JPS63264459A - Novel 1,4-dihydropyridine derivative and production thereof - Google Patents
Novel 1,4-dihydropyridine derivative and production thereofInfo
- Publication number
- JPS63264459A JPS63264459A JP30925687A JP30925687A JPS63264459A JP S63264459 A JPS63264459 A JP S63264459A JP 30925687 A JP30925687 A JP 30925687A JP 30925687 A JP30925687 A JP 30925687A JP S63264459 A JPS63264459 A JP S63264459A
- Authority
- JP
- Japan
- Prior art keywords
- group
- lower alkyl
- dimethyl
- alkyl group
- compound
- 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.)
- Pending
Links
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000004450 alkenylene group Chemical group 0.000 claims abstract description 5
- 125000004419 alkynylene group Chemical group 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000002785 azepinyl group Chemical group 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 1
- 125000000168 pyrrolyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 69
- 238000010992 reflux Methods 0.000 abstract description 10
- 150000001412 amines Chemical class 0.000 abstract description 8
- 150000008065 acid anhydrides Chemical class 0.000 abstract description 5
- 150000004820 halides Chemical class 0.000 abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 2
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 206010003119 arrhythmia Diseases 0.000 abstract description 2
- 230000006793 arrhythmia Effects 0.000 abstract description 2
- 230000000747 cardiac effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- 150000002367 halogens Chemical class 0.000 abstract 2
- 206010061216 Infarction Diseases 0.000 abstract 1
- JGDXOAKKXJBIEQ-UHFFFAOYSA-N dimethyl 2,6-dimethyl-4-[5-nitro-2-[4-(3-phenoxypropylamino)butoxy]phenyl]-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC([N+]([O-])=O)=CC=C1OCCCCNCCCOC1=CC=CC=C1 JGDXOAKKXJBIEQ-UHFFFAOYSA-N 0.000 abstract 1
- 125000000623 heterocyclic group Chemical group 0.000 abstract 1
- 230000007574 infarction Effects 0.000 abstract 1
- 208000001286 intracranial vasospasm Diseases 0.000 abstract 1
- -1 inpentyl group Chemical group 0.000 description 203
- 238000006243 chemical reaction Methods 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 230000002213 calciumantagonistic effect Effects 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 230000008485 antagonism Effects 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 230000005923 long-lasting effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000000542 sulfonic acid group Chemical group 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 230000004872 arterial blood pressure Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000035487 diastolic blood pressure Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000000304 vasodilatating effect Effects 0.000 description 3
- YYULDJCBOJBWHI-UHFFFAOYSA-N 2-[4-(1,3-dioxoisoindol-2-yl)butylsulfanyl]-5-nitrobenzaldehyde Chemical compound O=CC1=CC([N+](=O)[O-])=CC=C1SCCCCN1C(=O)C2=CC=CC=C2C1=O YYULDJCBOJBWHI-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 229960001597 nifedipine Drugs 0.000 description 2
- 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 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical group CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- 125000005923 1,2-dimethylpropyloxy group Chemical group 0.000 description 1
- 125000004720 1,2-dimethylpropylthio group Chemical group CC(C(C)C)S* 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004812 1-ethylethylene group Chemical group [H]C([H])([H])C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 125000004717 1-ethylpropylthio group Chemical group C(C)C(CC)S* 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- WGLLSSPDPJPLOR-UHFFFAOYSA-N 2,3-dimethylbut-2-ene Chemical group CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004714 2-methylbutylthio group Chemical group CC(CS*)CC 0.000 description 1
- JMMZCWZIJXAGKW-UHFFFAOYSA-N 2-methylpent-2-ene Chemical group CCC=C(C)C JMMZCWZIJXAGKW-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QIJCTJUOELGAEC-UHFFFAOYSA-N 4-[2-(4-aminobutylsulfanyl)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC([N+]([O-])=O)=CC=C1SCCCCN QIJCTJUOELGAEC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- SSUFDOMYCBCHML-UHFFFAOYSA-N CCCCC[S](=O)=O Chemical group CCCCC[S](=O)=O SSUFDOMYCBCHML-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000002431 aminoalkoxy group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 210000002376 aorta thoracic Anatomy 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 150000001639 boron compounds Chemical class 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000005569 butenylene group Chemical group 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
- 125000005622 butynylene group Chemical group 0.000 description 1
- OKLAEQBUDFSNDL-UHFFFAOYSA-N calcium;1,4-dihydropyridine Chemical compound [Ca].C1C=CNC=C1 OKLAEQBUDFSNDL-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 238000000354 decomposition reaction Methods 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 229940085304 dihydropyridine derivative selective calcium channel blockers with mainly vascular effects Drugs 0.000 description 1
- DYYYPIJLRRHUPR-UHFFFAOYSA-N dimethyl 1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=CNC=C(C(=O)OC)C1 DYYYPIJLRRHUPR-UHFFFAOYSA-N 0.000 description 1
- OOZCFDZVXLWKOS-UHFFFAOYSA-N dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC([N+]([O-])=O)=CC=C1OCCCCN OOZCFDZVXLWKOS-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000005949 ethanesulfonyloxy group Chemical group 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- ZYBWTEQKHIADDQ-UHFFFAOYSA-N ethanol;methanol Chemical compound OC.CCO ZYBWTEQKHIADDQ-UHFFFAOYSA-N 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 230000001965 increasing effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000005921 isopentoxy group Chemical group 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([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])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000005767 propoxymethyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])[#8]C([H])([H])* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 102220082456 rs116157972 Human genes 0.000 description 1
- 102220127451 rs267597943 Human genes 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc 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
- 125000005922 tert-pentoxy group Chemical group 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 231100000691 up-and-down procedure Toxicity 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (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、医薬殊に持続性に優れたカルシララム拮抗剤
として有用な、下記一般式(1)で示される新規1,4
−ジヒドロピリジン誘導体及びその塩、並びにこれらの
製造法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides a novel 1,4 compound represented by the following general formula (1) which is useful as a medicine, especially as a long-lasting calcilaram antagonist.
- Dihydropyridine derivatives and salts thereof, and methods for producing them.
(式中の記号は以下の意味を示す。(The symbols in the formula have the following meanings.
R1及びR2;同−又は異って、酸素原子によって中断
されていてもよいアルキル基、シクロアルキル置換低級
アルキル基、又は)・ロゲン置換低級アルキル基。R1 and R2; the same or different, an alkyl group optionally interrupted by an oxygen atom, a cycloalkyl-substituted lower alkyl group, or a)-logen-substituted lower alkyl group.
R3及びR4m同−又は異って、低級アルキル基。R3 and R4m are the same or different, lower alkyl groups.
R5及びR6;同−又は異って、水素原子、ニトロ基、
ハロゲン原子、低級アルキル基、低級アルコキシ基、低
級アルキルチオ基、低級アルキルスルホニル基、又は低
級アルキルスルフィニル基。R5 and R6; same or different, hydrogen atom, nitro group,
A halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfonyl group, or a lower alkylsulfinyl group.
R7;水素原子又は低級アルキル基。R7; hydrogen atom or lower alkyl group.
R8;低級アルキル基、ヒドロキシ低級アルキル基、ア
ラルキル基、アリール基、低級アシル基、低級アルキル
スルホニル基、アリールオキシ低級アルキル基、又はア
リールオキシ低級アルコキシ基。R8; lower alkyl group, hydroxy lower alkyl group, aralkyl group, aryl group, lower acyl group, lower alkylsulfonyl group, aryloxy lower alkyl group, or aryloxy lower alkoxy group.
但し、R7及びR8とは窒素原子と一体となりビロール
環、ピペリジン環9モルホリン環。However, R7 and R8 are combined with a nitrogen atom to form a virol ring, a piperidine ring, and a 9-morpholine ring.
4位が低級アルキル基又はアラルキル基で置換されてい
てもよいピペラジン環、又番まアゼピン環を形伐してい
てもよい。A piperazine ring, which may be substituted at the 4-position with a lower alkyl group or an aralkyl group, or a round azepine ring may be formed.
Y;酸素原子又は硫黄原子。Y: oxygen atom or sulfur atom.
A;アルキレン基、アルケニレン基、又はアルキニレン
基。)
(従来の技術)
ニフェジピンやニカルジピンがカルシウム拮抗作用に基
づいて脳及び/又は冠血管拡張作用を示すことが確認さ
れて一1以来、1,4−ジヒドロピリジン骨格を有する
種々のカルシウム拮抗剤の開発が盛んである。A; alkylene group, alkenylene group, or alkynylene group. ) (Prior art) Since it was confirmed that nifedipine and nicardipine exhibit cerebral and/or coronary vasodilatory effects based on their calcium antagonistic effects, various calcium antagonists having a 1,4-dihydropyridine skeleton have been developed. is popular.
本発明の化合物は、これら公知の1.4−ジヒドロピリ
ジン系カルシウム拮抗剤と、4位フェニル基の置換基を
異にする点に化学構造上の特徴を有する新規化合物であ
り、かつカルシウム拮抗作用の持続性に優れている点に
薬理上の特徴を有する。The compound of the present invention is a novel compound having chemical structural characteristics that differs from these known 1,4-dihydropyridine calcium antagonists in that the substituent on the phenyl group at the 4-position is different, and it also exhibits calcium antagonistic action. It has pharmacological characteristics in that it is long-lasting.
従来、特開昭61−12662号、特開昭61−233
669号に、一般式
(置換基の種類は特開昭61−12662号を参照)等
で示される化合物が、カルシウム拮抗作用及びベータ遮
断作用を併有するものとして記載されている。これに対
し1本願の化合物はベータ遮断作用は無く、カルシウム
拮抗作用のみを有し、しかもこの作用が従来に無く持続
的である点を特徴とする。Previously, JP-A-61-12662, JP-A-61-233
No. 669 describes compounds represented by the general formula (see JP-A-61-12662 for types of substituents) as having both calcium antagonistic and beta-blocking actions. On the other hand, the compound of the present application has no beta-blocking action, but only a calcium antagonistic action, and is characterized in that this action is unprecedented and sustained.
また、特開昭60−136558号に、一般式(置換基
の種類は特開昭60−136558号を参照)で示され
る化合物が、カルシウム拮抗作用及びベータ遮断作用を
併有するものとして開示されている。これに対し本願化
合物は先述の薬効の差のみならず、構造も異なる新規の
化合物である。Furthermore, JP-A No. 60-136558 discloses a compound represented by the general formula (see JP-A No. 60-136558 for types of substituents) as having both calcium antagonistic and beta-blocking actions. There is. In contrast, the compound of the present application is a novel compound that not only has the above-mentioned difference in medicinal efficacy but also has a different structure.
(解決手段)
本発明者らは9種々の1,4−ジヒドロピリジン系の新
規化合物を創製し、持続性に優れたカルシウム拮抗作用
を発現する化合物をスクリーニングした結果9頭記一般
式(I)で示される化合物及びその塩が格別顕著な効果
を有することを知見して本発明を完成した。(Solution Means) The present inventors created nine different 1,4-dihydropyridine-based novel compounds, and as a result of screening for compounds that exhibit excellent long-lasting calcium antagonism, nine compounds with the general formula (I) The present invention was completed based on the finding that the shown compound and its salt have particularly remarkable effects.
すなわち9本発明は頭記一般式(I)で示される化合物
及びその塩とその製造法の提供を目的とする。That is, the object of the present invention is to provide a compound represented by the above general formula (I), a salt thereof, and a method for producing the same.
本発明化合物について詳述すると以下の通りである。The details of the compound of the present invention are as follows.
