CN1052724C

CN1052724C - Novel optically active 2,3-dihydroimidazo[1,2-C]quinazoline derivatives and their preparation and use

Info

Publication number: CN1052724C
Application number: CN96108272A
Authority: CN
Inventors: 陈基旺
Original assignee: Purzer Pharmaceutical Co Ltd
Current assignee: Purzer Pharmaceutical Co Ltd
Priority date: 1996-07-01
Filing date: 1996-07-01
Publication date: 2000-05-24
Anticipated expiration: 2016-07-01
Also published as: CN1169430A

Abstract

The invention relates to novel optically active 3-substituted methyl-5-methylthio-2, 3-dihydroimidazo [1, 2-c ] s]Quinazoline and 3-substituted methyl-2, 3-dihydroimidazo [1, 2-c ]]Quinazolin-5 (6H) -one (II) and pharmaceutically acceptable salts thereof, wherein: r is halogen, hydrogen, methoxy, trifluoromethyl, C₁-C₄Alkyl, nitro, acetyl, cyano or hydroxy groups. The invention also relates to the therapeutic use of these novel compounds.

Description

Newly optically active 2, the 3-glyoxalidine is [1,2-C] quinazoline derivant and its production and use also

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:

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:

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

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

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

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:

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:

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:

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; 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 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:

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.