DE69408750T2 - 4-Aminopyrimidin Derivate - Google Patents
4-Aminopyrimidin DerivateInfo
- Publication number
- DE69408750T2 DE69408750T2 DE69408750T DE69408750T DE69408750T2 DE 69408750 T2 DE69408750 T2 DE 69408750T2 DE 69408750 T DE69408750 T DE 69408750T DE 69408750 T DE69408750 T DE 69408750T DE 69408750 T2 DE69408750 T2 DE 69408750T2
- Authority
- DE
- Germany
- Prior art keywords
- imidazolyl
- thienyl
- methylaminopyrimidine
- formula
- dioxaindan
- 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.)
- Expired - Fee Related
Links
- 150000005007 4-aminopyrimidines Chemical class 0.000 title claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 35
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims abstract description 26
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 10
- 239000001301 oxygen Substances 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 239000005864 Sulphur Substances 0.000 claims abstract description 6
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 83
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 46
- -1 cyano, ethynyl Chemical group 0.000 claims description 41
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 claims description 13
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 206010030113 Oedema Diseases 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 7
- 206010019280 Heart failures Diseases 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 claims description 5
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 229930192474 thiophene Chemical group 0.000 claims description 5
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 4
- OJLDJKZTZBYMHB-UHFFFAOYSA-N 2-[2-[[2-imidazol-1-yl-5-[(3-methoxyphenyl)methyl]pyrimidin-4-yl]amino]ethoxy]ethanol Chemical compound COC1=CC=CC(CC=2C(=NC(=NC=2)N2C=NC=C2)NCCOCCO)=C1 OJLDJKZTZBYMHB-UHFFFAOYSA-N 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 230000004060 metabolic process Effects 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- OFTYZKGTDGDJRM-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-imidazol-1-yl-5-thiophen-2-ylpyrimidin-4-amine Chemical compound C=1C=C2OCOC2=CC=1CNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 OFTYZKGTDGDJRM-UHFFFAOYSA-N 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical group C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 3
- YUDIWFWZRACPND-UHFFFAOYSA-N 2-[2-[[2-imidazol-1-yl-5-[(4-methoxyphenyl)methyl]pyrimidin-4-yl]amino]ethoxy]ethanol Chemical compound C1=CC(OC)=CC=C1CC1=CN=C(N2C=NC=C2)N=C1NCCOCCO YUDIWFWZRACPND-UHFFFAOYSA-N 0.000 claims description 3
- QSHNAASDRSASGQ-UHFFFAOYSA-N 2-imidazol-1-yl-n-(2-methoxyethyl)-5-[(3-methoxyphenyl)methyl]pyrimidin-4-amine Chemical compound COCCNC1=NC(N2C=NC=C2)=NC=C1CC1=CC=CC(OC)=C1 QSHNAASDRSASGQ-UHFFFAOYSA-N 0.000 claims description 3
- XBSNJAGAIYNPQG-UHFFFAOYSA-N 2-imidazol-1-yl-n-(2-methoxyethyl)-5-[(4-methoxyphenyl)methyl]pyrimidin-4-amine Chemical compound COCCNC1=NC(N2C=NC=C2)=NC=C1CC1=CC=C(OC)C=C1 XBSNJAGAIYNPQG-UHFFFAOYSA-N 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010012289 Dementia Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 108010069102 Thromboxane-A synthase Proteins 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 206010006451 bronchitis Diseases 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 230000007812 deficiency Effects 0.000 claims description 3
- 230000002440 hepatic effect Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- JFHHKIKFDMEQCN-UHFFFAOYSA-N n,5-dibenzyl-2-imidazol-1-ylpyrimidin-4-amine Chemical compound C=1C=CC=CC=1CNC1=NC(N2C=NC=C2)=NC=C1CC1=CC=CC=C1 JFHHKIKFDMEQCN-UHFFFAOYSA-N 0.000 claims description 3
- DEXBJDYTILITIS-UHFFFAOYSA-N n-benzyl-2-imidazol-1-yl-5,6-dimethylpyrimidin-4-amine Chemical compound CC=1C(C)=NC(N2C=NC=C2)=NC=1NCC1=CC=CC=C1 DEXBJDYTILITIS-UHFFFAOYSA-N 0.000 claims description 3
- QNQBXNSLCLMHLL-UHFFFAOYSA-N n-benzyl-2-imidazol-1-yl-5-(imidazol-1-ylmethyl)pyrimidin-4-amine Chemical compound C=1C=CC=CC=1CNC1=NC(N2C=NC=C2)=NC=C1CN1C=CN=C1 QNQBXNSLCLMHLL-UHFFFAOYSA-N 0.000 claims description 3
- ZOQGANUYHAUGMO-UHFFFAOYSA-N n-benzyl-2-imidazol-1-yl-5-methylpyrimidin-4-amine Chemical compound CC1=CN=C(N2C=NC=C2)N=C1NCC1=CC=CC=C1 ZOQGANUYHAUGMO-UHFFFAOYSA-N 0.000 claims description 3
- BHLSDEMYHGXDEB-UHFFFAOYSA-N n-benzyl-2-imidazol-1-ylpyrimidin-4-amine Chemical compound C=1C=CC=CC=1CNC(N=1)=CC=NC=1N1C=CN=C1 BHLSDEMYHGXDEB-UHFFFAOYSA-N 0.000 claims description 3
- VMXDVIPVHZVXJP-UHFFFAOYSA-N n-benzyl-5-ethyl-2-imidazol-1-ylpyrimidin-4-amine Chemical compound CCC1=CN=C(N2C=NC=C2)N=C1NCC1=CC=CC=C1 VMXDVIPVHZVXJP-UHFFFAOYSA-N 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- BAYGASIGYNCQTC-UHFFFAOYSA-N 2-[2-[(2-imidazol-1-yl-5-thiophen-2-ylpyrimidin-4-yl)amino]ethoxy]ethanol Chemical compound OCCOCCNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 BAYGASIGYNCQTC-UHFFFAOYSA-N 0.000 claims description 2
- CZZSANABJINKSI-UHFFFAOYSA-N 2-imidazol-1-yl-5-thiophen-2-yl-n-(thiophen-2-ylmethyl)pyrimidin-4-amine Chemical compound C=1C=CSC=1CNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 CZZSANABJINKSI-UHFFFAOYSA-N 0.000 claims description 2
- AVJSDFHDBZTXAO-UHFFFAOYSA-N 2-imidazol-1-yl-n-(2-methoxyethyl)-5-thiophen-2-ylpyrimidin-4-amine Chemical compound COCCNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 AVJSDFHDBZTXAO-UHFFFAOYSA-N 0.000 claims description 2
- ORQDYKRHWSTDSR-UHFFFAOYSA-N 2-imidazol-1-yl-n-(pyridin-3-ylmethyl)-5-thiophen-2-ylpyrimidin-4-amine Chemical compound C=1C=CN=CC=1CNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 ORQDYKRHWSTDSR-UHFFFAOYSA-N 0.000 claims description 2
- YTUPTZQENLNNLS-UHFFFAOYSA-N 2-imidazol-1-yl-n-[(3-methoxyphenyl)methyl]-5-thiophen-2-ylpyrimidin-4-amine Chemical compound COC1=CC=CC(CNC=2C(=CN=C(N=2)N2C=NC=C2)C=2SC=CC=2)=C1 YTUPTZQENLNNLS-UHFFFAOYSA-N 0.000 claims description 2
- ZDSOBGLTWDBZSK-UHFFFAOYSA-N 2-imidazol-1-yl-n-[(4-methoxyphenyl)methyl]-5-thiophen-2-ylpyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 ZDSOBGLTWDBZSK-UHFFFAOYSA-N 0.000 claims description 2