本明細書の一般式の定義において、特に断わらない限り
、「低級」なる用語は炭素数が1乃至6個の直鎖又は分
岐状の炭素鎖を意味する。In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.
従って、「低級アルキル基」としては、具体的には例え
ばメチル基、エチル基、プロピル基、イソプロピル基、
ブチル基、イソブチル基、5ec−ブチル基、 ter
t−ブチル基、ペンチル基、インペンチル基、ネオペン
チル基+ tert−ペンチル基。Therefore, the "lower alkyl group" specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
Butyl group, isobutyl group, 5ec-butyl group, ter
t-butyl group, pentyl group, inpentyl group, neopentyl group + tert-pentyl group.
1−メチルブチル基、2−メチルブチル基、1,2−ジ
メチルプロピル基、ヘキシル基、イソヘキシル基、1−
メチルペンチル基、2−メチルペンチル基、3−メチル
ペンチル基、1,1−ジメチルブチル基、1,2−ジメ
チルブチル基、2,2−ジメチル基、1,3−ジメチル
ブチル基、2,3−ジメチルブチル基、3,3−ジメチ
ルブチル基、1−エチルブチル基、2−エチルブチル基
、1,1,2−)ジメチルプロピル基、 1,2.2
−1−ジメチルプロピル基。1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-
Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethyl group, 1,3-dimethylbutyl group, 2,3 -dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-)dimethylpropyl group, 1,2.2
-1-dimethylpropyl group.
1−エチル−1−メチルプロピル基、1−エチル−2−
メチルプロピル基等が挙げられる。1-ethyl-1-methylpropyl group, 1-ethyl-2-
Examples include methylpropyl group.
また、[低級アル゛コキシ基」としては、メトキシ基、
エトキシ基、プロポキシ基、インプロポキシ基、ブトキ
シ基、インブトキシ基、 Bee−ブトキシ基、 te
rt−ブトキシ基、ペンチルオキシ(アミルオキシ)基
、イソペンチルオキシ基、 tert−ペンチルオキシ
基、ネオペンチルオキシ基、2−メチルブトキシ基、1
,2−ジメチルプロポキシ基、1−エチルプロポキシ基
、ヘキシルオキシ基等が挙げられる。In addition, as [lower alkoxy group], methoxy group,
Ethoxy group, propoxy group, impropoxy group, butoxy group, imbutoxy group, Bee-butoxy group, te
rt-butoxy group, pentyloxy (amyloxy) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1
, 2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, and the like.
「低級アルキルチオ基」としては、上記低級アルコキシ
基の酸素原子が、硫黄原子となったもので、具体的には
、メチルチオ基、エチルチオ基。A "lower alkylthio group" is one in which the oxygen atom of the above-mentioned lower alkoxy group has become a sulfur atom, and specifically, a methylthio group and an ethylthio group.
プロピルチオ基、インプロピルチオ基、ブチルチオ基、
5ee−ブチルチオ基、 tert−ブチルチオ
基。propylthio group, inpropylthio group, butylthio group,
5ee-butylthio group, tert-butylthio group.
ペンチルチオ基、ネオペンチルチオ基、2−メチルブチ
ルチオ基、1,2−ジメチルプロピルチオ基。pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group.
1−エチルプロピルチオ基、ヘキシルチオ基等が、また
、低級アルキルスルホニル基、及び低級アルキルスルフ
ィニル基としては、前記低級アルキル基によって置換さ
れたスルホニル基及びスルフィニル基を意味し。1-ethylpropylthio group, hexylthio group, etc., and lower alkylsulfonyl group and lower alkylsulfinyl group mean a sulfonyl group and sulfinyl group substituted with the above-mentioned lower alkyl group.
具体的には、メチルスルホニル(又ハスルフィニル)基
、エチルスルホニル(又&−tスルフィニル)基、プロ
ピルスルホニル(又ハスルフィニル)基。Specifically, methylsulfonyl (also hasulfinyl) group, ethylsulfonyl (also &-tsulfinyl) group, propylsulfonyl (also hasulfinyl) group.
ブチルスルホニル(又はスルフィニル)基、イソブチル
スルホニル(又はスルフィニル)Lペンチルスルホニル
(又はスルフィニル)基、ヘキシルスルホニル(又はス
ルフィニル)基等が挙げられる。Examples include butylsulfonyl (or sulfinyl) group, isobutylsulfonyl (or sulfinyl) L pentylsulfonyl (or sulfinyl) group, hexylsulfonyl (or sulfinyl) group, and the like.
また、「シクロアルキル置換低級アルキル基」は、上記
「低級アルキル基」の任意の水素原子が「シクロアルキ
ル基」で置換された基を意味し。Furthermore, the term "cycloalkyl-substituted lower alkyl group" means a group in which any hydrogen atom of the above-mentioned "lower alkyl group" is substituted with a "cycloalkyl group".
[シクロアルキル基」としては具体的には、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
キシル基環炭素数3乃至6個の脂環式基が好適である。As the [cycloalkyl group], specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and an alicyclic group having 3 to 6 ring carbon atoms are preferable.
従って、「シクロアルキル置換低級アルキル基」の具体
例としては、クロロヘキシル基で例示すれば、シクロヘ
キシルメチル基。Therefore, a specific example of a "cycloalkyl-substituted lower alkyl group" is a cyclohexylmethyl group, exemplified by a chlorohexyl group.
2−シクロヘキシルエチル基、3−シクロヘキシルプロ
ピル基、2−シクロへキシル−1−メチルエチル基、4
−シクロへキシルブチル基、5−シクロヘキシルペンチ
ル基、6−シクロ全キシルヘキシル基等が挙げられる。2-cyclohexylethyl group, 3-cyclohexylpropyl group, 2-cyclohexyl-1-methylethyl group, 4
-cyclohexylbutyl group, 5-cyclohexylpentyl group, 6-cycloall-xylhexyl group, and the like.
さらに、「ハロゲン置換低級アルキル基」は。Furthermore, "halogen-substituted lower alkyl group".
上記[低級アルキル基」の任意の1乃至3個の水素原子
が「ハロゲン原子」で置換された基を意味し、この場合
の「ハロゲン原子」としては、フッ素原子、塩素原子、
臭素原子等が好適である。従って、「ハロゲン置換低級
アルキル基」の具体例としては、塩素原子で例示すれば
、クロロメチル基、トリクロロメチル基、2−クロロエ
チル基。It means a group in which any 1 to 3 hydrogen atoms of the above [lower alkyl group] are substituted with a "halogen atom", and in this case, the "halogen atom" includes a fluorine atom, a chlorine atom,
A bromine atom or the like is preferred. Therefore, specific examples of the "halogen-substituted lower alkyl group" include a chloromethyl group, a trichloromethyl group, and a 2-chloroethyl group, as exemplified by a chlorine atom.
3−クロロプロピル基、2−クロロ−1−メチルエチル
基、4−クロロブチル基、5−クロロペンチル基、6−
クロロヘキシル基等が挙げられる。3-chloropropyl group, 2-chloro-1-methylethyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-
Examples include chlorohexyl group.
また「ヒドロキシ低級アルキル基」は、上記「低級アル
キル基」の任意の水素原子が、[ヒドロキシ基」で置換
された基を意味し、具体的には。Moreover, "hydroxy lower alkyl group" means a group in which any hydrogen atom of the above-mentioned "lower alkyl group" is substituted with a [hydroxy group], specifically.
ヒドロキシメチル基、2−ヒドロキシエチル基。Hydroxymethyl group, 2-hydroxyethyl group.
1−ヒドロキシエチル基、3−ヒドロキシプロピ/L/
基+2−ヒドロキシプロピル基、2−ヒドロキシ−2−
メチルエチル基、1−ヒドロキシ−2−メチルエチル基
、4−ヒドロキシブチル基、5−ヒドロキンペンチル基
、6−ヒドロキシヘキシル基等が挙げられる。1-hydroxyethyl group, 3-hydroxypropy/L/
group +2-hydroxypropyl group, 2-hydroxy-2-
Examples include methylethyl group, 1-hydroxy-2-methylethyl group, 4-hydroxybutyl group, 5-hydroxypentyl group, and 6-hydroxyhexyl group.
「アリールオキシ低級アルキル基」や「アリールオキシ
低級アルコキシ基」は、上記「低級アルキル基jや「低
級アルコキシ基jの任意の水素原子が「アリールオキシ
基」で置換された基を意味し、「アリールオキシ基」と
しては具体的にはフェノキシ基、ナフチルオキシ基等で
あり、特にフェノキシ基が好適である。従って、「アリ
ールオキシ低級アルキル基」の具体例としては、フェノ
キシ基で例示すれば、フェノキンメチル基、フェノキシ
エチル基、フェノキシプロピル基、1−メチル−2−フ
ェノキシエチル基、フェノキシブチル基、1−メチル−
3−フェノキシプロピル基、フェノキシペンチル基、フ
ェノキシヘキシル基等が挙げられる。"Aryloxy lower alkyl group" and "aryloxy lower alkoxy group" mean a group in which any hydrogen atom of the above-mentioned "lower alkyl group j or "lower alkoxy group j is substituted with an "aryloxy group"; Specific examples of the "aryloxy group" include phenoxy group and naphthyloxy group, with phenoxy group being particularly preferred. Therefore, specific examples of "aryloxy lower alkyl groups" include phenoxy groups such as fenoquinemethyl group, phenoxyethyl group, phenoxypropyl group, 1-methyl-2-phenoxyethyl group, phenoxybutyl group, -Methyl-
Examples include 3-phenoxypropyl group, phenoxypentyl group, phenoxyhexyl group, and the like.
また、「アリールオキシ低級アルコキシ基」の具体例と
しては、フェノキシ基で例示すれば、フェノキシメトキ
シ基、フェノキシエトキシ基、フェノキンプロポキシ基
、l−メチル−2−フェノキシエトキン基、フェノキシ
ブトキシ基、1−メチル−3−フェノキシプロポキン基
、フェノキシペンチルオキン基、フェノキンヘキシルオ
キシ基等が挙げられる。Specific examples of the "aryloxy lower alkoxy group" include phenoxy groups such as phenoxymethoxy group, phenoxyethoxy group, phenoxypropoxy group, l-methyl-2-phenoxyethoxy group, phenoxybutoxy group, Examples include a 1-methyl-3-phenoxypropoquine group, a phenoxypentyloquine group, and a phenoxyhexyloxy group.
「酸素原子によって中断されていてもよいアルキル基1
は、[アルキル基j及び「酸素原子によって中断された
アルキル基」の双方を含む。「アルキル基」は炭素数が
1乃至10個の直鎖又は分岐状のものが好適である。従
って、「アルキル基」としては、具体的には前記「低級
アルキル基」の具体例に加えて、さらにヘプチル基、5
−メチルヘキシル基、オクチル基、6−メチルヘプチル
基。"Alkyl group optionally interrupted by an oxygen atom 1
includes both [alkyl group j and "alkyl group interrupted by an oxygen atom"]. The "alkyl group" is preferably a straight chain or branched group having 1 to 10 carbon atoms. Therefore, in addition to the specific examples of the above-mentioned "lower alkyl group", examples of "alkyl group" include heptyl group, 5
-Methylhexyl group, octyl group, 6-methylheptyl group.
ノニル基、7−メチルオクチル基、デシル基、8−メチ
ルノニル基等が挙げられる。Examples include nonyl group, 7-methyloctyl group, decyl group, and 8-methylnonyl group.
一方、「酸素原子で中断されたアルキル基」としては、
1乃至3個の酸素原子で炭素数が2乃至10個のものが
好適であり、具体的には例えば。On the other hand, as an "alkyl group interrupted by an oxygen atom",
One having 1 to 3 oxygen atoms and 2 to 10 carbon atoms is preferable, and specifically, for example.
メトキンメチル基、1−メトキ7エチル基、2−メトキ
シエチル基、エトキシメチル基、3−メトキシプロピル
基、2−メトキシプロピル基、2−ニトキシエチル基、
プロポキシメチル基、インプロポキシメチル基、4−メ
トキシブチル基、3−エトキシグロビル基、2−プロポ
キシエチル基。Metquinmethyl group, 1-methoxyethyl group, 2-methoxyethyl group, ethoxymethyl group, 3-methoxypropyl group, 2-methoxypropyl group, 2-nitoxyethyl group,
Propoxymethyl group, inpropoxymethyl group, 4-methoxybutyl group, 3-ethoxyglobyl group, 2-propoxyethyl group.
ブトキシメチル基、5−メトキシペンチル基、4−エト
キシブチル基、2−(2−エトキクエトキシ)エチル基
[3,6−シオキサオクチル基コ、2−ブトキシエチル
基、ペンチルオキシメチル基。Butoxymethyl group, 5-methoxypentyl group, 4-ethoxybutyl group, 2-(2-ethoxyethoxy)ethyl group [3,6-thioxaoctyl group, 2-butoxyethyl group, pentyloxymethyl group.
6−メドキシヘキシル基、5−エトキシペンチル基、2
−ペンチルオキシエチル基、ヘキシルオキシメチル基、
7−メドキシヘプチル基、6−ニトキシヘキシル基、2
−[2−(2−エトキシエトキシ)エトキシコニチル基
[3,6,9−トリオキサウンデシル基]、2−ヘキシ
ルオキシエチル基。6-medoxyhexyl group, 5-ethoxypentyl group, 2
-pentyloxyethyl group, hexyloxymethyl group,
7-medoxyheptyl group, 6-nitoxyhexyl group, 2
-[2-(2-ethoxyethoxy)ethoxyconityl group [3,6,9-trioxaundecyl group], 2-hexyloxyethyl group.
ヘプチルオキシメチル基、8−メトキシオクチル基、7
−ニトキシヘプチル基、2−へブチルオキシエチル基、
オクチルオキシメチル基、9−メトキシノニル基等が挙
げられる。heptyloxymethyl group, 8-methoxyoctyl group, 7
-nitoxyheptyl group, 2-hebutyloxyethyl group,
Examples include octyloxymethyl group and 9-methoxynonyl group.
「アリール基」としては、具体的にはフェニル基、ナフ
チル基等が挙げられるが特にフェニル基が好ましい。Specific examples of the "aryl group" include phenyl group, naphthyl group, etc., with phenyl group being particularly preferred.
[アラルキル基」としては、ベンジル基、)工ネチル基
、フェニルプロピル基等、前記「低級アルキル基」の任
意の水素原子が前記「アリール基Jで置換された基を意
味する。[Aralkyl group] refers to a group in which any hydrogen atom of the above-mentioned "lower alkyl group" is substituted with the above-mentioned "aryl group J, such as a benzyl group, a netethyl group, or a phenylpropyl group.
Aが示すアルキレン基としては、炭素数が1乃至12個
のアルキレン基が好適であり、具体的には、メチレン基
、エチレン、メチルメチレン基メチレン基、2−メチル
トリメチレン基、3−メチルトリメチレン基、1−エチ
ルエチレン基トラメチレン基、2−メチルテトラメチレ
ン基。The alkylene group represented by A is preferably an alkylene group having 1 to 12 carbon atoms, specifically, methylene group, ethylene, methylmethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, etc. Methylene group, 1-ethylethylene group, tramethylene group, 2-methyltetramethylene group.
3−メチルテトラメチレン基、4−メチルテトラメチレ
ン基、1,1−ジメチルトリメチレン基。3-methyltetramethylene group, 4-methyltetramethylene group, 1,1-dimethyltrimethylene group.
2.2−ジメチルトリメチレン基、3,3−ジメチルト
リメチレン基、1,3−ジメチルトリメチレン基。2.2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group.
2.3−ジメチルトリメチレン基、1,2−ジメチルト
リメチレン基、1−エチルトリメチレン基。2.3-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1-ethyltrimethylene group.
1.1.2− )リメチルエチレン基、ジエチルメチレ
ン基、ヘキサメチレン基、1−メチルペンタメチレン基
、1,1−ジメチルテトラメチレン基、2,2−ジメチ
ルテトラメチレン基、3,3−ジメチルテトラメチレン
基、4,4−ジメチルテトラメチレン基、 1,1.
3−1リメチルトリメチレン基、 1,1.2−ドリ
メチルトリメチレン基、 1,1,2.2−テトラメ
チルエチレン基g 1,1−ジメチル−2−エチルエチ
レン基、 1.1−ジエチルエチレン基、ヘプタメチ
レン基、1−メチルへキサメチレン基、1,1−ジメチ
ルペンタメチレン基、2,2−ジメチルペンタメチレン
基、3,3−ジメチルペンタメチレン基、4,4−ジメ
チルペンタメチレン基、5,5−ジメチルペンタメチレ
ン基、 1,1.4−1−ジメチルテトラメチレン基
、1,1.2−)ジメチルテトラメチレン基、 1,
1.3−1−ジメチルテトラメチレン基。1.1.2-) Limethylethylene group, diethylmethylene group, hexamethylene group, 1-methylpentamethylene group, 1,1-dimethyltetramethylene group, 2,2-dimethyltetramethylene group, 3,3-dimethyl Tetramethylene group, 4,4-dimethyltetramethylene group, 1,1.
3-1-trimethyltrimethylene group, 1,1.2-drimethyltrimethylene group, 1,1,2.2-tetramethylethylene groupg 1,1-dimethyl-2-ethylethylene group, 1.1- Diethylethylene group, heptamethylene group, 1-methylhexamethylene group, 1,1-dimethylpentamethylene group, 2,2-dimethylpentamethylene group, 3,3-dimethylpentamethylene group, 4,4-dimethylpentamethylene group , 5,5-dimethylpentamethylene group, 1,1.4-1-dimethyltetramethylene group, 1,1.2-)dimethyltetramethylene group, 1,
1.3-1-dimethyltetramethylene group.
1.1,2.2−テトラメチルトリメチレン基、 1
,1,3゜3−テトラメチルトリメチレン基、1.1−
ジメチル−2−エチルトリメチレン基、1.l−ジメチ
ル−3−エチルトリメチレン基、オクタメチレン基。1.1,2.2-tetramethyltrimethylene group, 1
,1,3゜3-tetramethyltrimethylene group, 1.1-
Dimethyl-2-ethyltrimethylene group, 1. l-dimethyl-3-ethyltrimethylene group, octamethylene group.
1−メチルへブタメチレン基、1,1−ジメチルへキサ
メチレン基、ノナメチレン基、1−メチルオクタメチレ
ン基、1,1−ジメチルへブタメチレン基、デカメチレ
ン基、1−メチルノナメチレン基。1-methylhebutamethylene group, 1,1-dimethylhexamethylene group, nonamethylene group, 1-methyloctamethylene group, 1,1-dimethylhebutamethylene group, decamethylene group, 1-methylnonamethylene group.
1.1−ジメチルオクタメチレン基、ウンデカメチレン
基、1−メチルデカメチレン基、1,1−ジメチルノナ
メチレン基、ドデカメチレン基、1.1−ジメチルデカ
メチレン基等が挙げられる。Examples thereof include 1.1-dimethyloctamethylene group, undecamethylene group, 1-methyldecamethylene group, 1,1-dimethylnonamethylene group, dodecamethylene group, and 1.1-dimethyldecamethylene group.
また、Aが示すアルケニレン基としては、炭素数が2乃
至12個のものが好ましく、具体的には。Further, the alkenylene group represented by A preferably has 2 to 12 carbon atoms, specifically.
例、t ハヒニレン基、フロペニレン基(−CH2CH
=CH−) 。Examples, t hahinylene group, flopenylene group (-CH2CH
=CH-).
2−プロペニレン基(−CH=CH−CH2−)、 1
−メチルビニレン基、2−メチルビニレン基、ブテニレ
ン基、2−ブテニレン基+ 3 7”7ニレン基、1
−メチルプロペニレン基、1−メチル−2−プロペニレ
ン基、ヘンテニレン基、1−メチルブテニレン基、1−
メチル−2−フテニレン基、1−ifルー3−7’fニ
レン基、 1.1−ジメチル−2−グロペニレン基、
ヘキセニレン基、2−ヘキセニレン基、3−ヘキセニレ
ン基、4−ヘキセニレン基。2-propenylene group (-CH=CH-CH2-), 1
-Methylvinylene group, 2-methylvinylene group, butenylene group, 2-butenylene group + 3 7"7nylene group, 1
-Methylpropenylene group, 1-methyl-2-propenylene group, hentenylene group, 1-methylbutenylene group, 1-
Methyl-2-phthenylene group, 1-if-3-7'f nylene group, 1.1-dimethyl-2-gropenylene group,
hexenylene group, 2-hexenylene group, 3-hexenylene group, 4-hexenylene group.
5−ヘキセニレン基、1−メチル−2−ペンテニレン基
、1−メチルー3−ペンテニレン基t 1,1−ジメ
チル−2−ブテニレン基、1,1−ジメチル−3−ブテ
ニレン基、ヘキセニレン基、2−へブチニレ7es
3−へブテニレン基、4−へブテニレン基、5−へブテ
ニレン基、6−へブテニレン基、1,1−ジメチル−2
−ペンテニレン基、1,1−ジメチル−3−ペンテニレ
ン基、1,1−ジメチル−4−ペンテニレン基、2−オ
クテニレン基。5-hexenylene group, 1-methyl-2-pentenylene group, 1-methyl-3-pentenylene group t 1,1-dimethyl-2-butenylene group, 1,1-dimethyl-3-butenylene group, hexenylene group, 2- spotted elm 7es
3-hebutenylene group, 4-hebutenylene group, 5-hebutenylene group, 6-hebutenylene group, 1,1-dimethyl-2
-pentenylene group, 1,1-dimethyl-3-pentenylene group, 1,1-dimethyl-4-pentenylene group, 2-octenylene group.
4−オクテニレン基、7−オクテニレン基、1,1−ジ
メチル−2−ヘキセニレン基、 1.1−ジメチル−
3−ヘキセニレン基、 1.1−ジメチル−5−ヘキ
セニレン!、2−ノネニレン基、4−ノネニレン基、5
−/ネニレン基、8−ノネニレン基。4-octenylene group, 7-octenylene group, 1,1-dimethyl-2-hexenylene group, 1,1-dimethyl-
3-hexenylene group, 1,1-dimethyl-5-hexenylene! , 2-nonenylene group, 4-nonenylene group, 5
-/nenylene group, 8-nonenylene group.
1.1−ジメチル−2−へブテニレン基、1,1−ジメ
fk−3−ヘプテニレン基、1,1−ジメチル−4−へ
ブテニレン基+ 1t1−;メチル−6−へブテニレ
ン基、2−デセニレン基+ S、−デセニレン基、9
−fセニレン基、1.l−ジメチル−2−オクテニレン
基、1.l−ジメチル−4−オクテニレン基、 1.
1−ジメチル−7−オクテニレン基、2−ウンデセニレ
ン基、5−ウンデセニレン基、6−ウンゾセニレン基、
10−ウンデセニレン基。1.1-dimethyl-2-hebutenylene group, 1,1-dimefk-3-heptenylene group, 1,1-dimethyl-4-hebutenylene group + 1t1-; methyl-6-hebutenylene group, 2-decenylene group Group + S, -decenylene group, 9
-f senylene group, 1. l-dimethyl-2-octenylene group, 1. l-dimethyl-4-octenylene group, 1.
1-dimethyl-7-octenylene group, 2-undecenylene group, 5-undecenylene group, 6-unzosenylene group,
10-undecenylene group.
1.1−ジメチル−2−ノネニレン基、1,1−ジメチ
ル−4−ノネニレン基、 1.1−シメーy−ルー5
−ノネニレン基、1,1−ジメチル−8−ノネニレン基
、2−ドデセニレン基、6−ドデセニレン基。1.1-dimethyl-2-nonenylene group, 1,1-dimethyl-4-nonenylene group, 1.1-dimethyl-2-nonenylene group 5
-nonenylene group, 1,1-dimethyl-8-nonenylene group, 2-dodecenylene group, 6-dodecenylene group.
11−ドデセニレン基、1,1−ジメチル−2−デセニ
レン基、 1,1−ジメチル’−5−fセニレン基。11-dodecenylene group, 1,1-dimethyl-2-decenylene group, 1,1-dimethyl'-5-f senylene group.
1.1−ジメチル−9−デセニレン基等が挙げられる。Examples include 1,1-dimethyl-9-decenylene group.
さらに、Aが示すアルキニレン基としては、炭素数が2
乃至12個のものが好ましく、具体的にid 例t ハ
エチニレン基、グロピニレン基(−CH2−CEC−)
。Furthermore, the alkynylene group represented by A has 2 carbon atoms.
1 to 12 are preferable, specifically id Example t Haethynylene group, gropinylene group (-CH2-CEC-)
.
2−プロビニレン基(−CEC−CH2−)、 ブチ
ニレン基。2-provinylene group (-CEC-CH2-), butynylene group.
2−ブチニレン基、3−プチニレン基、3−メチルプロ
ビニレン基、1−メチル−2−グロピニレン基、ヘンチ
ニレン基、2−ペンチニレン基、3−ペンチニレン基、
4−ペンチニレン基、 3−メチルフチニレン基、4
−メチルプチニレン基4−メチル−2−プチニレン基、
1,1−ジメチルチルグロピニレン基、ヘキシニレン基
、2−ヘキシニレン基、3−ヘキシニレン基、4−ヘキ
シニレン基、5−へキシニレン基、1−メチルー2−ペ
ンチニレン基、1−メチル−3−ペンチニレン基、1−
メチルー4−ペンチニレン基、 1.1−ジメチル−
2−ブチニレン基、1,1−ジメチル−3−フチニレン
基、ヘブチニレノ基、2−ヘプチニレン基、3−ヘグチ
ニレン基、4−へプチニレン基、5−ヘプチニレン基、
6−ヘグチニレン基。2-butynylene group, 3-butynylene group, 3-methylprovinylene group, 1-methyl-2-gropynylene group, henchynylene group, 2-pentynylene group, 3-pentynylene group,
4-pentynylene group, 3-methylfuthynylene group, 4
-methylbutynylene group 4-methyl-2-butynylene group,
1,1-dimethyltylglopynylene group, hexynylene group, 2-hexynylene group, 3-hexynylene group, 4-hexynylene group, 5-hexynylene group, 1-methyl-2-pentynylene group, 1-methyl-3-pentynylene group group, 1-
Methyl-4-pentynylene group, 1,1-dimethyl-
2-butynylene group, 1,1-dimethyl-3-phthynylene group, hebutynylene group, 2-heptynylene group, 3-heptynylene group, 4-heptynylene group, 5-heptynylene group,
6-heguthynylene group.
1.1−ジメチル−2−ペンチニレン基、1,1−ジメ
チル−4−ペンチニレン基、2−オクチニレン基、4−
オクチニレン基、7−オクチニレン基。1.1-dimethyl-2-pentynylene group, 1,1-dimethyl-4-pentynylene group, 2-octynylene group, 4-
Octynylene group, 7-octynylene group.
1.1−ジメチル−2−ヘキシニレン基、1,1−ジメ
チル−3−ヘキシニレン基、 1.1−ジメチル−5
−ヘキシニレン基、2−ノ二二レン基、4−ノニニレン
基、5−ノニニレン基、8−ノニニレン基、1,1−ジ
メチル−2−ヘプチニレン基、1,1−ジメチル−3−
ヘブチニレン基、1,1−ジメチル−4−ヘプチニレン
基、 1.1−ジメチル−6−ヘプチニレン基、2−
デシニレン基、5−デシニレン基、9−デシニレン基、
1,1−ジメチル−2−オクチニレン基、1,1−ジメ
チル−4−オクチニレン基、1,1−ジメチル−7−オ
クチニレン基。1.1-dimethyl-2-hexynylene group, 1,1-dimethyl-3-hexynylene group, 1.1-dimethyl-5
-hexynylene group, 2-nonynylene group, 4-nonynylene group, 5-nonynylene group, 8-nonynylene group, 1,1-dimethyl-2-heptynylene group, 1,1-dimethyl-3-
Hebutynylene group, 1,1-dimethyl-4-heptynylene group, 1,1-dimethyl-6-heptynylene group, 2-
Decynylene group, 5-decynylene group, 9-decynylene group,
1,1-dimethyl-2-octynylene group, 1,1-dimethyl-4-octynylene group, 1,1-dimethyl-7-octynylene group.
2−ウンデシニレン基、5−ウンデシニレン基。2-undecynylene group, 5-undecynylene group.
6−ウンゾシニレン基、10−ウンデシニレン基。6-unzocynylene group, 10-undecynylene group.
1.1−ジメチル−2−ノ二二しン基、1,1−ジメチ
ル−4−ノ二二しン基、 1.1−シメfルー5−ノ
ニニレン基、 1.1−ジメチル−8−ノ二二しン基
、2−ドデシニレン基、6−ドデシニレン基。1.1-dimethyl-2-nonylene group, 1,1-dimethyl-4-nonylene group, 1.1-dimethyl-5-nonynylene group, 1.1-dimethyl-8- Nodinidine group, 2-dodecynylene group, 6-dodecynylene group.
11−ドデシニレン基、 1.1−ジメチル−2−デ
’i=vン基+ 1.1−ジメチル−5−デシニレン
基。11-dodecynylene group, 1.1-dimethyl-2-de'i=vn group + 1.1-dimethyl-5-decynylene group.
1.1−ジメチル−9−デシニレン基等が挙げられる。Examples include 1,1-dimethyl-9-decynylene group.
一般式(1)で示される化合物は塩を形成する。The compound represented by general formula (1) forms a salt.
本発明には、化合物(I)の塩も含まれ、そのような塩
としては、塩酸、臭化水素酸、ヨウ化水素酸。The present invention also includes salts of compound (I), such as hydrochloric, hydrobromic, and hydroiodic acids.
硫酸、硝酸、リン酸等の鉱酸やギ酸、酢酸、ンエウ酸、
クエン酸、コハク酸、フマール酸、マレイン酸、リンゴ
酸、酒石酸、メタンスルホン酸、エタンスルホン酸等の
各種の有機酸との酸付加塩が挙げられる。Mineral acids such as sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, phosphoric acid,
Examples include acid addition salts with various organic acids such as citric acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, methanesulfonic acid, and ethanesulfonic acid.
また9本発明化合物は、ジヒドロピリジン環4位に不斉
炭素原子を有する場合、また4位フェニル基の置換基の
種類によっては更に不斉炭素原子を含む場合もありさら
に本発明化合物中には二重結合を有する化合物が含まれ
ている。このような化合物にあっては、光学異性体やジ
アステレオマー及び幾何異性体などの各種異性体が存在
する。In addition, if the compound of the present invention has an asymmetric carbon atom at the 4-position of the dihydropyridine ring, or depending on the type of substituent of the phenyl group at the 4-position, the compound of the present invention may further contain an asymmetric carbon atom. Contains compounds with heavy bonds. Such compounds exist in various isomers such as optical isomers, diastereomers, and geometric isomers.
本発明はこれら光学及び立体異性体の分離されたもの及
びその混合物を包含する。The present invention includes separated optical and stereoisomers and mixtures thereof.
本発明化合物(I)は種々の方法によって合成すること
が可能である。以下にその代表的製法を詳述する。Compound (I) of the present invention can be synthesized by various methods. The typical manufacturing method will be explained in detail below.
第1製法
S
(反応式中、 R’、 R2,R3,R’、 R’、
R’、 R)、R’、Y及びAは前記の意味を有し R
Qは低級アルキル基。First production method S (in the reaction formula, R', R2, R3, R', R',
R', R), R', Y and A have the meanings given above;
Q is a lower alkyl group.
ヒドロキシ低級アルキル基、アラルキル基。Hydroxy lower alkyl group, aralkyl group.
アリール基、低級アシル基、低級アルキルスルホニル基
、アリールオキシ低級アルキル基。Aryl group, lower acyl group, lower alkylsulfonyl group, aryloxy lower alkyl group.
アリールオキシ低級アルコキシ基又は式−Bxiで示さ
れる基を、xLはノ・ロゲン原子、有機スルホン酸残基
、又は低級アシルオキシ基を、Bはテトラメチレン基、
ペンタメチレン基。An aryloxy lower alkoxy group or a group represented by the formula -Bxi, xL is a nitrogen atom, an organic sulfonic acid residue, or a lower acyloxy group, B is a tetramethylene group,
Pentamethylene group.
ヘキサメキレン基、3−オキサペンタメチレン基(−C
H2CH2OCH2CH2−)又は式−CH2CH2N
CH2CH,−RIO
で示される基を XlはXlが・・ロゲン原子のとき
Xlと同−又は相異るノ・ロゲン原子を。Hexamethylene group, 3-oxapentamethylene group (-C
H2CH2OCH2CH2-) or formula -CH2CH2N
The group represented by CH2CH, -RIO is Xl when Xl is a rogen atom
A rogen atom that is the same as or different from Xl.
RIOは水素原子、低級アルキル基又はアラルキル基を
、R11は低級アルキル基を、それぞれ意味する)
絃にハロゲン原子としては、ヨウ素原子、臭素原子、塩
素原子等が挙げられる。また、有機スルホン酸残基とし
てはメタンスルホニルオキシ基、エタンスルホニルオキ
シ基などのアルカンスルホン酸残基やベンゼンスルホニ
ルオキシ基、 )ルエン(%Kp−)ルエン)スルホ
ニルオキシ基などの芳香族スルホン酸残基等が挙げられ
る。低級アシルオキシ基としては、アセトキシ基、プロ
ピオニルオキシ基等が挙げられる。RIO means a hydrogen atom, a lower alkyl group, or an aralkyl group, and R11 means a lower alkyl group.) Examples of the halogen atom in the string include an iodine atom, a bromine atom, and a chlorine atom. In addition, organic sulfonic acid residues include alkanesulfonic acid residues such as methanesulfonyloxy group and ethanesulfonyloxy group, and aromatic sulfonic acid residues such as benzenesulfonyloxy group and )luene (%Kp-)ruene)sulfonyloxy group. Examples include groups. Examples of the lower acyloxy group include an acetoxy group and a propionyloxy group.
本発明化合物(I)は。The compound (I) of the present invention is.
(り一般式(n)で示されるアミンと、一般式(III
)で示されるノ・ライド、酸無水物又はスルホネートと
を反応させるか。(Amine represented by general formula (n) and general formula (III
) with the acid anhydride or sulfonate.
(2) (1)で得られる第二アミ/に、一般式(I
V)で示されるノ・ライド、酸無水物又はスルホネート
とを反応させることによって製造される。(2) The second amino acid obtained in (1) is added to the general formula (I
It is produced by reacting V) with the acid anhydride, acid anhydride or sulfonate.
なお、化合物(m)がXI−B Xl であるときは
XlとXlとは共にノ・ロゲ/原子であり、殊に同一の
ノ・ロゲン原子が有利である。Incidentally, when the compound (m) is XI-B Xl , both Xl and Xl are atom, and it is particularly advantageous that they are the same atom.
上記(11及び(2)の反応はいずれも同様の反応条件
下に実施可能であり、xIがノ・ロゲン原子及び低級ア
シルオキシ基のとき、有機スルホン酸残基であるときに
分けて詳述する。The reactions (11 and (2) above) can all be carried out under the same reaction conditions, and will be explained in detail separately for when xI is a norogen atom and lower acyloxy group, and when xI is an organic sulfonic acid residue. .
、原料化合物(III)としてXlがノ・ロゲン原子又
は低級アシルオキシ基である化合物を用(・る反応は、
無溶媒下でも進行するが通常ベンゼン、トルエン、キシ
レン、シメチルホルアミド、ジメチルスルホキシド、ア
セトニトリル。, the reaction using a compound in which Xl is a norogen atom or a lower acyloxy group as the starting compound (III) is as follows:
Although it can proceed without solvent, it is usually used with benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, and acetonitrile.
ジクロルメタン、ジクロルエタン、などの有機溶媒中に
実施するのが有利である。Advantageously, it is carried out in an organic solvent such as dichloromethane, dichloroethane.
原料化合物の使用量は、化合物(n)と化合物(FIT
)とをほぼ等モルある(・は化合物(rlDをやや過剰
量とする。The amounts of raw material compounds used are compound (n) and compound (FIT
) is approximately equimolar (. indicates a slight excess amount of the compound (rID).
反応は室温乃至加温下ある(・は加熱還流して実施する
のが好適である。The reaction is carried out at room temperature or under heating (. is preferably carried out under heating to reflux.
この反応に際し、ピリジン、ピコリン、N。During this reaction, pyridine, picoline, and N.
N−ジメチルアニリン、N−メチルモルホリン、トリメ
チルアミン、トリエチルアミン。N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine.
ジメチルアミン等の二、三級塩基や炭酸カリウム、炭酸
ナトリウム、炭酸水素ナトリウム等の無機塩基を添加す
ることが9反応を円滑に進行させる上で有利な場合があ
る〇
また。副反応を抑制する上で化合物(TI)のアミノ基
に保護基を導入して反応させ1反応後保護基を脱離させ
る方法を採用することもできる。このような保護基とし
てはトルエンスルホニル基、アセチル基、フェナシルス
ルホニル基、iJフルオロメタンスルホニル基。Adding a secondary or tertiary base such as dimethylamine or an inorganic base such as potassium carbonate, sodium carbonate, or sodium bicarbonate may be advantageous in making the reaction proceed smoothly. In order to suppress side reactions, it is also possible to adopt a method in which a protecting group is introduced into the amino group of the compound (TI), the reaction is caused, and the protecting group is removed after one reaction. Such protecting groups include toluenesulfonyl group, acetyl group, phenacylsulfonyl group, and iJ fluoromethanesulfonyl group.
ビスベンゼンスルホニル基等が挙げられる。Examples include bisbenzenesulfonyl group.
保護基の脱離は酸や塩基などを用(・る常法の加水分解
によって容易に達成できる。Removal of the protecting group can be easily accomplished by conventional hydrolysis using acids, bases, etc.
原料化合物([)として有機スルホン酸残基で置換され
た化合物を使用する反応は、化合物(II)と、化合物
(II)に対し等モル乃至過剰モルの化合物(III)
とを1反応に不活性な有機溶媒2例えばエーテル、メタ
ノール、エタノール、トルエン、テトラヒドロフラン等
中。In a reaction using a compound substituted with an organic sulfonic acid residue as the starting compound ([), compound (II) and compound (III) in an equimolar to excess molar amount relative to compound (II) are used.
and an organic solvent inert to the reaction, such as ether, methanol, ethanol, toluene, tetrahydrofuran, etc.
冷却下あるいは室温下に行うのが有利である。It is advantageous to carry out the reaction under cooling or at room temperature.
反応時間は移々の反応条件を考慮して適宜設定される。The reaction time is appropriately set in consideration of changing reaction conditions.
非対称型アミンを製造するには、上記の反応によって得
られた第二アミンに9次いで化合物(V)を反応せしめ
る。In order to produce an asymmetric amine, the secondary amine obtained by the above reaction is then reacted with compound (V).
反応条件や方法は、前記と同様である。The reaction conditions and method are the same as described above.
第2製法
S
(I)
(反応式中、 R1,R2,R3,R’、 R’、 R
6,R’、 R8,Y、 A及びXlは前記の意味を有
する)
本発明化合物(I)は、一般式(V)で示されるハライ
ド、酸無水物又はスルホネートと一般式(VI)で示さ
れるアミンと反応させることによっても製造することが
できる。Second production method S (I) (In the reaction formula, R1, R2, R3, R', R', R
6, R', R8, Y, A and Xl have the above-mentioned meanings) The compound (I) of the present invention comprises a halide, acid anhydride or sulfonate represented by the general formula (V) and a halide represented by the general formula (VI). It can also be produced by reacting with an amine.
反応は第1製法のN−アルキル化とほぼ同様である。The reaction is almost the same as the N-alkylation in the first production method.
第3製法
S
(Ia)
(反応式中、 R’* R”* R”+ R’、R”+
R’及びYは前記の意味を有し、他の記号は以下の意
味を有する。Third production method S (Ia) (In the reaction formula, R'* R"* R"+ R', R"+
R' and Y have the meanings given above and other symbols have the following meanings.
A1;A、又はAより炭素数が1個少ないアルキレン基
、アルケニレン基若しくは
アルキニレン基。A1; A, or an alkylene group, alkenylene group, or alkynylene group having one fewer carbon atoms than A;
X3及びX4;一方がホルミル基、他方がアミノ基。X3 and X4; one is a formyl group, the other is an amino group.
D;式−CH=N−又は−N=CH−で示される基。D: a group represented by the formula -CH=N- or -N=CH-.
E;式−CH2NH−又は−NHCH,−で示される基
)
一般式(Ia)で示される化合物は、一般式(■)で示
されるアルデヒド又はアミンと、一般式(■)で示され
るアミン又はアルデヒドとを反応せしめ、得られたシッ
ク塩基(IX)を次いでニトロ基の還元しな℃・条件下
に還元する還元的縮合により製造することができる。E; a group represented by the formula -CH2NH- or -NHCH,-) The compound represented by the general formula (Ia) is a compound represented by the aldehyde or amine represented by the general formula (■) and the amine or amine represented by the general formula (■). It can be produced by reductive condensation in which a thick base (IX) is reacted with an aldehyde and the resulting thick base (IX) is then reduced under conditions such that the nitro group is not reduced.
前段の反応は、無溶媒下でも進行するが9通常メタノー
ル、エタノールなどのアルコールやペンゼ/等の反応に
不活性な有機溶媒中、化合物(■)と化合物(■)とを
当モルあるいは一方を過剰モルとして、室温乃至加温下
、あるいは加熱還流下に行われる。反応条件によっては
、水酸化カリウムを添加したり、あるいはディーンース
ターク(Dean−8tark ) )ラップを用(・
て生成する水を除去するのが好適な場合がある。The first reaction proceeds even in the absence of a solvent.9 Usually, compound (■) and compound (■) are mixed in equimolar amounts or one of them in an organic solvent inert to the reaction, such as an alcohol such as methanol or ethanol, or penze. The reaction is carried out in molar excess at room temperature or under heating, or under heating under reflux. Depending on the reaction conditions, potassium hydroxide may be added or a Dean-Stark wrap may be added.
It may be suitable to remove the water produced by
還元反応においては、前段の反応により生成するシック
塩基を単離せずに、シッフ塩基を含む反応液に還元剤を
添加して反応させることもできる。In the reduction reaction, the reaction can be carried out by adding a reducing agent to the reaction solution containing the Schiff base, without isolating the Schick base produced in the previous reaction.
また、ニトロ基を還元することなく2選択的にシッフ塩
基のイミノ基のみを還元して本発明化合物(Ia)を製
造するためには、還元剤として水素化ホウ素ナトリウム
、水素化ホウ素リチウムや水素化シアノホウ素ナトリウ
ムなどのホウ素化合物を用いるのが有利である。In order to produce the compound (Ia) of the present invention by biselectively reducing only the imino group of the Schiff base without reducing the nitro group, sodium borohydride, lithium borohydride, hydrogen It is advantageous to use boron compounds such as sodium cyanoborohydride.
還元反応は、メタノール、エタノ−ルナトノアルコール
、酢酸等の有機溶媒や水ある(・はこれらの混合溶媒中
1通常室温乃至加温下に行われる。The reduction reaction is usually carried out at room temperature or under heating in an organic solvent such as methanol, ethanol, natonoalcohol, acetic acid, or a mixed solvent thereof.
反応に際し1反応液の液性を中性な(・し塩基性に保持
するのが反応を円滑に進行させる上で有利な場合があり
、必要に応じて、メチルアミン、エチルアミン、プロピ
ルアミン、ジメチルアミン、水酸化カリウムや酢酸ナト
リウム等を添加して反応させる。During the reaction, it may be advantageous to maintain the liquid nature of one reaction solution at a neutral (or basic) level for the reaction to proceed smoothly, and if necessary, methylamine, ethylamine, propylamine, dimethyl Amine, potassium hydroxide, sodium acetate, etc. are added and reacted.
その他の製造法
以上、4位フェニル基に置換した置換アミノアルコキシ
基のアミン部分に注目した製造法のみを開示したが2本
発明化合物(I)中には種々の官能基を含んでいるばか
りでなく、ジヒドロピリジン骨格を有する化合物であり
1個々の官能基に着目した合成法、あるいは1.4−ジ
ヒドロピリジン骨格の合成法(Hantzschの合成
法)によっても製造しうる。Other Production Methods In the above, only the production method focusing on the amine moiety of the substituted aminoalkoxy group substituted with the phenyl group at the 4-position was disclosed; however, the compound (I) of the present invention contains various functional groups. However, it is a compound having a dihydropyridine skeleton and can be produced by a synthesis method focusing on each functional group, or by a synthesis method of a 1,4-dihydropyridine skeleton (Hantzsch's synthesis method).
このようにして製造された本発明化合物は。The compound of the present invention thus produced is:
遊離のままあるいはその塩として単離され精製される。It is isolated and purified in its free form or as its salt.
単離、精製は、抽出、結晶化、再結晶。Isolation and purification include extraction, crystallization, and recrystallization.
各種クロマトグラフィー等の通常の化学操作を適用して
行われる。This is carried out by applying ordinary chemical operations such as various chromatography.
尚1本発明化合物には前記の如く、ラセミ体。As mentioned above, the compound of the present invention is a racemate.
光学活性体、ジアステレオマー等の異性体が単独である
(・は混合物として存在する。ラセミ化合物は適当な原
料化合物を用いることにより。Optically active isomers, diastereomers, and other isomers exist individually (* means they exist as a mixture. Racemic compounds can be created by using appropriate starting compounds.
