Method of producing bicyclic compounds or additive salts of hydrochloric acid thereof

专利摘要:
The invention relates to substituted heterocyclic substances, in particular compounds of the general formula: where m O or 1; n 1, 2 or 3; - each is independently alkyl; alkoxyl (non- or substituted with C-alkoxy); WITH . - Alkylsulfonyl, chlorine, C niloxide; -C, .4 is an alkylthio group; C, -alkyl-amino or phenyl; R, with n 1 and m O and R, should not be 4-methoxy, 3- or 4-chloro, or hydrochloric acid addition salts, which have positive isotropic activity. The goal is to create new-active substances of the specified class. Their synthesis will be carried out from disubstituted NHR pyridine, where R AND or CH ,,, provided that both are not simultaneously CH, and the substituted (R) -benzoic acid methyl ester - or its derivative - anhydride; morfolid or thiomorpholide. The target substance is isolated in free form or in the form of an hydrochloric acid salt. New substances can increase the main cardiac contraction by 75% at a concentration of IO- -IO- M or. 3 tab. c (p CO s oo 00 1C
公开号:SU1384200A3
申请号:SU823513949
申请日:1982-11-09
公开日:1988-03-23
发明作者:Ричард Кинг Уилльям
申请人:Дзе Веллкам Фаундейшн Лимитед (Фирма)；
IPC主号:

专利说明:

