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 themInfo
- Publication number
- IL103265A IL103265A IL10326592A IL10326592A IL103265A IL 103265 A IL103265 A IL 103265A IL 10326592 A IL10326592 A IL 10326592A IL 10326592 A IL10326592 A IL 10326592A IL 103265 A IL103265 A IL 103265A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- oxo
- amino
- phenylpropyl
- carboxylic acid
- Prior art date
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
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- 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
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- 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
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 8
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- 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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- 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
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- 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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- 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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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- 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
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
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- 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
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- 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
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- 239000004033 plastic Substances 0.000 description 1
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- 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
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- 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
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
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- 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
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- 241000894007 species Species 0.000 description 1
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- 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
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- 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)
- Biochemistry (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Psychiatry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Peptides Or Proteins (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 (fr) |
| EP (1) | EP0534492B1 (fr) |
| JP (1) | JP3173673B2 (fr) |
| KR (1) | KR100273734B1 (fr) |
| AT (1) | ATE146482T1 (fr) |
| AU (1) | AU657794B2 (fr) |
| CA (1) | CA2078759C (fr) |
| DE (1) | DE69216026T2 (fr) |
| DK (1) | DK0534492T3 (fr) |
| ES (1) | ES2097847T3 (fr) |
| FI (1) | FI101304B1 (fr) |
| GR (1) | GR3022654T3 (fr) |
| HU (1) | HU214596B (fr) |
| IL (1) | IL103265A (fr) |
| NO (1) | NO300844B1 (fr) |
| NZ (1) | NZ244442A (fr) |
| ZA (1) | ZA927211B (fr) |
Families Citing this family (44)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2078758C (fr) * | 1991-09-27 | 2003-12-09 | Alan M. Warshawsky | Derives de substitution en 2 d'indane-2-mercaptoacetylamide, utiles comme inhibiteurs de l'enkephalinase et de l'enzyme de conversion de l'angiotensine |
| DE69317764T2 (de) * | 1992-02-14 | 1998-07-30 | Merrell Pharmaceuticals Inc., Cincinnati, Ohio | Aminoacetylmercaptoacetylamid derivate mit enkephalinase- und ace-hemmwirkung |
| US5552397A (en) * | 1992-05-18 | 1996-09-03 | E. R. Squibb & Sons, Inc. | Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase |
| 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 |
| US5508272A (en) * | 1993-06-15 | 1996-04-16 | Bristol-Myers Squibb Company | Compounds containing a fused bicycle ring and processes therefor |
| EP0706525A1 (fr) * | 1993-06-30 | 1996-04-17 | Novartis AG | Derives d'azepine tricycliques antihypertension utilises comme inhibiteurs d'encephalinase et d'ace |
| 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 |
| 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 |
| 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 |
| US5635504A (en) * | 1995-06-07 | 1997-06-03 | Bristol-Myers Squibb Co. | Diazepine containing dual action inhibitors |
| US5650408A (en) * | 1995-06-07 | 1997-07-22 | Karanewsky; Donald S. | Thiazolo benzazepine containing dual action inhibitors |
| US6929953B1 (en) * | 1998-03-07 | 2005-08-16 | Robert A. Levine | Apparatus for analyzing biologic fluids |
| WO1999065500A1 (fr) | 1998-06-17 | 1999-12-23 | Bristol-Myers Squibb Company | Prevention de l'infarctus cerebral par administration d'une combinaison d'un anti-agregant plaquettaire bloquant les recepteurs d'adp et d'un medicament antihypertenseur |
| SE9903028D0 (sv) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| DK1216038T3 (da) | 1999-08-30 | 2005-12-27 | Sanofi Aventis Deutschland | Anvendelse af inhibitorer af reninangiotensinsystemet ved forebyggelsen af cardiovaskulære hændelser |
| EP1443919A4 (fr) | 2001-11-16 | 2006-03-22 | Bristol Myers Squibb Co | Inhibiteurs doubles de la proteine de liaison des acides gras des adipocytes et de la proteine de liaison des acides gras des keratinocytes |
| US7459474B2 (en) | 2003-06-11 | 2008-12-02 | Bristol-Myers Squibb Company | Modulators of the glucocorticoid receptor 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 |
| 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 |
| 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 |
| 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 |
| 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 |
| WO2008151257A2 (fr) | 2007-06-04 | 2008-12-11 | Synergy Pharmaceuticals Inc. | Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles |
| 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 (fr) | 2008-06-24 | 2011-06-22 | Bristol-Myers Squibb Company | Modulateurs de cyclopentathiopène du récepteur glucocorticoïde, ap-1, et/ou activité nf-kappa b et utilisation de ceux-ci |
| 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 |
| CA2763565A1 (fr) | 2009-05-28 | 2010-12-02 | Novartis Ag | Derives aminobutyriques substitues en tant qu'inhibiteurs de neprilysine |
| PL2435409T3 (pl) | 2009-05-28 | 2015-01-30 | Novartis Ag | Podstawione pochodne aminopropionowe jako inhibitory neprylizyny |
| JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| WO2014126972A1 (fr) | 2013-02-14 | 2014-08-21 | Novartis Ag | Dérivés de l'acide butanoïque bisphényle substitué utiles en tant qu'inhibiteurs de nep présentant une meilleure efficacité in vivo |
| SG11201506018PA (en) | 2013-02-14 | 2015-08-28 | Novartis Ag | Substituted bisphenyl butanoic phosphonic acid derivatives as nep (neutral endopeptidase) inhibitors |
| US9708367B2 (en) | 2013-03-15 | 2017-07-18 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase and their uses |
| EP2968439A2 (fr) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Compositions utiles pour le traitement de troubles gastro-intestinaux |
| 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 (fr) | 2013-08-22 | 2015-02-26 | Bristol-Myers Squibb Company | Dérivés imide et acylurée utilisés comme modulateurs du récepteur de glucocorticoïdes |
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| 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 |
| US4320057A (en) * | 1980-06-23 | 1982-03-16 | American Home Products Corporation | Aryl--pyrrolo--thiazepin--diones and aryl--piperidino--thiazepin--diones |
| US4415496A (en) * | 1981-03-23 | 1983-11-15 | Merck & Co., Inc. | Bicyclic lactams |
| GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
| NZ204130A (en) * | 1982-05-12 | 1986-03-14 | Hoffmann La Roche | Bicyclic heterocyclic compounds and pharmaceutical compositions |
| US4552889A (en) * | 1983-06-09 | 1985-11-12 | Eli Lilly And Company | 3-Mercaptomethyl-2-oxo-1-pyrrolidine acetic acids and use for hypertension |
| US4584294A (en) * | 1984-11-07 | 1986-04-22 | Merck & Co., Inc. | Fused tricyclic lactams as angiotensin converting enzyme inhibitors and as antihypertensive agents |
| CA1337654C (fr) * | 1986-06-13 | 1995-11-28 | Gary A. Flynn | Lactames tricycliques fondus servant d'agents antihypertenseurs |
| ZA874106B (en) * | 1986-06-13 | 1987-12-08 | Merrell Dow Pharmaceuticals Inc. | Novel antihypertensive agent |
| 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 |
| DE3901291A1 (de) * | 1988-01-27 | 1989-08-03 | Hoechst Ag | Verbindungen mit psychotroper wirkung, diese enthaltende mittel und deren verwendung bei der behandlung und prophylaxe von stoerungen des zentralen nervensystems |
| EP0331609A3 (fr) * | 1988-01-27 | 1992-07-01 | Hoechst Aktiengesellschaft | Inhibiteurs de l'enzyme de conversion à activité psychotrope |
| HU904967D0 (en) * | 1988-04-22 | 1991-01-28 | Hoechst Ag | Process for producing new azabicyclo(3.3.o)octane-3-carboxylic acid-octylesther derivatives |
| GB8926512D0 (en) * | 1989-11-23 | 1990-01-10 | Pfizer Ltd | Therapeutic agents |
| US5407960A (en) * | 1989-12-22 | 1995-04-18 | Schering Corporation | Mercaptocycloacyl aminoacid endopeptidase inhibitors |
| CA2053340C (fr) * | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Derives de mercaptoacetylamide utiles comme inhibiteurs de l'encephalinase et de l'ace |
| US5208230A (en) * | 1990-12-21 | 1993-05-04 | Merrell Dow Pharmaceuticals | Amino and nitro containing tricyclic compounds useful as inhibitors of ACE |
| ATE158303T1 (de) * | 1990-12-21 | 1997-10-15 | Merrell Pharma Inc | Neue trizyklische amino- und nitro verbindungen mit ace-hemmenden eigenschaften |
| EP0605589A1 (fr) * | 1991-09-16 | 1994-07-13 | Schering Corporation | Compositions pharmaceutiques comprenant des peptides natriuretiques ou des inhibiteurs d'endopeptidase neutres utilises dans le traitement ou la prevention de la proliferation dans la myointima |
| 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 |
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-
1992
- 1992-09-21 ZA ZA927211A patent/ZA927211B/xx unknown
- 1992-09-21 CA CA002078759A patent/CA2078759C/fr not_active Expired - Fee Related
- 1992-09-22 AU AU25247/92A patent/AU657794B2/en not_active Ceased
- 1992-09-22 NZ NZ244442A patent/NZ244442A/xx unknown
- 1992-09-23 IL IL10326592A patent/IL103265A/en not_active IP Right Cessation
- 1992-09-25 NO NO923743A patent/NO300844B1/no not_active IP Right Cessation
- 1992-09-25 HU HU9203076A patent/HU214596B/hu not_active IP Right Cessation
- 1992-09-25 FI FI924312A patent/FI101304B1/fi active
- 1992-09-25 JP JP28066792A patent/JP3173673B2/ja not_active Expired - Fee Related
- 1992-09-26 KR KR1019920017614A patent/KR100273734B1/ko not_active Expired - Fee Related
- 1992-09-28 ES ES92116575T patent/ES2097847T3/es not_active Expired - Lifetime
- 1992-09-28 DK DK92116575.9T patent/DK0534492T3/da active
- 1992-09-28 EP EP92116575A patent/EP0534492B1/fr not_active Expired - Lifetime
- 1992-09-28 DE DE69216026T patent/DE69216026T2/de not_active Expired - Fee Related
- 1992-09-28 AT AT92116575T patent/ATE146482T1/de not_active IP Right Cessation
-
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 |
|---|---|
| KR100273734B1 (ko) | 2001-02-01 |
| IL103265A0 (en) | 1993-02-21 |
| JPH05213950A (ja) | 1993-08-24 |
| US5472959A (en) | 1995-12-05 |
| HU214596B (hu) | 1998-04-28 |
| ATE146482T1 (de) | 1997-01-15 |
| FI101304B (fi) | 1998-05-29 |
| ES2097847T3 (es) | 1997-04-16 |
| GR3022654T3 (en) | 1997-05-31 |
| HUT65174A (en) | 1994-05-02 |
| NZ244442A (en) | 1995-01-27 |
| AU657794B2 (en) | 1995-03-23 |
| NO300844B1 (no) | 1997-08-04 |
| HU9203076D0 (en) | 1992-12-28 |
| NO923743D0 (no) | 1992-09-25 |
| EP0534492B1 (fr) | 1996-12-18 |
| JP3173673B2 (ja) | 2001-06-04 |
| CA2078759C (fr) | 2003-09-16 |
| DK0534492T3 (da) | 1997-01-06 |
| FI101304B1 (fi) | 1998-05-29 |
| NO923743L (no) | 1993-03-29 |
| ZA927211B (en) | 1993-03-24 |
| DE69216026D1 (de) | 1997-01-30 |
| CA2078759A1 (fr) | 1993-03-28 |
| EP0534492A2 (fr) | 1993-03-31 |
| FI924312A0 (fi) | 1992-09-25 |
| DE69216026T2 (de) | 1997-07-17 |
| KR930006026A (ko) | 1993-04-20 |
| EP0534492A3 (en) | 1993-06-09 |
| AU2524792A (en) | 1993-04-01 |
| FI924312L (fi) | 1993-03-28 |
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| FF | Patent granted | ||
| KB | Patent renewed | ||
| HC | Change of name of proprietor(s) | ||
| KB | Patent renewed | ||
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| HC | Change of name of proprietor(s) |
Owner name: AVENTIS INC. Free format text: FORMER NAME:MERRELL PARMACEUTICALS, INC. |
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| MM9K | Patent not in force due to non-payment of renewal fees |