Method for preparing 3-[1-(1h-imidazol-4-yl)alkyl]-hydroxy benzenemethanols

专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of 3-Ј1- (1H-imidazol-4-yl) agg -ylT-hydroxybenzenemethanol f-OH OH YI where RJ, Ra, R3, .H Rs which may be the same or different each represents a hydrogen atom or an alkyl radical containing 1-4. atom C; One of the v and Y2 H radicals, and the other a hydroxyl radical, which exhibit anti-heemic properties. The goal is to develop a method for producing these compounds. The preparation is carried out by hydrolysis in the aqueous acid medium of the corresponding (2,2-dimethyl-4I-1,3-benzodioxin-6 (or 8) shLalkyl -1H-imidazole. Table 1)
公开号:SU1628857A3
申请号:SU884613197
申请日:1988-12-22
公开日:1991-02-15
发明作者:Коссман Эрик；Герт Жан-Пьер；Гобер Жан；Мишель ФИЛИПП
申请人:Юцб С.А. (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new 3-1- (1H-imidazol-4-yl) alkyl-G-oxybenzenemethanol or their salts, which can be used in the field of therapy.
 Delimitation is the synthesis of new compounds of the benzyl-1H-imidazole series, which, besides the types of activity characteristic of this series of compounds, also have anti-ischemic properties.
Examples are given without limitation, for the preparation of sG1- (1H-imidazol-4-yl) alkgH-oxybenzenemethanols of the invention and their intermediates. In these examples, nuclear magnetic resonance (KS) spectra were determined using a Perkin-Elmer instrument at 60 MHz using tetramethylsilane as an internal standard, chemical substitutions are indicated in delta (ppm).
Example 1. Preparation of imidazole compounds ;,
A. Preparation of brominated derivatives, prototypes of organometallic derivatives.
oh
1HE
00 00 SP

sc
1. 8-Bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin.
1a 3-Bromo-5-chloro-2-hydroxybenzene tanol.
830 g (A, 241 mol) of 2-bromo-4-chlorophenol is dissolved in 8.2 l of an aqueous formaldehyde solution with 38% (approximately 100 mol). The mixture is cooled in an ice bath, then 1.380 g (24 mol) of potassium hydroxide are added simultaneously in parts of 100 g. The addition was carried out for 150 minutes at 18 ° C to 23 ° C. The still peremegaivanie is maintained for 2 hours at room temperature, then heated gradually to 40 ° C in a water bath. The reaction is slightly exothermic and the temperature of the medium stabilizes at about 45 ° C. Continue stirring for 178 hours at 40 ° C. Then the reaction medium is cooled. 2 L of water is added to it and acidified to pH 3 with 1420 ml of concentrated hydrochloric acid. Extracted with 2 liters of dichpormethane, then another 6 times t l of dihpormethane. The organic phase is washed with 2 l of water, dried on sodium sulfate and the solvent is evaporated under reduced pressure.
The resulting crude residue (1490 g) contains approximately 68.8% of 3-bromo 5-chloro-2-hydroxybenzenemethanol and approximately 23.8% of unreacted starting 2-bromo-4-chlorophenol. This mixture is used in the same form in the next stage.
1b. 8-Bromo-6-hporo-2,2-dimethyl-4H-1,3-benzodioxin.
The crude residue (1490 g) recovered in the previous step is dissolved in 20 liters of toluene and 4.68 liters of 2,2-dimethoxypropane in the presence of 296 g of montmorillonite K10 (freshly dehydrated by azeotropic distillation with toluene). The temperature of the mixture itself rises to 30 ° C, maintain stirring at this temperature for 115 hours. Filter the reaction medium and remove the toluene under reduced pressure. The residue obtained is purified by distillation under reduced pressure.
527 g of 90% pure 8-bromo-6-hporo-2,2-dimethyl-4H-1,3bazodioxin are obtained (analysis by HPLC chromatography). Bp 100-112 ° C / 0.026 mbar. Total yield 75% (calculated with respect to the used - bromo-4-chlorofenol).
Nuclear Magnetic Resonance Spectrum (SPN), Ј: 1.55 (6H, S C (CH3) z.); 4.78 (2H, S, CHg); 6.9 (1H m, Ar H); 7.4 (y, t, Ar H).
2. 6-Bromo-2,2-dimethyl-4H-1,3-ben EDIOXIN.
2a 5-Bromo-2-hydroxybenzenemethanol.
This compound is prepared, as indicated in 1a, from 4-bromophenol.
After evaporation of dichloromethane, which was used for extraction, 709 g of residue is taken up, which is chromatographed on 1.2 kg of silica (solvent is dichloromethane). After evaporation of the solvent, 602 g of residue are obtained, containing approximately 50% of 5-bromo-2-hydroxybenzene-methanol (analysis by HPLC chromatography). This residue is used in the same form in the next stage.
26. 6-Bromo-2,2-dimethyl-4H-1,3-benzodioxin.
572 g of the residue obtained in the previous step are dissolved in 12.5 liters of dry toluene and 2.94 liters of 2,2-dimetho-xpropane. Add 1k to a solution of 186 g of montmorillonite K10 and stir the mixture for 25 hours at room temperature.
Filter, distil the organic phase under reduced pressure and redissolve the residue in 600 ml of toluene. This solution is passed through a column containing 3 kg of alumina (solvent 6 liters of toluene). The eluate is evaporated under reduced pressure and 180 g of residue is left, which is distilled under reduced pressure. 60 g of 6-bromo-2,2-dimethyl-4H-1,3-benzodioxin are obtained. Bp 110 PO ° C / 0.027 mbar. The yield calculated with respect to the 4-bromophenol used. about 1 10%.
Nuclear Magnetic Resonance Spectrum (CDCl,) ,: 1.52 (6H, S, C (CH5) 2); 4.80 (2H, S, CH4); 6.71 (1H, d, 9 Hz, Arn); 7.07 - 7.5 (2H, t, AgN).
3. 8-Bromo-2,2,6-trimethyl-4H-1,3-benzodioxin.
This compound is prepared according to the method of H.E.KATZ and D.I.CRAM. It is isolated in the form of a residue, which is used in the same form in the next step.
B. Preparation of 4- (Ka-CO) -1H-imidazoles.
1. 1-T. rifenshetil-1H- "midazol-4-carboxaldehyde.
la. 1-Triphenylmethyl-1H-imidazole-4-methanol.
This compound is prepared according to the method of I.L. Kelley et al. Yield 71.3%. M.p. 236aC.
16. 1-Triphenylmethyl-1H-imidazole-4-carboxaldehyde.
This compound is also prepared according to the method of I.L. Kelley et al. In a yield of 87.5%. M.p. 190-198 ° C.
2.1-Methyl-1H-imidazol-4-carboxaldehyde.
This product is obtained by the method of G. Lindgren et al.
3.5-Methyl-1-triphenylmetl-1H-imidazole-4-carboxaldehyde.
Behind . 5-Methyl-1H-imidazol-4-methanol.
This compound is obtained by a known method. Yield 59.3%.
36. 5-Methyl-1-triphenylmethyl-1H-imidazol-4-methanol.
To a solution of 100 g (0.673 mol) of 5-methyl-1H-imidazole-4-methanol in 1.5 liters of dimethylformamide, maintained between 10 and 14 ° C, 230 ml (1.659 mol) of triethylamine are added in 15 minutes. Then a solution containing 192 g (0.69 mol) of triphenylmethyl chloride in 2 liters of dimethyl Lorimide is introduced between 8 and 11 ° C.
The reaction medium is stirred for 2 hours, then it is poured onto 14 liters of ice. Stirring is continued for 1 hour, then the precipitate is filtered, which is washed with 6 l of water and dried. This precipitate is then taken up in 4 liters of ethanol at the boil and the insoluble fraction is separated by filtration at high temperature. In this way, the first stream (19 g, mp. 255-260 ° C) of the desired product is taken. The alcoholic filtrate is filtered at high temperature in norite, then concentrated and cooled with stirring. The second product stream crystallizes and is separated by filtration: 28.3 (m.p. 255-2: 2 ° C). Finally, the filtrate is distilled under reduced pressure and the residue is dissolved in 1 l of a mixture of dichloromethane-methanol 95: 5 and the resulting solution is purified by passing through a column of 1.8 kg of silica (0.2-0.5 mm) (solvent dichloromethane-methanol mixture 80:20). Take away
another 72.1 g of product. I
In general, 119.4 g are obtained, containing almost one of two possible
0
five
0
five
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five
0
4- and 5-position isomers, namely 5-methyl-1-triphechylmethyl-1H-imidazole-4-methanol. Yield 50.1%.
The resulting product is used in the same form in the next stage.
Zs. 5-Methyl-1 triphenylmethyl-1H-imidazole-4-carboxaldehyde.
Heated under reflux for 85 minutes in the presence of 32.65 g (0.375 mol) MpOd, a solution of 19 g (0.0536 mol) of the product obtained in the previous step in 400 ml. chloroform. The manganese salts were removed by filtration on dicalite and the filtrate was distilled. Recrystallize the residue from 200 ml of ethyl acetate. A first stream of 4.37 g of product is obtained. A second stream of 9.43 g is obtained even after concentration of the mother liquors to a volume of 60 ml and crystallization. Yield 73.5%. M.p. 195-t96 ° C.
t
The resulting product contains one position isomer.
Found,%: C 81.37; H 6.25; N 7.95.
C24H20 g °
Calculated,%: C 81.18; H 5.68; N 7.95.
4. 1 (1-Triphenylmethyl-1H-imidazol-4-yl) -1-ethanol.
4a. Alpha-methyl-1-triphenylmethyl-1 H-imidazole-4-methanol.
This compound is prepared according to the method of I.L. Kelley et al.
4b. 1 (1-Triphenylmethyl-1H-imndazol-4-yl) -1-ethanol.
A mixture of 221.3 g (2.544 mol) of manganese dioxide and 56.9 g (0.161 mol) of alphamethyl-1-triphenylmethyl-1H-imzd -; - azole-4-methanol, dissolved in 2.5 l is heated under reflux for 90 minutes. chloroform. The solution is then cooled to approximately 50 ° C, filtered and the chloroform is removed by distillation. Dissolve the residue in 400 ml of isopropyl alcohol and filter the solution at high temperature in norite. The product is crystallized by cooling. 32.8 g of (1- (1-triphenylmethyl-1H-imidazol-4-yl) -1-ethanol) are obtained.
N
Yield 58%. M.p. 158-160 ° C. Found,%: C 81.89; H 5.65; 7.90.
C 4H20N20.
Calculated,%: C 81.82; H 5.68; N 7.95.
5. 1- (1-Triphenylmethyl-1H-imidazol-4-yl) -1-pentanone.
5a. Alpha-p-butyl-1-triphenylmethyl-1P-imidazole-4-methanol.
Under an argon atmosphere, a solution of 0.22 mol of u-butshagni bromide in 75 ml of tetrahydrofuran is slowly added to 67.6 g (.0.2 mol) of 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde, obtained as indicated in 16, in 500 ml of tetrahydrofuran. The temperature of the mixture is maintained at about 20 ° C. by cooling in an ice bath. When the addition is complete, stir for another 30 minutes at room temperature, then 11 g of ammonium chloride and 100 ml of water are added successively. Extracted with dichloromethane. The organic phases are dried over sodium sulfate, then evaporated under reduced pressure. The residue is recrystallized from ethyl acetate-simple diethyl ether 2: 1. 45.8 g of alpha-p-butyl-1-triphenylmethyl-1H-imidazole-4-methanol are obtained.
Yield 58%. M.p. 119-120 ° C.
Found,%: C 79.13; H 6.82; N 6.65 ..
C2TH2gN20.
Calculated,%: C 81.82; H 7.07; N 7.07.
56. 1 (1-Triphenylmethyl-1H-imidazol-4-yl) -1-pentanone.
This compound is prepared as indicated in 4bg of alpha-p-butyl-1-triphenylmethyl-1H-imidazol-4-methanol, obtained in the previous step. 1
The oily residue obtained after evaporation of chloroform is purified by chromatography on silica (dichloromethane solvent). 39 g of 1- (1-triphenylmethyl-1H-imidazol-4-yl) -1-pentanone are obtained,
Yield 85.3%. m.p. 115-118 ° C. Found,%: C 82.18; H 6.61; N 7.14.
C27HZ6N20.
Calculated,%: C 82.23; H 6.60; N 7.11.
C. Reactions of an organometallic derivative with 4- (K -CO2) -1H-imidazoles.
1. Alpha- (6-chloro-2,2-dimethyl-4H-1, 3-benzodioxin-B-H H-triphenylmethyl-1H-imida-e-4-methanol.
To a suspension of 26.73 g (1 mol + 10% excess) of magnesium in 250 ml of anhydrous tetrahydrofuran, add 2 ml of dibromomethane and heat to approximately 30 ° C to start the reaction. Then, 277.5 g (1 mol) of 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin dissolved in 250 ml of tetrahydrofuran are added dropwise to the drop so that the temperature of the medium does not exceed 40 ° C .
Joining takes approximately 150 minutes. Magnesium compound is cooled to approximately 10 ° C (partial precipitation) and to a solution of 338 g (1 mol) of 1-triphenylmethyl-III-imidazole-4-carboxaldehyde in 2.8 l of tetrahydrofuran, previously cooled to 0 ° C. During the addition, the temperature of the mixture gradually rises to 20 ° C. Stirring is continued for another 1 hour at this temperature, then 53.5 g (1 mol) of ammonium chloride is added.
After stirring for 1 hour, another 18 ml of water is added and stirring is maintained for an additional hour.
The tetrahydrofuran is removed under reduced pressure. The residue is taken up in 5 liters of dichloromethane and washed with 2 liters of water containing 30 g of sodium bisulfite. The aqueous phase is separated and washed with 1 l of dichloromethane. The organic phases are washed with more water, then dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is recrystallized from approximately 4 liters of toluene at 80 ° C and filtered at a high temperature in norite. 335.6 g of alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxyn-8-yl) -1-triphenylmethyl-1H-imidazole-4-methanol are obtained in this way, which contains one toluene molecule.
m.p. 120 ° C to 188 ° C.
Found,%: C 74.78; H 5.24; N 4.73.
C H29C1N2 ° 3 + C7HS.
Calculated,%: C, 76.81; H 5.78; N 4.37.
The following compounds are obtained according to the method given in 1.
2. Alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-methyl-1H-imidazol-4-methanol.
From 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin and 1-methyl-1Nimidazole-4-carboxaldehyde. The organomagnesium compound is attached at 0 ° C. The yield is 63.5%. M.p. 131-136 ° C (ethyl acetate).
Found,%: C 58.47; H 5.54;
N 8.97; C1 11.49. C TH 7C1N203.
Calculated,%: C 58.35; H 5.51; N 9.08; C1 11.55.
3. Alfa- (6-chloro-2,2-dimethyl-4H1, 3-benzodioxin-8-yl) -5-methyl-1-triphenylmethyl-1H-nmidazol-4-methanol.
From 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin and 5-methyl-1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The organomagnesium compound is attached at 0 ° C. Yield 50%. M.p. 100-120 ° C (acetonitrile).
Nuclear Magnetic Resonance Spectrum (CDCl1), a: 1.4 (6H, ha CHa-C-CH); 1.94 (3N, S, CH3); 4.79 (2H, S, CH2); 5.98 (1H, S, CHOH); 6.65-7.70 (18H, n, ArH + lraH).
4.Alpha- (2,2,6-trimethyl-4H 1,3-benzodioxin-8-yl) -1-triphenylmethyl 1H-imidazol-4-methanol.
From 8-bromo-2,2,6-trimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The magnesium organic compound is added at room temperature. The reaction product is purified by chromatography on silica () (solvent: dichloromethane-methanol 98: 2). Exit 31%. M.p. 205-215 ° C (acetonitrile).
Nuclear Magnetic Resonance Spectrum (CDCla),: 1.3 (3N, s, CH3-C-CH3); 1.38 (3N, S, CH3-C-CH3); 2.2 (3N, S, CH3); 4.78 (2H, S, CH2); 6.02 (1H, br. S, SNOP); 6.72 (2H, t, 1taH + + OH); 7.0-7.65 (18H, ta, Agn-MtN).
5. Alfa- (2,2-dimethyl-4H-1,3-benzodioxin-6-yl) -1-triphenyl-1H-imidazole-4-methanol.
From 6-bromo-2,2-dimethyl-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The temperature of the reaction mixture does not exceed 40 ° C. Yield 54.5%. M.p. 155-162 ° C (acetonitrile).
Nuclear Magnetic Resonance Spectrum (DMSO), ff: 1.43 (6H, S, CH-C-CH3); 4.77 (2H, S, CH2); 5.53 (2H, S, SI and OH); 6.6-7.7 (20H, t, ArN + 1TN).
i
6. Alfa- (6-chloro-2,2-dimethyl-4H1, 3-benzodioxin-8-yl) alpha-methyl-1-triphenylmethyl-1H-imidazol-4-methanol.
five
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50
five
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five
An organomagnesium compound 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin is obtained, as indicated in 1. Then, within 20 minutes and at a temperature not exceeding 25 ° C, 15 g are added ( 0.046 mol) of this organic magnesium compound to 15 g (0.0426 mol) of 1- (1-triphenylmethyl-1H-imidazol-4-yl) -1-ethanol in solution in 150 ml of tetrahydrofuran. Stir for 165 minutes, then the reaction medium is decomposed with 2.5 g of ammonium chloride dissolved in 50 ml of water. Extracted with dichloromethane. The organic phase is dried on sodium sulfate, then distilled. The residue is purified by chromatography on silica (solvent: dichloromethane-methanol mixture 98: 2).
5.68 g of alpha- (6-chloro-2,2-dimethyl-4H-1, 3-benzodioxin-8-yl) alpha-methyl-1-triphenylmethyl-1H-imidazol-4-methanol are obtained. M.p. 182-184 ° C (ethyl acetate). This compound is identical to the compound obtained in example 2B.
7. Alpha-p-butyl-alpha (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-triphenylmethyl-1H-imidazole-4-methanol.
This compound is prepared, as the previous compound, by reacting the organomagnesium compound 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin with 1- (1-triphenylmethyl-1H-imidazol-4-yl) - 1-pentanone. Yield 54.6%. M.p. 124 ° C (petroleum ether).
Nuclear Magnetic Resonance Spectrum (SPNC), G: 0.6 - 3.3 (15H, t, C4H9 and CH3-C-CH3) 4.26 (W, br S, OH); 4.78 (2H, S, CHZ); 6.7- 8.0 (19H, t, Agn-NtN).
8. Alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-methyl-1H-imidazol-4-methanol (hydrochloride).
15.88 g of alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-methyl-1H-imidazole-4-methanol (prepared above and in paragraph 2) dissolved in 160 ml of methanol in the presence of 3 g of palladium carbon with 10% at a hydrogen pressure of 3.5 bar at 50 ° C for 150 minutes. The catalyst is then filtered, the solvent is removed and the residue is stirred in diethyl ether. The ether phase is decanted and the resulting residue is used in the next step.
Example 2. Preparation of imidazole compounds according to method b). A. Preparation of ketones (6-Chloro-2, 2-dimethyl-4H-1,3-benzodioxin-8-yl) - (1-triphenylmethyl-1H-imidazol-4-yl) ketone.
The compound was prepared as in Example 1B, 46 from alpha- (6-chloro-2,2-dimethyl-4H-1.31 benzodioxin-8-yl) -1-triphenylmethyl-1H-imidazol-4-methanol (obtained in example 1C.1). Output 88% (almost pure product). M.p. 200-205 ° C.
Found,%: D 74.17; H 5.03;
N 5.22; C1 6.73. C33H2TC1N203.
Calculated,%: C 74.08; H 5.05; N 5.24; G1 6.64.
B. Reaction of ketone with organomagnesium compound.
Alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) alpha-methyl-1-triphenylmethyl-1H-imidaeol-4-methanol.
A suspension of 0.148 mol is added.
methylmagnesium iodide in 150 ml of diethyl ether at 30 ° C at room temperature to 17.6 g (0.033 mol) (6-chloro-2,2-dimethyl-4H-1, 3-benzodioxin-8-yl) - (1- Triphenylmethyl-1H-imide sol 4-yl) ket it in solution in 200 ml of tetrahydrofuran. The temperature of the reaction medium is raised to 40 ° C. When the addition is complete, stirring is maintained for 1 hour at room temperature. 8 g of ammonium chloride are added and stirring is maintained for another 1 hour. 100 ml of water are then added and the reaction medium is extracted twice with dichloromethane. The organic phases are dried on sodium sulfate and the solvent is removed under reduced pressure. The resulting residue is crystallized from diethyl ether with stirring. 14.5 g of alpha- (6-chloro-2, 2-dimethyL-4H-1, 3-benzodioxin-8-yl, alpha-methyl-triphenylmethyl-1H-imidazol-4-methanol are obtained. 80% y mp 182-184 ° C (ethyl acetate).
Found,%: C 73.98; H 5.65; N 5.00; C} 6.49. С54Н3 | С1МгО ,.
Calculated,%: C 74.11; H 5.63; N 5.08; C1 6.45.
This compound is identical to the compound obtained in Example 1.C.6.
Example 3. Preparation of imidazole compounds.
1. 4-G (2,2-Dimethyl-4H-1,3-benzodioxin-8-yl) (methoxy) methyl JIH-imide sol (hydrochloride) and alpha- (2,2-dimethyl 4H-1, G -benzodioxin-8-yl) -1H-imidazole-4-methanol (hydrochloride).
125.4 g (0.23 mol) of alpha- (6-chloro-2,2-dime TIL-4H-1, 3-benzodioxin-8-yl) -1-triphenylmethyl-1H-imidacol-4-methanol is subjected to hydrogenolysis ), obtained in example 1.C.1 partially dissolved in 1250 ml of methanol, in the presence of 6 g of palladium carbon with 10% and with an initial hydrogen pressure of 2.7 bar.
The reaction is carried out at 60 ° C. The catalyst is then filtered through a hybrid gas and the methanol is removed under reduced pressure. Absorb the residue in 100 ml of methanol and cool in an ice bath. Triphenylmethane was removed by filtration, which crystallized and the filtrate was then evaporated. The residue obtained is stirred for at least 12 hours in 650 ml of diethyl ether. “Filtrate precipitate and wash with diethyl ether. 64.59 g of an amorphous powder is obtained, which is formed by a mixture of the desired alcohol and a C-methylated derivative in the ratio 35/65, which is determined by NMR. This mixture is used in the same form in the next stage.
A sample of 5.36 g of this product mixture is recrystallized from 20 ml of a 1: 1 mixture of ethanol-ether. 1.35 g of pure alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1H-imidazol-4-methanol hydrochloride was isolated. This product does not have a clear melting point (decomp.).
Found,%: C 55.81; H 5.77; N 8.94; C1-11.83.
CWH16NZ03-HC1.
Calculated,%: C 56.66; H 5.40; N 9.44; C1 11.97.
The 0-methylated derivative, which is formed during hydrogenolysis, is isolated from the reaction medium, neutralized by addition of ammonia and simultaneously purified by chromatography. The resulting 4- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) (methoxy) methyl-1H-imidazole is converted to the hydrochloride by addition of a solution of hydrochloric acid in methanol. M.p. 150-155 C (decomp.).
Found,%: C 58,12; H 6.08; N 9.10; C1 11.40.
, 8NZ03 HC1.
Calculated,%: C 57.97; H 6.12; N 9.02; C1 11.43.
2. Alpha- (2,2-dimethyl-4H-1,3-benzodoxin-8-yl) -5-methyl-1H-imidzol-4-methanol (hydrochloride) and 4- (2,2-dime - Tyl-4H-1,3-benzodioxin-8-yl) (methoxy) methyl-5-methyl-1H-imidazole (hydrochloride).
