SK772002A3 - 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 PDF

Info

Publication number: SK772002A3
Authority: SK; Slovakia
Prior art keywords: alkyl; phenyl; alkoxy; alkylthio; haloalkyl
Prior art date: 1999-07-20

Application number

SK77-2002A

Other languages

English (en)

Slovak (sk)

Inventor

Wilhelm Amberg

Georg Kettschau

Original Assignee

Basf Ag

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-07-20

Filing date

2000-07-05

Publication date

2003-01-09

2000-07-05 Application filed by Basf Ag filed Critical Basf Ag

2003-01-09 Publication of SK772002A3 publication Critical patent/SK772002A3/sk

Links

229940118365 Endothelin receptor antagonist Drugs 0.000 title claims description 10
239000002308 endothelin receptor antagonist Substances 0.000 title claims description 10
238000004519 manufacturing process Methods 0.000 title claims description 5
150000001732 carboxylic acid derivatives Chemical class 0.000 title description 7
125000000714 pyrimidinyl group Chemical group 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 49
-1 alkali metal cation Chemical class 0.000 claims description 84
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 36
150000003254 radicals Chemical class 0.000 claims description 33
229910052736 halogen Inorganic materials 0.000 claims description 26
150000002367 halogens Chemical class 0.000 claims description 26
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
125000000217 alkyl group Chemical group 0.000 claims description 21
102000002045 Endothelin Human genes 0.000 claims description 20
108050009340 Endothelin Proteins 0.000 claims description 20
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 20
125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 19
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 18
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 17
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
229910052760 oxygen Inorganic materials 0.000 claims description 15
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
125000004093 cyano group Chemical group *C#N 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
125000004414 alkyl thio group Chemical group 0.000 claims description 9
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
125000001188 haloalkyl group Chemical group 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
229910052739 hydrogen Inorganic materials 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
125000006650 (C2-C4) alkynyl 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
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239000004480 active ingredient Substances 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
239000003814 drug Substances 0.000 claims description 5
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
229910052757 nitrogen Inorganic materials 0.000 claims description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 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
102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 4
108010019530 Vascular Endothelial Growth Factors Proteins 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
125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 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
125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 3
206010033645 Pancreatitis Diseases 0.000 claims description 3
150000002431 hydrogen Chemical class 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
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 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
230000001154 acute effect Effects 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
125000003545 alkoxy group Chemical group 0.000 claims description 2
239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 2
208000006673 asthma Diseases 0.000 claims description 2
239000002876 beta blocker Substances 0.000 claims description 2
229940097320 beta blocking agent Drugs 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
229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
239000000825 pharmaceutical preparation 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
108090000312 Calcium Channels Proteins 0.000 claims 1
102000003922 Calcium Channels Human genes 0.000 claims 1
125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
239000002981 blocking agent Substances 0.000 claims 1
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 31
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 20
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
239000000243 solution Substances 0.000 description 14
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
102000005962 receptors Human genes 0.000 description 12
108020003175 receptors Proteins 0.000 description 12
239000002904 solvent Substances 0.000 description 12
238000005160 1H NMR spectroscopy Methods 0.000 description 10
239000002585 base Substances 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
230000027455 binding Effects 0.000 description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
241001465754 Metazoa Species 0.000 description 7
239000012071 phase Substances 0.000 description 7
238000002360 preparation method Methods 0.000 description 7
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
238000006243 chemical reaction Methods 0.000 description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
238000003756 stirring Methods 0.000 description 6
125000001424 substituent group Chemical group 0.000 description 6
239000000725 suspension Substances 0.000 description 6
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 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
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
239000007787 solid Substances 0.000 description 5
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
102100033902 Endothelin-1 Human genes 0.000 description 4
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
239000005557 antagonist Substances 0.000 description 4
238000003556 assay Methods 0.000 description 4
125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
230000036772 blood pressure Effects 0.000 description 4
230000000694 effects Effects 0.000 description 4
239000005457 ice water Substances 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
239000000126 substance Substances 0.000 description 4
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
RCJNDDNXUYCUOY-UHFFFAOYSA-N 2-chloro-4-methoxy-5-methylpyrimidine Chemical compound COC1=NC(Cl)=NC=C1C RCJNDDNXUYCUOY-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
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical group NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
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108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
150000001340 alkali metals Chemical class 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
150000001735 carboxylic acids Chemical class 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
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 3
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
239000000543 intermediate Substances 0.000 description 3
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
229910052943 magnesium sulfate Inorganic materials 0.000 description 3
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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239000011734 sodium Substances 0.000 description 3
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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 2
MFDUCCDTBLZMSZ-UHFFFAOYSA-N 2-(4-methoxy-5-methylpyrimidin-2-yl)oxy-3,3-diphenyl-3-propan-2-yloxypropanoic acid Chemical compound C1=C(C)C(OC)=NC(OC(C(O)=O)C(OC(C)C)(C=2C=CC=CC=2)C=2C=CC=CC=2)=N1 MFDUCCDTBLZMSZ-UHFFFAOYSA-N 0.000 description 2
JDOXCEWQNADMCF-UHFFFAOYSA-N 2-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid Chemical compound COC(C(Oc1ncc2CCCc2n1)C(O)=O)(c1ccccc1)c1ccccc1 JDOXCEWQNADMCF-UHFFFAOYSA-N 0.000 description 2
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
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
OQAWIDVMPODGCQ-UHFFFAOYSA-N 3,3-bis(4-fluorophenyl)-3-methoxy-2-(4-methoxy-5-methylpyrimidin-2-yl)oxypropanoic acid Chemical compound C1=C(C)C(OC)=NC(OC(C(O)=O)C(OC)(C=2C=CC(F)=CC=2)C=2C=CC(F)=CC=2)=N1 OQAWIDVMPODGCQ-UHFFFAOYSA-N 0.000 description 2
125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 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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COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
206010027476 Metastases Diseases 0.000 description 2
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
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GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
102000001708 Protein Isoforms Human genes 0.000 description 2
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JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
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NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
229910000105 potassium hydride Inorganic materials 0.000 description 1
239000000843 powder Substances 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
108090000765 processed proteins & peptides Proteins 0.000 description 1
FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
210000002307 prostate Anatomy 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
238000000159 protein binding assay Methods 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
239000002287 radioligand Substances 0.000 description 1
229940044551 receptor antagonist Drugs 0.000 description 1
239000002464 receptor antagonist Substances 0.000 description 1
238000001525 receptor binding assay Methods 0.000 description 1
230000000717 retained effect Effects 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
239000007909 solid dosage form Substances 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
230000002459 sustained effect Effects 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
150000003536 tetrazoles Chemical class 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
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
230000006442 vascular tone 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)
Life Sciences & Earth Sciences (AREA)
Veterinary Medicine (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Chemical Kinetics & Catalysis (AREA)
Pharmacology & Pharmacy (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Urology & Nephrology (AREA)
Pulmonology (AREA)
Vascular Medicine (AREA)
Diabetes (AREA)
Endocrinology (AREA)
Hospice & Palliative Care (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Hydrogenated Pyridines (AREA)

SK77-2002A 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 SK772002A3 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
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
SK772002A3 true SK772002A3 (en)	2003-01-09

Family

ID=7914884

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK77-2002A SK772002A3 (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)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ES2462065T3 (es) *	2009-07-10	2014-05-22	Cadila Healthcare Limited	Proceso mejorado para la preparación de Ambrisentán e intermedios novedosos de este
CA2792473A1 (en)	2010-03-15	2011-09-22	Natco Pharma Limited	A process for the preparation of highly pure ambrisentan

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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
PL340871A1 (en) *	1997-10-31	2001-03-12	Basf Ag	Novel derivatives of carboxylic with admidic side chains, method of obtaining them and application of such novel derivatives as antagonists of endothelin rceptors

1999
- 1999-07-20 DE DE19933164A patent/DE19933164A1/de not_active Withdrawn
2000
- 2000-07-05 IL IL14766600A patent/IL147666A0/xx unknown
- 2000-07-05 JP JP2001511432A patent/JP2003505377A/ja not_active Abandoned
- 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 HU HU0202646A patent/HUP0202646A3/hu unknown
- 2000-07-05 CZ CZ2002190A patent/CZ2002190A3/cs unknown
- 2000-07-05 WO PCT/EP2000/006293 patent/WO2001005771A1/de not_active Ceased
- 2000-07-05 MX MXPA02000616A patent/MXPA02000616A/es unknown
- 2000-07-05 CA CA002379545A patent/CA2379545A1/en not_active Abandoned
- 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 CN CN00810533A patent/CN1367778A/zh active Pending
- 2000-07-05 BR BR0012592-0A patent/BR0012592A/pt not_active IP Right Cessation
- 2000-07-05 SK SK77-2002A patent/SK772002A3/sk unknown
- 2000-07-05 TR TR2002/00622T patent/TR200200622T2/xx 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
AU6561500A (en)	2001-02-05
TR200200622T2 (cs)	2002-06-21
HUP0202646A3 (en)	2003-03-28
CZ2002190A3 (cs)	2003-08-13
JP2003505377A (ja)	2003-02-12
IL147666A0 (en)	2002-08-14
HUP0202646A2 (hu)	2003-02-28
BG106321A (en)	2002-08-30
NO20020254L (no)	2002-02-20
ZA200200333B (en)	2003-04-30
CA2379545A1 (en)	2001-01-25
EP1196394A1 (de)	2002-04-17
BR0012592A (pt)	2002-05-28
DE19933164A1 (de)	2001-01-25
CN1367778A (zh)	2002-09-04
AR030026A1 (es)	2003-08-13
MXPA02000616A (es)	2002-08-30
TW555749B (en)	2003-10-01
KR20020019550A (ko)	2002-03-12
NO20020254D0 (no)	2002-01-17
PL353165A1 (en)	2003-10-20
WO2001005771A1 (de)	2001-01-25

Publication	Publication Date	Title
KR20000068446A (ko)	2000-11-25	아지닐옥시, 및 페녹시-디아릴-카르복실산 유도체, 그의 제조 방법 및 혼합된 ｅｔａ/ｅｔｂ 엔도델린 수용체 길항물질로서의 용도
NO311801B1 (no)	2002-01-28	Nye hydroksykarboksylsyre-derivater og deres anvendelse
HRP980560A2 (en)	1999-08-31	New carboxylic acid derivatives, carrying amido side-chains, their production and use as endothelin receptor antagonists
SK77799A3 (en)	2000-02-14	Heterocyclic carboxylic acid derivatives, the production and use thereof as endothelin receptor antagonists
HRP980331A2 (en)	1999-02-28	New beta-amino and beta-azido carboxylic acid derivatives, the production and the use thereof as endothelin receptor antagonists
SK11512000A3 (sk)	2001-04-09	5-substituované deriváty pyrimidín-2-yloxy karboxylových kyselín, ich príprava a ich využitie ako antagonistov endotelínu
AU9533398A (en)	1999-03-22	Novel carboxylic acid derivatives, their production and their their use as mixed ETa/ETb endothelin-receptor antagonists
SK4932000A3 (en)	2001-02-12	Heterocyclically substituted alpha-hydroxycarboxlic acid derivatives, method for producing the same and their use as endothelin receptor antagonists
AU765345B2 (en)	2003-09-18	Novel carboxylic acid derivatives comprising aryl-substituted nitrogen heterocycles, their production and their use as endothelin receptor antagonists
AU6561500A (en)	2001-02-05	Novel carboxylic acid derivatives with 5,6 substituted pyrimidine ring, the production and utilization thereof as endothelin receptor antagonists
KR20010101279A (ko)	2001-11-14	신규 β-아미드 및 β-설폰아미드 카르복실산 유도체,그의 제조 방법 및 엔도텔린 수용체 길항제로서의 그의 용도
MXPA00001479A (en)	2001-05-07	Novel carboxylic acid derivatives, their production and their use as mixed eta
JP2002505324A (ja)	2002-02-19	不斉に置換された新規のカルボン酸誘導体、その製造方法ならびに混合ｅｔａ／ｅｔｂ受容体アンタゴニストとしての使用
CA2340167A1 (en)	2000-02-24	New carboxylic acid derivatives carrying keto side-chains, their production and their use as endothelin-receptor antagonists
MXPA00006463A (en)	2001-07-03	5-substituted pyrimidine-2-yloxy carboxylic acid derivatives, the production of the same and their utilization as endothelin antagonists
MXPA99011504A (es)	2000-09-04	Novedosos derivados de acido beta-amino y beta-azido carboxilicos, su preparacion y uso como antagonistas receptores de endotelina
HRP970503A2 (en)	1999-06-30	Novel carboxylic acid derivatives, their production and their use as mixed eta/etb receptor antagonists
CZ20002963A3 (cs)	2000-11-15	Nové deriváty karboxylové kyseliny, obsahující 5- substituovaný pyrimidinový kruh, jejich příprava a použiti