 cm
m n
Ri. The invention relates to the chemistry of heterocyclic compounds, in particular, to a process for the preparation of new bicyclic compounds of the general formula
J
(g}
where m O or 1; 10
1, 2 or 3;
each independently C, -C4-, alkyl, coxy (unsubstituted or substituted), C -C-alkylsulfonyl, chlorine, C-2C-alkenyloxy, C, -C4-alkylthio, -alkylamino or phenyl, hydrogen or methyl in position 1 or 3 of the imidazole ring, provided that n is 1 and m O, then R is not 4-methoxy, 3- or 4-chloro, or their hydrochloric acid addition salts having a positive inotropic activity, and which can be used to treat and prevent heart disease and heart muscle failure.
Example 1. 2- (2,4-Dimethoxy-30phenyl) -1H-imidazo 4,5-c pyridine.
A mixture of 2.5 g of 2,4-dimethoxybenzoic acid and 1.5 g of 3,4-diaminopyridine is ground into a fine powder and added in portions to 50 ml of phosphorus oxychloride 35 with stirring. The reaction mixture is stirred and heated at the boil under reflux for 2.5 h, after which, of the 20
25
Example 2. 2- (4-Methoxyphenyl-1H-imidazo 4,5-c pyridine dichlorohydra
A mixture of 1.5 g of 3,4-diaminopyridine and 2.1 g of 4-methoxybenzoic acid is pulverized and added in portions to 50 ml of phosphorus oxychloride with stirring.
The reaction mixture is heated under reflux for 2.5 hours, after which the excess oxychloride is removed in vacuo. OctaTOK is cooled, 20 MP of water is added to it and the pH is adjusted to 7.1 n. sodium hydroxide solution, resulting in a light yellow solid. the residue which is collected is washed with water and dried. After recrystallization from an aqueous solution of ethanol, a light yellow crystalline product is obtained in an amount of 1.06 g.
This product is extracted with hot acetone (30 ml) and insoluble products are removed by filtration; the filtrate is treated with ethereal HC1, precipitating the salt (dichlorohydrate), which is collected, washed with dry ether and dried, so pl. 263-266
Examples 3-15. Similarly to the method described in Example 1, the following compounds were prepared.
3) 2- (3,4,5-Trimethoxyphenyl) -1H-imidazo 4, pyridine dichlorohydrate, m.p. 250-254 ° C, yield 30%.
4) 2- (2-Methoxy-4-methylthiophenyl) - 1H-imidazo G4,5-c Zpiridine dichlorohydrate, mp. 205-206 ° C, yield 50%.
5) 2- (2,3,4-Trimethoxyphenyl) -1 The loss of phosphorus oxychloride is removed to 40-imidazo C4,5-c pyridine dichlorohydrate,
m.p. 250-252 C (with decomposition).
vacuum. The residue is cooled, 20 ml of water are added to it and the pH is adjusted to a value of 7 by means of ammonium hydroxide, to give a light yellow solid residue, which is collected, washed with water and dried. The specified solid product is recrystallized twice from an aqueous solution of ethanol to obtain a cream-colored crystalline substance, which has a Q. melting point of 195-198 ° C. Yield 12%.
Calculated,%: C 65.88; H 5.09; N 16.47.
Found,% 5 C 65.70; H 5.15; 55 N 16.05.
The structure of the product is confirmed by NMR and molecular FDI data.
0
five
0
five
0
five
Example 2. 2- (4-Methoxyphenyl) - -1H-imidazo 4,5-c pyridine dichlorohydrate,
A mixture of 1.5 g of 3,4-diaminopyridine and 2.1 g of 4-methoxybenzoic acid is pulverized and added in portions to 50 ml of phosphorus oxychloride with stirring.
The reaction mixture is heated under reflux for 2.5 hours, after which the excess oxychloride is removed in vacuo. OctaTOK is cooled, 20 MP of water is added to it and the pH is adjusted to 7.1 n. sodium hydroxide solution, resulting in a light yellow solid. the residue which is collected is washed with water and dried. After recrystallization from an aqueous solution of ethanol, a light yellow crystalline product is obtained in an amount of 1.06 g.
This product is extracted with hot acetone (30 ml) and insoluble products are removed by filtration; The filtrate is treated with ethereal HCl solution, while precipitating the salt (dichlorohydrate), which is collected, washed. dry ether and dry, so pl. 263-266 С
Examples 3-15. Similarly to the method described in Example 1, the following compounds were prepared.
3) 2- (3,4,5-Trimethoxyphenyl) -1H-imidazo 4, pyridine dichlorohydrate, m.p. 250-254 ° C, yield 30%.
4) 2- (2-Methoxy-4-methylthiophenyl) - 1H-imidazo G4,5-c Zpiridine dichlorohydrate, mp. 205-206 ° C, yield 50%.
5) 2- (2,3,4-Trimethoxyphenyl) -1H-imidazo4, 5-c pyridine dichlorohydrate,
m.p. 250-252 C (with decomposition).
6) 2- (2-Metsh1amnnophenyl) -1H-imide, 5-c pyridine hydrochloride, m.p.
218-221 s, yield 8%.
7) 2- (2-Methoxyphenyl) -1H-imvda zo-4, .5-c pyridine hydrochloride, m.p. 190-194 ° C, yield 37%.
8) 2- (3,4-Dimethoxyphenyl) -1H-imidazo 4,5-sZpyridine hydrochloride, m.p. 262 ° C (with decomposition), yield 15%.
9) 2- (3,4-Diethoxyphenyl) -1H-imide, 5-with pyridine hydrate, so pl. 259-.
10) 2- (2-Methoxy-4-chlorophenyl) -1H- -imidazo 4,5-c pyridine sesquihydrate-hydrochloride, mp, 185-191 ° C.
11) 2- (2-Propyloxy-4-methoxyphenyl) - H-imidazo t4,5-c pyridine hydrochloride, so pl. 228-231 ° C, yield 58212) 2- (2,4-Dimethylphenyl) -1H-imide-, 5-C1pyridine, so pl. 108-112 ° C,
and its dihydrochloride, so pl. 182-185 ° e.
13) (2-Methoxy-ethoxy) -4-labels syphenyl -1H-imide, 5-c pyridine, m.p. 130-132 ° C, and its hydrochloride, so pl. 211-214 ° C.
In a similar way, the following compounds and their salts are also prepared.
14) 2- (2,4-Dimethoxyphenyl) -4-methyl -1H-imidazo 4,5-c pyridine, yield 31%.
15) 2- (2,4-Dimethoxyphenyl) -7-methyl-1H-imide 3 about 4.5 - with pyridine, 1 emihydrate hydrochloride, yield 26%.
Example 16. 2- (2,5-Dimethoxy-fevil) -1H-imidazo 4,5-c pyridine dichloro hydrate.
2,5-Dimethoxy benzaldehyde, morpholine and sulfur are heated for 3 hours at 120 ° C. The solid mixture is then melted to form a liquid. The reaction mixture is cooled and dissolved in hot methanol. The methanol solution is cooled, the solid residue (t humorphide) is filtered off and dried. This thiomorpholide is heated under reflux for about 2 hours in acetone with methyl iodide (1,2-equivalent). The acetone is then removed in vacuo to give a viscous brown oil (thiomorpholididimethioid), which is mixed with 3,4-diaminopyridine in ethylene glycol. and the resulting mixture is heated for 2 hours. The reaction mixture is then diluted with water and the precipitated solid is filtered off, suspended in water and the suspension is made basic with 0.88 ammonia. The solid product is filtered, dried and converted to the title salt in the title (dihydride), having a melting point of 188-190 ° C (with decomposition). Yield 55%.
Example 17. 2- (2,4-Dimethoxy-3-methylthiophenyl) -1H-imidazo 4, hydrochloride-containing hemihydrate.
The title compound is obtained according to a method similar to that described in Example 16. The product has a melting point of 205-207 ° C. Yield 7%.
Examples 18-2. The following compounds are as follows:
18) 2- (4-diphenyl-4-yl) -1H-imidazo-C4,5-c3pyridine 1.5 HC1, m.p. 352 yield 36%;
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five
five
0
five
19) 2- (2,4-dichlorophenyl) -1H-imidazo 4,5-c pyridine hydrochloride, m.p. 230-232 ° C, yield 85%;
20) 2- (2- -methylthiophenyl) -1H-imide & t4,5-c} pyridine hydrochloride hemihydrate, m.p. 158-160 ° C, yield 81%;
21) 2- (3-methylthiophenyl) -1H-imidazo 4,5-c pyridine dihydrochloride, m.p. 123.5-125 ° C, yield 30%;
22) 2- (4-methylthiophenyl) -1H-imidazo 4,5-c pyridine dihydrochloride, m.p. 301-303 C, yield 51%; receive in accordance with the following general method.
The corresponding diaminopyridine; it is dispersed with the appropriate substituted benzoic acid and the mixture is added in portions to polyphosphoric acid. The resulting reaction mixture is heated at 180 ° C for approximately 3 hours. The cooled reaction mixture is poured onto ice and the solid which has been precipitated is filtered off, suspended in water and neutralized with aqueous ammonia (d 0.88 g / cm). The solid compound thus obtained is filtered, dried and converted into the hydrochloride salt.
Example 23. Dihydrochloride: 2- (3-methylthio-4-methoxy-phenyl) -1 H-imidazo 4,5-c pyridine.
H-methylthio-4-methoxybenzoic acid (obtained by diazotization of 3-α-amino-4-methoxybenzoic acid and further treatment with methyl mercaptan) is suspended in dry toluene and thionyl chloride (1S, 1-molar excess :) is slowly added to this suspension. The mixture was heated under reflux for 3.5 hours. Thin layer chromatography indicated that the reaction was complete. The solvent is evaporated off under vacuum and a dark brown residue is obtained.
The resulting acid chloride is suspended in the minimum amount of dry ether and added in portions to a suspension of 3,4-diaminopyridine (taken in equimolar ratio) in pyridine and triethylamine. The resulting mixture was heated under reflux for 5 hours. Thin layer chromatography indicated that the reaction was complete.
The cooled reaction mixture is filtered through hyflo and the filtrate is evaporated under vacuum. The residue is triturated with ether and dissolved in methanol.
The separated solid is filtered off and the methanol filtrate is evaporated under reduced pressure to give a viscous oil. NMR analysis indicates that it is mainly an intermediate amide. This oil is dissolved in ethylene glycol and the resulting solution is heated at 200 ° C for 4 hours. According to thin layer chromatography, the reaction is complete. The cooled reaction mixture was poured into water. The solid white compound that has precipitated is filtered off and
cue on the column (silica gel; chloroform / methanol 19: 1) to obtain the indicated compound in the form of a free base (t, mp 123-125 ° C). The free base is dissolved in acetone and treated with ethereal hydrochloric acid to precipitate the hydrochloride salt, m.p. 175- (with decomposition). Yield 85%.
Example 25. 3-Methyl-2- (2,4-dimethoxyphenyl) t1H-imidazo 4, Ridin and its hydrochloride salt.
A mixture of 2,4-dimethoxybenzoic acid
dried The solid compound is triturated in | 5 lots and 3-methylamino-4-aminopyridine ethyl acetate / ether mixture to give a solid (obtained from 3-bromo-4-nitropyride compound, which is converted into
din-N-oxide and methylamine, followed by reduction) in phosphorus oxychloride is boiled with reverse refrigeration. Example 24. Hydrochloride 2 (2-20 hours, 4 hours). After cooling
the specified dihydrochloride, so pl. 275-277 ° C. Yield 28%.
-allyloxy-4-methoxyphenyl) -1H-imide-ZO-G4,5-c pyridine.
A. 2-Allyloxy-4-methoxybenzoyl-morpholide.
In a stirred solution of 2-allyloc-25, dried over magnesium sulfate
morpholine (12 ml) is added to sy-4-methoxybenzochloride (14 g) in dry toluene and stirring is continued for 1 hour.
Toluene is removed at reduced pressure-39 so pl. .162-163C. Base solution
In addition, 2N is added to the residue. hydrochloric acid (20 ml) and the mixture is extracted with ethyl acetate. The combined extracts are thoroughly washed with sodium bicarbonate solution, water, and then dried over magnesium sulfate. red by filtration and evaporation to give a yellow oil. (The purity is confirmed by thin layer chromatography, and the structure by NM). .Q
B. Sesquigate 2- (2-allyloxy-4-methoxyphenyl) -1H-imidazo-C4, pyridine sesquihydrate.
To a mixture of 2-allyloxy-4-methoxybenzoylmorpholide (9 g) -i and 3,4-diaminopiridine (3.9 g) dropwise, with stirring, phosphorus oxychloride (16.5 ml) is added.
The mixture is boiled under reflux with acetone and treated with ethereal HC1 and the indicated base is obtained, m.p. 162-163 ° C. A solution of the base in acetone is treated with an ethereal HCl solution and the indicated hydrochloride is obtained, m.p. 235-237 ° C, yield 30%.
Example 26. 1-Metsch1-2- (2,4-dimethoxyphenyl) -1H-imidazo C4, Ridin and its chlorides, salt.
This base is obtained from 4-methylamino-3-yminopyridine (obtained from 4-chloro-3-nitropyridine and methylamine, followed by reduction) and 2,4-dimethoxybenzoic acid in phosphorus oxychloride, m.p. 180-181 ° C. A solution of the base in acetone is treated with ethereal HC1 to obtain the specified hydrochloride, m.p. 225-227 ° С ..
nobody for 3 hours, after which the excess phosphorus oxychloride is removed under reduced pressure. Water (50 ml) is added to the residue and the solution is basified with ammonia with alcohol before extraction with chloroform. The combined extracts are dried over magnesium sulfate before filtration and evaporated to give a slightly colored solid compound, which is purified by chromatography
the solid compound is triturated with ether and subjected to separation extraction with D system chloroform / saturated sodium bicarbonate solution. The solvent is evaporated and the residue is chromatographed on silica gel. Recrystallization from a mixture of benzene / gasoline receive the specified base,
 , Q

