CH640852A5 - 1,4-Dihydropyridine derivatives, their preparation and use - Google Patents
1,4-Dihydropyridine derivatives, their preparation and use Download PDFInfo
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- CH640852A5 CH640852A5 CH1288878A CH1288878A CH640852A5 CH 640852 A5 CH640852 A5 CH 640852A5 CH 1288878 A CH1288878 A CH 1288878A CH 1288878 A CH1288878 A CH 1288878A CH 640852 A5 CH640852 A5 CH 640852A5
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- 238000002360 preparation method Methods 0.000 title claims description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title abstract 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 92
- 150000001875 compounds Chemical class 0.000 claims description 71
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 239000001301 oxygen Substances 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- -1 nitro, hydroxy, azido, amino Chemical group 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000005422 alkyl sulfonamido group Chemical group 0.000 claims description 4
- 125000005518 carboxamido group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 11
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 claims 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 206010052895 Coronary artery insufficiency Diseases 0.000 abstract description 2
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 150000002431 hydrogen Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DELJOESCKJGFML-DUXPYHPUSA-N (e)-3-aminobut-2-enenitrile Chemical compound C\C(N)=C/C#N DELJOESCKJGFML-DUXPYHPUSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YBBRQAXNTWMMFZ-UHFFFAOYSA-N 2,1,3-benzoxadiazole-4-carbaldehyde Chemical compound O=CC1=CC=CC2=NON=C12 YBBRQAXNTWMMFZ-UHFFFAOYSA-N 0.000 description 1
- ZYXNLVMBIHVDRH-UHFFFAOYSA-N 2-Methylpropyl 3-oxobutanoate Chemical compound CC(C)COC(=O)CC(C)=O ZYXNLVMBIHVDRH-UHFFFAOYSA-N 0.000 description 1
- 101100097467 Arabidopsis thaliana SYD gene Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 101100495925 Schizosaccharomyces pombe (strain 972 / ATCC 24843) chr3 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The 1,4-dihydropyridine derivatives of the formula I, <IMAGE> in which R1 to R6 and X have the meanings in accordance with claim 1, can be used for treating coronary-artery insufficiency, in particular for treating angina pectoris and hypertension.
Description
**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.
d) Verbindungen der Formel
EMI2.1
worin R2 bis R6 und X obige Bedeutung besitzen, und Z und Z' unabhängig voneinander für Sauerstoff oder NRI stehen, einer Cyclisierungsreaktion unterwirft, wobei, falls Z und Z' jeweils Sauerstoff bedeuten, die Reaktion in Gegenwart einer Verbindung der Formel IV durchgeführt wird.
3. Heilmittel, gekennzeichnet durch einen Gehalt an Verbindungen der Formel I.
Die Erfindung betrifft organische Verbindungen der Formel I,
EMI2.2
worin Ri für Wasserstoff, Alkyl mit 1-6 Kohlenstoffatomen, Hydroxylalkyl mit 2-6 Kohlenstoffatomen, Alkoxyalkyl mit 3-6 Kohlenstoffatomen, Alkenyl oder Alkinyl mit jeweils 3-6 Kohlenstoffatomen, Cycloalkyl mit 3-7 Kohlenstoffatomen, Cycloalkyl alkyl mit 4-8 Kohlenstoffatomen, Phenylalkyl mit 7-9 Kohlenstoffatomen oder Phenylalkenyl mit 9-12 Kohlenstoffatomen, wobei der Phenylring unsubstituiert oder durch ein, zwei oder drei Substituenten, die unabhängig voneinander Halogen, Hydroxy, Alkyl oder Alkoxy mitjeweils 1-4 Kohlenstoffatomen bedeuten, substituiert ist, steht, R2 und Rs unabhängig voneinander Wasserstoff,
Alkyl mit 1-6 Kohlenstoffatomen oder Phenylalkyl mit 7-10 Kohlenstoffatomen bedeuten, R3 und R4 unabhängig voneinander für CN, CORD, COLORS, S(O)nR, worin n 0, 1 oder 2 bedeutet und R7 für Alkyl mit 1-6 Kohlenstoffatomen, Alkenyl oder Alkinyl mit jeweils 3-6 Kohlenstoffatomen, Cycloalkyl mit 3-7 Kohlenstoffatomen, Cycloalkylalkyl mit 4-8 Kohlenstoffatomen, Hydroxyalkyl mit 2-6 Kohlenstoffatomen, Alkoxyalkyl mit 3-6 Kohlenstoffatomen, Hydroxyalkoxyalkyl mit 4-8 Kohlenstoffatomen, Aminoalkyl mit 2-6 Kohlenstoffatomen, Alkyl (Clv)aminoalkyl(C2-6), Phenyl, Phenylalkyl mit 7-10 Kohlenstoffatomen, einen 5- oder 6gliedrigen Heterocyclus, der als Heteroatom ein Stickstoff-, Sauerstoff- oder Schwefelatom enthält, oder für Heteroarylalkyl steht,
worin der Heteroarylteil einen 5- oder 6gliedrigen Heterocyclus, der als Heteroatom ein Stickstoff-, Sauerstoff- oder Schwefelatom enthält, bedeutet und der Alkylteil 1-4 Kohlenstoffatome enthält, stehen, R6 Wasserstoff, Halogen, Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl mit jeweils 1-4 Kohlenstoffatomen, Trifluormethyl, Nitro, Hydroxy, Azido, Amino, Alkylamino mit 1-4 Kohlenstoffatomen, Acylamino mit 1-5 Kohlenstoffatomen, Carbalkoxy mit 1-4 Kohlenstoffatomen, Carboxamido, Trifluormethoxy, Cyano, Sulfonamido, Alkylsulfonamido oder Dialkylsulfonamido, wobei die Alkylgruppen 1-4 Kohlenstoffatome besitzen, bedeutet, und X für Sauerstoff oder Schwefel steht, mit der Massgabe, dass, falls Rl für Wasserstoff, Alkyl, Alkenyl, Alkinyf, Cycloalkyl, Cycloalkylalkyl, Phenylalkyl oder Phenylalkenyl steht,
wobei der Phenylring unsubstituiert oder durch ein, zwei oder drei Substituenten, die unabhängig voneinander Halogen, Hydroxy, Alkyl oder Alkoxy bedeuten, substituiert ist, R2 und Rs unabhängig voneinander Wasserstoff oder Alkyl, R6 Wasserstoff, Halogen, Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl, Trifluormethyl, Nitro oder Hydroxy, und X Sauerstoff oder Schwefel bedeuten, dann besitzt mindestens einer der Substituenten R3 und R4 eine andere Bedeutung als COR7i, worin R71 für Alkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkylalkyl steht, oder eine andere Bedeutung als COLOR7", worin R7tl für Alkyl, Hydroxyalkyl, Alkoxyalkyl, Hydroxyalkoxyalkyl, Alkenyl, Alkinyl, Cycloalkyl, Cycloalkylalkyl steht.
Jede der oben erwähnten 1-6 Kohlenstoffatome enthaltenden Alkylgruppen besitzt vorzugsweise 1-4 Kohlenstoffatome, insbesondere 1 oder 2 Kohlenstoffatome. Jedes 1-4 Kohlenstoffatome enthaltendes Alkyl, Alkoxy, Alkylthio oder Alkylsulfonyl besitzt vorzugsweise 1 oder 2 Kohlenstoffatome. Der Alkylteil von Cycloalkylalkyl steht zweckmässigerweise für Methyl. Halogen bedeutet Fluor, Chlor oder Brom und steht insbesondere für Chlor. Cycloalkyl oder der Cycloalkylteil von Cycloalkylalkyl bedeutet zweckmässigerweise Cyclopropyl oder Cyclopentyl oder Cyclohexyl. Die Mehrfachbindung von Alkenyl, Alkinyl oder Phenylalkenyl befindet sich vorzugsweise nicht in der a,-Stellung. Alkenyl oder Alkinyl besitzt vorzugsweise 3-5 Kohlenstoffatome.
Phenylalkenyl hat vorzugsweise die trans-Konfiguration und bedeutet z.B. Cinnamyl. Falls Rl ein gegebenenfalls substituiertes Phenylalkyl bedeutet, so ist der Phenylring vorzugsweise unsubstituiert. Falls der Phenylring 2- oder 3fach substituiert ist, so sind die Substituenten vorzugsweise gleich.
Falls R7 für Alkoxyalkyl oder Hydroxylalkoxyalkyl steht, so enthält der Alkylteil vorzugsweise 2 Kohlenstoffatome. R steht vorzugsweise für Wasserstoff. R2 hat zweckmässigerweise die gleiche Bedeutung wie Rs. R2 und/oder Rs stehen vorzugsweise für Methyl. R6 steht zweckmässigerweise für Halogen, Alkyl oder Alkoxy oder insbesondere für Wasserstoff. Der Dihydropyridinteil steht vorzugsweise in 4-Stellung.
Erfindungsgemäss gelangt man zu den Verbindungen der Formel I, indem man a) eine Verbindung der Formel
EMI2.3
worin R6 und X obige Bedeutung besitzen, mit einer Verbindung der Formel Rs-CO-CH2-R4 III worin R4 und Rs obige Bedeutung besitzen, in Gegenwart einer Verbindung der Formel H2NRI IV worin Rl obige Bedeutung besitzt, oder eine Verbindung der Formel II mit einer Verbindung der Formel Rs-C(NH-RI)=CHR4 V worin Rl, R4 und Rs obige Bedeutung besitzen, umsetzt, oder b) eine Verbindung der Formel II mit einer Verbindung der Formel III und einer Verbindung der Formel R2-C(HN-Rl)=CHR3 VI worin Ri, Rund R3 obige Bedeutung besitzen, umsetzt, oder c) eine Verbindung der Formel
EMI3.1
worin R2, R3, R6 und X obige Bedeutung besitzen und Z für Sauerstoff oder NRI steht,
mit einer Verbindung der Formel III oder V umsetzt und, falls Z für Sauerstoff steht, die Umsetzung in Gegenwart einer Verbindung der Formel IV durchführt, oder d) Verbindungen der Formel
EMI3.2
worin R2 bis R6 und X obige Bedeutung besitzen, und Z und Z' unabhängig voneinander für Sauerstoff oder NRI stehen, einer Cyclisierungsreaktion unterwirft, wobei, falls Z und Z' jeweils Sauerstoff bedeuten, die Reaktion in Gegenwart einer Verbindung der Formel IV durchgeführt wird.
Vorzugsweise steht Rl für Wasserstoff.
In Verfahrensvariante a) verwendet man vorzugsweise mindestens 2 Mol einer Verbindung der Formel III bzw. V pro Mol einer Verbindung der Formel II. Eine Verbindung der Formel V kann als Zwischenprodukt während der Reaktion einer Verbindung der Formel III und einer Verbindung der Formel IV entstehen. Verbindungen der Formel IIa oder IIb können als Zwischenprodukte in den obigen Rekationen entstehen. Sie können aber auch nach anderen Verfahren hergestellt werden.
In den obigen Reaktionen ist es möglich, dass, wenn R2, R3, R4 und Rs nicht gleich sind, mehr als ein Isomeres der Verbindungen der Formel I entsteht. Diese können in an sich bekannter Weise, z.B. dünnschichtchromatographisch, getrennt werden.
Die obigen Reaktionen können alle unter denselben Bedingungen durchgeführt werden.
Das Verfahren wird zweckmässigerweise in Lösung durchgeführt. Geeignete Lösungsmittel sind Wasser, Äthanol, Dioxan, Dimethylformamid, Dimethylsulfoxid, Pyridin oder Eisessig. Die Reaktionstemperaturen liegen zwischen 20 und 160"C, vorzugsweise zwischen 60 und 1200C.
Soweit die Herstellung der Ausgangsverbindungen nicht beschrieben wird, sind diese bekannt oder analog zu bekannten Verbindungen herstellbar.
Die basischen Verbindungen der Formel I können in an sich bekannter Weise in ihre Säureadditionssalze übergeführt werden und umgekehrt. Als Säuren sind z.B. Chlorwasserstoffsäure, Fumarsäure oder Oxalsäure geeignet.
Die erfindungsgemäss erhaltenen Verbindungen der Formel I besitzen günstige pharmakodynamische Eigenschaften. Insbesondere bewirken die Verbindungen der Formel I eine Erweiterung der Herzkranzgefässe, wie dies Resultaten von Versuchen zu entnehmen ist, wobei der Blutfluss zum Myokard einer anästhetisierten Katze mit Hilfe der Mikrosphärenmethode nach Verabreichung der Wirksubstanz in Dosen von 30 bis 50 Fg/kg i.v. oder 150 ug/kg i.d.
gemessen wird. Die Verbindungen der Formel I besitzen ebenfalls eine günstige Wirkung gegen Angina pectoris, wie dies der Erhöhung der Koronardurchblutung bei einer anästhetisierten Katze nach Verabreichung der Wirksubstanz zu entnehmen ist.
Die Verbindungen der Formel I sind deshalb zur Behandlung von Koronarinsuffizienz geeignet. Die Verbindungen steigern ferner die Durchblutung der Beinmuskulatur bei der anästhesierten Katze, wie dies mit Hilfe der Mikrospärenmethode in Dosen von 30-50 llg/kg i.v. oder 150 FLg/kg i.d.
gezeigt werden kann. Die Verbindungen sind daher zur Gefässerweiterung in diesem Bereich geeignet.
Die zu verwendenden Dosen variieren naturgemäss je nach Art der Substanz, der Administration und des zu behandelnden Zustandes. Zufriedenstellende Resultate erhält man bei Verabreichung von Verbindungen der Formel I in einer täglichen Dosis von 0,01 bis 10 mg/kg Tierkörpergewicht.
Bei grösseren Säugetieren ist eine täglich zu verabreichende Menge zwischen 5 und 100 mg angezeigt. Diese Dosis kann auch in kleineren Dosen 2 bis 4 mal täglich oder in Retardform verabreicht werden. Eine Einheitsdosis, beispielsweise eine zur oralen Verabreichung geeignete Tablette kann zwischen 1 und 500 mg des Wirkstoffes zusammen mit geeigneten pharmazeutisch indifferenten Hilfsstoffen enthalten.
Die Verbindungen der Formel I wirken überdies auf den Blutdruck. Insbesondere besitzen sie antihypertensive Eigenschaften, wie sich bei Tierversuchen an der hypertonen Grollman-Ratte (Methode nach A. Grollman, [Proc. Soc.
Exptl. Biol. and Med. 57, 104, 1944]) bei Dosen von 0,1 bis
10 mg/kg zeigt. Die Verbindungen der Formel I sind daher zur Behandlung der Hypertonie geeignet. Die zu verwendenden Dosen variieren naturgemäss je nach Art der Sub stanz, der Administration und des zu behandelnden Zustandes. Zufriedenstellende Resultate erhält man bei Verabreichung von Verbindungen der Formel I in einer täglichen Dosis von 0,5 bis 50 mg/kg Tierkörpergewicht. Bei grösseren Säugetieren ist eine täglich zu verabreichende Menge zwischen 5 und 1000 mg angezeigt. Diese Dosis kann auch in kleineren Dosen 2-4 mal täglich oder in Retardform verabreicht werden. Eine Einheitsdosis, beispielsweise eine zur oralen Verabreichung geeignete Tablette kann zwischen 1,25 und 500 mg des Wirkstoffes zusammen mit geeigneten pharmazeutisch indifferenten Hilfsstoffen enthalten.
Die basischen Verbindungen der Formel I können ebenfalls in Form ihrer pharmazeutisch verträglichen Säureadditionssalze verabreicht werden, die den gleichen Grad an Aktivität besitzen wie die freien Basen.
Die Verabreichung von Verbindungen der Formel I kann entweder oral in Form von Tabletten, Granulaten, Kapseln oder Dragees, oder parenteral in Form von Injektionslösungen erfolgen.
In der ersten Gruppe von Verbindungen steht Rl für Hydroxyalkyl.
In der zweiten Gruppe von Verbindungen steht Rl für Alkoxyalkyl.
In der dritten Gruppe von Verbindungen steht R2 für Phenylalkyl.
In der vierten Gruppe von Verbindungen steht R3 oder R4 für Cyano.
In der fünften Gruppe von Verbindungen steht R3 oder RI für S(O)nR7.
In der sechsten Gruppe von Verbindungen steht R6 für Azido.
In der siebenten Gruppe von Verbindungen steht R6 für Amino.
In der achten Gruppe von Verbindungen steht R6 für Alkylamino.
In der neunten Gruppe von Verbindungen steht R6 für Acylamino.
In der zehnten Gruppe von Verbindungen steht R6 für Carbalkoxy.
In der elften Gruppe von Verbindungen steht R6 für Carboxamido.
In der zwölften Gruppe von Verbindungen steht R6 für Trifluormethoxy.
In der dreizehnten Gruppe von Verbindungen steht R6 für Cyano.
In der vierzehnten Gruppe von Verbindungen steht R6 für Sulfonamido.
In der fünfzehnten Gruppe von Verbindungen steht R6 für Alkylsulfonamido.
In der sechzehnten Gruppe von Verbindungen steht R6 für Dialkylsulfonamido.
In den nachfolgenden Beispielen sind die Temperaturen in Grad-Celsius angegeben und sind unkorrigiert.
Beispiel 1
4-(2,1 ,3-Benzoxadiazolyl-4)-5-cyan- 1 ,4-dihydro-2,6dimethyl-pyridin-3-carbonsäure-isobutylester
3 g 2,1,3-Benzoxadiazol-4-aldehyd, 3,2 g Acetessigsäureisobutylester, 1,7 g ss-Aminocrotonsäurenitril und 10 ml Äthanol werden zusammen unter Rühren 3 Stunden zum Rückfluss erhitzt. Das Reaktionsgemisch wird anschliessend eingedampft und der obige Rückstand über Silicagel mit Chloroform/Essigester (8:1) chromatographiert, wobei man die Titelverbindung erhält, die aus Diisopropyläther umkristallisiert bei 123-124,5"C schmilzt.
Analog Beispiel 1 und unter Verwendung geeigneter Ausgangsverbindungen gelangt man zu folgenden Verbindungen der Formel I, worin y die Stellung des Dihydropyridinrestes angibt: Beispiel Rl R2 R3 R4 Rs R6 Y X Smp. C 2 H CH3 SO2CH3 COOC2Hs CH3 H 4 0 204-205 3 H CH3 CN COOC1Hs CH3 H 4 0 167-177 4 H CH3 CN COOC2Hs CH3 H 4 S 187-190 5 H CH3 CN COOCH2CH(CH3)2 CH3 H 4 S 166-171
** WARNING ** beginning of DESC field could overlap end of CLMS **.
d) compounds of the formula
EMI2.1
wherein R2 to R6 and X are as defined above, and Z and Z 'independently of one another are oxygen or NRI, are subjected to a cyclization reaction, where, if Z and Z' are each oxygen, the reaction is carried out in the presence of a compound of the formula IV.
3. Remedies, characterized by a content of compounds of formula I.
The invention relates to organic compounds of the formula I
EMI2.2
wherein Ri is hydrogen, alkyl with 1-6 carbon atoms, hydroxylalkyl with 2-6 carbon atoms, alkoxyalkyl with 3-6 carbon atoms, alkenyl or alkynyl with 3-6 carbon atoms each, cycloalkyl with 3-7 carbon atoms, cycloalkyl alkyl with 4-8 carbon atoms , Phenylalkyl with 7-9 carbon atoms or phenylalkenyl with 9-12 carbon atoms, where the phenyl ring is unsubstituted or substituted by one, two or three substituents which independently of one another represent halogen, hydroxy, alkyl or alkoxy each having 1-4 carbon atoms, R2 and Rs are independently hydrogen,
Alkyl with 1-6 carbon atoms or phenylalkyl with 7-10 carbon atoms mean R3 and R4 independently of one another for CN, CORD, COLORS, S (O) nR, where n denotes 0, 1 or 2 and R7 for alkyl with 1-6 carbon atoms , Alkenyl or alkynyl each with 3-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 4-8 carbon atoms, hydroxyalkyl with 2-6 carbon atoms, alkoxyalkyl with 3-6 carbon atoms, hydroxyalkoxyalkyl with 4-8 carbon atoms, aminoalkyl with 2- 6 carbon atoms, alkyl (Clv) aminoalkyl (C2-6), phenyl, phenylalkyl with 7-10 carbon atoms, a 5- or 6-membered heterocycle which contains a nitrogen, oxygen or sulfur atom as the hetero atom, or represents heteroarylalkyl,
in which the heteroaryl part is a 5- or 6-membered heterocycle which contains a nitrogen, oxygen or sulfur atom as the hetero atom and the alkyl part contains 1-4 carbon atoms, R6 is hydrogen, halogen, alkyl, alkoxy, alkylthio or alkylsulfonyl each having 1 -4 carbon atoms, trifluoromethyl, nitro, hydroxy, azido, amino, alkylamino with 1-4 carbon atoms, acylamino with 1-5 carbon atoms, carbalkoxy with 1-4 carbon atoms, carboxamido, trifluoromethoxy, cyano, sulfonamido, alkylsulfonamido or dialkylsulfonamido, the alkyl groups Have 1-4 carbon atoms, and X stands for oxygen or sulfur, with the proviso that if R1 is hydrogen, alkyl, alkenyl, alkinyf, cycloalkyl, cycloalkylalkyl, phenylalkyl or phenylalkenyl,
where the phenyl ring is unsubstituted or substituted by one, two or three substituents which independently of one another represent halogen, hydroxyl, alkyl or alkoxy, R2 and Rs independently of one another are hydrogen or alkyl, R6 is hydrogen, halogen, alkyl, alkoxy, alkylthio or alkylsulfonyl, Trifluoromethyl, nitro or hydroxy, and X is oxygen or sulfur, then at least one of the substituents R3 and R4 has a different meaning than COR7i, where R71 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or a different meaning than COLOR7 ", wherein R7tl stands for alkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl.
Each of the above-mentioned alkyl groups containing 1-6 carbon atoms preferably has 1-4 carbon atoms, especially 1 or 2 carbon atoms. Each alkyl, alkoxy, alkylthio or alkylsulfonyl containing 1-4 carbon atoms preferably has 1 or 2 carbon atoms. The alkyl part of cycloalkylalkyl is expediently methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine. Cycloalkyl or the cycloalkyl part of cycloalkylalkyl expediently means cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl, alkynyl or phenylalkenyl is preferably not in the a, position. Alkenyl or alkynyl preferably has 3-5 carbon atoms.
Phenylalkenyl preferably has the trans configuration and means e.g. Cinnamyl. If R 1 is an optionally substituted phenylalkyl, the phenyl ring is preferably unsubstituted. If the phenyl ring is substituted twice or three times, the substituents are preferably the same.
If R7 is alkoxyalkyl or hydroxylalkoxyalkyl, the alkyl part preferably contains 2 carbon atoms. R preferably represents hydrogen. R2 expediently has the same meaning as Rs. R2 and / or Rs preferably represent methyl. R6 expediently represents halogen, alkyl or alkoxy or in particular hydrogen. The dihydropyridine part is preferably in the 4-position.
According to the invention, the compounds of the formula I are obtained by a) a compound of the formula
EMI2.3
wherein R6 and X have the above meaning, with a compound of the formula Rs-CO-CH2-R4 III in which R4 and Rs have the above meaning, in the presence of a compound of the formula H2NRI IV in which Rl has the above meaning, or a compound of the formula II with a compound of the formula Rs-C (NH-RI) = CHR4 V in which Rl, R4 and Rs have the above meaning, or b) a compound of the formula II with a compound of the formula III and a compound of the formula R2-C ( HN-Rl) = CHR3 VI in which R 1, R 3 have the above meaning, or c) a compound of the formula
EMI3.1
in which R2, R3, R6 and X have the above meaning and Z represents oxygen or NRI,
with a compound of the formula III or V and, if Z is oxygen, the reaction is carried out in the presence of a compound of the formula IV, or d) compounds of the formula
EMI3.2
wherein R2 to R6 and X are as defined above, and Z and Z 'independently of one another are oxygen or NRI, are subjected to a cyclization reaction, where, if Z and Z' are each oxygen, the reaction is carried out in the presence of a compound of the formula IV.
Rl is preferably hydrogen.
In process variant a), preference is given to using at least 2 moles of a compound of the formula III or V per mole of a compound of the formula II. A compound of the formula V can be formed as an intermediate during the reaction of a compound of the formula III and a compound of the formula IV. Compounds of formula IIa or IIb can arise as intermediates in the above recations. However, they can also be produced by other processes.
In the above reactions, it is possible that if R2, R3, R4 and Rs are not the same, more than one isomer of the compounds of formula I will be formed. These can be done in a manner known per se, e.g. be separated by thin layer chromatography.
The above reactions can all be carried out under the same conditions.
The process is conveniently carried out in solution. Suitable solvents are water, ethanol, dioxane, dimethylformamide, dimethyl sulfoxide, pyridine or glacial acetic acid. The reaction temperatures are between 20 and 160 "C, preferably between 60 and 1200C.
If the preparation of the starting compounds is not described, they are known or can be prepared analogously to known compounds.
The basic compounds of formula I can be converted into their acid addition salts in a manner known per se and vice versa. As acids are e.g. Hydrochloric acid, fumaric acid or oxalic acid are suitable.
The compounds of formula I obtained according to the invention have favorable pharmacodynamic properties. In particular, the compounds of the formula I bring about an enlargement of the coronary arteries, as can be seen from the results of experiments in which the blood flow to the myocardium of an anesthetized cat using the microsphere method after administration of the active substance in doses of 30 to 50 Fg / kg IV. or 150 ug / kg i.d.
is measured. The compounds of the formula I also have a favorable action against angina pectoris, as can be seen from the increase in coronary blood flow in an anesthetized cat after administration of the active substance.
The compounds of formula I are therefore suitable for the treatment of coronary insufficiency. The compounds also increase blood flow to the leg muscles in the anesthetized cat, as is done with the microspheres method in doses of 30-50 llg / kg IV. or 150 FLg / kg i.d.
can be shown. The connections are therefore suitable for vessel expansion in this area.
The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. Satisfactory results are obtained when compounds of the formula I are administered in a daily dose of 0.01 to 10 mg / kg of animal body weight.
For larger mammals, a daily dose of between 5 and 100 mg is indicated. This dose can also be administered in smaller doses 2 to 4 times a day or in extended release. A unit dose, for example a tablet suitable for oral administration, can contain between 1 and 500 mg of the active ingredient together with suitable pharmaceutically indifferent auxiliaries.
The compounds of formula I also act on blood pressure. In particular, they have antihypertensive properties, as can be seen in animal experiments on the hypertonic Grollman rat (method according to A. Grollman, [Proc. Soc.
Exptl. Biol. And Med. 57, 104, 1944]) at doses from 0.1 to
10 mg / kg shows. The compounds of formula I are therefore suitable for the treatment of hypertension. The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated. Satisfactory results are obtained when compounds of the formula I are administered in a daily dose of 0.5 to 50 mg / kg of animal body weight. For larger mammals, a daily dose of between 5 and 1000 mg is indicated. This dose can also be administered in smaller doses 2-4 times a day or in sustained release. A unit dose, for example a tablet suitable for oral administration, can contain between 1.25 and 500 mg of the active ingredient together with suitable pharmaceutically indifferent auxiliaries.
The basic compounds of formula I can also be administered in the form of their pharmaceutically acceptable acid addition salts which have the same level of activity as the free bases.
Compounds of the formula I can be administered either orally in the form of tablets, granules, capsules or dragées, or parenterally in the form of injection solutions.
In the first group of compounds, R1 is hydroxyalkyl.
In the second group of compounds, R1 is alkoxyalkyl.
In the third group of compounds, R2 represents phenylalkyl.
In the fourth group of compounds, R3 or R4 is cyano.
In the fifth group of compounds, R3 or RI is S (O) nR7.
In the sixth group of compounds, R6 stands for azido.
In the seventh group of compounds, R6 represents amino.
In the eighth group of compounds, R6 stands for alkylamino.
In the ninth group of compounds, R6 stands for acylamino.
In the tenth group of compounds, R6 represents carbalkoxy.
In the eleventh group of compounds, R6 represents carboxamido.
In the twelfth group of compounds, R6 stands for trifluoromethoxy.
In the thirteenth group of compounds, R6 represents cyano.
In the fourteenth group of compounds, R6 represents sulfonamido.
In the fifteenth group of compounds, R6 represents alkylsulfonamido.
In the sixteenth group of compounds, R6 represents dialkylsulfonamido.
In the following examples, the temperatures are given in degrees Celsius and are uncorrected.
example 1
Isobutyl 4- (2,1, 3-benzoxadiazolyl-4) -5-cyano-1,4-dihydro-2,6-dimethyl-pyridine-3-carboxylate
3 g of 2,1,3-benzoxadiazol-4-aldehyde, 3.2 g of isobutyl acetoacetate, 1.7 g of ss-aminocrotonitrile and 10 ml of ethanol are refluxed together with stirring for 3 hours. The reaction mixture is then evaporated and the above residue is chromatographed over silica gel with chloroform / ethyl acetate (8: 1), giving the title compound, which recrystallizes from diisopropyl ether at 123-124.5 ° C.
Analogously to Example 1 and using suitable starting compounds, the following compounds of the formula I are obtained, in which y indicates the position of the dihydropyridine radical: Example R1 R2 R3 R4 Rs R6 YX mp C 2 H CH3 SO2CH3 COOC2Hs CH3 H 4 0 204-205 3 H CH3 CN COOC1Hs CH3 H 4 0 167-177 4 H CH3 CN COOC2Hs CH3 H 4 S 187-190 5 H CH3 CN COOCH2CH (CH3) 2 CH3 H 4 S 166-171
Claims (3)
Priority Applications (20)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1288878A CH640852A5 (en) | 1978-12-18 | 1978-12-18 | 1,4-Dihydropyridine derivatives, their preparation and use |
| DE19792949464 DE2949464A1 (en) | 1978-12-18 | 1979-12-08 | BENZOXADIAZOLES AND BENZOTHIADIAZOLES, THEIR PRODUCTION AND USE |
| DK525179A DK525179A (en) | 1978-12-18 | 1979-12-10 | PROCEDURE FOR PREPARING BENZOXADIAZOLES AND BENZOTHIAZOLES |
| SE7910151A SE7910151L (en) | 1978-12-18 | 1979-12-10 | BENZOXADIAZOLES AND BENSTIADIAZOLES |
| FI793848A FI793848A (en) | 1978-12-18 | 1979-12-10 | BENZOXADIAZOLER OCH BENZOTHIADIAZOLER DERAS FRAMSTAELLNING OCH PHARMACEUTICAL COMPOSITION INNEHAOLLANDE DESSA |
| IT51096/79A IT1120900B (en) | 1978-12-18 | 1979-12-14 | 1,4-DI HYDROPYRIDINS REPLACED IN POSITION 4 WITH A REST |
| GB7943112A GB2041358B (en) | 1978-12-18 | 1979-12-14 | Benzoxadiazoles and benzothiadiazoles |
| NL7909028A NL7909028A (en) | 1978-12-18 | 1979-12-14 | Benzoxadiazole- or benzothiadiazole-substd. 1,4-di:hydro-pyridine(s) - prepd. by cyclisation of benzoxa:diazole- or benzothiadiazole-carboxaldehyde cpds., useful as coronary vasodilators ( NL 20.6.80) |
| ES486989A ES8104276A1 (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazole- or benzothiadiazole-substd. 1,4-di:hydro-pyridine(s) - prepd. by cyclisation of benzoxa:diazole- or benzothiadiazole-carboxaldehyde cpds., useful as coronary vasodilators ( NL 20.6.80) |
| IL58974A IL58974A (en) | 1978-12-18 | 1979-12-17 | Dihydropyridinyl benzoxadiazole and benzothiadiazole derivatives,their preparation and pharmaceutical compositions containing them |
| PT70601A PT70601A (en) | 1978-12-18 | 1979-12-17 | PROCESS FOR THE PREPARATION OF NOVEL ORGANIC COMPOUNDS WITH PHARMACEUTICAL EFFECT |
| AU53897/79A AU538515B2 (en) | 1978-12-18 | 1979-12-17 | Derivatives of 4-dihydropyridine substituted with benzoxadiazoles and benzothiadizoles |
| CA342,085A CA1131228A (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| JP16396479A JPS5589281A (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazole and benzothiadiazole*their manufacture and drug composition containing them |
| BE1/9650A BE880650A (en) | 1978-12-18 | 1979-12-17 | NEWS 1,4 (DIHYDROPYRIDINES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS |
| NZ192421A NZ192421A (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazoles and benzothiadiazoles with 1,4-dihydroxy-pyridine moiety and pharmaceutical compositions |
| FR7930827A FR2444680A1 (en) | 1978-12-18 | 1979-12-17 | Benzoxadiazole- or benzothiadiazole-substd. 1,4-di:hydro-pyridine(s) - prepd. by cyclisation of benzoxa:diazole- or benzothiadiazole-carboxaldehyde cpds., useful as coronary vasodilators ( NL 20.6.80) |
| ZA00796841A ZA796841B (en) | 1978-12-18 | 1979-12-18 | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
| PH24383A PH19536A (en) | 1977-06-20 | 1980-08-01 | Benzoxadiazoles and benzothiadiazoles and pharmaceutical composition containing them |
| US06/359,751 US4466972A (en) | 1977-06-20 | 1982-03-19 | Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1288878A CH640852A5 (en) | 1978-12-18 | 1978-12-18 | 1,4-Dihydropyridine derivatives, their preparation and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH640852A5 true CH640852A5 (en) | 1984-01-31 |
Family
ID=4387327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1288878A CH640852A5 (en) | 1977-06-20 | 1978-12-18 | 1,4-Dihydropyridine derivatives, their preparation and use |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5589281A (en) |
| BE (1) | BE880650A (en) |
| CH (1) | CH640852A5 (en) |
| ZA (1) | ZA796841B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5978186A (en) * | 1982-10-27 | 1984-05-04 | Yoshitomi Pharmaceut Ind Ltd | 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5373327A (en) * | 1976-12-13 | 1978-06-29 | Matsushita Electric Ind Co Ltd | Power source system |
-
1978
- 1978-12-18 CH CH1288878A patent/CH640852A5/en not_active IP Right Cessation
-
1979
- 1979-12-17 BE BE1/9650A patent/BE880650A/en not_active IP Right Cessation
- 1979-12-17 JP JP16396479A patent/JPS5589281A/en active Pending
- 1979-12-18 ZA ZA00796841A patent/ZA796841B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE880650A (en) | 1980-06-17 |
| ZA796841B (en) | 1981-07-29 |
| JPS5589281A (en) | 1980-07-05 |
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