IL139142A - 4-CYANO-1,2,3,4,6,7,8,12b-OCTAHYDRO-6- OXOPYRIDO [2,1-A] [2] BENZAZEPINE AND ANALOGS THEREOF INTERMEDIATES FOR PREPARING TRI- AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSIN CONVERTING ENZYME - Google Patents
4-CYANO-1,2,3,4,6,7,8,12b-OCTAHYDRO-6- OXOPYRIDO [2,1-A] [2] BENZAZEPINE AND ANALOGS THEREOF INTERMEDIATES FOR PREPARING TRI- AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSIN CONVERTING ENZYMEInfo
- Publication number
- IL139142A IL139142A IL13914295A IL13914295A IL139142A IL 139142 A IL139142 A IL 139142A IL 13914295 A IL13914295 A IL 13914295A IL 13914295 A IL13914295 A IL 13914295A IL 139142 A IL139142 A IL 139142A
- Authority
- IL
- Israel
- Prior art keywords
- acid
- benzazepine
- octahydro
- cyano
- give
- Prior art date
Links
- 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 title description 13
- 239000000543 intermediate Substances 0.000 title description 13
- 102000003729 Neprilysin Human genes 0.000 title description 6
- 108090000028 Neprilysin Proteins 0.000 title description 6
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 title description 6
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 title description 6
- 239000003112 inhibitor Substances 0.000 title description 6
- GJXVFRKECCAQKS-UHFFFAOYSA-N 6-oxo-2,3,4,7,8,12b-hexahydro-1h-pyrido[2,1-a][2]benzazepine-4-carbonitrile Chemical compound O=C1CCC2=CC=CC=C2C2CCCC(C#N)N12 GJXVFRKECCAQKS-UHFFFAOYSA-N 0.000 title description 2
- -1 hydroxy, phenyl Chemical group 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- 239000002253 acid Substances 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000000034 method Methods 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
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- 239000000047 product Substances 0.000 description 14
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229960000587 glutaral Drugs 0.000 description 10
- CMIRWXFQPVROKZ-UHFFFAOYSA-N 5h-2-benzazepine-4-carboxylic acid Chemical compound C1C(C(=O)O)=CN=CC2=CC=CC=C21 CMIRWXFQPVROKZ-UHFFFAOYSA-N 0.000 description 9
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- 238000002360 preparation method Methods 0.000 description 8
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- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 6
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000008064 anhydrides Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 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 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000003377 acid catalyst Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- QGLQAPPNLSDXHB-AWEZNQCLSA-N (2s)-2-(1,3-dioxoisoindol-2-yl)-3-phenylpropanamide Chemical compound C([C@@H](C(=O)N)N1C(C2=CC=CC=C2C1=O)=O)C1=CC=CC=C1 QGLQAPPNLSDXHB-AWEZNQCLSA-N 0.000 description 3
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- 238000010533 azeotropic distillation Methods 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
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- 238000006703 hydration reaction Methods 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
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- 238000003828 vacuum filtration Methods 0.000 description 3
- OGNVQLDIPUXYDH-ZPKKHLQPSA-N (2R,3R,4S)-3-(2-methylpropanoylamino)-4-(4-phenyltriazol-1-yl)-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid Chemical compound CC(C)C(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(O)=O)=C[C@@H]1N1N=NC(C=2C=CC=CC=2)=C1 OGNVQLDIPUXYDH-ZPKKHLQPSA-N 0.000 description 2
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QKDLQFSLLCQTOH-UHFFFAOYSA-N Trichodonin Natural products C1C(O)C2C3(COC(=O)C)C(C=O)C(C)(C)CCC3OC(=O)C22C(=O)C(=C)C1C2 QKDLQFSLLCQTOH-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical class [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- YIUPHEPARZCBPW-UHFFFAOYSA-N piperidine-2,6-dicarbonitrile Chemical compound N#CC1CCCC(C#N)N1 YIUPHEPARZCBPW-UHFFFAOYSA-N 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36091594A | 1994-12-21 | 1994-12-21 | |
| US08/535,403 US5641880A (en) | 1994-12-21 | 1995-10-24 | Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
| IL11642895A IL116428A (en) | 1994-12-21 | 1995-12-18 | Process for preparing intermediates of tri- and tetracyclic inhibitors of enkephalinase and angiotensin converting enzyme and 1-(3-aryl-2-phthalimidopropanoyl)-1, 4 dihydropyridine intermediates thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL139142A true IL139142A (en) | 2004-07-25 |
Family
ID=27001069
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13914295A IL139142A (en) | 1994-12-21 | 1995-12-18 | 4-CYANO-1,2,3,4,6,7,8,12b-OCTAHYDRO-6- OXOPYRIDO [2,1-A] [2] BENZAZEPINE AND ANALOGS THEREOF INTERMEDIATES FOR PREPARING TRI- AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSIN CONVERTING ENZYME |
| IL13914195A IL139141A (en) | 1994-12-21 | 1995-12-18 | 7-Phthalimido-1,2,6,7,8,12b hexahydro-pyrido Ä2,1-aÜbenzazepin-6-one and analogs thereof intermediates for preparing tri-and tetracyclic inhibitors ofenkephalinase and angiotensin converting enzyme |
| IL11642895A IL116428A (en) | 1994-12-21 | 1995-12-18 | Process for preparing intermediates of tri- and tetracyclic inhibitors of enkephalinase and angiotensin converting enzyme and 1-(3-aryl-2-phthalimidopropanoyl)-1, 4 dihydropyridine intermediates thereof |
| IL12899699A IL128996A0 (en) | 1994-12-21 | 1999-03-15 | A novel process for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
| IL13914100A IL139141A0 (en) | 1994-12-21 | 2000-10-19 | 1,2,6,7,8, 12b-HEXAHYDRO-6-OXOPYRIDO[2,1-a] [2] AZEPINE INTERMEDIATES FOR PREPARING TRI-AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSION CONVERTING ENZYME |
| IL13914200A IL139142A0 (en) | 1994-12-21 | 2000-10-19 | 4-CYANO-1,2,3,4,6,7,8,12B-OCTAHYDRO-6- OXOPYRIDO[2,1-a] [2] BENZAZEPINE INTERMEDIATES FOR PREPARING TRI-AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSIN CONVERTING ENZYME |
Family Applications After (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13914195A IL139141A (en) | 1994-12-21 | 1995-12-18 | 7-Phthalimido-1,2,6,7,8,12b hexahydro-pyrido Ä2,1-aÜbenzazepin-6-one and analogs thereof intermediates for preparing tri-and tetracyclic inhibitors ofenkephalinase and angiotensin converting enzyme |
| IL11642895A IL116428A (en) | 1994-12-21 | 1995-12-18 | Process for preparing intermediates of tri- and tetracyclic inhibitors of enkephalinase and angiotensin converting enzyme and 1-(3-aryl-2-phthalimidopropanoyl)-1, 4 dihydropyridine intermediates thereof |
| IL12899699A IL128996A0 (en) | 1994-12-21 | 1999-03-15 | A novel process for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
| IL13914100A IL139141A0 (en) | 1994-12-21 | 2000-10-19 | 1,2,6,7,8, 12b-HEXAHYDRO-6-OXOPYRIDO[2,1-a] [2] AZEPINE INTERMEDIATES FOR PREPARING TRI-AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSION CONVERTING ENZYME |
| IL13914200A IL139142A0 (en) | 1994-12-21 | 2000-10-19 | 4-CYANO-1,2,3,4,6,7,8,12B-OCTAHYDRO-6- OXOPYRIDO[2,1-a] [2] BENZAZEPINE INTERMEDIATES FOR PREPARING TRI-AND TETRACYCLIC INHIBITORS OF ENKEPHALINASE AND ANGIOTENSIN CONVERTING ENZYME |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5734049A (de) |
| EP (1) | EP0800527B1 (de) |
| JP (1) | JP3658408B2 (de) |
| CN (2) | CN1241924C (de) |
| AR (1) | AR000378A1 (de) |
| AT (2) | ATE266040T1 (de) |
| AU (1) | AU689362B2 (de) |
| CA (2) | CA2208569C (de) |
| DE (2) | DE69515517T2 (de) |
| DK (2) | DK0957109T3 (de) |
| ES (2) | ES2147863T3 (de) |
| FI (1) | FI121599B (de) |
| GR (1) | GR3033329T3 (de) |
| HU (1) | HU227675B1 (de) |
| IL (6) | IL139142A (de) |
| MX (1) | MX9704677A (de) |
| NO (2) | NO308900B1 (de) |
| NZ (2) | NZ298245A (de) |
| PT (2) | PT800527E (de) |
| SI (2) | SI0800527T1 (de) |
| TW (1) | TW401413B (de) |
| WO (1) | WO1996019492A1 (de) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6683075B1 (en) | 1996-12-23 | 2004-01-27 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use |
| US6635632B1 (en) | 1996-12-23 | 2003-10-21 | Athena Neurosciences, Inc. | Cycloalkyl, lactam, lactone and related compounds, pharmaceutical compositions comprising same, and methods for inhibiting β-amyloid peptide release and/or its synthesis by use of such compounds |
| JP6169193B2 (ja) * | 2013-01-30 | 2017-07-26 | ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ | ２，６−ビス（アミノメチル）ピペリジン誘導体 |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA874107B (de) * | 1986-06-13 | 1987-12-09 | ||
| US4973585A (en) * | 1986-06-13 | 1990-11-27 | Merrell Dow Pharmaceuticals | Tricyclic lactams active as antihypertensive agents |
| US4824832A (en) * | 1987-12-30 | 1989-04-25 | Merrell Dow Pharmaceuticals Inc. | Sulfhydryl containing tricyclic lactams and their pharmacological methods of use |
| US5430145A (en) * | 1990-10-18 | 1995-07-04 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
| CA2053340C (en) * | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
| EP0492369B1 (de) * | 1990-12-21 | 1997-09-17 | Merrell Pharmaceuticals Inc. | Neue trizyklische Amino- und Nitro Verbindungen mit ACE-hemmenden Eigenschaften |
| AU657793B2 (en) * | 1991-09-27 | 1995-03-23 | Merrell Pharmaceuticals Inc. | Novel 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
| US5457196A (en) * | 1991-09-27 | 1995-10-10 | Merrell Dow Pharmaceuticals Inc. | 2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE |
| DE69220744T2 (de) * | 1991-09-27 | 1997-11-13 | Merrell Pharma Inc | 2-Substituierte Indan-2-Mercaptoacetylamid-Verbindungen mit Enkephalinase und ACE-Hemmwirkung |
| RU2124503C1 (ru) * | 1992-05-18 | 1999-01-10 | И.Р.Сквибб энд Санз, Инк. | Гетероциклические азотсодержащие производные карбоновой кислоты, способ их получения и фармацевтическая композиция |
| US5238932A (en) * | 1992-05-20 | 1993-08-24 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase |
| US5525723A (en) * | 1993-11-18 | 1996-06-11 | Bristol-Myers Squibb Co. | Compounds containing a fused multiple ring lactam |
-
1995
- 1995-11-20 PT PT95942465T patent/PT800527E/pt unknown
- 1995-11-20 DK DK99114227T patent/DK0957109T3/da active
- 1995-11-20 CN CN02155715.2A patent/CN1241924C/zh not_active Expired - Fee Related
- 1995-11-20 SI SI9530326T patent/SI0800527T1/xx unknown
- 1995-11-20 PT PT99114227T patent/PT957109E/pt unknown
- 1995-11-20 AU AU43685/96A patent/AU689362B2/en not_active Ceased
- 1995-11-20 DE DE69515517T patent/DE69515517T2/de not_active Expired - Lifetime
- 1995-11-20 ES ES95942465T patent/ES2147863T3/es not_active Expired - Lifetime
- 1995-11-20 DK DK95942465T patent/DK0800527T3/da active
- 1995-11-20 AT AT99114227T patent/ATE266040T1/de active
- 1995-11-20 HU HU9901108A patent/HU227675B1/hu not_active IP Right Cessation
- 1995-11-20 JP JP51980096A patent/JP3658408B2/ja not_active Expired - Lifetime
- 1995-11-20 SI SI9530707T patent/SI0957109T1/xx unknown
- 1995-11-20 EP EP95942465A patent/EP0800527B1/de not_active Expired - Lifetime
- 1995-11-20 WO PCT/US1995/015225 patent/WO1996019492A1/en not_active Ceased
- 1995-11-20 CA CA002208569A patent/CA2208569C/en not_active Expired - Fee Related
- 1995-11-20 ES ES99114227T patent/ES2216386T3/es not_active Expired - Lifetime
- 1995-11-20 DE DE69533002T patent/DE69533002T2/de not_active Expired - Lifetime
- 1995-11-20 MX MX9704677A patent/MX9704677A/es not_active IP Right Cessation
- 1995-11-20 CA CA002297134A patent/CA2297134C/en not_active Expired - Fee Related
- 1995-11-20 CN CN95196905A patent/CN1113894C/zh not_active Expired - Fee Related
- 1995-11-20 AT AT95942465T patent/ATE190315T1/de active
- 1995-11-20 NZ NZ298245A patent/NZ298245A/en not_active IP Right Cessation
- 1995-12-16 TW TW084113469A patent/TW401413B/zh not_active IP Right Cessation
- 1995-12-18 IL IL13914295A patent/IL139142A/en not_active IP Right Cessation
- 1995-12-18 IL IL13914195A patent/IL139141A/xx not_active IP Right Cessation
- 1995-12-18 IL IL11642895A patent/IL116428A/xx not_active IP Right Cessation
- 1995-12-19 AR AR33467595A patent/AR000378A1/es unknown
-
1996
- 1996-11-04 US US08/743,481 patent/US5734049A/en not_active Expired - Lifetime
-
1997
- 1997-06-18 FI FI972620A patent/FI121599B/fi not_active IP Right Cessation
- 1997-06-20 NO NO972875A patent/NO308900B1/no not_active IP Right Cessation
-
1999
- 1999-03-11 NZ NZ334608A patent/NZ334608A/xx not_active IP Right Cessation
- 1999-03-15 IL IL12899699A patent/IL128996A0/xx unknown
-
2000
- 2000-04-07 NO NO20001822A patent/NO310025B1/no not_active IP Right Cessation
- 2000-04-26 GR GR20000401013T patent/GR3033329T3/el unknown
- 2000-10-19 IL IL13914100A patent/IL139141A0/xx unknown
- 2000-10-19 IL IL13914200A patent/IL139142A0/xx active IP Right Grant
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |