CA2379545A1 - Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists - Google Patents
Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists Download PDFInfo
- Publication number
- CA2379545A1 CA2379545A1 CA002379545A CA2379545A CA2379545A1 CA 2379545 A1 CA2379545 A1 CA 2379545A1 CA 002379545 A CA002379545 A CA 002379545A CA 2379545 A CA2379545 A CA 2379545A CA 2379545 A1 CA2379545 A1 CA 2379545A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkoxy
- alkylthio
- phenyl
- haloalkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940118365 Endothelin receptor antagonist Drugs 0.000 title claims description 5
- 239000002308 endothelin receptor antagonist Substances 0.000 title claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title description 8
- 238000004519 manufacturing process Methods 0.000 title description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- -1 C1-C4-alkylthio Chemical group 0.000 claims description 83
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 65
- 150000003254 radicals Chemical class 0.000 claims description 36
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000011593 sulfur Substances 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 12
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000003112 inhibitor Substances 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 5
- 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 claims description 5
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims description 5
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 4
- 150000005840 aryl radicals Chemical class 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000004434 sulfur atom Chemical group 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- 102000002045 Endothelin Human genes 0.000 claims description 3
- 108050009340 Endothelin Proteins 0.000 claims description 3
- 206010033645 Pancreatitis Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 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)=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=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 3
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
- 230000036454 renin-angiotensin system Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 208000009304 Acute Kidney Injury Diseases 0.000 claims description 2
- 229940123413 Angiotensin II antagonist Drugs 0.000 claims description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 2
- 201000006474 Brain Ischemia Diseases 0.000 claims description 2
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 2
- 206010033647 Pancreatitis acute Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 208000033626 Renal failure acute Diseases 0.000 claims description 2
- 201000011040 acute kidney failure Diseases 0.000 claims description 2
- 201000003229 acute pancreatitis Diseases 0.000 claims description 2
- 208000012998 acute renal failure Diseases 0.000 claims description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
- 206010008118 cerebral infarction Diseases 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 2
- 239000002934 diuretic Substances 0.000 claims description 2
- 229940030606 diuretics Drugs 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 239000002461 renin inhibitor Substances 0.000 claims description 2
- 229940086526 renin-inhibitors Drugs 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims 3
- 102000003729 Neprilysin Human genes 0.000 claims 2
- 108090000028 Neprilysin Proteins 0.000 claims 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims 1
- 239000000480 calcium channel blocker Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 102000005962 receptors Human genes 0.000 description 11
- 108020003175 receptors Proteins 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 101150041968 CDC13 gene Proteins 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000027455 binding Effects 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 229940044551 receptor antagonist Drugs 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000008186 active pharmaceutical agent Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
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- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 102100040611 Endothelin receptor type B Human genes 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 102100033902 Endothelin-1 Human genes 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 4
- HQAKVYGASUTQHH-UHFFFAOYSA-N carbazole butanoic acid Chemical group C1=CC=C2N(CCCC(=O)O)C3=CC=CC=C3C2=C1 HQAKVYGASUTQHH-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- FXTPUVLWVRTMHV-UHFFFAOYSA-N 2-(4-methoxy-5-methylpyrimidin-2-yl)oxy-3,3-diphenyl-3-phenylmethoxypropanoic acid Chemical compound C1=C(C)C(OC)=NC(OC(C(O)=O)C(OCC=2C=CC=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 FXTPUVLWVRTMHV-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- IKVBTRHAPPNLNI-UHFFFAOYSA-N 4-methoxy-5-methyl-2-methylsulfanylpyrimidine Chemical compound COC1=NC(SC)=NC=C1C IKVBTRHAPPNLNI-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
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- IFQZZMKLFMUHRW-UHFFFAOYSA-N 2-methylsulfanyl-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound CSC1=NC=C2CCCC2=N1 IFQZZMKLFMUHRW-UHFFFAOYSA-N 0.000 description 2
- LPSCEUCZQDWXAF-UHFFFAOYSA-N 2-methylsulfonyl-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound CS(=O)(=O)C1=NC=C2CCCC2=N1 LPSCEUCZQDWXAF-UHFFFAOYSA-N 0.000 description 2
- QCMKYULRXYPSTG-UHFFFAOYSA-N 3-[(3,4-dimethylphenyl)methoxy]-2-(4-methoxy-5-methylpyrimidin-2-yl)oxy-3,3-diphenylpropanoic acid Chemical compound C1=C(C)C(OC)=NC(OC(C(O)=O)C(OCC=2C=C(C)C(C)=CC=2)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 QCMKYULRXYPSTG-UHFFFAOYSA-N 0.000 description 2
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- 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
- 210000000885 nephron Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000009871 nonspecific binding Effects 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
- 239000002674 ointment Substances 0.000 description 1
- 150000004010 onium ions Chemical class 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 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
- 239000002287 radioligand Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 238000005690 transetherification reaction Methods 0.000 description 1
- CMMXCVYESRODNH-UHFFFAOYSA-N trichloroepoxyethane Chemical class ClC1OC1(Cl)Cl CMMXCVYESRODNH-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 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
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/28—Oxygen atom
-
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- 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
-
- 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
-
- 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
- A61P35/00—Antineoplastic agents
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- 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
- A61P9/10—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
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19933164.2 | 1999-07-20 | ||
| DE19933164A DE19933164A1 (de) | 1999-07-20 | 1999-07-20 | Neue Carbonsäurederivate mit 5,6 substituiertem Pyrimidinring, ihre Herstellung und Verwendung als Endothelin Rezeptorantagonisten |
| PCT/EP2000/006293 WO2001005771A1 (de) | 1999-07-20 | 2000-07-05 | Neue carbonsäurederivate mit 5,6 substituiertem pyrimidinring, ihre herstellung und verwendung als endothelin rezeptorantagonisten |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2379545A1 true CA2379545A1 (en) | 2001-01-25 |
Family
ID=7914884
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002379545A Abandoned CA2379545A1 (en) | 1999-07-20 | 2000-07-05 | Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists |
Country Status (21)
| Country | Link |
|---|---|
| EP (1) | EP1196394A1 (cs) |
| JP (1) | JP2003505377A (cs) |
| KR (1) | KR20020019550A (cs) |
| CN (1) | CN1367778A (cs) |
| AR (1) | AR030026A1 (cs) |
| AU (1) | AU6561500A (cs) |
| BG (1) | BG106321A (cs) |
| BR (1) | BR0012592A (cs) |
| CA (1) | CA2379545A1 (cs) |
| CZ (1) | CZ2002190A3 (cs) |
| DE (1) | DE19933164A1 (cs) |
| HU (1) | HUP0202646A3 (cs) |
| IL (1) | IL147666A0 (cs) |
| MX (1) | MXPA02000616A (cs) |
| NO (1) | NO20020254L (cs) |
| PL (1) | PL353165A1 (cs) |
| SK (1) | SK772002A3 (cs) |
| TR (1) | TR200200622T2 (cs) |
| TW (1) | TW555749B (cs) |
| WO (1) | WO2001005771A1 (cs) |
| ZA (1) | ZA200200333B (cs) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8962832B2 (en) * | 2009-07-10 | 2015-02-24 | Cadila Healthcare Limited | Process for the preparation of ambrisentan and novel intermediates thereof |
| WO2011114338A1 (en) | 2010-03-15 | 2011-09-22 | Natco Pharma Limited | A process for the preparation of highly pure ambrisentan |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19636046A1 (de) * | 1996-09-05 | 1998-03-12 | Basf Ag | Neue Carbonsäurederivate, ihre Herstellung und Verwendung als gemischte ET¶A¶/ET¶B¶-Rezeptorantagonisten |
| CN1278251A (zh) * | 1997-10-31 | 2000-12-27 | Basf公司 | 新的带酰胺侧链的羧酸衍生物及其制备方法和作为内皮素受体拮抗剂的用途 |
-
1999
- 1999-07-20 DE DE19933164A patent/DE19933164A1/de not_active Withdrawn
-
2000
- 2000-07-05 PL PL00353165A patent/PL353165A1/xx not_active Application Discontinuation
- 2000-07-05 EP EP00953009A patent/EP1196394A1/de not_active Withdrawn
- 2000-07-05 CZ CZ2002190A patent/CZ2002190A3/cs unknown
- 2000-07-05 CN CN00810533A patent/CN1367778A/zh active Pending
- 2000-07-05 IL IL14766600A patent/IL147666A0/xx unknown
- 2000-07-05 CA CA002379545A patent/CA2379545A1/en not_active Abandoned
- 2000-07-05 BR BR0012592-0A patent/BR0012592A/pt not_active IP Right Cessation
- 2000-07-05 AU AU65615/00A patent/AU6561500A/en not_active Abandoned
- 2000-07-05 KR KR1020027000815A patent/KR20020019550A/ko not_active Ceased
- 2000-07-05 WO PCT/EP2000/006293 patent/WO2001005771A1/de not_active Application Discontinuation
- 2000-07-05 MX MXPA02000616A patent/MXPA02000616A/es unknown
- 2000-07-05 HU HU0202646A patent/HUP0202646A3/hu unknown
- 2000-07-05 JP JP2001511432A patent/JP2003505377A/ja not_active Abandoned
- 2000-07-05 TR TR2002/00622T patent/TR200200622T2/xx unknown
- 2000-07-05 SK SK77-2002A patent/SK772002A3/sk unknown
- 2000-07-13 TW TW089113992A patent/TW555749B/zh active
- 2000-07-17 AR ARP000103661A patent/AR030026A1/es unknown
-
2002
- 2002-01-15 ZA ZA200200333A patent/ZA200200333B/en unknown
- 2002-01-17 NO NO20020254A patent/NO20020254L/no not_active Application Discontinuation
- 2002-01-18 BG BG106321A patent/BG106321A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL147666A0 (en) | 2002-08-14 |
| CZ2002190A3 (cs) | 2003-08-13 |
| TR200200622T2 (cs) | 2002-06-21 |
| EP1196394A1 (de) | 2002-04-17 |
| AR030026A1 (es) | 2003-08-13 |
| DE19933164A1 (de) | 2001-01-25 |
| HUP0202646A2 (hu) | 2003-02-28 |
| PL353165A1 (en) | 2003-10-20 |
| NO20020254D0 (no) | 2002-01-17 |
| CN1367778A (zh) | 2002-09-04 |
| AU6561500A (en) | 2001-02-05 |
| HUP0202646A3 (en) | 2003-03-28 |
| BG106321A (en) | 2002-08-30 |
| TW555749B (en) | 2003-10-01 |
| MXPA02000616A (es) | 2002-08-30 |
| BR0012592A (pt) | 2002-05-28 |
| ZA200200333B (en) | 2003-04-30 |
| NO20020254L (no) | 2002-02-20 |
| SK772002A3 (en) | 2003-01-09 |
| KR20020019550A (ko) | 2002-03-12 |
| WO2001005771A1 (de) | 2001-01-25 |
| JP2003505377A (ja) | 2003-02-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |