JPH0240385A - Condensed ring dihydropyridine derivative - Google Patents
Condensed ring dihydropyridine derivativeInfo
- Publication number
- JPH0240385A JPH0240385A JP63191070A JP19107088A JPH0240385A JP H0240385 A JPH0240385 A JP H0240385A JP 63191070 A JP63191070 A JP 63191070A JP 19107088 A JP19107088 A JP 19107088A JP H0240385 A JPH0240385 A JP H0240385A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- nitroxy
- substituted
- aralkyl
- 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.)
- Granted
Links
- 125000004925 dihydropyridyl group Chemical class N1(CC=CC=C1)* 0.000 title description 2
- -1 (substituted) phenyl Chemical group 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 abstract description 15
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 6
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002148 esters Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 abstract 1
- 239000000480 calcium channel blocker Substances 0.000 abstract 1
- 150000002545 isoxazoles Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- 238000000034 method Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000036772 blood pressure Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 102200073741 rs121909602 Human genes 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- IAXWZYXUKABJAN-UHFFFAOYSA-N 1,2-oxazol-5-amine Chemical class NC1=CC=NO1 IAXWZYXUKABJAN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- GDMUWXHYYIOKHS-UHFFFAOYSA-N 2-benzylidene-3-oxobutanoic acid Chemical class CC(=O)C(C(O)=O)=CC1=CC=CC=C1 GDMUWXHYYIOKHS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- OMBRFUXPXNIUCZ-UHFFFAOYSA-N dioxidonitrogen(1+) Chemical compound O=[N+]=O OMBRFUXPXNIUCZ-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 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
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 235000012976 tarts Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は抗高血圧作用およびカルシウム拮抗作用を示す
医薬として有用である新規な縮環ジヒドロピリジン誘導
体に関するものである。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel fused dihydropyridine derivative useful as a medicine exhibiting antihypertensive and calcium antagonistic effects.
本発明者等は循環器系薬の開発を目的として縮環ジヒド
ロピリジン誘導体を合成し、その薬理試験を実施し、そ
の構造−活性相関を検討した結果、後記一般式（１）を
有する本発明の化合物が、カルシウム拮抗作用、抗高血
圧作用、血管拡張作用、高脂血症改善作用および過酸化
脂質生成阻害作用などの薬理活性を示し、しかも毒性が
低いものであることを見い出し、高血圧症。The present inventors synthesized ring-fused dihydropyridine derivatives for the purpose of developing cardiovascular drugs, conducted pharmacological tests on the derivatives, and investigated the structure-activity relationship. It was discovered that the compound exhibits pharmacological activities such as calcium antagonistic action, antihypertensive action, vasodilatory action, hyperlipidemia improving action, and lipid peroxide formation inhibiting action, and has low toxicity.
狭心症などの循環系疾病を治療する医薬として有用であ
ることを認めて本発明を完成するに至った。The present invention was completed after recognizing that the present invention is useful as a medicine for treating circulatory system diseases such as angina pectoris.
発明の構成 本発明は。Composition of the invention The present invention is.
一般式
で表わされる縮環ジヒドロピリジン誘導体又はその酸付
加塩に関するものである。This invention relates to a fused ring dihydropyridine derivative represented by the general formula or an acid addition salt thereof.
上記式中、Ａｒは置換基としてニトロ基、ハロゲン低級
アルキル基、ハロゲノ低級アルコキシ基、シアノ基ま念
は１若しくは２個のハロゲン原子を有していてもよいフ
ェニル基、あるいは水素原子、低級アルキル基、シクロ
アルキル基。In the above formula, Ar is a nitro group, a halogen lower alkyl group, a halogen lower alkoxy group, a cyano group, or a phenyl group which may have one or two halogen atoms, a hydrogen atom, or a lower alkyl group as a substituent. group, cycloalkyl group.
水酸基ま次は低級アル；キシカルボニル基を示し、Ｒ２
はニトロキシ基で置換されたアルキル基。The hydroxyl group represents a lower alkoxycarbonyl group, and R2
is an alkyl group substituted with a nitroxy group.
ニトロキシ基で置換され九シクロアルキル基。Nine cycloalkyl groups substituted with nitroxy groups.
ヘテロアラルキル基を示し５ｍは１乃至３の整数を示す
。）またはシンナミル基を示す。It represents a heteroaralkyl group, and 5m represents an integer of 1 to 3. ) or a cinnamyl group.
前記一般式（１）において、好適にはＡｒは置換基とし
てニトロ基、トリフルオロメチル、２，２゜２−トリフ
ルオロエチルのような炭素数１乃至２個のハロゲノアル
キル基、ジフルオロメトキシ、トリフルオロメトキシ、
２．２−ジフルオロエトキシのような炭素数１乃至２個
のハロゲノアルコキシ基、シアノ基ま九は１若しくは２
個のフッ素、塩素、臭素、沃素のようなハロゲンＲ３は
水素原子、低級アルキル基またはアラル 基を示し。In the general formula (1), Ar preferably represents a substituent such as a nitro group, trifluoromethyl, a halogenoalkyl group having 1 to 2 carbon atoms such as 2,2゜2-trifluoroethyl, difluoromethoxy, or trifluoromethoxy. fluoromethoxy,
2. Halogenoalkoxy group having 1 to 2 carbon atoms such as 2-difluoroethoxy, cyano group or 1 or 2
Halogen R3 such as fluorine, chlorine, bromine, and iodine represents a hydrogen atom, a lower alkyl group, or an aral group.
