II.
32. ) k compound of claim 6 R. an< 3 R are respectively 2, H, 4 5 wherein n, R^ , A, P- 2 , Rj, -(CH 2 ) 3 “, -CHj, p-dimethylwherein n, R , A, Rj, R^, -(CII ? ) 3 -, -CIIj, m-tolyl, wherein n, P^, A, Rj, Rj, -(αι 2 ) 3 -, -n-c 3 H 7 , wherein n, , A, P_ 2 , Rj, - (CH 2 )j-, “CHj, m-chlorowherein n, R , A, Rj, Rj, -(CHjJj-, “CHj, p-chlorowherein n, R , A, Rj, Rj, -(CH 2 )j-, “CHj, 3,5-diwherein η, P^, A, , , -(CH 2 )j-, -CHj, 3,4,5wherein n, R , A, Rj, Rj, '( ch 2^3'' -C,, 3' °“ methox y“ wherein n, R^, A, Rj, Rj, -(CH 2 )j-, -CHj, 2-furyl, II, II. 4 7 2 0 9 - 27
33. ) Λ compound of claim 6 wherein n, R^, A, Rg , R_,, R^ and Rg are respectively 3, II, -CHg, 2-furyl, Η, H.
34. ) A compound of claim 6 wherein n, R^ , A, Pg , Rg, R^ and Rg are respectively 3, II, ~( CH 2^3~' “CHg, 2-thienyl, H. H
35. ) A compound of claim 6 wherein n, R^, A, Pg , Rg R 4 and Rg are respectively 3, H, -(CHg)g-, -CHg, 2-pyridyl Η, H. 10
36. ) A compound of claim 6 wherein n, R^, A, R 2 , Rg R 4 and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 3-pyridyl Η, H.
37. ) A compound of claim 6 wherein n, Rg , A, Rg , Rg, R 4 and Rg are respectively 3, H, -(CH 2 )g~, -CHg, 4-pyridyl 15 Η, H. 3¾) A compound of claim 6 wherein n, Rg, A, Rg , Rg, R 4 and Rg are respectively 3, II, ~(CH 2 )g~, “CHg, pyrazinyl Η, II.
38. 39) A compound of claim 6 wherein n, Itg , A, Rg , Rg, 20 R 4 and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 2-pyridyl methyl,.II, H.
39. 40) A compound of claim 6 wherein n, Rg, A, Rg, Rg, R 4 and Rg are respectively 3, II, - (CHg)g-, -CHg, 2-pyrrolyl, II, II.
40. 43) A compound of claim 6 wherein η, K , A, Rg , Rg, R 4 and Rg are respectively 2, -CHg, -CHg-CH-CHg-, -CHg, CHg phenyl, Η, II. -23 42) A compound of claim 6 wherein n, R , A, R 2 , Rg , R^ and Rg are respectively 2, It, - (Cil 2 ) -, -CHg, 4-hydroxy phenyl, Η, II, 43) A compound of claim 6 wherein n, R^, A, R^ , R 3r 5 R^ and Rg are respectively 3, H, -(CH 2 )g-, -CHg, 4-hydroxy phenyl, H, II. R 4 44) A compound of claim 6 wherein η , H, -(CH 2 ) 3 -, f A / t t -CH 3 , phenyl, and Rg are respectively 3, H, 6-CH 3 , 45) A compound of claim 6 wherein η , R^, A, Rg, Rg, R 4 and Rg are respectively 3, H, -(CH 2 ) 3 -, -CHg , phenyl, H, 5-CH 3 . 46) A compound of claim 6 wherein η, Rl, A, R 2 , R 3 , R 4 and R_ □ are respectively 3, ii, -{ch 2 ) 3 -, - dig , phenyl, , 4-ΟΠ 3 . 47) Λ compound of claim 6 wherein η, R x , A, R 2 , Rg, R 4 and Rg are respectively 3, II, -(CH 2 ) 3 -, -C 2 Hg, phenyl, II, II. 48) A compound of claim 6 which is N-phenylcarba- moyl-N'-I 2-(3-indolyl)ethyl]-Ν'-methy1-1,3 -diaminopropane 49) A compound of claim 4 wherein A is optionally substituted methylene. 50) Λ compound of claim 4 which is N-Benzoyl-N'~ [2-(3-indolyl) ethyl)-1,3-diaminopropane. -29 51) Λ compound of claim 4 having the formula 52) A compound of claim 51 wherein I< 2 , R^ and R^ are respectively -n-CjII^, p-tolyl, II. 5 53) A compound of claim 51 wherein R^, and R^ are respectively -CH 3 , p-methoxyphenyl, H. 54) A compound of claim 51 wherein 1^, R^ and R^ are respectively -CH 3 , p-chlorophenyl, H. 55) A compound of claim 51 wherein > R 3 and R ^ 10 are respectively -CH 3 , phenyl, H. 56) A compound of claim 51 wherein R%r R 3 ant ^ R 4 are respectively -CH 3 , 2-furyl, H. 57) A compound of claim 51 wherein R 2 , Rj and R^ are respectively —CII^, phenyl, Br. 15 58) A compound of claim 4 having the formula II wherein t? 2 and R 3 are as defined in claim 1. 59) A compound of claim 58 wherein -n, R 2 and R 3 are respectively 2, -CH 3 , phenyl. - 30 60) A compound of claim 5θ wherein -n, Rg and Rg are respectively 3, -CHg, phenyl. 61) A compound of claim 58 wherein -n, Rg and Rg are respectively 2, iso-C 4 H g , phenyl. 62) A compound of claim 58 wherein -n, Rg and Rg are respectively 2, II, phenyl. 63) A compound of claim 5 8 wherein -η, Rg and Rg are respectively 2, “CHg, phenylamino. 64) A compound of claim 58 wherein -n, R and R ~ J are respectively 2, H, dimethylamino. 65) A compound of claim 4 wherein n is 3, A is trimethylene, Rg is hydrogen or (Cg_g)alkyl, Rg is hydrogen or (Cg_g)alkyl, Rg is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (Cg^) alkyl, (Cg_^) alkoxy or di-(Cg_ 4 ) alky lamino; (Cg_g)cycloaikyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R^ is hydrogen, chlorine, bromine or (Cg_ 4 )alkyl, R 5 is hydrogen, (Cg_ 4 )alkyl, (Cg_ 4 )alkoxy, or (Cg_ 4 ) alkylthio, and X is -CO-. 10 r 5 and 10 r 5 and 66) A compound of claim 1 wherein n is 2 A is trimethylene and R^ is hydrogen or (Cj_ 5 ) alkyl, A together with and the nitrogen atom to which is bound form a 4-piperidyl radical, is hydrogen or (C^_g)alkyl, is (Cj_ 4 )alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C^ ^)alkyl or (C^_ 4 )alkoxy; (C 3 _g)eycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur is hydrogen, chlorine, bromine or (C^_ 4 )alkyl, is hydrogen, (C^_ 4 )alkyl or (C^^) alkoxy, X is -CO- or -CS67) A compound of any one of claims 3 to 66 in free base form. 68) A compound of any one of claims 3 to 66 in acid addition suit form. 69) A pharmaceutical composition comprising a compound according to any one of claims 3 to 66 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH858977 | 1977-07-12 | ||
| CH300878 | 1978-03-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE781382L IE781382L (en) | 1979-01-12 |
| IE47209B1 true IE47209B1 (en) | 1984-01-11 |
Family
ID=25691930
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1382/78A IE47209B1 (en) | 1977-07-12 | 1978-07-10 | Improvements in or relating to organic compounds |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0000355B1 (en) |
| JP (1) | JPS5436259A (en) |
| AU (1) | AU521641B2 (en) |
| CA (1) | CA1114381A (en) |
| DE (1) | DE2861502D1 (en) |
| DK (1) | DK300978A (en) |
| ES (1) | ES471593A1 (en) |
| FI (1) | FI782138A (en) |
| IE (1) | IE47209B1 (en) |
| IL (1) | IL55116A (en) |
| IT (1) | IT7850140A0 (en) |
| NZ (1) | NZ187813A (en) |
| PH (1) | PH14993A (en) |
| PT (1) | PT68270A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2960547D1 (en) * | 1978-02-24 | 1981-11-05 | Pfizer Ltd | 3-(imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them |
| US4634713A (en) * | 1982-05-28 | 1987-01-06 | Ciba-Geigy Corporation | Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives |
| JPH0283380A (en) * | 1988-09-21 | 1990-03-23 | Kotobuki Seiyaku Kk | Novel diamine derivative, antiarrhythmic agent and production thereof |
| FR2642422A1 (en) * | 1988-12-22 | 1990-08-03 | Roussel Uclaf | NOVEL ACYLATED POLYAMINES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS FUNGICIDES |
| WO1994022826A1 (en) * | 1993-04-07 | 1994-10-13 | Otsuka Pharmaceutical Co., Ltd. | Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients |
| MY142362A (en) | 2004-01-29 | 2010-11-30 | Otsuka Pharma Co Ltd | Pharmaceutical composition for promoting angiogenesis |
| US11764679B2 (en) | 2020-01-15 | 2023-09-19 | Solaredge Technologies Ltd. | Power device |
| CN115433164B (en) * | 2022-09-14 | 2023-12-12 | 南京师范大学 | Nicotinamide derivative, preparation method thereof and application thereof in resisting aging and prolonging life |
-
1978
- 1978-06-12 PH PH21359A patent/PH14993A/en unknown
- 1978-06-29 DE DE7878100274T patent/DE2861502D1/en not_active Expired
- 1978-06-29 EP EP78100274A patent/EP0000355B1/en not_active Expired
- 1978-07-03 DK DK783009A patent/DK300978A/en not_active Application Discontinuation
- 1978-07-03 FI FI782138A patent/FI782138A/en not_active Application Discontinuation
- 1978-07-03 IT IT7850140A patent/IT7850140A0/en unknown
- 1978-07-10 PT PT68270A patent/PT68270A/en unknown
- 1978-07-10 ES ES471593A patent/ES471593A1/en not_active Expired
- 1978-07-10 IL IL55116A patent/IL55116A/en unknown
- 1978-07-10 NZ NZ187813A patent/NZ187813A/en unknown
- 1978-07-10 IE IE1382/78A patent/IE47209B1/en unknown
- 1978-07-11 CA CA307,174A patent/CA1114381A/en not_active Expired
- 1978-07-11 AU AU37939/78A patent/AU521641B2/en not_active Expired
- 1978-07-11 JP JP8363778A patent/JPS5436259A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IE781382L (en) | 1979-01-12 |
| PH14993A (en) | 1982-03-22 |
| EP0000355A1 (en) | 1979-01-24 |
| DE2861502D1 (en) | 1982-02-25 |
| CA1114381A (en) | 1981-12-15 |
| DK300978A (en) | 1979-01-13 |
| IL55116A (en) | 1982-02-28 |
| IT7850140A0 (en) | 1978-07-03 |
| EP0000355B1 (en) | 1982-01-06 |
| PT68270A (en) | 1978-08-01 |
| NZ187813A (en) | 1981-03-16 |
| AU521641B2 (en) | 1982-04-22 |
| IL55116A0 (en) | 1978-09-29 |
| JPS5436259A (en) | 1979-03-16 |
| FI782138A (en) | 1979-01-13 |
| ES471593A1 (en) | 1979-10-01 |
| AU3793978A (en) | 1980-01-17 |
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