JPH01249756A - Novel dihydropyrimidine derivative - Google Patents
Novel dihydropyrimidine derivativeInfo
- Publication number
- JPH01249756A JPH01249756A JP7732188A JP7732188A JPH01249756A JP H01249756 A JPH01249756 A JP H01249756A JP 7732188 A JP7732188 A JP 7732188A JP 7732188 A JP7732188 A JP 7732188A JP H01249756 A JPH01249756 A JP H01249756A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- alkyl
- compound
- group
- benzyl
- 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
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 title description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- OKGNMRKOGWTADH-UHFFFAOYSA-N 1,4-dihydropyrimidine Chemical class C1C=CNC=N1 OKGNMRKOGWTADH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 16
- -1 N-substituted 3,4-dihydropyrimidine Chemical class 0.000 abstract description 7
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002490 cerebral effect Effects 0.000 abstract description 3
- 230000004087 circulation Effects 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 229940127291 Calcium channel antagonist Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 230000000304 vasodilatating effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 239000000480 calcium channel blocker Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229960001783 nicardipine Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 238000005377 adsorption chromatography Methods 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 2
- 229910000105 potassium hydride Inorganic materials 0.000 description 2
- 102200073741 rs121909602 Human genes 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 210000002385 vertebral artery Anatomy 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-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
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
- XBGRMKUFDAGJDV-UHFFFAOYSA-N 2,2,2-trifluoroethanimidamide;hydrochloride Chemical compound Cl.NC(=N)C(F)(F)F XBGRMKUFDAGJDV-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
- WOUANPHGFPAJCA-UHFFFAOYSA-N 2-[benzyl(methyl)amino]ethanol Chemical compound OCCN(C)CC1=CC=CC=C1 WOUANPHGFPAJCA-UHFFFAOYSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 241000159375 Ashima Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000024172 Cardiovascular disease 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
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000004703 alkoxides Chemical class 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
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000000649 benzylidene group Chemical class [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 description 1
- 229960004166 diltiazem Drugs 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 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
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000004810 partition chromatography Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000005326 tetrahydropyrimidines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 238000000772 tip-enhanced Raman spectroscopy Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
〔式中 Ｒ１は炭素数１から１０のアルキル基ま（式中
、ｎは２から５の整数を表わし；Ｒ３およびＲ４は、／
％Ｃ１’ン原子または低級アルコキシ基で１置換または
２置換されていてもよいベンジル基またはナフチルメチ
ル基を表わす。＞ｙ’ａ−表わし。Detailed Description of the Invention [In the formula, R1 is an alkyl group having 1 to 10 carbon atoms (in the formula, n represents an integer of 2 to 5; R3 and R4 are /
% represents a benzyl group or a naphthylmethyl group which may be mono- or di-substituted with a C1' atom or a lower alkoxy group. >y'a-representation.
Ｒ２は炭素数１から５のアルキル基を表わす。〕を有す
るＮ置換３．４−ジヒドロピリミジン誘導体およびその
薬理学的に許容されつる酸付加塩に関する。R2 represents an alkyl group having 1 to 5 carbon atoms. ] and a pharmacologically acceptable phosphoric acid addition salt thereof.
上記−数式（１）で表わされる新規ジヒドロピリミジン
誘導体は強力な血管拡張作用を有しているので、降圧薬
、脳循環改善薬、抗狭心症薬等の循環系疾患治療剤とし
て使用されるものである。The above-mentioned novel dihydropyrimidine derivative represented by formula (1) has a strong vasodilatory effect and is therefore used as a therapeutic agent for circulatory system diseases such as an antihypertensive drug, a cerebral circulation improving drug, and an antianginal drug. It is something.
従来の技術
近年、新らしいタイプの循環器障害治療薬として脚光を
浴びてきたカルシウム拮抗薬（Ｃａ＋十拮十薬抗薬広範
囲な薬効を示し、高血圧症、狭心症。Background of the Invention In recent years, calcium channel blockers (Ca + 10-10 drug antagonists) have been in the spotlight as a new type of therapeutic drug for cardiovascular disorders.
脳循環障害、不整脈などに有効であり現在これらの治療
に使用されているばかりでなく、最近では動脈硬化の防
止や制ガン剤の作用増強などに有効であることが判明し
適応症がさらに増加しつつある。Not only is it effective for cerebral circulation disorders and arrhythmia, and it is currently being used to treat these conditions, but it has also recently been found to be effective in preventing arteriosclerosis and enhancing the effects of anticancer drugs, and the number of indications for it is increasing. be.
現在知らｎているカルシウム拮抗薬としては二フエジビ
ｙ （Ｎｉｆｅｄｉｐｉｎｅ）、ニカルジピン（Ｎｉｃ
ａｒｄｉｐｉｎｅ） 、ベラパミル（Ｖｅｒａｐａｍｉ
ｌ） 。Currently known calcium channel blockers include Nifedipine and Nicardipine.
ardipine), verapamil (Verapami)
l).
ジルチアゼム（Ｄｉｌｔｉａｚｅｍ）などがある。Examples include diltiazem.
現在までジヒドロピリミジン誘導体の研究はあまりなさ
れておらず、わずかにＳｉｌｖｅｒｓｍｉｔｈ 。Until now, there has been little research on dihydropyrimidine derivatives, with only a few studies being carried out by Silversmith.
Ｅ、Ｆ、Ｊ、Ｏｒｇ、Ｃｈｅｍ、 ２人４０９０（１
９６２）、 Ｎａ５ｉｐｕｒｉ。E, F, J, Org, Chem, 2 people 4090 (1
962), Na5ipuri.
Ｄ、ら５ｙｎｔｈｅｓｉｓ １０７３（１９８２）、Ｋ
ａｓｈｉｍａ、Ｃ０らＴｅｔｒａｈｅｄｒｏｎ Ｌｅｔ
ｔｅｒｓ ２０９（１９８３）、 及び特開昭５９−
７３５７２（バイエルＡ、Ｇ、 ）等の文献に見られる
程度である。この理由はジヒドロピリミジン誘導体の不
安定性、互変異性が考えられる。D. et al. Synthesis 1073 (1982), K.
ashima, C0 and others Tetrahedron Let
TERS 209 (1983), and JP-A-1983-
73572 (Bayer A, G, ). The reason for this is thought to be the instability and tautomerism of the dihydropyrimidine derivative.
発明が解決しようとする問題点
上記公知カルシウム拮抗薬は作用持続時間、臓器選択性
、光、熱などに対する安定性、および副作用などの特性
に改善の余地が認められるため。Problems to be Solved by the Invention The above-mentioned known calcium antagonists have room for improvement in properties such as duration of action, organ selectivity, stability against light, heat, etc., and side effects.
本発明者らはこれらの特性を改善したカルシウム拮抗薬
ン創製すべ（鋭意研究を重ねた結果、安定性に優れ１強
い血管拡張作用を有するＮ−置換−６，４−ジヒドロピ
リミジン誘導体を見出しり〔特開昭６０−２１４７７８
．特開昭６０−２４６３７６、特開昭６０−２５２４７
１．％開昭６１−４３１７１．特開昭６２−５９６８１
゜しかし１本発明者らは、より優れた安定性、活性、お
よび作用持続性さらにより低い毒性への改善ｔめざし鋭
意研究を続けた。その結果。The present inventors aimed to create a calcium channel blocker with improved properties (as a result of intensive research, they discovered an N-substituted-6,4-dihydropyrimidine derivative with excellent stability and strong vasodilatory action). [Unexamined Japanese Patent Publication No. 60-214778
．． JP-A-60-246376, JP-A-60-25247
1. % Kaisho 61-43171. Japanese Patent Publication No. 62-59681
However, the present inventors have continued to conduct intensive research aimed at improving the stability, activity, and duration of action as well as lower toxicity. the result.
前記−数式（１）で表わされるＮ−置換−３，４−ジヒ
ドロピリミジン誘導体が安定性に優れ、強い血管拡張作
用を有するだけでなく１作用持続性および急性毒性が低
−・点において非常に優れていることを見出し１本発明
を完成した。The N-substituted-3,4-dihydropyrimidine derivative represented by formula (1) not only has excellent stability and strong vasodilatory effect, but also has very low duration of action and low acute toxicity. They discovered that the invention was superior and completed the present invention.
問題ケ解決するための手段
本発明に従えば、前記−数式（１）で表わされる新規Ｎ
置換３．４−ジヒドロピリミジン誘導体およびその酸付
加塩が提供される。Means for Solving the Problem According to the present invention, the new N expressed by the above-mentioned formula (1)
Substituted 3,4-dihydropyrimidine derivatives and acid addition salts thereof are provided.
（式中Ｒ１とＲ２は上記定義のとおりである。）式
（式中、Ｒ２は前記定義と同じである。）で表わされる
互変異性体であるジヒドロピリミジン誘導体にも血管拡
張作用が認められるが、さらに−層、化学的に安定なも
のにし、且つ作用を増強させる目的で、前記−数式（１
）で表わさ几る化合物を合成した。(In the formula, R1 and R2 are as defined above.) The tautomer dihydropyrimidine derivative represented by the formula (In the formula, R2 is the same as the above definition) also has a vasodilatory effect. However, for the purpose of making the layer chemically stable and enhancing its action, the above-mentioned formula (1) is added.
) was synthesized.
前記−数式（１）で表わされるＮ置換３．４−ジヒドロ
ピＩ） ミジン誘導体の製造工程は例えば下記のようで
ある。The manufacturing process of the N-substituted 3,4-dihydropiI) midine derivative represented by formula (1) is, for example, as follows.
（ｒ） −数式（２）および（２′）（２）
（２’）（式中 Ｒ２は前記定義と同
じである。）で示される互変異性体は以下の方法により
得ることができる。即ちＲ２０Ｈ（式中Ｒ２は前記と同
一意義を表わｊ）と１当量のジケテン′％：１００〜２
００℃。(r) - Formulas (2) and (2') (2)
The tautomer represented by (2') (wherein R2 is the same as defined above) can be obtained by the following method. That is, R20H (in the formula, R2 represents the same meaning as above) and 1 equivalent of diketene'%: 100-2
00℃.
好ましくは１２０℃で６０分から６０分加熱することで
反応は進み一般式（６）で示すβ−ケトエステルが得ら
れる。Preferably, the reaction proceeds by heating at 120° C. for 60 to 60 minutes, and a β-ketoester represented by the general formula (6) is obtained.
（式中Ｒ２は前記と同一意義）
又はＲ２０Ｈと１当量のトリアルキルアミンなどの塩基
存在下室温もしくは０℃でジケテンと処理するか、水素
化ナトリウムまたは水素化カリウム存在下ジケテンと反
応させることによりても一般式（６）の化合物は得られ
る。(In the formula, R2 has the same meaning as above) or by treating R20H with diketene in the presence of 1 equivalent of a base such as trialkylamine at room temperature or 0°C, or by reacting it with diketene in the presence of sodium hydride or potassium hydride. However, the compound of general formula (6) can be obtained.
コノβ−ケトエステル（６）にニトロ基で芳香環置換し
たベンズアルデヒドを加え脱水縮合することによりベン
ジリデン化合物（４）とする。A benzaldehyde having an aromatic ring substituted with a nitro group is added to the cono β-ketoester (6) and subjected to dehydration condensation to obtain a benzylidene compound (4).
（式中Ｒｚは前記と同一意義χ表わす）このベンジリデ
ン（４）Ｖ）リフルオロアセトアミジン又はトリフルオ
ロアセトアミジン塩酸塩ビ用〜・縮合してテトラヒドロ
ピリミジン化合物（５）とする。(In the formula, Rz has the same meaning as above and represents χ) This benzylidene (4) V) Lifluoroacetamidine or trifluoroacetamidine hydrochloride is condensed to give a tetrahydropyrimidine compound (5).
このテトラヒドロピリミジン（５）を合成するにあたり
上記縮合反応は塩基存在下に行う。ここで使用される塩
基としては金属アルコキシド、金属ハイドライドが好ま
しく、又溶媒はアルコール系。In synthesizing this tetrahydropyrimidine (5), the above condensation reaction is carried out in the presence of a base. The base used here is preferably a metal alkoxide or metal hydride, and the solvent is alcohol-based.
エーテル系、ジメチルホルムアミドがよい。Ether type and dimethylformamide are preferable.
このピリミジン（５）’ｋｍ、例えばｐ−）ルエンスル
ホン酸、三フ、化ホウ素、カンファースルホン酸などの
触媒上加熱するか、シリカゲル、アルミナ又はモレキ、
ラシープスと加熱することにより一般式（２）および（
２′）で表わされる化合物は得られる。The pyrimidine (5)'km can be heated over a catalyst such as p-)luenesulfonic acid, trifluoride, boron, camphorsulfonic acid, or silica gel, alumina or molten,
General formula (2) and (
A compound represented by 2') is obtained.
得らｎた化合物は吸着クロマトグラフィー、イオン交換
クロマトグラフィー、分配クロマトグラフィー、蒸留、
再結晶などの一般的精製法により精製できる。又塩酸、
硫酸、リン酸などの無機酸。The obtained compound was subjected to adsorption chromatography, ion exchange chromatography, partition chromatography, distillation,
It can be purified by general purification methods such as recrystallization. Also, hydrochloric acid,
Inorganic acids such as sulfuric acid and phosphoric acid.
シュウ酸、酒石酸、コハク酸、マレイン酸などの有機酸
の塩として結晶化させ再結晶により精製することもでき
る。It can also be purified by recrystallization by crystallizing it as a salt of an organic acid such as oxalic acid, tartaric acid, succinic acid, or maleic acid.
（ＩＩ） Ｎ置換３．４−ジヒドロピリミジン誘導体
の製造 ゛
（Ｉ）で得らｎた前記−数式（２）および（２りで表わ
ｇｎる化合物を塩素系、芳香族炭化水素系、エーテル系
の有機溶媒にとかし、塩基１例えばトリアルキルアミン
、好ましくはトリエチルアミン。(II) Production of N-substituted 3,4-dihydropyrimidine derivative ゛The compound represented by formula (2) and (2) obtained in (I) is converted into a chlorine-based, aromatic hydrocarbon-based, ether A base 1, such as a trialkylamine, preferably triethylamine, is dissolved in an organic solvent of the system.
水素化ナトリウム、水素化カリウム、存在下０℃以下、
好ましくは−１０〜−３５℃でホスゲンまたはホスゲン
ダイマーの有機溶媒溶液に加え１反応終了後さらに一数
式Ｒ’ＯＨ（式中Ｒ１は前記と同−意！！１１を表わす
）を有する慟素原子Ｚ含む、アルコール化合物の溶液を
室温以下で加えることにより本発明化合物（１）は得ら
れる。ここで用いられる有機溶媒としては反応に関与し
ないものであればよいが、エーテル系または塩素系溶媒
が好ましい。Below 0°C in the presence of sodium hydride, potassium hydride,
Preferably, in addition to the organic solvent solution of phosgene or phosgene dimer at -10 to -35°C, after completion of one reaction, a chlorine atom having one formula R'OH (wherein R1 represents the same as above!!11) is added. The compound (1) of the present invention can be obtained by adding a solution of an alcohol compound containing Z at room temperature or below. The organic solvent used here may be any organic solvent as long as it does not participate in the reaction, but ether or chlorine solvents are preferred.
この本発明化合物である前記−数式（１）で表わされる
化合物は前述した反応後一般的な吸着カラムクロ寸トゲ
ラフイー、イオンタークロマトグラフィー。再結晶、な
どにより精製することが出来るし、又は塩酸、硫酸、リ
ン酸などの無機酸、シュウ酸、コハク酸、リンゴ酸など
の有機酸で処理し、再結晶、吸着クロマトグラフィー、
イオン交換クロマトグラフィーを用い精製することが出
来る。The compound represented by formula (1), which is the compound of the present invention, is subjected to general adsorption column chromatography or ion terchromatography after the above-mentioned reaction. It can be purified by recrystallization, etc., or treated with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, succinic acid, and malic acid, followed by recrystallization, adsorption chromatography,
It can be purified using ion exchange chromatography.
作 用 このようにして得られた本発明化合物（１）は。For production The compound (1) of the present invention thus obtained is:
以下に示す薬理試験の結果１代表的な既存薬剤であるニ
カルジピンよりも強（そして持続時間の長い作用を有す
る。Results of the pharmacological tests shown below: 1. It has stronger (and longer lasting) action than nicardipine, a typical existing drug.
試験方法
雌雄雑犬（７〜１４ｋｇ）’にチオベンタールナトリウ
ム（３５ｍ９Ａ９．腹腔内投与）で導入麻酔後、ウレタ
ンＣ４００Ｃ４０Ｏ、静脈内投与）およびα−クロラロ
ースＣ６０ｍｇ／ユ、静脈内投与）で麻酔し１人工呼吸
下にて試験を行った。胸部筒−助間切開により左椎骨動
脈Ｚ露出させ、その起始部に血流測定用プローブを装着
し、電磁血流計（ＭＦ−２７１日本光電（株）〕にて血
流量を測定した。Test method Male and female mongrel dogs (7-14 kg) were anesthetized with sodium thiobental (35m9A9.intraperitoneal administration), then urethane C400C40O (intravenous administration) and α-chloralose C60mg/U (intravenous administration). 1 The test was conducted under artificial respiration. The left vertebral artery Z was exposed through a thoracic tube-assistant incision, a blood flow measuring probe was attached to its origin, and the blood flow was measured using an electromagnetic blood flow meter (MF-271 Nihon Kohden Co., Ltd.).
また同時に右大腿動脈より全身血圧（平均血圧）Ｚ、第
■誘導により心電図を、又心電図のＲ波でタコメーター
乞駆動し【心拍数？、平均血圧値と平均椎骨動脈血流量
のめ力を乗除算ユ＝、）［ＥＯ−６０１Ｇ、日本光電（
株）〕に入力して血管抵抗値を連続測定し、ｊぺてのパ
ラメーターｔポリグラフ（ＲＭ−６００，日本光電（株
）〕上忙同時記録しこれよりＥＤ３ｏμｐ／’に９
’％：得た。尚、薬物はすべて予め大腿動脈に挿入した
カニユーレより注入した。At the same time, the systemic blood pressure (mean blood pressure) Z was measured from the right femoral artery, the electrocardiogram was measured from lead ①, and the R wave of the electrocardiogram was used to drive the tachometer. , Multiply and divide the mean blood pressure value and the mean vertebral artery blood flow rate (U=,) [EO-601G, Nihon Kohden (
The vascular resistance value was continuously measured using a polygraph (RM-600, Nihon Kohden Co., Ltd.).
'%:Obtained. All drugs were injected through a cannula inserted into the femoral artery in advance.
ま７Ｃ，ＥＤ（資）のときの血管抵抗の経時変化を測定
することにより、 ＴＨ＜分）〔最大反応に達してから
５０％回復するまでの時間〕を得た。By measuring the time-course changes in vascular resistance during 7C and ED, TH<min) [time from reaching maximum response to 50% recovery] was obtained.
結 果
上記薬理試験の結果、実施例１の化合物はＥＤ３゜１．
９μｇ次、実施例２．５．９の化合物は各々１号が８．
８ 、１１．７ 、６．６分であった。これらはいずれ
も本発明化合物が１代表的な既存薬剤であるニカルジピ
ン（ＥＤ３ｏ ＝ ３．Ｏｐｇ／に９．Ｔ ｙ２＝ ５
．０分）よりも強くそして持続時間の長い作用を有する
ことを示すものである。Results As a result of the above pharmacological test, the compound of Example 1 had an ED of 3°1.
9 μg of the compounds of Example 2.5.9, No. 1 and 8.9 μg, respectively.
8, 11.7, and 6.6 minutes. In all of these cases, the compound of the present invention is a typical existing drug, nicardipine (ED3o = 3.Opg/9.T y2 = 5
．． 0 minutes), indicating that it has a stronger and longer-lasting effect.
実 施 例
本発明は以下に示す実施例によりより詳細に説明される
。EXAMPLES The present invention will be explained in more detail by the following examples.
実施例１
３−（２−（Ｎ−ベンジル−Ｎ−メチルアミノ）エトキ
シカルボニル−６〜メチル−５−（１−メチルエトキシ
カルボニル）−４−（２−二ト四フェニル）−２−トリ
フルオロメチル−３，４−ジヒドロピリミジホスゲンダ
イマー２４μｅの無水ＴＨＦ２１１Ｌｔ溶液に。Example 1 3-(2-(N-benzyl-N-methylamino)ethoxycarbonyl-6-methyl-5-(1-methylethoxycarbonyl)-4-(2-dithoteprhenyl)-2-trifluoro A solution of 24 μe of methyl-3,4-dihydropyrimidiphosgene dimer in 211 Lt of anhydrous THF.
−２６℃で攪拌下２−トリフルオロメチル−５−イソプ
ロポキシカルボニル−６−メチル−４−（２−ニトロフ
ェニ／Ｉ／）−１，４（３，４）−ジヒドロピリミジン
６１ｍｇとトリエチルアミン１６８μｌ’ｌπ正２１に
溶かした溶液ケ加え、そのまま１．５時間攪拌する。次
いで、２−（Ｎ−ベンジル−Ｎ−メチルアミノ）エタン
−１−オール１６２ｍｇ ’ｋ ＴＨＦ ３ｍに溶かし
た溶液を０℃で加え、１時間撹拌した。さらに室温で１
９時間攪拌した後、精製水で反応混合物を希釈し、塩化
メチレンで抽出した。抽出液ン乾燥後、溶媒留去し、残
渣２２７ｍｇ’にシリカゲルクロマトグラフィーに付し
く展開溶媒：酢酸エチル−ｎ−ヘキサン）、２７ｍｇＣ
５０％）の目的化合物ケ得た。その物性データを表１に
示した。実施例２〜９を実施例１の方法に従って行い、
得られた化合物のデー２７表１に示す。61 mg of 2-trifluoromethyl-5-isopropoxycarbonyl-6-methyl-4-(2-nitropheny/I/)-1,4(3,4)-dihydropyrimidine and 168 μl of triethylamine under stirring at -26°C. Add the solution dissolved in Sei 21 and stir as it is for 1.5 hours. Then, a solution of 162 mg of 2-(N-benzyl-N-methylamino)ethan-1-ol in 3 m of THF was added at 0°C and stirred for 1 hour. Furthermore, 1 at room temperature
After stirring for 9 hours, the reaction mixture was diluted with purified water and extracted with methylene chloride. After drying the extract, the solvent was distilled off, and 227 mg of the residue was subjected to silica gel chromatography.
50%) of the target compound was obtained. The physical property data are shown in Table 1. Examples 2-9 were carried out according to the method of Example 1,
The data of the obtained compound is shown in Table 27.
表１のＮＭＲのデータ中Ｓは単一巌、ｄは二重線、 ｂ
ｒｓは広巾単一線、ｔは三重線、ｑは 四重ｄ、ｑｕｉ
ｎｔｅｔは三重線１ｍは多重１［’示す。In the NMR data in Table 1, S is single line, d is double line, b
rs is a wide single line, t is a triple line, q is a quadruple line, d, qui
ntet indicates that triplet line 1m indicates multiplex 1['.
手続補正書Procedural amendment
Claims (1)
基 ▲数式、化学式、表等があります▼ （式中、ｎは２から５の整数を表わし；Ｒ＾３およびＲ
＾４は、ハロゲン原子または低級アルコキシ基で１置換
または２置換されていてもよいベンジル基またはナフチ
ルメチル基を表わす。）を表わし、Ｒ＾２は炭素数１か
ら５のアルキル基を表わす。〕を有するＮ置換３，４−
ジヒドロピリミジン誘導体およびその薬理学的に許容さ
れうる酸付加塩。[Claims] 1) General formula (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) [In the formula, R^1 is an alkyl group or group having 1 to 10 carbon atoms ▲ Numerical formulas, chemical formulas, tables, etc. etc. ▼ (In the formula, n represents an integer from 2 to 5; R^3 and R
^4 represents a benzyl group or a naphthylmethyl group which may be mono- or di-substituted with a halogen atom or a lower alkoxy group. ), and R^2 represents an alkyl group having 1 to 5 carbon atoms. ] with N-substitution 3,4-
Dihydropyrimidine derivatives and pharmacologically acceptable acid addition salts thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7732188A JPH01249756A (en) | 1988-03-30 | 1988-03-30 | Novel dihydropyrimidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7732188A JPH01249756A (en) | 1988-03-30 | 1988-03-30 | Novel dihydropyrimidine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01249756A true JPH01249756A (en) | 1989-10-05 |
Family
ID=13630671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7732188A Pending JPH01249756A (en) | 1988-03-30 | 1988-03-30 | Novel dihydropyrimidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01249756A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
-
1988
- 1988-03-30 JP JP7732188A patent/JPH01249756A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7157461B2 (en) | 2003-07-23 | 2007-01-02 | Bristol-Myers Squibb Co. | Substituted dihydropyrimidine inhibitors of calcium channel function |
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