CA2501534A1 - Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity - Google Patents
Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity Download PDFInfo
- Publication number
- CA2501534A1 CA2501534A1 CA002501534A CA2501534A CA2501534A1 CA 2501534 A1 CA2501534 A1 CA 2501534A1 CA 002501534 A CA002501534 A CA 002501534A CA 2501534 A CA2501534 A CA 2501534A CA 2501534 A1 CA2501534 A1 CA 2501534A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- alkenyl
- alkynyl
- methyl
- optionally substituted
- 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
- 102000004016 L-Type Calcium Channels Human genes 0.000 title abstract description 15
- 108090000420 L-Type Calcium Channels Proteins 0.000 title abstract description 15
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title description 15
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title description 15
- 230000000694 effects Effects 0.000 title description 12
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 238000000034 method Methods 0.000 claims abstract description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 23
- 208000035475 disorder Diseases 0.000 claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 8
- 208000006011 Stroke Diseases 0.000 claims abstract description 8
- 206010015037 epilepsy Diseases 0.000 claims abstract description 8
- 206010027599 migraine Diseases 0.000 claims abstract description 8
- -1 carbonyl oxygen Chemical compound 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- 125000003342 alkenyl group Chemical group 0.000 claims description 58
- 125000000304 alkynyl group Chemical group 0.000 claims description 56
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 45
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 239000001301 oxygen Substances 0.000 claims description 30
- 206010019280 Heart failures Diseases 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 27
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 25
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 24
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 17
- 125000004450 alkenylene group Chemical group 0.000 claims description 15
- 125000002947 alkylene group Chemical group 0.000 claims description 15
- 125000004419 alkynylene group Chemical group 0.000 claims description 15
- 230000004094 calcium homeostasis Effects 0.000 claims description 14
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 10
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 9
- KOHMLUDLOFJRBM-UHFFFAOYSA-N 3-o-ethyl 5-o-methyl 2-[2-[[2-[2-chloro-4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]acetyl]amino]ethoxymethyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound N1C(C)=C(C(=O)OC)C(C=2C(=CC=CC=2)Cl)C(C(=O)OCC)=C1COCCNC(=O)COC(C(=C1)Cl)=CC=C1C1=NNC(=O)CC1 KOHMLUDLOFJRBM-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 206010003119 arrhythmia Diseases 0.000 claims description 8
- 230000006793 arrhythmia Effects 0.000 claims description 8
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 7
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 5
- 210000001992 atrioventricular node Anatomy 0.000 claims description 5
- 206010020871 hypertrophic cardiomyopathy Diseases 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 16
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical group O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 1
- OVWHHXGHCGYQOL-UHFFFAOYSA-N methyl 4-(2-chlorophenyl)-2,6-dimethyl-5-[2-[[2-[4-(6-oxo-4,5-dihydro-1h-pyridazin-3-yl)phenoxy]acetyl]amino]ethylcarbamoyl]-1,4-dihydropyridine-3-carboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)NCCNC(=O)COC=2C=CC(=CC=2)C=2CCC(=O)NN=2)C1C1=CC=CC=C1Cl OVWHHXGHCGYQOL-UHFFFAOYSA-N 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 101100135867 Caenorhabditis elegans pde-3 gene Proteins 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- 239000000243 solution Substances 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- 239000007787 solid Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 101150041968 CDC13 gene Proteins 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000011575 calcium Substances 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 13
- 229910052791 calcium Inorganic materials 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
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- 150000003839 salts Chemical class 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 201000010099 disease Diseases 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- VJDNUQLZSIVKGX-UHFFFAOYSA-N 2-[4-(5-cyano-2-methyl-6-oxo-1h-pyridin-3-yl)phenoxy]acetic acid Chemical compound N1C(=O)C(C#N)=CC(C=2C=CC(OCC(O)=O)=CC=2)=C1C VJDNUQLZSIVKGX-UHFFFAOYSA-N 0.000 description 8
- KEGMAEFVJNPESF-UHFFFAOYSA-N 4-(dimethylamino)-3-(4-methoxyphenyl)but-3-en-2-one Chemical compound COC1=CC=C(C(=CN(C)C)C(C)=O)C=C1 KEGMAEFVJNPESF-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 229940125898 compound 5 Drugs 0.000 description 8
- 230000008602 contraction Effects 0.000 description 8
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 8
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- XUXGMIWDGMXMNT-UHFFFAOYSA-N 5-(4-hydroxyphenyl)-6-methyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound N1C(=O)C(C#N)=CC(C=2C=CC(O)=CC=2)=C1C XUXGMIWDGMXMNT-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 239000002585 base Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- NIANUYPKTNSJDV-UHFFFAOYSA-N ethyl 2-[4-(5-cyano-2-methyl-6-oxo-1h-pyridin-3-yl)phenoxy]acetate Chemical compound C1=CC(OCC(=O)OCC)=CC=C1C1=C(C)NC(=O)C(C#N)=C1 NIANUYPKTNSJDV-UHFFFAOYSA-N 0.000 description 6
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
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- 239000000651 prodrug Substances 0.000 description 5
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- 125000001424 substituent group Chemical group 0.000 description 5
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 4
- RHIYBCQHCZZWDU-UHFFFAOYSA-N 5-(4-methoxyphenyl)-6-methyl-2-oxo-1h-pyridine-3-carbonitrile Chemical compound C1=CC(OC)=CC=C1C1=C(C)NC(=O)C(C#N)=C1 RHIYBCQHCZZWDU-UHFFFAOYSA-N 0.000 description 4
- 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 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41625402P | 2002-10-07 | 2002-10-07 | |
| US60/416,254 | 2002-10-07 | ||
| PCT/US2003/031592 WO2004033444A1 (en) | 2002-10-07 | 2003-10-07 | Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2501534A1 true CA2501534A1 (en) | 2004-04-22 |
Family
ID=32093831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002501534A Abandoned CA2501534A1 (en) | 2002-10-07 | 2003-10-07 | Dihydropyridine compounds having simultaneous ability to block l-type calcium channels and to inhibit phosphodiesterase type 3 activity |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US7098211B2 (https=) |
| EP (1) | EP1554267A1 (https=) |
| JP (1) | JP2006504738A (https=) |
| KR (1) | KR20050070036A (https=) |
| CN (1) | CN1720243A (https=) |
| AU (1) | AU2003275450A1 (https=) |
| BR (1) | BR0315103A (https=) |
| CA (1) | CA2501534A1 (https=) |
| MX (1) | MXPA05003640A (https=) |
| NO (1) | NO20052169L (https=) |
| PL (1) | PL376405A1 (https=) |
| RU (1) | RU2005110062A (https=) |
| WO (1) | WO2004033444A1 (https=) |
| ZA (1) | ZA200502711B (https=) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7094806B2 (en) * | 2000-07-07 | 2006-08-22 | Trustees Of Tufts College | 7, 8 and 9-substituted tetracycline compounds |
| WO2005016885A2 (en) * | 2003-08-14 | 2005-02-24 | Artesian Therapeutics, Inc. | COMPOUNDS WITH COMBINED CALCIUM CHANNEL BLOCKER AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITIES FOR TREATMENT OF HEART DISEASE |
| WO2005035505A2 (en) * | 2003-09-30 | 2005-04-21 | Artesian Therapeutics, Inc. | Compounds with phosphodiesterase inhibiting and calcium channel blocking activities |
| DE102004011512B4 (de) | 2004-03-08 | 2022-01-13 | Boehringer Ingelheim Vetmedica Gmbh | Pharmazeutische Zubereitung enthaltend Pimobendan |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US20090298872A1 (en) * | 2004-12-13 | 2009-12-03 | Irm Llc | Compounds and compositions as modulators of steroidal receptors and calcium channel activities |
| NL1028564C2 (nl) * | 2005-03-17 | 2006-09-20 | Rademaker Holding B V | Toepassing van een coumarine-groep omvattende derivaten voor de bereiding van een antiviraal middel, coumarine-group omvattende derivaten, een werkwijze voor de bereiding daarvan, en farmaceutische preparaten die deze bevatten. |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| CN101215258A (zh) * | 2008-01-21 | 2008-07-09 | 中国药科大学 | 二氢吡啶类钙拮抗剂化合物及其制备方法与医药用途 |
| US8551989B2 (en) | 2008-06-09 | 2013-10-08 | Bayer Intellectual Property Gmbh | Substituted 4-(indazolyl)-1,4-dihydropyridines and methods of use thereof |
| CN102223882B (zh) * | 2008-11-25 | 2016-02-03 | 贝林格尔.英格海姆维特梅迪卡有限公司 | 用于治疗肥厚型心肌病的III 型磷酸二酯酶(PPE III)抑制剂或Ca2+敏化剂 |
| EP2509596B1 (en) | 2009-12-08 | 2019-08-28 | Case Western Reserve University | Gamma aminoacids for treating ocular disorders |
| GB201017783D0 (en) | 2010-10-21 | 2010-12-01 | Shire Llc | Process for the preparation of anagrelide and analogues thereof |
| EP3167876B1 (en) | 2012-03-15 | 2021-09-08 | Boehringer Ingelheim Vetmedica GmbH | Pharmaceutical tablet formulation for the veterinary medical sector, method of production and use thereof |
| EP3021832B9 (en) | 2013-07-19 | 2023-03-15 | Boehringer Ingelheim Vetmedica GmbH | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| CA2930033C (en) | 2013-12-04 | 2022-12-13 | Boehringer Ingelheim Vetmedica Gmbh | Improved pharmaceutical compositions of pimobendan |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
| BR112020018094A2 (pt) | 2018-03-08 | 2020-12-22 | Incyte Corporation | Compostos de aminopirazina diol como inibidores de pi3k-¿ |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| CN115838351B (zh) * | 2022-12-06 | 2025-01-28 | 昆明理工大学 | 4-烷基-1,4-二氢吡啶化合物及其制备方法和应用 |
| CN116693454A (zh) * | 2023-06-06 | 2023-09-05 | 中山大学 | 一种取代氰基喹啉酮类化合物及其制备方法与应用 |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57200386A (en) | 1981-06-04 | 1982-12-08 | Yoshitomi Pharmaceut Ind Ltd | Novel 1,4-dihydropyridine-3,5-dicarboxylic ester derivative and its salts |
| CH655110A5 (de) * | 1982-09-03 | 1986-03-27 | Otsuka Pharma Co Ltd | Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten. |
| PL140069B1 (en) | 1982-12-21 | 1987-03-31 | Pfizer | Method of obtaining new derivatives of dihydropiridine |
| GB8306666D0 (en) * | 1983-03-10 | 1983-04-13 | Pfizer Ltd | Therapeutic agents |
| US4568677A (en) | 1983-07-23 | 1986-02-04 | Pfizer Inc. | 2-(4-Pyrimidone alkoxyalkyl) dihydropyridine anti-ischaemic and antihypertensive agents |
| DE3445852A1 (de) * | 1984-12-15 | 1986-06-19 | Bayer Ag, 5090 Leverkusen | Dihydropyridin-carbonsaeureamide, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| GB8501395D0 (en) * | 1985-01-19 | 1985-02-20 | Pfizer Ltd | Dihydropyridine anti-ischaemic & anti-hypertensive agents |
| US4820842A (en) | 1986-11-19 | 1989-04-11 | Warner-Lambert Company | 2-substituted-1,4-dihydropyridines |
| US4723014A (en) | 1986-11-19 | 1988-02-02 | Warner-Lambert Company | Process for the preparation of 2-substituted-1,4-dihydropyridines |
| DE3712371A1 (de) * | 1987-04-11 | 1988-10-27 | Bayer Ag | Substituierte 1,4-dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung |
| DE3712369A1 (de) * | 1987-04-11 | 1988-10-27 | Bayer Ag | Substituierte 5-nitro-1,4-dihydropyridine, verfahren zur herstellung und ihre verwendung |
| DE3716652A1 (de) * | 1987-05-19 | 1988-12-08 | Bayer Ag | Dioxyalkylenaryl-dihydropyridine, zwischenprodukte zu ihrer herstellung, verfahren zu ihrer herstellung und ihre verwendung |
| DE3724909A1 (de) * | 1987-07-28 | 1989-02-09 | Bayer Ag | Neue substituierte nitro-dihydropyridine, verfahren zu ihrer herstellung und ihre verwendung |
| US5096904A (en) | 1989-09-01 | 1992-03-17 | Glaxo Inc. | Pyridazinones having cardiotonic and beta blocking activities |
| WO1992006087A1 (en) * | 1990-10-02 | 1992-04-16 | Kaken Pharmaceutical Co., Ltd. | Pyridazinone-substituted ethynylphenyl derivative and remedy for circulatory organ disease containing the same as active ingredient |
| US5258519A (en) | 1990-11-13 | 1993-11-02 | Glaxo Inc. | Dihydropyridine vasodilators agents |
| US5100892A (en) * | 1990-11-13 | 1992-03-31 | Glaxo Inc. | Dihydropyridine vasodilator agents |
| US20030232860A1 (en) | 2000-07-18 | 2003-12-18 | Hironori Harada | Medicine comprising dicyanopyridine derivative |
| DE10110747A1 (de) | 2001-03-07 | 2002-09-12 | Bayer Ag | Substituierte 2,6-Diamino-3,5-dicyano-4-aryl-pyridine und ihre Verwendung |
-
2003
- 2003-10-07 BR BR0315103-4A patent/BR0315103A/pt not_active IP Right Cessation
- 2003-10-07 RU RU2005110062/04A patent/RU2005110062A/ru not_active Application Discontinuation
- 2003-10-07 MX MXPA05003640A patent/MXPA05003640A/es unknown
- 2003-10-07 CA CA002501534A patent/CA2501534A1/en not_active Abandoned
- 2003-10-07 WO PCT/US2003/031592 patent/WO2004033444A1/en not_active Ceased
- 2003-10-07 JP JP2004543386A patent/JP2006504738A/ja active Pending
- 2003-10-07 AU AU2003275450A patent/AU2003275450A1/en not_active Abandoned
- 2003-10-07 KR KR1020057005919A patent/KR20050070036A/ko not_active Withdrawn
- 2003-10-07 PL PL03376405A patent/PL376405A1/xx not_active Application Discontinuation
- 2003-10-07 CN CNA2003801052200A patent/CN1720243A/zh active Pending
- 2003-10-07 EP EP03759728A patent/EP1554267A1/en not_active Withdrawn
- 2003-10-07 US US10/679,303 patent/US7098211B2/en not_active Expired - Fee Related
-
2005
- 2005-04-04 ZA ZA200502711A patent/ZA200502711B/en unknown
- 2005-05-03 NO NO20052169A patent/NO20052169L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200502711B (en) | 2006-07-26 |
| RU2005110062A (ru) | 2006-01-10 |
| AU2003275450A1 (en) | 2004-05-04 |
| US20040242648A1 (en) | 2004-12-02 |
| CN1720243A (zh) | 2006-01-11 |
| JP2006504738A (ja) | 2006-02-09 |
| MXPA05003640A (es) | 2005-11-17 |
| BR0315103A (pt) | 2005-08-16 |
| NO20052169L (no) | 2005-06-08 |
| PL376405A1 (en) | 2005-12-27 |
| WO2004033444A1 (en) | 2004-04-22 |
| US7098211B2 (en) | 2006-08-29 |
| KR20050070036A (ko) | 2005-07-05 |
| EP1554267A1 (en) | 2005-07-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |