Method of producing derivatives of thieno-(2,3-d)-imidazole

专利摘要:
Derivatives of thieno[2,3-d]imidazoles of the formula I of the formula sheet in which R1 denotes hydrogen, lower alkyl, chlorine, bromine, acetyl, cyclopropylcarbonyl, methoxycarbonyl or ethoxycarbonyl, R2 denotes hydrogen or lower alkyl, R3, R5 and R6 independently of one another denote hydrogen or lower alkyl, R4 denotes hydrogen or lower alkoxy and n denotes 0 or 1, and their pharmaceutically tolerable acid addition salts, a process for their preparation and pharmaceutical preparations which contain these compounds are described. The novel compounds cause a blockade of (H<+> + K<+>) ATPase and can be used as active substances for medicaments for the treatment and prophylaxis of diseases which are caused by increased gastric secretion.
公开号:SU1456018A3
申请号:SU864027477
申请日:1986-05-06
公开日:1989-01-30
发明作者:Биндер Дитер；Ровенски Франц
申请人:Хеми Линц,Аг (Фирма)；
IPC主号:

专利说明:

one
This invention relates to the preparation of new heterocyclic compounds, in particular to the preparation of thieno- (2,3-d) -imidazole derivatives of the general formula
K4
Rz

II n - „TOG
K.
"(0)„ Re
where R, is hydrogen or acert;
R
R
R6 and
and
hydrogen;
independently of each other
hydrogen or C-C4 alkyl;
hydrogen or C —C alkoxyl
Oh or 1,
possessing the property of lowering gastric secretion, i.e. antisecretory action.
The aim of the invention is the creation of new compounds, derivatives of thieno (2,3 CX), based on known methods.
 Crj
1456018
-6) -im1adazole with high antisecretory, anti-ulcer activity and low toxicity.
EXAMPLE 1. 2 (2-Pyridyl) -methyl-thio-3H-thieno (2,3-d) imidazole (1, where R, is hydrogen atoms in Rj).
1.20 g (7.68 mmol) 1,3-dihydrothieno (2,3-th) imidazole-2-thione (11, where R and R. are hydrogen atoms) and 1.13 g (6.91 mmol) of 2-chloromethylpyridine hydrochloride is dissolved in 15 ml of methyl alcohol, after which 7.4 ml (14.8 mmol) of 2N solution are added dropwise to the prepared solution with stirring sodium hydroxide. Then the reaction mixture is additionally stirred for 1.5 hours and stirred at room temperature for 4 hours at room temperature. Immediately after this, the reaction mixture was evaporated in vacuo, the residue was dissolved in 50 ml of water, after which the solution was acidified to pH 4.5 by adding dropwise glacial acetic acid. The resulting precipitate is dissolved in 80 ml of chloroform, the mixture is vigorously shaken and filtered through auxiliary filtering material to separate the phases. The phases are separated from each other. The aqueous phase is extracted three times with chloroform, each time using 40 ml of the latter. The combined organic phases are dried over sodium sulfate and evaporated. The crude product (5.8 g, 82.2% of the theoretical temperature and a directly 20 calculated value) is dissolved
in 400 ml of acetonitrile when heated to the boiling point, filtering is carried out in a hot state in the presence of activated carbon, the solution is evaporated to 150 ml and maintained in order to crystallize the resulting product.
Barely this evaporated on a rotary evaporator. The residue is distributed between 60 MP of water and 80 ml of methylene chloride. To separate the phases, it is first filtered through an auxiliary filtering material, and then the aqueous phase is extracted three more times with methylene chloride, each time 70 ml of the latter is used. The combined organic phases are dried over sodium sulfate and evaporated. , Crude product (1.52 g of crystalline brown 25
Yield: 4.34 g brown colored crystalline substance (61.8% of theoretically calculated value).
T.PL. la) .
140-141 C (from acetonitrile- 3. 5-Atstsh1-2- (4T. PL. La).
Prim
140-141 C (from acetonitrile- 3. 5-Acetsh1-2- (4e p
92.4% of the theoretical ... .. ...
The calculated value of) is oversized by 35-methoxy-3,5-dimethyl-2-pyridyl) -metalized from acetonitrile with tiltio-3H-thieno (2,3-a) imidazole by the addition of activated carbon. (j where R is COCH,, R,
Yield; 1.10 g of a colorless crystalline hydrogen; RjH Ry is a methyl radical substance (64.3% of theoreti- j R methoxy residue,). calculated value). 40
atoms
5.64 g (28.4 mmol) of 5-acetyl- -1,3-dihydrothieno (2,3-d) -imidazol-2-thione and 6.00 g (27.0 mmol) of 2-chloromethyl hydrochloride 4-methoxy-3,5-dimethylpyridine is suspended in
R 1} in 250 ml of methyl alcohol, after which 28 ml of 2N sodium hydroxide solution (56.0 mmol) are added to the prepared suspension with stirring over 15 min. 155-156 C (from acetonitrile).
Example 2. 2- (4-Methoxy-2- -pyridyl) -methylthioZ-3H-thieno (2,3-d) imidazole (I, where hydrogen atoms; tatok).
4.65 g (29.76 mmol) 1,3-dihydrothieno (2, 3-d) imidazole-2-thione and 4.91 g
R is methoxyl wasp (25.30 mmol) of 2-chloromemegg hydrochloride and the temperature rises.
tyl-4-methoxypyridine is suspended in 60 ml of methyl alcohol, after which 27.6 ml: (55.2 mmol) of 2N potassium hydroxide solution are slowly added dropwise to the prepared suspension with stirring over 25 minutes. At the same time, the temperature rises to 32 ° C. After the addition is completed, the reaction mass additionally reaches 27 ° C. After a short period of time, the crystalline product begins to precipitate out of the resulting solution. 55 The reaction mixture is additionally stirred for 4 hours at room temperature and immediately thereafter evaporated completely. The residue obtained is dissolved in
but stirred for 4 hours at room temperature. Immediately after this, the reaction mixture was evaporated in vacuo, the residue was dissolved in 50 ml of water, after which the solution was acidified to pH 4.5 by adding dropwise glacial acetic acid. The precipitate formed is dissolved in 80 ml of chloroform, the mixture is vigorously shaken and the phases are separated by filtering to separate the phases. The aqueous phase is extracted three times with chloroform, each time using 40 ml of the latter. The combined organic phases are dried over sodium sulfate and evaporated. Crude yield: 4.34 g brown colored crystalline substance (61.8% of theoretically calculated value).
T.PL. la) .
Prim
140-141 C (from acetonitrile- 3. 5-Acetsh1-2- (4e p
.. .. .. ...
-methoxy-3,5-dimethyl-2-pyridyl) -methylthio -ZH-thieno (2,3-a) imidazole (j where R is COCH, R,
)-a piece of chalk
atoms
up to 27 C. After a short period of time, the crystalline product begins to precipitate out of the resulting solution. 55 The reaction mixture is additionally stirred for 4 hours at room temperature and immediately thereafter evaporated completely. The residue obtained is dissolved in
200 ml of water and then by adding approximately 2 ml of glacial acetic acid, the pI value of the solution is adjusted to 4.5. The suspension that forms with the mixture is extracted four times with chloroform, 250 ml of the latter are used in total, the combined organic phases are dried over sodium sulfate with the addition of activated carbon and then evaporated.
The oily substance obtained in the form of a residue and colored in dark color is crystallized from 80 ml of acetonitrile, cooled, and then the precipitate is filtered off. The product is washed three times, after which the precipitate is filtered off. The product is washed three times with cold acetonitrile and dried under vacuum at 40 ° C.
Yield: 8.92 g of a slightly yellowish crystalline substance (95.0% of the theoretically calculated value).
M.p. 177-180 ° C (from acetonitrile).
Example 4. 5-Acetyl-2 (L-me toxi-2-pyridyl) -methylthio-3H-thieno) (2,3-d) imidazole (1, where R is COCH., Rj, Rj, Ry and Rfe - hydrogen atoms, methoxyl residue,).
1.30 g (6.567 mmol) of 5-acetyl--1,3-dihydrothieno (2,3-ε) -imidazole-2-β-thion and 1.08 g (5.565 mmol) of 2-chloromethyl-4-methoxypyridine hydrochloride suspended in 15 ml of methyl alcohol, then added dropwise to the prepared suspension with stirring for 10 minutes. 6.2 ml of 2K sodium hydroxide solution (12.4 mmol), the temperature rising to 27 ° C. After this reaction mixture is additionally stirred for 1.5 hours at room temperature.
Immediately thereafter, the reaction mixture was completely evaporated, the residue was dissolved in 50 ml of water, after which the solution was acidified to pH 4 by adding approximately 1 ml of glacial acetic acid. Then the solution is extracted three times with chloroform, and each time 40 ml of the latter are used, the combined organic phases are dried over sodium sulfate and evaporated.
The crude product (1.52 g of a brown oily substance) is triturated with acetonitrile and then recrystallized.

20
25
.j.
456P186
from acetonitrile with the addition of activated carbon.
Yield: 0.76 g of a colorless crystalline substance (42.8% of the theoretically calculated value).
M.p. 192-194 e (from acetonitrile).
Example 5. 5-Acetyl-2- (2-pyridyl) -methylthio-ZN-thieno (2,3-d) imidazole (I, where COCH, R - R - hydrogen atoms,).
1.50 g (7.565 mmol) of 5-acetyl-1,3-dihydrothieno (2,3-d) -imidaz ol-2-thione and 1.12 g (6,809 imol) of 2-chloromethylpyridine hydrochloride are suspended in 60 ml of methyl alcohol and then 7.2 ml of 2N of drops are added dropwise to the prepared suspension with stirring over 8 minutes. sodium hydroxide solution (14.4 mmol), the temperature rising to 26 ° C. Thereafter, the reaction mixture is further stirred for 2 hours at room temperature.
The resulting clear solution is completely evaporated, the residue is dissolved in 80 ml of water, and then the resulting solution is EDUCATED to a pH of 4.5 by adding 1.2 ml of glacial acetic acid. The solution is extracted three times, and for this purpose 150 ml of chloroform are used in total, the organic phase is dried over sodium sulfate and evaporated. The residue, crystallized as a residue, is recrystallized from acetonitrile.
Yield: 1.85 g of a colorless crystalline substance (84.5% of the theoretically calculated value).
M.p. 171-173 C (from acetonitrile). Example 6. 2- (2-Pyridyl) -methylsulfinyl-3H-thieno (2,3-d) imidazole (I, where R, is Rg-atoms of hydrogen, 45).
0.45 g (1.82 mmol) of 2- (2-pyridyl} - methylthio-ZN-thieno (2,3-d) imidazole is dissolved in 10 ml of chloroform, and then to the prepared solution 50 at a temperature in the range between -11 and, a solution of 0.37 g (1.82 mmol) of 85% 3-chloroperbenzoic acid in 5 Nm chloroform form is added dropwise with stirring. The reaction mixture is stirred for 30 minutes at a temperature below O C, the solution is diluted with a small amount of methylene chloride and washed twice with a saturated
thirty
7145
a solution of sodium hydrogen carbonate, 5 ml of this solution being used each time.
The aqueous phase is extracted twice with methylene chloride, each time 5 ml of the latter are used, the combined organic solutions are dried over sodium sulfate and evaporated.
The crystalline residue formed after trituration with acetonitrile (0.42 g, 87.7% of the theoretically calculated value) is recrystallized from acetonitrile upon addition of activated carbon.
Yield: 0.33 g of a colorless crystalline substance (68.9% of the theoretically calculated value).
M.p. ISI-ISZ C (decomp.) (From acetonitrile).
Example 7. 2- (4-Mutoxy--2-pyridyl) -methylsulfinyl1-ZN-thieno (2,3-d) imidazole (I, where R, Rj, Ry and Rg are hydrogen atoms, is a methoxy residue , n 1).
4.30 g (15.50 mmol) of 2- (4-methoxy-2-pyridyl) -methylthib-3H-thieno (2,3-e) imidazole is dissolved at room temperature in 90 ml of chloroform, after which the prepared the solution is cooled to -10 ° C. A solution of 3.08 g (15.19 mmol) of 85% 3-chloroperbenzoic acid in 35 ml is added dropwise to the cooled solution with stirring and at a temperature between -8 ° C and 30 minutes. ml of chloroform .. After that, the reaction mixture is additionally stirred for 15 min at C.
The resulting solution is extracted twice with lacquer; with a solution of acid sodium carbonate, a total of 30 ml of this solution is used, the aqueous phase is extracted three times with chloroform, each time 20 ml of the latter is used, after which the combined organic solutions are dried over sodium sulfate and evaporated .
The crude product (5.2 g of a red colored oily substance) is triturated with a small amount of acetonitrile and the brown crystalline product formed is dissolved at 80 ° C in 22 ml of dimethylformamide. The solution is mixed with activated carbon, produced
88
hot filtration, after which the filtrate is introduced into 130 ml of acetonitrile heated to 60 ° C. The mixture is cooled slowly and then crystallized in a refrigerator overnight.
Yield: 4.03 g of a colorless crystalline substance (88.6% of the theoretically calculated value).
M.p. 157-159 C (decomp.) (From acetonitrile).
Example 8. 5-Acetyl-2-C (- methoxy-3,5-dimethyl-2-pyridyl) methyl-sulfinyl-3-ZN-thieno (2,3-d) imidazole (I, where R, is an acetyl residue, RZ and R are hydrogen atoms, R, and Rj. Are methyl radicals, R4 is a methoxy residue,).
4.5 g (12.95 mmol) of 5-acetyl-2- (4-methoxy-3,5-dimethyl-2-pyridyl) -methylthio-CH-thieno (2,3-d) imidazole is almost completely dissolved at room temperature in 120 ml of chloroform, after which the prepared solution is cooled to. At a temperature between -8 ° C and a solution of 2.58 g (12.69 mmol) of 85% 3-chloroperbenzoic acid in 40 ml of chloroform are added dropwise to the cooled solution during 25 minutes. .
The reaction mixture is then further stirred at -100 ° C for 10 minutes, after which the resulting clear solution is extracted three times with a saturated solution of sodium bicarbonate, with a total of 60 ml of this solution being used. The aqueous phase is washed three times with a small amount of chloroform and the combined organic solutions are dried over sodium sulfate and evaporated.
The resulting oily residue (approximately 5 g of a red colored oily substance) is dissolved at 80 ° C in 50 ml of dimethylformamide, after which the solution is filtered using activated carbon. The filtrate is introduced into 300 ml heated to acetonitrile, slowly cooled, after which crystallization occurs overnight in a refrigerator. The resulting product is filtered and washed three times with acetonitrile.
9U
Yield: 3.30 g of a colorless crystalline substance (70.1% of the theoretically calculated value).
M.p. 190-191 with (from a mixture of dimethylformamide and acetonitrile).
Example 9. 5-Acetyl-2- (4- -methoxy-2-pyridyl) -methylsulfinyl - -ZH-thieno (2,3-d) imidazole (I, where R, is an acetyl residue, R, EZ 5 RU atoms hydrogen, 4 toxicyl residue,),
0.53 g (1.608 mmol) of 5-acetyl-2-. ((4-methoxy-2-pyridyl) -methylthio-β-3H-thieno (2,3-d) w-ovdaeol is suspended in 15 ml of chloroform, then at a temperature between -12 ° C and, to the prepared while stirring, a solution of 0.33 g (1.608 mmol) of 85% 3-chloroperbenzoic acid in 6 ml of chloroform is added dropwise over 7 minutes, resulting in a clear solution. Then it is further stirred for 10 minutes at -10 C. Immediately after this, the resulting solution is extracted twice with a saturated solution of sodium bicarbonate, and Each time 6 ml of this solution is used, the aqueous phase is extracted twice with chloroform, 5 ml of the latter each time, and the combined organic solutions are dried over sodium sulfate and evaporated.
Yield: 0.37 g of a non-crystalline solid (67.8% of the theoretically calculated value).
M.p. 159-1b2 ° C (decomp.) (From acetonitrile).
Example 10. 5-Acetyl-2- (4- -methoxy-2-pyridyl) -methylsulfinyl | - -ZH-thieno (2,3-d) imidazole (1, where R, is an acetyl residue, Rj, R and Rg hydrogen atoms, R is methoxy residue,).
0.53 g (1.608 mmol) of 5-acetyl-2. (4-mutoxy-2-pyridsh1) -methylthio} -ZH-thieno (2,3-d) imidazole is dissolved in 15 ml of glacial acetic acid, after which the prepared solution is slowly mixed at a temperature of from 5 to 10 ° C. with 181 ml (1.628 mmol) of hydrogen peroxide, applied as a 30% solution, resulting in a clear solution.
1810
This solution is further stirred for 20 minutes at room temperature. Immediately after this, the solution is diluted by adding 100 ml of water, extraction is carried out three times with chloroform, 20 ml of the latter each time used, and the combined organic solutions are washed until neutral with sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude oily product is recrystallized from acetonitrile upon addition of activated carbon.
Yield: 0.28 g of a colorless crystalline substance (61.5% of the theoretically calculated value).
M.p. 159-1b2 with (dec. Hiz acetonitrile).
EXAMPLE 11. 5-Acetyl-2- (2-pyridyl) -methylsulfonyl-3H-thieno (2,3-d) by them; azol (1, where Rf is acetyl
residue, Rjno R - hydrogen atoms,
t
),
1.0 g (3.46 mmol) of 5-acetyl-2- - (2-pyridyl) -methylthio-ZN-thieno (2,3-d) imidazole is almost completely dissolved at room temperature in 15 ml of chloroform, after the prepared solution is cooled to -12 ° C. At a temperature between -14 ° C and a solution of 0.69 g (3.39 mmol) of 95% 3-chloroperbenzoic acid in 10 ml of chloroform.
Then the reaction mixture is added .; mix well for 10 min.
