Method of producing derivatives of 2-alkylbenzimidazole

专利摘要:
The invention relates to heterocyclic compounds, in particular to the preparation of derivatives of 2-alkylbenzimidazole F. I @, where X is N or the group CR 8, where R 8 is H or methyl Y is N or N-oxide group Z - S, sulfinyl or sulfonyl group R 1 is H, halogen, branched or unbranched C 1 -C 4-alkyl or C 1 -C 4-alkoxy, benzoyl, acetyl, nitro or trifluoromethyl group, methoxy or ethoxycarbonyl R 2 - H, CH 3 R 3 - H, C 1 - C 4 -alkyl or group COR 10, where R 10 - C 1 - C 4 -alkyl R 4 - H or C 1 - C 4 -alkyl R 5 - H, methyl or hydroxyl R 6 - H, methyl or nitro R 7 is H or C 1 -C 4 -alkyl with the exception of compound I, where X is CH, Y is N, Z is S and R 1 is R 7 is H, which have inhibitory activity of gastric secretion. The goal is to develop a method for producing more active compounds. The preparation is carried out by the reaction of the 2-halo-chloromethylbenzimidazole derivative with 2-mercaptopyrimidine at the respective values of the indicated radicals. 6 tab.
公开号:SU1586513A3
申请号:SU874028881
申请日:1987-01-19
公开日:1990-08-15
发明作者:Фригола Констанса Хорди；Коломбо Пиноль Аугусто；Парес Короминас Хуан
申请人:Лабораторьос Дель Др.Эстев, С.А. (Фирма)；
IPC主号:

专利说明:

ate
00
This invention relates to a process for the preparation of new 2-alkylbenzimidazole derivatives, biologically active compounds that can be used in medicine.
The purpose of the invention is a method for producing new 2-alkhenbenzimidazole derivatives with a higher inhibitory activity of gastric secretion.
The method is illustrated by the following: examples synthesis of compounds.
Example 1. Preparation of 2- (2-benzimidazolylmethylthio) -pyrimidine 10.0 g (0.06 mol) of 2-chloromethylbenzimidazole is added to a solution of 6.7 g (0.06 mol) of 2-mercaptopyrimidine and 2.4 g (0.06 mol) sodium hydroxide in 200 ml of ethanol and 20 MP of water. Hold for two hours at reflux.