- QLFGUSQOQSNXIL-UHFFFAOYSA-N 2-imidazol-1-yl-n-phenylmethoxy-5-thiophen-2-ylpyrimidin-4-amine Chemical compound C=1C=CC=CC=1CONC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 QLFGUSQOQSNXIL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- XHPNSEBZTMVRMX-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-(2-methylimidazol-1-yl)-5-thiophen-2-ylpyrimidin-4-amine Chemical compound CC1=NC=CN1C(N=C1NCC=2C=C3OCOC3=CC=2)=NC=C1C1=CC=CS1 XHPNSEBZTMVRMX-UHFFFAOYSA-N 0.000 claims description 2
- YARDYRWSUXBCDX-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-imidazol-1-yl-5-(4-methoxyphenyl)pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1C1=CN=C(N2C=NC=C2)N=C1NCC1=CC=C(OCO2)C2=C1 YARDYRWSUXBCDX-UHFFFAOYSA-N 0.000 claims description 2
- IJDXBAMPQCPICE-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-imidazol-1-yl-5-(4-methylphenyl)pyrimidin-4-amine Chemical compound C1=CC(C)=CC=C1C1=CN=C(N2C=NC=C2)N=C1NCC1=CC=C(OCO2)C2=C1 IJDXBAMPQCPICE-UHFFFAOYSA-N 0.000 claims description 2
- VGDOBWREXYTIEW-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-2-imidazol-1-yl-5-(5-methylthiophen-2-yl)pyrimidin-4-amine Chemical compound S1C(C)=CC=C1C1=CN=C(N2C=NC=C2)N=C1NCC1=CC=C(OCO2)C2=C1 VGDOBWREXYTIEW-UHFFFAOYSA-N 0.000 claims description 2
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- GDKSNCLLBYNHLG-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-5-(4-chlorophenyl)-2-imidazol-1-ylpyrimidin-4-amine Chemical compound C1=CC(Cl)=CC=C1C1=CN=C(N2C=NC=C2)N=C1NCC1=CC=C(OCO2)C2=C1 GDKSNCLLBYNHLG-UHFFFAOYSA-N 0.000 claims description 2
- JDIQSJILCXTEPZ-UHFFFAOYSA-N n-(1,3-benzodioxol-5-ylmethyl)-5-(furan-3-yl)-2-imidazol-1-ylpyrimidin-4-amine Chemical compound C=1C=C2OCOC2=CC=1CNC1=NC(N2C=NC=C2)=NC=C1C=1C=COC=1 JDIQSJILCXTEPZ-UHFFFAOYSA-N 0.000 claims description 2
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- IWFMVFNSXAFYIR-UHFFFAOYSA-N n-(furan-2-ylmethyl)-2-imidazol-1-yl-5-thiophen-2-ylpyrimidin-4-amine Chemical compound C=1C=COC=1CNC1=NC(N2C=NC=C2)=NC=C1C1=CC=CS1 IWFMVFNSXAFYIR-UHFFFAOYSA-N 0.000 claims description 2
- QLJYJLBRTBRKTK-UHFFFAOYSA-N n-[(3-chlorophenyl)methyl]-2-imidazol-1-yl-5-thiophen-2-ylpyrimidin-4-amine Chemical compound ClC1=CC=CC(CNC=2C(=CN=C(N=2)N2C=NC=C2)C=2SC=CC=2)=C1 QLJYJLBRTBRKTK-UHFFFAOYSA-N 0.000 claims description 2
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- OYPHRJNZVAUEEV-UHFFFAOYSA-N n-benzyl-2-imidazol-1-yl-5-[(4-methoxyphenyl)methyl]pyrimidin-4-amine Chemical compound C1=CC(OC)=CC=C1CC1=CN=C(N2C=NC=C2)N=C1NCC1=CC=CC=C1 OYPHRJNZVAUEEV-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- SGUKUZOVHSFKPH-YNNPMVKQSA-N prostaglandin G2 Chemical compound C1[C@@H]2OO[C@H]1[C@H](/C=C/[C@@H](OO)CCCCC)[C@H]2C\C=C/CCCC(O)=O SGUKUZOVHSFKPH-YNNPMVKQSA-N 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11190693A | 1993-08-26 | 1993-08-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69408750D1 DE69408750D1 (de) | 1998-04-09 |
| DE69408750T2 true DE69408750T2 (de) | 1998-07-23 |
Family
ID=22341063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69408750T Expired - Fee Related DE69408750T2 (de) | 1993-08-26 | 1994-08-12 | 4-Aminopyrimidin Derivate |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5525604A (show.php) |
| EP (1) | EP0640599B1 (show.php) |
| JP (1) | JPH0789958A (show.php) |
| KR (1) | KR100204433B1 (show.php) |
| CN (1) | CN1109055A (show.php) |
| AT (1) | ATE163647T1 (show.php) |
| CA (1) | CA2130878C (show.php) |
| DE (1) | DE69408750T2 (show.php) |
| DK (1) | DK0640599T3 (show.php) |
| ES (1) | ES2114662T3 (show.php) |
| TW (1) | TW273548B (show.php) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12384772B2 (en) | 2017-03-31 | 2025-08-12 | Vivoryon Therapeutics N.V. | Inhibitors |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9325217D0 (en) * | 1993-12-09 | 1994-02-09 | Zeneca Ltd | Pyrimidine derivatives |
| EP1005343A4 (en) | 1996-03-08 | 2000-06-07 | Smithkline Beecham Corp | USE OF CSAIDS AS ANGIOGENESIS INHIBITORS |
| DE19644228A1 (de) * | 1996-10-24 | 1998-04-30 | Merck Patent Gmbh | Thienopyrimidine |
| KR100239800B1 (ko) * | 1996-11-28 | 2000-03-02 | 손경식 | 4,5-디아미노 피리미딘 유도체 및 이의 제조방법 |
| US6432947B1 (en) | 1997-02-19 | 2002-08-13 | Berlex Laboratories, Inc. | N-heterocyclic derivatives as NOS inhibitors |
| CN1100777C (zh) * | 1997-02-19 | 2003-02-05 | 伯莱克斯实验室公司 | 作为nos抑制剂的n－杂环衍生物 |
| IN188411B (show.php) | 1997-03-27 | 2002-09-21 | Yuhan Corp | |
| US6440965B1 (en) | 1997-10-15 | 2002-08-27 | Krenitsky Pharmaceuticals, Inc. | Substituted pyrimidine derivatives, their preparation and their use in the treatment of neurodegenerative or neurological disorders of the central nervous system |
| ATE245641T1 (de) | 1998-02-17 | 2003-08-15 | Tularik Inc | Antivirale pyrimidinderivate |
| DE19819023A1 (de) | 1998-04-29 | 1999-11-04 | Merck Patent Gmbh | Thienopyrimidine |
| KR100272471B1 (ko) | 1998-11-17 | 2000-11-15 | 김선진 | 신규의 피리미딘 유도체 및 그의 제조방법 |
| JP4709388B2 (ja) * | 1999-01-25 | 2011-06-22 | 全薬工業株式会社 | 複素環式化合物及びそれを有効成分とする抗腫瘍剤 |
| US6583148B1 (en) | 1999-04-08 | 2003-06-24 | Krenitsky Pharmaceuticals, Inc. | Neurotrophic substituted pyrimidines |
| KR100546992B1 (ko) * | 1999-04-09 | 2006-02-01 | 씨제이 주식회사 | 4,5-다이아미노 피리미딘 유도체 및 이의 제조방법 |
| US7037916B2 (en) | 1999-07-15 | 2006-05-02 | Pharmacopeia Drug Discovery, Inc. | Pyrimidine derivatives as IL-8 receptor antagonists |
| CA2383466C (en) * | 1999-09-16 | 2009-08-25 | Tanabe Seiyaku Co., Ltd. | Aromatic nitrogen-containing 6-membered cyclic compounds |
| ATE314362T1 (de) * | 1999-10-12 | 2006-01-15 | Takeda Pharmaceutical | Pyrimidin-5-carboximidverbindungen, verfahren zur herstellung derselben und deren verwendung |
| JP2003519153A (ja) | 1999-12-24 | 2003-06-17 | バイエル アクチェンゲゼルシャフト | イソオキサゾロピリミジノン類及びその使用 |
| US6943161B2 (en) * | 1999-12-28 | 2005-09-13 | Pharmacopela Drug Discovery, Inc. | Pyrimidine and triazine kinase inhibitors |
| US6410726B1 (en) | 2000-01-12 | 2002-06-25 | Tularik Inc. | Arylsulfonic acid salts of pyrimidine-based antiviral |
| US6525051B2 (en) | 2000-03-27 | 2003-02-25 | Schering Aktiengesellschaft | N-heterocyclic derivatives as NOS inhibitors |
| JP5154728B2 (ja) | 2000-07-24 | 2013-02-27 | クレニツキー・ファーマシューティカルズ，インコーポレイテッド | 神経栄養活性を有する置換５−アルキニルピリミジン |
| IT1318674B1 (it) * | 2000-08-08 | 2003-08-27 | Nicox Sa | Faramaci per l'incontinenza. |
| EP1351691A4 (en) * | 2000-12-12 | 2005-06-22 | Cytovia Inc | SUBSTITUTED 2-ARYL-4-ARYLAMINOPYRIMIDINES AND ANALOGUES AS ACTIVATORS OF CASPASES AND APOPTOSIS INDUCERS, AND USE THEREOF |
| US6716851B2 (en) | 2000-12-12 | 2004-04-06 | Cytovia, Inc. | Substituted 2-aryl-4-arylaminopyrimidines and analogs as activators or caspases and inducers of apoptosis and the use thereof |
| US7081470B2 (en) | 2001-01-31 | 2006-07-25 | H. Lundbeck A/S | Use of GALR3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods |
| US20040127502A1 (en) | 2001-01-31 | 2004-07-01 | Synaptic Pharmaceutical Corporation | Use of GAL3 antagonist for treatment of depression |
| EP1364950A4 (en) * | 2001-02-26 | 2005-03-09 | Tanabe Seiyaku Co | Pyridopyrimidine and naphthyridine derivatives |
| KR100833371B1 (ko) | 2001-04-27 | 2008-05-28 | 젠야쿠코교가부시키가이샤 | 헤테로시클릭 화합물 및 이를 유효 성분으로 하는 항종양제 |
| US6982259B2 (en) | 2002-04-30 | 2006-01-03 | Schering Aktiengesellschaft | N-heterocyclic derivatives as NOS inhibitors |
| JP2006502107A (ja) | 2002-07-02 | 2006-01-19 | エフ．ホフマン−ラ ロシュ アーゲー | Ｃｃｒ−３レセプターアンタゴニストｉｘとしての２，５−置換ピリミジン誘導体 |
| US7482350B2 (en) | 2004-05-08 | 2009-01-27 | Neurogen Corporation | 4,5-disubstituted-2-aryl pyrimidines |
| MX2007005857A (es) | 2004-11-17 | 2007-10-10 | Mikana Therapeutics Inc | Inhibidores de cinasa. |
| SI1864665T1 (sl) | 2005-03-11 | 2012-09-28 | Zenyaku Kogyo Kk | Imunosupresivno sredstvo, ki obsega heterociklično spojino kot učinkovino |
| WO2006123639A1 (ja) * | 2005-05-18 | 2006-11-23 | Asahi Kasei Pharma Corporation | ピリミジン誘導体 |
| US20060293343A1 (en) * | 2005-05-18 | 2006-12-28 | Asahi Kasei Pharma Corporation | Pyrimidine derivatives |
| BRPI0616630B8 (pt) * | 2005-09-30 | 2021-05-25 | Miikana Therapeutics Inc | compostos de pirazol substituídos |
| GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
| JP2010529193A (ja) * | 2007-06-11 | 2010-08-26 | ミイカナ セラピューティクス インコーポレイテッド | 置換ピラゾール化合物 |
| WO2009064388A2 (en) * | 2007-11-09 | 2009-05-22 | Liu Jun O | Inhibitors of human methionine aminopeptidase 1 and methods of treating disorders |
| KR101324329B1 (ko) * | 2008-09-04 | 2013-10-31 | 미쓰비시 타나베 파마 코퍼레이션 | 삼치환된 피리미딘 화합물 및 ｐｄｅ10 억제제로서의 그의 용도 |
| JP5951600B2 (ja) | 2010-05-21 | 2016-07-13 | インフィニティー ファーマシューティカルズ， インコーポレイテッド | キナーゼ調節のための、化合物、組成物および方法 |
| ES2698847T3 (es) * | 2011-07-07 | 2019-02-06 | Merck Patent Gmbh | Azaheterociclos sustituidos para el tratamiento del cáncer |
| PE20141371A1 (es) | 2011-08-29 | 2014-10-13 | Infinity Pharmaceuticals Inc | Compuestos heterociclicos y usos de los mismos |
| US9481667B2 (en) | 2013-03-15 | 2016-11-01 | Infinity Pharmaceuticals, Inc. | Salts and solid forms of isoquinolinones and composition comprising and methods of using the same |
| US9868722B2 (en) | 2013-12-10 | 2018-01-16 | Cleave Biosciences, Inc. | Monocyclic pyrimidine/pyridine compounds as inhibitors of P97 complex |
| PL3089971T3 (pl) | 2014-01-01 | 2021-01-25 | Medivation Technologies Llc | Związki i sposoby ich zastosowania |
| US9828363B2 (en) | 2014-01-20 | 2017-11-28 | Cleave Biosciences, Inc. | Fused pyrimidines as inhibitors of P97 complex |
| CN105294661B (zh) * | 2015-07-27 | 2017-10-24 | 西南大学 | 5‑氟尿嘧啶苯并咪唑类化合物及其制备方法和应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US3992320A (en) * | 1974-08-24 | 1976-11-16 | Basf Aktiengesellschaft | Manufacture of a modified titanium component for catalysts of the Ziegler-Natta type |
| US4018770A (en) * | 1975-03-03 | 1977-04-19 | Sterling Drug Inc. | N-(2-(pyridinyl)-4-pyrimidinyl)-aminomethylenemalonates and analogs |
| US3992380A (en) * | 1975-03-03 | 1976-11-16 | Sterling Drug Inc. | 5,8-Dihydro-5-oxo-2-(4-or 3-pyridinyl)pyrido[2,3-d]pyrimidine-6-carboxylic acids and esters |
| US4032523A (en) * | 1975-03-03 | 1977-06-28 | Sterling Drug Inc. | 4-amino (or halo or hydroxy or hydrazino)-2-(pyridinyl)pyrimidines |
| DE3922735A1 (de) * | 1989-07-11 | 1991-01-24 | Hoechst Ag | Aminopyrimidin-derivate, verfahren zu ihrer herstellung, sie enthaltende mittel und ihre verwendung als fungizide |
| WO1994007867A1 (en) * | 1992-09-28 | 1994-04-14 | Pfizer Inc. | Substituted pyrimidines for control of diabetic complications |
| US5318975A (en) * | 1993-02-16 | 1994-06-07 | Berlex Laboratories, Inc. | 5-pyrimdineamine derivatives |
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1994
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- 1994-08-12 DE DE69408750T patent/DE69408750T2/de not_active Expired - Fee Related
- 1994-08-12 DK DK94305973T patent/DK0640599T3/da active
- 1994-08-12 AT AT94305973T patent/ATE163647T1/de not_active IP Right Cessation
- 1994-08-12 ES ES94305973T patent/ES2114662T3/es not_active Expired - Lifetime
- 1994-08-24 US US08/295,377 patent/US5525604A/en not_active Expired - Fee Related
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- 1994-08-25 CA CA002130878A patent/CA2130878C/en not_active Expired - Fee Related
- 1994-08-25 KR KR1019940021017A patent/KR100204433B1/ko not_active Expired - Fee Related
- 1994-08-25 CN CN94109363A patent/CN1109055A/zh active Pending
- 1994-08-29 TW TW083107897A patent/TW273548B/zh active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US12384772B2 (en) | 2017-03-31 | 2025-08-12 | Vivoryon Therapeutics N.V. | Inhibitors |
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|---|---|
| TW273548B (show.php) | 1996-04-01 |
| JPH0789958A (ja) | 1995-04-04 |
| KR100204433B1 (ko) | 1999-06-15 |
| ES2114662T3 (es) | 1998-06-01 |
| ATE163647T1 (de) | 1998-03-15 |
| DE69408750D1 (de) | 1998-04-09 |
| CA2130878C (en) | 1999-03-23 |
| EP0640599A1 (en) | 1995-03-01 |
| US5525604A (en) | 1996-06-11 |
| CN1109055A (zh) | 1995-09-27 |
| DK0640599T3 (da) | 1998-09-28 |
| CA2130878A1 (en) | 1995-02-27 |
| EP0640599B1 (en) | 1998-03-04 |
| KR950005825A (ko) | 1995-03-20 |
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