in acetone, treated with ethereal solution of HC1 and get the specified base so pl. 162-163 ° C. A solution of the base in acetone is treated with an ethereal HCl solution and the indicated hydrochloride is obtained, m.p. 235-237 ° C, yield 30%.
Example 26. 1-Metsch1-2- (2,4-dimethoxyphenyl) -1H-imidazo C4, Ridin and its chlorides, salt.
This base is prepared from 4-methylamino-3-yminopyridine (obtained from 4-chloro-3-nitropyridine and methylamine, followed by reduction) and 2,4-dimethoxybenzoic acid in phosphorus oxychloride, m.p. 180-181 ° C. A solution of the base in acetone is treated with ethereal HC1 to obtain the specified hydrochloride, m.p. 225-227 ° С ..
EXAMPLE 27 2.5 Hydrochloride 2-114-methoxy-2- (3-dimethyl Minopropoxy) phenyl -1 H-imidazo 4,5-c pyridine.
A. 2-4-Methoxy-2- (3-chloropropoxy) -phenyl -1H-imidazo 4,5-cJpyridine.
A mixture of 3,4-diaminopyridine and 2- (3-chloropropoxy) -4-methoxybenzoic acid in phosphorus oxychloride is stirred and heated to reflux 50
55
NIKOM for 4 hours. After that, the excess phosphorus oxychloride is removed under vacuum and the residue is thoroughly treated with water, alkalinized with a dilute solution of ammonium hydroxide and extracted with chloroform. Then, the crude product is dissolved in ethyl acetate, decolorized with activated carbon, triturated with ethereal HCl solution and the indicated compound is obtained, m.p., 174-176 ° C (34%).
B. Hydrochloride 2- 4-methoxy-2- (3- -dimethylaminopropoxy) -phenyl 1H-imi-, 5-c pyridine.
The solution of the compound obtained in step A is stirred at 100 ° C for 8 hours in a mixture of 33% dimethylamine / ethanol. The volatile components are then removed in vacuo and the residue is subjected to separation extraction in the system of chloroform / saturated sodium bicarbonate solution. After drying over magnesium sulfate, the solvent is evaporated, the residue is recrystallized from benzene / gasoline and the indicated base is obtained. The ethanol solution of the base is treated with an ethereal solution of HC1 and this hydrochloride is obtained in the form of a hydrate, m.p. 206-208 ° C. Yield 33%.
Example 28. 2- (2,4,5-trimethoxyphenyl) -1H-imide-, 5-c pyridine hemihydrate dihydrochloride.
This compound is obtained according to the method similar to example 1, so pl. 258-260 ° C. Yield 74%.
The following examples illustrate the pharmaceutical formulations of the invention, in which the active compound can be any compound of the formula.
Example 29. Formulation tablets mg:
Active connection
(in base form) 100
Lactose100
. Sodium salt
glycol starch 20
Polyvinylpyrrolidone4
Magnesium stearate 2
226
The active compound is mixed with i-lactose and sodium starch glycolate 55. The mixture is granulated with a solution of polyvinylpyrrolidone in 50% aqueous alcohol. Dried granulate and mix
with magnesium stearate. Tablets having an average weight of 226 mg are compressed.
Example 30. The recipe capsules.
mg:
Active connection
(base form)
Lactose
Starch
Methyl cellulose
Stearic acid
five
0 5 Q

0
45
50
five
The active compound is mixed with lactose and starch. Granularized with a solution of methylcellulose in water. Dry and mix with stearic acid. 238 mg is placed in a dense gelatin capsule.
Example 31. Injection of IV (lyophilized). Active compound (hydrochloride), mg 50 Mannitol, mg. 50 Water for injection, ml2 The active compound is dissolved in water for injection. The solution is sterilized by passing through a membrane filter having a pore size of 0.2 µm, collecting the filtrate into a sterile glass receptacle. Transfer to sterile 2 ml glass ampoules under aseptic conditions and protect with aluminum seals. Prior to administration, the composition of the injection is restored by adding a convenient volume of water for injection or sterile saline if more volume is required for administration.
Example 32. IV injection (ampoule for multiple dose). Active compound (hydrochloride), mg 250 Benzyl alcohol, ml 0.075 Water for injection, mp 5 Benzyl alcohol is dissolved in water for injection. The active compound is added and dissolved. Make up to volume with water for injection. Pass through a membrane filter with a pore diameter of 0.2 μm, collect the filtrate c. sterile glass receiver. Fill sterile glass ampoules. Capsules are closed with sterile rubber caps and sealed with Ashomin seals. Example 33. Suppository
, 91384200
Compound (base form) 100 mg, Massa Esterinum suppository base C up to 2 g.
The suppository base is melted at 40 ° C. The active compound is introduced into the ground base in the form of a finely divided powder and mixed until homogeneous. Pour the mixture into suitable molds, 2 g per mold, and leave to stand.
Biological activity.
Determination of inotropic activity in vitro.
ten
The baseline and contractile force (usually after 15 min) are used to add test compounds in a concentrated form, with the concentration being twisted stepwise, each time 5 times from –10 M (final concentration in the tank) or to the limit dissolve 10, which is always higher.
The compounds presented are tested and it is established that, in the indicated concentrated interval, these Male Guinea Pigs (Halls, 275-15 compounds have a positive 350 g), who had free access to inotropic activity and are capable of food and water being hit on the head. The heart is quickly removed and washed with a Krebs-Geneselate solution containing a / 3-adrenoceptor antagonist20 as follows (see Table 1). Carazolol () and at 34 ° C are flushed with a gas mixture of 95% 5% CO. The heart is placed in a Petri dish containing the same buffer maintained
25 Concentrate interval to at least 75% increase in the main reducing force (FC). Compounds may be divided into groups.
Table 1
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ten- -
3, 25, 26 1, 7, 20, 8.10
23
35
at a constant temperature (34 C) and 25 Concentrated interval. Example passed through a dissection. A fresh buffer is used for each dissection and the buffer is discarded after use. From each heart, one papillary muscle of the first ventricle npa-jg is used; the end of the tendon is tied to a stainless steel hook, and the lower end is tied up, removed from the ventricular wall and attached to a perspex clamp, and thus the fabric is in contact with the platinum needle electrode. Hook stainless steel under-, and vasodilator activity. The connections are hung to the Grass FT 03 sensor, which, according to examples 1 and 2, test isometric tension. The drug is placed in an organ receptacle (made from Pyrex) that contains a buffer that is purged with a gas mixture of 95% O h. 5% CO and maintained at 34 C. A tensile load of 500 mg is imposed on the preparation. The stimulation is carried out with rectangular pulses with a duration of 1 ms and a frequency of 1.5 Hz, at a voltage 30% higher than the threshold voltage (1-5 V), using an SRI stimulator. The sensor inputs are connected to a potentiometer recorder using a 6-ka-. nilny transition sensor Grass. After 90 min, the drug is not capable of producing (INO) and, in order to reduce diastolic, uniform reductions, therefore, blood pressure by 30% (ED jpu is limited to this time period) for anesthetized hounds. After reaching as a stabilizer, are listed in Table. 2
45
Determination of in vivo inotropic
in comparison with amrinone and vardax. In anesthetized beagle dogs with an opened chest, intravenous administration of the test compound (see Table 2) results in a dose-dependent positive ortropic stimulation (measured by the increase in the rate of pressure change in the left ventricle of the heart dp / dt in the dose interval of 0.003-3, 0 mg / kg). This is accompanied by a dose-dependent increase in blood flow in the aorta and a drop in total blood pressure.
Doses of compounds effective to achieve a 50% increase (ED
84200
ten
The baseline and contractile force (usually after 15 min) are used to add test compounds in a concentrated form, with the concentration being twisted stepwise, each time 5 times from –10 M (final concentration in the tank) or to the limit dissolve 10, which is always higher.
The compounds presented are tested and it is established that, in the indicated concentrated range, these compounds have positive inotropic activity and are capable of as follows (see Table 1).
at least 75% increase in base force reduction (FC). Compounds may be divided into groups.
the presented ones connect that in the indicated interval this is a positive awn and is capable (see Table 1).
Table 1
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tore to a zodil

ten- -
3, 25, 26 1, 7, 20, 8.10
23
the interval is concentrated - Example of vasodilator activity. The compounds of both Examples 1 and 2 undergo a BUT) and in order to reduce the diastolic blood pressure by 30% (EDP jp) for anesthetized hounds, they are given in Table. 2
Condensed area - Example of azodilator activity. The compounds of examples 1 and 2 are tested) and to reduce the diastolic blood pressure by 30% (ED jp O) in anesthetized hounds, are given in Table. 2
Determination of in vivo inotropic
Concentration interval Example and vasodilator activity. The compounds of examples 1 and 2 undergo INO testing) and to reduce the diastolic blood pressure by 30% (ED jp VAZO) for anesthetized beagle dogs, are given in Table. 2
in comparison with amrinone and vardax. In anesthetized beagle dogs with an opened chest, intravenous administration of the test compound (see Table 2) results in a dose-dependent positive ortropic stimulation (measured by the increase in the rate of pressure change in the left ventricle of the heart dp / dt in the dose interval of 0.003-3, 0 mg / kg). This is accompanied by a dose-dependent increase in blood flow in the aorta and a drop in total blood pressure.
Doses of compounds effective to achieve a 50% increase (ED
table 2
In vitro determination of inotropic activity.
Male guinea pigs (Halls, weight 275-350 g), which had free access to food and water, were clogged with a heart blow, the heart was quickly removed and washed with Krebs-Geneseslate solution containing the p-adrenoceptor antagonist carazolol (5 10 ® M) and a saturated mixture of 95% CO at. The heart is transferred to a Petri dish containing the same buffer maintained at a constant temperature (34 ° C) throughout the experiment. Fresh buffer is used for each experiment and the wash buffer is discarded after use. In each heart, a single papillary muscle of the right ventricle is used; ka; the tendon end is attached to a stainless steel hook, and the lower end is tied, cut off from the ventricular wall and attached to the translucent clip, with the result that the tissue comes in contact with a platinum needle electrode. A steel hook serves the load from the Grass F.T.0.3 sensor, which records the isothermal tension. The preparation is placed in an organ bath, made from Pyrex and having a volume of 20 ml, containing buffer, saturated with a mixture of 95% SAL and maintained
at 34 s. The drug serves load 500 mg. The stimulation is carried out with pulsed pulses with a duration of 1 ms and a frequency of 1.5 Hz at a voltage of 30% above the threshold (1–5 V) using an SRI stimulus 20
In this way, a log-molar concentration (pAj-) is obtained, at which a 50% increase in the basal contractile force is achieved (see Table 3).
Table 3
50
Compounds of the general formula and their salts may be administered orally .. both rectally and parenterally. In general, these compounds can be administered at a dose in the range of 1-1200 mg per day, although the exact dosage depends on a number of clinical factors, for example, the type of patient (i.e. cher. Sensor inputs are connected to a potential or animal) , age, with a recording recorder using a 6-channel Grass-connector of the sensor. After 90 minutes
Parameters that are not capable of uniform cuts longer than this period are discarded. After obtaining a stable baseline and stable contractile force (typically 15 minutes), test compounds are added in concentrated portions at 0.5 log intervals in the range from to (resulting concentration in solution) or to the concentration corresponding to the limiting solubility, which always above.
In this way, a log-molar concentration (pAj-) is obtained, at which a 50% increase in the basal contractile force is achieved (see Table 3).
Table 3
Compounds of the general formula and their salts may be administered orally .. both rectally and parenterally. In general, these compounds can be administered at a dose in the range of 1-1200 mg per day, although the exact dosage depends on a number of clinical factors, for example, on the type of patient (i.e. the body of the treatment object, the treatment conditions and its intensity, as well as from the specific used compound-13 .1
nothing When the compounds are administered orally, dosages in the range of 10-400 mg can be used, for example, about 200 mg per day, whereas when administered parenterally, especially when administered intravenously, dosage regimens in the range of 20-300 mg are preferred. more precisely - in the range of 35-70 mg, for example, about 50 mg per day. The compounds may be administered as an intravenous infusion; in this case, dosages in the range of 1-4 mg / min are used.
Compounds of the general formula and physiologically compatible acid addition salts are preferably administered in the form of pharmaceutical formulations (compositions).
The compositions include at least one compound of the general formula or a physiologically compatible acid addition salt together with at least one suitable carrier or diluent for pharmaceutical use. The pharmaceutical compositions can be adapted for perord, flax, para-: enteral (in particular, intravenous) or the rectal route of administration.
; The compositions may exist as unit dosages and may be prepared according to any known method used in headlamps. Such methods include the step of mixing the active component with the carrier, which may include one or more additional components. In general, the compositions are obtained by uniformly mixing the active component with liquid carriers or finely divided solid carriers (or with both types of carriers). tel) with the subsequent formation of the product if necessary.
Compositions suitable for peroral administration may exist as discrete dosages, e.g., capsules, tablets, or wafers, each containing a predetermined amount of active ingredient; in the form of powders or granules; in the form of solutions or suspensions in an aqueous or non-ambient medium; or in the form of. liquid emulsions like oil in water and water in oil.
84200 14
Tablets can be made by compression or molding, optionally with one or more additional components. Compressed tablets can be obtained by compressing, in an appropriate device, the active component in a free flowing state, for example, in the form of powder or granules, possibly mixed with a binder, lubricant, inert diluents, softeners, surface active or dispersing agents.
. agents. Molded tablets can be made by molding in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent.
2Q Tablets can be additionally coated or can be cut into them for breaking; their formulation may be such as to provide a slow or controlled release of the active ingredient contained therein.
The formulations for the rectal route can be suppositories and are prepared using carriers commonly used for this purpose, for example coke oil.
thirty
35
40
45
Compositions suitable for parenteral administration include sterile injectable aqueous solutions which may contain antioxidants, buffers, antibacterial agents, and solvents, which give the solution the property of narrowness with the blood of the corresponding treatment object; as well as aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Compositions of this type may exist in the form of unit dosages and in the form of containers containing a certain co-. The number of unit doses, for example, in the form of sealed vials and flames; they can also be stored as products dried by cooling (lyophilization), which only require the addition of a sterile liquid carrier, such as water for injection, just before use, - Improvised solutions for injection and suspension can be obtained from sterile powders, granules or tablets.
A preferred unit dosage form is a daily containing form. A dose or form containing a portion of the Daily dose (the value of which is indicated above), or a form containing a proportion of the active component.