O4
the refrigerator and ethanol evaporated. The residue is treated with water (50 ml) and extracted with ethyl acetate (3 x 50 ml), the organic phase is dried with sodium sulfate, filtered and evaporated to a volume of 40 ml of a solution, from which 10.2 g (70%) of 2- (2-benzimidazolylmethylthio) crystallize out pi; rimidina, m.p. 154-155 With,
The compounds of Examples 2 to 18 and 21 to 26, shown in Table-1, were prepared in the same manner as in Example 1.
PRI me R 6. Preparation of 5,6-dimethyl-2- (2-pyridylthiomethyl) benzimidazol. Fi
A solution of 3.84 g (0.02 mol) of 5,6-dimethyl-2-mercaptomethylbenzimidazole and I, 9 g (0.02 mol) of N-oxide pyridine in j 50 ml of acetic anhydride is heated for 4 hours. Acetic anhydride is evaporated and the residue is treated with acetone, filtered and concentrated to a volume of 20 ml. 26 g (48%) of 5,6-dimethyl-2- (2-pyridylthiomethyl) benzimidazole crystallize out of this solution. The resulting product is identical to the product obtained in Example 1.
I Example 10: Preparation of 5-benzo-1yl-2- (2-pyridylthiomethyl) benzimidazole; 8.45 g of 2- (2-pyridyl-thio) acetic acid (0.05 mol) and 10.6 g of 4-benzoyl-1,2-phenylenediamine (0.05 mol) are refluxed for 2 days. ) 100 MP 4 n. hydrochloric acid. The mixture is allowed to cool and is neutralized with ammonia. Extracted with ethyl acetate (3x100 NP), dried with sodium sulfate, filtered and concentrated down to a volume of 125 ml. 11., 7 g (68%) of 5-benzoyl-2- (2-pyridylthiomethyl) benzimidazole crystallized out of this solution.
Example 22. Preparation of 5-methoxy-2 (4-metsh-2-pyridylthiomethyl) -benzimidazole.
10.6 g of ethyl 2- (4-methyl-2-pyridylthio) acetate (0.05 mol) and 8.8 g of 4-methoxy-1,2 hydrochloride are boiled in a refrigerator for 2 days. -phenylenediamine (0.05 mol) in 400 ml 6 n. hydrochloric acid. The mixture is allowed to cool and is neutralized with ammonia. Extracted with ethyl acetate (3x100 ml), dried with sodium sulfate, filtered and concentrated to a volume of -75 ml. 8.4 g (59%) of 5-methoxy-2- (4-methyl) crystallize out of this solution.
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 2-pyridylthiomethyl) benzimidazole, T.Sh1. 138-140 0.
Example 27. Obtaining 5-benzoyl-2- (2-pyridylsulfinylmethyl) benzimidazole.
To a solution of 17.3 g (0.05 mol) of 5-benzoyl-2- (2-pyridylthiomethyl) benzimidazole in 250 ml of dichloromethane, cooled to, is slowly added 10.1 g (0.05 mol) of 85% (m-chloroperoxybenzoic acid. Stir at a lower temperature for 30 minutes and add 100 ml of sodium carbonate solution. Decant the organic phase, wash with sodium carbonate and water and then dry with sodium sulfate. After filtration, the solvent is evaporated and the residue is recrystallized from acetone. This gives 12 , 0 g (66.5%) of 5-, benzoyl-2- (2-pyridylsulfinylmethyl) benzimidazole, mp 142-145 C.
Examples 28-53. Compounds 28-53 in Table. 2 get in a manner similar to that described in example 27.
Example 54. Preparation of 5-chloro--2- (2-pyridylsulfonylmethyl) benzimidazole.
5.7 g (0.028 mol) of 85% m-chloroperoxybenzoic acid are added to a solution of 2.76 g (0.01 mol) of 5-chloro-2- (2-pyridylthiomethyl) benzimidazole in 75 ml of chloroform. Stir when. at room temperature over 4 hours, t-solution of 2.76 g (0.01 mol) of 5-chloro-2- (2-pyridylthiomethyl) benzimidazole in 75 ml of chloroform is added to the solution. Stir at room temperature for 4 hours and add 50 ml of sodium carbonate solution. The organic phase is decanted, washed with sodium bicarbonate and water and dried with sodium sulfate. After filtering off the drying agent, the solvent is evaporated, the residue is recrystallized from ethyl acetate, and 2.55 g (83%) of 5-chloro-2- (2-pyridylsulfonylmethyl) benzimidazole are obtained, m.p. 1YAZ-186 S.
Examples 55-58. The compounds of Examples 55-58 in Table. 3, obtained by the method described in example 54.
EXAMPLE 59. Preparation of 5-nitro-2- (2-pyridylsulfinshmethyl) benzimidazole.
To a solution of 2.57 g (0.01 mol) of 2- (2-pyridylsulfinylmethyl) benzimidazole in 20 ml of concentrated sulfuric acid, cooled to –5 ° C, add 5i
Chill the mixture, 2 units of 65% nitric acid and 3 ml of concentrated sulfuric acid at a rate such that the temperature does not exceed. Immediately after the end of the addition, sprinkle 1 hour with stirring and pour on ice.
The mixture is neutralized with sodium hydroxide pH 7.1-7.2, filtered, and washed with water. After drying, 2.93 g (97%) of 5-nitro-2- (2-pyridyl sulfinylmethyl) benzimidazole are obtained, m.p. 207-209 ° C.
Example 59. Preparation of 5-carboxymethyl-2- (4-methyl-2-pyridylthiomethyl benzimidazole.
A solution of 5.98 g of 5-carbox-2- (4-methyl-2-pyrdiothiomethyl) g of benzimidazole (0.02 mol) in 100 ml of methanol saturated with hydrochloric acid is boiled under reflux for 6 hours. methanol and treated with 25 ml of ethanol. From this solution, 5.82 g (93%) of 5-carboxymethyl-2- (4-methyl--2-pyridylthiomethyl) benzimidazole hydrochloride crystallized out, mp. 121-124 ° C.
Examples 60 and 61. Preparation of 5-benzoyl-1-methyl-2- (2-pyridylsulfonylmethyl) benzimidazole.
Preparation of 5-benzoyl-1-methyl-2- (2-pyridylsulfinylmethyl) benzimidazole.

A mixture of 3.61 g of 5-benzoyl-2- (2-pyridylsulfinylmethyl) benzyl1 1dazole (0.01 mol), 0.40 g of sodium hydroxide (0.01 mol) and 2 ml of dimethyl sulfate (0.02 mol) in 50 ml of ethanol and 5 ml of water are refluxed for 3 hours. Ethanol is evaporated, diluted with water and extracted with chloroform. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel using chloroform / methanol (99: 1) as an eluting agent and then chloroform / methanol (95: 5). By fractional crystallization from ethyl acetate of the last fraction, 0.47 g (12.5%) of 5-benzoyl-1-methyl-2- (2-pyridylsulfinylmethyl) benzimidazole are obtained, m.p. 174-177 C and 1.5 g (40%) of 6-benzoyl-1-methyl-2- (2-pyridylsulfinylmethyl) benzimidazole, t „pl. 181-183 S.
Similarly, the compounds listed in Table 2 are obtained. four.
136
P p and m: p 1G 62-63. Getting
5-benzoyl-1-carboxyethyl-2- (2-pyridylsulfinylmethylbenzymevdazole.
To a solution of 3.61 g of 5-benzoyl-2- (2-pyridylsulfinylmethyl) benzimidazole (0.01 mol) and 1.41 g of triethylamine (0.014 mol) in 60 ml of methylene chloride was added 1.54 g of ethyl chloroformate (0.014 mole). Stir for 24 hours at room temperature and wash with dilute sodium hydroxide solution, then with water and dry with sodium sulfate. The organic phase is evaporated to dryness and chromatographed on silica gel using ethyl acetate as eluant to give two isomers: 1.2 g (27.7%) of 5-benzoyl -1 -1 carboxyethyl 2- (2-pyridi-sulfinyl-methyl) benzimidazole and 1.6 g (36.9%
6-benzoyl-1-carboxyethyl-2- (2-pyridyl-methylphenylmethyl) benzimidazole.
PRI me R 64. The compound of example 64 table. 4 is obtained by the method described in examples 60 and 61.
Inhibition of gastric acidity. In this test, male Wistar rats weighing 200-250 g are used, which are kept without food, starting with the previous day to day experience with free access to water. Use batches of 4 animals each at a minimum.
The rats are anesthetized with diethyl ether, laparotomy is performed and the pylorus is bandaged, then the abdominal incision is stapled. The introduction of products with a solvent for the control lot is carried out intraduodenally before suturing the abdominal incision. The dose administered in the first test is 40 mg / kg, and in the second test the intraduodenally effective dose is determined. The solvent used is 5% gum arabic in bidistilled water.
After 2 hours, after peeling the pilo, the rats were sacrificed by prolonged anesthesia with diethyl ether, the volume of the gastric juice was measured and the total acidity was determined using a pH meter equipped with an automatic burette. For each compound and for; Each dose tested is determined by the percentage of inhibition of gastric acid secretion relative to the control batch of animals.
In tab. 5 shows the results obtained for several derivatives of the invention.
Acute toxicity is observed in menopay. The compound in the form of a suspension in 5% gum arabic in double-distilled water is administered orally. The volume injected is 10 ml / kg. According to the well-known method, the summer is calculated for 50% of the mice dose (LD p). I The results obtained for some derivatives of the proposed shadow image are presented in Table. 6
L
formula of invention
; The method of obtaining 2-alsylbenzimidazole derivatives of general formula I
p R
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  I
I.
Ra
where X is nitrogen or a CR group, where Rj is hydrogen or methyl;
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Rj is hydrogen, C-C-alkyl or COR JJ group, where R, is C, kil;
K is hydrogen or C, -C4-alkyl; RJ is hydrogen, methyl or hydroxyl; K is hydrogen, methyl or nitro.
Group;
R, is hydrogen or C, -C 4 -alkyl, with the exception of compound I, where X is CH, Y is N, Z is S and K, -R is hydrogen,
characterized in that the cohesion of the general formula II
VCH-Z,
subjected to interaction with the compound of General formula III
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Table 5
Editor M, Nedoluzhenko
Compiled by V. Volkov
Tehred L, Serdyukov Proofreader S. Shevkun
Order 2333
Circulation 322
VNIIPI State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 113 () 35, Moscow, Zh-35, 4/5 Raushsk nab.
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Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
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Subscription

权利要求:
Claims (1)
[1]
SUMMARY OF THE INVENTION Method for the preparation of 2-alkylbenzimidazole derivatives of the general formula I
I 'I.
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Y is nitrogen or an N-oxide group; Z is sulfur, a sulfinyl or sulfonyl group; ^ 0 hydrogen, halogen, branched or unbranched C ₁ alkyl or C ·, -C ₄ ~ alkoxyl, benzoyl, acetyl, nitro or trifluoromethyl group, methoxy-35 or ethoxycarbonyl; hydrogen, CH ₅ ; hydrogen, C, -C ^ -alkyl or the group COR _Jo , where R ₁₀ is C -C ₄ -alkyl; hydrogen or C ^ C ^ alkyl; hydrogen, methyl or hydroxy;
hydrogen, methyl or nitro, a group; hydrogen or C, -C ₄ -alkyl, with the exception of compound I, where X-CH, YN, ZS and R, -R are hydrogen, wherein the com-> where R of general formula II is subjected to general reaction with the compound of formula III yes * ^{6 Z} 2 Y
X and Y have the indicated
I, where Z is sully compound I, Y and Z have the indicated compounds I, where either compound I, Y and Z have the indicated R ₃ is hydrogen, R, where R, -R _T ,
Ζ ₁ iXu, one is a SH group, and the other is fluorine, chlorine or bromine, followed by isolation of the target product or oxidation of compound I, where RyR , X and Y have the indicated values, and Z is sulfur, with a stoichiometric amount of m-chloroperbenzoic acid to obtain compounds I, where Z is a sulfinyl group, or by oxidation in an amount 2-3 times higher than the stoichiometric phonyl group, where Ry, R is R ₇ , X, the values given, and R ₂ and R ₅ are hydrogen, are nitrated with a mixture nitric and sulfuric acids to obtain r _r - a nitro group, wherein r _t, r ₄ -R _7, X, associated value, arboksil, esterified with methanol or ethanol to obtain a compound I, wherein R, - methoxy- or ethoxycarbonyl, or a compound I, wherein _{X, Y, Z, R n} R t, R4-R1 are as defined above, a Rj- hydrogen is alkylated with dimethyl sulfate or an alkyl halide to obtain compound I, where Rj is Cj-Cj-alkyl, or compound I, where X, Y, Z, R ,, R ₄ -R ₇ have the indicated meanings, a R ₃ ~. hydrogen, treated with a compound of the general formula CI-CO-R _l0 to obtain compound I, the group COR _fo , where R, _o has the indicated meanings.
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Continuation of the table.
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1536513
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Table and c a 5 I_____________ _ ^{t a}blitz 6Compound Floor LC Ha. mg / kg Compound- The percentage of inhibitory ED „, mg / kg 5 following the exampleorally Yie by vania secretions - intraduode1 <3 3200 an example acid secretion personally ABOUT1 2700. gastric juice 4Dose 40 mg / g 3 * ABOUT > 3200 intraduodenally 1014yy > 320027 9 3200 g4 3200 129888thirteen1628 <3 o 3200 47421 fifteen14 3200 6921929th <3 2400 79519 1 . 2400 109314 27957 ep 31 about0 > 6400 28908 1 + > 6400 29th3190964fifteen10 3.ABOUT 3200 329217353200> 3200 418010 251 > 3200 44661044 3 > 3200 547024 ABOUT1 > 3200 607521 4 . 6381fifteen57 3 . > 6400 Omeprazole thirtyRI > 6400 (famous 63 from 3200 conn.)953, / 3200

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FR2593178A1|1987-07-24|

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PT84141A|1987-02-01|

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CN87100363A|1987-09-02|

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YU45932B|1992-09-07|

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HUT44781A|1988-04-28|

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KR890002291B1|1989-06-28|

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NO870228L|1987-07-21|

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ZA87343B|1987-08-26|

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BR8700191A|1987-12-08|

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DE234980T1|1988-02-25|

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KR870007157A|1987-08-17|

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HU197566B|1989-04-28|

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AT80625T|1992-10-15|

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PT84141B|1989-05-31|

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AU6762187A|1987-07-23|

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NO170931B|1992-09-21|

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ES2003658A6|1988-11-01|

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EP0234980B1|1992-09-16|

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JPS62181274A|1987-08-08|

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PL263733A1|1988-07-07|

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CA1296336C|1992-02-25|

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GR3006109T3|1993-06-21|

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YU6087A|1988-08-31|

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DK23887D0|1987-01-16|

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NO170931C|1992-12-30|

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GR880300076T1|1988-12-16|

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DD259401A5|1988-08-24|

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DE3781703D1|1992-10-22|

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NO870228D0|1987-01-20|

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AU587680B2|1989-08-24|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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GB1234058A|1968-10-21|1971-06-03|

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SE418966B|1974-02-18|1981-07-06|Haessle Ab|ANALOGY PROCEDURE FOR THE PREPARATION OF COMPOUNDS WITH Gastric Acid Secretion Inhibitory Effects|

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US4045564A|1974-02-18|1977-08-30|Ab Hassle|Benzimidazole derivatives useful as gastric acid secretion inhibitors|

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US4619944A|1981-06-01|1986-10-28|Usv Pharmaceutical Corporation|Antihypertensive compounds|DK8600939A|1985-03-05|1986-09-06|

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SE8804628A|1988-12-22|1988-12-22|

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US6245913B1|1999-06-30|2001-06-12|Wockhardt Europe Limited|Synthetic procedure for 5-methoxy-2-[-methylthio]-IH-benzimidazole hydrochloride and its conversion to omeprazole|

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ES2171116B1|2000-04-14|2003-08-01|Esteve Quimica Sa|PROCEDURE FOR OBTAINING DERIVATIVES OFMETAL) UNCLE) BENCIMIDAZOL.|

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GB0108592D0|2001-04-05|2001-05-23|Merck Sharp & Dohme|Therapeutic agents|

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CA2756104C|2009-04-09|2013-01-22|Arigen Pharmaceuticals, Inc.|Pyridine thio derivative, and pharmaceutical composition which contains same and has anti-helicobacter pylori action|

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US9708272B2|2014-08-29|2017-07-18|Tes Pharma S.R.L.|Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase|

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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FR8600695A|FR2593178B1|1986-01-20|1986-01-20|2-BENZIMIDAZOLYLALKYLTHIODERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS.|

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