IL103265A - N-carboxytricyclic benzazepinone derivatives of 2-carboxyalkyl 3-phenylpropanamide useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them - Google Patents

N-carboxytricyclic benzazepinone derivatives of 2-carboxyalkyl 3-phenylpropanamide useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them

Info

Publication number: IL103265A
Authority: IL; Israel
Prior art keywords: compound; oxo; amino; phenylpropyl; carboxylic acid
Prior art date: 1991-09-27

Application number

IL10326592A

Other languages

English (en)

Other versions

IL103265A0 (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

1996-09-12

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

1993-02-21 Publication of IL103265A0 publication Critical patent/IL103265A0/xx

1996-09-12 Publication of IL103265A publication Critical patent/IL103265A/en

Links

102000003729 Neprilysin Human genes 0.000 title claims abstract description 33
108090000028 Neprilysin Proteins 0.000 title claims abstract description 33
239000008194 pharmaceutical composition Substances 0.000 title claims description 20
239000003112 inhibitor Substances 0.000 title abstract description 10
AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical class O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 152
-1 methylenedioxy Chemical group 0.000 claims abstract description 136
239000001257 hydrogen Substances 0.000 claims abstract description 29
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
125000000217 alkyl group Chemical group 0.000 claims abstract description 13
150000002431 hydrogen Chemical class 0.000 claims abstract description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 10
239000001301 oxygen Substances 0.000 claims abstract description 10
229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 9
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 8
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
229910052717 sulfur Inorganic materials 0.000 claims abstract description 8
239000011593 sulfur Substances 0.000 claims abstract description 8
125000003118 aryl group Chemical group 0.000 claims abstract description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 4
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
239000000203 mixture Substances 0.000 claims description 39
230000002401 inhibitory effect Effects 0.000 claims description 30
239000002253 acid Substances 0.000 claims description 27
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 25
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
101800001288 Atrial natriuretic factor Proteins 0.000 claims description 17
101800001890 Atrial natriuretic peptide Proteins 0.000 claims description 17
230000001404 mediated effect Effects 0.000 claims description 13
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
230000001077 hypotensive effect Effects 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
239000000546 pharmaceutical excipient Substances 0.000 claims description 9
230000000202 analgesic effect Effects 0.000 claims description 8
125000002947 alkylene group Chemical group 0.000 claims description 7
230000001882 diuretic effect Effects 0.000 claims description 7
206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
206010019280 Heart failures Diseases 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
239000003937 drug carrier Substances 0.000 claims description 5
150000002148 esters Chemical class 0.000 claims description 5
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 3
IZWHMJMPRWSESV-ZDUSSCGKSA-N C1=CN2[C@H](C(=O)O)C=CC2=C2C=CC=CC2=C1 Chemical compound C1=CN2[C@H](C(=O)O)C=CC2=C2C=CC=CC2=C1 IZWHMJMPRWSESV-ZDUSSCGKSA-N 0.000 claims description 2
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
239000004615 ingredient Substances 0.000 claims 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 207
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 133
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 85
238000003756 stirring Methods 0.000 description 81
229940073584 methylene chloride Drugs 0.000 description 69
239000002904 solvent Substances 0.000 description 63
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 52
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
238000000034 method Methods 0.000 description 42
238000010898 silica gel chromatography Methods 0.000 description 33
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
150000004702 methyl esters Chemical class 0.000 description 31
239000000243 solution Substances 0.000 description 31
239000012074 organic phase Substances 0.000 description 27
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
239000000284 extract Substances 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
102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 19
108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 19
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
239000000010 aprotic solvent Substances 0.000 description 18
239000012299 nitrogen atmosphere Substances 0.000 description 18
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
238000006243 chemical reaction Methods 0.000 description 16
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
102400001282 Atrial natriuretic peptide Human genes 0.000 description 15
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
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 15
IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 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
108010092674 Enkephalins Proteins 0.000 description 13
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 13
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class 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 description 12
239000002934 diuretic Substances 0.000 description 12
239000003921 oil Substances 0.000 description 12
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
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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 class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
238000005192 partition Methods 0.000 description 10
238000002360 preparation method Methods 0.000 description 10
239000012267 brine Substances 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
108090000765 processed proteins & peptides Proteins 0.000 description 9
102000004196 processed proteins & peptides Human genes 0.000 description 9
239000000376 reactant Substances 0.000 description 9
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
239000008346 aqueous phase Substances 0.000 description 8
150000001732 carboxylic acid derivatives Chemical group 0.000 description 8
230000000694 effects Effects 0.000 description 8
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 8
125000001424 substituent group Chemical group 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
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CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 7
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229940024606 amino acid Drugs 0.000 description 7
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UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 7
