ZA200300167B - Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme. - Google Patents
Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme. Download PDFInfo
- Publication number
- ZA200300167B ZA200300167B ZA200300167A ZA200300167A ZA200300167B ZA 200300167 B ZA200300167 B ZA 200300167B ZA 200300167 A ZA200300167 A ZA 200300167A ZA 200300167 A ZA200300167 A ZA 200300167A ZA 200300167 B ZA200300167 B ZA 200300167B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- compound according
- arylalkyl
- aryl
- pyrrolidine
- Prior art date
Links
- 102000048186 Endothelin-converting enzyme 1 Human genes 0.000 title claims description 15
- 108030001679 Endothelin-converting enzyme 1 Proteins 0.000 title claims description 15
- 239000003112 inhibitor Substances 0.000 title description 4
- 150000003235 pyrrolidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 104
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 63
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 45
- -1 arylcarbonylalkyl Chemical group 0.000 claims description 36
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 31
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 21
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 19
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 17
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000005097 aminocarbonylalkyl group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 206010019280 Heart failures Diseases 0.000 claims description 11
- 206010020772 Hypertension Diseases 0.000 claims description 11
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 11
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims description 11
- 230000001966 cerebroprotective effect Effects 0.000 claims description 11
- 239000000824 cytostatic agent Substances 0.000 claims description 11
- 230000001085 cytostatic effect Effects 0.000 claims description 11
- 208000031225 myocardial ischemia Diseases 0.000 claims description 11
- 210000000056 organ Anatomy 0.000 claims description 11
- 201000001320 Atherosclerosis Diseases 0.000 claims description 10
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 10
- 208000002249 Diabetes Complications Diseases 0.000 claims description 10
- 206010012655 Diabetic complications Diseases 0.000 claims description 10
- 206010014824 Endotoxic shock Diseases 0.000 claims description 10
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 10
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 10
- 206010040047 Sepsis Diseases 0.000 claims description 10
- 206010040070 Septic Shock Diseases 0.000 claims description 10
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 10
- 206010043540 Thromboangiitis obliterans Diseases 0.000 claims description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 10
- 206010003119 arrhythmia Diseases 0.000 claims description 10
- 206010003246 arthritis Diseases 0.000 claims description 10
- 208000006673 asthma Diseases 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 10
- 208000001286 intracranial vasospasm Diseases 0.000 claims description 10
- 208000017169 kidney disease Diseases 0.000 claims description 10
- 230000005906 menstruation Effects 0.000 claims description 10
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 10
- 230000029663 wound healing Effects 0.000 claims description 10
- 208000010412 Glaucoma Diseases 0.000 claims description 9
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 9
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 9
- 201000005202 lung cancer Diseases 0.000 claims description 9
- 208000020816 lung neoplasm Diseases 0.000 claims description 9
- 201000011461 pre-eclampsia Diseases 0.000 claims description 9
- 206010052779 Transplant rejections Diseases 0.000 claims description 8
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 238000011321 prophylaxis Methods 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 8
- 229910052725 zinc Inorganic materials 0.000 claims description 8
- 102000004157 Hydrolases Human genes 0.000 claims description 6
- 108090000604 Hydrolases Proteins 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000003386 piperidinyl group Chemical group 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000005120 alkyl cycloalkyl alkyl group Chemical group 0.000 claims description 5
- 125000005119 alkyl cycloalkyl group Chemical group 0.000 claims description 5
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- LVVNTXNLOMBDBY-OCCSQVGLSA-N (2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 LVVNTXNLOMBDBY-OCCSQVGLSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000006193 alkinyl group Chemical group 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- DHIQNDDDYDYAOK-VWNXMTODSA-N (2s,4r)-n-[2-[4-(hydroxymethyl)-n-methylanilino]-2-oxoethyl]-n-methyl-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carboxamide Chemical compound O=C([C@H]1N(C[C@H](S)C1)S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)N(C)CC(=O)N(C)C1=CC=C(CO)C=C1 DHIQNDDDYDYAOK-VWNXMTODSA-N 0.000 claims description 2
- URQLGFMFTYMWQJ-GGAORHGYSA-N (2s,4r)-n-benzyl-1-naphthalen-2-ylsulfonyl-4-sulfanyl-n-[2-(2h-tetrazol-5-yl)ethyl]pyrrolidine-2-carboxamide Chemical compound O=C([C@@H]1C[C@H](CN1S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)S)N(CC=1C=CC=CC=1)CCC1=NN=NN1 URQLGFMFTYMWQJ-GGAORHGYSA-N 0.000 claims description 2
- RASBKWUKAAKWET-IRLDBZIGSA-N (2s,4r)-n-benzyl-n-methyl-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carboxamide Chemical compound O=C([C@H]1N(C[C@H](S)C1)S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)N(C)CC1=CC=CC=C1 RASBKWUKAAKWET-IRLDBZIGSA-N 0.000 claims description 2
- HIFRPZYHLKDAGD-CTNGQTDRSA-N (2s,4r)-n-hexyl-n-methyl-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carboxamide Chemical compound CCCCCCN(C)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 HIFRPZYHLKDAGD-CTNGQTDRSA-N 0.000 claims description 2
- LNQKCRQYWZQGDY-CTNGQTDRSA-N (2s,4r)-n-methyl-n-(4-methyl-2-oxopentyl)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carboxamide Chemical compound CC(C)CC(=O)CN(C)C(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 LNQKCRQYWZQGDY-CTNGQTDRSA-N 0.000 claims description 2
- VTHPWPGJXZCYHN-GGAORHGYSA-N 4-[methyl-[2-[methyl-[(2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carbonyl]amino]acetyl]amino]benzoic acid Chemical compound O=C([C@H]1N(C[C@H](S)C1)S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)N(C)CC(=O)N(C)C1=CC=C(C(O)=O)C=C1 VTHPWPGJXZCYHN-GGAORHGYSA-N 0.000 claims description 2
- 241001465754 Metazoa Species 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- RPXYGMUPGVJLRX-NOZRDPDXSA-N methyl 4-[[2-[[(2s,4r)-4-acetylsulfanyl-1-naphthalen-2-ylsulfonylpyrrolidine-2-carbonyl]amino]acetyl]-methylamino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N(C)C(=O)CNC(=O)[C@H]1N(S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)C[C@H](SC(C)=O)C1 RPXYGMUPGVJLRX-NOZRDPDXSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 7
- 239000000126 substance Substances 0.000 claims 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- OMNHCFHMYDCIKF-AEFFLSMTSA-N 3-methyl-1-[(2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidin-2-yl]butan-1-one Chemical compound CC(C)CC(=O)[C@@H]1C[C@@H](S)CN1S(=O)(=O)C1=CC=C(C=CC=C2)C2=C1 OMNHCFHMYDCIKF-AEFFLSMTSA-N 0.000 claims 1
- 208000032843 Hemorrhage Diseases 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 claims 1
- XPZWAPFROPIRGN-UHFFFAOYSA-N butyl pyrrolidine-1-carboxylate Chemical compound CCCCOC(=O)N1CCCC1 XPZWAPFROPIRGN-UHFFFAOYSA-N 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims 1
- APMDTOUBZRTXII-VWNXMTODSA-N methyl 4-[methyl-[2-[methyl-[(2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carbonyl]amino]acetyl]amino]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N(C)C(=O)CN(C)C(=O)[C@H]1N(S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)C[C@H](S)C1 APMDTOUBZRTXII-VWNXMTODSA-N 0.000 claims 1
- XBDYTZCQNDHGJO-SJORKVTESA-N pentyl (2s,4r)-2-[benzyl(methyl)carbamoyl]-4-sulfanylpyrrolidine-1-carboxylate Chemical compound CCCCCOC(=O)N1C[C@H](S)C[C@H]1C(=O)N(C)CC1=CC=CC=C1 XBDYTZCQNDHGJO-SJORKVTESA-N 0.000 claims 1
- LNGMYPHQOVNMRM-CABCVRRESA-N propan-2-yl (2s,4r)-2-[benzyl(methyl)carbamoyl]-4-sulfanylpyrrolidine-1-carboxylate Chemical compound CC(C)OC(=O)N1C[C@H](S)C[C@H]1C(=O)N(C)CC1=CC=CC=C1 LNGMYPHQOVNMRM-CABCVRRESA-N 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000000460 chlorine Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 102000005741 Metalloproteases Human genes 0.000 description 5
