CN1052724C - Optical active 2, 3-dihydro-imidazole and [1, 2-c] quinazoline derivative, preparation method and use thereof - Google Patents
Optical active 2, 3-dihydro-imidazole and [1, 2-c] quinazoline derivative, preparation method and use thereof Download PDFInfo
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- CN1052724C CN1052724C CN96108272A CN96108272A CN1052724C CN 1052724 C CN1052724 C CN 1052724C CN 96108272 A CN96108272 A CN 96108272A CN 96108272 A CN96108272 A CN 96108272A CN 1052724 C CN1052724 C CN 1052724C
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- 238000002360 preparation method Methods 0.000 title claims description 35
- 230000003287 optical effect Effects 0.000 title abstract 2
- LWTIGYSPAXKMDG-UHFFFAOYSA-N 2,3-dihydro-1h-imidazole Chemical compound C1NC=CN1 LWTIGYSPAXKMDG-UHFFFAOYSA-N 0.000 title 1
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 96
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical group 0.000 claims abstract description 19
- 239000001257 hydrogen Chemical group 0.000 claims abstract description 19
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- -1 quinazoline compound Chemical class 0.000 claims description 69
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 6
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 6
- 238000011287 therapeutic dose Methods 0.000 claims description 6
- 238000006751 Mitsunobu reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000012545 processing Methods 0.000 claims description 5
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 230000001631 hypertensive effect Effects 0.000 claims 2
- 125000004193 piperazinyl group Chemical group 0.000 claims 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 abstract 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical group N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 14
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000004458 analytical method Methods 0.000 description 12
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 238000007738 vacuum evaporation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
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- 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 2
- INKLSJITWMAFRT-UHFFFAOYSA-N 2-(4-methoxyphenyl)piperazine Chemical compound C1=CC(OC)=CC=C1C1NCCNC1 INKLSJITWMAFRT-UHFFFAOYSA-N 0.000 description 2
- PUPFOFVEHDNUJU-UHFFFAOYSA-N 2-sulfanylidene-1h-quinazolin-4-one Chemical compound C1=CC=C2C(=O)NC(S)=NC2=C1 PUPFOFVEHDNUJU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
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- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- KSILMCDYDAKOJD-UHFFFAOYSA-N 2-aminoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(N)C(=O)C2=C1 KSILMCDYDAKOJD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
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- 238000006482 condensation reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- PMPYSSMGWFNAAQ-UHFFFAOYSA-N dichloromethane;n,n-diethylethanamine Chemical compound ClCCl.CCN(CC)CC PMPYSSMGWFNAAQ-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
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- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- HKJZDEUEWZSNFY-UHFFFAOYSA-N imidazo[1,2-c]quinazoline Chemical compound C1=CC=C2C3=NC=CN3C=NC2=C1 HKJZDEUEWZSNFY-UHFFFAOYSA-N 0.000 description 1
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- KFOPKOFKGJJEBW-ZSSYTAEJSA-N methyl 2-[(1s,7r,8s,9s,10r,13r,14s,17r)-1,7-dihydroxy-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]acetate Chemical compound C([C@H]1O)C2=CC(=O)C[C@H](O)[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](CC(=O)OC)[C@@]1(C)CC2 KFOPKOFKGJJEBW-ZSSYTAEJSA-N 0.000 description 1
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- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to new 3-substituted methy-5-methylthio-2, 3-dihydroimidazo [1, 2-c] quinazoline (I) and 3-substituted methyl-2, 3-dihydroimidazo [1, 2-c] quinazoline-5 (6H)-ketone (II) with optical activities and adacceptable salt thereof in pharmacy. In the formula, R is halogen, hydrogen, methoxy group and trifluoromethyl group; C1-C4 is alkyl group, or nitryl group, or acetyl group, or cyanogen group or hydroxy base group. The present invention also relates to the therapeutic use of the novel compounds.
Description
As 3-[[4-(2-p-methoxy-phenyl) piperazine-1-yl] ethyl] quinazoline-2,4-diketone, (SGB-1534, III) (Imagawa, J.; Sakai, K.Eur.J.Pharmacol. 1986,131,257-264) the analogue of conformation restriction, people have synthesized methyl-5-methylthio group-2 that racemic compound 3-replaces recently, 3-glyoxalidine also [1,2-c] quinazoline (I) (Chern, J.-W. wait people, J.Med.Chem.1993,36,2196-2207) and the methyl-2 that replaces of 3-, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone (II) also, and they are to α
1-adrenergic receptor demonstrates potent and highly selective.One of these compounds just stand intensive research as hypotensive agent at present.Bioactive stereochemistry requires to still need clearing, and the present invention has confirmed the being easy to get property of (R)-(+) and (S)-(-)-Racemic glycidol and had effectiveness aspect the enantiomorph of compound of general formula I and II in preparation.
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
The purpose of this invention is to provide new optically actively 2, the 3-glyoxalidine is [1,2-c] quinazoline derivant also.
Another object of the present invention provides new optically active 2, and the 3-glyoxalidine is the preparation method of [1,2-c] quinazoline derivant also.
A further object of the present invention provide use new optically active 2, the 3-glyoxalidine also [1,2-c] quinazoline derivant as the method for hypotensive agent and anti-misnicturition medicine (antidysuria agents).
For realizing purpose of the present invention, in the present invention, at first synthesized following compounds: 1. have the methyl-5-methylthio group-2 of (S)-(+)-3-replacement of formula (S)-(+)-I, the 3-glyoxalidine is [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, acetyl
Base, cyano group or oh group.2. have the methyl-5-methylthio group-2 of (R)-(-)-3-replacement of formula (R)-(-)-I, the 3-glyoxalidine is [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl,
Cyano group or oh group.3. have the methyl-2 of (S)-(-)-3-replacement of formula (S)-(-)-II, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, acetyl
Base, cyano group or oh group.4. have the methyl-2 of (R)-(+)-3-replacement of formula (R)-(+)-II, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, acetyl
Base, cyano group or oh group.
The present invention also discloses the methyl-5-methylthio group-2 of (S)-(+)-3-replacement with following formula (S)-(+)-I, and the 3-glyoxalidine is the preparation method of [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group; Described preparation method is: a) make formula IV compound
React under the Mitsunobu reaction conditions with phthalimide, obtain formula V compound:
B) make compound V and the formula VI compound that obtains
Reaction obtains formula VII compound:
The definition of R is the same in the formula; C) make compound VI I and the hydrazine reaction that obtains, obtain formula VIII compound:
The definition of R is the same in the formula; D) with IX or X
The compound VIII that processing obtains obtains formula XI compound:
E) with the compounds X I cyclisation that obtains, production (S)-(+)-I compound.
The present invention also discloses the methyl-5-methylthio group-2 of (R)-(-)-3-replacement with following formula (R)-(-)-I, and the 3-glyoxalidine is the preparation method of [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group; Described preparation method is: a) make formula IV compound
React under the Mitsunobu reaction conditions with phthalimide, obtain formula V compound:
B) make compound V and the formula VI compound that obtains
Reaction obtains formula VII compound:
The definition of R is the same in the formula; C) make compound VI I and the hydrazine reaction that obtains, obtain formula VIII compound:
The definition of R is the same in the formula; D) with IX or X
The compound VIII that processing obtains obtains formula XI compound:
E) with the compounds X I cyclisation that obtains, production (R)-(-)-I compound.
The present invention also discloses the methyl-2 that has (S)-(-)-3-replacement of formula (S)-(-)-II by heating compound (S)-(+) under acidity or alkaline condition-I preparation, and the 3-glyoxalidine is the method for [1,2-c] quinazoline-5 (6H)-ketone compound also; Described formula (S)-(-)-II is as follows:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
The present invention also discloses the methyl-2 that has (R)-(+)-3-replacement of formula (R)-(+)-II by heating compound (R)-(-) under acidity or alkaline condition-I preparation, and the 3-glyoxalidine is the method for [1,2-c] quinazoline-5 (6H)-ketone compound also; Described formula (R)-(+)-II is as follows:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
The present invention also discloses and is used for the treatment of hypertension and dysuric medicinal compositions, it comprise above-mentioned formula (S)-(+)-I compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
The present invention also discloses and is used for the treatment of hypertension and dysuric medicinal compositions, it comprise above-mentioned formula (S)-(-)-II compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
Should be synthetic with Racemic glycidol (IV) and phthalimide at Mitsunobu reaction conditions (Mitsunobu; O.Synthesis.1981,1-28) under in THF the condensation reaction in room temperature begin, obtain 1; 2-epoxy-3-phthaloyl aminopropane (V), yield 80-86%.Racemic glycidol is (Johnson, R.A., Encyclopedia of Reagents for Organic Synthesis according to reports; Paquette, L.A. edit Jon Willey ﹠amp; Sons, Inc.:New York, 1995; The 4th volume, the 2609-2613 page or leaf) instability, and in the presence of micro-acid as catalyst, can carry out from condensation the oxirane ring open loop.Therefore, for obtaining pure compound V, require to use new distillatory Racemic glycidol without special chromatogram purification.Yield is in the 73-83% scope.The condensation of the 4-of epoxy derivative V and equimolar amount (the adjacent phenyl that replaces) piperazine (VI) refluxes in THF and carries out 3 days, and the yield of the 1-O-phthalic amido-3-that obtains after column chromatography (piperazine of replacement-1-yl) propane-2-alcohol (VII) is 68-72%.Yet, when this reaction is carried out with excessive bridged piperazine derivatives, by with ether simply the washed product crude product can be separated to chromatogram purification compound VII with the yield of 73-83% to remove excessive piperazine.Described formula IV, V, VI, VII and VIII are as follows:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
Next step successfully obtains 1-amino-3-[4-(2-p-methoxy-phenyl) piperazine-1-yl by handle compound VI I in room temperature with hydrazine hydrate in ethanolic soln] propane-2-alcohol (VIII), be monohydrate, yield 86-94%.Compound VIII is water-soluble as a result, and sedimentary Phthalocyclohydrazide is leached from mixture.
Make amino alcohol VIII and 2 then, 4-diformazan sulfenyl quinazoline (IX) back flow reaction in acetonitrile obtains 4-[3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] amino-2-methylthio group quinazoline (XI).But this result's yield changes in the 24-56% scope, and should reaction discharge disgusting thiomethyl alcohol.Also studied the possibility of use 4-chloro-2-methylthio group quinazoline (X) synthetic compound XI.Compounds X can obtain with good yield (90-93%): from anthranoyl amine, obtain 2-sulfydryl quinazoline-4-one (XII) (Zakerinia by the yield that heats in the water-alcohol solution of potassium hydroxide with dithiocarbonic anhydride with 91%, M. wait the people, Helv.Chim.Acta.1990,73,912-915); Then compounds X II is methylated with methyl iodide, obtain 2-methylthio group quinazoline-2-ketone (XIII); Subsequently by using POCl
3Processing changes into 4-chloro-2-methylthio group quinazoline (X) with it with high yield (90-93%), then its water is precipitated out from acetone soln.Compounds X and amino alcohol VIII be reaction smoothly in the presence of triethylamine, and the yield with 72% obtains compounds X I smoothly.Realize that with methylsulfonyl chloride (MsCl) and triethylamine XI changes into the cyclization of Compound I.This cyclization carried out 12-17 hour, behind chromatogram purification, obtained Compound I with the yield of 47-69%.Add salt of wormwood to absorb the hydrogenchloride that generates in reaction mixture, without the column chromatography purifying, the yield with 77% obtains the chromatographically pure Compound I.
It should be noted that and compared by crystalline racemic compound I in the above-mentioned solvent, the enantiomorph of Compound I for example has extraordinary solubleness in acetonitrile, Virahol and the ethanol at multiple solvent.Therefore, when with the acetonitrile solution of enantiomorph (S)-I and (R)-I when making one of them excessive mixing, this racemize (RS)-I will quantitatively precipitate with fine crystallization shape solid form immediately, and that a kind of staying in the filtrate of excessive use only.This just feasible this synthetic compound that might obtain enantiomeric purity.Can adopt acetonitrile that this sample is carried out simple process, by filtering enantiomorph (S)-I or (R)-I and racemic (RS)-I crystal separation.Analyze through HPLC, the enantiomorph of the I that obtains after acetonitrile solution is evaporated is greater than 98.5%ee.The polarimetry purity of raw material only influences the yield of pure enantiomorph I.Under acidity or alkaline condition, handle (S)-(+)-I or (R)-(-)-I and generate (S)-(-)-II or (R)-(+)-II respectively.
Same chirality (homochiral) compound is carried out α
1-adrenergic receptor binding affinity is measured.PRELIMINARY RESULTS shows: enantiomorph (S)-I is to α
1The avidity of-adrenergic receptor (Ki=1.88nM) is higher 295 times than (R)-I (Ki=554nM), and the Ki value of racemic (RS)-I is 3.55nM.(S)-(-)-effectiveness of II is the strongest, Ki=0.1Nm.In the experiment below, the pharmacologically active of The compounds of this invention has been described.In this experiment, used test compound is stated as follows.Be used for the preparation of the film of combination research in conjunction with the method 1. of research
Be used for [
3H] Prazosin or [
3H] clonidine catapresan bonded rat brain cortex film by will organize with the tissue and the ratio of damping fluid be 1: 10 ratio 0.32M with 50mMTris buffer reagent (pH7.4) buffered sucrose solution in homogenizing prepare.After removing stoning in centrifugal 10 minutes, by making the P2 film form sheet in centrifugal 20 minutes at 22000xg supernatant liquor at 1000xg.After twice, this film suspension (approximately 2mg/ml protein) can use in fresh damping fluid for centrifugal and resuspending at 22000xg.2. in conjunction with measuring
α
1-adrenergic receptor is used 0.2nM[in conjunction with measuring (in triplicate)
3H] Prazosin carried out 30 minutes in room temperature at pH7.4 in final volume is the Tris buffer reagent of 1.0ml, used the 10nM phentolamine to measure non-specific binding.Be used to compete the concentration of bonded synthetic compound in 0.1-200 μ M scope.Be used to compete the concentration of bonded synthetic compound in 0.1-100 μ M scope.After reaching balance,, film stops on the Whatman GF/B filter paper cultivating by being collected in; Filter paper is washed 2 times in 4 ℃ with 5ml 50mM Tris buffer reagent (pH7.4).The amount of the membrane protein that uses in each mensuration is measured with people's such as Lowry method in the 300-400mg scope.The results are shown in Table 1.Material
[
3H] Prazosin (76.6 Ci/mmol) and [
3H] clonidine catapresan (47.0 Ci/mmol) is available from NEN.Other pharmaceutical chemicals of used all is SILVER REAGENT, available from Sigma (St.Louis, Mo).
The α of table 1 imidazo [1,2-c] quinazoline derivant
1-adrenergic receptor binding affinity
Compound α
1In conjunction with (Ki, nM)
Embodiment 16 1.88
Embodiment 17 554
Embodiment 18 0.1
Embodiment 19 26
Preferred compound is those compounds that made by the following example: embodiment 16 (S)-(+)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2,3-glyoxalidine also [1,2-c] quinazoline embodiment 17 (R)-(-)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2,3-glyoxalidine also [1,2-c] quinazoline embodiment 18 (S)-(-)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-2,3-glyoxalidine also [1,2-c] quinazoline-5 (6H)-ketone embodiment 19 (R)-(+)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-2, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone also.
Embodiment 1
The preparation of 4-(2-p-methoxy-phenyl) piperazine
With 1-(2-p-methoxy-phenyl) piperazine hydrochloride (6.86g, 30ml), the NaOH aqueous solution (2.5N, 36ml, 90mmol) and the mixture vigorous stirring of chloroform (30ml) 0.5 hour.The chloroform layer separation was also stirred 0.5 hour with water (50ml) again.Make chloroform layer filter Na after the separation
2SO
4(2g), and vacuum-evaporation to doing.With the vacuum-drying of oily resistates (2mmHg, 1 hour, 80 ℃), obtain 5.50g (95%) 4-(2-p-methoxy-phenyl) piperazine, be faint yellow oily thing.Without be further purified be directly used in synthetic in.
Embodiment 2
(S)-(+)-1, the preparation of 2-epoxy-3-phthaloyl aminopropane
To the phthalimide (1.93g that is stirring, 13.11mmol) add triphenyl phosphine (3.44g in the solution in exsiccant THF (20ml), 13.11mmol), then add (S)-(+)-Racemic glycidol (1.12g, 15.08mmol) and diethyl azodiformate (2.28g, 13.11mmol).With reaction mixture in stirring at room 18 hours, solvent removed in vacuo.Resistates is stirred 2 hours with ether (50ml), and leach throw out.With filtrate vacuum-evaporation, and with resistates with the column chromatography purifying (eluent: ethyl acetate/chloroform=1/10), obtain 1.48g (80%) title compound, be colorless solid:
Mp 102-103 ℃; [α]
D 26+ 9 (c 2.2, CHCl
3);
1H NMR (CDCl
3) δ 7.87-7.82 (m, 2H, Ar-H), 7.76-7.71 (m, 2H, ArH), 3.95 (dd, 1H, J=14.3,5.1Hz, CH
2O), 3.80 (dd, 1H, J=14.3Hz, J=5.1Hz, CH
2O), and 3.25-3.20 (m, 1H, CHO), 2.78 (false t, 1H, J=4.4Hz, NCH
2), 2.68 (dd, 1H, J=4.80,2.61Hz, NCH
2);
13C NMR (CDCl
3) δ 168.56,134.71,132.50,124.02,49.65,46.68,40.22.
Embodiment 3
(R)-(-)-1, the preparation of 2-epoxy-3-phthaloyl aminopropane
With with similar method described in the embodiment 2, the yield with 86% obtains title compound, is colorless solid:
102 ℃ of mp; [α]
D 26-9 (c 2.2, CHCl
3);
1H NMR (CDCl
3) δ 7.90-7.84 (m, 2H, ArH), 7.77-7.71 (m, 2H, ArH), 3.96 (dd, J=14.4,5.0Hz), 3.81 (dd, 1H, J=14.4,5.0Hz), 3.27-3.21 (m, 1H, CHO), 2.81 (dd, 1H, J=4.6,4.1Hz), 2.70 (dd, 1H, J=4.8,2.5Hz);
13CNMR (CDCl
3) δ 168.58,134.73,132.50,124.03,49.65,46.70,40.23; MS m/z 203 (M
+). ultimate analysis theoretical value C
11H
9NO
3: C 64.92; H 4.46; N6.89. measured value C 64.70; H 4.37; N 6.92.
Embodiment 4
(R)-(+)-and 5-(1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] preparation of propane-2-alcohol
Method 1 is to the 4-that is stirring (2-p-methoxy-phenyl) piperazine (5.07g; 26.37mmol) add (S)-(+)-1 in the solution in exsiccant THF (50ml); 2-epoxy-3-phthaloyl aminopropane (4.15g 20.42mmol), and with mixture heating up backflow 3 days.Solvent removed in vacuo, with resistates with the column chromatography purifying (eluent: methanol/ethyl acetate/methylene dichloride=1/1/20), obtain 5.47g (68%) title compound, be colorless solid:
Mp 155-157 ℃; [α]
D 26+ 8 (c 0.5, CHCl
3);
1H NMR (CDCl
3) δ 7.88-7.83 (m, 2H, ArH), 7.75-7.71 (m, 2H, ArH), 7.02-6.90 (m, 4H, ArH), 4.12-4.06 (m, 1H, CH), 3.85-3.77 (m, 5H, CH
3, CH
2), 3.06 (br s, 4H, NCH
2), 2.87-2.44 (m, 7H, NCH
2, CH
2, OH);
13C NMR (CDCl
3) δ 169.13,152.78,141.65,134,58,132.62,123.94,123.59,121.53,118.76,111.74,65.47,62.13,55.92,54.02,51,28,42.61; MS m/z 395 (M
+). ultimate analysis theoretical value C
22H
25N
3O
4: C 66.82; H 6.37; N 10.60. measured value C 66.86; H 6.34; N 10.43.
Embodiment 5
(S)-(-)-and 5-(1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] preparation of propane-2-alcohol
Use (R)-(-)-1 by being similar to embodiment 4 described methods, 2-epoxy-3-phthaloyl aminopropane, the yield with 72% obtains title compound:
[α]
D 28-8 (c 0.3, CHCl
3);
1H NMR (CDCl
3) δ 7.90-7.84 (m, 2H, ArH), 7.75-7.71 (m, 2H, ArH), 7.03-6.84 (m, 4H, ArH), 4.12-4.05 (m, 1H, CH), and 3,79-3.72 (m, 2H, CH
2), 3.86 (s, 3H, CH
3), 3.06 (br s, 4H, NCH
2), 2.87-2.44 (m, 7H, NCH
2, CH
2, OH);
13C NMR (CDCl
3) δ 169.13,152.78,141.63,134.59 132.62,123.94,123.61,121.53,118.76,111.71,65.46 62.13,55.92,54.13,51.26,42.61; MS m/z 395 (M
+). ultimate analysis theoretical value C
22H
25N
3O
40.5H
2O:C 65.33; H 6.48; N10.39. measured value C 65.05; H 6.31; N 10.24.
Embodiment 6
(S)-(-)-and 5-(1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] preparation method 2 of propane-2-alcohol is to the 4-that is stirring (2-p-methoxy-phenyl) piperazine (6.03g; 31.0mmol) add (R)-(-)-1 in the solution in exsiccant THF (150ml); 2-epoxy-3-phthaloyl aminopropane (5.49g 27.0mmol), and with mixture heating up backflow 3 days.Solvent removed in vacuo stirs resistates 3 hours in ether (200ml).Filter collection precipitation with ether (50ml) washing, obtains 7.81g (73%) title compound.
Embodiment 7
(R)-(+)-and 5-(1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] preparation of propane-2-alcohol
Use (S)-(+)-1 by being similar to embodiment 6 described methods, 2-epoxy-3-phthaloyl aminopropane, the yield with 83% obtains title compound.
Embodiment 8
(S)-(+)-preparation of 1-amino-3-(4-(2-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol
To (R)-(+)-5-that is stirring (1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] add a hydrazine hydrate (4.31ml in the suspension of propane-2-alcohol (7.0g 17.7mmol) in ethanol (180ml); 88.7mmol), and this solution stirred 12 hours in 25 ℃.Mixture is filtered, and filtrate is evaporated to dried.In resistates water-soluble (125ml), and with solution chloroform extraction (2 * 125ml).Make extraction liquid filter Na
2SO
4(20g), and be evaporated to driedly, obtain faint yellow oily thing.It after ether (60ml) stirs, is separated out crystallization, obtains 4.03g (86%) title compound, be white crystals shape solid:
Mp 76-80 ℃; [α]
D 26+ 22.3 (c 2.1, CHCl
3);
1H NMR (CDCl
3) δ 7.03-6.85 (m, 4H, ArH), 3.86 (s, 3H, OCH
3), 3.72-3.77 (m, 1H, CHOH), 2.87-2.80 (m, 3H), 2.68-2.61 (m, 3H), 2.46-2.40 (m, 2H), 2.23 (br.s, 3H, NH
2, OH, can with D
2The O exchange). ultimate analysis theoretical value C
14H
23N
3O
2H
2O:C 59.34; H 8.89; N14.82. measured value C 59.50; H 9.06; N 14.83.
Embodiment 9
(R)-(-)-preparation of 1-amino-3-(4-(2-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol
By being similar to embodiment 8 described methods, with (S)-(-)-5-(1-phthaloyl amino)-3-[4-(2-p-methoxy-phenyl)] piperazine-1-yl] propane-2-alcohol makes raw material, and the yield with 94% obtains title compound:
[α]
D 26-22.3 (c 1.9, CHCl
3);
1H NMR (CDCl
3) δ 7.04-6.85 (m, 4H, ArH), 3.86 (s, 3H OCH
3), 3.78-3.73 (m, 1H, CHOH), 2.90-2.81 (m, 3H), 2.68-2.60 (m, 3H), 2.50-2.36 (m, 2H), 2.30 (br.s, 3H, NH
2, OH, can with D
2The O exchange);
13C NMR (CDCl
3) δ 152.79,141.70,123.60,121.54,118.76,111.71,68.37,62.07,55.92,54.09,51.29,45.41; MS m/z 265 (M
+). ultimate analysis theoretical value C
14H
23N
3O
20.5H
2O:C61.29; H 8.82; N 15.32. measured value C 61.41; H 8.83; N 15.11.
Embodiment 10
(S)-(+)-and 4-[(3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] preparation of amino-2-methylthio group quinazoline
With 2, and 4-diformazan sulfenyl quinazoline (0.7g, 3.15mmol) and (S)-(+)-(0.76g, 2.86mmol) vlil in acetonitrile (25ml) is 4 days for 1-amino-3-(4-(2-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol.With solvent vacuum-evaporation, and with resistates with column chromatography purifying (ethyl acetate is made eluent), obtain 0.41g (33%) title compound, be faint yellow solid: mp＞78 ℃ (decomposition); [α]
D 28+ 6 (c 2.9, CHCl
3);
1H NMR (CDCl
3+ D
2O) δ 7.70-7.63 (m, 3H, ArH), 7.35-7.29 (m, 1H, ArH), 7.04-6.86 (m, 4H, ArH), 4.09-4.06 (m, 1H, CHOH), 3.95 (dd, 1H, J=3.30,13.75 Hz, CH
2), 3.87 (s, 1H, OCH
3), 3.63 (dd, 1H, J=6.0,13.9Hz, CH
2), 3.11 (br s, 4H, NCH
2), 2.88-2.84 (m, 2H, NCH
2), 2.67-2.51 (m, 7H, SCH
3, NCH
2, CH
2);
13CNMR (CDCl
3) δ 159.43,152.83,150.89,141.59,133.44,127.66.125.03,123.71,121.56,118.75,113.36,111.81,66.17,61.92,55.96,54.25,54.12,51.25,45.14,14.69. ultimate analysis theoretical value C
23H
29N
5O
2S0.5H
2O:C 61.58 H 6.74; N 15.61. measured value C 61.44; H 6.72; N 15.68.
Embodiment 11
(R)-(-)-and 4-[(3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] preparation of amino-2 methylthio group quinazolines
Make raw material by being similar to embodiment 10 described methods with (R)-(-)-1-amino-3-(4-(2-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol, the yield with 72% obtains title compound: [α] D
28-6 (c 2.4, CHCl
3);
1H NMR (CDCl
3) δ 7.70-7.66 (m, 3H, ArH), 7.35-7.30 (m, 1H, ArH), 7.05-7.00 (m, 1H, ArH), 7.05-6.86 (m, 3H, Ar-H), 6.46 (t, 1H, J=5.0Hz, NH), 4.11-4.05 (m, 1H, CHOH), 3.95 (ddd, 1H, J=3.6,5.3,13.7Hz, CH
2), 3.87 (s, 3H, OCH
3), 3.65 (ddd, 1H, J=5.4,5.4,13.7Hz, CH
2), 3.11 (br s, 4H, NCH
2), 2.91-2.86 (m, 2H, NCH
2), 2.68-2.64 (m, 2H), 2.62 (s, 3H, SCH
3), 2.58-2.48 (m, 2H);
13C NMR (CDCl
3) δ 159.41,152.82,150.89,141.59,133.45,127.67,125.03,123.71,121.55,118.74,113.35,111.78,66.13,61.90,55.96,54.12,54.12,51.25,45.11,14.71; MS m/z 439 (M
+) ultimate analysis theoretical value C
23H
29N
5O
2SH
2O:C 60.37; H 6.39; N 15.30. measured value C 60.51; H 6.57; N 15.21.
Embodiment 12
The preparation of 2-methylthio group quinazoline-4 (3H)-ketone
To 2-sulfydryl quinazoline-4 (3H)-ketone (4.45g, 25mmol) and NaOH (1.1g, (1.72ml 27.5mol), and stirs mixture 3 hours in 25 ℃ 27.5mmol) to add methyl iodide in the solution in water (125ml).Filter collection precipitation, (silica dehydrator 24 hours are used in 3 * 20ml) washings to water in vacuum drier, obtain 3.66g (73%) title compound, are colorless solid: mp 224-225 ℃.Analytic sample methanol-water recrystallization:
mp?225℃；
1H?NMR(CDCl
3)δ11.25(br?s，1H，NH)，8.27(dd，1H，J＝1.25，6.3Hz，ArH)，7.62(d，1H，J＝7.3Hz)，7.44-7.38(m，1H，ArH)，2.70(s，3H，SCH
3)；
13C?NMR(CDCl
3)δ163.73，155.76，149.77，135.50，127.30，126.96，126.40，120.37，13.97。
Embodiment 13
The preparation method 1. of 4-chloro-2-methylthio group quinazoline with 2-methylthio group quinazoline-4 (3H)-ketone (1.92g, 10mmol) and POCl
3(4.7ml, mixture 50mmol) be in stirring at room 15 minutes, and with this suspension reflux 1.5 hours.After being chilled to room temperature, mixture is poured in the mixture of ice (40g) and methylene dichloride (20ml) into vigorous stirring 5 minutes.Then organic layer is told, used 5%K
2CO
3The aqueous solution (2 * 20ml) washings.With organic layer Na
2SO
4(3g) drying makes it filter 1g silica gel then.With filtrate vacuum-evaporation, obtain 1.91g (91%) title compound, be colorless solid, mp 107-108 ℃;
1H NMR (CDCl
3) δ 8.15-8.12 (m, 1H, ArH), 7.85-7.83 (m, 2H, ArH), 7.58-7.52 (m, 1H, ArH), 2.67 (s 1H, SCH
3);
13C NMR (CDCl
3) δ 152.38,135.79,135.75,127.72,127.63,127.58,126.69,126.64,14.99. ultimate analysis theoretical value C
8H
7ClN
2S:C 48.37; H 3.55; N 14.10. measured value C 48.32; H 360; N 14.04.Method 2. is when pouring in the ice reaction mixture under vigorous stirring, and the filter collection precipitates, and uses 5%K
2CO
3The aqueous solution (2 * 50ml), water (100ml) washing.Crude product is dissolved in the acetone (100ml), and water (100ml) redeposition, obtain 1.73g (82%) title compound, be colourless needle: mp108-109 ℃.Method 3. to 2-methylthio group quinazoline-4 (the 3H)-ketone that is stirring (0.5g, 2.60mmol) and triphenyl phosphine (0.82g 3.12mmol) adds tetracol phenixin (2.5ml) in the suspension in methylene dichloride, and with the suspension that obtains in 20-25 ℃ of stirring.After 6 hours, reaction finishes (TLC), make reaction product filter silicagel column (2.5 * 15cm), make eluent with methylene dichloride.Collect correct stream part, and vacuum-evaporation.Resistates is dissolved in the acetone (10ml), and water (30ml) makes its redeposition, through using CaCl
2Vacuum-drying obtains 0.46g (83%) title compound, is 108 ℃ of white crystal: mp.
Embodiment 14
(S)-(+)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2, the 3-glyoxalidine is the preparation of [1,2-c] quinazoline also
Under argon atmospher in 0 ℃ to (S)-(+)-4-[(3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] amino-2-methylthio group quinazoline (1.72g, 3.9mmol) add in the solution in the exsiccant methylene dichloride triethylamine (2.73ml, 19.6mol).Mixture was stirred 15 minutes, and with 30 minutes time adding methylsulfonyl chloride (0.40ml, 5.1mmol).Mixture was stirred 1 hour in 0 ℃, and stirred 7 hours in 25 ℃.Then with it with methylene dichloride (20ml) dilution, and water (50ml), NaHCO successively
3Saturated aqueous solution (20ml) and water (20ml) washing.Make organic layer filter Na
2SO
4(2g) also concentrate, obtain crude product.It is used the flash chromatography purifying, make eluent with ethyl acetate.The resistates that obtains behind the evaporating solvent is stirred 1 hour with acetonitrile (2ml), and collecting precipitation, 0.148g (9.0%) racemic product obtained: mp 172-173 ℃; [α]
D 26+ 5.72 (c0.278, CHCl
3), this racemic mixture of HPLC analysis revealed contains 55.7% title compound and 44.7% (R)-(-)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2, the 3-glyoxalidine is [1,2-c] quinazoline also.
Vacuum-evaporation filtrate in 60-70 ℃ of vacuum (5mm) heating, obtains 1.13g (69%, ee＞98.5%) title compound with resistates, is colourless foam shape solid: mp58-61 ℃ (softening), 62-63 (transparent);
[α]
D 26+ 39.6 (c 4.7, CHCl
3);
1H NMR (CDCl
3) δ 7.96 (dd, J=1.4,7.9Hz, 1H, ArH), 7.52 (t, J=7.7Hz, 1H, Ar-H), 7.41 (d, J=8.0Hz, 1H, ArH), 7.24 (t, J=8.4Hz, 1H, ArH), 6.98-6.85 (m, 4H, ArH), 4.50-4.42 (m, 1H, (S)-CH), 4.20-4.10 (m, 2H ,=NCH
2), 3.86 (s, 3H, OCH
3), 3.09 (m, 4H), 2.91-2.8 (m, 3H), 2.71-2.55 (m, 3H), 2.65 (s, 3H, SCH
3);
13C NMR (CDCl
3) δ 154.90,154.47,152.82,147.16,141.82,133.517,126.35,125.92,125.72,123.52,121.56,118.79,117.67,111.77,60.42,59.95,57.08,55.94,54.51,54.38,51.16,14.15; MS m/z 421 (M
+). ultimate analysis theoretical value C
23H
27N
5OS0.5H
2O:C 64.16; H6.55; N 16.27. measured value C 64.37; H 6.49; N 16.25.
Embodiment 15
(R)-(-)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2, the 3-glyoxalidine is the preparation of [1,2-c] quinazoline also
By being similar to embodiment 14 described methods, use (R)-(-)-4-[(3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] amino-2-methylthio group quinazoline makes raw material, and the yield with 71% obtains title compound: [α]
D 26-39.6 (c 4.7, CHCl
3);
1H NMR (CDCl
3) δ 7.96 (dd, J=1.4,7.9Hz, 1H, ArH), 7.52 (t, J=7.1Hz, 1H, ArH), 7.41 (d, J=8.2Hz, 1H, ArH), 7.24 (t, J=7.1Hz, 1H, ArH), 7.03-6.85 (m, 4H, ArH), 4.50-4.42 (m, 1H, (S)-CH), 4.21-4.10 (m, 2H ,=NCH
2), 3.86 (s, 3H, OCH
3), 3.09 (m, 4H), 2.91-2.8 (m, 3H), 2.71-2.55 (m, 2H), 2.65 (s, 3H, SCH
3), 2.59-2.55 (m, 1H);
13C NMR (CDCl
3) δ 154.90,154.47,152.82,147.16,141.83,133.51,126.35,125.92,125.71,123.51 121.56,118.78,117.67,111.75,60.43,59.99,57.08,55.94,54.51,51.16,14.15; MS m/z 421 (M
+). ultimate analysis theoretical value C
23H
27N
5OS0.5H
2O:C 64.16; H6.55; N 16.27. measured value C 64.45; H 6.54; N 15.94.
Embodiment 16
(S)-(+)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2,3-glyoxalidine also [1,2-c] preparation method 2. of quinazoline in 2 ℃ to (S)-(+)-4-[(3-that is stirring (4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] amino-2-methylthio group quinazoline (2.54g, 5.57mmol), salt of wormwood (2.31g, 16.72mmol) and triethylamine (2.33ml, 16.72mmol) in the suspension in exsiccant methylene dichloride (170ml) with time of 0.5 hour add MsCl (0.56ml, 7.25mmol).Mixture was stirred 1 hour in 2 ℃, and stirred 24 hours in 25 ℃.Extract with methylene dichloride (50ml) then with its water (70ml) washing, and with water layer.With the organic extract liquid Na that merges
2SO
4(5g) drying, and be evaporated to dried.Add acetonitrile (30ml) in resistates, stir after 40 minutes, filter collection precipitation obtains 0.57g (24%) racemic product: mp 173-174 ℃.The evaporation acetonitrile solution with resistates heating under vacuum (2mmHg, 50 ℃), obtains 1.80g (75%, ee＞98.5%) title compound, is colourless foam shape solid.
Embodiment 17
(R)-(-)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2, the 3-glyoxalidine is the preparation of [1,2-c] quinazoline also
By being similar to embodiment 16 described methods, use (R)-(-)-4-[(3-(4-p-methoxy-phenyl) piperazine-1-yl) propane-2-alcohol-1-yl] amino-2-methylthio group quinazoline makes raw material, and the yield with 72% obtains title compound.
Embodiment 18
(S)-(-)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-2, the 3-glyoxalidine is the preparation of [1,2-c] quinazoline-5 (6H)-ketone also
With (S)-(+)-3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2,3-glyoxalidine also [1,2-c] quinazoline (1.2g, 2.85mmol) and NaOH (5.69g, 142mmol) vlil in methyl alcohol (60ml) and water (35ml) is 17 hours.In refrigerative solution, add c.HCl (6.0ml, 68mmol), and with methyl alcohol vacuum-evaporation.After adding entry (60ml), with dichloromethane extraction mixture (3 * 60ml).With organic solution Na
2SO
4(5g) drying, vacuum evaporating solvent.With resistates column chromatography purifying (eluent EtOAc: CH
3OH=10: 1), obtain 1.05g (94.5%) colourless foam shape title compound:
[α]
D 25-33.0 (c 1.342, CHCl
3);
1H NMR (CDCl
3) δ 9.65 (br s, 1H, NH), 7.97 (dd, 1H, J=9.2,1.3Hz, ArH), 7.47 (t, 1H, J=7.5Hz, ArH), 7.13 (1H, t, J=7.2Hz, ArH), 7.01-6.85 (m, 5H, ArH), 4.68-4.56 (m, 1H, (S)-CH), 4.25-4.09 (m, 2H ,=NCH
2), 3.86 (s, 3H, OCH
3), 3.08-3.03 (m, 5H), 2.85-2.83 (m, 2H), 2.73-2.71 (m, 1H);
13C NMR (CDCl
3) δ 154.02,152.82,150.29,141.86,139.60,133.87,126.91,123.74,123.49,121.54,118.78,115.70,112.72,111.74,60.51,59.93,55.92,54.99,54.62,51.24; MS m/z391 (M
+). ultimate analysis theoretical value C
22H
25N
5O
2H
2O:C 64.53; H 6.65; N 17.10. measured value C 64.40; H 6.59; N 17.0.
Embodiment 19
(R)-(+)-and 3-[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-2, the 3-glyoxalidine is the preparation of [1,2-c] quinazoline-5 (6H)-ketone also
By being similar to embodiment 18 described methods, by (R)-(-)-3[(4-(2-p-methoxy-phenyl) piperazine-1-yl] methyl-5-methylthio group-2,3-glyoxalidine also [1,2-c] quinazoline sets out, and the yield with 98% obtains title compound: [α]
D 25+ 30.9 (c 3.178, CHCl
3);
1H NMR (CDCl
3) δ 9.67 (br s, 1H, NH), 7.89 (d, 1H, J=8.8Hz, ArH), 7.37 (t, 1H, J=7.7Hz, ArH), 7.03 (1H, t, J=7.5Hz, ArH), 6.91-6.75 (m, 5H, ArH), 4.54-4.49 (m, 1H, (S)-CH), 4.14-4.00 (m, 2H ,=NCH
2), 3.86 (s, 3H, OCH
3), 3.00-2.94 (m, 5H), 2.82-2.75 (m, 2H), 2.73-2.71 (m, 1H), 2.51-2.46 (m, 1H);
13C NMR (CDCl
3) δ 153.45,152.23,149.72,141.26,139.02,133.29,126.33,123.15,122.90,120.96,118.19,115.12,112.11,111.18,59.92,59.31,55.31,54.40,54.01,50.63; MS m/z 391 (M
+). ultimate analysis theoretical value C
22H
25N
5O
20.75H
2O:C 65.19; H 6.72; N 17.29. measured value C65.31; H 6.48; N 17.34.
Claims (14)
1. have the methyl-5-methylthio group-2 of (S)-(+)-3-replacement of following formula (S)-(+)-I, the 3-glyoxalidine is [1,2-c] quinazoline compound and pharmacy acceptable salt thereof also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
2. have the methyl-5-methylthio group-2 of (R)-(-)-3-replacement of following formula (R)-(-)-I, the 3-glyoxalidine is [1,2-c] quinazoline compound and pharmacy acceptable salt thereof also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
3. have the methyl-2 of (S)-(-)-3-replacement of following formula (S)-(-)-II, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone compound and pharmacy acceptable salt thereof also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
4. have the methyl-2 of (R)-(+)-3-replacement of following formula (R)-(+)-II, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone compound and pharmacy acceptable salt thereof also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
5. have the methyl-5-methylthio group-2 of (S)-(+)-3-replacement of following formula (S)-(+)-I, the 3-glyoxalidine is the preparation method of [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group; Described preparation method is: a) make formula IV compound
React under the Mitsunobu reaction conditions with phthalimide, obtain formula V compound:
B) make compound V and the formula VI compound that obtains
Reaction obtains formula VII compound:
The definition of R is the same in the formula; C) make compound VI I and the hydrazine reaction that obtains, obtain formula VIII compound:
The definition of R is the same in the formula; D) with IX or X
The compound VIII that processing obtains obtains formula XI compound:
E) with the compounds X I cyclisation that obtains, production (S)-(+)-I compound.
6. have the methyl-5-methylthio group-2 of (R)-(-)-3-replacement of following formula (R)-(-)-I, the 3-glyoxalidine is the preparation method of [1,2-c] quinazoline compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group; Described preparation method is: a) make formula IV compound
React under the Mitsunobu reaction conditions with phthalimide, obtain formula V compound:
B) make compound V and the formula VI compound that obtains
Reaction obtains formula VII compound:
The definition of R is the same in the formula; C) make compound VI I and the hydrazine reaction that obtains, obtain formula VIII compound:
The definition of R is the same in the formula; D) with IX or X
The compound VIII that processing obtains obtains formula XI compound:
E) with the compounds X I cyclisation that obtains, production (R)-(-)-I compound.
7. have the methyl-2 of (S)-(-)-3-replacement of following formula (S)-(-)-II by heating compound (S)-(+) under acidity or alkaline condition-I preparation, the 3-glyoxalidine is the method for [1,2-c] quinazoline-5 (6H)-ketone compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
8. have the methyl-2 of (R)-(+)-3-replacement of following formula (R)-(+)-II by heating compound (R)-(-) under acidity or alkaline condition-I preparation, the 3-glyoxalidine is the method for [1,2-c] quinazoline-5 (6H)-ketone compound also:
In the formula: R is a halogen, hydrogen, methoxyl group, trifluoromethyl, C
1-C
4Alkyl, nitro, ethanoyl, cyano group or oh group.
9. be used for the treatment of hypertensive medicinal compositions, it comprise the described formula of claim 1 (S)-(+)-I compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
10. be used for the treatment of hypertensive medicinal compositions, it comprise the described formula of claim 3 (S)-(-)-II compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
11. be used for the treatment of dysuric medicinal compositions, it comprise the described formula of claim 1 (S)-(+)-I compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
12. be used for the treatment of dysuric medicinal compositions, it comprise the described formula of claim 3 (S)-(-)-II compound of effective therapeutic dose or its pharmacy acceptable salt as activeconstituents and with it blended be used for the pharmaceutically acceptable carrier or the thinner of this activeconstituents.
13. the imidazo of claim 1 [1,2-c] quinazoline compound and pharmacy acceptable salt thereof, it is (S)-(+)-3-[4-[1-(2-p-methoxy-phenyl) piperazinyl]] methyl-5-methylthio group-2, the 3-glyoxalidine is [1,2-c] quinazoline also.
14. the imidazo of claim 3 [1,2-c] quinazoline compound and pharmacy acceptable salt thereof, it is (S)-(-)-3-[4-[1-(2-p-methoxy-phenyl) piperazinyl]] methyl-2, the 3-glyoxalidine is [1,2-c] quinazoline-5 (6H)-ketone also.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96108272A CN1052724C (en) | 1996-07-01 | 1996-07-01 | Optical active 2, 3-dihydro-imidazole and [1, 2-c] quinazoline derivative, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96108272A CN1052724C (en) | 1996-07-01 | 1996-07-01 | Optical active 2, 3-dihydro-imidazole and [1, 2-c] quinazoline derivative, preparation method and use thereof |
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|---|---|
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|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000298A1 (en) * | 1990-06-22 | 1992-01-09 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
| WO1993013103A1 (en) * | 1991-12-20 | 1993-07-08 | Novo Nordisk A/S | Imidazoquinazoline compounds and their preparation and use |
-
1996
- 1996-07-01 CN CN96108272A patent/CN1052724C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992000298A1 (en) * | 1990-06-22 | 1992-01-09 | Novo Nordisk A/S | Heterocyclic compounds and their preparation and use |
| WO1993013103A1 (en) * | 1991-12-20 | 1993-07-08 | Novo Nordisk A/S | Imidazoquinazoline compounds and their preparation and use |
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