RJYHDGIROIUCQP-UHFFFAOYSA-N 2-benzyl-2-tert-butylbutanedioic acid Chemical compound OC(=O)CC(C(C)(C)C)(C(O)=O)CC1=CC=CC=C1 RJYHDGIROIUCQP-UHFFFAOYSA-N 0.000 description 6
XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 6
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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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
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XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
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UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 5
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238000010791 quenching Methods 0.000 description 5
230000001105 regulatory effect Effects 0.000 description 5
QFWZQNUAZRYHFF-UHFFFAOYSA-N 2-benzyl-2-methylbutanedioic acid Chemical compound OC(=O)CC(C)(C(O)=O)CC1=CC=CC=C1 QFWZQNUAZRYHFF-UHFFFAOYSA-N 0.000 description 4
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UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
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OQROAIRCEOBYJA-UHFFFAOYSA-N bromodiphenylmethane Chemical compound C=1C=CC=CC=1C(Br)C1=CC=CC=C1 OQROAIRCEOBYJA-UHFFFAOYSA-N 0.000 description 3
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
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YOIONBBMZSLNLR-UHFFFAOYSA-N methyl 2-(benzylideneamino)acetate Chemical compound COC(=O)CN=CC1=CC=CC=C1 YOIONBBMZSLNLR-UHFFFAOYSA-N 0.000 description 3
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238000004128 high performance liquid chromatography Methods 0.000 description 1
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239000003701 inert diluent Substances 0.000 description 1
229910052740 iodine Inorganic materials 0.000 description 1
125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000007788 liquid Substances 0.000 description 1
239000011344 liquid material Substances 0.000 description 1
239000000314 lubricant Substances 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
238000002844 melting Methods 0.000 description 1
230000008018 melting Effects 0.000 description 1
QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
229910052753 mercury Inorganic materials 0.000 description 1
NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
STZCRXQWRGQSJD-GEEYTBSJSA-M methyl orange Chemical compound [Na+].C1=CC(N(C)C)=CC=C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-GEEYTBSJSA-M 0.000 description 1
229940012189 methyl orange Drugs 0.000 description 1
239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
229960001047 methyl salicylate Drugs 0.000 description 1
229960002216 methylparaben Drugs 0.000 description 1
229940016286 microcrystalline cellulose Drugs 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
239000008108 microcrystalline cellulose Substances 0.000 description 1
210000000110 microvilli Anatomy 0.000 description 1
210000002464 muscle smooth vascular Anatomy 0.000 description 1
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
210000001640 nerve ending Anatomy 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
231100000252 nontoxic Toxicity 0.000 description 1
230000003000 nontoxic effect Effects 0.000 description 1
239000000346 nonvolatile oil Substances 0.000 description 1
125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
238000007248 oxidative elimination reaction Methods 0.000 description 1
230000037040 pain threshold Effects 0.000 description 1
238000007911 parenteral administration Methods 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
125000001151 peptidyl group Chemical group 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
235000021317 phosphate Nutrition 0.000 description 1
150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
239000004033 plastic Substances 0.000 description 1
229920003023 plastic Polymers 0.000 description 1
OKBMCNHOEMXPTM-UHFFFAOYSA-M potassium peroxymonosulfate Chemical compound [K+].OOS([O-])(=O)=O OKBMCNHOEMXPTM-UHFFFAOYSA-M 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
UJYZRNWTLPBNOR-UHFFFAOYSA-N prop-2-enyl 2,2,2-trichloroethanimidate Chemical compound ClC(Cl)(Cl)C(=N)OCC=C UJYZRNWTLPBNOR-UHFFFAOYSA-N 0.000 description 1
238000011321 prophylaxis Methods 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
230000002797 proteolythic effect Effects 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
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238000005932 reductive alkylation reaction Methods 0.000 description 1
230000029865 regulation of blood pressure Effects 0.000 description 1
230000004044 response Effects 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
229940081974 saccharin Drugs 0.000 description 1
235000019204 saccharin Nutrition 0.000 description 1
239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
239000012056 semi-solid material Substances 0.000 description 1
239000004208 shellac Substances 0.000 description 1
ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
229940113147 shellac Drugs 0.000 description 1
235000013874 shellac Nutrition 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
150000003385 sodium Chemical class 0.000 description 1
239000011734 sodium Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
239000011343 solid material Substances 0.000 description 1
239000011877 solvent mixture Substances 0.000 description 1
241000894007 species Species 0.000 description 1
230000009870 specific binding Effects 0.000 description 1
210000000278 spinal cord Anatomy 0.000 description 1
238000012289 standard assay Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000012258 stirred mixture Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
239000000829 suppository Substances 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
210000001519 tissue Anatomy 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
230000000304 vasodilatating effect Effects 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
235000012431 wafers Nutrition 0.000 description 1
238000005406 washing Methods 0.000 description 1
239000008215 water for injection Substances 0.000 description 1
238000005303 weighing Methods 0.000 description 1
NXSIJWJXMWBCBX-NWKQFZAZSA-N α-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)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 NXSIJWJXMWBCBX-NWKQFZAZSA-N 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)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Chemical Kinetics & Catalysis (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Molecular Biology (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Cardiology (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Heart & Thoracic Surgery (AREA)
Psychiatry (AREA)
Hospice & Palliative Care (AREA)
Pain & Pain Management (AREA)
Diabetes (AREA)
Hematology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Hydrogenated Pyridines (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Peptides Or Proteins (AREA)
Plural Heterocyclic Compounds (AREA)
Pyrrole Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