at -10 ° C, whereby a completely clear solution is formed, which is diluted with a small amount of chloroform, after which it is extracted twice with a complete solution of sodium hydrogen carbonate, using each time 6 ml of this solution. The organic solution is dried over sodium sulfate and evaporated. The resulting residue
crystallized from acetonitrile, and then recrystallized from acetonitrile with the addition of activated charcoal.
Yield: 0.78 g of a colorless crystalline substance (73.9% of the theoretically calculated value).
M.p. 194-197 ° C (from acetonitrile).
11145601
Example 12. 2- (4-Methoxy-3,5-dimethyl-2-pyridyl) methylthio - 3H-thieno (2,3-d) imidazole.
10.0 g (64.0 mmol) 1,3-dihydro-yeno (2,3-6) -imidazole-2-thione and 95 g (44.8 mmol) of chloromethyl-4-methoxy-3,5 hydrochloride The dimesh1-iridine is suspended in 120 ml of methylic alcohol, after which the acidic suspension is slowly added dropwise 2 and. sodium hydroxide solution (0.12 molb),
The mixture is stirred for 4 hours at room temperature. Since it was completely discontinued, another 0.50 g (2.24 mmol) of 2-chloromethyl-4-methoxy-3,5-dimesh.pyridine hydrochloride and 1.5 ml of 2 was added. NaOH solution. Then the reaction mixture Q is evaporated in vacuo. The resulting residue is dissolved in 100 ml of water, and then by adding glacial acetic acid, the pH of the solution is adjusted to 4.5. The formed precipitate is dissolved in 160 ml of chloroform, the mixture is vigorously shaken and drained, the organic phase is separated, the aqueous phase is washed three times with 100 ml of chloroform. The combined organic phases are dried over sodium sulfate with the addition of activated carbon and then evaporated. 14.8 g of a crude brown product are obtained. Crystallized from acetonitrile.
Output: 9.94 g of colorless crystals (69.2% of theoretical.).
T pl. 134 ° C (acetonitrile). Example 13. 2- (4-Methoxy- -3,5-dimethyl-2-pyridyl) etylsulfinyl-ZH-thieno (2,3-d) imidazole.
9.40 g (30.8 mmol) of 2- (4-methoxy-3,5-dimethyl-2-pyridyl) -methyl-tir-th-yeno (2,3-d) -imidazole are dissolved at room temperature 5 ml of 180 ml of chloroform, after which the prepared solution is cooled to -10 ° C. To a cooled solution, a solution of 5.20 g (30.2 mmol 85% 3-) is added dropwise with stirring chloroperbenzoic acid in 80 ml of chloroform.
The reaction mixture is then further stirred for 15 minutes at −10 ° C. Since the conversion was incomplete, a further 0.08 g (0.40 mmol) of 3 x t; ornadbenzoic acid (85%) was added. After 15 minutes, the dvds are shaken with a saturated solution.
ki su su 45 ki ro
in p
five
sodium carbonate, with a total of 60 ml of this solution. The aqueous phase is washed three times with 45 ml of chloroform, the combined organic solutions are dried over sodium sulfate, treated with activated carbon, filtered and evaporated
10.46 g of a light brown crude product is obtained, which is dissolved in 44 ml of DMF with and introduced into 260 ml of acetonitrile heated to 70 s. Hot as it is treated with activated carbon, filtered and crystallized in a refrigerator. Yield: 6.7 g of colorless crystals (69.0% of theoretical).
M.p. 175 ° С with decomposition (СН2.0Н / DMF).
The following research method is used to study the pharmacological properties.
The compound was dissolved in 20% dimethyl sulfoxide, after which 8 waking female rats (strain Charles River CD) in increasing doses of 125, 250 and 500 µmol / kg were administered through the mouth a single metered volume of 20 ml / kg. After 60 min, pylorus ligatures were introduced into the animals. 4 hours after the administration of the vaginal ligature, the acid concentration and total acidity is determined in the gastric volume of the animals. Groups of control animals receive dimethyl sulfoxide in the amount of 20 ml / kg, distilled water in the amount of 20 ml / kg.
In this standard test, compounds of the general formula I, for example, 5-acetyl-2-; (4-methoxy-3,5-dimethyl-2-pyridyl) methylsulfinyl-3H-thieno (2,3-d) imidazole (compound A ) or 2- (; 4-methoxy-2-pyridyl) -methylsulfinyl-ZN-thieno (2,3-d) imidazole (compound B), caused significant and dose-dependent inhibition of gastric secretion (Tables 1 and 2) .
Compounds of formula I are non-toxic. Thus, upon administration of compound A at a dose of 6000 mg / kg, all experimental animals survived. No signs of poisoning were found.

权利要求:
Claims (6)
[1]
1. A process for the preparation of thieno- (2,3-d) -Il derivatives of idazole of general formula I,
13
R
R2
RI
,one
four
I jl
W,
(oV Re
H
where Rf is hydrogen or acetyl; Rj and Rg are hydrogen; 10
R, and R, are independently of each other hydrogen or C, -C4 alkyl;
R is hydrogen or C, -C4-alkoxy;
p - O or 1,
characterized in that, 15 compound of general formula II
R
2
UN
Rav-s
n
where R, and R have the indicated meanings,
subjected to interaction with the compound of General formula III
114
ciCH
Re
S
ten
forces;
, 15
20
cene25
thirty
where R, .R., R5 H R have indicated
meaning, in the presence of two equivalents, the strong leg of the base and the desired product, or, if necessary, the resulting compound of general formula I, where, is oxidized with an equivalent amount of organic peracid or hydrogen peroxide to a compound of general formula I, where.
[2]
2. A method according to claim 1, characterized in that the reaction of the compounds of general formulas II and III is carried out in a low boiling alcohol such as methyl alcohol.
[3]
3. The method according to claims 1 and 2, characterized in that the compound of the general formula II is used in excess.
[4]
4. A method according to claim 1, characterized in that the oxidation is carried out with an equivalent amount of 3-chloroperbenzoic acid.
[5]
5. Method according to Claims 1 and 4, characterized in that the oxidation is carried out in chloroform or at a temperature of (.-6) - (-14) C.
[6]
6. A process according to claim 1, characterized in that the oxidation is carried out with 30% hydrogen peroxide in glacial acetic acid.
Table 1
Gastric secretion in rats with pylorus ligature after administration
compounds A
Water
(control live)
Dimethyl sulfoxide (carrier)
Compound A: 125 µmol / kg
250 µmol / kg 500 µmol / kg
0.12 ± 0.005
0.56 ± 0.09
0.34 ± 0.07
0.37 ± 0.06 0.16 ± 0.03 0.13 ± 0.03
15145601816
table 2
Gastric secretion in rats with pylorus ligature after administration
compounds B
Compound
Quantity, ml

4.9 ± 0.60.13 ± 0.003
5.1 ± O, A0.10 ± 0.006
4,5 ± 0,60,08 t 0,007
5.0 ± 0.60.005 ± 0.004
4.5 ± 0.40.003 + 0.004
I I
Total acidity, mEq
0.62 1 0.50 ± 0.05
0.37 + 0.07 0.27 t 0.05 0.14 +. 0.02

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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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SE416649B|1974-05-16|1981-01-26|Haessle Ab|PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion|

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SE7804231L|1978-04-14|1979-10-15|Haessle Ab|Gastric acid secretion|

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ES2032394T3|1986-02-20|1993-02-16|Hoechst Aktiengesellschaft|PROCEDURE FOR PREPARING SUBSTITUTED TENOIMIDAZOLE DERIVATIVES.|

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WO1987005296A1|1986-03-07|1987-09-11|Pfizer Inc.|2-[methylsulfinyl]thienoimidazoles and related compounds as antiulcer agents|

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DE3639926A1|1986-11-22|1988-06-01|Hoechst Ag|SUBSTITUTED THIENOIMIDAZOLTOLUIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE AS AN INGESTIC ACID INHIBITOR|AU580042B2|1984-03-22|1988-12-22|Bresatec Limited|Non-radioactive biological probes|

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ES2032394T3|1986-02-20|1993-02-16|Hoechst Aktiengesellschaft|PROCEDURE FOR PREPARING SUBSTITUTED TENOIMIDAZOLE DERIVATIVES.|

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WO1987005296A1|1986-03-07|1987-09-11|Pfizer Inc.|2-[methylsulfinyl]thienoimidazoles and related compounds as antiulcer agents|

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AU622866B2|1987-07-21|1992-04-30|Hoechst Aktiengesellschaft|Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical formulations containing them and their use as gastric acid secretion inhibitors|

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CA1256109A|1986-09-10|1989-06-20|Franz Rovenszky|Process for the preparation of derivatives of 4,5-dihydrooxazoles|

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DE3639926A1|1986-11-22|1988-06-01|Hoechst Ag|SUBSTITUTED THIENOIMIDAZOLTOLUIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING IT AND THEIR USE AS AN INGESTIC ACID INHIBITOR|

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DE3723327A1|1987-07-15|1989-02-02|Hoechst Ag|SUBSTITUTED THIENOIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR USE AS ANTI-ACIDIC SECRETION AGENT, ANTI-STAGE AGENT AND AS A MEDICINE AGAINST INTESTINALS|

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IT1222412B|1987-07-31|1990-09-05|Chiesi Farma Spa|THYOMETHYL AND SULFINYL METHYL DERIVED WITH ANTI-SECRET ACID GASTRIC ACTION, THEIR PREPARATION PROCEDURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

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FI89602C|1987-08-15|1993-10-25|Hoechst Ag|Process for the preparation of therapeutically useful substituted thienoimidazole derivatives|

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DE3851133D1|1987-11-13|1994-09-22|Hoechst Ag|Substituted thienoimidazole derivatives, processes for their preparation, pharmaceutical preparations containing them and their use as gastric acid secretion inhibitors.|

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SE508669C2|1996-04-26|1998-10-26|Astra Ab|New procedure|

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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AT136085|1985-05-07|

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