Derivative-(tertiary aminomethyl)benzoimidazole and pharmaceutical composition based on them

 

(57) Abstract:

Offers new compounds of General formula (I), where the substituent R1is selected from alkyl, alkoxy, alkenylacyl, Allakaket, alkylthio and alkanity groups, the substituent R2selected from halogen atom, hydroxy group, alkyl, alkoxy, alkenylacyl, alkylthio, alkanity, alkylamino groups, triptorelin, cyano-, nitro-, alkylsulfonyl, alkylsulfonyl and acyl groups, the substituents R3and R4or independently of one another represent alkyl or alkenyl, or together form a heterocyclic system with the nitrogen atom, optionally containing one or more additional heteroatoms, and their pharmaceutically acceptable salts. Also the use of these compounds as therapeutic agents, particularly as agents for bladder control, and to obtain medications that control urination. In addition, there are farmatsevticheskii compositions containing these compounds, and methods of obtaining new compounds. 3 S. and 2 C.p. f-crystals, 1 table.

The invention relates to new derivatives -(tertiary aminomethyl)benzoimidazole that have pharmacologist the Nations, containing these derivatives, and to methods of treatment using them.

Incontinence is a fairly common disease for men and women. More or less urine involuntarily ejected from the bladder. There are two main types of urinary incontinence - motive incontinence and incontinence when voltage. To ensure the latter type of incontinence is available to a very small number of medicines, and as a set, they have low efficacy and significant side effects.

In the application form DD-A-210031 disclosed a method of obtaining a pharmacologically active 1-aryl-2-aminoethanol. In particular, it describes phenylethanolamine, which are either unsubstituted or monosubstituted on 2 or 4 positions of the phenyl ring, or tizanidine in position 3, 4 and 5.

In the application form DD-A-103830 revealed growth stimulating derivatives phenylethanolamine. However, not described compounds, which are disubstituted in position 2 and 3 of the phenyl ring.

In the application form DD-A-213108 disclosed pharmaceutical formulations containing and/or sympathomimetic agent in the form of a derived phenylethanolamine. Only mentioned specific with the hypertensive activity-aryl- -hydroxyethylpiperazine heterocycles.

In accordance with the invention it was found that a new class of derivatives of 2,3-disubstituted -(tertiary aminomethyl)benzoimidazole has properties which make them suitable for the treatment of diseases associated with urinary incontinence, and these new derivatives have a higher efficacy and fewer side effects than drugs prior.

One of the objects of the invention is to provide new compounds which can be represented by the General formula (I)

< / BR>
where substituent R1is selected from alkyl, alkoxy, alkenylacyl, Allakaket, alkylthio and alkanity groups;

Deputy R2selected from halogen atom, hydroxy-group, the alkyl, alkoxy-groups, alkenylacyl, alkylthio, alkanity, alkylamino group, triptorelin group, cyano, nitro, alkylsulfanyl, alkylsulfonyl and acyl groups;

the substituents R3and R4or independently of one another represent alkyl or alkenyl, or the substituents R3and R4combined with the formation of heterocyclic systems with the nitrogen atom, optionally containing one or more additional heteroatoms, and their physiologically Priboy formula (I), for therapeutic applications, especially as agents that control urination.

In accordance with another object the invention provides a method of treating an organism suffering from a disease associated with incontinence, and this method includes a step of assigning the above-mentioned living body an effective amount of the compounds having General formula (I) above.

Another object of the invention features a pharmaceutical composition comprising one or more compounds of General formula (I) above as an active ingredient, preferably together with a pharmaceutically acceptable carrier and, if desired, other pharmacologically active agents.

Another object of the invention refers to the use of compounds having the above General formula (I), to obtain medication intended for treatment of diseases associated with urination.

An additional object of the invention provides methods for producing compounds having the above General formula (I).

In the compounds having the above formula (I), the term "alkyl" or separately, or in the op is a saturated hydrocarbon group. Examples of alkyl groups are methyl, ethyl, n-propyl, ISO-propyl, n-butyl, n-pentyl, n-hexyl.

The concept of "alkenyl or separately, or in such combinations as alkenylacyl, alkanity, means linear or branched hydrocarbon group containing one or more unsaturated bonds. Examples alkenyl groups are ethynyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, ethylbutanal.

The term "alkoxy", alone or in such combinations as arylalkyl means linear and branched, saturated alkoxygroup. Examples of alkoxy groups are methoxy, ethoxy, h-propyloxy-, ISO -, propyloxy, h-Butylochka-, n-pentyloxy, n-hexyloxy group.

The notion of "alkenylacyl" means linear and branched, alkenylamine group containing one or more unsaturated bonds. Examples of alkenylamine groups are atenolok, propenyloxy, butenyloxy, pentyloxy, hexenoate, methylpropyloxy, ethylbutyrate group.

The term "aryl", alone or in combination, means an aromatic systems that are, or heterocyclic, or containing only carbon atoms. Examples of heterocyclic aromatic systems are Tiina, pyridazin, benzofuran, isobenzofuran, benzothiazole, benzothiophene, pyridazine, benzofuran, isobenzofuran, benzothiazole, benzothiophene, indole, isoindole, oxadiazol, benzoxazol. Examples of the aromatic system containing only carbon atoms are phenyl and naphthyl.

The term "acyl" includes linear, branched or cyclic, saturated, unsaturated or aromatic acyl group. Examples of acyl groups are formyl, acetyl, proponila, Butyrina, Coccinella, crotonylene, cinnamonny, benzoline.

The term "halogen" means fluorine atoms, chlorine, bromine and iodine.

Deputy R1preferably selected from alkoxygroup and lower alkylthio-group containing 1-5 carbon atoms.

Deputy R2is selected from a halogen atom, alkoxygroup, alkylthio group, triptorelin group, cyano and nitro groups, lower alkylsulfonyl, lower alkylsulfonyl and lower acyl groups, lower alkyl, lower acyl and lower alkoxy groups, preferably containing 1 to 5 carbon atoms.

The substituents R3and R4independently from each other preferably selected from the group comprising Nissi will formed a 5 - or 6-membered heterocyclic ring, such as pyrrolidine, piperidine, morpholine.

To the General formula (I) include the enantiomeric and racemic forms. The compounds of formula (I), which contain soleobrazutaya basic nitrogen atoms, can also be in the form of salts that are acceptable for pharmaceutical use.

Preferred are the following specific compounds:

-/(dimethylamino)methyl/-2-(1-methylethoxy)-3-methylbenzonitrile;

3-chloro-o-/(dimethylamino)methyl/-2-ethoxybenzonitrile;

-/(diethylamino)methyl/-3-methoxy-2-(1-methylethoxy)-benzoimidazol;

-/(dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy)benzoimidazol;

-/(dimethylamino)methyl/-3-methoxy-2-(2-propenyloxy)benzoimidazol;

3-methoxy-2-(1-methylethoxy)- -pyrrolidinone-benzoimidazol;

3-methoxy-2-(2-propenyloxy)- -pyrrolidinone-benzoimidazol;

3-chloro-2-(1-methylethoxy)- -pyrrolidinone-benzoimidazol;

3-chloro- -/(dimethylamino)methyl/-2-(1-methylethoxy)-benzoimidazol;

3-chloro- -/(N-ethyl-N-methylamino)methyl/-2-(1-methylethoxy)-benzoimidazol;

3-chloro- -/(diethylamino)methyl/-2-(1-methylethoxy)-benzoimidazol;

-/(dimethylamino)methyl/-2-(1-methylethoxy)-3-nitrobenzamide;

3-chloro- -/(dimethylamino)methyl/-2-(1-metalicity)) methyl/-2-(1-methylthio)benzoimidazol;

-/(dimethylamino)methyl/-3-methoxy-2-(1-methylthio)benzoimidazol;

-/(dimethylamino)methyl/-2-ethylthio-3-methoxybenzylamine;

-/(dimethylamino)methyl/-2-(1-methylethoxy)-3-methylthiazolidine;

-/(dimethylamino)methyl/-2-(1-methylethoxy)-3-methylsulfonylbenzoyl;

-/(dimethylamino)methyl/-2-(1-methylethoxy)-3-methylsulfonylbenzoyl.

Compounds having General formula (I) can be obtained by conventional means, in particular the following (methods a-e):

method a). The compound of General formula (II)

< / BR>
where the substituents R1and R2take the values defined previously

interacts with the amine of General formula HNR3R4where the substituents R3and R4take the previously defined values, with the formation of the compounds of formula (I);

method b). The compound of General formula (III)

< / BR>
where the substituents R1, R2, R3and R4take the previously defined values, is restored to the compounds of General formula (I);

method c). The compound of General formula (IV)

< / BR>
where the substituents R1and R2take the previously defined values, interacts with the reactive derivative of the tertiary amine of the formula NR3R43and R4together form a saturated cyclic system with the formation of compounds of General formula (I);

method d), the Compound of General formula (V)

< / BR>
where the substituents R1, R2, R3and R4take the values defined above, and Deputy Q represents oxygen atom or sulfur, is restored to the compounds of General formula (I);

method e). The compound of General formula (VI)

< / BR>
where the substituents R1and R2take the previously defined meanings, is subjected to reductive alkylation of the aldehyde with the formation of compounds of General formula (I).

The described method (a) (which is illustrated further in example 1) can be carried out by mixing the reagents, or reagents may be dissolved or suspended in an inert solvent such as an alcohol, e.g. ethanol, water, dimethylsulfoxide, acetonitrile, etc. may Also be used mixtures of more than one solvent. Acceptable temperature interval for the reaction is the interval between approximately 20 and 150oC, usually between about 20 and 100oC. the reaction Products can be isolated in the usual way.

The source is hedzon 39 (1983), 2323, S. S. Matteson, Tetraheszon Zett, 27, (1986), 795 and links in them. The crude epoxide II preferably used directly in the reaction with the desired amine.

In method b (which is further illustrated in example 2) aminoketone III can be recovered using conventional reducing agents, such as LiAlH4, BH3-THF, NaBH4and others, or by catalytic hydrogenation. The reaction can be carried out in an inert solvent, compatible with the regenerating agent, for example, hydrocarbons, ethers, alcohols, carboxylic acids. Mixture of several solvents can also be used. Acceptable temperature range for carrying out the method is the interval between approximately 20 and 100oC.

The original product III can be obtained using the General methods described in Houben-Weyl, Methods der organischen Chemie, Ketone, III 7/2c. 2253, and references therein.

Method c (which is further illustrated in example 3) can be carried out in excess of non-activated amine NR3R4R5or in an inert solvent, generally at a temperature of -70oC or below. Reactive amine derivative may be, for example, LiCH2NR3R4where the substituents R the system.

Reactive amine derivatives can be prepared according to the method described in Tetrahedron Lett, 24, (1984), 1353 or (n-C4H9)3- Sn CH2NR3R4described in Synthesis (1984), 495. Source amines, such as CH3NR3R4are known compounds. Compounds having General formula (IV) are also known compounds or can be prepared according to conventional methods described in Houben - Weye, Methods der Organischen Chemie, Aldehyde E3, 767, Sanerstoffyerhindugen 117/1 537 and links in them.

In method d (which is further illustrated in example 4) recovery of the tertiary amide (formula Y, Q = 0) or the tertiary of timida (formula Y, Q = S) using a reducing agent to the compounds of General formula (I) can be carried out using conventional reducing agents, such as LiAlH4, BH3- S(CH3)2, NaBH4-CoCl2etc. the Process is carried out in an inert organic solvent that is compatible with the regenerating agent, usually in the temperature range between approximately 20 and 100oC. Such recovery can also be accomplished by catalytic hydrogenation by known methods.

The initial product of General formula (V) can be obtained from pvcam, described in P. Beak, Chemical Reviews. 78 (1978), 275, ibid 84 (1984), 471 and links in them.

In method e (which is additionally illustrated in example 5) amerosport VI may be subjected to reductive alkylation using conventional reducing agents such as NaBH3CH, NaBH4, formic acid and others, or by catalytic hydrogenation. The method can be carried out in an inert solvent, compatible with the regenerating agent, for example, hydrocarbons, ethers, alcohols, carboxylic acids. Can also be used a mixture of more than one solvent. Usually the process is carried out in the temperature range approximately between 0 and 100oC. the Original compound VI can be obtained using the General methods described in Comprehensive Organic Chemistry (1979) v. 2, 94 and links in them.

Also, of course, it is possible to obtain compounds having General formula (I), other compounds within the definition of General formula, by known methods. Examples of such transformations are the following: free hydroxy groups, for example, can be obtained by removal of the acyl group of the esters of carboxylic acids. Lower alkylsulfonyl and lower alkylsulfonyl group get rolchiliolo to the corresponding amines, amides can be restored to the corresponding amines.

In the synthesized according to any one of the above methods of the compounds having General formula (I), each group in the molecule of the original compound must be compatible with the current method or, if necessary, must be protected in one or several stages, and then converted into the desired group. Examples of groups which may be protected when carrying out these processes are the hydroxy-group, and primary and secondary amino groups.

Racemic compounds of General formula (I) can be separated using known methods, for example, by using different digestive acids. Crystallization of salts digestive acids and compounds of General formula (I) can be made in any acceptable conventional solvent and at a temperature preferably the boiling temperature of the solvent to -20oC. Preferred solvents are ethanol, 1-propanol, 2-propanol and acetone. Can also be used water and its mixtures with solvents.

The racemate separation of individual optical enantiomers additionally illustrated in the example 6.

Compounds of the invention are generally characterized by pharmacological activity above that makes them useful to counter some physiological disorders in humans or animals. The effective amount of the pharmacologically active compounds of the invention can be introduced into the body of a human or animal in various ways, for example, orally in the form of capsules or tablets, parenterally in the form of sterile solutions, suspensions, emulsions, subcutaneous or intramuscular implantation with either a supercharger. Among the methods of parenteral administration, you can specify intravenous, sublingual, subcutaneous, intramuscular, intraperitoneal, intradermal, intravesical, vnutriepetelialnaya and vnutrenniy. Other methods of introduction are vaginal, rectal and local ways, for example, in the form of ointments, suppositories, powders, platelets, solutions for irrigation and endovaginal devices.

Pharmaceutical formulations are usually prepared from the previously calculated quantities of one or more compounds of the present invention. Such receptorse, emulsions, oil solutions and other with or without added, but preferably with the addition of a single solvent or carrier of a large number of pharmaceutically acceptable diluents or carriers.

When used in a mixture with a pharmaceutically acceptable carrier or solvent amount of the active ingredient usually makes up from about 0.01 to 75,0%, usually approximately from 0.05 to 15.0% based on the weight of the composition. In such formulations can be used in devices such as starch, sugar, talc, conventional synthetic and natural resins, water, and similar materials. Also in recipes can be used binders such as polyvinylpyrrolidone, as well as lubricants, such as sodium stearate. In addition, the tablets may include dispersing agents, for example, sodium carbonate.

Although a relatively small number of active compounds of the invention, even less than 0.5 mg, can be used in cases assigned to subjects having a relatively low body weight, single dose preferably is 2 mg or higher, preferably 10, 20, 50 or 100 mg, and even more, depending on the patient and the desired conduc be from 1 to 1000 mg per unit dose.

Thus, the compounds of the invention of formula (I) can be assigned numbers from 1 to 1000 mg, with a preferred range of doses ranging from 2 to 250 mg per day to a subject or patient, in a single application or split into four doses for reception within a reasonable period of time and depending on the subject.

The following examples serve to illustrate the invention and do not limit its scope, and specifically these compounds are of particular interest for the invention. The compounds in the examples marked with the numbers of relevant examples that describe how to obtain them and given their systematic names. These compounds are further indicated by code number a:b, where a is the number of the example, which describes obtaining the considered connection, and the connection serial number received in accordance with this example. For example, connection 1:2 represents a second connection is obtained in accordance with example 1.

The structure of the compounds is confirmed by PMR spectra, and elemental and titrimetric analysis. The PMR spectra obtained on the instrument BRUKER 250 MHz. Elemental analysis was performed on the analyzer Carlo Erba Elementar Analyzer mod.11 is mperature -15oC in an autoclave add 2-/3-methyl-2-(1-methylethoxy)phenyl/oxiran (1.92 g, 0.01 mol) and warmed to room temperature with stirring for 8 hours Then the mixture was kept at room temperature for 40 hours, the Mixture is cooled, evaporated the excess amine and purified by chromatographytandem on silica gel (eluent toluene-methanol, 9:1, containing 20 wt.% ammonia). If necessary, the desired fraction is isolated in a form acceptable salt.

1. -/(Dimethylamino)methyl/2-(1-methylethoxy)-3-methyl-benzoimidazol, hydrochloride, T. pl. 104oC.

Similarly receive the following connections from the appropriate starting compounds:

2. 3-Chloro--/(dimethylamino)methyl/-2-ethoxybenzonitrile, hydrochloride, T. pl. 135oC.

3. -/(Diethylamino)methyl/-3-methoxy-2-(1-methylethoxy)-benzoimidazol, hydrocalc, so pl. 95oC.

4. -/(Dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy) -benzoimidazol, hydrocalc, so pl. 126oC.