IL10326592A 1991-09-27 1992-09-23 N-carboxytricyclic benzazepinone derivatives of 2-carboxyalkyl 3-phenylpropanamide useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them IL103265A (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US76728191A	1991-09-27	1991-09-27

Publications (2)

Publication Number	Publication Date
IL103265A0 IL103265A0 (en)	1993-02-21
IL103265A true IL103265A (en)	1996-09-12

Family

ID=25079018

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL10326592A IL103265A (en)	1991-09-27	1992-09-23	N-carboxytricyclic benzazepinone derivatives of 2-carboxyalkyl 3-phenylpropanamide useful as inhibitors of enkephalinase and ace and pharmaceutical compositions containing them

Country Status (17)

Country	Link
US (1)	US5472959A (de)
EP (1)	EP0534492B1 (de)
JP (1)	JP3173673B2 (de)
KR (1)	KR100273734B1 (de)
AT (1)	ATE146482T1 (de)
AU (1)	AU657794B2 (de)
CA (1)	CA2078759C (de)
DE (1)	DE69216026T2 (de)
DK (1)	DK0534492T3 (de)
ES (1)	ES2097847T3 (de)
FI (1)	FI101304B (de)
GR (1)	GR3022654T3 (de)
HU (1)	HU214596B (de)
IL (1)	IL103265A (de)
NO (1)	NO300844B1 (de)
NZ (1)	NZ244442A (de)
ZA (1)	ZA927211B (de)

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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
EP2089389A2 (de)	2006-11-01	2009-08-19	Bristol-Myers Squibb Company	Heterocyclische verbindungen als modulatoren der glucocorticoidrezeptor,- ap1- und/oder nf-kappa-b-aktivität
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1992
- 1992-09-21 CA CA002078759A patent/CA2078759C/en not_active Expired - Fee Related
- 1992-09-21 ZA ZA927211A patent/ZA927211B/xx unknown
- 1992-09-22 NZ NZ244442A patent/NZ244442A/xx unknown
- 1992-09-22 AU AU25247/92A patent/AU657794B2/en not_active Ceased
- 1992-09-23 IL IL10326592A patent/IL103265A/en not_active IP Right Cessation
- 1992-09-25 JP JP28066792A patent/JP3173673B2/ja not_active Expired - Fee Related
- 1992-09-25 FI FI924312A patent/FI101304B/fi active
- 1992-09-25 HU HU9203076A patent/HU214596B/hu not_active IP Right Cessation
- 1992-09-25 NO NO923743A patent/NO300844B1/no not_active IP Right Cessation
- 1992-09-26 KR KR1019920017614A patent/KR100273734B1/ko not_active Expired - Fee Related
- 1992-09-28 AT AT92116575T patent/ATE146482T1/de not_active IP Right Cessation
- 1992-09-28 EP EP92116575A patent/EP0534492B1/de not_active Expired - Lifetime
- 1992-09-28 DE DE69216026T patent/DE69216026T2/de not_active Expired - Fee Related
- 1992-09-28 DK DK92116575.9T patent/DK0534492T3/da active
- 1992-09-28 ES ES92116575T patent/ES2097847T3/es not_active Expired - Lifetime
1994
- 1994-12-01 US US08/348,778 patent/US5472959A/en not_active Expired - Fee Related
1997
- 1997-02-26 GR GR970400341T patent/GR3022654T3/el unknown

Also Published As

Publication number	Publication date
AU2524792A (en)	1993-04-01
FI924312L (fi)	1993-03-28
NO300844B1 (no)	1997-08-04
FI101304B1 (fi)	1998-05-29
FI101304B (fi)	1998-05-29
KR100273734B1 (ko)	2001-02-01
NO923743L (no)	1993-03-29
EP0534492A2 (de)	1993-03-31
EP0534492B1 (de)	1996-12-18
US5472959A (en)	1995-12-05
FI924312A0 (fi)	1992-09-25
HUT65174A (en)	1994-05-02
AU657794B2 (en)	1995-03-23
NZ244442A (en)	1995-01-27
HU214596B (hu)	1998-04-28
IL103265A0 (en)	1993-02-21
ATE146482T1 (de)	1997-01-15
CA2078759A1 (en)	1993-03-28
DE69216026D1 (de)	1997-01-30
KR930006026A (ko)	1993-04-20
JPH05213950A (ja)	1993-08-24
ES2097847T3 (es)	1997-04-16
EP0534492A3 (en)	1993-06-09
JP3173673B2 (ja)	2001-06-04
HU9203076D0 (en)	1992-12-28
ZA927211B (en)	1993-03-24
NO923743D0 (no)	1992-09-25
CA2078759C (en)	2003-09-16
DE69216026T2 (de)	1997-07-17
DK0534492T3 (da)	1997-01-06
GR3022654T3 (en)	1997-05-31

Legal Events

Date	Code	Title	Description
1997-02-18	FF	Patent granted
1997-07-13	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
EP0534492B1 (de)	1996-12-18	Karboxyalkylsubstituierte Enkephalinase und ACE-Hemmer
EP0534396B1 (de)	1996-10-09	2-Substituierte Indane-2-Carboxyalkyl-Verbindungen mit Enkephalinase und ACE-Hemmwirkung
EP0534363B1 (de)	1997-07-09	2-Substituierte Indan-2-Mercaptoacetylamid-Verbindungen mit Enkephalinase und ACE-Hemmwirkung
EP0481522B1 (de)	1997-12-29	Neue Mercaptoacetylamid-Derivate zur Verwendung als Enkephalinase- und ACE-Hemmer
CA2130116C (en)	1998-04-07	Aminoacetylmercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace
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
US5529997A (en)	1996-06-25	Carboxyalkyl tricyclic derivatives useful as inhibitors of enkephalinase and ace
US5527795A (en)	1996-06-18	Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace