CN1033644C - 3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物,其制备与用途 - Google Patents
3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物,其制备与用途 Download PDFInfo
- Publication number
- CN1033644C CN1033644C CN 93100378 CN93100378A CN1033644C CN 1033644 C CN1033644 C CN 1033644C CN 93100378 CN93100378 CN 93100378 CN 93100378 A CN93100378 A CN 93100378A CN 1033644 C CN1033644 C CN 1033644C
- Authority
- CN
- China
- Prior art keywords
- alkyl
- formula
- quinazoline
- compound
- methyl
- 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.)
- Expired - Fee Related
Links
- 241001597008 Nomeidae Species 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title description 6
- OVBRSTFUGIUYNH-UHFFFAOYSA-N 2-methyl-2,3-dihydroimidazo[1,2-c]quinazoline Chemical compound C1=CC=C2C3=NC(C)CN3C=NC2=C1 OVBRSTFUGIUYNH-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 206010020772 Hypertension Diseases 0.000 claims abstract description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 68
- 239000002585 base Substances 0.000 claims description 49
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 46
- -1 4Be halogen Chemical class 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 15
- 239000004480 active ingredient Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- HKJZDEUEWZSNFY-UHFFFAOYSA-N imidazo[1,2-c]quinazoline Chemical compound C1=CC=C2C3=NC=CN3C=NC2=C1 HKJZDEUEWZSNFY-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 15
- 150000002431 hydrogen Chemical class 0.000 claims 12
- 150000002367 halogens Chemical class 0.000 claims 11
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims 8
- 230000003287 optical effect Effects 0.000 claims 4
- 230000006340 racemization Effects 0.000 claims 4
- 230000001225 therapeutic effect Effects 0.000 claims 4
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 3
- 206010013990 dysuria Diseases 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 84
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000001953 recrystallisation Methods 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
- 238000013016 damping Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- NPNDIKQZGVCHMQ-UHFFFAOYSA-N 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-1h-quinazoline-2,4-dione;hydrochloride Chemical compound Cl.COC1=CC=CC=C1N1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 NPNDIKQZGVCHMQ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000294743 Gamochaeta Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000013519 translation Methods 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 244000025254 Cannabis sativa Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 239000000951 adrenergic alpha-1 receptor antagonist Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- GHLITDDQOMIBFS-UHFFFAOYSA-H cerium(3+);tricarbonate Chemical compound [Ce+3].[Ce+3].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O GHLITDDQOMIBFS-UHFFFAOYSA-H 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 210000001105 femoral artery Anatomy 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000007788 liquid Substances 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 229960001289 prazosin Drugs 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910001958 silver carbonate Inorganic materials 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 description 1
- PZIBVWUXWNYTNL-UHFFFAOYSA-N 1-(3-methoxyphenyl)piperazine Chemical compound COC1=CC=CC(N2CCNCC2)=C1 PZIBVWUXWNYTNL-UHFFFAOYSA-N 0.000 description 1
- ZEQIWKHCJWRNTH-UHFFFAOYSA-N 1h-pyrimidine-2,4-dithione Chemical class S=C1C=CNC(=S)N1 ZEQIWKHCJWRNTH-UHFFFAOYSA-N 0.000 description 1
- YYFLDZZDOUDZQM-UHFFFAOYSA-N 3-[1-[[4-(3-phenylquinolin-2-yl)phenyl]methyl]piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C(CC1)CCN1CC(C=C1)=CC=C1C1=NC2=CC=CC=C2C=C1C1=CC=CC=C1 YYFLDZZDOUDZQM-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 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
- 239000004475 Arginine Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- GCLVAJFFRHHQAN-UHFFFAOYSA-N CC1=C2C=C3C(=CC=C(C3=CC2=CC=C1)C#N)C Chemical compound CC1=C2C=C3C(=CC=C(C3=CC2=CC=C1)C#N)C GCLVAJFFRHHQAN-UHFFFAOYSA-N 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
- 241000282326 Felis catus Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- WVAHKIQKDXQWAR-UHFFFAOYSA-N anthracene-1-carbonitrile Chemical compound C1=CC=C2C=C3C(C#N)=CC=CC3=CC2=C1 WVAHKIQKDXQWAR-UHFFFAOYSA-N 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- FPCCSQOGAWCVBH-UHFFFAOYSA-N ketanserin Chemical compound C1=CC(F)=CC=C1C(=O)C1CCN(CCN2C(C3=CC=CC=C3NC2=O)=O)CC1 FPCCSQOGAWCVBH-UHFFFAOYSA-N 0.000 description 1
- 229960005417 ketanserin Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- MRDGZSKYFPGAKP-UHFFFAOYSA-N para-methoxyphenylpiperazine Chemical compound C1=CC(OC)=CC=C1N1CCNCC1 MRDGZSKYFPGAKP-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- WRLGYAWRGXKSKG-UHFFFAOYSA-M phenobarbital sodium Chemical compound [Na+].C=1C=CC=CC=1C1(CC)C(=O)NC([O-])=NC1=O WRLGYAWRGXKSKG-UHFFFAOYSA-M 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明供提一新系列的3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉的化合物,这些化合物被发现可用于高血压及排尿困难的预防和治疗。
Description
本发明是有关于新颖3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物I-IV及其可药用盐,及其制法及用以防治高血压及排尿困难。
喹唑啉环包含著一系列的抗高血压试剂。发表在美国专利3,51,836的Prazosin,是一个2-取代喹唑啉衍生物,已经在临床上证实为α1-肾上腺素拮抗剂。
3-取代喹唑啉如美国专利4,335,127揭示的Ketanserin,thioke-tanserin及日本药理学志1987,44,35揭示的SGB-1534已经分别发现具有5-羟基色氨-S2及α1-肾上腺受体拮抗性抗高血压作用。
在我们稠合喹唑啉环系的合成研究当中,合成了角状三环稠合喹唑啉衍生物,如2-取代喹唑啉衍生物具有刚性结构特点,为兼有Kelanserin及SGB-1534的生物学活性所需,当作α1-肾上腺受体拮抗剂强力降血压(陈基旺等获准的美国专利申请案07/744,534),最近在Drugof the Future,1989,14,400及英国药理学杂志1988,93,702-14报告α1-肾上腺受体拮抗剂可用以治疗用于因前列腺肥大所引起排尿困难。
因此,仍需更强力而临床上有效的抗高血压剂。
故本发明的目的为开发更强力而临床上有效的抗高血压及排尿困难剂。
本发明另一目的是提供新型而且可利用的3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物I-IV以及其可药用的盐类。
本发明的另一目的是提供3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物I-IV和其盐类的制备方法。
本发明的进一步目的是提供以3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物I-IV或其盐类为活性成份的药物组合物。
本发明的其它目的是提供治疗高血压及排尿困难用药物的制造,包括3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物I-IV或其可药用的盐类。
现开发了如下式I-IV一系列新化合物具有优异的抗高血压活性。
R1为囟素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R2为囟素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R4为囟素,氢,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;
R5为C1-4烷基或芳基-(C1-4)烷基;或其可药用的盐;式中R3为氢,C1-4烷基或芳基-(C1-4)烷基,当R3为氢时,式为III,当R3为C1-4烷基或芳基-(C1-4)烷基时,式为IV;
X为O或S,
R1为囟素,氢,C1-6烷基,三氟甲基或C1-6烷氧基,
R2为囟素,氢,C1-6烷基,三氟甲基或C1-6烷氧基,
R4为囟素,氢,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;
或其可药用的盐。
医药上允许的盐类包括无机酸盐如盐酸盐,硫酸盐,氢溴酸盐,磷酸盐;以及有机酸盐如乙酸盐,顺丁烯二酸盐,酒石酸盐,甲磺酸盐,苯磺酸盐及甲苯磺酸盐,及与如精氨酸,天冬氨酸及谷氨酸等氨基酸的盐。
本发明化合物也可以水合物或立体异构体存在,它们也包括在本发明范围内。
“囟素”的定义包括氟,氯,溴,优选氟,尤其是氯。
结构式I-IV的化合物的制备方法包括
(b)将所得化合物VI与化学式R5-Y的烷化剂反应,得下式VII化合物其中R1,R2和R5与前述的定义相同,Y为囟素;
(e)使所得化合物IX与适当侧链如化合物X反应,得到下式I化合物,式中R4同前,式中R1,R2,R4及R5同前;
(f)将化合物I以化合物R5-OH在碱存在下用适当条件处理,得化合物II,其中R5同前;
(h)化合物III与烷化剂R3-Y反应,得化合物IV,其中R3为C1-4烷基或芳基-(C1-4)烷基,Y为囟素。
过程a)可在任何适当溶剂中进行,只要不干涉反应剂即可,反应常在回流下2小时内完成。
过程b)中化合物VI的烷化在如NaOH水等碱的存在下进行,一般在室温约3小时完成。
过程c)可在无或有适当溶剂下进行,只要不干扰反应,任何溶剂均可用,如水,醇,醚,二甲亚砜,常在不锈钢罐于130℃约24小时完成
过程d)中化合物VIII的囟环化可在N-囟代琥珀酰亚胺或囟素的存在下用或不用适当溶剂进行。只要不影响反应,任何溶剂均可用,如水、醇、醚、及二甲亚砜,常在室温约12小时完成。
过程e)中化合物IX与适当侧链X的反应可在适当碱如三甲胺,碳酸氢钠及碳酸钠的存在下,于适当溶剂如乙腈,二噁烷,二甲基甲酰胺及二甲基乙酰氨中,在50-120℃进行2-24小时。
过程f)中适宜反应温度为0-55℃。能适用于此反应的适当碱包括无机碱,例如NaOH,碳酸钠,碳酸钾,碳酸氢钠,碳酸氢钾,碳酸银,碳酸铈和此类似物等;和有机碱,例如三乙胺,吡啶,N,N-二甲苯胺,N-甲基吗啉,DBU,DBN和此类似物等,而且,过量的侧链基R5-OH在此反应中亦具有作为碱的功能。
过程g)中适宜反应温度为70℃。能适用于此反应的适当碱包括无机碱,例如NaOH,碳酸钠,碳酸钾,碳酸氢钠,碳酸氢钾,碳酸银,碳酸铈等,而且,过量的侧链基R5-OH在此反应中亦具有作为碱的功能。
过程h)中,化合物III的烷化反应在有或无适当溶剂存在下来进行。此反应通常在室温下进行,约3小时即可反应完全。
结构式I-IV的化合物和其盐类具有很好的抗高血压活性,因此,可用作药物。
本发明化合物的药理活性,可经由下列试验结果得到明显的证实。所用供试化合物如下述。
抗高血压活性
2-3千克重不分性别的成年猫先利用苯巴比妥钠(30毫克/千克,腹腔注射)麻醉,以Harvard呼吸器(呼吸率=16-20/分钟,管柱=40-50毫升/每呼吸)。并于气管接导管以提供空气做人工呼吸,股动脉和静脉分别接上PE 150的套管以监测血压及给予药物。体温利用加热来维持在37.5℃,并用直肠温度计来测量。利用Statham P23D压力转换器经由聚乙烯套管接在右股动脉以测量血压。心跳速率可利用Grass Model7B血流速度描记放大器通过动脉血压的脉动来测量,全部资料都纪录在Grass Model 7B多种描记器上。结果如表1。
表1
化合物 剂量 MBP(2小时)
例6 1mg/Kg 77mmHg
例9 1mg/Kg 30mmHg
例16 1mg/Kg 23mmHg
例18 1mg/Kg 50mmHg
例21 1mg/Kg 35mmHg
例22 1mg/Kg 50mmHg
例23 1mg/Kg 63mmHg
0.25mg/Kg 40mmHg
结合研究的方法
1.结合研究用膜的制备
为[3H]prozosin或[3H]clonidine结合制造鼠脑皮质膜,乃将组织均化于以50mM Tris缓冲液(pH7.4)缓冲的0.32M蔗糖液,组织/缓冲液比为1∶10。以1000×g离心10分钟来除去核后,将上清液以22,000×g离心2次,再悬浮于新缓冲液,得膜悬浮液(约2mg/ml蛋白质)即可使用。
2.结合分析
用0.2nM[3H]prazosin最后容量1.0ml Tris缓冲液pH7.4在室温进行α1-肾上腺受体结合分析(三次重复)30分钟,用10μMphentolamine测定非特异结合。竞争性结合用合成物的浓度为0.1-220nM。用有10mM MgCl2存在的1nM[3H]clonidine最后容量1.0ml TRIS缓冲液pH7.4在室温进行α2肾上腺受体结合分析(三次重复)30分钟,用10μM clonidine测定非特异结合,竞争性结合用合成化合物的浓度为0.1-100μM。结合达平衡后,以whatman GF/B滤器滤集膜来终止培养,将滤液以5ml 50mM Tris缓冲液(pH7.4)4℃洗2次。依Lowry等的方法测定,用于各分析的膜蛋白量为300-400μg,结果如表2。材料
[3H]Prazosin(76.6 Ci/mmol)及[3H]clonidine(47.0Ci/mmol)用NEN购得,所有其他药品为试剂级,购自Sigma(密苏里州,圣路易市)。
表2
咪唑并[1,2-c]喹唑啉衍生物的α1及α2肾上腺受体结合亲和性
化合物 α1结合(Ki,nM) α2结合(Ki,nM) α2/α1比
例5 >10
例6 0.54±0.09
例7 48.9±20.4 8356±588 171
例9 0.34±0.06 180.4±7 529
例12 0.07±0.007
例14 >100
例16 0.11±0.02
例17 1.75±0.5 962±29 566
例18 0.45±0.09
例19 5.76±0.48
例21 0.58±0.07
例22 0.068±0.006
例23 0.36±0.05
SGB-1534 0.25±0.06
由下列实施例制造的化合物为优选化合物:
例5
3-[4-(1-苯基)六氢吡嗪基]甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
例6
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
例9
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
例12
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
例13
3-{4-[1-(苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
例14
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
例17
3-(4-苯基-L-六氢吡嗪基)甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
例18
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹咪啉-5(6H)-酮
例21
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
例22
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-6-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
例23
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-6-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
例29
3-[4-(1-苯基)六氢吡嗪基]甲基-5-甲硫基-8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
本发明的化合物可配制用于药物组合物中,因此,本发明的进一步目的是提供一个药物组合物,包括结构式I-IV或其可药用盐类的化合物以及可药用的载体或赋形剂。
能经由口服给予人体的组合物,可能是以糖浆,片剂或胶囊的形式。当为片剂时,可以使用任何适用于配制的药物载体例如固体成份如硬脂酸镁,淀粉,乳糖,葡萄糖和芳香剂。这些化合物也可能存在于无菌的液体载体中,以便于注射。
本发明以下列实施例做详尽的描述,该实施例并非用于限制本发明范围。
例1
喹唑啉-2,4-(1H,3H)-二硫酮
混合蒽腈(3.0g,25.4mmol)及二硫化碳(10mL,0.13mole)于吡啶(10mL)中,回流8小时。冷却至室温1小时后,加乙醇(150mL),滤集黄色固体,以乙醚(15mL)洗涤,得5.43g(92%)喹唑啉-2,4-(1H,3H)-二硫酮,mp 234-237℃[235-238℃,E.C.Taylor,et al.in"Heteroxyclic syntheses from o-aminonitriles-XXVII.A.one-step synthesis of fused pyrimidinedithiones",Tetrahedron,1967,23,891].1H-NMR(100MHz,DMSO-d6):δ7.23-7.37(m,2H,Ar-H),7.65-7.81(m,1H,Ar-H),8.23-8.33(m,1H,Ar-H),13.05(s,2H,NH2,D2O可交换);13C-NMR(25MHz,DMSO-d6):δ116.02,122.52,125.04,129.90,135.82,136.11,170.21,187.57。例22,4-二甲硫基喹唑啉
溶解喹唑啉-2,4-(1H,3H)-二硫酮(10g,51.5mmol)于10%NaOH水(50mL)中,滴加甲基碘(10ml,0.1mole)。在室温搅拌24小时,滤集白色固体,以水10mL洗涤,得10.65g(93%)2,4-二甲硫基喹唑啉,mp 85℃,1H-NMR(100MHz,DMSO-d6):δ2.61(s,3H,CH3),2.65(s,3H,CH3),7.53-7.82(m,4H,Ar-H);13C-NMR(25MHz,DMSO-d6):δ12.13,13.71,120.23,123.45,126.03,126.56,134.30,147.60,165.78,170.50;ms:m/z221(M+-1),206(M+-15),188(M+-60),159(M+-62)。例34-烯丙基-2-甲硫基喹唑啉
混合2,4-二甲硫基喹唑啉(10g,45mmol)及烯丙氨(68mL,0.9mol)于乙腈(200mL)中,在不锈钢容器中加热120-130℃48小时,在50℃真空浓缩至20mL,放在冰箱中6小时,滤集固体,以乙腈洗涤,得9.47g(91%)4-烯丙基-2-甲硫基喹唑啉。用乙酸乙酯重结晶分析样品,mp133-135℃;1H-NMR(100MHz,DMSO-d6):δ2.50(s,3H,CH3),4.16(t,2H,J=6.0Hz,CH2),5.02-5.26(m,2H,CH2),5.76-6.18(m,1H,Ar-H),7.26-7.74(m,3H,Ar-H),8.18(d,1H,J=8.5Hz,Ar-H),8.50(t,1H,J=5.9Hz,NH,D2O可交换);13C-NMR(25MHz,DMSO-d6):δ13.48,42.77,112.67,115.49,122.75,124.10,125.74,132.71,134.65,149.30,158.20,166.37;ms:m/z 231(M+),205(M+-26),183(M+-48).元素分析计算值:C12H13N3S(231.31):C,62.31;H,18.17;N,5.66.实测值:C,62.12;H,17.84;N,5.70.
例4
悬浮4-烯丙基-2-甲硫基喹唑啉(10g,43mmol)于乙腈(50mL)中,加NBS(9g,50mmol)使成溶液。在室温搅拌,10分后,渐渐生成白色固体,再成悬浮液。反应在3小时内完。滤集固体,以乙腈(10mL)洗涤,得11.75g(85%)3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,mp 162-163℃,1H-NMR(100MHz,
DMSO-d6):δ27.8(s,3H,CH3),4.00-4.43(m,4H,
2CH2),5.45-5.49(m,1H,CH),7.68-7.73(m,1H,
Ar-H),7.80(d,1H,Ar-H),8.06(t,1H,Ar-H),
8.38(d,1H,Ar-H),13C-NMR(25MHz,DMSO-d6):δ
13.02,35.80,57.37,59.08,116.77,124.98,
125.36,125.48,133.06,145.75,152.63,153.69;
ms:m/z 310(M+),309(M+-1),230(M+-80),174
(M+-136),元素分析计算值:C12H12N3SBr(310.21):C,
46.46;H,13.55;N,3.90.实测值:C,46.60;H,
13.70;N,3.88.
例5
3-[4-(1-苯基)六氢吡嗪基]甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(3.0g,9.7mol)及1-苯基六氢吡嗪(3.0mL,18.5mmol)于乙腈(60mL)中,用油浴回流24小时后,在40℃真空浓缩至30mL。滤集白色固体,以水25mL洗净。得2.13g(56%)3-[4-(1-苯基)六氢吡嗪基]甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,mp
133-134℃,1H-NMR(400MHz,DMSO-d6):δ2.50-2.56
(m,4H,2CH2),2.59(s,3H,CH3),2.68-2.75(m,
2H,CH2),3.09-3.13(m,4H,2CH2),3.92-4.09(m,
2H,CH2),4.51(m,1H,CH),6.76(t,J=7.3Hz,1H,
Ar-H),6.89(d,J=7.8Hz,2H,Ar-H),7.17-7.26(m,
3H,Ar-H),7.33(d,J=7.8Hz,1H,Ar-H),7.56(t,
J=7.8Hz,1H,Ar-H),7.84(d,J=7.8Hz,1H,
Ar-H).;13C-NMR(100MHz,DMSO-d6):δ12.96,
48.02,52.96,55.87,58.68,59.14,115.19,116.79,
118.58,124.63,124.94,125.27,128.67,132.64,
145.86,150.76,152.26,153.95.;ms:m/z 391(M+),
344(M+-47),259(M+-132),216(M+-175),175
(M+-216,100%),132(M+-259),元素分析计算值:
C22H25N5S(391.51):C,67.49;H,17.89;N,6.43.
实测值:C,67.44;H,17.72;N,6.48.
例6
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(3.0g,9.7mmol)及1-(2-甲氧苯基)六氢吡嗪(3.2mL,6.7mmol)于乙腈(60mL)中,回流24小时后,加碳酸氢钠(2.5g,30mmol),再回流12小时。在40℃真空浓缩至20mL。滤集白色固体,以水(30mL)洗净,得3.37g(82%)3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,mp 174-175℃,
1H-NMR(400MHz,DMSO-d6):δ2.43-2.56(m,4H,
2CH2),2.59(s,3H,-SCH3),2.86-2.87(m,2H,
CH2),2.96(m,4H,2CH2),3.77(s,3H,OCH3),
3.91-4.09(m,2H,CH2),4.52(m,1H,CH),6.87(s,
2H,Ar-H),6.92(s,2H,Ar-H),7.25(t,J=7.3Hz,
1H,Ar-H),7.33(d,J=7.3Hz,1H,Ar-H),7.55(t,
J=6.8Hz,1H,Ar-H),7.83(d,J=7.3Hz,1H,
Ar-H).;13C-NMR(100MHz,DMSO-d6):δ12.91,
49.81,53.33,55.21,55.87,58.67,59.29,112.05,
116.75,117.77,120.70,122.11,124.58,124.91,
125.23,132.60,141.11,145.83,151.88,152.23,
153.96.;ms:m/z 422(M+),374(M+-48),205
(M+-217,100%),元素分析计算值:C22H27N5SO
(421.56):C,65.53;H,6.46;N,16.61.实测值:C,
65.21;H,6.40;N,16.60.
例7
3-{4-[1-(3-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(3.0g,9.7mmol)及1-(3-甲氧苯基)六氢吡嗪(3.5mL,9.7mmol)于乙腈(60mL)中,用油浴回流12小时后,在40℃真空浓缩至20mL。滤集固体,以水(30mL)洗净,得2.31g(57%)3-{4-[1-(3-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈再结晶,mp 138-139℃,1H-NMR(400MHz,DMSO-d6):δ2.50-2.56(m,2H,CH2),2.59(s,3H,-SCH3),2.67-2.74(m,4H,2CH2),3.11(m,4H,2CH2),3.70(s,3H,OCH3),3.91-4.05(m,2H,CH2),4.51(m,1H,CH),6.35(d,J=7.8Hz,1H,Ar-H),6.43(s,1H,Ar-H),6.49(d,J=8.3Hz,1H,Ar-H),7.09(t,J=8.3Hz,1H,Ar-H),7.24(t,J=7.8Hz,1H,Ar-H),7.33(d,J=8.3Hz,1H,Ar-H),7.54(t,J=7.8Hz,1H,Ar-H),7.83(d,J=7.8Hz,1H,Ar-H).;13C-NMR(100MHz,DMSO-d6):δ12.96,47.99,52.94,54.68,55.87,58.68,59.12,101.42,103.97,107.88,116.77,124.63,124.94,125.27,129.35,132.64,145.85,152.12,152.25,153.95,160.07;ms:m/z422(M+),374(M+-48),259(M+-163),205(M+-217,100%),元素分析计算值:C22H23N5SO(421.56):C, 65.53;H,6.46;N,16.61.实测值:C,65.50;H,6.47;N,16.66.
例8
3-{4-[1-(4-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(3.0g,9.7mmol)及1-(4-甲氧苯基)六氢吡嗪(3.5mL,20.3mmol)于乙腈(60mL)中。用油浴回流24小时后,加碳酸氢钠(2.5g,30mmol),再回流12小时。在40℃真空浓缩至20mL。滤集固体,以水(30mL)洗净,得2.27g(54%)3-{4-[1-(4-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,mp.
133-135℃,1H-NMR(400MHz,DMSO-d6):δ2.51-2.57
(m,4H,2CH2),2.60(s,3H,-SCH3),2.72-2.75(m,
2H,CH2),2.99(m,4H,2CH2),3.68(s,3H,OCH3),
3.91-4.03(m,2H,CH2),4.51(m,1H,CH),6.83(m,
4H,Ar-H),7.24(t,J=7.3Hz,1H,Ar-H),7.33(d,
J=7.8Hz,1H,Ar-H),7.54(t,J=6.8Hz,1H,Ar-H),
7.83(d,J=7.8Hz,1H,Ar-H).;13C-NMR(100MHz,
DMSO-d6):δ12.91,49.38,53.07,55.05,55.89,
58.65,59.12,114.13,116.77,117.11,124.59,
124.89,125.23,132.59,145.19,145.83,152.23,
152.78,153.91;ms:m/z 421(M+),406(M+-15),373
(M+-48),259(M+-162),216(M+-205),205(M+-207,
100%),元素分析计算值:C22H23N5SO(421.56):C,
65.53;H,6.46;N,16.60.实测值:C,65.53;H,6.51;
N,16.61.
例9
悬浮3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(2.0g,6.4mmol)及碳酸氢钠(0.8g,8.8mmol)于乙腈(40mL),加1-(2-氯苯基)六氢吡嗪盐酸盐(1.9g,7.7mmol),用油浴回流24小时。滤集白色固体,以水(30mL)洗净,得1.23g(45%)3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙醇重结晶,mp 184-185℃,1H-NMR(400MHz,CDCl3):
δ2.17-2.54(m,2H,CH2),2.56(s,3H,-SCH3),
2.58-2.82(m,4H,2CH2),2.96-3.02(m,4H,2CH2),
4.05-4.07(m,2H,CH2),4.36-4.37(m,1H,CH),
6.86-7.89(m,8H,Ar-H);13C-NMR(100MHz,
CDCl3):δ13.50,51.09,53.81,56.43,59.28,
59.68,117.05,120.32,123.64,125.10,125.30,
125.74,127.51,128.72,130.57,132.89,146.53,
149.17,153.81,154.27;元素分析计算值:
C22H24N5SCl(425.98):C,62.03;H,5.68;N,16.44.
实测值:C,61.72;H,5.65;N,16.43.
例10
混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并并[1,2-c]喹唑啉(3.0g,9.7mmol)及3-吖螺[5.5]十一烷(2.3mL,14.2mmol)及碳酸氢钠(0.9g,10.7mmol)于乙腈(80mL)中。用油浴回流10小时后,滤除不溶固体。滤液在40℃真空浓缩至20mL。滤集白色固体,以水(30mL)洗净,得2.47g(67%)3-(3-吖螺[5.5]十一基)甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,mp
114-115℃,1H-NMR(300MHz,DMSO-d6):δ1.28-1.35
(m,16H,8CH2),2.30(s,2H,CH2),2.37-2.68(m,
2H,CH2),2.64(s,3H,CH3),3.83-4.04(m,2H,
CH2),4.45(m,1H,CH),7.24(t,1H,J=7.4Hz,
Ar-H),7.32(d,1H,J=8.0Hz,Ar-H),7.54(t,1H,
J=7.4Hz,Ar-H),7.81(d,1H,J=8.0Hz,Ar-H);ms:
m/z 382(M+),367(M+-15),336(M+-46),228(M+-
154),元素分析计算值:C22H30N4S(382.56):C,69.07;
H,7.90;N,14.64.实测值:C,69.10;H,7.89;,N,
14.65.
例11
3-(1-咪唑基)甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉
混合3-溴甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(3.0g,9.7mmol),咪唑(1.32g,19.4mmol)及碳酸氢钠(0.8g,9.5mmol)于乙腈(80mL)。用油浴回流96小时后,滤除不溶物。将滤液予以柱层分析。收集所需部分,真空蒸发。所得油状残渣加乙醚20mL在室温放置2日。收集白色固体得0.75g(26%)3-(1-咪唑基)甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用丙酮重结晶,
mp 97-99℃;1H-NMR(100MHz,DMSO-d6):δ2.64(s,3H,CH3),3.78-4.08(m,2H,CH2),4.25-4.44(m,2H,CH2),4.74(m,1H,CH),6.82(s,1H,Ar-H),7.04(s,1H,Ar-H),7.22-7.76(m,5H,Ar-H);13C-NMR(75MHz,DMSO-d6):δ,13.16,14.43,57.41,57.72,116.70,119.75,124.80,125.29,125.48,128.66,132.97,137.70,145.72,152.48,153.90;ms:m/z 297(M+),250(M+-47),228(M+-69),216(M+-81,100%).元素分析计算值:C15H15N5SH2O(315.39):C,57.12;H,4.43;N,22.21.实测值:C,57.10;H,4.48;N,22.24.
例12
将3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉(0.57g,1.35mmol)悬浮于1 NNaOH/乙醇(25mL),用油浴加热55℃,45小时后,冷却至室温。滤集固体而以水(30mL)洗净,得0.33g(60%)3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉。分析样品用乙腈重结晶,
mp 171-172℃,1H-NMR(400MHz,DMSO-d6):δ2.47-2.72(m,6H,3CH2),2.94(m,4H,2CH2),3.77(s,3H,OCH3),3.85-4.07(m,2H,CH2),3.96(s,3H,OCH3),4.57-4.59(m,1H,CH),6.86(s,2H,Ar-H),6.91(s,2H,Ar-H),7.19(t,1H,J=7.7Hz,Ar-H),7.27(d,1H,J=8.1Hz,Ar-H),7.52(t,J=7.2Hz,Ar-H),7.82(d,1H,J=7.7Hz,Ar-H);13C-NMR(100MHz,DMSO-d6):δ50.02,53.47,54.55,54.64,55.28,58.89,60.15,111.89,116.40,117.88,120.81,122.33,123.90,124.94,125.02,132.81,141.16,147.05,151.94,152.17,153.67.;ms:m/z404(M+-1),355(M+-150);元素分析计算值:C23H27N5O2(405.50):C,68.12;H,6.71;N,17.27.实测值:C,68.17;H,6.66;N,17.30.
例13
3-{4-[1-(苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉仿例12制造,产率75%,分析样品用乙腈重结晶′mp 146-147℃,ms:m/z 375(M+);1H-NMR(400MHz,CDCl3):δ2.51-2.78(m,6H,3CH2),3.14-3.18(m,4H,2CH2),4.03(s,3H,CH3),4.06-4.19(m,2H,CH2),4.47-4.53(m,1H,CH),6.85(t,J=7.3Hz,1H,Ar-H),6.91(d,J=8.3Hz,2H,Ar-H),7.18(t,J=7.3Hz,1H,Ar-H),7.26(t,J=7.8Hz,1H,Ar-H),7.34(d,J=7.8Hz,1H,Ar-H),7.49(t,J=8.3Hz,1H,Ar-H),7.96(d,J=6.9Hz,1H,Ar-H);13C-NMR(100MHz,CDCl3):δ49.07,53.70,54.52,55.26,59.43,60.49,116.01,116.56,119.67,124.18,125.26,125.32,129.05,132.91,147.35,151.18,152.04,155.44;元素分析计算值:C22H25N5O(375.47):C,70.38;H,6.71;N,18.64.实测值:C,70.48;H,6.67;N,18.81.例143-{4-[1-(3-甲氧苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
仿例12制造,产率90%,分析样品用乙腈重结晶,mp 99-100℃,ms:m/z 405(M+);270(M+-135),243(M+-162),205(M+-200,100%);1H-NMR(400MHz,DMSO-d6):δ2.51-2.62(m,6H,3CH2),3.09(m,4H,2CH2),3.70(s,3H,CH3),3.95(s,3H,CH3),3.87-4.03(m,2H,CH2),4.54(m,1H,CH),6.35(d,J=8.3Hz,1H,Ar-H),6.43(s,1H,Ar-H),6.49(d,J=8.3Hz,1H,Ar-H),7.09(t,J=8.3Hz,1H,Ar-H),7.19(t,J=7.8Hz,1H,Ar-H),7.27(d,J=8.3Hz,1H,Ar-H),7.51(t,J=7.8Hz,1H,Ar-H),7.82(d,J=7.3Hz,1H,Ar-H),7.84(m,8H,Ar-H);13C-NMR(100MHz,DMSO-d6):δ48.13,53.11,54.53,54.66,54.79,58.90,59.98,101.44,104.02,107.99,116.42,123.88,124.94,124.99,129.53,132.77,147.05,152.14,152.28,153.67,160.15;元素分析计算值:C23H27N5O2(405.50):C,68.13;H,6.71;N,17.27.实测值:C,67.77;H,6.68;N,17.67.
例15
仿例12制造,产率90.4%,分析样品用乙腈重结晶,
mp 149-150℃,ms:m/z 405(M+);1H-NMR(400
MHz,CDCl3):δ2.21-2.76(m,6H,3CH2),3.06-3.08
(m,4H,2CH2),3.76(s,3H,CH3),4.03(s,3H,
CH3),4.05-4.19(m,2H,CH2),4.48-4.53(m,1H,
CH),6.86(m,4H,Ar-H),7.18(t,J=7.8Hz,1H,
Ar-H),7.34(d,J=7.8Hz,1H,Ar-H),7.49(t,J=
8.3Hz,1H,Ar-H),7.96(d,J=7.8Hz,1H,Ar-H);
13C-NMR(100MHz,CDCl3):δ50.57,53.83,54.54,
55.29,55.51,59.39,60.49,114.38,118.15,124.20,
125.28,125.35,132.93,145.60,147.37,152.05,
153.77,155.47;元素分析计算值:C23H27N5O2(405.50):
C,68.13;H,6.71;N,17.27.实测值:C,67.94;H,
6.61;N,17.33.
例16
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
仿例12制造,产率84%,分析样品用乙腈重结晶,mp 148-149℃;1H-NMR(400MHz,DMSOd6):δ2.50-2.69(m,6H,3CH2),2.96(m,4H,2CH2),3.86-4.08(m,2H,CH2),3.96(s,3H,OCH3),4.57(m,1H,CH),7.02(t,J=7.8Hz,1H,Ar-H),7.14(t,J=7.8Hz,1H,Ar-H),7.19(t,J=7.4Hz,1H,Ar-H),7.27(d,J=8.3Hz,2H,Ar-H),7.38(d,J=7.8Hz,1H,Ar-H),7.51(t,J=7.4Hz,1H,Ar-H);7.82(d,J=7.8Hz,1H,Ar-H);13C-NMR(100MHz,DMSO-d6):δ50.80,53.33,54.55,54.62,58.87,60.02,116.40,120.83,123.81,123.90,124.96,125.02,127.58,128.03,130.26,132.81,147.05,148.94,152.15,153.67.;元素分析计算值:C22H24N5OCl(409.92):C,64.46;H,5.90;N,17.09.实测值:C,64.19;H,5.87;N,16.93.
例17
3-(4-苯基-1-六氢吡嗪基)甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
混合3-{4-[1-(苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑[1,2-c]喹唑啉(0.34g,0.87mmol)于甲醇(30mL),加NaOH(5g,0.1mol)。用油浴回流6小时后,真空蒸干,加水(50mL)而以乙酸中和至pH7。滤集固体,得0.29g(93%)3-(4-苯基-1-六氢吡嗪基)甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮。分析样品用乙醇重结晶,
mp 252-253℃;1H-NMR(400MHz,DMSO-d6):
δ2.45-2.80(m,6H,3CH2),3.08(m,4H,2CH2),
3.86-4.06(m,2H,CH2),4.48(m,1H,CH),6.73
(t,J=7.3Hz,1H,Ar-H),6.89(d,J=8.3Hz,2H,
Ar-H),7.06(t,J=9.3Hz,2H,Ar-H),7.18(t,J=
7.8Hz,2H,Ar-H),7.47(t,J=7.8Hz,1H,Ar-H),
7.78(d,J=7.8Hz,1H,Ar-H),10.55(s,1H,NH).;
13C-NMR(100MHz,DMSO-d6):δ48.10,53.13,53.71,
58.34,59.03,111.48,114.92,115.16,118.54,
121.96,125.47,128.67,132.79,139.63,148.00,
150.86,152.41.;ms:m/z 361(M+),296(M+-65),
285(M+-76),275(M+-86),175(M+-185,100%).元素
分析计算值:C21H23N5O(361.45):C,69.78;H,6.41;
N,19.38.实测值:C,69.78;H,6.43;N,19.33.
例18
仿例17制造,产率34%,分析样品用乙醇重结晶,
mp 211-212℃。 IR(KBr):1635,1688,2829,2946,3226cm-1;1H-NMR(400MHz,DMSO-d6):δ2.45-2.85(m,6H,3CH2),2.95(m,4H,2CH2),3.77(s,3H,OCH3),3.87-4.08(m,2H,CH2),4.48(m,1H,CH),6.86-6.94(m,4H,Ar-H),7.09(t,J=6.5Hz,2H,Ar-H),7.48(t,J=7.3Hz,1H,Ar-H),7.80(d,J=8.3Hz,1H,Ar-H),10.50(s,1H,NH).;13C-NMR(100MHz,DMSO-d6):δ50.05,53.60,53.67,55.25,58.47,59.34,111.56,111.85,115.10,117.85,120.81,122.13,122.31,125.58,132.99,139.79,141.18,148.13,151.94,152.54.;ms:m/z 391(M+),376(M+-15),205(M+-187,100%).元素分析计算值:C22H25N5O2(391.47):C,67.50;H,6.44;N,17.89.实测值:C,67.40;H,6.43;N,17.83.例193-{4-[1-(3-甲氧苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
仿例17制造,产率90%,分析样品用乙醇重结晶,
mp 200-201℃。ms:m/z 391(M+),376.(M+-15),205
(M+-186,100%).:1H-NMR(400MHz,CDCl3):δ2.47-
2.93(m,6H,3CH2),3.09-4.12(m,4H,2CH2),3.70
(s,3H,OCH3),4.00-4.14(m,2H,CH2),4.50-4.52
(m,1H,CH),6.32-6.45(m,3H,Ar-H),6.92(d,
J=8.3Hz,1H,Ar-H),7.02-7.10(m,2H,Ar-H),7.37
(t,J=7.4Hz,1H,Ar-H),7.87(d,J=7.8Hz,1H,
Ar-H),9.93(s,1H,NH).;13C-NMR(100MHz,
DMSO-d6):δ48.51,53.23,53.69,54.81,58.45,
59.16,101.41,104.06,107.97,111.56,115.14,
122.11,125.56,129.53,132.97,139.83,148.17,
152.34,152.56,160.15,174.63.元素分析计算值:
C22H25N5O2(391.47):C,67.50;H,6.44;N,17.89.
实测值:C,67.44;H,6.43;N,17.93.
例20
仿例17制造,产率99%,用DMF重结晶,mp 250-251℃。ms:m/z 391(M+),376(M+-15),205(M+-171,100%).:1H-NMR(400MHz,DMSO-d6):δ2.50-2.82(m,6H,3CH2),2.98(br s,4H,2CH2),3.67(s,3H,OCH3),3.87-4.06(m,2H,CH2),4.47(m,1H,CH),6.86(d,J=8.7Hz,2H,Ar-H),6.79(d,J=8.7Hz,2H,Ar-H),7.07(d,J=6.4Hz,2H,Ar-H),7.45(t,J=7.3Hz,1H,Ar-H),7.78(d,J=7.8Hz,1H,Ar-H),10.85(s,1H,NH).;13C-NMR(100MHz,DMSO-d6):δ49.50,53.27,53.75,55.08,58.32,59.03,111.48,114.17,115.01,117.15,121.92,125.44,132.79,139.76,145.30,148.06,152.47,152.78.元素分析计算值:C22H25N5O2(391.47):C,67.50;H,6.44;N,17.89.实测值:C,67.55;H,6.38;N,17.97.
例21
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
仿例17制造,产率68%,分析样品用乙醇重结晶,
mp 227-228℃。ms:m/z 395(M+):1H-NMR(400MHz,
DMSO-d6):δ2.45-2.86(m,6H,3CH2),2.94(m,4H,
2CH2),3.85-4.06(m,2H,CH2),4.44-4.49(m,1H,
CH),6.98-7.12(m,4H,Ar-H),7.25(t,J=7.8Hz,
1H,Ar-H),7.34(d,J=7.8Hz,1H,Ar-H),7.45(t,
J=7.4Hz,1H,Ar-H),7.77(d,J=7.4Hz,1H,Ar-H),
10.51(s,1H,NH).;13C-NMR(100MHz,DMSO-d6):δ
50.82,53.44,53.67,58.47,59.23,111.56,115.05,
120.75,122.13,123.75,125.58,127.58,127.98,
130.26,132.97,139.74,148.09,148.94,152.50.元
素分析计算值:C21H22N5OCl(395.89):C,63.71;H,
5.60;N,17.69.实测值:C,63.71;H,5.66;N,
17.72.
例22
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮(1.52g,3.8mmol)溶在DMF(45mL)中,加50%NaOH(0.4g,7.6mmol)。在室温搅拌1小时后,加甲基碘(0.28mL,4.56mmol)。在室温搅拌24小时后,倒入冰水(200mL)中,滤集沉淀,得目的物(1.4g,90%)。分析样品用乙醇重结晶,m.p.154-155℃;1H-NMR(400MHz,DMSO-d6):δ2.46-2.86(m,4H,2CH2),2.70(br s,1H,CH),2.83-2.85(m,1H,CH),2.96(br s,4H,2CH2),3.36(s,3H,CH3),3.86-3.91(m,1H,CH),4.01-4.08(m,1H,CH),4.52(m,1H,CH),7.02(t,J=7.4Hz,1H,Ar-H),7.13(d,J=8.3Hz,1H,Ar-H),7.18(t,J=7.8Hz,1H,Ar-H),7.28(m,2H,Ar-H),7.38(d,J=7.8Hz,1H,Ar-H),7.60(t,J=7.8Hz,1H,Ar-H),7.89(d,J=7.8Hz,1H,Ar-H);13C-NMR(100.40MHz,DMSO-d6):δ29.37,50.80,53.42,54.79,58.28,59.20,112.65,114.63,120.77,122.40,123.75,125.73,127.54,128.00,130.25,133.30 140.47,148.09,148.94,151.57.;ms:m/z 409(M+),394(M+-15),269(M+-140),209
(M+-200).元素分析计算值:C22H24N5OCl(409.92):C,
64.46;H,5.90;N,17.09.实测值:C,64.38;H,5.90;
N,16.90.
例23
仿例22制造,产率65%,分析样品用乙腈重结晶,
mp 147-148℃。ms:m/z 405(M+):1H-NMR(400MHz,
DMSO-d6):δ2.43-2.50(m,4H,2CH2),2.65(m,2H,
CH2),2.80-2.94(m,4H,2CH2),3.36(s,3H,CH3),
3.76(s,3H,CH3),3.85-4.07(m,2H,CH2),4.50
(m,1H,CH),6.85-6.93(m,4H,Ar-H),7.17(t,
J=7.8Hz,1H,Ar-H),7.25(d,J=8.3Hz,1H,Ar-H),
7.59(t,J=7.4Hz,1H,Ar-H),7.88(d,J=7.8Hz,
1H,Ar-H);13C-NMR(100MHz,DMSO-d6):δ29.33,
50.02,53.56,54.79,55.23,58.30,59.31,11.85,
112.65,114.57,117.81,120.77,122.27,125.71
133.24,140.43,141.16,148.06,151.55,151.92;元
素分析計算值:C23H27N5O2(405.50):C,68.13;H,
6.71;N,17.27.实测值:C,68.17;H,6.63;N,
17.23.
例24
3-{4-[1-(3-甲氧苯基)六氢吡嗪基]}甲基-6-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮
仿例22制造,产率84%,分析样品用乙腈重结晶,
mp 139-140℃。ms:m/z 405(M+):1H-NMR(400MHz,
CDCl3):δ2.50-2.98(m,6H,3CH2),3.16-3.17(m,
4H,2CH2),3.45(s,3H,OCH3),3.77(s,3H,CH3),
4.05-4.18(m,2H,CH2),4.59(m,1H,CH),6.40(d,
J=8.3Hz,1H,Ar-H),6.44(s,1H,Ar-H),6.51(d,
J=8.3Hz,1H,Ar-H),7.06(d,J=8.3Hz,1H,Ar-H),
7.13-7.26(m,3H,Ar-H),7.54(t,J=8.3Hz,1H,
Ar-H),8.03(d,J=7.8Hz,1H,Ar-H);13C-NMR(100
MHz,CDCl3):δ29.91,49.28,53.99,55.40,55.64,
59.28,60.05,102.64,104.65,109.04,113.47,
114.20,123.07,126.87,129.98,133.62,140.99,
149.09,152.93,153.10,160.80;元素分析计算值:
C23H27N5O2(405.50):C,68.13;H,6.71;N,17.27.
实测值::C,68.18;H,6.65;N,17.20.
例25
混合4,5-二甲基蒽腈(10g,56.2mmol)及二硫化碳(30ml,0.4mmol)于吡啶(90mL),在油浴回流8小时后,冷却至室温,加乙醇(250mL)收集黄色固体,以乙醚10mL洗净,得6,7-二甲氧基喹唑啉-2,4-(1H,3H)-二硫酮
13.28g(93%)。1H-NMR(100MHz,DMSO-d6):δ3.83
(s,3H,CH3),3.86(s,3H,CH3),6.86(s,1H,Ar-
H),7.68(s,1H,Ar-H),12.96(s,1H,NH,D2O可交
换),13.47(s,1H,NH,D2O可交换);ms:m/z 254
(M+),238(M+-16),221(M+-33),196(M+-58),180
(M+-74)。
例26
仿例2制造,产率95%,
δ2.59(s,3H,CH3),2.65(s,3H,CH3),3.91(s,
3H,CH3),3.94(s,3H,CH3),7.10(s,1H,Ar-H),
7.15(s,1H,Ar-H);ms:m/z 282(M+),268(M+-14),
249(M+-33),235(M+-47),221(M+-61),204(M+-78),
189(M+-93),177(M+-105).
例27
仿例3制造,产率3%;mp 122-124℃。
例28
仿例4制造,产率75%;分析样品用乙腈重结晶,mp
225℃。ms:m/z 371(M+-1),369(M+-1),356
(M+-14),354(M+-80)。
例29
3-[4-(1-苯基)六氢吡嗪基]甲基-5-甲硫基-8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉
混合3-溴甲基-5-甲硫基-8,9-二甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉(0.36g,0.97mmol),1-苯基六氢吡嗪(0.3mL,1.85mmol)及碳酸氢钠(0.1g,1.2mmol)于乙腈(40mL)。用油浴回流18小时后,冷却至室温,以水(20mL)洗净,得0.32g(53%)4-烯丙氨基-6,7-二甲氧基-2-甲硫基喹唑啉。分析样品用乙腈重结晶,mp 207-209℃;
1H-NMR(300MHz,DMSO-d6):δ2.40-2.52(m,2H,CH2),
2.55(s,3H,SCH3),2.70-2.73(m,4H,2CH2),3.12
(m,4H,2CH2),3.79(s,3H,CH3),3.84(s,3H,CH3),3.91-4.05(m,2H,CH2),4.53(m,1H,CH),6.76(t,1H,J=7.1Hz,1H,Ar-H),6.86(s,1H,Ar-H),6.91(d,2H,J=8.2Hz,Ar-H),7.17-7.22(m,3H,Ar-H);13C-NHR(75MHz,DHSO-d6):δ13.08,48.12,53.10,55.56,55.95,58.49,59.28,105.07,107.38,108.94,115.34,118.77,128.85,141.54,147.17,150.91,152.13,152.36,153.09;ms:m/z 451(H+),404(H+-47),320(M+-131),277(M+-174).元素分析计算值:C24H29N5SO2(451.59):C,63.83;H,6.47;N,15.51.实测值:C,63.75;H,6.48;N,15.57.
Claims (15)
1.一种具有下列结构式的咪唑并[1,2-c]喹唑啉衍生物,及其光学活性的消旋混合化合物和光学的纯R和S立体异构体,及其可药盐式中X为S或O,当X为S时,式为I;当X为O时,式为II;
R1为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R2为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R4为卤素,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;并且R4在邻位;
R5为C1-4烷基或芳基-(C1-4)烷基。
2.一种具有下列结构式的咪唑并[1,2-c]喹唑啉衍生物,及其光学活性的消旋混合化合物和光学的纯R和S立体异构体,及其可药用盐式中R3为氢,C1-4烷基或芳基-(C1-4)烷基,当R3为氢时,式为III;当R3为C1-4烷基或芳基-(C1-4)烷基时,式为IV;
X为O;
R1为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R2为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R4为卤素,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;并且该R4在邻位。
3.一种具有下列结构式的咪唑并[1,2-c]喹唑啉衍生物,及其光学活性的消旋混合化合物和光学的纯R和S立体异构体,及其可药用盐的制法式中X为S或O,当X为S时,式为I;当为O时,式为II;
R1为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R2为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R4为卤素,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;并且R4在邻位;
R5为C1-4烷基或芳基-(C1-4)烷基;包含以下步骤:
(a)将具有下V式的化合物与二硫化碳在吡啶中反应,得有下VI式的化合物
(c)将所获得的化合物VII与烯丙胺反应,得下式VIII化合物其中R1,R2和R5与前述的定义相同;
(d)将所获得化合物VIII予以卤环化,得下式IX化合物其中R1,R2,R5,Y与前述的定义相同;
(f)将化合物I以化合物R5-OH在破存在下用适当条件处理,得化合物II,其中R5同前。
4.一种具有下列结构式的咪唑并[1,2-c]喹唑啉衍生物,及其光学活性的消旋混合化合物和光学的纯R和S立体异构体,及其可药用盐的制法式中R3为氢,C1-4烷基或芳基-(C1-4)烷基,当R3为氢时,式为III;当R3为C1-4烷基或芳基-(C1-4)烷基时,式为IV;X为O;
R1为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R2为卤素,氢,C1-6烷基,三氟甲基或C1-6烷氧基;
R4为卤素,甲氧基,三氟甲基,C1-4烷基,硝基,乙酰基,氰基或羟基;并且该R4处在邻位;此制法包括如权利要求3所述的过程a)-e),及
(g)将化合物I以化合物R5-OH在碱的存在下用适当条件处理,得化合物III,式中R5的定义同权利要求3所述,及
(h)化合物III与烷化剂R3-Y反应,得化合物IV,其中R3为C1-4烷基或芳基-(C1-4)烷基,Y为卤素。
5.一种适用于高血压治疗的药物组合物,包含一治疗有效量并作为活性成份的权利要求1所述结构式I的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
6.一种适用于高血压治疗的药物组合物,包含一治疗有效量并作为活性成分的权利要求1所述结构式II的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
7.一种适用于高血压治疗的药物组合物,包含一治疗有效量并作为活性成分的权利要求2所述结构式III的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
8.一种适用于高血压治疗的药物组合物,包含一治疗有效量并作为活性成份的权利要求2所述结构式IV的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
9.一种适用于排尿困难治疗的药物组合物,包含一治疗有效量并作为活性成份的权利要求1所述结构式I的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
10.一种适用于排尿困难治疗的药物组合物,包含一治疗有效量并作为活性成分的权利要求1所述结构式II的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
11.一种适用于排尿困难治疗的药物组合物,包含一治疗有效量并作为活性成份的权利要求2所述结构式III的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
12.一种适用于排尿困难治疗的药物组合物,包含一治疗有效量并作为活性成份的权利要求2所述结构式IV的咪唑并[1,2-c]喹唑啉衍生物或其可药用的盐类,及与该活性成份共同使用的可药用载体或稀释剂。
13.按照权利要求1所述的咪唑并[1,2-c]喹唑啉衍生物,或其可药用的盐,乃选自
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉;
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲硫基-2,3-二氢咪唑并[1,2-c]喹唑啉;
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉;
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-5-甲氧基-2,3-二氢咪唑并[1,2-c]喹唑啉。
14.按照权利要求2所述的咪唑并[1,2-c]喹唑啉衍生物,或其可药用的盐,乃选自
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮;
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮;
3-{4-[1-(2-氯苯基)六氢吡嗪基]}甲基-6-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮;
3-{4-[1-(2-甲氧苯基)六氢吡嗪基]}甲基-6-甲基-2,3-二氢咪唑并[1,2-c]喹唑啉-5(6H)-酮。
15.按照权利要求2所述的化合物,其中的R3为C1-4烷基或苯基-(C1-4)烷基。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 93100378 CN1033644C (zh) | 1993-01-02 | 1993-01-02 | 3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物,其制备与用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 93100378 CN1033644C (zh) | 1993-01-02 | 1993-01-02 | 3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物,其制备与用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1089266A CN1089266A (zh) | 1994-07-13 |
CN1033644C true CN1033644C (zh) | 1996-12-25 |
Family
ID=4982986
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 93100378 Expired - Fee Related CN1033644C (zh) | 1993-01-02 | 1993-01-02 | 3-取代甲基-2,3-二氢咪唑并[1,2-c]喹唑啉衍生物,其制备与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1033644C (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2326881C9 (ru) * | 2002-09-30 | 2009-04-10 | Байер Фармасьютикалс Корпорейшн | Конденсированные производные азолпиримидина, обладающие свойствами ингибитора фосфатидилинозитол-3-киназы (pi3k) |
-
1993
- 1993-01-02 CN CN 93100378 patent/CN1033644C/zh not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN1089266A (zh) | 1994-07-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1043639C (zh) | 新的哌啶化合物、其制备方法和含有它们的药用组合物 | |
CN1165535C (zh) | 抑制胃酸分泌的咪唑并吡啶衍生物 | |
CN1034175C (zh) | 吡唑并嘧啶类化合物 | |
CN1094929C (zh) | 乙酰胺衍生物,其制备方法,及含该衍生物的药物组合物 | |
CN1148189C (zh) | 作为tnf抑制剂和pdc-iv抑制剂的喹啉甲酰胺类化合物 | |
CN1039322C (zh) | 吲哚衍生物的制备方法 | |
CN1138546C (zh) | 用作细胞因子的某些1,4,5-三取代咪唑化合物 | |
CN1060841A (zh) | 喹唑啉衍生物及其制备方法 | |
CN1055182A (zh) | N-(吡咯并《2,3-d》嘧啶-3-基酰基)-谷氨酸衍生物 | |
CN1213307A (zh) | 新的取代的咪唑化合物 | |
CN1646529A (zh) | 咪唑并稠合化合物 | |
CN1802159A (zh) | 治疗哮喘及其它炎症或免疫性疾病的具有ccr3拮抗活性的2-苯氧基-和2-苯基磺酰胺衍生物 | |
CN1812980A (zh) | 哌啶基-和哌嗪基-烷基氨基甲酸酯衍生物,其制备及治疗用途 | |
CN1072219C (zh) | 二氮杂䓬酮、其生产和用途 | |
CN1845921A (zh) | 金刚烷和氮杂双环-辛烷及壬烷衍生物、其制备方法及其作为dpp-iv抑制剂的用途 | |
CN1058963C (zh) | 三唑衍生物、杀虫剂、杀螨剂及其制备方法 | |
CN1433407A (zh) | 双芳基砜 | |
CN1413205A (zh) | 具有抗肿瘤活性的2-(1h-吲哚-3-基)-2-氧代-乙酰胺 | |
CN1097591C (zh) | 制备嘧啶衍生物的方法 | |
CN1458922A (zh) | 尿素衍生物及以其作为有效成分的粘连分子阻断剂 | |
CN87108111A (zh) | 一种新颖的咪唑衍生物及其制备方法 | |
CN1821217A (zh) | 反式-4-氨基-1-环己烷羧酸衍生物的制备方法 | |
CN1083812A (zh) | 苯并咪唑类,含有这些化合物的药物组合物和它们的制备 | |
CN1575176A (zh) | 制备取代的吡唑的方法 | |
CN1049161A (zh) | 具有血清素2-受体拮抗活性的杂环化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |