JPH10511348A - エンケファリナーゼおよびアンギオテンシン変換酵素の阻害剤の中間体を製造する新規な方法およびその中間体 - Google Patents
エンケファリナーゼおよびアンギオテンシン変換酵素の阻害剤の中間体を製造する新規な方法およびその中間体Info
- Publication number
- JPH10511348A JPH10511348A JP8519800A JP51980096A JPH10511348A JP H10511348 A JPH10511348 A JP H10511348A JP 8519800 A JP8519800 A JP 8519800A JP 51980096 A JP51980096 A JP 51980096A JP H10511348 A JPH10511348 A JP H10511348A
- Authority
- JP
- Japan
- Prior art keywords
- group
- acid
- compound
- dihydro
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 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 abstract description 7
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 title abstract description 7
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 title abstract description 5
- 239000000543 intermediate Substances 0.000 title description 17
- 102000003729 Neprilysin Human genes 0.000 title description 7
- 108090000028 Neprilysin Proteins 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 73
- -1 hydroxy, phenyl Chemical group 0.000 claims description 69
- 229910052717 sulfur Inorganic materials 0.000 claims description 52
- 239000002253 acid Substances 0.000 claims description 51
- 238000000034 method Methods 0.000 claims description 33
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 32
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 26
- 229910052760 oxygen Inorganic materials 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 22
- PZIIEQUJVYVLRJ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine-2-carbonitrile Chemical compound N#CC1CCC=CN1 PZIIEQUJVYVLRJ-UHFFFAOYSA-N 0.000 claims description 17
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 12
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical compound N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims description 11
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 10
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 10
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 8
- 150000008064 anhydrides Chemical class 0.000 claims 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 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 4
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 238000011065 in-situ storage Methods 0.000 claims description 4
- YIUPHEPARZCBPW-UHFFFAOYSA-N piperidine-2,6-dicarbonitrile Chemical compound N#CC1CCCC(C#N)N1 YIUPHEPARZCBPW-UHFFFAOYSA-N 0.000 claims description 4
- 230000000887 hydrating effect Effects 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- 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 32
- 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 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- 235000011054 acetic acid Nutrition 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
- 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
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LLRVWEHGZKXEOH-XBMUEBEBSA-N (4s)-7-(1,3-dioxoisoindol-2-yl)-6-oxo-2,3,4,7,8,12b-hexahydro-1h-pyrido[2,1-a][2]benzazepine-4-carboxylic acid Chemical compound C([C@H]1C(=O)O)CCC(C2=CC=CC=C2C2)N1C(=O)C2N1C(=O)C2=CC=CC=C2C1=O LLRVWEHGZKXEOH-XBMUEBEBSA-N 0.000 description 4
- QADZTADIBLLKJP-GGYWPGCISA-N 2-[(7s)-6-oxo-2,7,8,12b-tetrahydro-1h-pyrido[2,1-a][2]benzazepin-7-yl]isoindole-1,3-dione Chemical compound C1C2=CC=CC=C2C2CCC=CN2C(=O)[C@H]1N1C(=O)C2=CC=CC=C2C1=O QADZTADIBLLKJP-GGYWPGCISA-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
- 239000003377 acid catalyst Substances 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000005755 formation reaction Methods 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-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
- 238000002360 preparation method Methods 0.000 description 4
- PWNUBDVZGJEXRA-UHFFFAOYSA-N pyrido[2,1-a][2]benzazepine-4-carboxylic acid Chemical compound C1=CN2C(C(=O)O)=CC=CC2=C2C=CC=CC2=C1 PWNUBDVZGJEXRA-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
- PXBFQCNMLUWSAY-AWEZNQCLSA-N 2-[[(2S)-1-chloro-1-oxo-3-phenylpropan-2-yl]carbamoyl]benzoic acid Chemical compound C(C=1C(C(=O)O)=CC=CC=1)(=O)N[C@@H](CC1=CC=CC=C1)C(=O)Cl PXBFQCNMLUWSAY-AWEZNQCLSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 150000003862 amino acid derivatives Chemical class 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 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
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000003828 vacuum filtration Methods 0.000 description 3
- 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 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 150000001371 alpha-amino acids Chemical class 0.000 description 2
- 235000008206 alpha-amino acids Nutrition 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
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- 239000002274 desiccant Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-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
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- ZENNTZUZBRESKJ-ZETCQYMHSA-N (2s)-2-(1-benzothiophen-2-ylamino)propanoic acid Chemical compound C1=CC=C2SC(N[C@@H](C)C(O)=O)=CC2=C1 ZENNTZUZBRESKJ-ZETCQYMHSA-N 0.000 description 1
- OAIVNLHMAFVPQB-ZETCQYMHSA-N (2s)-2-(1h-indol-2-ylamino)propanoic acid Chemical compound C1=CC=C2NC(N[C@@H](C)C(O)=O)=CC2=C1 OAIVNLHMAFVPQB-ZETCQYMHSA-N 0.000 description 1
- WRQSUCJAKAMYMQ-YFKPBYRVSA-N (2s)-2-(thiophen-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC=1C=CSC=1 WRQSUCJAKAMYMQ-YFKPBYRVSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
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- 125000001931 aliphatic group Chemical group 0.000 description 1
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- 150000001340 alkali metals Chemical class 0.000 description 1
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- 239000007822 coupling agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- DUYAAUVXQSMXQP-UHFFFAOYSA-N ethanethioic S-acid Chemical compound CC(S)=O DUYAAUVXQSMXQP-UHFFFAOYSA-N 0.000 description 1
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- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 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
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- 125000005543 phthalimide group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 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
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 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
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 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
- 238000005406 washing Methods 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)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (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)
- Peptides Or Proteins (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式I 〔式中、Gは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される芳香環である〕の化合物の製造法であって 、 (a)式 (式中、Arは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして RはフェニルおよびC1-C4アルコキシからなる群より選択される)からなる群 より選択される基である)のフタルイミドアリールアミノ酸アミドをグルタルジ アルデヒドと反応させて式 (式中、Arは上記で定義された通りである)の1,4−ジヒドロピリジン誘導体を 得; (b)1,4−ジヒドロピリジン誘導体を適当な環化酸と反応させて式 (式中、Gは上記で定義された通りである)の1,2,6,7,8,12bヘキサヒドロ−6 −オキソピリド[2,1-a][2]アゼピンを得; (c)1,2,6,7,8,12bヘキサヒドロ−6−オキソピリド[2,1-a][2]アゼピンを適当 な酸の存在下で一酸化炭素と反応させ、次に水和することからなる前記方法。 2.適当な環化酸はトリフルオロメタンスルホン酸/無水トリフルオロ酢酸の混 合物である請求項1記載の方法。 3.適当な環化酸は硫酸/無水トリフルオロ酢酸の混合物である請求項1記載の 方法。 4.式 〔式中、Gは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される芳香環である〕の化合物の製造法であって 、 (a)式 (式中、Aは-OH、-Cl、-Br、無水物、混成無水物および活性エステルからな る群より選択され; Arは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして RはフェニルおよびC1-C4アルコキシからなる群より選択される)からなる群 より選択される基である)のフタルイミドアリールアミノ酸誘導体を2−シアノ −1,2,3,4−テトラヒドロ-ピリジンと反応させて式 (式中、Arは上記で定義された通りである)の2−シアノ−1,2,3,4-テトラヒド ロ−ピリジン誘導体を得; (b)2−シアノ−1,2,3,4−テトラヒドロ−ピリジン誘導体を適当な環化酸と反 応させて式 (式中、Gは上記で定義された通りである)の4−シアノ−1,2,3,4,6,7,8,12 b−オクタヒドロ−6−オキソピリド[2,1-a][2]ベンズアゼピンを得; (c)4−シアノ−1,2,3,4,6,7,8,12b−オクタヒドロ−6−オキソピリド[2,1-a ][2]ベンズアゼピンを加水分解することからなる前記方法。 5.適当な環化酸はトリフルオロメタンスルホン酸/無水トリフルオロ酢酸の混 合物である請求項4記載の方法。 6.適当な環化酸は硫酸/無水トリフルオロ酢酸の混合物である請求項4記載の 方法。 7.現場で2,6−ジシアノ−ピペリジンから2−シアノ−1,2,3,4−テトラヒドロ −ピリジンを生成する請求項4記載の方法。 8.式 〔式中、Arは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される基である〕の化合物。 9.化合物は(S)−N−〔2−(1,3−ジヒドロ−1,3−ジオキソ−2H−イソイン ドール−2−イル)−1−オキソ−3−フェニルプロピル〕−1,4−ジヒドロ−ピ リジンである請求項8記載の化合物。 10.化合物は(R)−N−〔2−(1,3−ジヒドロ−1,3−ジオキソ−2H−イソイン ドール−2−イル)−1−オキソ−3−フェニルプロピル〕−1,4−ジヒドロ−ピ リジンである請求項8記載の化合物。 11.式 〔式中、Gは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される芳香環である〕の化合物。 12.化合物は(S)−7−[(1,3−ジヒドロ−1,3−ジオキソ−2H−イソインドー ル−2−イル)]−1,2,6,7,8,12b−ヘキサヒドロ−6−オキソピリド[2,1-a][2] ベンズアゼピンである請求項11記載の化合物。 13.化合物は(R)−7−[(1,3−ジヒドロ−1,3−ジオキソ−2H−イソインドー ル−2−イル)]−1,2,6,7,8,12b−ヘキサヒドロ−6−オキソピリド[2,1-a][2] ベンズアゼピンである請求項11記載の化合物。 14.式 〔式中、Arは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される基である〕の化合物。 15.化合物はN−〔2(S)−(1,3−ジヒドロ−1,3−ジオキソ−2H−イソイン ドール−2−イル)−1−オキソ−3−フェニルプロピル〕−2−シアノ−1,2, 3,4−テトラヒドロ−ピリジンである請求項14記載の化合物。 16.化合物はN−〔2(R)−(1,3−ジヒドロ−1,3−ジオキソ−2H−イソインド ール−2−イル)−1−オキソ−3−フェニルプロピル〕−2−シアノ−1,2,3, 4−テトラヒドロ−ピリジンである請求項14記載の化合物。 17.式 〔式中、Gは (ここで、X1はSおよびNHからなる群より選択され; X2はS、OおよびNHからなる群より選択され;そして Rは水素、ヒドロキシ、フェニルおよびC1-C4アルコキシからなる群より選 択される)からなる群より選択される芳香環である〕の化合物。 18.化合物は4−シアノ−(S)−7−[(1,3−ジヒドロ−1,3−ジオキソ−2H− イソインドール−2−イル)]−1,2,3,4,6,7,8,12b−オクタヒドロ−6−オキソ ピリド[2,1-a][2]ベンズアゼピンである請求項17記載の化合物。 19.化合物は4−シアノ−(R)−7−[(1,3−ジヒドロ−1,3−ジオキソ−2H− イソインドール−2−イル)]−1,2,3,4,6,7,8,12b−オクタヒドロ−6−オキソ ピリド[2,1-a][2]ベンズアゼピンである請求項17記載の化合物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US36091594A | 1994-12-21 | 1994-12-21 | |
US08/360,915 | 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 |
US08/535,403 | 1995-10-24 | ||
PCT/US1995/015225 WO1996019492A1 (en) | 1994-12-21 | 1995-11-20 | Novel processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof |
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JPH10511348A true JPH10511348A (ja) | 1998-11-04 |
JP3658408B2 JP3658408B2 (ja) | 2005-06-08 |
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US (1) | US5734049A (ja) |
EP (1) | EP0800527B1 (ja) |
JP (1) | JP3658408B2 (ja) |
CN (2) | CN1113894C (ja) |
AR (1) | AR000378A1 (ja) |
AT (2) | ATE190315T1 (ja) |
AU (1) | AU689362B2 (ja) |
CA (2) | CA2208569C (ja) |
DE (2) | DE69533002T2 (ja) |
DK (2) | DK0957109T3 (ja) |
ES (2) | ES2216386T3 (ja) |
FI (1) | FI121599B (ja) |
GR (1) | GR3033329T3 (ja) |
HK (1) | HK1066009A1 (ja) |
HU (1) | HU227675B1 (ja) |
IL (6) | IL139141A (ja) |
MX (1) | MX9704677A (ja) |
NO (2) | NO308900B1 (ja) |
NZ (2) | NZ298245A (ja) |
PT (2) | PT957109E (ja) |
SI (2) | SI0800527T1 (ja) |
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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 |
US9695121B2 (en) * | 2013-01-30 | 2017-07-04 | Basf Se | 2,6-bis-(aminomethyl)piperidine derivatives |
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ZA874107B (ja) * | 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 |
CA2053340C (en) * | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
US5430145A (en) * | 1990-10-18 | 1995-07-04 | Merrell Dow Pharmaceuticals Inc. | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
NZ241023A (en) * | 1990-12-21 | 1994-10-26 | Merrell Dow Pharma | Condensed benzazepine derivatives and pharmaceutical compositions |
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 |
ES2106112T3 (es) * | 1991-09-27 | 1997-11-01 | Merrell Pharma Inc | Derivados de indano-2-mercaptoacetilamida con una actividad inhibidora de encefalinasa y de ace. |
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 |
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