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

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

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

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰基，氰基或羟基基团。 As 3-[[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]quinazoline-2,4-dione, (SGB-1534, III) (Imagawa, J.; Sakai, K.Eur.J.Pharmacol. 1986,131,257-264) conformationally constrained analogues, racemic compound 3-substituted methyl-5-methylthio-2,3-di Hydrogenimidazo[1,2-c]quinazoline (I) (Chern, J.-W. et al., J.Med.Chem.1993, 36, 2196-2207) and 3-substituted methyl-2 , 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-ones (II), which exhibit potent and high selectivity for α ₁ -adrenergic receptors. One of these compounds is currently undergoing intensive research as an antihypertensive agent. The stereochemical requirements for biological activity have yet to be clarified, and the present invention demonstrates the availability of (R)-(+) and (S)-(-)-glycidol and their use in the preparation of compounds of general formula I and II. enantiomeric effects.

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group.

The object of the present invention is to provide novel optically active 2,3-dihydroimidazo[1,2-c]quinazoline derivatives.

Another object of the present invention is to provide a method for preparing novel optically active 2,3-dihydroimidazo[1,2-c]quinazoline derivatives.

Yet another object of the present invention is to provide methods for using novel optically active 2,3-dihydroimidazo[1,2-c]quinazoline derivatives as antihypertensives and antidysuria agents .

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰For realizing the purpose of the present invention, in the present invention, at first synthesized following compound: 1. have (S)-(+)-3-substituted methyl-5-methyl of formula (S)-(+)-I Sulfuryl-2,3-dihydroimidazo[1,2-c]quinazoline compounds:

In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰基，group, cyano or hydroxyl group. 2. (R)-(-)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2-c] having the formula (R)-(-)-I Quinazoline compounds:

In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl,

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰cyano or hydroxyl groups. 3. (S)-(-)-3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazoline-5 with formula (S)-(-)-II ( 6H)-keto compounds:

In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl

group, cyano or hydroxyl group. 4. (R)-(+)-3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazoline-5 with formula (R)-(+)-II ( 6H)-keto compounds: In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl

, cyano or hydroxyl groups.

与苯邻二甲酰亚胺在Mitsunobu反应条件下反应，得到式V化合物：b)使得到的化合物V与式VI化合物反应，得到式VII化合物：

式中R的定义同上；c)使得到的化合物VII与肼反应，得到式VIII化合物：  式中R的定义同上；d)用IX或X

处理得到的化合物VIII，得到式XI化合物：e)将得到的化合物XI环化，生成式(S)-(+)-I化合物。The present invention also discloses (S)-(+)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2 having the following formula (S)-(+)-I -c] the preparation method of quinazoline compound: In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group; the preparation method is: a) make formula IV compound

Reaction with phthalimide under Mitsunobu reaction conditions to obtain the compound of formula V: b) the obtained compound V and formula VI compound Reaction, obtains formula VII compound:

In the formula, the definition of R is the same as above; c) the obtained compound VII is reacted with hydrazine to obtain the compound of formula VIII: The definition of R in the formula is the same as above; d) use IX or X

Treatment of the resulting compound VIII affords the compound of formula XI: e) Cyclize the obtained compound XI to generate a compound of formula (S)-(+)-I.

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰基，氰基或羟基基团；所述制备方法为：a)使式IV化合物与苯邻二甲酰亚胺在Mitsunobu反应条件下反应，得到式V化合物：

b)使得到的化合物V与式VI化合物

反应，得到式VII化合物：

式中R的定义同上；c)使得到的化合物VII与肼反应，得到式VIII化合物：

式中R的定义同上；d)用IX或X处理得到的化合物VIII，得到式XI化合物：e)将得到的化合物XI环化，生成式(R)-(-)-I化合物。The present invention also discloses (R)-(-)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2 having the following formula (R)-(-)-I -c] the preparation method of quinazoline compound:

In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group; the preparation method is: a) make formula IV compound Reaction with phthalimide under Mitsunobu reaction conditions to obtain the compound of formula V:

b) the obtained compound V and formula VI compound

Reaction, obtains formula VII compound:

In the formula, the definition of R is the same as above; c) the obtained compound VII is reacted with hydrazine to obtain the compound of formula VIII:

The definition of R in the formula is the same as above; d) use IX or X Treatment of the resulting compound VIII affords the compound of formula XI: e) Cyclize the obtained compound XI to generate a compound of formula (R)-(-)-I.

The present invention also discloses the preparation of (S)-(-)-3-substituted methyl having formula (S)-(-)-II by heating compound (S)-(+)-I under acidic or basic conditions -2, the method for 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one compound; The formula (S)-(-)-II is as follows: In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group.

The present invention also discloses the preparation of (R)-(+)-3-substituted methyl having formula (R)-(+)-II by heating compound (R)-(-)-I under acidic or basic conditions -2, the method for 3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one compound; The formula (R)-(+)-II is as follows: In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group.

The present invention also discloses a pharmaceutical composition for the treatment of hypertension and dysuria, which comprises a therapeutically effective amount of the above-mentioned compound of formula (S)-(+)-I or a pharmaceutically acceptable salt thereof as an active ingredient, and A pharmaceutically acceptable carrier or diluent for the active ingredient.

The present invention also discloses a pharmaceutical composition for the treatment of hypertension and dysuria, which comprises a therapeutically effective amount of the above-mentioned compound of formula (S)-(-)-II or a pharmaceutically acceptable salt thereof as an active ingredient, and A pharmaceutically acceptable carrier or diluent for the active ingredient.

式中：R是卤素，氢，甲氧基，三氟甲基，C₁-C₄烷基，硝基，乙酰基，氰基或羟基基团。The synthesis starts with the condensation reaction of glycidol (IV) with phthalimide in THF at room temperature under Mitsunobu reaction conditions (Mitsunobu, O. Synthesis. 1981, 1-28) to give 1,2-cyclo Oxygen-3-phthaloylaminopropane (V), yield 80-86%. Glycidol is reported (Johnson, RA, Encyclopedia of Reagents for Organic Synthesis; Paquette, LA ed. Jon Willey & Sons, Inc.: New York, 1995; Vol. 4, pp. 2609-2613) to be unstable, and In the presence of a catalyst, it can undergo self-condensation and open the epoxy ring. Therefore, to obtain pure compound V without special chromatographic purification requires the use of freshly distilled glycidol. Yields ranged from 73-83%. The condensation of epoxy derivative V and equimolar amount of 4-(o-substituted phenyl)piperazine (VI) was refluxed in THF for 3 days, and the 1-phthaloylamino-3 obtained after column chromatography The yield of -(substituted piperazin-1-yl)propan-2-ols (VII) was 68-72%. However, when the reaction was carried out with an excess of piperazine derivative, chromatographically pure compound VII could be isolated in 73-83% yield by simply washing the crude product with ether to remove excess piperazine. Said formulas IV, V, VI, VII and VIII are as follows:

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group.

The next step by treatment of compound VII with hydrazine hydrate in ethanol solution at room temperature yielded 1-amino-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-2-ol ( VIII) is a monohydrate with a yield of 86-94%. As a result compound VIII was dissolved in water and the precipitated phthalohydrazide was filtered from the mixture.

Amino alcohol VIII is then reacted with 2,4-dimethylthioquinazoline (IX) at reflux in acetonitrile to give 4-[3-(4-methoxyphenyl)piperazin-1-yl)propane- 2-ol-1-yl]amino-2-methylthioquinazoline (XI). But the yields for this result ranged from 24-56%, and the reaction liberated the objectionable methyl mercaptan. The possibility of using 4-chloro-2-methylthioquinazoline (X) to synthesize compound XI was also investigated. Compound X was obtained in good yields (90-93%): starting from anthranilamide, 2-mercaptoquinazoline was obtained in 91% yield by heating with carbon disulfide in aqueous-alcoholic potassium hydroxide solution -4-keto (XII) (Zakerinia, M. et al., Helv. Chim. Acta. 1990, 73, 912-915); compound XII is then methylated with methyl iodide to give 2-methylthioquinazoline -2-one (XIII); it was subsequently converted in high yield (90-93%) to 4-chloro-2-methylthioquinazoline (X) by treatment with POCl ₃ , which was then converted from acetone with water precipitated out of the solution. Compound X reacted smoothly with aminoalcohol VIII in the presence of triethylamine to obtain compound XI in a yield of 72%. The cyclization of XI to compound I was achieved using methanesulfonyl chloride (MsCl) and triethylamine. The cyclization reaction was carried out for 12-17 hours, and compound I was obtained in a yield of 47-69% after chromatographic purification. Potassium carbonate was added to the reaction mixture to absorb the generated hydrogen chloride, and the chromatographically pure compound I was obtained in a yield of 77% without column chromatography purification.

Notably, the enantiomers of Compound I have very good solubility in various solvents such as acetonitrile, isopropanol and ethanol compared to racemic Compound I crystallized from the above solvents. Thus, when the acetonitrile solutions of the enantiomers (S)-I and (R)-I were mixed by making one of them into excess, the racemic (RS)-I would immediately precipitate quantitatively as a fine crystalline solid , and only the one used in excess remained in the filtrate. This makes it possible to obtain the synthesized compounds in enantiomeric purity. The sample can be treated briefly with acetonitrile to separate the enantiomers (S)-I or (R)-I from the racemic (RS)-I crystals by filtration. The enantiomer of I obtained after evaporation of the acetonitrile solution was greater than 98.5% ee by HPLC analysis. The optical purity of the starting material only affects the yield of pure enantiomer I. Treatment of (S)-(+)-I or (R)-(-)-I under acidic or alkaline conditions yields (S)-(-)-II or (R)-(+)-II, respectively.

[alpha _]i -adrenergic receptor binding affinity assays were performed on homochiral compounds. Preliminary results showed that the affinity of enantiomer (S)-I to α ₁ -adrenoceptor (Ki=1.88nM) was 295 times higher than that of (R)-I (Ki=554nM), while the racemic (RS)-I has a Ki value of 3.55 nM. (S)-(-)-II was the most potent with Ki=0.1 Nm. In the following experiments, the pharmacological activity of the compounds of the invention is described. In this experiment, the test compounds used are described below. Methods for Binding Studies 1. Preparation of Membranes for Binding Studies

Rat cerebral cortical membranes for [ ³ H]prazosin or [ ³ H]clonidine binding were prepared by displacing the tissue with 50 mM Tris buffer (pH7. 4) Prepare by homogenizing in buffered sucrose solution. After removing the nuclei by centrifugation at 1000xg for 10 minutes, the P2 membrane was pelleted by centrifuging the supernatant at 22000xg for 20 minutes. The membrane suspension (approximately 2 mg/ml protein) was ready for use after centrifugation at 22000 xg and resuspension twice in fresh buffer. 2. Binding Assays

α ₁ -Adrenergic receptor binding assay (triplicate) was performed with 0.2 nM [ ³ H]prazosin in a final volume of 1.0 ml Tris buffer at pH 7.4 for 30 minutes at room temperature using 10 nM phenyto Lamin assay for non-specific binding. Concentrations of synthetic compounds used to compete for binding ranged from 0.1-200 [mu]M. Concentrations of synthetic compounds used to compete for binding ranged from 0.1-100 [mu]M. After binding equilibrated, the incubation was terminated by harvesting the membranes on Whatman GF/B filter paper; the filter paper was washed twice with 5 ml of 50 mM Tris buffer (pH 7.4) at 4°C. The amount of membrane protein used in each assay ranged from 300-400 mg, as determined by the method of Lowry et al. The results are shown in Table 1. Material

[ ³ H]prazosin (76.6 Ci/mmol) and [ ³ H]clonidine (47.0 Ci/mmol) were purchased from NEN. All other chemicals used were of reagent grade and purchased from Sigma (St. Louis, Mo).

The α ₁ -adrenergic receptor binding affinity of table 1 imidazo[1,2-c]quinazoline derivatives

Compound α ₁ binding (Ki, nM)

Example 16 1.88

Example 17 554

Example 18 0.1

Example 19 26

Preferred compounds are those prepared in the following examples: Example 16 (S)-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl- 5-Methylthio-2,3-dihydroimidazo[1,2-c]quinazoline Example 17 (R)-(-)-3-[(4-(2-methoxyphenyl) Piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1,2-c]quinazoline Example 18 (S)-(-)-3-[(4 -(2-methoxyphenyl)piperazin-1-yl]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one embodiment 19 (R )-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-2,3-dihydroimidazo[1,2-c]quinazoline- 5(6H)-ketone.

Example 1

Preparation of 4-(2-methoxyphenyl)piperazine

A mixture of 1-(2-methoxyphenyl)piperazine hydrochloride (6.86g, 30ml), aqueous NaOH (2.5N, 36ml, 90mmol) and chloroform (30ml) was vigorously stirred for 0.5 hours. The chloroform layer was separated and stirred with water (50ml) for another 0.5 hours. After _separation the chloroform layer was filtered through _Na2SO4 (2g) and evaporated to dryness in vacuo. The oily residue was dried in vacuo (2 mmHg, 1 hour, 80°C) to afford 5.50 g (95%) of 4-(2-methoxyphenyl)piperazine as a pale yellow oil. Used directly in the synthesis without further purification.

Example 2

Preparation of (S)-(+)-1,2-epoxy-3-phthaloylaminopropane

To a stirred solution of phthalimide (1.93g, 13.11mmol) in dry THF (20ml) was added triphenylphosphine (3.44g, 13.11mmol) followed by (S)-(+) - Glycidol (1.12 g, 15.08 mmol) and diethyl azodicarboxylate (2.28 g, 13.11 mmol). The reaction mixture was stirred at room temperature for 18 hours and the solvent was removed in vacuo. The residue was stirred with diethyl ether (50ml) for 2 hours and the precipitate was filtered off. The filtrate was evaporated in vacuo, and the residue was purified by column chromatography (eluent: ethyl acetate/chloroform = 1/10) to give 1.48 g (80%) of the title compound as a colorless solid:

mp 102-103°C; [α] _D ²⁶ +9 (c 2.2, CHCl ₃ ); ¹ H 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 ₂ O), 3.80 (dd, 1H, J=14.3Hz, J=5.1Hz, CH ₂ O), 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 ); ¹³ C NMR (CDCl ₃ ) δ168.56, 134.71, 132.50, 124.02, 49.65, 46.68, 40.22.

Example 3

Preparation of (R)-(-)-1,2-epoxy-3-phthaloylaminopropane

Using a procedure similar to that described in Example 2, the title compound was obtained in 86% yield as a colorless solid:

mp 102°C; [α] _D ²⁶ -9 (c 2.2, CHCl ₃ ); ¹ H 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); ¹³ CNMR (CDCl ₃ ) δ168.58, 134.73, 132.50, 124.03, 49.65, 46.70, 40.23; MS m/z 203 (M ⁺ ). Elemental analysis theory Values _{for C11H9NO3} : C 64.92; H 4.46; N 6.89 _. Found C 64.70; H 4.37; N 6.92.

Example 4

Preparation of (R)-(+)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazin-1-yl]propan-2-ol

Method 1 To a stirred solution of 4-(2-methoxyphenyl)piperazine (5.07g, 26.37mmol) in dry THF (50ml) was added (S)-(+)-1,2- Epoxy-3-phthaloylaminopropane (4.15g 20.42mmol), and the mixture was heated to reflux for 3 days. The solvent was removed in vacuo and the residue was purified by column chromatography (eluent: methanol/ethyl acetate/dichloromethane = 1/1/20) to afford 5.47 g (68%) of the title compound as a colorless solid:

mp 155-157°C; [α] _D ²⁶ +8 (c 0.5, CHCl ₃ ); ¹ H 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); ¹³ C NMR (CDCl ₃ ) δ169.13, 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 ⁺ ). Elemental Analysis Theoretical C ₂₂ H ₂₅ N ₃ O ₄ : C 66.82; H 6.37; N 10.60. Found C 66.86; H 6.34; N 10.43.

Example 5

Preparation of (S)-(-)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazin-1-yl]propan-2-ol

Using (R)-(-)-1,2-epoxy-3-phthaloylaminopropane in a manner similar to that described in Example 4, the title compound was obtained in 72% yield:

[α] _D ²⁸ -8 (c 0.3, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ7.90-7.84 (m, 2H, ArH), 7.75-7.71 (m, 2H, ArH), 7.03-6.84 ( m, 4H, ArH), 4.12-4.05 (m, 1H, CH), 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); ¹³ C NMR (CDCl ₃ ) δ169.13, 152.78, 141.63, 134.59 132.62, 123.94, 123.61, 121.53, 118.76, 111.71, 61.436 62. , 55.92, 54.13, 51.26, 42.61; MS m/z 395(M ⁺ ). Elemental analysis theoretical value C ₂₂ H ₂₅ N ₃ O ₄ ·0.5H ₂ O: C 65.33; H 6.48; N10.39. Found value C 65.05; H 6.31; N 10.24.

Example 6

Preparation of (S)-(-)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazin-1-yl]propan-2-ol Method 2 To a stirred solution of 4-(2-methoxyphenyl)piperazine (6.03g, 31.0mmol) in dry THF (150ml) was added (R)-(-)-1,2- Epoxy-3-phthaloylaminopropane (5.49 g 27.0 mmol), and the mixture was heated to reflux for 3 days. The solvent was removed in vacuo and the residue was stirred in diethyl ether (200ml) for 3 hours. The precipitate was collected by filtration and washed with diethyl ether (50ml) to give 7.81g (73%) of the title compound.

Example 7

Preparation of (R)-(+)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazin-1-yl]propan-2-ol

Using (S)-(+)-1,2-epoxy-3-phthaloylaminopropane in a manner similar to that described in Example 6, the title compound was obtained in 83% yield.

Example 8

Preparation of (S)-(+)-1-amino-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol

To stirred (R)-(+)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazin-1-yl]propane-2 - To a suspension of alcohol (7.0 g 17.7 mmol) in ethanol (180 ml) was added hydrazine monohydrate (4.31 ml, 88.7 mmol), and the solution was stirred at 25°C for 12 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in water (125ml), and the solution was extracted with chloroform (2 x 125ml). The extract was filtered through _Na2SO4 (20 _g ) and evaporated to dryness to give a pale yellow oil. After stirring this with diethyl ether (60ml), crystals precipitated to give 4.03g (86%) of the title compound as a white crystalline solid:

mp 76-80°C; [α] _D ²⁶ +22.3 (c 2.1, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ7.03-6.85 (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 be exchanged with D ₂ O). Elemental analysis theoretical value C ₁₄ H ₂₃ N ₃ O ₂ ·H ₂ O: C 59.34; H 8.89; N 14.82. Found value C 59.50; H 9.06; N 14.83.

Example 9

Preparation of (R)-(-)-1-amino-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol

In a manner similar to that described in Example 8, using (S)-(-)-5-(1-phthaloylamino)-3-[4-(2-methoxyphenyl)]piperazine Starting from -1-yl]propan-2-ol, the title compound was obtained in 94% yield:

[α] _D ²⁶ -22.3 (c 1.9, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ7.04-6.85 (m, 4H, ArH), 3.86 (s, 3HOCH 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 be combined with D ₂ O exchange); ¹³ C NMR (CDCl ₃ ) δ152.79, 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 ⁺ ). Elemental analysis theoretical value C ₁₄ H ₂₃ N ₃ O ₂ ·0.5 H ₂ O: C 61.29; H 8.82; N 15.32. Found C 61.41; H 8.83; N 15.11.

Example 10

(S)-(+)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propan-2-ol-1-yl]amino-2-methylthioquinazoline preparation of

2,4-Dimethylthioquinazoline (0.7g, 3.15mmol) and (S)-(+)-1-amino-3-(4-(2-methoxyphenyl)piperazine-1 -yl)propan-2-ol (0.76g, 2.86mmol) in acetonitrile (25ml) was heated at reflux for 4 days. The solvent was evaporated in vacuo and the residue was purified by column chromatography (ethyl acetate as eluent) to afford 0.41 g (33%) of the title compound as a light yellow solid: mp>78°C (dec); [α] _D ²⁸ +6 (c 2.9, CHCl ₃ ); ¹ H NMR (CDCl ₃ +D ₂ O) δ7.70-7.63 (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 ); ¹³ CNMR (CDCL ₃ ) Δ159.43, 152.83, 150.89, 141.59, 133.44, 127.66.125.03, 123.71, 121.56, 118.75, 111.817, 66.92, 55.96, 54.25, 54.25, 54.25, 54.25, 54.25, 54.25, 54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25,54.25. Theoretical value of elemental analysis C ₂₃ H ₂₉ N ₅ O ₂ S·0.5H ₂ O: C 61.58 H 6.74; N 15.61. Found value C 61.44; H 6.72; N 15.68.

Example 11

(R)-(-)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propan-2-ol-1-yl]amino-2methylthioquinazoline preparation

Starting from (R)-(-)-1-amino-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol in a manner similar to that described in Example 10 , the title compound was obtained in 72% yield: [α]D ²⁸ -6 (c 2.4, CHCl ₃ ); ¹ H 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); ¹³ C NMR (CDCl ₃ ) δ159.41, 152.82, 150.89, 141.59, 133.45, 127.67, 125.03, 123.71, 121.55, 118.74, 113.35, 111.78, 66.13, 61.950, 55.96, 54.12 45.11, 14.71; MS m/z 439 (M ⁺ ) Elemental Analysis Theoretical C ₂₃ H ₂₉ N ₅ O ₂ S H ₂ O: C 60.37; H 6.39; N 15.30. Found C 60.51; H 6.57; N 15.21 .

Example 12

Preparation of 2-methylthioquinazolin-4(3H)-one

To a solution of 2-mercaptoquinazolin-4(3H)-one (4.45 g, 25 mmol) and NaOH (1.1 g, 27.5 mmol) in water (125 ml) was added iodomethane (1.72 ml, 27.5 mol), and The mixture was stirred at 25°C for 3 hours. The precipitate was collected by filtration, washed with water (3 x 20 ml) and dried over silica gel in a vacuum desiccator for 24 hours to afford 3.66 g (73%) of the title compound as a colorless solid: mp 224-225°C. Analytical samples were recrystallized from methanol-water:

mp 225°C; ¹ H 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 ); ¹³ C NMR (CDCl ₃ ) δ 163.73, 155.76, 149.77, 135.50, 127.30, 126.96, 126.40, 120.37, 13.97.

Example 13

The preparation method of 4-chloro-2-methylthioquinazoline 1. the mixture of 2-methylthioquinazolin-4 (3H)-one (1.92g, 10mmol) and POCl ₃ (4.7ml, 50mmol) Stir at room temperature for 15 minutes, and heat the suspension at reflux for 1.5 hours. After cooling to room temperature, the mixture was poured into a mixture of ice (40 g) and dichloromethane (20 ml) and stirred vigorously for 5 minutes. _The organic layer was then separated and washed with 5% aqueous _K2CO3 (2 x 20ml). The organic layer was dried over Na ₂ SO ₄ (3 g), then it was filtered through 1 g of silica gel. The filtrate was evaporated in vacuo to afford 1.91 g (91%) of the title compound as a colorless solid, mp 107-108°C;

¹ H NMR (CDCl ₃ ) δ8.15-8.12 (m, 1H, ArH), 7.85-7.83 (m, 2H, ArH), 7.58-7.52 (m, 1H, ArH), 2.67 (s 1H, SCH ₃ ) ; ¹³ C NMR (CDCl ₃ ) δ152.38, 135.79, 135.75, 127.72, 127.63, 127.58, 126.69, 126.64, 14.99. Elemental analysis theoretical value C ₈ H ₇ ClN ₂ S: C 48.37; H 3.55; N 14.10. Measured Values C 48.32; H 360; N 14.04. Method 2. When the reaction mixture was poured into ice with vigorous stirring, the precipitate was collected by filtration and washed with 5% aqueous _K2CO3 (2 x 50ml), _water (100ml). The crude product was dissolved in acetone (100ml) and reprecipitated with water (100ml) to give 1.73g (82%) of the title compound as colorless needles: mp 108-109°C. Method 3. To a stirred suspension of 2-methylthioquinazolin-4(3H)-one (0.5g, 2.60mmol) and triphenylphosphine (0.82g, 3.12mmol) in dichloromethane was added Carbon tetrachloride (2.5ml) and the resulting suspension stirred at 20-25°C. After 6 hours, the reaction was complete (TLC) and the reaction product was filtered through a silica gel column (2.5 x 15 cm) using dichloromethane as eluent. The correct fractions were collected and evaporated in vacuo. The residue was dissolved in acetone (10ml) and reprecipitated with water (30ml) and dried under vacuum with _CaCl2 to give 0.46g (83%) of the title compound as white crystals: mp 108°C.

Example 14

(S)-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1, 2-c] Preparation of quinazoline

To (S)-(+)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propan-2-ol-1-yl]amino- To a solution of 2-methylthioquinazoline (1.72g, 3.9mmol) in dry dichloromethane was added triethylamine (2.73ml, 19.6mol). The mixture was stirred for 15 minutes and methanesulfonyl chloride (0.40 mL, 5.1 mmol) was added over 30 minutes. The mixture was stirred at 0°C for 1 hour and at 25°C for 7 hours. It was then diluted with dichloromethane (20ml) and washed successively with water (50ml), saturated aqueous NaHCO ₃ (20ml) and water (20ml). The organic layer was filtered through _Na2SO4 (2g) and concentrated to give crude product _. It was purified by flash chromatography using ethyl acetate as eluent. The residue obtained after evaporation of the solvent was stirred with acetonitrile (2 ml) for 1 hour and the precipitate collected to give 0.148 g (9.0%) of the racemic product: mp 172-173°C; [α] _D ²⁶ +5.72 (c0. 278, CHCl ₃ ), HPLC analysis showed that the racemic mixture contained 55.7% of the title compound and 44.7% of (R)-(-)-3-[(4-(2-methoxyphenyl)piperazine-1- Base] methyl-5-methylthio-2,3-dihydroimidazo[1,2-c]quinazoline.

The filtrate was evaporated in vacuo and the residue was heated under vacuum (5 mm) at 60-70°C to afford 1.13 g (69%, ee > 98.5%) of the title compound as a colorless foamy solid: mp 58-61°C (softened), 62- 63 (transparent);

[α] _D ²⁶ +39.6 (c 4.7, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ7.96 (dd, J=1.4, 7.9 Hz, 1H, ArH), 7.52 (t, J=7.7 Hz, 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 ); ¹³ C NMR (CDCl ₃ ) δ154.90, 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 ⁺ ). Elemental analysis theoretical value C ₂₃ H ₂₇ N ₅ OS·0.5H ₂ O: C 64.16 H 6.55; N 16.27. Found C 64.37; H 6.49; N 16.25.

Example 15

(R)-(-)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1, 2-c] Preparation of quinazoline

In a manner similar to that described in Example 14, using (R)-(-)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propan-2-ol-1-yl ]amino-2-methylthioquinazoline as starting material, the title compound was obtained in a yield of 71%: [α] _D ²⁶ -39.6 (c 4.7, CHCl ₃ ); ¹ H NMR (CDCl ₃ ) δ7.96 ( 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); ¹³ C NMR(CDCl ₃ )δ154.90，154.47，152.82，147.16，141.83，133.51，126.35，125.92，125.71，123.51 121.56，118.78，117.67，111.75，60.43，59.99，57.08，55.94，54.51，51.16，14.15；MS m/z 421 (M ⁺ ). Elemental Analysis Theoretical C ₂₃ H ₂₇ N ₅ OS·0.5H ₂ O: C 64.16; H 6.55; N 16.27. Found C 64.45; H 6.54; N 15.94.

Example 16

(S)-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1, 2-c] Preparation method of quinazoline 2. Adding (S)-(+)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propane at 2°C with stirring -2-ol-1-yl]amino-2-methylthioquinazoline (2.54g, 5.57mmol), potassium carbonate (2.31g, 16.72mmol) and triethylamine (2.33ml, 16.72mmol) in a dry MsCl (0.56ml, 7.25mmol) was added to a suspension in dichloromethane (170ml) over a period of 0.5 hours. The mixture was stirred at 2°C for 1 hour and at 25°C for 24 hours. Then it was washed with water (70ml) Washed and the aqueous layer was extracted with dichloromethane (50ml). The combined organic extracts were dried over _Na2SO4 (5g) and evaporated to _dryness . Acetonitrile (30ml) was added to the residue and stirred for 40 minutes , and the precipitate was collected by filtration to give 0.57 g (24%) of the racemic product: mp 173-174° C. The acetonitrile solution was evaporated and the residue was heated under vacuum (2 mmHg, 50° C.) to give 1.80 g (75%, ee > 98.5% ) the title compound as a colorless foamy solid.

Example 17

(R)-(-)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1, 2-c] Preparation of quinazoline

In a manner similar to that described in Example 16, using (R)-(-)-4-[(3-(4-methoxyphenyl)piperazin-1-yl)propan-2-ol-1-yl ]amino-2-methylthioquinazoline as starting material, the title compound was obtained in 72% yield.

Example 18

(S)-(-)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-2,3-dihydroimidazo[1,2-c]quinazole Preparation of Lin-5(6H)-one

(S)-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2,3-dihydroimidazo[1 ,2-c] A solution of quinazoline (1.2g, 2.85mmol) and NaOH (5.69g, 142mmol) in methanol (60ml) and water (35ml) was heated at reflux for 17 hours. To the cooled solution was added c.HCl (6.0ml, 68mmol), and the methanol was evaporated in vacuo. After adding water (60ml), the mixture was extracted with _{dichloromethane} (3 x 60ml). The organic solution was dried over _Na2SO4 (5g), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (eluent EtOAc: _CH3OH =10:1) to afford 1.05 g (94.5%) of the title compound as a colorless foam:

[α] _D ²⁵ -33.0 (c 1.342, CHCl ₃ ); ¹ H 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); ¹³ C NMR (CDCl ₃ ) δ154.02, 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, 5, 69931, 46.59 , 51.24; MS m/z 391 (M ⁺ ). Elemental Analysis Theoretical C ₂₂ H ₂₅ N ₅ O ₂ ·H ₂ O: C 64.53; H 6.65; N 17.10. Found C 64.40; H 6.59; N 17.0.

Example 19

(R)-(+)-3-[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-2,3-dihydroimidazo[1,2-c]quinazole Preparation of Lin-5(6H)-one

By a method similar to that described in Example 18, from (R)-(-)-3[(4-(2-methoxyphenyl)piperazin-1-yl]methyl-5-methylthio-2 , 3-dihydroimidazo[1,2-c]quinazoline, the title compound was obtained in 98% yield: [α] _D ²⁵ +30.9 (c 3.178, CHCl ₃ ); ¹ H NMR (CDCl ₃ )δ9.67(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=7.5 Hz, 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); ¹³ C NMR (CDCl ₃ ) δ153.45 , 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. Anal. C ₂₂ H ₂₅ N ₅ O ₂ ·0.75 H ₂ O: C 65.19; H 6.72; N 17.29. Found C 65.31; H 6.48; N 17.34.

Claims (14)

1. (S)-(+)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2-c having the following formula (S)-(+)-I ] quinazoline compounds and pharmaceutically acceptable salts thereof:

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 2. (R)-(-)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2-c having the following formula (R)-(-)-I ] quinazoline compounds and pharmaceutically acceptable salts thereof:

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 3. (S)-(-)-3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazoline-5 having the following formula (S)-(-)-II (6H)-keto compounds and pharmaceutically acceptable salts thereof:

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 4. (R)-(+)-3-substituted methyl-2,3-dihydroimidazo[1,2-c]quinazoline-5 having the following formula (R)-(+)-II (6H)-keto compounds and pharmaceutically acceptable salts thereof: In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 5. (S)-(+)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2-c having the following formula (S)-(+)-I ] The preparation method of quinazoline compound: In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group; the preparation method is: a) make formula IV compound Reaction with phthalimide under Mitsunobu reaction conditions to obtain the compound of formula V: b) the obtained compound V and formula VI compound

Reaction, obtains formula VII compound:

In the formula, the definition of R is the same as above; c) the obtained compound VII is reacted with hydrazine to obtain the compound of formula VIII:

The definition of R in the formula is the same as above; d) use IX or X

Treatment of the resulting compound VIII affords the compound of formula XI:

e) Cyclize the obtained compound XI to generate a compound of formula (S)-(+)-I. 6. (R)-(-)-3-substituted methyl-5-methylthio-2,3-dihydroimidazo[1,2-c having the following formula (R)-(-)-I ] The preparation method of quinazoline compound:

In the formula: R is halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group; the preparation method is: a) make formula IV compound

Reaction with phthalimide under Mitsunobu reaction conditions to obtain the compound of formula V:

b) the obtained compound V and formula VI compound

Reaction, obtains formula VII compound:

In the formula, the definition of R is the same as above; c) the obtained compound VII is reacted with hydrazine to obtain the compound of formula VIII: The definition of R in the formula is the same as above; d) use IX or X

Treatment of the resulting compound VIII affords the compound of formula XI:

e) Cyclize the obtained compound XI to generate a compound of formula (R)-(-)-I. 7. Preparation of (S)-(-)-3-substituted methyl- 2,3-Dihydroimidazo[1,2-c]quinazolin-5(6H)-one compound method: In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 8. Preparation of (R)-(+)-3-substituted methyl- 2,3-Dihydroimidazo[1,2-c]quinazolin-5(6H)-one compound method:

In the formula: R is a halogen, hydrogen, methoxy, trifluoromethyl, C ₁ -C ₄ alkyl, nitro, acetyl, cyano or hydroxyl group. 9. The pharmaceutical composition for the treatment of hypertension, it comprises formula (S)-(+)-I compound or its pharmaceutically acceptable salt described in claim 1 of effective therapeutic amount as active ingredient, and with A pharmaceutically acceptable carrier or diluent for the active ingredient. 10. The pharmaceutical composition for the treatment of hypertension, it comprises formula (S)-(-)-II compound or its pharmaceutically acceptable salt described in claim 3 of effective therapeutic amount as active ingredient, and with A pharmaceutically acceptable carrier or diluent for the active ingredient. 11. The pharmaceutical composition for the treatment of dysuria, it comprises the compound of formula (S)-(+)-I described in claim 1 or its pharmaceutically acceptable salt of therapeutically effective amount as active ingredient, and with A pharmaceutically acceptable carrier or diluent for the active ingredient. 12. The pharmaceutical composition for the treatment of dysuria, it comprises formula (S)-(-)-II compound or its pharmaceutically acceptable salt described in claim 3 of effective therapeutic amount as active ingredient, and with A pharmaceutically acceptable carrier or diluent for the active ingredient. 13. The imidazo[1,2-c]quinazoline compound and its pharmaceutically acceptable salt according to claim 1, which is (S)-(+)-3-[4-[1-(2-methyl oxyphenyl)piperazinyl]]methyl-5-methylthio-2,3-dihydroimidazo[1,2-c]quinazoline. 14. The imidazo[1,2-c]quinazoline compound and pharmaceutically acceptable salt thereof according to claim 3, which is (S)-(-)-3-[4-[1-(2-methyl oxyphenyl)piperazinyl]]methyl-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one.