17.5 g (0.032 mol) of alpha- (6 chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -5-methyl-1-triphenyl-methyl-1H-imidazole is subjected to hydrogenolysis - 4-methanol (obtained in Example 1.C, 3), dissolved in 300 ml of methanol, in the presence of 1.5 g of palladium carbon with 10% at a hydrogen pressure of 3.5 bar at 50 ° C for 3 The catalyst is then filtered, the solvent is removed and the residue is stirred in diethyl ether to remove the triphenylmethane. The residue obtained after decanting the ether phase is distinguished by its NMR spectrum and is a mixture containing 65% of the hydrochloride of the 0-methylated derivative and 35% of the hydrochloride of alcohol. This mixture is used in the same form in the next stage.
3.4-Ј (2,2,6-Trimethyl-4H-1,3-benzo-dioxin-8-yl) (methoxy) metshG | -1H-imide sol and 4-(2-2,6-trimethyl-4H- 1,3-6-enzo-dioxin-8-yl) metht -1H-imidazole.
9,45 g (0,0183 mol) alpha- (2,2,6-trimethyl-4H-1, 3-benzodioxin-8-yl) -1-triphenylmethyl-1H-imidazol-4-methanol ( obtained in Example 1.0.4), dissolved in 300 ml of methanol, in the presence of. 0.6 g of palladium carbon with 10% for 4 hours at 80 ° C with a hydrogen pressure of 2 bar. The catalyst is then filtered and the solvent is removed. The residue obtained is stirred in ethyl ether to remove triphenylmethane, then chromatographed on 700 g of silica (10 | CM) (solvent dichloromethane-methanol 95: 5).
 A 40:60 mixture of 4- (2,2,6-trimethyl-4H-1, 3-benzodioxin-8-yl) methyl -1H-imidazole and 4-Ј (2,2,6-trimethyl-4H -1, 3-benzodioxin-8-yl) (methoxy) methyl -1H-imidazole, identify the NMR spectrum the presence of the corresponding peak methoxy radical
(DMSO: J 3,13). This mixture is used in the same form in the next stage.
4. Alpha (2,2-dimethyl-4H-1,3-benzodioxin-6-yl) -1H-imidazol-4-methanol.
Carried out as described above in 2, but starting from alpha- (2,2-dimethyl 4H-1,3-benzodioxin-6-yl) -1-triphenylmethyl-1H-imidazole-4-methanol (obtained in example 1C, 5). The residue obtained is chromatographed on silica () (solvent dichloromethane-methanol 95: 5). The isolated alpha- (2,2-dimethyl-4H-1, 3-benzodioxin-6-yl) -1H-imidaeol-4-methanol is recrystallized from ethyl acetate. M.p. 96 ° C.
Found,%; C, 64.37; H 6.40; N 10.68.
From 4H16% 03.
Calculated,%: C 64.62; H 6.15; N 10.77.
5. Alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1H-imidazol-4-methanol.
I
To suspension of 21.46 g (0.04 mol)
alpha- (b-chloro-2,2-dimethyl-4H-1,3-benodeiodin-8-yl) -1-triphenylmethyl-1H-imidazol-4-methanol (obtained in Example 1C, 1) in 2 l of ammonia and 200 ml of toluene is added in pieces of 5.75 g (0.25 mol) of sodium. Stirring is maintained for 40 minutes, then the reaction medium is decomposed by adding 6.42 g (0.12 mol) of ammonium chloride. 500 ml of toluene containing 10% methanol are added, ammonia is distilled off and another 500 ml of water are added. The toluene phase is decanted, dried over sodium sulfate, then distilled. The residue, which contains triphenylmethane, is partially dissolved in 50 ml of water containing 3.3 ml of concentrated hydrochloric acid, and the resulting suspension is extracted with ether. The aqueous phase is then adjusted to pH 8 by addition of sodium bicarbonate, then extracted with dichloromethane. The solvent is removed by distillation and 3.5 g of alpha- (2,2-dimethyl-4H-1, 3-benzodioxin-8-yl- (1I- imidazole-4-methanol. Yield 33%.
The product forms a hydrochloride (recrystallized from a mixture of ethanol / ether 1: 1), which has a glassy appearance and does not have a clear melting point. (
15
Found,%: C 55.81; H 5.77; N 8.94; SG 11.83. C (4H 6N2n3HCl. Calculated,%: C 56.66; H
-one
N 9.44; 11.97.
5.40;
6. Alpha-p-butyl-alpha- (2,2-dime-4H-1,3-benzodioxin-8-yl) -1H-imidazol-4-methanol.
162885716
(2H, S, SNg); 6.5-7.7 (5H, t. Agn + 1 T).
2a 4- (2,2 Dimethyl-4H-1,3-benzodioxin-8-yl) methyl -1H imidazole.
Introduce 94.13 g TO, 317 mol) alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1H-imidazole-4-me-tanol hydrochloride (obtained in Example 3.1).
Carried out as in 1, but at 30 ° C, Yu or 3.5) in 1 liter of anhydrous liquid am20
starting from alpha-p-butyl-alpha- (6-chloro-2,2-dimethyl-4H-t, 3-benzodioxin-8-yl) -1-triphenylmethyl-1H-imidazol-4-methanol (obtained in Example 1. C. 7. The residue obtained after filtering 15 neither triphenylmethane and evaporation of methanol is used in the same form in the next stage.
(7. Chloride hydrate alpha (2,2-dimetshg-4H-1,3-benzodioxin-8-yl) alpha-methyl-1H-imidazol-4-methanol.
Carried out as in 2, but at 20 ° C, starting from alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) alpha-methyl-1-triphenylmethyl-1H - imidazole-4-methanol (obtained in example 2.B). The output is almost quantitative. M.p. 85-100 ° C (decomp.).
A sample for analysis is obtained by stirring in diethyl ether. M.p. 72-90 ° C (decomp.).
Found,%: C H 6.95; N 8.12; C1 9.51. With NyMgO -NS.
Calculated,%: with 57.97j H 6.12; N 9.01; C1 11.43.
PRI me R 4. Getting the source
25
miak. Complement the dissolution of the reagent by addition of 1 l of tetrahydrofuran. Then, 14.6 g of sodium (0.634 mol) is added in pieces. After 5 minutes after the disappearance of sodium, 34 g of ammonium chloride are added and the reaction medium is kept stirring for half an hour. 1.56 L of 10% methanol in toluene is added. Then ammonia is distilled off in a water bath. A further 780 ml of water is added and the organic phase is separated. The aqueous phase is extracted twice with 500 ml of toluene. The organic phases are combined and washed with 1 l of water, then dried over sodium sulfate and distilled under reduced pressure.
The residue obtained is recrystallized from 900 ml of acetone at reflux. In this way, 57.8 g of 4- Ј (2,2-dimethyl-4H-1, 3-benzodioxin-8-yl) Metersht-1H imidazole are obtained, with a mp. between 160-170 ° C. The yield of 74.6%.
Found,%: C 69.15; H 6.70; 35 N 11.53.
CHH 6N208.
Calculated,%: C 68.85; H 6.56; N 11.48.
26. The same product can be obtained 40 on the basis of 0.8 g (0.0015 mol) alpha- (6-chloro-2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1- triAenylmethyl-1H-imidazole, Subject to hydrogenolysis (3.4 g4-methanol) obtained in Example I
(0.013 mol) alpha- (2,2-dimethyl-4H-1CJ and p (0,010 mol) sodium
1,3-6 "isodaoxin-6-sh1) -1P - imidazole-4-D5 according to 3.5. Balance received
after evaporation of the toluene phase,
thirty
4-JJ1- [2,2-dimethyl-4H-1,3-benzodioxin-6- (or 8) -yl / alkyl -1 H-imidazoles.
1.4- (2,2-Dimethyl-4H-1,3-benzodioxin-6-yl) methyl -1H-imidazole
methanol (obtained in Example 3.4) in methanol at 80 ° C for 5 hours in the presence of carbon with 10% and with a hydrogen pressure of 2.8 bar. Then the catalyst is filtered and the solvent is removed under reduced pressure. The remaining balance is stored on bent of silicon (solvent dichloromethane-methanol 90:10). 3 g of 4-G (2,2-dimethyl-4H-1,3-benzodioxyn-6-yl) methyl -1H are obtained. - imndazole. Exit 947 ,. M.p. 150-170 ° C
Nuclear Magnetic Resonance Spectrum (WfSO), ii 1.45 (6H, S,
OIj-C-CHjH t2K s 2 4 "77
50
Chromatograph over 150 g of silica (10 μm) (ethyl acetate-methanol solvent 95: 5). 123 mg of product are obtained, corresponding to the product isolated in 2a.
The following products were prepared according to 2a.
3. 4- (2,2-Dimethyl-4H-1,3-benzodis oxyn-8-yl) methyl -1-methyl-1H-imidazole.
This compound is obtained on the basis of alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-methyl-1H-imidazole-4-methanol hydrochloride (obtained in the example
Chromatograph over 150 g of silica (10 μm) (ethyl acetate-methanol solvent 95: 5). 123 mg of product are obtained, corresponding to the product isolated in 2a.
The following products were prepared according to 2a.
3. 4- (2,2-Dimethyl-4H-1,3-benzodioxin-8-yl) methyl -1-methyl-1H-imidazole.
This compound is obtained on the basis of alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) -1-methyl-1H-imidazole-4-methanol hydrochloride (obtained in example 17
Re 1.C, 8). The residue obtained is purified by chromatography on silica (dichloromethane-methanol solvent 98: 2). Yield 67%. M.p. 67-72 ° C (simple isopropyl ether-hexane).
Found,%: C 69.93; H 7.54; N 10.78,
C (H (8N202.
Calculated,%: C 69.74; H 7.02; N 10.84.
4.4-Ј (2,2-Dimethyl-4H-1,3-benzodioxyn-8-yl) methyl-5-methyl-1H-imidazole
This compound is obtained from 9.68 g of the 0-methylated chlorohydrate and alcohol derivative mixture obtained in Example 3.2. It is purified by chromatography on silica (dichloromethane-methanol solvent 90:10). 4 g of product are obtained. M.p. 172-178 ° C (dichloromethane).
Found,%: C 67.55; H 6.98; N 10.38.
With ijfys igrg.
Calculated,%: C 69.74; H 7.02;
N 10.84.
5.4- (2,2,6-Trimethyl-4H-1,3-benzodioxin-8-yl) methyl | -1H-imidazac.
This compound is prepared on the basis of 2., 3 g of a mixture containing the 0-methylated derivative obtained in Example 3.3. 0.9 g of product is isolated. M.p. 152-155 ° C (ethyl acetate).
Found,%: C 69.82; H 7.04; N 10.64.
, eN202.
Calculated,%: C 69.74; H 7.02; N 10.84.
6. 4-Јl- (2,2-Limethyl-4H-1,3-benzodioxin-I-yl) ethyl -1 I-imidazole.
This compound is prepared on the basis of alpha- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) alpha-methyl-1H-imidazole-4-methanol hydrochloride (prepared in Example 3.7). Residue received45
after evaporation of the toluene, it is crystallized by stirring at 60 ° C in isopropyl ether. Yield 60%. M.p. 118-130 ° C
40
35
C, 69.64; H 6.95;
50
Found, N 10.72.
 C (.I
Calculated,%: C 69.74; H 7.02; N 10.84.
7. 4-Ј1- (2,2-Dimethyl-4H-1,3-benzo-55 5.6 g of the product. Yield 73%. M.p. dioxin-8-yl) pentyl | -1H-imidazole.139 -144 ° C (acetonitrile).
The compound is obtained by reduction of alpha-p-butyl-alpha- (2,2-dimethyl2. 3- j (1-Methyl-1H-imidazol-4til -2-hydroxybenzene-methanol.
The compound is obtained on the basis of 4- Ј (2,2-dimethyl-4.H-1,3-benzodiok 8-yl) methyl -1-methyl-1H-imidazole obtained in Example 4.3. Receiving
Found,%: N 12.55.
C, 65.81; H 6.65;

885718
4H-1, 3-benzodioxin-8-yl) -1H-imidazole-4-methanol (prepared in Example 3.6). Yield 23.6%, m.p. 108-112 ° C (cyclohexane).
Found,%: N 9,32.
C, 72.08; And 8.15;
0
0
C flHMN2Ot.
0
five
five
Calculated,%: C 72.0; H 8.0; N 9.33.
Example 5. Preparation of 3-l- (1H-imidazol-4-yl) alkyl -2 (or 6) -oxy-benzenemethanols.
1. 3- Ј (1 H-Imidazol-4-yl) methyl -2-hydroxybenzenemethanol.
82.83 g (0.339 mol) 4-Ј (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) methyl J-IH-imide ash (prepared in Example 4.2) is suspended in 1645 ml of water (pH 7.9) and 349 ml of an aqueous solution of 1N are dissolved by addition within 80 minutes. hydrochloric acid. When this addition is complete, the pH of the solution is 2.5. The reaction medium is then heated for 1 hour in an oil bath to 120 ° C. Cool the solution, process it with 5 g of norite and filter on hyflocele. Then this solution is alkalinized by addition of 242.5 ml of a 1N aqueous solution. sodium hydroxide (pH 8.5). Filter the precipitate, wash it with water and dehydrate. This precipitate is then dissolved in 3.3 liters of ethyl acetate in the presence of norite and a few grams of sodium sulfate. Filter, concentrate to a volume of 400 ml and leave to crystallize. 55.67 g of 3-T1H-imidazol-4-yl) methyl - 0 3-hydroxybenzenemethanol are obtained. The output of 80.4%. M.p. 152-155 ° C.
Found,%: C 65.05; H 5.69; N 13.72.
С °нЛ ° 2Calculated,%: С 64,69; H 5.92; N 13.72.
The following compounds were prepared according to the described method.
five
5.6 g of product. Yield 73%. M.p. 139-144 ° C (acetonitrile).
2. 3- j (1-Methyl-1 H-imidazol-4yl) methyl -2-hydroxybenzene-methanol.
The compound is obtained on the basis of 7 g of 4- Ј (2,2-dimethyl-4.H-1,3-benzodioxin-8-yl) methyl -1-methyl-1H-imidazole (obtained in Example 4.3). Get
Found,%: N 12.55.
C, 65.81; H 6.65;
C, rH, 4MgOg.
Calculated,%: C 66.03; H 6.46; N 12.83.
3.3-Ј (5-Methyl-1H; -imidazol-4-yl) me- TRnJ-2-hydroxybenzenemethanol.
The compound is obtained on the basis of 4 g of 4- (2,2-dimethyl-4H-1,3-benzodioxin-8-yl) methyl-5-methyl-1H-imidazole (obtained in Example 4.4). 2.7 g of product are obtained. Yield 80%. M.p. 126-130 ° C (acetonitrile).
Found,%: C, 66.25; H 6.44; N 12.76.
G tlH14N2 ° 2.
Calculated,%: C 66.03; H 6.46;
N 12.83.
4.3-Ј (1-H-Imidazol-4-yl) metsh1-2-hydroxy-5-methyl-benzenemethanol.
(The compound is obtained on the basis of 3 t of 4-(2,2,6-trimethyl-4H-1,3-benzodioxin-8-yl) methyl -1H-imidazole (obtained in Example 4.5). g product. The yield of 95%. T. PLO 170-175 ° C (decomposition).
Found,%: C 66.02; And 6.56; N 12.73.
C12H14N202.
Calculated,%: C 66.03; H 6.46; N 12, KAN.
5.3-H1- (1H-Imidazol-4-yl) ethyl1-2-hydroxybenzenemethanol.
The compound is obtained by hydrolysis of 4-P- (2,2-dimethyl-4H-1,3-benzodioxin 8-yl) ethyl -1H-imidazole (obtained in Example 4.6). Yield 60%. M.p. 135-136 ° C.
Found,%: C 65.97; H 6.44; N 12.80.
hc2nl ° g-
Calculated,%: C 66.03; H 6.46;
N 12.83.
6. (1H-Imidazol-4; -yl) pentyl | - D-hydroxybenchol-methanol.
The compound is obtained by hydrolysis
4- 1- (2,2-dimethyl-4H-1,3-benzodioxin-3-yl) pentium-1H-imidazole (semi
in example 4.7). Yield 94%. M.p. 93 ° C.
Found,%: C 69.30; H 7.70; N 10.81.
C, NgoMg02.
Calculated,%: C 64.23; H 7.69; N 10.77.
7. 3- (1H-Imidazol-4-yl) methyl | -6- scsibenzenemethanol.
The compound is obtained on the basis of 4 g of 4-(2,2-dimethyl-4H-1,3-benzodioxin6-yl) methyl -1H-imidazole (obtained in Example 4.1). 1.6 g of product are obtained. Yield 48%. M.p. 149-155 ° C (decomp.
Found,%: C 65.11; H 6.11; N 13.45.
Calculated,%: C 64.70; H 5.88;
N 13.72.
The following substances obtained according to the invention were subjected to pharmacological tests: 3-Ј (1H-imidazolyl) methylJ-2-hydroxybenzenemethanol (product A); 3-Ј (1H-imidazol-4-yl) methyl - 2-hydroxy-5-methyl-benzenemethanol (product B); 3-Ј (1P-imidazol-4-yl) mett-6-hydroxybenzenemethanol (product C); 3.-Ј1- (1H-imide, azol-4-yl) penth-2-hydroxy benzene methanol (product D); 3-Ј1- (1H-imidazol-4-yl) ethyl-2-hydroxybenzene-methanol (product E).
Anti-ischemic heart activity.
In the rat that has been anesthetized and thoracotomy, ligation of the coronary arteries causes sustained cardiac ischemia, which is expressed by an increase in the R wave of the epicardial electrocardiogram. The anti-heemic effect of the product is manifested by a decrease in the increase in wave R.
The dose shown below is that when administered intravenously, a group of 5 rats causes an average decrease of at least 20% increase in the R wave in all animals:

AEZO, mg / kg
0,006
0.22
0.20
0.26
0.02
five
-
0
Pr opranolol 9,47
Verapamil 0.32
NiLedipin1,70
The following products are used as reference substances: propranolol: 1- (isopropylamino) -3- (1-naphthyloxy) -2-propanol; verapamil: al-2- (3,4-dimethoxyphenyl) ethyl methylamino-propyl-3,4-dimethoxy-alpha- (1-methylethyl) benzeneacetonitrile; nifedipine: 1,4-dihydro-2,6-dimethyl-4- (2 nitrophenyl) -3,5-pyridinedicarboxylic acid dimethyl ester
A live dog that has a coronary respiratory obturator (oss- jl.uder) has a blockage of the coronary arteries.
21
causes an increase in the ST segment of the electrocardiogram of the epicardium. The anti-ischemic effect of the compound is manifested by a decrease in the increase in the ST segment.
The following is the dose that, when administered intravenously, to a group of
10 animals causes an average decrease of t
at least 20% increase in ST of all animals:
sixteen
ol
DE40 mg / kg
0,007.
0.02
0.02
0.03
0.0007
0.53
Thus, the products obtained according to the invention are very active and are superior to reference substances.
Anti-haemorrhagic cerebral activity.
Transposition of two carotid arteries in anesthetized mice gradually causes the death of at least half of the animals after 90 minutes.
In this experiment, a group of 18 animals is administered intraperitoneally 30 minutes before dressing a dose of 0.2 mg / kg of compound A dissolved in 10 ml of physiological saline solution. The control group, also composed of 18 animals, receives at the same time only a physiological solution of sodium chloride (an aqueous solution of sodium chloride with 0.9%). Then, 30 minutes and 90 minutes after the dressing, the number of surviving animals in the control group and in the treated group is noted. The results are shown in the table.
J 50
This table shows that compound A significantly increases the number of living animals in the group treated with compound A, compared with the number of surviving animals in the control
15

885722
group. The protection is carried out and calculated using the formula D Akbotta, it is 66% after 90 minutes.
Anti-ischemic tissue activity.
The accumulation of Ca ions in ischemic tissues in the pathophysiology of animals is an indication of a diseased state of the cells. Occlusion of the coronary arteries for a long time (150 minutes), carried out on rats that were anesthetized, causes accumulation of calcium ions (+ 250%) in the tissues of the necrosis zone. In this experiment, the test compound is administered in the range of 1 minute 10 minutes before blocking the coronary arteries in a group of at least six rats intravenously at a dose of 100 µg / kg dissolved in 0.8 ml of saline calcium chloride. This assignment immediately follows the slow perfusion of the test compound at a dose of 100 µg / kg per hour for 2.5 hours. After opening the zone of necrosis, accumulation in Ca tissues is measured in it by atomic absorption spectrometry using the known method In a measure of 6 rats, only physiological saline is administered.
The activity of product A is compared with the activity of verapamil administered under the same conditions, however, a dose of 320 µg / kg of verapamil is used instead of 100 µg / kg.
20
25
thirty
35
The following shows a decrease in the average value of the concentration of Ca ions in the tissues of the treated group affected by ischemia compared with the control group:
Products Decrease in Cat 1 concentration in fabrics,%
Verapamil18
A40
The results show that although Compound A is prescribed at a dose of 3 times less than the dose of verapamil, Compound A is more than 2 times more potent with calcium infiltration in the tissues of the necrosis zone.
Toxicity.
The toxicity of the products obtained according to the invention is determined in the mouse
male No. IRI using the IRWIN test.
Increasing doses of the test product are administered intraperitoneally to groups of three mice until a lethal dose is reached (the dose causing the death of two animals out of three within 48 hours).
Below is the lethal dose observed for the products according to the invention, mg / kg:
A204
C613
D260
Thus, these products are very little toxic, the lethal dose is much higher than the active doses.
Pharmaceutical compositions containing the products of the invention may be administered orally, parenterally or rectally.
The pharmaceutical compositions used for oral administration can be solid or liquid, for example tablets (coated or uncoated), pills, dragees, gelatin capsules, solutions, syrups, etc. Compositions for parenteral administration can also be of various pharmaceutical forms, for example, solutions, suspensions, or oily or aqueous emulsions.
For rectal administration, the compositions are usually in the form of suppositories. The compounds are usually mixed with a solid or liquid solvent, non-toxic, pharmaceutically acceptable, and, if necessary, with a dispersant, cleaving agent, stabilizer, etc. Sweeteners, colorants, etc. can be added to the mixture if needed.
The percentage of active substance in the pharmaceutical composition
The chixes can vary over a very wide range depending on the patient and on the method of administration, especially on the frequency of administration. The daily dosage may vary over a wide range of unit doses, e.g. 0.1 µg to 1 mg of active substance, depending on the route of administration. Thus, it may, for example, be 0.1-160 µg, preferably 1-80 µg, when the compound is administered intravenously.

权利要求:
Claims (1)
[1]
15 claims
The method of obtaining (1H-imidazol-4-yl) alkyl-oxybenzenemethanol of the general formula
20
OH YI
in which R (, R2, R3J
koto
each may be the same or different, each represents a hydrogen atom or an alkyl radical containing 1-4 carbon atoms;
one of the Y4 and v radicals is hydrogen, and the other is a hydrophilic radical, characterized in that it is hydrolyzed in an aqueous acidic vs4 4-1, 2, 2-dimethyl-4I-1,3-benzodioxyn-6Oshi 8) -yl alkyl 1-1H-imidazole formula
in which R, pR2, Rj, R4 and R have the indicated meanings, one of the radicals X
Hydrogen is hydrogen and the other is radical
OZ2, with 7. C and Z representing together the group-C (CH) g.

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US29761A|1860-08-28|Improvements in telegraphic apparatus |

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US8119807B2|2007-01-12|2012-02-21|Allergan, Inc.|Quinolynylmethylimidizoles as therapeutic agents|

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868626287A|GB8626287D0|1986-11-04|1986-11-04|Substituted 1h-imidazoles|

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