キル基を示す。）ま７？＋は酸素原子を示し、Ｒ１は
Ｘは式Ｒ５−Ｎざ基（式中、Ｒ３は水素原子、メチ
ル、エチル、ｎ−プロピル、イソプロピルのような炭素
数１乃至３個のアルキル基またはベンジル、フェネチル
、３−フェニルプロピルのようなアラルキル基を示す。Indicates a kill group. )Ma7? + indicates an oxygen atom, R1 is
and Indicates an aralkyl group.
〕または酸素原子を示し。] or indicates an oxygen atom.
Ｒ１は水素原子、メチル、エチル、ｎ−グロビル、イン
グロビル、ｎ−ブチル、イソブチル。R1 is a hydrogen atom, methyl, ethyl, n-glovir, inglovir, n-butyl, isobutyl.
□□□−ブチル、 ｔｅｒｔ−ブチル、ｎ−ペンチル、
ｎ−ヘキシルのような炭素数１乃至６個の直鎖状若しく
は分枝鎖状のアルキル基；シクロプロピル、シクロブチ
ル、シクロペンチル、シクロヘキシルのような炭素数３
乃至６個のシクロアルキル基；水酸基ま九はメトキシカ
ルボニル、エトキシカルボニル、ｎ−プロポキシカルボ
ニル。□□□-butyl, tert-butyl, n-pentyl,
Straight chain or branched alkyl group having 1 to 6 carbon atoms such as n-hexyl; 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
to 6 cycloalkyl groups; the hydroxyl groups are methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl;
イソプロポキシカルボニルのような炭素数２乃至４個の
アルコキシカルボニル基を示し。Indicates an alkoxycarbonyl group having 2 to 4 carbon atoms such as isopropoxycarbonyl.
Ｒ２はニトロキシ基で置換されたメチル、エチル、ｎ−
プロピル、イソプロピル、ｎ−ブチル、イソフチル、ｎ
−ペンチル、ｎ−ヘキシル、ｎ −−、プデル、ｎ−オ
クチル、デシルのような炭素数１乃至１０個の直鎖状若
しくは分枝鎖状のアルキル基；ニトロキシ基で置換され
次シクロプロピル、シクロブチル、シクロペンチル。R2 is nitroxy-substituted methyl, ethyl, n-
propyl, isopropyl, n-butyl, isophthyl, n
- Straight-chain or branched alkyl groups having 1 to 10 carbon atoms such as pentyl, n-hexyl, n--, pudel, n-octyl, decyl; substituted with a nitroxy group and then cyclopropyl, cyclobutyl , cyclopentyl.
シクロヘキシルのような炭素数３乃至６個のシンジル、
フェネチル、３−フェニルプロピルベンズヒドリルのよ
うなアラルキル基またはλ３−若しくは４−ピリジルメ
チル＆ え４．ト若しくは６−ピリミジニルメチル、フ
ルフリル、２−若しくは３−テニル、２．４−若しくは
６−チアゾリルメチル、２．４−若しくは５−オキサシ
リルメチル、２．４１しくけ５−イミダゾリルメチル、
２−ペンゾチアゾリルノ′チル、２−ベンゾオキサシリ
ルメチル、２−ベンゾイミダゾリルメチルｍは１乃至３
の整数を示す。〕またはシンナミル基を示す。Syndyl having 3 to 6 carbon atoms such as cyclohexyl,
an aralkyl group such as phenethyl, 3-phenylpropylbenzhydryl or λ3- or 4-pyridylmethyl;4. or 6-pyrimidinylmethyl, furfuryl, 2- or 3-thenyl, 2.4- or 6-thiazolylmethyl, 2.4- or 5-oxasilylmethyl, 2.41- or 5-imidazolylmethyl,
2-penzothiazolylnot'thyl, 2-benzoxasilylmethyl, 2-benzimidazolylmethyl m is 1 to 3
indicates an integer. ] or a cinnamyl group.
なお、上記の置換基において、「了り−ル基。In addition, in the above-mentioned substituents, "Riryl group.
アラルキル基およびヘテロアラルキル基」の芳香環は、
メチル、エチル、ｎ−プロピル、イソプロピルのような
炭素数１乃至３個のアルキル基、メトキシ、エトキシ、
ｎ−プロポキシ、インプロポキシのような炭素数１乃至
３個のアルコキシ基、フッ素、塩素、臭素。沃素のよう
なハロゲン原子などで１換されていてもよい。The aromatic ring of "aralkyl group and heteroaralkyl group" is
Alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy,
Alkoxy groups having 1 to 3 carbon atoms such as n-propoxy and inpropoxy, fluorine, chlorine, and bromine. It may be substituted with a halogen atom such as iodine.