权利要求:
Claims (1)
[1]
In addition to these commonly used components of a composition, it may also contain other components used in this field of pharmaceuticals, the set of which depends on the KOHkpeTHbix types of compositions; thus, for example, compositions intended for cerebral administration may also contain flavoring agents and substances that give the product a certain taste. Invention Formula
The method of obtaining bicyclic compounds of the general formula
f
- J4R2 m
 Oh or 1
thirty
m
n 1, 2 or 3;
R, each independently
other C-C-alkyl, C, -C4-alkoxy (unsubstituted or substituted), C-C-alkylsulfonyl.s
0
J 0
chlorine, C-Cc-alkenyloxy, C, -C4 alkylthio, C, -C 4. -al kilo-amino or phenyl}
RJ is hydrogen or methyl in position 1 or 3 of the imidazole ring, provided that n is 1 and m O, then RI is not 4- methoxy, 3- or 4-chloro, or their hydrochloric acid salts, different the fact that the compound of the general formula
™ R.
N NHRj,.
where Rj is hydrogen or methyl, provided that both R2 are not methyl at the same time, iodide to react with the compound of the general formula
25
-CROn
where R and n are above,
Z - carboxylmethyl group or its functional derivative - anhydride, morpholide or thiomorpholide,
with the target product in the CBOI
bodice or additive co-i
Do hydrochloric acid.

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公开号 | 公开日

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ZA828213B|1984-06-27|

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JPS5890586A|1983-05-30|

引用文献:

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US4904621A|1987-07-16|1990-02-27|Texas Instruments Incorporated|Remote plasma generation process using a two-stage showerhead|

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BR112012023382A2|2010-03-17|2018-05-15|F Hoffmann La Roche Ag T|imidazopyridine compounds, compositions and methods of use.|

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US10364243B2|2014-02-17|2019-07-30|Bayer Cropscience Aktiengesellschaft|2-aryl-substituted fused bicyclic heterocycle derivatives as pesticides|

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WO2016026848A1|2014-08-21|2016-02-25|Syngenta Participations Ag|Pesticidally active heterocyclic derivatives with sulphur containing substituents|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

---

GB8133930|1981-11-10|

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