あるいは一般的なラセミ分割法により[たとえば、一般
的な光学活性酸(酒石酸等)とのジアステレオマー塩に
導き、光学分割する方法等]立体化学的に純粋な異性体
に導くことができる。Alternatively, a stereochemically pure isomer can be obtained by a general racemic resolution method [for example, a method of forming a diastereomeric salt with a general optically active acid (tartaric acid, etc.) and optically resolving it].
また、ジアステレオマーの混合物は常法2例えば分別結
晶化またはクロマトグラフィー等により分離できる。Also, mixtures of diastereomers can be separated by conventional methods such as fractional crystallization or chromatography.
(発明の効果)
本発明によって提供される化合物(1)及びその塩は、
持続性に優れたカルシウム拮抗作用を有する。(Effect of the invention) Compound (1) and its salt provided by the present invention are:
It has a long-lasting calcium antagonistic effect.
本発明化合物のこれらの薬理効果は以下に示す試験方法
によって確認されたものであるが静脈内投与による血圧
降下作用および冠面流量増加作用については0.01〜
1■/kgの範囲内で有効で。These pharmacological effects of the compounds of the present invention were confirmed by the test methods shown below, and the blood pressure lowering effect and coronary flow increasing effect by intravenous administration were 0.01 to 0.01.
Effective within the range of 1■/kg.
かつ心仕事量、心筋酸素消費の低下カー認められ。In addition, a decrease in cardiac workload and myocardial oxygen consumption was observed.
冠動脈内投与による冠血管拡張作用につ−・てヲ11〜
300μgの範囲内で有効であった。また、(−ずれの
投与経路においても薬効の持続時間力を既知のジヒドロ
ピリジン化合物よりも長〜・こと力を確認された。Regarding the coronary vasodilatory effect of intracoronary administration - Tewo 11~
It was effective within the range of 300 μg. In addition, it was confirmed that the duration of the drug's efficacy was longer than that of known dihydropyridine compounds even through different administration routes.
以下に本発明化合物中、主な化合物につ℃・て。The main compounds of the present invention are listed below.
これらの効果を裏付ける試験方法及び試験結果を掲記す
る。Test methods and test results that support these effects are listed.
方 法
l、 カルシウム拮抗作用
本発明化合物のカルシウム拮抗作用は、 [’H]−二
トレンジビンパインディングアッセイによって検討した
。ラット脳膜標本における[3H]一ニトレンジピン結
合に対する被験化合物の抑制活性は、 Gouldらの
方法[Gould、 R,J、、 Murphy、 K
、H,IL。Method 1: Calcium antagonism The calcium antagonism of the compounds of the present invention was examined by ['H]-nitrendivin binding assay. The inhibitory activity of the test compound against [3H]-nitrendipine binding in rat brain membrane preparations was determined using the method of Gould et al. [Gould, R.J., Murphy, K.
,H,IL.
& 5nyder、 S、H,: Proe、 Nat
l、 Aead、 Sc1. USA、 79.365
6−3660(19p2)]によって評価した。& 5nyder, S.H.: Proe, Nat.
l, Aead, Sc1. USA, 79.365
6-3660 (19p2)].
特異的結合を50%抑制するのに要する濃度であるIC
5o値をログーロジット分析法により算出し、抑制定数
(Ki値、単位はnM)を得た。IC, the concentration required to inhibit specific binding by 50%
The 5o value was calculated by log logit analysis to obtain the inhibition constant (Ki value, unit: nM).
結果を第1表に示す。The results are shown in Table 1.
第1表 値は3例の平均値である。Table 1 The value is the average value of 3 cases.
()内の数値は、95%信頼限界を示す。Numbers in parentheses indicate 95% confidence limits.
2、降圧活性 本発明化合物の動脈血圧[収縮期血圧(SBP)。2. Antihypertensive activity Arterial blood pressure [systolic blood pressure (SBP)] of the compound of the present invention.
平均血圧(MBP)、拡張期血圧(DBP) ]及び心
拍数(HR)に対する作用は、無麻酔正常血圧ラットで
検討した。実験を行う4〜6日前に、動脈血圧測定用ポ
リエチレンカテーテルをエーテル麻酔下に頚動脈より胸
部大動脈に外科的に挿入した。動脈血圧及び心拍数は無
拘束下に記録した。The effects on mean blood pressure (MBP), diastolic blood pressure (DBP)] and heart rate (HR) were examined in unanesthetized normotensive rats. Four to six days before the experiment, a polyethylene catheter for measuring arterial blood pressure was surgically inserted into the thoracic aorta from the carotid artery under ether anesthesia. Arterial blood pressure and heart rate were recorded without restraint.
被験化合物は0.5%メチルセルロース溶液に懸濁し、
経口投与した。被験化合物(3orng/kg)及び対
照化合物であるニフェジピン(3mg/kg )の経口
投与後における無麻酔正常血圧ラットのHR,SBP、
MBP、及びDBPの変化をそれぞれ第2表及び第3
表に示す。The test compound was suspended in a 0.5% methylcellulose solution,
Administered orally. HR, SBP of unanesthetized normotensive rats after oral administration of the test compound (3 orng/kg) and the control compound nifedipine (3 mg/kg),
Changes in MBP and DBP are shown in Tables 2 and 3, respectively.
Shown in the table.
3、急性毒性
被験化合物の急性毒性はp Brownleeらの方法
[少量サンプルにおけるアップアンドダウン法。J、
Am、 5tat、 As、、 48.262−277
(1953)]によって評価した。3. Acute toxicity The acute toxicity of the test compound was determined by the method of Brownlee et al. [up-and-down method using a small sample. J.
Am, 5tat, As, 48.262-277
(1953)].
ICR−8LCマウスに静脈内投与して求めたLD、。LD determined by intravenous administration to ICR-8LC mice.
値を第4表に示す。The values are shown in Table 4.
第4表
化合物 例数 LD50 (IT1g/kg t
、’V、 )実施例1 10 29.0
ベラパミル 1010.3
従って9本発明化合物(I)及びその塩は。Table 4 Compound Number of Examples LD50 (IT1g/kg t
, 'V, ) Example 1 10 29.0 Verapamil 1010.3 Therefore, 9 Compound (I) of the present invention and its salt.
カルシウム拮抗作用に基づく体血管及び冠血管拡張作用
を示し、狭心症や心筋梗塞などの虚血性心疾患、高血圧
症、不整脈などの循環器疾患の予防及び治療剤として、
既存のジヒドロピリジン系カルシウム拮抗剤よりも副作
用が少なく、かつ少な(・投与回数で適応しうるものと
して有用である。また9本発明化合物は循環器作用以外
にも脳血管重縮改善作用および中枢機能改善作用をも有
しており、脳血管重縮改善剤、中枢機能改善剤としても
有用である。It exhibits systemic and coronary vasodilatory effects based on calcium antagonism, and is used as a prophylactic and therapeutic agent for ischemic heart diseases such as angina and myocardial infarction, as well as cardiovascular diseases such as hypertension and arrhythmia.
It has fewer side effects than existing dihydropyridine-based calcium antagonists, and is useful because it can be adjusted to the number of administrations.9 In addition to its cardiovascular effects, the compound of the present invention also has an effect on improving cerebrovascular congestion and central function. It also has ameliorating effects and is useful as an agent for improving cerebral vascular condensation and as an agent for improving central function.
一般式(1)で示される化合物又はその塩の1種または
2種以上を有効成分として含有する製剤は1通常用いら
れる製剤用の担体や賦形剤、その他の添加剤を用いて錠
剤、散剤。Preparations containing one or more of the compounds represented by general formula (1) or their salts as active ingredients are prepared as tablets, powders, etc. using commonly used carriers, excipients, and other additives. .
細粒剤、顆粒剤、カプセル剤、丸剤、液剤。Fine granules, granules, capsules, pills, and liquids.
注射剤、坐剤、軟膏、貼付剤等に調製され。It is prepared into injections, suppositories, ointments, patches, etc.
経口的(舌下投与を含む)または非経口的に投与される
。Administered orally (including sublingually) or parenterally.
製剤用の担体や賦形剤としては、固体又は液体状の非毒
性医薬用物質が挙げられる。これらの例としては、たと
えば乳糖、ステアリン酸マグネシウム、スターチ、タル
ク、ゼラチン、寒天、ペクチン、アラビアゴム、オリー
ブ油、ゴマ油、カカオバター、エチレングリコール等、
その他常用のものが例示される。Pharmaceutical carriers and excipients include solid or liquid non-toxic pharmaceutical substances. Examples of these include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, etc.
Other commonly used items are exemplified.
本発明化合物の臨床的投与量は、適用される患者の症状
1体重9乍令や性別等を考慮して適宜決定されるが9通
常成人1人あたり経口で50〜200111gであり、
これを1〜2回に分けて投与する。The clinical dosage of the compound of the present invention is appropriately determined taking into consideration the symptoms, weight, age, gender, etc. of the patient to whom it is applied, but is usually 50 to 200,111 g orally per adult.
This is administered in 1 to 2 doses.
(実施例) 以下に実施例を掲記し1本発明を更に詳細に説明する。(Example) EXAMPLES The present invention will be explained in more detail by way of examples below.
実施例 1
ジメチル 4−[2−(4−アミノブトキシ)−5−二
トロフェニル] −2,6−シメチルー1.4−ジヒド
ロピリジン−3,5−ジカルボキシレート4.33g
及U 1−ブロモ−3−7工ノキシプロパン1gをN、
N−ジメチルホルムアミド20 mlに溶解し。Example 1 Dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 4.33 g
and U 1 g of 1-bromo-3-7-hydroxypropane with N,
Dissolve in 20 ml of N-dimethylformamide.
100℃で1.5時間加熱オる。反応液を氷水500
mlに注加して析出した油状物を酢酸エチルで抽出して
無水硫酸ナトリウムで乾燥した後、減圧下で溶媒な留去
する。得られた残留物をシリカゲルカラムクロブトに付
し、クロロホルム:メタノール(96’−4v/v )
で溶出して得られた粗結晶をエタノールから再結晶し、
ジメチル 4−[2−[4−(3−フェノキシプロピル
アミン)プトキシコー5−ニトロフェニルコ−2,6−
シメチルー1.4−ジヒドロピリジン−3,5−ジカル
ボキシレートを1.2g得た。この化合物は次の理化学
的性状を有する。Heat at 100°C for 1.5 hours. Pour the reaction solution into ice water 500ml
ml, the precipitated oil was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column clotting and chloroform:methanol (96'-4v/v)
The crude crystals obtained by elution with were recrystallized from ethanol,
Dimethyl 4-[2-[4-(3-phenoxypropylamine)ptoxyco-5-nitrophenylco-2,6-
1.2 g of dimethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained. This compound has the following physical and chemical properties.
(1)融点 128〜130°C
(11)元素分析値(CC50H37N30・H,Oと
して)(CX19 H(−N(彌
計算値 61.53 6.71 7.17実測値
61.42 6,45 7.00実施例 2゜
ジメチル 、+ −[2−(4−ブロモブトキシ)−5
−二トロフェニル] 216−シメチルー1,4−シ
ヒドロビリジン−3,5−ジカルボキシレート3g、お
よびジエチルアミン0.88 g をアセトニトリル3
0 mlに溶解し25時間加熱還流する。減圧下。(1) Melting point 128-130°C (11) Elemental analysis value (as CC50H37N30・H,O) 7.00 Example 2゜dimethyl, + -[2-(4-bromobutoxy)-5
-nitrophenyl] 3 g of 216-dimethyl-1,4-cihydrobiridine-3,5-dicarboxylate and 0.88 g of diethylamine were added to 3 g of acetonitrile.
0 ml and heated under reflux for 25 hours. Under reduced pressure.
溶媒を留去して得られた残留物を塩化メチレンに溶解し
、10%水酸化す) IJウム水で洗浄し0次にIN−
塩酸で洗浄する。有機層を減圧下溶媒を留去し、得られ
た粗結晶をメタノール−エタノールから再結晶し、ジメ
チル 4−[2−(4−ジエチルアミンブトキシ)−5
−二トロフェニルコ−2,6−シメチルー1,4−ジヒ
ドロピリジン−3,5−ジカルポキシレート塩酸塩1.
3gを得た、この化合物は次の理化学的性状を有する。The residue obtained by distilling off the solvent was dissolved in methylene chloride and 10% hydroxylated.
Wash with hydrochloric acid. The solvent of the organic layer was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from methanol-ethanol to give dimethyl 4-[2-(4-diethylaminebutoxy)-5
-nitrophenylco-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarpoxylate hydrochloride 1.
3 g was obtained, and this compound has the following physical and chemical properties.
fi) 融点 216〜219°C
(ii) 元素分析値(C2,H36N、07C1−
0,3H,Oとして)C(@H(4N(@cl(te
計算値 56.50 6.94 7.91 6.67
実測値 56.49 6.84 7.71 6.40
曲)核磁気共鳴スペクトル(DMSO−da )δ;
1.26 (6H,t )
1.7〜2.0 (4H,m )
2.29 (6H,s)
3.52 (6H,s)
4.0〜4.2 (2H,m 、)
5.21 (IH,s)
7.12 (IH,d)
7.9〜8.1 (2H,m)
9.21 (IH,s)
実施例 3〜13
同様にして以下の化合物を得た。fi) Melting point 216-219°C (ii) Elemental analysis value (C2, H36N, 07C1-
0,3H,O)C(@H(4N(@cl(te) Calculated value 56.50 6.94 7.91 6.67
Actual value 56.49 6.84 7.71 6.40
Song) Nuclear magnetic resonance spectrum (DMSO-da) δ;
1.26 (6H,t) 1.7~2.0 (4H,m) 2.29 (6H,s) 3.52 (6H,s) 4.0~4.2 (2H,m,) 5 .21 (IH,s) 7.12 (IH,d) 7.9-8.1 (2H,m) 9.21 (IH,s) Examples 3-13 The following compounds were obtained in the same manner.
実施例 14゜
ジメチル 4−[2−(4−アミノブトキシ)−5−ニ
トロフェニル] −2,6−シメチルー1,4−ジヒド
ロピリジン−3,5−ジカルボキシレート0.31 g
を塩化メチレン2 mtに溶解し、水冷下に無水酢酸2
mtを加えた後、室温で30分間攪拌する。Example 14゜Dimethyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 0.31 g
was dissolved in 2 mt of methylene chloride, and 2 mt of acetic anhydride was added under water cooling.
After adding mt, stir at room temperature for 30 minutes.
反応液を減圧上濃縮し、残渣にエーテルを加えて固化さ
せ、クロロホルム−n−ヘキサンかう再結晶し、ジメチ
ル 4−[2−[4−(アセチルアミノ)プトキシコー
5−ニトロフェニル] −2,6−シメチルー1,4−
ジヒドロピリジン−3,5−ジカルボキシレート0.2
6gを得た。この化合物は次の理化学的性状を有する。The reaction solution was concentrated under reduced pressure, the residue was solidified by adding ether, and recrystallized from chloroform-n-hexane to give dimethyl 4-[2-[4-(acetylamino)ptoxyco-5-nitrophenyl] -2,6 -cymethyl-1,4-
Dihydropyridine-3,5-dicarboxylate 0.2
6g was obtained. This compound has the following physical and chemical properties.
(1) 融点 212〜213℃
(11) 元素分析値(C23H2@ Ns Ogと
して)C(%) H(%l N(%)
計算値 58.10 6,15 8.84実測値
57.67 6,01 8.74実施例 15
゜
ジメチル 4−[2−(4−アミノブトキン)−5−ニ
トロフェニルコー2,6−ジメテルー1.・1−ジヒド
ロピリジン−3,5−ジカルボキシレート0.43gを
塩化メチレン4 mlに溶解し、水冷下にトリエチルア
ミン0.138m1及び塩化メタンスルホン酸0.07
7mtを加えた後、室温で3日間攪拌する。(1) Melting point 212-213°C (11) Elemental analysis value (as C23H2@Ns Og) C (%) H (%l N (%) Calculated value 58.10 6,15 8.84 Actual value 57.67 6 ,01 8.74 Example 15
゜Dimethyl 4-[2-(4-aminobutquin)-5-nitrophenyl-2,6-dimethyl 1.・Dissolve 0.43 g of 1-dihydropyridine-3,5-dicarboxylate in 4 ml of methylene chloride, and add 0.138 ml of triethylamine and 0.07 ml of methanesulfonic acid chloride while cooling with water.
After adding 7 mt, stir at room temperature for 3 days.
反応液に酢酸エチル50mt及び2規定塩U 20 m
lを加えて有機層を分取し、減圧下で溶媒を留去する。Add 50 mt of ethyl acetate and 20 m of 2N salt to the reaction solution.
1 was added to separate the organic layer, and the solvent was distilled off under reduced pressure.
得られた残渣をシリカゲルカラムクロマトに付し、クロ
ロホルム−メタノール(9: 1 v/v )で溶出し
て得られた粗結晶をクロロホルム−n−ヘキサンから再
結晶し、ジメチル 4−[2−[4−(メタンスルホニ
ルアミノ)ブトキシ]−5−二トロフェニルコ−2,6
−ジメテルー1,4−ジヒドロピリジン−3,5−ジカ
ルボキシレート0.31gを得た。この化合物は次の理
化学的性状を有する。The obtained residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (9:1 v/v), and the obtained crude crystals were recrystallized from chloroform-n-hexane, and dimethyl 4-[2-[ 4-(methanesulfonylamino)butoxy]-5-nitrophenylco-2,6
-dimetheru-1,4-dihydropyridine-3,5-dicarboxylate 0.31 g was obtained. This compound has the following physical and chemical properties.
(1)融点 213〜216℃
(11) 元素分析値(CtxH29Ns 09 S
・1/2H,Oとして)C(%) H(四 N(殉
計算値 50.76 5.81 8.07実測値
50.09 5.44 7.83参考例 1゜
υ
金属ナトリウム0.7gをメタノール40m1に溶解し
た。この溶液を4−フタルイミドブチルチオール7.1
6gをメタノール54mtに溶解した溶液を加え、室温
で15分間攪拌した。次いで2−クロル−5−二トロペ
ンズアルデヒド4.64 g tJlll、t 6時間
加熱還流した。溶媒を留去後、残渣にメタノール15m
/、を加え析出物を涙取した。これを、水及びメタノー
ルで洗うことにより3.94gの5−ニトロ−2−(4
−フタルイミドブチルチオ)ベンズアルデヒドを得た。(1) Melting point 213-216℃ (11) Elemental analysis value (CtxH29Ns 09 S
・1/2 H, O) C (%) H (4 N (calculated value 50.76 5.81 8.07 actual value 50.09 5.44 7.83 reference example 1゜υ metallic sodium 0.7 g was dissolved in 40ml of methanol.This solution was dissolved in 7.1ml of 4-phthalimidobutylthiol.
A solution of 6 g dissolved in 54 mt of methanol was added, and the mixture was stirred at room temperature for 15 minutes. Then, 4.64 g of 2-chloro-5-nitropenzaldehyde was heated under reflux for 6 hours. After distilling off the solvent, add 15 m of methanol to the residue.
/ was added to remove the precipitate. By washing this with water and methanol, 3.94 g of 5-nitro-2-(4
-phthalimidobutylthio)benzaldehyde was obtained.
核磁気共鳴スペクトル(DMS O−da )δ: 1
.5〜2.0 (4H,m )3.16 (2H,
t )
3.64 (2H,t )
7.70 (IH,d )
7.86 (4H,bs)
8.32 (LH,d )
8.70 (IH,d )
10.16 (LH,s )
参考例 2゜
1)参考例1で得た5−ニトロ−2−(4−フタルイミ
ドブチルチオ)ベンズアルデヒド4gKベンゼンLOO
m4.アセト酢酸メチル1.21g、 ピペリジン0
.04m1及び酢酸0.12m1を加え、ディーンスタ
ーク装置を用いて4時間加熱還流した。冷後、飽和炭酸
水素すl−IJウム水溶液及び2規定塩酸でそれぞれ2
回洗い無水硫酸マグネシウムで乾燥後、減圧下で溶媒を
留去して油状物を得た。これにエーテルを加えて固化さ
せ4.9gの固体を得た。このものは更に精製すること
なく次の工程に用いた。Nuclear magnetic resonance spectrum (DMS O-da) δ: 1
.. 5-2.0 (4H, m)3.16 (2H,
t ) 3.64 (2H, t ) 7.70 (IH, d ) 7.86 (4H, bs) 8.32 (LH, d ) 8.70 (IH, d ) 10.16 (LH, s ) Reference example 2゜1) 5-nitro-2-(4-phthalimidobutylthio)benzaldehyde obtained in Reference example 1 4gK benzene LOO
m4. Methyl acetoacetate 1.21g, piperidine 0
.. 0.04 ml and acetic acid 0.12 ml were added, and the mixture was heated under reflux for 4 hours using a Dean-Stark apparatus. After cooling, each solution was diluted with saturated sodium bicarbonate solution and 2N hydrochloric acid.
After washing twice and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain an oil. Ether was added to this to solidify it to obtain 4.9 g of solid. This product was used in the next step without further purification.
2)上記で得た固体4.9gにイングロビルアルコール
4.9 ml 及び3−アミノクロトン酸メチルエステ
ル1.17gを加え一夜加熱還流した。この反応液にエ
タノール100m1及び抱水ヒドラジン6.38gを加
え1時間加熱還流した。冷後、不溶物を戸去し。2) 4.9 ml of inglovir alcohol and 1.17 g of 3-aminocrotonic acid methyl ester were added to 4.9 g of the solid obtained above, and the mixture was heated under reflux overnight. To this reaction solution were added 100 ml of ethanol and 6.38 g of hydrazine hydrate, and the mixture was heated under reflux for 1 hour. After cooling, remove the insoluble matter.
減圧下で溶媒を留去した。残渣に酢酸エチル80m4及
び水80mtを加えて分液した。有機層を無水硫酸マグ
ネシウムで乾燥後、減圧下で溶媒を留去して、残渣にエ
ーテルを加えて結晶化することにより3.4gのジメチ
ル 4−[2−(4−アミノブチルチオ)−5−ニトロ
フェニル] −2,6−シメチルー1,4−ジヒドロピ
リジン−3,5−ジカルボキシレートをi4だ。このも
のは以下の理化学的性状を有する。The solvent was distilled off under reduced pressure. 80 m4 of ethyl acetate and 80 mt of water were added to the residue to separate the layers. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was crystallized by adding ether to give 3.4 g of dimethyl 4-[2-(4-aminobutylthio)-5. -nitrophenyl] -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate is i4. This material has the following physical and chemical properties.
(1)融点 260℃(分解)
(11) 核磁気共鳴スペクトル(DMSO−d6)
δ: 1.4〜2.0 (4H,m )2.24
(6H* s )
2.4〜2.6 (2H,m )
2.6〜2.9 (2H,m )
5.30 (LH,bs )
7.50 (LH,d )
7.90 (IH,d )
8.00 (IH,d )
実施例 16゜
参考例2で得たジメチル 4−[2−(4−アミノブチ
ルチオ)−5−二トロフェニル] −2,6−シメチル
ー1,4−ジヒドロピリジン−3,5−ジカルボキシレ
ート1.35g及び1−ブロモ−3−フェノキシプロパ
ン0.645gt−アセトニトリル30m1に溶解し、
30分間加熱還流する。減圧下、溶媒を留去して得られ
た残留物をシリカゲルカラムクロマトに付し、クロロホ
ルム:メタノール(9: 1 v/v )で溶出して得
られた黄色油状物を塩酸−エタノールにより塩酸塩とし
、減圧下乾燥することによって0.37gのジメチル
4−[2−[4−(3−フェノキシプロピルアミン)プ
チルチオコー5−二トロフェニル] −2,6−ジメテ
ルー1,4−ジヒドロピリジン−3,5−ジカルボキシ
レート塩酸塩を得た。この化合物は次の理化学的性状を
有する。(1) Melting point 260°C (decomposition) (11) Nuclear magnetic resonance spectrum (DMSO-d6)
δ: 1.4-2.0 (4H, m)2.24
(6H*s) 2.4~2.6 (2H, m) 2.6~2.9 (2H, m) 5.30 (LH, bs) 7.50 (LH, d) 7.90 (IH ,d) 8.00 (IH,d) Example 16゜Dimethyl obtained in Reference Example 2 4-[2-(4-aminobutylthio)-5-nitrophenyl]-2,6-dimethyl-1,4 - 1.35 g of dihydropyridine-3,5-dicarboxylate and 0.645 g of 1-bromo-3-phenoxypropane dissolved in 30 ml of t-acetonitrile,
Heat to reflux for 30 minutes. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform:methanol (9:1 v/v). and drying under reduced pressure to obtain 0.37 g of dimethyl
4-[2-[4-(3-phenoxypropylamine)butylthioko-5-nitrophenyl]-2,6-dimether-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride was obtained. This compound has the following physical and chemical properties.
(i) 無晶形粉末
(11) 元素分、所領(C,H38N、078CI
として)C(%) H(%1 N(%)
計算値 58.10 6.18 6.78実測値
58,24 6.13 6.62(ili)
核磁気共鳴スペクトル(DMSO−d、 )δ: 1
.6〜2.0 (6H,m )2.24 (6H
,s )
2.5〜3.3 (6H,m )
3.50 (6H,s )
4.60 (2H,t )
5.30 (IH,s )
7.92 (IH,d )
7.96 (LH,bs)
6.8〜7.6 (6H,m )
9.12 (IH,bs)
実施例 17゜
ジメチル4−[2−(4−アミノブチルチオ)−5−二
トロフェニル]−2,6−シメチルー1,4−ジヒドロ
ピリジン−3,5−ジヵルボキシレート0.45 g’
、ヨウ化エチル0.16g及びトリエチルアミン0.
10gをアセトニトリル10m乙に溶解し、30分間加
熱還流する。減圧下、溶媒を留去して4’−’rられた
残留物をシリカゲルカラムクロマトに付し。(i) Amorphous powder (11) Element content, area (C, H38N, 078CI
) C (%) H (%1 N (%) Calculated value 58.10 6.18 6.78 Actual value 58.24 6.13 6.62 (ili)
Nuclear magnetic resonance spectrum (DMSO-d, )δ: 1
.. 6-2.0 (6H, m)2.24 (6H
,s) 2.5-3.3 (6H,m) 3.50 (6H,s) 4.60 (2H,t) 5.30 (IH,s) 7.92 (IH,d) 7.96 (LH, bs) 6.8-7.6 (6H, m) 9.12 (IH, bs) Example 17゜Dimethyl 4-[2-(4-aminobutylthio)-5-nitrophenyl]- 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate 0.45 g'
, 0.16 g of ethyl iodide and 0.16 g of triethylamine.
Dissolve 10 g in 10 m of acetonitrile and heat under reflux for 30 minutes. The solvent was distilled off under reduced pressure, and the 4'-'r residue was subjected to silica gel column chromatography.
アンモニア飽和クロロホルム:イソプロピルアルコール
(9: 1 v/v )で溶出して1()られた黄色油
状物を塩酸−エタノールにより塩酸塩とし、減圧上乾燥
することによって0.19gのジメチル 4−[2−(
4−ジエチルアミンブチルチオ)−5−ニトロフェニル
] −2,6−シメチルー1,4−ジヒドロピリジン−
3,5−ジカルボキシレート塩酸塩を得た。この化合物
は次の理化学的性状を有する。The yellow oil obtained by elution with ammonia-saturated chloroform:isopropyl alcohol (9:1 v/v) was made into a hydrochloride with hydrochloric acid-ethanol, and dried under reduced pressure to obtain 0.19 g of dimethyl 4-[2 −(
4-diethylaminebutylthio)-5-nitrophenyl]-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate hydrochloride was obtained. This compound has the following physical and chemical properties.
(1)無晶形粉末
(11) 元素分析値(C25HヨN、0.3C1と
して)CFI)H(%) N(%)
計算値 55.39 6.69 7.75実測値
55.74 6.49 7.69(110核磁
気共鳴スペクトル(DMSO−d6)δ: 1.42
(6H,t)
1.6〜2.3 (4H,m)
2.40 (6H,s )
2.8〜3.4 (8H,m )
3.56 (6H,s )
5.42 (IH,bs)
7.20 (LH,d )
7.90 (LH,d )
8.20 (LH,d )
1 −0− −(CH,)4− −H
−(CH2)sOPh2 〃〃−H−C2式
%式%(1) Amorphous powder (11) Elemental analysis value (as C25H, 0.3C1) CFI) H (%) N (%) Calculated value 55.39 6.69 7.75 Actual value 55.74 6. 49 7.69 (110 nuclear magnetic resonance spectrum (DMSO-d6) δ: 1.42
(6H, t) 1.6-2.3 (4H, m) 2.40 (6H, s) 2.8-3.4 (8H, m) 3.56 (6H, s) 5.42 (IH , bs) 7.20 (LH, d) 7.90 (LH, d) 8.20 (LH, d) 1 -0- -(CH,)4- -H
-(CH2)sOPh2 〃〃-H-C2 formula % formula %
Claims (1)
中断されていてもよいアルキル基、シクロ アルキル置換低級アルキル基、又はハロゲ ン置換低級アルキル基、 R^3及びR^4;同一又は異って、低級アルキル基、
R^5及びR^6;同一又は異って、水素原子、ニトロ
基、ハロゲン原子、低級アルキル基、低 級アルコキシ基、低級アルキルチオ基、低 級アルキルスルホニル基、又は低級アルキ ルスルフィニル基、 R^7;水素原子又は低級アルキル基、 R^8;低級アルキル基、ヒドロキシ低級アルキル基、
アラルキル基、アリール基、低級ア シル基、低級アルキルスルホニル基、アリ ールオキシ低級アルキル基、又はアリール オキシ低級アルコキシ基。 但し、R^7及びR^8とは窒素原子と一体となりピロ
ール環、ピペリジン環、モルホリン環、4位が低級アル
キル基又はアラルキル基で 置換されていてもよいピペラジン環又はア ゼピン環を形成していてもよい。 Y;酸素原子又は硫黄原子、 A;アルキレン基、アルケニレン基又はアルキニレン基
。) で示される1,4−ジヒドロピリジン誘導体又はその塩
。[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (Symbols in the formula indicate the following meanings. R^1 and R^2; Same or different. an alkyl group, a cycloalkyl-substituted lower alkyl group, or a halogen-substituted lower alkyl group, R^3 and R^4; the same or different, a lower alkyl group, which may be interrupted by an oxygen atom;
R^5 and R^6; the same or different, hydrogen atom, nitro group, halogen atom, lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylsulfonyl group, or lower alkylsulfinyl group, R^7; Hydrogen atom or lower alkyl group, R^8; lower alkyl group, hydroxy lower alkyl group,
an aralkyl group, an aryl group, a lower acyl group, a lower alkylsulfonyl group, an aryloxy lower alkyl group, or an aryloxy lower alkoxy group. However, R^7 and R^8 are combined with the nitrogen atom to form a pyrrole ring, piperidine ring, morpholine ring, piperazine ring or azepine ring whose 4-position may be substituted with a lower alkyl group or an aralkyl group. It's okay. Y: oxygen atom or sulfur atom; A: alkylene group, alkenylene group, or alkynylene group. ) A 1,4-dihydropyridine derivative or a salt thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP30925687A JPS63264459A (en) | 1986-12-08 | 1987-12-07 | Novel 1,4-dihydropyridine derivative and production thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP29269486 | 1986-12-08 | ||
JP61-292694 | 1986-12-08 | ||
JP30925687A JPS63264459A (en) | 1986-12-08 | 1987-12-07 | Novel 1,4-dihydropyridine derivative and production thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS63264459A true JPS63264459A (en) | 1988-11-01 |
Family
ID=26559098
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP30925687A Pending JPS63264459A (en) | 1986-12-08 | 1987-12-07 | Novel 1,4-dihydropyridine derivative and production thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63264459A (en) |
-
1987
- 1987-12-07 JP JP30925687A patent/JPS63264459A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DK170891B1 (en) | 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives and process for their preparation as well as pharmaceutical agent containing them | |
US4707486A (en) | Diaryl piperidine containing esters of 1,4-dihydropyridines and coronary therapeutic use | |
KR920005742B1 (en) | Process for the preparation of pharmaceutically useful dihydropyridinyl dicanboxylate amide and esters | |
US6603006B2 (en) | Intermediate for the synthesis of amlodipine, a process for the preparation thereof and corresponding use | |
AU642992B2 (en) | Use of N-alkylated 1, 4-dihydropyridinedicarboxylic acid esters as medicaments, new compounds and processes for their preparation | |
CZ219895A3 (en) | The use of substituted derivatives of 4-phenyl-6-aminonicotinic acid as medicaments | |
US5110820A (en) | Dihydropyridine compounds which process both calcium (2+)-antagonistic and beta receptor blocking activities | |
FI91634B (en) | A process for the preparation of therapeutically useful 1,4-dihydropyridine derivatives | |
US4857644A (en) | Aryl sulfonopiperazines as anti-inflammatory agents | |
HU204786B (en) | Process for producing new dihydropyridine amide derivatives and pharmaceutical compositions comprising such compounds | |
US4895846A (en) | Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moieties | |
US4814455A (en) | Dihydro-3,5-dicarboxylates | |
US4782160A (en) | 1,4-dihydropyridine derivatives | |
EP0207674B1 (en) | 1,4-dihydropyridine derivatives, their preparation and their pharmaceutical use | |
JPS63264459A (en) | Novel 1,4-dihydropyridine derivative and production thereof | |
CA1323876C (en) | Dihydropyridine derivatives and pharmaceutical composition thereof | |
JPS63130581A (en) | Production of 2-substituted-1, 4- dihydropyridines | |
JPS60208960A (en) | 2,6-disubstituted-1,4-dihydropyridine derivative and its preparation | |
JP2664941B2 (en) | 1,4-dihydropyridine compound | |
EP0190364A1 (en) | Novel 1,4-dihidropyridine-3,5-dicarboxylate derivatives | |
EP0079740B1 (en) | Anthraniloyloxyalkanoates | |
HU194210B (en) | Process for preparing novel diaryl-dihydropyridine compounds and pharmaceuticals comprising the same | |
KR820001835B1 (en) | Process for preparing 4-aminozpiperidonoquina-zoline derivatives | |
JPS635089A (en) | 1,4-dihydropyridine derivative, manufacture and medicine | |
JPH0527624B2 (en) |