前記一般式（１）における特に好適な化合物としては、
Ａｒが２−若しくは３−ニトロフェニル基。Particularly suitable compounds in the general formula (1) include:
Ar is a 2- or 3-nitrophenyl group.
２−ｔＬ＜Ｕ３−トリフルオロメチルフェニル基まｔは
２．３−ジクロルフェニル基でア！５． Ｘがイミノ基
、ベンジルイミノ基または酸素原子であツ、Ｒ１が水素
原子、メチル基、エチル基、ｎ−プロピル基、イングロ
ビル基、ｎ−ブチル基、５ｅｅ−ブチル基、 ｔａｒｔ
−ブチル基のような炭素数１乃至４個のアルキル基、シ
クロプロピル基、シクロブチル基、シクロペンチル基、
シクロヘキシル基のような炭素数３乃至６個の７クロア
ルキル基、水酸基またはメトキシカルボニル基、エトキ
シカルボニル基のような炭素数２ま九は３個のアルコキ
シカルボニル基テアｊ５ 。2-tL<U3-trifluoromethylphenyl group or t is 2,3-dichlorophenyl group and a! 5. X is an imino group, a benzylimino group, or an oxygen atom, R1 is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an inglovir group, an n-butyl group, a 5ee-butyl group, tart
- an alkyl group having 1 to 4 carbon atoms such as a butyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group,
a 7-chloroalkyl group having 3 to 6 carbon atoms such as a cyclohexyl group; a hydroxyl group or a methoxycarbonyl group; an alkoxycarbonyl group having 2 to 9 carbon atoms such as an ethoxycarbonyl group;
Ｒ２が２−二トロキシエチル基、３−ニトロキシプロピ
ル基、２−ニトロキシグロビル基、４ニトロキシブチル
基、５−二トロキシベ／チル基、６−ニトロキシヘキシ
ル基、２．３−ジニトロキシプロピル基、１．３−ジニ
トロキシイソプロビル基のようなニトロキシ基で置換さ
れた炭素数２乃至Ｂのアルキル基、２−ニトロキシシク
ロペンチル基、２−ニトロキシシクロヘキシル基、４−
ニトロキシシクロヘキシル基のようなニトロキシ基で置
換され次炭素数５ま几は６個のシクロアルキル基、１−
ベンジル−３−ピペリジル基またはシンナミル基である
化合物をあげることができる。R2 is a 2-nitroxyethyl group, 3-nitroxypropyl group, 2-nitroxyglobyl group, 4-nitroxybutyl group, 5-nitroxybe/thyl group, 6-nitroxyhexyl group, 2,3-dinitroxy Propyl group, alkyl group having 2 to B carbon atoms substituted with nitroxy group such as 1,3-dinitroxyisopropyl group, 2-nitroxycyclopentyl group, 2-nitroxycyclohexyl group, 4-
Substituted with a nitroxy group, such as nitroxycyclohexyl group, and the next cycloalkyl group having 5 or more carbon atoms, 1-
Mention may be made of compounds which are benzyl-3-piperidyl groups or cinnamyl groups.
前記一般式（１）を有する化合物は、必要に応じて薬理
上許容し得る酸付加塩にすることができるが、そのよう
な塩としては塩酸塩、臭化水素酸塩、沃化水素酸塩、硫
酸塩のような鉱酸の酸付加塩、メタンスルホン酸塩、エ
タンスルホン酸塩、ベンゼンスルホン酸塩、ｐ−トルエ
ンスルホン酸塩のようなスルホン酸の酸付加塩あるイハ
シュウ酸塩、マレイン酸塩、フマル酸塩。The compound having the general formula (1) can be converted into a pharmacologically acceptable acid addition salt if necessary, and examples of such salts include hydrochloride, hydrobromide, and hydroiodide. Acid addition salts of mineral acids such as sulfate, acid addition salts of sulfonic acids such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, maleic acid Salt, fumarate.
酒石酸塩、クエン酸塩のような有機酸の酸付加塩があげ
られる。Examples include acid addition salts of organic acids such as tartrates and citrates.
才ｆＣ、前記一般式（１）を有する化合物におりで。It is a compound having the above general formula (1).
縮環ジヒドロピリジン環の４位またＩｔｉ −１−ステ
／ｌ／結合を形成するアルコール残基中の不斉炭素原子
に基づく光学異性体、あるいは前記アルコール３１ｉの
種類によっては幾何（シス、トランス）異性体が存在す
るが１本発明においては、これらの異性体またはそれら
の混合物を包含するものである。Optical isomers based on the asymmetric carbon atom in the alcohol residue forming the 4-position of the condensed dihydropyridine ring or the Iti-1-ste/l/bond, or geometric (cis, trans) isomers depending on the type of alcohol 31i. However, the present invention includes these isomers or mixtures thereof.
本発明によって得られる前記一般式（１）を有する化合
物としては、以下に例示する化合物をあ第１表
第
表
ムｒ
〔製造法〕
本発明の前記一般式（１）を有する新規化合物は。The compounds having the general formula (1) obtained by the present invention are exemplified below.
例えば以下に示す反応によって製造することができる。For example, it can be produced by the reaction shown below.
すなわち、一般式
を有する５−アミノ−ピラゾールあるいはインオキサゾ
ール誘導体と、一般式
を有する２−ベンジリデンアセト酢酸エステル誘導体と
を公知の方法〔例えば、特開昭５９−１１８７８６号明
細書〕忙よって製造することができる。（上記式中＆Ａ
ｒ 、Ｒ１、Ｒ２およびＸは前述したものと同意義を示
す。９
この方法を実施するには化合物（ＩＩ）と好ましくは等
モルの化合物（ｆ）とを混合し１例えばメタノール、エ
タノール、イソプロピルアルコール。That is, a 5-amino-pyrazole or inoxazole derivative having the general formula and a 2-benzylideneacetoacetate derivative having the general formula are produced by a known method [for example, JP-A-59-118786]. be able to. (&A in the above formula
r, R1, R2 and X have the same meanings as described above. 9 To carry out this process, compound (II) is mixed with preferably equimolar amounts of compound (f), such as methanol, ethanol, isopropyl alcohol.
ｔｅｒｔ−ブチルアルコール、ジオキサン、ジメチルホ
ルムアミド、ジメチルスルホキシド、アセトニ） ＩＪ
ルなどの有機晦媒若しくは水等の啓媒あるいはそれらの
混合醇媒の存在下または非存在下に室温で、あるいは加
熱下に常圧または加圧下に行われる。通常は上記有機醇
媒の存在下。tert-butyl alcohol, dioxane, dimethylformamide, dimethyl sulfoxide, acetonium) IJ
The reaction is carried out at room temperature in the presence or absence of an organic vehicle such as alcohol, a solvent such as water, or a mixed vehicle thereof, or under heating and normal pressure or increased pressure. Usually in the presence of the above organic vehicle.
常圧で、使用爵媒の沸点附近の温度で行われる。It is carried out at normal pressure and at a temperature near the boiling point of the catalyst used.
反応時間は反応温度などＫよって異なるが、数時間から
数日である。The reaction time varies depending on K such as the reaction temperature, but is from several hours to several days.
反応終了後、目的化合物（１）は常法に従って反応混合
物を処理することによって得られ、さらに必要に応じて
再結晶法、カラムクロマトグラフィーなどの通常の精製
手段を用いて精製するれる５−アミノピラゾール誘導体
１−ｎａ）は、一般式Ｒ１−Ｃｏ−０１（２−ＯＮ ■
で示される３−ケトニトリルと式Ｒ５−ＮＨＮＨ２（Ｉ
ｌｌ’）で示されるヒドラジンから公知の方法〔例えば
、 −Ｔｈｅ Ｃｈｅｍｉｓｔｒｙ ｏｆ Ｈｅｔｅ−
ｒｏｃｙｃｌｉｃ Ｃｏｍｐｏｕｎｄｓ’ ｖｏｌ、Ｘ
Ｘ、 ４ ｊ −４３頁、Ｗ１１８７ａｎｄ Ｗｉｌｅ
ｙ Ｐｕｂｌｉｓｈｅｒ、Ｎｅｗ Ｙｏｒｋ、 １９６
４年〕に５−アミノイソオキサゾール誘導体（Ｉｌｂ、
）は、β−ケトニトリル（ト）とヒドロキシルアミン塩
酸塩から公知の方法〔例えば、 ”Ｒｏｄａ ’ｓ Ｃ
ｈｅｍｉｓｔｒｙｏｆ ０ａｒｂｏｎ Ｃｏｍｐｏｕｎ
ｄｓ” ｖｏｌ、ＩＶ−ａ、２ｎｉ Ｅｄ、２４４頁、
Ｓ、ａｏｆ’ｆｅ７ ａｎｄ Ｍ、Ｆ、Ａｎｓｅｌｌ
、Ｆ！１ｓｅｖ１ｅｒ、ＮｅｗＹＯｒｋ、 １８８８年
〕によって製造される。After the completion of the reaction, the target compound (1) is obtained by treating the reaction mixture according to a conventional method, and if necessary, the 5-amino compound is purified using a conventional purification method such as recrystallization method or column chromatography. The pyrazole derivative 1-na) has the general formula R1-Co-01(2-ON
3-ketonitrile of formula R5-NHNH2(I
from hydrazine represented by ll') [for example, -The Chemistry of Hete-
rocyclic Compounds' vol,X
X, 4j-43 pages, W1187 and Wile
y Publisher, New York, 196
4 years], 5-aminoisoxazole derivatives (Ilb,
) can be prepared by known methods from β-ketonitrile (t) and hydroxylamine hydrochloride [for example, "Roda's C
hemistry of 0arbon Compoun
ds” vol, IV-a, 2ni Ed, 244 pages,
S, aof'fe7 and M, F, Ansell
, F! 1sev1er, NewYork, 1888].
また、化合物（ｊＤは１例えば式Ａｒ−ＣＨ０で示され
るアルデヒドと一般式ＣＨ３００ＣＨ２０００Ｒ２で示
されるアセト酢酸エステルとを公知の方法〔例えば 、
０＋Ｊｏｎｅｓ ”Ｔｈｅ Ｋｎ０８’１７
ｅｌｎａｇｅｌ Ｃ！ｏｎｄｅｎｓａｔｉｏｎ ’
□ｒｇ、Ｒｅａｃｔ１ｏｎｓ、Ｖｏｌｕｍｅ １５ 、
２０４〜（１９６７年〕〕によって脱水縮合させること
によシ得られる。In addition, a compound (jD is 1, for example, an aldehyde represented by the formula Ar-CHO and an acetoacetate represented by the general formula CH300CH2000R2) by a known method [for example,
0+Jones “The Kn08’17
elnagel C! ondensation'
□rg, React1ons, Volume 15,
204-(1967)] by dehydration condensation.
ここに使用されるアセト酢酸エステルはジケテンと式Ｒ
２０Ｈで示されるアルコールから公知の方法（例えばＡ
、Ｂ、Ｂｏｅｓｅ、Ｊｒ、工ｎｄｕｓｔｒｉａｌ ａｎ
ａ Ｋｎｇｉｎｅｅｒｉｎｇ Ｃｈｅｍｉｓｔｒｙ、
３２巻、１６頁１，１９４０年））によって製造される
。The acetoacetate used herein is a diketene and has the formula R
From the alcohol represented by 20H, known methods (for example A
, B., Boese, Jr., industrial an.
a Kngineering Chemistry,
32, p. 16, 1940).
前記Ｒ２０Ｈで示されるアルコール類のうち。Among the alcohols represented by R20H.
分子内にニトロキシ基を有するものは、公知の方法４例
えばハロゲン化アルコールを硝酸銀と反応サセル方法［
Ａ、ｙ、Ｆ’ｅｒｒｉｓ ｅｔ ａｌ、、Ｊ、Ａ、Ｏ，
Ｓ。Those having a nitroxy group in the molecule can be prepared using the known method 4, for example, the sacell method of reacting a halogenated alcohol with silver nitrate [
A,y,F'ellis et al,,J,A,O,.
S.
７５巻、４０７Ｂ頁（１９５３年〕〕あるいは１．２−
エポキシドを過酸化窒素ま次は硝酸で開環する方法［Ａ
、Ｍ、Ｐｕｊｏ ｅｔ ａｌ、 、Ｂｕｌｌ、Ｓｏｃ、
Ｃｈｉｍ、Ｆｒａｎｃｅ１９５５年、９７４頁； Ｐ、
Ｌ、Ｎ１ｃｈｏｌｓ Ｊｒ、ｅｔ ａｌ、。Volume 75, page 407B (1953)] or 1.2-
Method of ring-opening epoxide with nitrogen peroxide or nitric acid [A
,M.,Pujo et al., ,Bull,Soc.
Chim, France 1955, p. 974; P.
L, N1chols Jr, et al.
Ｊ 、Ａ、Ｃ，Ｓ、 ７５巻、４２５５頁（１９５３年
〕〕に従って製造される。J, A, C, S, Vol. 75, p. 4255 (1953)].
ま；２’（、Ｒ２０Ｈで示されるアルコール類のうち反
応させることによ！ｌｌ製造される。（上記式中Ａｒ
、Ｒ１、Ｒ２、Ｒ５、Ｒ４、ｍおよびＸは前述したもの
と同意義を示し、Ｙは塩素、臭素、沃素などの〕・ロゲ
ン原子を示す。〕
（Ｗ
（ＶＤ
発明の効果
本発明の前記一般式（１）を有する縮環ジヒドロピリジ
ン誘導体は、以下に示す抗高血圧作用を目的とする薬理
試験において有意な薬効を表わす。M;2'(, is produced by reacting among the alcohols represented by R20H. (In the above formula, Ar
, R1, R2, R5, R4, m and X have the same meanings as described above, and Y represents a ].logen atom such as chlorine, bromine, iodine, etc. ] (W (VD) Effects of the Invention The ring-fused dihydropyridine derivative of the present invention having the general formula (1) exhibits significant medicinal efficacy in the following pharmacological tests aimed at antihypertensive action.
抗高血圧作用
高血圧自然発生ラット（以下ＳＨＲ）に検体を経口投与
して抗高血圧作用を試験した。Antihypertensive effect The antihypertensive effect was tested by orally administering the sample to spontaneously hypertensive rats (hereinafter referred to as SHR).
生後１５週令の雄性ＳＨＲをソジウム ベンドパルビタ
ール（５０ｎＱ／に’４腹腔内投与］で麻酔し、 Ｗｅ
θｌ（８とＪｏｎｅｓ法［、Ｔ、Ｒ１Ｗｅｅｋ８ ａｎ
ｄ Ｊ、Ａ。A 15-week-old male SHR was anesthetized with sodium bendoparbital (50 nQ/'4 intraperitoneal administration).
θl(8 and Jones method [, T, R1Week8 an
d J, A.
Ｊｏｎｅｓ 、Ｐｒｏｃ、Ｓｏｃ、Ｅｘｐｔｌ、Ｂｉｌ
、Ｍｅａ、 、 １０４巻、６４Ｂ−６４８頁（１１０
年り〕に準じて腹部大動脈にポリエチレンカニユーレ１
ｆｌ１人し、カニユーレの他端を体外に導出、頚部に固
定した。術後１週間を経て動物が手術のしん襲から回復
し念時点で、動物のカニユーレの他端を血圧測定装置に
接続し、無麻酔、無拘束状態で血圧および心拍数を直接
法によシ測定した。血圧測定装置はＬａｆｆａｎ等法（
Ｐ、Ｊ、Ｌａｆｆａｎ、Ａ、Ｐ＋３ｔ８ｒ８０ｎ、８．
Ｗ。Jones, Proc, Soc, Exptl, Bill
, Mea, , vol. 104, pp. 64B-648 (110
polyethylene cannula 1 in the abdominal aorta according to
The other end of the cannula was brought out of the body and fixed to the neck. One week after the surgery, when the animal has recovered from the shock of the surgery, the other end of the animal's cannula is connected to a blood pressure measuring device, and the blood pressure and heart rate are directly measured without anesthesia or restraint. It was measured. The blood pressure measuring device uses the Laffan et al. method (
P, J, Laffan, A, P+3t8r80n, 8.
W.
Ｈｌｔｃｈ ａｎｄ Ｏ，Ｊｅｕｎｅｌｏｔ、
（４ｒｄ１ｏｖａｓｃｕユａｒＲｅ８．。Hltch and O, Jeunelot,
(4rd1ovasc uarRe8.
６巻、３１９−３２４頁（１９７２年〕〕 を改良した
ものを使用した。6, pp. 319-324 (1972)] was used.
被験薬物は０．３％カルボキシメチルセルローズに懸濁
させて経口投与し友。投与は、検体投与前１時間コント
ロールの血圧および心拍数を観察し、それらが安定した
時におこなった。検体投与後、血圧および心拍数を１５
分毎に２４時間にわたシ測定し比。The test drug was suspended in 0.3% carboxymethyl cellulose and administered orally. The blood pressure and heart rate of the control subjects were observed for 1 hour before administration of the sample, and administration was performed when they became stable. After administering the sample, blood pressure and heart rate were adjusted to 15%.
Measure and compare every minute over 24 hours.
その結果１例えば実施例５化合物は、ニフェジピンある
いはニカルジピンに比べて緩徐でかつ著しく持続性の降
圧作用を示し友。Results 1 For example, the compound of Example 5 exhibited a slower and significantly more sustained hypotensive action than nifedipine or nicardipine.
被験薬物
実施例５化合物：
従って、前記一般式（１）を有する化合物および狭心症
、心筋梗塞、不整脈、動脈硬化症あるいは脳血管障害な
どの循環器系疾病の治療薬として有用である。その投与
形態としては例えば錠剤、カプセル剤、顆粒剤、散剤、
シロップ剤などによる経口投与法あるいは皮下注射、静
脈内注射、当量などによる非経口投与法があげられる。Compound of Test Drug Example 5: Therefore, the compound having the general formula (1) is useful as a therapeutic agent for circulatory system diseases such as angina pectoris, myocardial infarction, arrhythmia, arteriosclerosis, and cerebrovascular disorders. Examples of dosage forms include tablets, capsules, granules, powders,
Examples include oral administration using syrup, etc., parenteral administration via subcutaneous injection, intravenous injection, and equivalent doses.
これらの各種製剤は常法に従って、目的に応じて生薬に
賦形剤、結合剤、崩壊剤、滑沢剤。These various preparations are prepared according to conventional methods using crude drugs, excipients, binders, disintegrants, and lubricants depending on the purpose.
矯味剤、溶解補助剤、懸濁化剤などの製剤技術分野にお
いて通常使用し得る補助剤を用いて製剤化することがで
きる。その薬用量は症状１年令１体重等および投与方法
、投与回数によって異なるが２通常は成人に対して１日
約３η乃至３００１１Ｉｇであり、１回または数回に分
けて投与することができる。The formulation can be formulated using adjuvants commonly used in the field of formulation technology, such as flavoring agents, solubilizing agents, and suspending agents. The dosage varies depending on symptoms, age, body weight, etc., administration method, and number of administrations, but is usually about 3η to 30,011 Ig per day for adults, and can be administered once or in divided doses.
次に実施例をあげて本発明をさらに具体的に説明する。Next, the present invention will be explained in more detail with reference to Examples.
実施例１
４．７−シヒドロピラゾロ［：３，４−ｂ：ｌピリジン
ｆ１．４７ （ＩＨ，ｓ、 ンＮ且） ＋ ７．１〜
８．１ ５ （８Ｈ、ｍ 。Example 1 4.7-Sihydropyrazolo[:3,4-b:l pyridine f1.47 (IH, s, N and) + 7.1~
8.1 5 (8H, m.
エステル
５−アミノピラゾール０．５０ ｆ （０，００６モル
）、！−２−（３−ニトロベンジリデン〕アセト酢酸５
時間加熱還流した。減圧濃縮後、残渣をシリカゲルカラ
ムクロマトグラフィー（トルエン：酢酸エチル＝３：１
）に付し、黄白色結晶の目的物を得た。トルエン／酢酸
エチルで再結晶した。Ester 5-aminopyrazole 0.50 f (0,006 mol),! -2-(3-nitrobenzylidene)acetoacetic acid 5
The mixture was heated to reflux for an hour. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (toluene:ethyl acetate = 3:1).
) to obtain the desired product as yellowish-white crystals. Recrystallized from toluene/ethyl acetate.
収量 １．５４ｙ（［１３％）ｍｐ１３４ Ｓ−１３６
℃工Ｒスペクトル（ＫＢｒ）νｆｆ１ａＸ ６１１１：
３２００ 。Yield 1.54y ([13%) mp134 S-136
°C engineering R spectrum (KBr) νff1aX 6111:
3200.
３１２ｏ（＞ＮＨ）、目１９０（）Ｏ＝Ｏ）１ｇ２０．
１２７５８８０（、−ＯＮ○２）
ＭＳスペクトルけりｍ／ｅ ： ４０３ （Ｍ＋りＮＭ
Ｒスペクトル（ｃＤａＡ！３）δ：１Ｏ（２Ｈ，ｑｕｌ
ｎ。312o(>NH), 190()O=O)1g20.
1275880 (, -ON○2) MS spectrum cut m/e: 403 (M+riNM
R spectrum (cDaA!3) δ: 1O(2H, qul
n.
Ｊ＝５Ｈｚ 、 −ＣＨ２］Ｈ２０Ｈ２−）、 Ｚ ５
Ｑ （３Ｈ、８、−ＯＨＭ、）。J=5Hz, -CH2]H20H2-), Z5
Q (3H, 8, -OHM,).
４、１５ （２Ｈ、ｔ 、Ｊ ＝５Ｈｚ、−Ｃｏ−ＯＨ
２−） 、４．３２ （２Ｈ。4, 15 (2H, t, J = 5Hz, -Co-OH
2-), 4.32 (2H.
元紫分析易。１７Ｈ１７Ｎ５゜７として計算値（％ｉ）
０．５Ｇ、６２；Ｈ，４゜２５；Ｎ、１７．３６実
測値（＠Ｃ，５α８４；Ｈ，４，３９；Ｎ、１″７．３
１実施例１と同様に反応して、第３表に示した化合物を
得に０
特許出題大 三Original purple analysis easy. Calculated value (%i) as 17H17N5°7
0.5G, 62; H, 4°25; N, 17.36 Actual value (@C, 5α84; H, 4,39; N, 1″7.3
1 React in the same manner as in Example 1 to obtain the compounds shown in Table 3.
Claims (1)
ルキル基、ハロゲノ低級アルコキシ基、シアノ基または
１若しくは２個のハロゲン原子を有していてもよいフエ
ニル基、あるいは式▲数式、化学式、表等があります▼
基を示し、Ｘは式▲数式、化学式、表等があります▼基
（式中、 Ｒ＾３は水素原子、低級アルキル基またはアラルキル基
を示す。）または酸素原子を示し、Ｒ＾１は水素原子、
低級アルキル基、シクロアルキル基、水酸基または低級
アルコキシカルボニル基を示し、Ｒ＾２はニトロキシ基
で置換されたアルキル基、ニトロキシ基で置換されたシ
クロアルキル基、式▲数式、化学式、表等があります▼
基（式中、Ｒ＾４はアラルキル基またはヘテロアラルキ
ル基を示し、ｍは１乃至３の整数を示す。）またはシン
ナミル基を示す。〕を有する縮環ジヒドロピリジン誘導
体又はその酸付加塩。[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, Ar is a nitro group, a halogeno lower alkyl group, a halogeno lower alkoxy group, a cyano group, or one or two halogen atoms as a substituent. There are phenyl groups that may have ▲ mathematical formulas, chemical formulas, tables, etc. ▼
represents a group, and X represents a formula ▲ mathematical formula, chemical formula, table, etc. ▼ group (in the formula, R^3 represents a hydrogen atom, lower alkyl group, or aralkyl group) or an oxygen atom, and R^1 represents hydrogen atom,
Indicates a lower alkyl group, cycloalkyl group, hydroxyl group, or lower alkoxycarbonyl group, R^2 is an alkyl group substituted with a nitroxy group, a cycloalkyl group substituted with a nitroxy group, formula ▲ Numerical formula, chemical formula, table, etc. ▼
group (wherein R^4 represents an aralkyl group or a heteroaralkyl group, m represents an integer of 1 to 3) or a cinnamyl group. ] or an acid addition salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63191070A JP2634640B2 (en) | 1988-07-29 | 1988-07-29 | Fused dihydropyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63191070A JP2634640B2 (en) | 1988-07-29 | 1988-07-29 | Fused dihydropyridine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0240385A true JPH0240385A (en) | 1990-02-09 |
| JP2634640B2 JP2634640B2 (en) | 1997-07-30 |
Family
ID=16268371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63191070A Expired - Fee Related JP2634640B2 (en) | 1988-07-29 | 1988-07-29 | Fused dihydropyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2634640B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5067739A (en) * | 1990-12-21 | 1991-11-26 | Kuan Chung A | Structure of motorcycle stand |
| US6538004B2 (en) | 2000-03-03 | 2003-03-25 | Abbott Laboratories | Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers |
| WO2011003604A1 (en) | 2009-07-10 | 2011-01-13 | Bayer Schering Pharma Aktiengesellschaft | Indazolyl-substituted dihydroisoxa-zolopyridines and methods of use thereof |
-
1988
- 1988-07-29 JP JP63191070A patent/JP2634640B2/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5067739A (en) * | 1990-12-21 | 1991-11-26 | Kuan Chung A | Structure of motorcycle stand |
| US6538004B2 (en) | 2000-03-03 | 2003-03-25 | Abbott Laboratories | Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers |
| US6780872B2 (en) | 2000-03-03 | 2004-08-24 | Abbott Laboratories | Tricyclic dihydropyrazolone and tricyclic dihydroisoxazolone potassium channel openers |
| WO2011003604A1 (en) | 2009-07-10 | 2011-01-13 | Bayer Schering Pharma Aktiengesellschaft | Indazolyl-substituted dihydroisoxa-zolopyridines and methods of use thereof |
| US9073939B2 (en) | 2009-07-10 | 2015-07-07 | Bayer Intellectual Property Gmbh | Indazolyl-substituted dihydroisoxa-zolopyridines and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2634640B2 (en) | 1997-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4892875A (en) | Substituted heterocyclylalkyl esters of 1,4-dihydropyridine-3,5-dicarboxylic acids | |
| US4707486A (en) | Diaryl piperidine containing esters of 1,4-dihydropyridines and coronary therapeutic use | |
| JPS63253082A (en) | Dihydropyridine derivative | |
| CA2174969C (en) | Short-acting dihydropyridines | |
| WO1993022298A1 (en) | Oxazolidine derivative and pharmaceutically acceptable salt thereof | |
| KR920005742B1 (en) | Process for the preparation of pharmaceutically useful dihydropyridinyl dicanboxylate amide and esters | |
| DK2157083T3 (en) | Pharmaceutical compositions containing the crystalline form (I) of lercanidipine hydrochloride | |
| CZ396591A3 (en) | Enantiomers of 1,4-dihydropyridine process of their preparation and pharmaceutical compositions prepared therefrom | |
| CA1330994C (en) | Flavone derivatives | |
| KR960009427B1 (en) | 1,4-dihydropyridine derivatives | |
| JPS61257983A (en) | 1,4-dihydropyridine and medicinal composition | |
| JPH036151B2 (en) | ||
| JPH0240385A (en) | Condensed ring dihydropyridine derivative | |
| US4874773A (en) | 3-Aminocarbonyl-1,4-dihydropyridine-5-carboxylic acid compounds, and pharmaceutical composition containing the same | |
| JPH01319479A (en) | Novel derivative of 5-aminomethyl-2- flanomethanol, its production and use | |
| JPS6256474A (en) | Dihydropyridine-2-hydroxyamines | |
| JPS6289662A (en) | 1,4-dihydropyridine derivative | |
| US5064839A (en) | 1,4-dihydropyridines with a 2-amino group or with an ether group in a side chain | |
| JPS58208271A (en) | 1,4-dihydropyridine derivative | |
| NZ202473A (en) | 6-(pyridinylvinyl)pyridazinone derivatives and pharmaceutical compositions | |
| JP2664941B2 (en) | 1,4-dihydropyridine compound | |
| JPH0714931B2 (en) | Novel dihydropyridine derivative, production method and use thereof | |
| EP0280239B1 (en) | 1,4-dihydropyridine derivatives, production and use thereof | |
| JPH0755955B2 (en) | Optically active dihydropyridine-5-phosphonate | |
| JPS63233992A (en) | Dihydropyridine-5-phosphonic acid cyclic esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |