IL103263A - 2-Substituted indane-2-mercaptoacetamide derivatives useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them - Google Patents

2-Substituted indane-2-mercaptoacetamide derivatives useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them

Info

Publication number: IL103263A
Authority: IL; Israel
Prior art keywords: compound; stir; evaporate; solvent; vacuo
Prior art date: 1991-09-27

Application number

IL10326392A

Other languages

English (en)

Other versions

IL103263A0 (en

Original Assignee

Merrell Dow Pharma

Priority date (The priority date 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 date listed.)

1991-09-27

Filing date

1992-09-23

Publication date

1996-11-14

1992-09-23 Application filed by Merrell Dow Pharma filed Critical Merrell Dow Pharma

1993-02-21 Publication of IL103263A0 publication Critical patent/IL103263A0/xx

1996-11-14 Publication of IL103263A publication Critical patent/IL103263A/en

Links

102000003729 Neprilysin Human genes 0.000 title claims abstract description 33
108090000028 Neprilysin Proteins 0.000 title claims abstract description 33
-1 2-Substituted indane-2-mercaptoacetamide Chemical class 0.000 title claims description 135
239000008194 pharmaceutical composition Substances 0.000 title claims description 16
239000003112 inhibitor Substances 0.000 title abstract description 9
150000001875 compounds Chemical class 0.000 claims description 145
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 claims description 56
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 53
239000000203 mixture Substances 0.000 claims description 50
239000002253 acid Substances 0.000 claims description 37
230000002401 inhibitory effect Effects 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 20
229910052739 hydrogen Inorganic materials 0.000 claims description 20
101800001288 Atrial natriuretic factor Proteins 0.000 claims description 17
101800001890 Atrial natriuretic peptide Proteins 0.000 claims description 17
108010092674 Enkephalins Proteins 0.000 claims description 13
URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 claims description 13
230000001404 mediated effect Effects 0.000 claims description 13
229910052717 sulfur Inorganic materials 0.000 claims description 11
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
230000001077 hypotensive effect Effects 0.000 claims description 9
239000000546 pharmaceutical excipient Substances 0.000 claims description 9
230000000202 analgesic effect Effects 0.000 claims description 8
150000002431 hydrogen Chemical group 0.000 claims description 8
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 7
125000004432 carbon atom Chemical group C* 0.000 claims description 7
230000001882 diuretic effect Effects 0.000 claims description 7
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
125000002947 alkylene group Chemical group 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
239000011593 sulfur Substances 0.000 claims description 6
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
206010007559 Cardiac failure congestive Diseases 0.000 claims description 5
206010019280 Heart failures Diseases 0.000 claims description 5
125000003118 aryl group Chemical group 0.000 claims description 5
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 5
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
229910052796 boron Inorganic materials 0.000 claims description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
WLPPCFGXINTUNZ-UHFFFAOYSA-N 5h-1-benzazepine-4-carboxylic acid Chemical compound C1C(C(=O)O)=CC=NC2=CC=CC=C21 WLPPCFGXINTUNZ-UHFFFAOYSA-N 0.000 claims description 2
125000000217 alkyl group Chemical group 0.000 claims description 2
230000001939 inductive effect Effects 0.000 claims 5
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 3
208000004880 Polyuria Diseases 0.000 claims 1
230000019771 cognition Effects 0.000 claims 1
230000002708 enhancing effect Effects 0.000 claims 1
230000001506 immunosuppresive effect Effects 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 363
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 275
238000003756 stirring Methods 0.000 description 177
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 156
239000002904 solvent Substances 0.000 description 150
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 137
229940073584 methylene chloride Drugs 0.000 description 121
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 97
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 95
239000000243 solution Substances 0.000 description 89
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 86
238000010898 silica gel chromatography Methods 0.000 description 74
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 54
239000012074 organic phase Substances 0.000 description 51
238000000034 method Methods 0.000 description 41
239000000284 extract Substances 0.000 description 40
238000005192 partition Methods 0.000 description 40
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 39
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 34
150000004702 methyl esters Chemical class 0.000 description 33
239000008346 aqueous phase Substances 0.000 description 31
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 26
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
239000007787 solid Substances 0.000 description 24
239000012299 nitrogen atmosphere Substances 0.000 description 23
239000012267 brine Substances 0.000 description 22
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
239000003921 oil Substances 0.000 description 21
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
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 19
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 19
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 19
102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 19
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
239000000010 aprotic solvent Substances 0.000 description 18
150000001732 carboxylic acid derivatives Chemical class 0.000 description 17
238000006243 chemical reaction Methods 0.000 description 17
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
102400001282 Atrial natriuretic peptide Human genes 0.000 description 15
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 14
239000007789 gas Substances 0.000 description 14
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 14
229910000037 hydrogen sulfide Inorganic materials 0.000 description 14
BRMYZIKAHFEUFJ-UHFFFAOYSA-L mercury diacetate Chemical compound CC(=O)O[Hg]OC(C)=O BRMYZIKAHFEUFJ-UHFFFAOYSA-L 0.000 description 14
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
238000011282 treatment Methods 0.000 description 14
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 13
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 13
238000010791 quenching Methods 0.000 description 13
229920006395 saturated elastomer Polymers 0.000 description 13
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
239000012312 sodium hydride Substances 0.000 description 13
229910000104 sodium hydride Inorganic materials 0.000 description 13
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 12
QQIRAVWVGBTHMJ-UHFFFAOYSA-N [dimethyl-(trimethylsilylamino)silyl]methane;lithium Chemical compound [Li].C[Si](C)(C)N[Si](C)(C)C QQIRAVWVGBTHMJ-UHFFFAOYSA-N 0.000 description 12
NSQLIUXCMFBZME-MPVJKSABSA-N carperitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 NSQLIUXCMFBZME-MPVJKSABSA-N 0.000 description 12
239000002934 diuretic Substances 0.000 description 12
238000010992 reflux Methods 0.000 description 12
LNAZHVACIOCJFA-UHFFFAOYSA-N 1-methoxy-4-[[(4-methoxyphenyl)methyldisulfanyl]methyl]benzene Chemical compound C1=CC(OC)=CC=C1CSSCC1=CC=C(OC)C=C1 LNAZHVACIOCJFA-UHFFFAOYSA-N 0.000 description 11
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 11
WMYRYTHPUNNJQO-AWEZNQCLSA-N 2-[[(1s)-1-carboxy-2-phenylethyl]carbamoyl]benzoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)C=1C(=CC=CC=1)C(O)=O)C1=CC=CC=C1 WMYRYTHPUNNJQO-AWEZNQCLSA-N 0.000 description 11
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 10
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
229910000024 caesium carbonate Inorganic materials 0.000 description 9
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 9
230000000694 effects Effects 0.000 description 9
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
238000002360 preparation method Methods 0.000 description 9
108090000765 processed proteins & peptides Proteins 0.000 description 9
102000004196 processed proteins & peptides Human genes 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 8
235000019270 ammonium chloride Nutrition 0.000 description 8
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 8
PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 8
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 8
239000000376 reactant Substances 0.000 description 8
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 8
PTDVPWWJRCOIIO-UHFFFAOYSA-N (4-methoxyphenyl)methanethiol Chemical compound COC1=CC=C(CS)C=C1 PTDVPWWJRCOIIO-UHFFFAOYSA-N 0.000 description 7
108010049140 Endorphins Proteins 0.000 description 7
102000009025 Endorphins Human genes 0.000 description 7
CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 7
150000001299 aldehydes Chemical class 0.000 description 7
229940024606 amino acid Drugs 0.000 description 7
230000015556 catabolic process Effects 0.000 description 7
238000006731 degradation reaction Methods 0.000 description 7
201000010099 disease Diseases 0.000 description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
230000005764 inhibitory process Effects 0.000 description 7
230000002503 metabolic effect Effects 0.000 description 7
125000001424 substituent group Chemical group 0.000 description 7
DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 7
150000003573 thiols Chemical class 0.000 description 7
LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
102000004190 Enzymes Human genes 0.000 description 6
108090000790 Enzymes Proteins 0.000 description 6
206010020772 Hypertension Diseases 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
208000002193 Pain Diseases 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000012300 argon atmosphere Substances 0.000 description 6
GGRHYQCXXYLUTL-UHFFFAOYSA-N chloromethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCCl GGRHYQCXXYLUTL-UHFFFAOYSA-N 0.000 description 6
238000001816 cooling Methods 0.000 description 6
239000012043 crude product Substances 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
239000002480 mineral oil Substances 0.000 description 6
235000010446 mineral oil Nutrition 0.000 description 6
230000001452 natriuretic effect Effects 0.000 description 6
230000000269 nucleophilic effect Effects 0.000 description 6
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
229940030966 pyrrole Drugs 0.000 description 6
208000001953 Hypotension Diseases 0.000 description 5
239000004480 active ingredient Substances 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
238000007664 blowing Methods 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
238000004587 chromatography analysis Methods 0.000 description 5
235000008504 concentrate Nutrition 0.000 description 5
239000012141 concentrate Substances 0.000 description 5
229910000365 copper sulfate Inorganic materials 0.000 description 5
ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 5
150000002081 enamines Chemical class 0.000 description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
239000006260 foam Substances 0.000 description 5
208000021822 hypotensive Diseases 0.000 description 5
239000000463 material Substances 0.000 description 5
RMOPJLIMRSAIMD-UHFFFAOYSA-N methyl 2,3-dihydro-1h-indene-2-carboxylate Chemical compound C1=CC=C2CC(C(=O)OC)CC2=C1 RMOPJLIMRSAIMD-UHFFFAOYSA-N 0.000 description 5
125000005543 phthalimide group Chemical group 0.000 description 5
239000000843 powder Substances 0.000 description 5
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
230000001105 regulatory effect Effects 0.000 description 5
239000000725 suspension Substances 0.000 description 5
HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 4
BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 4
PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 4
PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 4
RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 4
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 4
239000012448 Lithium borohydride Substances 0.000 description 4
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
229960002478 aldosterone Drugs 0.000 description 4
150000008064 anhydrides Chemical class 0.000 description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
239000000872 buffer Substances 0.000 description 4
239000002775 capsule Substances 0.000 description 4
239000000969 carrier Substances 0.000 description 4
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239000008215 water for injection Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
239000011701 zinc Substances 0.000 description 1
GASYAMBJHBRTOE-WHDBNHDESA-N γ-endorphin Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 GASYAMBJHBRTOE-WHDBNHDESA-N 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
- 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
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Health & Medical Sciences (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Neurosurgery (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Genetics & Genomics (AREA)
Biochemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Molecular Biology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Biophysics (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pain & Pain Management (AREA)
Diabetes (AREA)
Hematology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Indole Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

IL10326392A 1991-09-27 1992-09-23 2-Substituted indane-2-mercaptoacetamide derivatives useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them IL103263A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US76728691A	1991-09-27	1991-09-27
US92948192A	1992-08-20	1992-08-20

Publications (2)

Publication Number	Publication Date
IL103263A0 IL103263A0 (en)	1993-02-21
IL103263A true IL103263A (en)	1996-11-14

Family

ID=27117891

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL10326392A IL103263A (en)	1991-09-27	1992-09-23	2-Substituted indane-2-mercaptoacetamide derivatives useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them

Country Status (16)

Country	Link
US (3)	US5428158A (de)
EP (1)	EP0534363B1 (de)
JP (1)	JP3173675B2 (de)
KR (1)	KR100271239B1 (de)
AT (1)	ATE155143T1 (de)
AU (1)	AU657166B2 (de)
CA (1)	CA2078758C (de)
DE (1)	DE69220744T2 (de)
DK (1)	DK0534363T3 (de)
ES (1)	ES2106112T3 (de)
FI (1)	FI101303B (de)
GR (1)	GR3024850T3 (de)
HU (1)	HU214820B (de)
IL (1)	IL103263A (de)
NO (1)	NO300848B1 (de)
NZ (1)	NZ244461A (de)

Families Citing this family (59)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CA2078758C (en) *	1991-09-27	2003-12-09	Alan M. Warshawsky	2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
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
US5552397A (en) *	1992-05-18	1996-09-03	E. R. Squibb & Sons, Inc.	Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase
JP3427937B2 (ja) *	1992-08-24	2003-07-22	メレルダウファ−マス−ティカルズインコーポレイテッド	エンケファリナーゼ阻害剤として有用な新規な２‐置換インダン‐２‐メルカプトアセチルアミド三環式誘導体類
US5504080A (en) *	1992-10-28	1996-04-02	Bristol-Myers Squibb Co.	Benzo-fused lactams
US5654294A (en) *	1993-05-13	1997-08-05	Bristol-Myers Squibb	Spiro lactam dual action inhibitors
JP3563738B2 (ja) *	1993-06-11	2004-09-08	エーザイ株式会社	アミノ酸誘導体
US5508272A (en) *	1993-06-15	1996-04-16	Bristol-Myers Squibb Company	Compounds containing a fused bicycle ring and processes therefor
EP0706525A1 (de) *	1993-06-30	1996-04-17	Novartis AG	Antihypertensive trizyklische azepin-derivate wirksam als ace inhibitoren und nep inhibitoren
US5362727A (en) *	1993-07-26	1994-11-08	Bristol-Myers Squibb	Substituted azepino[2,1-a]isoquinoline compounds
US5594106A (en) *	1993-08-23	1997-01-14	Immunex Corporation	Inhibitors of TNF-α secretion
US5525723A (en) *	1993-11-18	1996-06-11	Bristol-Myers Squibb Co.	Compounds containing a fused multiple ring lactam
CA2183314C (en) *	1994-02-14	1999-08-31	Gary A. Flynn	Novel 2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace
JPH09508906A (ja) *	1994-02-14	1997-09-09	メレルファーマスーティカルズインコーポレーテッド	エンケファリナーゼ及びａｃｅの阻害剤として有用な新規なメルカプトアセチルアミド１，３，４，５−テトラヒドロベンゾ［ｃ］アゼピン−３−オンジスルフィド誘導体類
CA2183313C (en) *	1994-02-14	2001-01-02	Gary A. Flynn	Novel indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase
US5616775A (en) *	1994-05-05	1997-04-01	Bristol-Myers Squibb Co.	Process for preparing homocystein analogs useful as intermediates for compounds containing a fused bicyclic ring
US5641880A (en) *	1994-12-21	1997-06-24	Hoechst Marion Roussel, Inc.	Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof
DK0800527T3 (da) *	1994-12-21	2000-06-05	Aventis Pharma Inc	Nye fremgangsmåder til fremstilling af mellemprodukter for inhibitorer af enkephalinase og angiotensinomdannende enzym og m
US5587375A (en) *	1995-02-17	1996-12-24	Bristol-Myers Squibb Company	Azepinone compounds useful in the inhibition of ACE and NEP
US5877313A (en)	1995-05-17	1999-03-02	Bristol-Myers Squibb	Benzo-fused azepinone and piperidinone compounds useful in the inhibition of ACE and NEP
US5650408A (en) *	1995-06-07	1997-07-22	Karanewsky; Donald S.	Thiazolo benzazepine containing dual action inhibitors
US5635504A (en) *	1995-06-07	1997-06-03	Bristol-Myers Squibb Co.	Diazepine containing dual action inhibitors
US6777550B1 (en)	1996-04-12	2004-08-17	Bristol-Myers Squibb Company	N-formyl hydroxylamine containing compounds useful as ACE inhibitors and/or NEP inhibitors
US6953788B1 (en)	1996-09-19	2005-10-11	Aventis Pharmaceuticals Inc.	3-mercaptoacetylamino-1,5-substituted-2-oxo-azepan derivatives useful as inhibitors of matrix metalloproteinase
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
WO1999065500A1 (en)	1998-06-17	1999-12-23	Bristol-Myers Squibb Company	Preventing cerebral infarction through administration of adp-receptor antiplatelet and antihypertensive drugs in combination
US6509330B2 (en)	2000-02-17	2003-01-21	Bristol-Myers Squibb Company	Hydroxamic acid containing compounds useful as ACE inhibitors and/or NEP inhibotors
GB0119305D0 (en)	2001-04-12	2001-10-03	Aventis Pharma Gmbh	Mercaptoacetylamide derivatives,a process for their preparation and their use
DE60202602T2 (de) *	2001-04-12	2006-03-23	Sanofi-Aventis Deutschland Gmbh	Mercaptoacetylamid-derivate, prozess zur herstellung sowie deren verwendung
EP1443919A4 (de)	2001-11-16	2006-03-22	Bristol Myers Squibb Co	Doppelte hemmer des adipozyten-fettsäure-bindungsproteins und des keratinozyten-fettsäure-bindungsproteins
DE10229180A1 (de) *	2002-06-28	2004-01-29	Aventis Pharma Deutschland Gmbh	Verwendung von Vasopeptidase-Inhibitoren bei der Behandlung von metabolischen Erkrankungen, Nephropathie und mit AGE assoziierten Erkrankungen
US8404852B2 (en)	2003-01-31	2013-03-26	Vertex Pharmaceuticals Incorporated	Gyrase inhibitors and uses thereof
US7582641B2 (en) *	2003-01-31	2009-09-01	Vertex Pharmaceuticals Incorporated	Gyrase inhibitors and uses thereof
AR042956A1 (es) *	2003-01-31	2005-07-13	Vertex Pharma	Inhibidores de girasa y usos de los mismos
US7459474B2 (en)	2003-06-11	2008-12-02	Bristol-Myers Squibb Company	Modulators of the glucocorticoid receptor and method
US7371759B2 (en)	2003-09-25	2008-05-13	Bristol-Myers Squibb Company	HMG-CoA reductase inhibitors and method
US7420059B2 (en)	2003-11-20	2008-09-02	Bristol-Myers Squibb Company	HMG-CoA reductase inhibitors and method
US7273881B2 (en)	2004-01-16	2007-09-25	Bristol-Myers Squibb Company	Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7888381B2 (en)	2005-06-14	2011-02-15	Bristol-Myers Squibb Company	Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity, and use thereof
US7592461B2 (en)	2005-12-21	2009-09-22	Bristol-Myers Squibb Company	Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7795291B2 (en)	2006-07-07	2010-09-14	Bristol-Myers Squibb Company	Substituted acid derivatives useful as anti-atherosclerotic, anti-dyslipidemic, anti-diabetic and anti-obesity agents and method
US7994190B2 (en)	2006-11-01	2011-08-09	Bristol-Myers Squibb Company	Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7968577B2 (en)	2006-11-01	2011-06-28	Bristol-Myers Squibb Company	Modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
JP2010508358A (ja)	2006-11-01	2010-03-18	ブリストル−マイヤーズスクイブカンパニー	グルココルチコイド受容体、ＡＰ−１、および／またはＮＦ−κＢ活性の調節剤、並びにその使用
WO2008151257A2 (en)	2007-06-04	2008-12-11	Synergy Pharmaceuticals Inc.	Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en)	2007-06-04	2015-03-03	Synergy Pharmaceuticals, Inc.	Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
ES2627848T3 (es)	2008-06-04	2017-07-31	Synergy Pharmaceuticals Inc.	Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros trastornos
EP2334671A1 (de)	2008-06-24	2011-06-22	Bristol-Myers Squibb Company	Cyclopentathiophene als modulatoren der aktivität des glucocorticoidrezeptors, von ap-1 und/oder von nf-kappa b, und anwendung davon
ES2624828T3 (es)	2008-07-16	2017-07-17	Synergy Pharmaceuticals Inc.	Agonistas de la guanilato ciclasa útiles para el tratamiento de trastornos gastrointestinales, inflamación, cáncer y otros
US8546377B2 (en)	2009-04-23	2013-10-01	Abbvie Inc.	Modulators of 5-HT receptors and methods of use thereof
US8518933B2 (en)	2009-04-23	2013-08-27	Abbvie Inc.	Modulators of 5-HT receptors and methods of use thereof
US9616097B2 (en)	2010-09-15	2017-04-11	Synergy Pharmaceuticals, Inc.	Formulations of guanylate cyclase C agonists and methods of use
EP2968439A2 (de)	2013-03-15	2016-01-20	Synergy Pharmaceuticals Inc.	Zusammensetzungen zur behandlung von magen-darm-störungen
US9708367B2 (en)	2013-03-15	2017-07-18	Synergy Pharmaceuticals, Inc.	Agonists of guanylate cyclase and their uses
PL3004138T3 (pl)	2013-06-05	2024-07-29	Bausch Health Ireland Limited	Ultra-oczyszczeni agoniści peptydowi cyklazy guanylanowej C, sposób ich uzyskiwania i ich zastosowanie
WO2015027021A1 (en)	2013-08-22	2015-02-26	Bristol-Myers Squibb Company	Imide and acylurea derivatives as modulators of the glucocorticoid receptor
US9815850B2 (en)	2016-02-05	2017-11-14	Denali Therapeutics Inc.	Compounds, compositions and methods
LT3552017T (lt)	2016-12-09	2022-05-10	Denali Therapeutics Inc.	Junginiai, naudotini kaip ripk1 inhibitoriai
EP4463229A1 (de)	2022-01-12	2024-11-20	Denali Therapeutics Inc.	Kristalline formen von (s)-5-benzyl-n-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b! [l,4)oxazepin-3-yl)-4h-1,2,4-triazol-3-carboxamid

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US3334095A (en) *	1965-02-16	1967-08-01	Sandoz Ag	Novel pyrrolo-oxazines and pyrrolo-oxazoles
US3334091A (en) *	1965-03-25	1967-08-01	Sandoz Ag	Sedatives
GB1525845A (en) *	1976-07-30	1978-09-20	Ucb Sa	1,2,4,5-tetrahydro-3h-2-benzazepin-3-ones
IE50839B1 (en) *	1980-02-26	1986-07-23	Wyeth John & Brother Ltd	Novel processes for preparing proline derivatives and analogous compounds
EP0042100A1 (de) *	1980-06-13	1981-12-23	F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft	Pyrazolopyridazin-Derivate, Zwischenprodukte und Verfahren zu deren Herstellung, sowie diese enthaltende Arzneimittel
US4320057A (en) *	1980-06-23	1982-03-16	American Home Products Corporation	Aryl--pyrrolo--thiazepin--diones and aryl--piperidino--thiazepin--diones
US4552889A (en) *	1983-06-09	1985-11-12	Eli Lilly And Company	3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension
US4692438A (en) *	1984-08-24	1987-09-08	Hoffmann-La Roche Inc.	Pyridazo-diazepines, diazocines, and -triazepines having anti-hypertensive activity
ES8801833A1 (es) *	1985-04-30	1988-02-16	Lilly Co Eli	Un procedimiento para la preparacion de un compuesto.
CA1337654C (en) *	1986-06-13	1995-11-28	Gary A. Flynn	Fused tricyclic lactams as antihypertensive agents
ZA874106B (en) *	1986-06-13	1987-12-08	Merrell Dow Pharmaceuticals Inc.	Novel antihypertensive agent
GB8629875D0 (en) *	1986-12-15	1987-01-28	Hoffmann La Roche	Pyridazodiazepine derivatives
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
ATE158303T1 (de) *	1990-12-21	1997-10-15	Merrell Pharma Inc	Neue trizyklische amino- und nitro verbindungen mit ace-hemmenden eigenschaften
US5208230A (en) *	1990-12-21	1993-05-04	Merrell Dow Pharmaceuticals	Amino and nitro containing tricyclic compounds useful as inhibitors of ACE
FR2679564A1 (fr) *	1991-07-23	1993-01-29	Inst Nat Sante Rech Med	Nouveaux acylmercaptoalcanoldipeptides, leur preparation et les compositions qui les contiennent.
EP0605589A1 (de) *	1991-09-16	1994-07-13	Schering Corporation	Natriuretische peptide oder neutrale endopeptidaseinhibitoren enthaltene pharmazeutische zusammensetzungen (arznei) der behandlung oder vorbeugung myointimaler wucherung
ZA927211B (en) *	1991-09-27	1993-03-24	Merrell Dow Pharma	Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE.
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
CA2078758C (en) *	1991-09-27	2003-12-09	Alan M. Warshawsky	2-substituted indane-2-mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and 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

1992
- 1992-09-21 CA CA002078758A patent/CA2078758C/en not_active Expired - Fee Related
- 1992-09-21 EP EP92116180A patent/EP0534363B1/de not_active Expired - Lifetime
- 1992-09-21 DE DE69220744T patent/DE69220744T2/de not_active Expired - Fee Related
- 1992-09-21 ES ES92116180T patent/ES2106112T3/es not_active Expired - Lifetime
- 1992-09-21 AT AT92116180T patent/ATE155143T1/de not_active IP Right Cessation
- 1992-09-21 DK DK92116180.8T patent/DK0534363T3/da active
- 1992-09-22 AU AU25245/92A patent/AU657166B2/en not_active Ceased
- 1992-09-23 IL IL10326392A patent/IL103263A/en not_active IP Right Cessation
- 1992-09-23 NZ NZ244461A patent/NZ244461A/en unknown
- 1992-09-25 FI FI924311A patent/FI101303B/fi not_active IP Right Cessation
- 1992-09-25 JP JP28066992A patent/JP3173675B2/ja not_active Expired - Fee Related
- 1992-09-25 HU HU9203074A patent/HU214820B/hu not_active IP Right Cessation
- 1992-09-25 NO NO923744A patent/NO300848B1/no unknown
- 1992-09-26 KR KR1019920017615A patent/KR100271239B1/ko not_active Expired - Fee Related
1993
- 1993-11-01 US US08/146,646 patent/US5428158A/en not_active Expired - Lifetime
1995
- 1995-03-01 US US08/396,947 patent/US5486513A/en not_active Expired - Fee Related
- 1995-03-01 US US08/397,298 patent/US5529996A/en not_active Expired - Fee Related
1997
- 1997-09-24 GR GR970402492T patent/GR3024850T3/el unknown

Also Published As

Publication number	Publication date
ES2106112T3 (es)	1997-11-01
CA2078758C (en)	2003-12-09
FI101303B1 (fi)	1998-05-29
HUT65192A (en)	1994-05-02
IL103263A0 (en)	1993-02-21
US5486513A (en)	1996-01-23
EP0534363A3 (en)	1993-06-09
GR3024850T3 (en)	1998-01-30
DE69220744T2 (de)	1997-11-13
HU9203074D0 (en)	1992-12-28
CA2078758A1 (en)	1993-03-28
DE69220744D1 (de)	1997-08-14
HU214820B (hu)	1998-06-29
NO923744L (no)	1993-03-29
NZ244461A (en)	1994-09-27
JPH05294963A (ja)	1993-11-09
EP0534363B1 (de)	1997-07-09
NO300848B1 (no)	1997-08-04
NO923744D0 (no)	1992-09-25
EP0534363A2 (de)	1993-03-31
KR930006027A (ko)	1993-04-20
KR100271239B1 (ko)	2001-02-01
US5428158A (en)	1995-06-27
US5529996A (en)	1996-06-25
ATE155143T1 (de)	1997-07-15
FI924311L (fi)	1993-03-28
AU2524592A (en)	1993-04-01
AU657166B2 (en)	1995-03-02
JP3173675B2 (ja)	2001-06-04
FI924311A0 (fi)	1992-09-25
DK0534363T3 (da)	1997-09-22
FI101303B (fi)	1998-05-29

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Date	Code	Title	Description
1997-04-15	FF	Patent granted
1998-02-08	KB	Patent renewed
1999-04-11	HC	Change of name of proprietor(s)
1999-07-14	KB	Patent renewed
2002-12-01	KB	Patent renewed
2006-09-05	HC	Change of name of proprietor(s)	Owner name: AVENTIS INC. Free format text: FORMER NAME:MERRELL PARMACEUTICALS, INC.
2007-07-06	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
EP0534363B1 (de)	1997-07-09	2-Substituierte Indan-2-Mercaptoacetylamid-Verbindungen mit Enkephalinase und ACE-Hemmwirkung
EP0534396B1 (de)	1996-10-09	2-Substituierte Indane-2-Carboxyalkyl-Verbindungen mit Enkephalinase und ACE-Hemmwirkung
EP0481522B1 (de)	1997-12-29	Neue Mercaptoacetylamid-Derivate zur Verwendung als Enkephalinase- und ACE-Hemmer
CA2078759C (en)	2003-09-16	Novel carboxyalkyl derivatives useful as inhibitors of enkephalinase and ace
CA2183315C (en)	1999-08-31	Novel mercaptoacetylamido 1,3,4,5-tetrahydro-benzo[c]azepin-3-one disulfide derivatives useful as inhibitors of enkephalinase and ace
EP0625987A1 (de)	1994-11-30	Aminoacetylmercaptoacetylamid derivate mit enkephalinase- und ace-hemmwirkung
US5430145A (en)	1995-07-04	Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
US5457196A (en)	1995-10-10	2-substituted indane-2-carboxyalkyl derivatives useful as inhibitors of enkephalinase and ACE
US5488047A (en)	1996-01-30	Carboxyalkyl tricylic derivatives useful as inhibitors of enkephalinase and ace
US5527795A (en)	1996-06-18	Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
CA2183314C (en)	1999-08-31	Novel 2-substituted indane-2-mercaptoacetylamide disulfide derivatives useful as inhibitors of enkephalinase and ace