- 108010006035 Metalloproteases Proteins 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 230000006793 arrhythmia Effects 0.000 description 5
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 101800004490 Endothelin-1 Proteins 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- HZZGDPLAJHVHSP-GKHTVLBPSA-N big endothelin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@@H]2CSSC[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSSC1)C1=CN=CN1 HZZGDPLAJHVHSP-GKHTVLBPSA-N 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 125000001544 thienyl group Chemical group 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- 125000000842 isoxazolyl group Chemical group 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108090000028 Neprilysin Proteins 0.000 description 2
- 102000003729 Neprilysin Human genes 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000005111 carboxyalkoxy group Chemical group 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 2
- 150000003573 thiols Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DFYKTMGIVVVHOT-CTNGQTDRSA-N (2s,4r)-n-(3-methylbutyl)-1-naphthalen-2-ylsulfonyl-n-(1,2,4-oxadiazol-3-ylmethyl)-4-sulfanylpyrrolidine-2-carboxamide Chemical compound O=C([C@H]1N(C[C@H](S)C1)S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)N(CCC(C)C)CC=1N=CON=1 DFYKTMGIVVVHOT-CTNGQTDRSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- PIMASLJEYMYKCL-UHFFFAOYSA-N 2-diazonioethenolate Chemical compound [N-]=[N+]=CC=O PIMASLJEYMYKCL-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- HSLOUYLTGMNCJP-GGAORHGYSA-N 3-[benzyl-[(2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carbonyl]amino]propanoic acid Chemical compound O=C([C@H]1N(C[C@H](S)C1)S(=O)(=O)C=1C=C2C=CC=CC2=CC=1)N(CCC(=O)O)CC1=CC=CC=C1 HSLOUYLTGMNCJP-GGAORHGYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 238000006218 Arndt-Eistert homologation reaction Methods 0.000 description 1
- 102400000687 Big endothelin-1 Human genes 0.000 description 1
- 101800001398 Big endothelin-1 Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 108050009340 Endothelin Proteins 0.000 description 1
- 102000002045 Endothelin Human genes 0.000 description 1
- 102400000686 Endothelin-1 Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102000004961 Furin Human genes 0.000 description 1
- 108090001126 Furin Proteins 0.000 description 1
- 102000056826 Gluzincins Human genes 0.000 description 1
- 108091007247 Gluzincins Proteins 0.000 description 1
- 101000971879 Homo sapiens Kell blood group glycoprotein Proteins 0.000 description 1
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 102100021447 Kell blood group glycoprotein Human genes 0.000 description 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102000036436 Metzincins Human genes 0.000 description 1
- 108091007161 Metzincins Proteins 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
- UQKBMRIWBZHJTI-UHFFFAOYSA-N N-[2-(2H-tetrazol-5-yl)ethyl]cyclopropanamine Chemical compound C1CC1NCCC=1N=NNN=1 UQKBMRIWBZHJTI-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108010033253 PHEX Phosphate Regulating Neutral Endopeptidase Proteins 0.000 description 1
- 102000007057 PHEX Phosphate Regulating Neutral Endopeptidase Human genes 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000005011 alkyl ether group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000003636 conditioned culture medium Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 208000002296 eclampsia Diseases 0.000 description 1
- 229940066758 endopeptidases Drugs 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- XQPOFONTMJXZRQ-XXBNENTESA-N methyl 2-[[2-[methyl-[(2s,4r)-1-naphthalen-2-ylsulfonyl-4-sulfanylpyrrolidine-2-carbonyl]amino]acetyl]amino]benzoate Chemical compound COC(=O)C1=CC=CC=C1NC(=O)CN(C)C(=O)[C@H]1N(S(=O)(=O)C=2C=C3C=CC=CC3=CC=2)C[C@H](S)C1 XQPOFONTMJXZRQ-XXBNENTESA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000369 oxido group Chemical group [*]=O 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000002071 phenylalkoxy group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 150000007970 thio esters Chemical group 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- JQZIKLPHXXBMCA-UHFFFAOYSA-N triphenylmethanethiol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(S)C1=CC=CC=C1 JQZIKLPHXXBMCA-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- 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
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/06—Antiarrhythmics
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Hospice & Palliative Care (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Ophthalmology & Optometry (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Gynecology & Obstetrics (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Transplantation (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Pregnancy & Childbirth (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00114947 | 2000-07-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200300167B true ZA200300167B (en) | 2004-04-07 |
Family
ID=8169224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200300167A ZA200300167B (en) | 2000-07-19 | 2003-01-07 | Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme. |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US6541638B2 (enExample) |
| EP (1) | EP1303485A1 (enExample) |
| JP (1) | JP4068452B2 (enExample) |
| KR (1) | KR100568841B1 (enExample) |
| CN (1) | CN1620433A (enExample) |
| AR (1) | AR033984A1 (enExample) |
| AU (1) | AU2001270627A1 (enExample) |
| BR (1) | BR0112580A (enExample) |
| CA (1) | CA2414311C (enExample) |
| GT (1) | GT200100145A (enExample) |
| MX (1) | MXPA03000223A (enExample) |
| PA (1) | PA8522501A1 (enExample) |
| PE (1) | PE20020294A1 (enExample) |
| UY (1) | UY26847A1 (enExample) |
| WO (1) | WO2002006222A1 (enExample) |
| ZA (1) | ZA200300167B (enExample) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002008185A1 (en) * | 2000-07-19 | 2002-01-31 | F. Hoffmann-La Roche Ag | Pyrrolidine derivatives as metalloprotease inhibitors |
| US7157487B2 (en) * | 2000-12-28 | 2007-01-02 | Daiichi Pharmaceutical Co., Ltd. | Vla-4 inhibitors |
| EP1481967B1 (en) | 2002-03-05 | 2011-05-04 | Sumitomo Chemical Company, Limited | Process for the preparation of biaryl compounds |
| US8088737B2 (en) | 2003-04-04 | 2012-01-03 | Incyte Corporation | Compositions, methods and kits relating to Her-2 cleavage |
| AU2004231070B2 (en) | 2003-04-10 | 2008-02-14 | Amgen, Inc. | Bicyclic compounds having bradykinin receptors affinity and pharmaceutical compositions thereof |
| CA2522084A1 (en) | 2003-04-10 | 2004-10-28 | Amgen Inc. | Cyclic amine derivatives and their use in the treatment of inflammation-related disorders mediated by bradykinin |
| WO2005061467A2 (en) | 2003-06-20 | 2005-07-07 | Amgen Inc. | Piperazine derivatives as bradykinin antagonists |
| MXPA06000850A (es) | 2003-07-24 | 2006-03-30 | Daiichi Seiyaku Co | Compuesto de acido ciclohexancarboxilico. |
| CN1294120C (zh) * | 2003-10-21 | 2007-01-10 | 山东大学 | 吡咯烷类基质金属蛋白酶抑制剂及其应用 |
| RU2435585C2 (ru) * | 2006-04-13 | 2011-12-10 | Актелион Фармасьютиклз Лтд | Антагонисты рецептора эндотелина, предназначенные для ранней стадии идиопатического фиброза легких |
| ES2350548B1 (es) * | 2009-06-25 | 2011-09-29 | Institut Univ. De Ciència I Tecnologia, S.A. | N-fenil-1-sulfonil-2-pirrolidinacarboxamidas para la identificacion de actividad biologica y farmacologica. |
| EP2730571A1 (en) * | 2012-11-12 | 2014-05-14 | Universitat De Barcelona | 1-[1-(benzoyl)-pyrrolidine-2-carbonyl]-pyrrolidine-2-carbonitrile derivatives |
| WO2017168174A1 (en) | 2016-04-02 | 2017-10-05 | N4 Pharma Uk Limited | New pharmaceutical forms of sildenafil |
| JP7163916B2 (ja) * | 2017-07-05 | 2022-11-01 | 日産化学株式会社 | ベンジル化合物 |
| CN110078593A (zh) * | 2018-11-15 | 2019-08-02 | 南通正达农化有限公司 | 一种苹果蠹蛾性信息素的合成方法 |
| WO2025124698A1 (en) | 2023-12-12 | 2025-06-19 | Idorsia Pharmaceuticals Ltd | Aryl sulfone and sulfanone derivatives as orexin receptor modulators |
| WO2025132542A1 (en) | 2023-12-19 | 2025-06-26 | Idorsia Pharmaceuticals Ltd | Macrocyclic orexin agonists |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1283906C (en) * | 1983-05-09 | 1991-05-07 | Makoto Sunagawa | .beta.-LACTAM COMPOUNDS AND PRODUCTION THEREOF |
| AU644008B2 (en) * | 1990-08-10 | 1993-12-02 | Sumitomo Pharmaceuticals Company, Limited | Beta-lactam compounds, and their production and use |
| JP3091297B2 (ja) * | 1992-01-10 | 2000-09-25 | 住友製薬株式会社 | ピロリジン誘導体およびその製造方法 |
| BR9712792A (pt) * | 1996-08-28 | 1999-12-14 | Procter & Gamble | Inibidores de metaloprotease bidentada. |
| SK25099A3 (en) * | 1996-08-28 | 2000-02-14 | Procter & Gamble | Substituted cyclic amine metalloprotease inhibitors |
| WO1999002492A1 (en) * | 1997-07-10 | 1999-01-21 | Merck & Co., Inc. | Crystalline forms of antibiotic side chain intermediates |
| TR200003199T2 (tr) * | 1998-05-01 | 2001-03-21 | Kyoto Pharmaceutical Industries, Ltd. | Karbapenem türevleri, bunların kullanımı ve ara birleşiği |
-
2001
- 2001-07-10 BR BR0112580-0A patent/BR0112580A/pt not_active IP Right Cessation
- 2001-07-10 MX MXPA03000223A patent/MXPA03000223A/es not_active Application Discontinuation
- 2001-07-10 AU AU2001270627A patent/AU2001270627A1/en not_active Abandoned
- 2001-07-10 CA CA002414311A patent/CA2414311C/en not_active Expired - Fee Related
- 2001-07-10 KR KR1020037000781A patent/KR100568841B1/ko not_active Expired - Fee Related
- 2001-07-10 EP EP01949485A patent/EP1303485A1/en not_active Withdrawn
- 2001-07-10 WO PCT/EP2001/007950 patent/WO2002006222A1/en not_active Ceased
- 2001-07-10 JP JP2002512128A patent/JP4068452B2/ja not_active Expired - Fee Related
- 2001-07-10 CN CNA018130232A patent/CN1620433A/zh active Pending
- 2001-07-16 PA PA20018522501A patent/PA8522501A1/es unknown
- 2001-07-16 PE PE2001000711A patent/PE20020294A1/es not_active Application Discontinuation
- 2001-07-17 AR ARP010103416A patent/AR033984A1/es unknown
- 2001-07-17 UY UY26847A patent/UY26847A1/es not_active Application Discontinuation
- 2001-07-17 US US09/907,135 patent/US6541638B2/en not_active Expired - Fee Related
- 2001-07-18 GT GT200100145A patent/GT200100145A/es unknown
-
2003
- 2003-01-07 ZA ZA200300167A patent/ZA200300167B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2414311C (en) | 2008-01-08 |
| BR0112580A (pt) | 2003-06-17 |
| KR100568841B1 (ko) | 2006-04-10 |
| WO2002006222A1 (en) | 2002-01-24 |
| CN1620433A (zh) | 2005-05-25 |
| AR033984A1 (es) | 2004-01-21 |
| JP2004504297A (ja) | 2004-02-12 |
| US20020049243A1 (en) | 2002-04-25 |
| MXPA03000223A (es) | 2003-06-06 |
| KR20030016416A (ko) | 2003-02-26 |
| EP1303485A1 (en) | 2003-04-23 |
| PA8522501A1 (es) | 2002-09-17 |
| JP4068452B2 (ja) | 2008-03-26 |
| CA2414311A1 (en) | 2002-01-24 |
| UY26847A1 (es) | 2002-01-31 |
| US6541638B2 (en) | 2003-04-01 |
| AU2001270627A1 (en) | 2002-01-30 |
| PE20020294A1 (es) | 2002-04-17 |
| GT200100145A (es) | 2002-05-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ZA200300167B (en) | Pyrrolidine derivatives as inhibitors of endothelin-converting enzyme. | |
| US6159938A (en) | Serine protease inhibitors comprising α-keto heterocycles | |
| ES2209337T3 (es) | Agentes antitromboticos. | |
| JP4361365B2 (ja) | Ｐｄｆ阻害剤としてのｎ−ホルミルヒドロキシルアミン化合物 | |
| AU2133297A (en) | Fibrinogen receptor antagonists | |
| WO2009100225A1 (en) | Inhibitors of cathepsin b | |
| ES2314112T3 (es) | Nuevos inhibidores de metalproteinasas. | |
| WO2019202052A1 (en) | Inhibitors of blood coagulation factor xiii | |
| EP1165506A1 (en) | Substituted azetidin-2-ones as cysteine protease inhibitors | |
| ZA200109007B (en) | Hydroxamic acid derivatives as matrix metalloprotease inhibitors. | |
| AU1174099A (en) | Biphenylamidine derivatives | |
| JP2000256396A (ja) | 複素環式化合物およびその中間体ならびにエラスターゼ阻害剤 | |
| ES2234133T3 (es) | Derivados de (hetero)aril-sulfonamida, su preparacion y su uso como inhibidores del factor xa. | |
| ZA200300170B (en) | Pyrrolidine derivatives as metalloprotease inhibitors. | |
| AU7463496A (en) | Thrombin inhibitors | |
| CA2859928A1 (en) | Novel pyrrolidine derivatives | |
| ES2627281T3 (es) | Derivados del ácido carboxílico sustituidos como agregados agrecanasa para el tratamiento de la artrosis | |
| ZA200300172B (en) | Pyrrolidine-2-carboxylic acid hydrazide derivatives for use as metalloprotease inhibitors. | |
| JP2024097099A (ja) | Ｍｍｐ７阻害作用を有するペプチドコンジュゲート | |
| EP1105412A1 (en) | Serine protease inhibitors comprising alpha-keto heterocycles | |
| ZA200300161B (en) | Pyrimidine derivatives. | |
| US5525617A (en) | Fibrinogen receptor antagonists |