NO811599L - Fremgangmaate ved fremstilling av cycliske amider - Google Patents
Fremgangmaate ved fremstilling av cycliske amiderInfo
- Publication number
- NO811599L NO811599L NO811599A NO811599A NO811599L NO 811599 L NO811599 L NO 811599L NO 811599 A NO811599 A NO 811599A NO 811599 A NO811599 A NO 811599A NO 811599 L NO811599 L NO 811599L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- hydrogen
- formula
- carboxylic acid
- aralkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 150000003950 cyclic amides Chemical class 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 21
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 125000001589 carboacyl group Chemical group 0.000 claims abstract description 4
- 150000001768 cations Chemical class 0.000 claims abstract description 4
- -1 cyano, amino Chemical group 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000005592 polycycloalkyl group Polymers 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000000732 arylene group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 2
- 125000005549 heteroarylene group Chemical group 0.000 claims description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 6
- 150000002431 hydrogen Chemical group 0.000 abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 2
- 239000005541 ACE inhibitor Substances 0.000 abstract 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FUVZDXDCPRQZSQ-UHFFFAOYSA-N 1,5,6,7-tetrahydroindazol-4-one Chemical compound O=C1CCCC2=C1C=NN2 FUVZDXDCPRQZSQ-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BWKMGYQJPOAASG-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN[C@H](C(=O)O)CC2=C1 BWKMGYQJPOAASG-VIFPVBQESA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VFVHNRJEYQGRGE-UHFFFAOYSA-N 3-acetylsulfanyl-2-methylpropanoic acid Chemical compound OC(=O)C(C)CSC(C)=O VFVHNRJEYQGRGE-UHFFFAOYSA-N 0.000 description 1
- SVSZJZJRCAJHRP-UHFFFAOYSA-N 5-[3-(2,2-dimethylpropanoylsulfanyl)-2-methylpropanoyl]-3,4-dihydro-2h-thieno[3,2-c]pyridine-3-carboxylic acid Chemical compound C1=CN(C(=O)C(CSC(=O)C(C)(C)C)C)CC2=C1SCC2C(O)=O SVSZJZJRCAJHRP-UHFFFAOYSA-N 0.000 description 1
- BPMFPOGUJAAYHL-UHFFFAOYSA-N 9H-Pyrido[2,3-b]indole Chemical class C1=CC=C2C3=CC=CC=C3NC2=N1 BPMFPOGUJAAYHL-UHFFFAOYSA-N 0.000 description 1
- ARLVFKCLBYUINL-UHFFFAOYSA-N 9h-pyrido[3,4-b]indole-3-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1C=NC(C(=O)O)=C2 ARLVFKCLBYUINL-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 150000002019 disulfides Chemical class 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 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
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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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
- A61P9/12—Antihypertensives
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
Fremgangsmåte ved fremstilling av
cycliske amider
Foreliggende oppfinnelse angår nye kjemiske forbindelser med verdifull farmasøytisk aktivitet. Oppfinnelsen angår særlig amider med antihypertens.iv aktivitet og inhiberende aktivitet overfor angiotensinomdannende enzym, og med struktu-ren:
hvori R^, 1*2' R3°9R4nver er hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralky1, cycloalkyl, polycycloalky1 eller heterocycloalky1; n er. et helt tall fra 0 til 4; Rj. er hydrogen, alkyl, aralkyl, aryl, hydroxyalky 1, aminoalkyl, alkanoyl,.aryloyl, arylalkanoyl, hydroxyalkanoyl, carboxyalkanoyl, aminoalkanoyl, cyano, amino, alkylamino, arylamino, amidino, alkylamidino, arylamidino, eller ZS-, ZS(CR1R2)n- eller ZSCO- hvori Z er alkyl, aryl, aralkyl eller et radikal av formelen
hvori R^, R2, R3, R4, -Rg, R7, n, X2og Y er som ovenfor definert,
Y er OH, OM, OR^^, NR^, --NR-^(CR1R2) n_CO-Y1
hvori M er et farmasøytisk akseptabelt kation, R.^, R2og n er som ovenfor definert, og Y1 er OH, OM, OR-j^eller N-R^R2;
X1og X2er 'hver S, SO, - S02, NR^, kjemisk binding, 0,"
(CR„Rn) , -CR0=CR0-^, og CHOH, forutsatt at minst én av X, bg o y m o y j-
X_ er (CRnRf,) , hvori RQog RQhver er hydrogen eller lavere2. o y m o y
alkyl, og m er ét helt tall fra 0 til 5;
Ar er et divalent arylen eller heteroarylen; og
Rg og R^er hver hydrogen, alkyl, halogen, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, nitro, trifluoromethyl, carboxy, carbalkoxy, COY og NHCONHR^, hvori R^og Y er som ovenfor definert.
Alkylgruppene per se og i alkyldelen i aralkyl, cyclo-alkylalkyl, polycycloalkylalkyl, heteroarylalkyl og lignende, og i alkoxy, alkylmercapto, alkanoyl, carbalkoxy, alkylamino og dialkylamino kan være rettkjedet eller forgrenet og er fortrinnsvis alkylgrupper inneholdende fra 1 til 20 carbonatomer. Slike grupper innbefatter methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, iso-amyl, hexyl, octyl, dodecyl og lignende. Fortrinnsvis er alkylgruppene lavere alkyl inneholdende fra 1 til 6 carbonatomer.
Alkenyl og alkynylgruppene kan også være forgrenet eller rettkjedet.og inneholde fra 2 til 6 carbonatomer. Slike grupper innbefatter vinyl, ethynyl, propenyl, allyl, isopropenyl . og lignende..
Disse alkyl, alkenyl og alkynylgrupper kan bære substituenter slik som hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, halogen og lignende.
Cycloalkyl, polycycloalkyl, aryl, heteroaryl, arylalkyl, kondensert ary1-cycloalkyl gruppene inneholder fra 3 til 16 carbonatomer og kan bære substituenter slik som lavere alkyl, alkenyl, alkynyl, hydroxy, mercapto, amino, alkoxy, alkylmercapto, alkylamino, dialkylamino, halogen, trifluoromethyl og lignende. Gruppene innbefatter slike radikaler som cyclopro-pyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adaman-tyl, norbornyl, fenyl, tolyl, benzyl, penethyl, dimethoxyfen-yl, hydroxybenzyl, indanyl, nafthyl, tetrahydronafthyl, decan-hydronafthyl, pyridyl, kinolyl, pyrrolidyl, pyrrolyl, morfo-linyl, furyl, furfuryl, tetrahydrofurfuryl, benzimidazolyl, thienyl, imidazolyl og lignende.
Halogengruppene innbefatter fluor, klor, brom og jod.
De farmasøytisk akseptable kationer innbefatter både monovalente og polyvalente metaller slik. som f.eks. natrium, kalium, kalsium, magnesium, jern og lignende,, og ammoni.um-kationer avledet fra ammoniakk, primære, sekundære og terti-ære aminer.
, De foretrukne forbindelser ifølge oppfinnelsen er de hvori en av X^og X2er CH2, og den annen er -CH2-CHRg-, Ar er o-fenylen, n er 0 eller 1, R1, R^, R^, Rg og R? er hydro^ gen, Y er hydroxy, R2er methyl, R^ er hydrogen eller acetyl, og Rg er hydrogen eller lavere alkyl.
Det er kjent for fagmannen at de amider ifølge oppfinnelsen som har et asymmetrisk carbonatom kan foreligge i race-misk eller optisk aktive levo eller dextroformer. Alle disse former omfattes av oppfinnelsens ramme.
Forbindelsene ifølge oppfinnelsen kan erholdes ved omsetning av en cyclisk aminoforbindelse av formelen:
med en carboxylsyre eller ekvivalent acylerende derivat av formelen: under dannelse av forbindelsen:
Der foretrekkes å anvende cycliske arainoforbindelser hvori Y er OR^, dvs. estrene, som kan hydrolys.eres til den frie carboxylsyre og omdannes til ethvert ønsket syrederivat derefter.
Ved egnede reaksjoner kan forskjellige forbindelser fremstilles under anvendelse av den ovenfor angitte omsetning. Når f.eks.. R^ er acetyl, kan forbindelsen hydrolyseres under dannelse av en forbindelse hvor R<- er hydrogen, og denne forbindelse kan i sin tur omdannes ved omsetning med egnede acyl-halogenider eller etherdannende grupper, under dannelse av andre ønskede R,- subs.tituenter.
Den frie carboxylsyre (Y er OH). kan omdannes til salter, estere og amider. Disulfidene (hvori R,- er ZS) fremstilles ved mild oxydasjon av det tilsvarende mercaptan med jod eller oxygen.
Representative synteseprosedyrer for fremstilling av forbindelser ifølge oppfinnelsen er angitt i metoder A, B, C og D som alle anvender den generelle aminacyleringsreaksjon ifølge oppfinnelsen.
I metode A erholdes forbindelsene ved direkte acylering av en egnet aminosyre eller en ester av en aminosyre.
Metode B illustrerer fremstillingen av 3-carbolinanalo-ger.
Metoder C og D illustrerer fremstillingen av visse he-. terocycliské analoger.
De ønskede mellomprodukter kan fremstilles efter vel-kjente reaksjoner.
Oppfinnelsen illustreres nærmere i de etterfølgende eksempler.
EKSEMPEL I L- l, 2, 3, 4- tetrahydroisokinolin- 3- carboxylsyre
En suspensjon av 75 g (0,455 moll. L---fenylalanin i 488 ml konsentrert saltsyre og 165 ml 37 %' s. forma,lin ble oppvar-met til en svak. tilbakeløpskokning under kraftig omrøring 30 minutter. Derefter ble en annen porsjon 37 %'s formalin (75 ml) og 165 ml konsentrert saltsyre tilsatt. Omrøring og opp-varmning ble fortsatt 4 timer. Reaksjonsblandingen ble av-kjølt til romtemperatur, og det faste materiale som var dan-net, ble filtrert og vasket med en liten mengde methanol under dannelse av hydrokloridet som.et farveløst fast materiale (68,9 g, 71. %), sm.p. 291 - 294°C.
EKSEMPEL II . N-benzylcarbethoxy-L-l,2,3,4--tetrahydroisO'-kinolin- 3- carboxylsyre
58,8 g (0,275 mol) L-l,2,3,4-tetrahydroisokinolin-3-carboxylsyre b.le oppløst i 600 ml IN natriumhydroxyd, og den resulterende oppløsning ble avkjølt på et isbad. 39,0 ml (0,263 mol) benzylklorformiat ble dråpevis tilsatt. Efter at alt benzylklorformiat var tilsatt (30 minutter), ble omrøringen fortsatt 1 time ved romtemperatur, og derefter ble en"annen porsjon av
100 ml IN natriumhydroxyd tilsatt. Omrøringen ble fortsatt
ytterligere 2 1/2 time. Reaksjonsblandingen ble surgjort til pH 4 med konsentrert saltsyre, og produktet ekstrahert i kloroform. Den organiske fase ble vasket to ganger med vann og tørket over magnesiumsulfat. Filtrering og fordampning av oppløsningsmidlet gav en farveløs olje (86,3 g, 91,5 %) som ble anvendt uten ytterligere rensning.
EKSEMPEL III tert-butyl N-benzylcarbethoxy~L--(1, 2 , 3 , 4-tetrahydroisokinolin)- 3- carboxylat
46,5 g (0,150 mol) N-benzylcarbethoxy-L-1,2,3,4-tetrahydroisokinolin- 3-carboxylsyre ble oppløst i 1000 ml methylenklorid, og 7 ml konsentrert svovelsyre ble tilsatt. Den resulterende blanding ble avkjølt på et tø.rris-acetonbad til~30°C, og derefter ble isobutylen boblet gjennom oppløsningen 3 timer. Reaksjonskaret ble lett stengt med en trykkventil og lagret natten over ved romtemperatur. Reaksjonsblandingen
ble forsiktig gjort alkalisk ved dråpevis. tilsetning av 10 %'s vandig kaliuiticarbonat. Den organiske fase ble fra^ skilt og vasket en gang til med 10 %'s J^CO^ og derefter to
ganger med vann. Det organiske ekstrakt ble tørket over magnesiumsulfat. Filtrering og fordampning av oppløsningsmidlet gav en lys gul olje (45,3 g, 82,4 %). som ble anvendt uten ytterligere rensning.
E KSEMPEL IV tert-butyl L-- (1, 2 , 3 , 4-tetrahydroisokinolin) -
3-- carboxy lat
45 g (0,123 mol) tert-butyl N-benzylcarbethoxy-L-(1, 2 , 3 , 4-tetrahydroisokinolin)-3--carboxylat ble oppløst i 600 ml absolutt ethanol, og 4 g 10 %'s Pd/c ble tilsatt. Den resulterende blanding ble hydrogenert i en lavtrykks Parr ris-ter ved et trykk på 3,5 kg/cm 2i 16 timer. Katalysatoren ble filtrert fra, og oppløsningsmidlet fordampet under d"annelse av urent produkt som en lys gul olje (24,8 g, 86,4 %) som ble anvendt uten ytterligere rensning.
EKSEMPEL V tert-butyl N- (3 ' -acetylthio--2 ' -methylpropanoyl) -L- (1,2,3, 4-tetrah-ydroisokinolin) - 3- carboxylat
Til en oppløsning av 8,1 g (0,0349 mol) tert-butyl-L-(1,2,3,4-tetrahydroisokinolin)-3-carboxylat og 5,6 g (0,0346 mol). 3-acetylthio-2-methylpropionsyre i 250 ml methylenklorid avkjølt på et isbad ble tilsatt 7,2 g (0,0350 mol) dicyclo--hexylcarbodiimid. Den resulterende blanding ble omrørt med utvendig avkjøling 30 minutter og derefter ca. 3 timer ved romtemperatur. Utfeldt dicyclohexylurea ble filtrert og vasket med en liten mengde methylenklorid. Konsentrering av filtratet gav urent produkt som en lys gul olje som ble anvendt uten ytterligere rensning.
EKSEMPEL VI N~ ( 3 '-acety lthio-2 '-^eth.y lpropany 1)-L--( 1, 2., 3, 4^ tetrahydroi. soki. nolin) -- 3- carboxylsyre 14 g (0,371 mol), urent tert-butyl N-r (3 '--acetylthio-2 '-methylpropanoyl).L- (1,2 ,3, 4-tetrahydroisokinolin) -3-carboxylat ble oppløst i en blanding av 25 ml anisol og 75 ml trifluor-eddiksyre. Den resulterende oppløsning ble omrørt ved rom-, temperatur ca. 1 time. Trifluoreddiksyré ble fjernet i vakuum og residuet fordelt mellom ethylacetat og mettet natrium--bicarbonat. Den vandige bicarbonatfase ble fraskilt og vasket to ganger med ethylacetat og derefter forsiktig surgjort til pH 2 - 4 med konsentrert saltsyre. Det utfeldte produkt ble ekstrahert flere ganger i kloroform,. og det kombinerte organiske ekstrakt ble vasket to ganger med vann, tørket over magnesiumsulfat, filtrert og fordampet under dannelse av
7,3 g av en lys gul olje. Dette råprodukt ble renset ved høytrykks væskekromatografi under anvendelse av en blanding av n-hexan/ethylacetat/eddiksyre (30:60:1) som elueringsmid-del under dannelse av rent produkt som en farveløs olje
(5,9 g). Produktet blekarakterisertsom sitt dicyclohexy1-amin (DCHA) salt, som ble fremstilt i.ether under dannelse av farveløse krystaller med sm.p. 161 - 163°C. '
EKSEMPEL VII N- (3 ' -mercapto--2 ' -methylpropanoyl) -L- (1, 2 , 3 , 4-tetrahydroisokinolin- 3- carboxylsyre
Vannfri ammoniakk ble boblet 15 minutter gjennom 100 ml methanol, og den resulterende mettede oppløsning ble tilsatt til 2,0 g (0,00623 mol) N-(3'-acetylthio-2'-methylpropanoyl)-L-(1,2,3,4-tetrahydroisokinolin-3-carboxylsyre og anbragt under nitrogen. Reaksjonsblandingen ble omrørt ved romtemperatur 1 time. Oppløsningsmidlet ble fjernet i vakuum, og residuet anbragt på en kolonne av AG-50W-X2 kationbytterharpiks og eluert med methanol. Methanolen ble fordampet og residuet oppløst i kloroform. Kloroformen ble vasket én gang med vann og tørket over magnesiumsulfat. Filtrering og fordampning av oppløsningsmidlet gav 1,7 g (98 %) av en farveløs olje. Den frie syre ble omdannet til sitt DCHA salt i ether under dannelse av farveløse krystaller; sm.p. 146 - 147°C. Produktet blekarakterisertsom sitt DCHA salt.
EKSEMPEL VIII 2-.(3 ' -acetylthio- 2 ' -methylpropanoly1) -1-fenyl-;3--'- c ar borne th. oxy- 1, 2, 3, 4- :- tetrahydro-( 3- carbolin 10 g (0,0327 mol) l-f enyl-.-3-carbomethoxy-l, 2 , 3 , 4-^tetra-r hydro-3-^carbolin og 4,1 g (0,04 mol), triethylamin ble oppløst i 250 ml acetonitril, og den resulterende blanding ble avkjølt på et isbad. 6,5 g (0,036 mol). 3-acetylthio-2-methy lpropionyl-:\ klorid ble ble porsjonsvis ti-lsatt. Ef ter at alt syreklorid var tilsatt, ble isbadet fjernet, og blandingen ble omrørt ved romtemperatur under nitrogen 2 1/2 time. Oppløsningsmid-let ble fordampet, og residuet oppløst i kloroform. Kloroformen ble vasket med vann, 5 %'s vandig NaOH, 5 %'s vandig HC1 og vann. Kloroformen ble tørket over magnesiumsulfat, filtrert og fordampet under dannelse av urent produkt som en svakt farvet olje. Produktet ble ytterligere renset ved kromatografi på silicagel (Ct^C^)under dannelse av rent produkt som en farveløs olje (9,6 g, 65 %) .
EKSEMPEL IX 2-(31-mercapto-2'-methylpropanoyl)-1-feny1-3-carbomethoxy- 1, 2, 3, 4- tetrahydro-&- carbolin 2 g (0,0045 mol) 2-(3'-aceiylthio-2'-methylpropanoyl)-1-fenyl-3-carbomethoxy-l,2,3,4-tetrahydro-3-carbolin ble opp-løst i 75 ml methanol, og vannfri ammoniakk ble boblet gjennom oppløsningen 15 minutter. Reaksjonsblandingen ble anbragt under nitrogen, og omrøringen ble fortsatt ved romtemperatur 1 time. Methanolen ble fordampet og residuet anbragt på en kationbytterkolonne (methanol). Methanolen ble fordampet, og residuet oppløst i kloroform, vasket med vann, tørket over magnesiumsulfat, filtrert og fordampet under dannelse av produktet som en farveløs olje (1,6 g, 88 %).
EKSEMPEL X N-(3'-acetylthio-21-methylpropanoyl)-L-( 1, 2, 3, 4- tetrahydroisokinolin)- 3- carboxylsyre Til en omrørt suspensjon av 40,0 g (187,2 mmol) L-l,2,3,4-tetrahydroisokinolin-3-carboxylsyre i ca. 1 liter p-dioxan og 200 ml vann ble tilsatt 78 ml (560,8 mmol) triethylamin efterfulgt av dråpevis tilsetning av 33,8 g (187,2 mmol). Blandingen ble praktisk talt homogen eftersom reak-sjonen forløp. Efter ca. 3 timer ble en liten mengde uopplø- selig materiale filtrert fra, og filtratet ble konsentrert på en.rotasjonsfordamper. Den resulterende oppløsning ble fortynnet med vann og surgjort til pH. 2 med konsentrert HC1 og ekstrahert i ethylacetat. Ethylacétatoppløsningen ble vasket to ganger med vann, én gang med saltvann, tørket over magnesiumsulfat, filtrert og fordampet under dannelse av ca.
55 g olje. Det urene materiale ble fraskilt ved preparativ
kromatografi og eluert med 2 % eddiksyre, 40 % ethylacetat og 60 % hexan under dannelse av 30,2 g (50,2 %) rent materiale.
Ved å følge den prosedyre som er beskrevet i de foregå-ende eksempler ble følgende forbindelser.fremstilt: N- ( 3 ' -acetylthio-2 ' -methylpropanoyl) -L^-6 , 7-dihydroxy-l ,2,3,4-
tetrahydroisokinolin-3-carboxylsyre
N-(3'-acetylthio-2'-methylpropanoyl)-L-6,7-dimethoxy-l,2,3,4-tetrahydroisokinolin-3-carboxylsyre
N- (3.' -acetylthio-2 1 -methylpropanoyl) -L-7-klor-l ,2,3, 4-tetrahydroisokinolin-3-carboxyl sy re N-(3'-mercapto-2'-methylpropanoyl)-L-6,7-dimethoxy-l,2,3,4-tetrahydroisokinolin-3-carboxylsyre N- (3 ' -mercapto-2 ' -methylpropanoyl) -L-7-hydroxy--6-methoxy-1,2,3,4-tetrahydroisokinolin-3-carboxylsyre N-(3<1->acetylthio-2'-methylpropanoyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisokinolin-l-carboxylsyré
N- (3'-mercapto-2'-methylpropanoyl)-L-3-methy1-1,2,3,4-tetrahydroisokinolin- 3- carboxyl sy re
2- (3 ' -acetylthio-2.' -methylpropanoyl) - 6-fluor-l,2,3, 4-tetrahydro-3"carbolin-3-carboxylsyre
2-(3'-mercapto-2'-methylpropanoyl)-l-methyl-3-1,2,3,4-tetrahydro-3-carbolin-3-carboxylsyre
N-(3'-acetylthio-2'-methylpropanoyl)-L-l-methy1-1,2,3,4-tetrahydroisokinolin- 3- carboxyl sy re
N-(3'-mercapto-2<1->methylpropanoyl)-L-l-methy1-1,2,3,4-tetrahydroisokinolin- 3- carboxyl sy re
N-(3<1->acetylthio-2'-methylpropanoyl)-1-(3'4'-dimethoxyfeny1)-1,2,3,4-tetrahydroisokinolin-3-carboxylsyre N-(3'-trimethylacetylthio-2'-methylpropanoyl)-1,2,3,4-tetra-hydrothieno[3,2-c]-pyridin-3-carboxylsyre
2 ' 6 ' -diklorbenzoylthio-2 ' -^methylpropanoyi-l, 3-benzothiazin--2-carboxylsyre
N-- (2 ' -acetylthiopropanoyl) ^benzo^-2r-azacycloheptan-3-carboxylsyre N- (3 ' -acetylthio-2 ' --methylpropanoyl).-1, 2-^-dihydroisokinolin-l-carboxylsyre
Forbindelsene fremstilt ifølge oppfinnelsen utviser en kraftig angiotensinenzyminihiberende aktivitet. Slik aktivitet indikerer at forbindelsene fremstilt ifølge oppfinnelsen, er nyttige i behandlingen av hypertensjon. Når de administreres intraperitonalt til spontant hypertensive rotter, gir de en.reduksjon i blodtrykket på 20 - 30 % ved 100 mg/kg.
Forbindelsene fremstilt ifølge oppfinnelsen kan administreres oralt eller parenteralt ved behandling av hypertensjon, og fagmannen vil kunne bestemme den nøyaktige mengde som administreres.
Claims (4)
1. Fremgangsmåte ved fremstilling av cycliske amider av
formelen
hvori
R , R2> R^ og R^ hver er hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralky1, cycloalkyl, polycycloalkyl el.ler heterocycloalkyl;
n er et helt tall fra 0 til 4;
R,- er hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, alkanoyl, aryloyl, arylalkanoyl, hydroxyalkanoyl, carboxyalkanoyl, aminoalkanoyl, cyano, amino, alkylamino, arylamino, amidino, alkylamidino, arylamidino eller ZS-, ZS(CR1 R2 )n~ eller ZSCO-, hvori Z er alkyl, aryl, aralkyl eller et radikal av formelen
hvori R.^ R2, R3 , R^ , Rg, R , n, X^^ , X2 og Y er som her definert.
Y er OH, OM, OR,, NR,R„, eller -NR,-(CR.R-) -CO-Y,,
-L A - A xa^n x hvori M er et farmasøytisk akseptabelt kation, R^ , R2 og n er som her definert, og Y1 er OH, OM, OR-^ eller NR± R2 ;
X1 og X2 er hver S, SO, -S02» NR1, en kjemisk binding, 0, (CRgRg). , CHOH. eller -CRg=CRg-^, forutsatt at minst én av X, og X-, må være (CR0R„) , hvori. RQ og RQ er uavhengig hydro-
± z o y m o y
gen eller lavere alkyl, pg m er et helt tall fra 0 til 5;
Ar er et di <y> alent arylen eller heteroarylen; og Rg og R7 er hver hydrogen, alkyl, halogen, cyano, hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylmercapto, nitro, trifluormethyl, carboxy, carbalkoxy, COY. eller NHCONHR^ , hvori R^ og Y er som her definert, karakterisert ved at et amin av formelen
acyleres med en mercaptosyre, eller ekvivalent acylerende derivat av formelen
og at eventuelt gruppen -COY omdannes til den frie syre (Y=0H). og derefter til andre derivater (hvori Y er forskjellig fra OH); eller at produktet hvori R,- er H, oxyderes under dannelse av disulfidet; eller at produktet hvori R,, er H, derivatiseres for å innføre substituenter representative for Rj. bortsett fra H.
2. Fremgangsmåte ifølge krav 1, karakterisert ved at Y subs tituenten i aminet er OR^ , og R^ i mercaptosyren er eri acylgruppe, fortrinnsvis acetyl.
3. Fremgangsmåte ifølge krav 2, karakterisert ved at R,- gruppen fjernes ved hydrolyse, og at den resulterende mercaptoforbindelse derivatiseres for å innføre R,- substituenter forskjellig fra H..
4. Fremgangsmåte ifølge krav 2 eller 3, karakterisert ved åt R1 er tertiært butyl.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/148,083 US5200416A (en) | 1980-05-12 | 1980-05-12 | Cyclic amides |
Publications (1)
Publication Number | Publication Date |
---|---|
NO811599L true NO811599L (no) | 1981-11-13 |
Family
ID=22524186
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO811599A NO811599L (no) | 1980-05-12 | 1981-05-11 | Fremgangmaate ved fremstilling av cycliske amider |
Country Status (18)
Country | Link |
---|---|
US (1) | US5200416A (no) |
EP (1) | EP0039804B1 (no) |
JP (1) | JPS577470A (no) |
KR (1) | KR850001088B1 (no) |
AT (1) | ATE21511T1 (no) |
AU (1) | AU546218B2 (no) |
DE (1) | DE3175150D1 (no) |
DK (1) | DK206881A (no) |
ES (1) | ES8203368A1 (no) |
FI (1) | FI811424L (no) |
IL (1) | IL62782A0 (no) |
IN (1) | IN152326B (no) |
NO (1) | NO811599L (no) |
NZ (1) | NZ197048A (no) |
SU (1) | SU1304748A3 (no) |
YU (1) | YU120481A (no) |
ZA (1) | ZA812941B (no) |
ZW (1) | ZW10881A1 (no) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2672598A1 (fr) * | 1991-02-11 | 1992-08-14 | Adir | Nouveaux inhibiteurs de n-myristoyltransferase, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
AU7724496A (en) * | 1995-11-09 | 1997-05-29 | Monsanto Company | An improved method for preparation of substituted tetrahydroisoquinolines |
US5627282A (en) * | 1996-01-03 | 1997-05-06 | Yukong Limited | Process for the preparation of optically pure 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid and its derivatives |
EP2518070A1 (en) * | 2011-04-29 | 2012-10-31 | Almirall, S.A. | Pyrrolotriazinone derivatives as PI3K inhibitors |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5572169A (en) * | 1978-11-27 | 1980-05-30 | Tanabe Seiyaku Co Ltd | Isoquinoline derivative and its preparation |
EP0018104B1 (en) * | 1979-03-26 | 1983-05-25 | Takeda Chemical Industries, Ltd. | Tetrahydroisoquinolines, their production and the compounds and pharmaceutical compositions containing them for use in the prevention or treatment of hypertension |
GB2048863B (en) * | 1979-05-16 | 1983-06-15 | Morton Norwich Products Inc | Tetrahydroisoquinoline-3-carboxylic acids |
DE2937779A1 (de) * | 1979-09-19 | 1981-04-09 | Hoechst Ag, 6000 Frankfurt | Aminosaeurederivate und verfahren zu ihrer herstellung |
FR2487829A2 (fr) * | 1979-12-07 | 1982-02-05 | Science Union & Cie | Nouveaux imino acides substitues, leurs procedes de preparation et leur emploi comme inhibiteur d'enzyme |
US4251444A (en) * | 1980-04-07 | 1981-02-17 | American Home Products Corporation | Thiazepino-[4,3-b]-isoquinoline-1,5-dione derivatives and precursors |
-
1980
- 1980-05-12 US US06/148,083 patent/US5200416A/en not_active Expired - Lifetime
-
1981
- 1981-04-23 AT AT81103072T patent/ATE21511T1/de not_active IP Right Cessation
- 1981-04-23 EP EP81103072A patent/EP0039804B1/en not_active Expired
- 1981-04-23 DE DE8181103072T patent/DE3175150D1/de not_active Expired
- 1981-05-04 IL IL62782A patent/IL62782A0/xx unknown
- 1981-05-04 ZA ZA00812941A patent/ZA812941B/xx unknown
- 1981-05-06 IN IN473/CAL/81A patent/IN152326B/en unknown
- 1981-05-07 ZW ZW108/81A patent/ZW10881A1/xx unknown
- 1981-05-08 FI FI811424A patent/FI811424L/fi not_active Application Discontinuation
- 1981-05-09 ES ES502064A patent/ES8203368A1/es not_active Expired
- 1981-05-11 AU AU70450/81A patent/AU546218B2/en not_active Ceased
- 1981-05-11 DK DK206881A patent/DK206881A/da not_active Application Discontinuation
- 1981-05-11 NZ NZ197048A patent/NZ197048A/en unknown
- 1981-05-11 NO NO811599A patent/NO811599L/no unknown
- 1981-05-11 SU SU813282548A patent/SU1304748A3/ru active
- 1981-05-12 KR KR1019810001634A patent/KR850001088B1/ko active IP Right Grant
- 1981-05-12 JP JP7024181A patent/JPS577470A/ja active Pending
- 1981-05-12 YU YU01204/81A patent/YU120481A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
ATE21511T1 (de) | 1986-09-15 |
FI811424L (fi) | 1981-11-13 |
JPS577470A (en) | 1982-01-14 |
ES502064A0 (es) | 1982-04-01 |
KR830006210A (ko) | 1983-09-20 |
ES8203368A1 (es) | 1982-04-01 |
YU120481A (en) | 1983-12-31 |
IL62782A0 (en) | 1981-07-31 |
KR850001088B1 (ko) | 1985-07-27 |
SU1304748A3 (ru) | 1987-04-15 |
AU546218B2 (en) | 1985-08-22 |
DE3175150D1 (en) | 1986-09-25 |
DK206881A (da) | 1981-11-13 |
IN152326B (no) | 1983-12-17 |
EP0039804B1 (en) | 1986-08-20 |
NZ197048A (en) | 1984-04-27 |
EP0039804A1 (en) | 1981-11-18 |
AU7045081A (en) | 1981-11-19 |
ZA812941B (en) | 1982-05-26 |
US5200416A (en) | 1993-04-06 |
ZW10881A1 (en) | 1981-07-29 |
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