5. 3-Methoxy-2-(1-methylethoxy)--pyrrolidinone-benzoimidazol, hydrochloride, T. pl. 213oC.

6. 3-Methoxy-2-(1-methylethoxy)--morpholinomethyl-benzene-methanol, hydrochloride, T. pl. 160oC.

7. 3-Chloro-2-(1-methylethoxy)--pyrrolidinone-benzoimidazol, hydroxylate, so PL oC.

9. 3-Chloro--/(dimethylamino)methyl-2-(1-methylethoxy)-benzoimidazol, hydrochloride, T. pl. 120oC.

10. 3-Chloro--/(diethylamino)methyl/-2-(1-methylethoxy)-benzoimidazol, hydrocalc, so pl. 91oC.

11. 3-Chloro--/(N-ethyl-N-methylamino)methyl/-2-(1-methylethoxy)-benzoimidazol, hydrochloride, T. pl. 127oC.

12. -/(Dimethylamino)-methyl/-2-(1-methylethoxy)-3-nitrobenzonitrile, hydrochloride, T. pl. 133oC.

13. 3-Chloro--/(dimethylamino)methyl/2-(1-metalicity)-benzoimidazol, hydrochloride, T. pl. 141oC.

14. -/(Dimethylamino)methyl-/-3-methoxy-2-(1-metalicity)- benzoimidazol, hydrochloride, T. pl. 141oC.

15. -/(Dimethylamino)methyl/-3-methoxy-2-(2-propenyloxy)-benzoimidazol, hydrocalc, so pl. 80oC.

16. -/(Dimethylamino)methyl/-2,3-di-(1-methylethoxy)-benzoimidazol, the base, so pl. 44oC.

17. -/(Dimethylamino)methyl/-3-methoxy-2-/(3-methyl-2-butenyl)-oxy/- benzoimidazol (oil).

Example 2. To a solution of the hydrochloride of 2-(dimethylamino)-1-(3-chloro-2-ethoxyphenyl)ethanone (2.25 g, 0,0081 mol) in methanol (50 ml) and water (15 ml) under stirring and cooling (-5oC) portions add sodium borohydride (0.65 g, 0,0171 mol). After stirring at room temperature for abayat a saturated solution of ammonia until alkaline environment. The mixture is extracted with ether, the ether layer is dried with anhydrous sodium sulfate. The desired product is isolated in the form below hydrochloride (1) and recrystallized from a mixture of 2-propanol-ether.

1. 3-Chloro--/(dimethylamino)methyl/-2-ethoxy-benzoimidazol, hydrochloride, T. pl. 135oC (compound 2:1 = connection 1:2).

Similarly receive the following connection from the appropriate starting compounds:

2. 3-Chloro--/(dimethylamino)methyl/-2-(1-methylethoxy)- benzoimidazol, hydrochloride, T. pl. 120oC (compound 2:2 = connection 1:9).

Example 3. To a mixture of 8 ml of triethylamine and tert.-of potassium butyl (1.12 g, 0.01 mol) in nitrogen atmosphere at -78oC with stirring, added dropwise Deut.-utility (1.3 M solution in hexane). The mixture was stirred at 0oC for 1 h and cooled to -78oC, then added dropwise to 35 ml of a 0.3 M solution of lithium bromide in ether. The mixture was stirred at 0oC for 1 h, cooled to -78oC and at this temperature, add a solution of 3-methoxy-2-(1-methylethoxy)-benzaldehyde (1.55 g, 0,008 mol) in 10 ml of ether. The reaction mixture is left overnight at room temperature, poured into a mixture of ice-water, acidified to pH 3 and extracted twice with ether. Essential extra the e oxalate (I) and recrystallized from a mixture of propanol-ether.

1. -/(Dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy)- benzoimidazol, hydrocalc, so pl. 126oC (compound 3:1 = connection 1:4).

Similarly receive the following connection from the appropriate starting compounds:

2. 3-Chloro--/Dimethylamino)methyl-2-/1-methylethoxy)-benzoimidazol, hydrochloride, T. pl. 120oC (compound 3:2 = connection 1:9).

Example 4. To a suspension of lithium aluminum hydride (1.5 g) in 15 ml anhydrous THF under nitrogen atmosphere with stirring a solution of N, N-dimethyl--hydroxy-3-methoxy-2-(1-methylethoxy)-benzoylacetone (2,87 g, 0.01 mol) in 20 ml of anhydrous THF, the mixture is boiled for 18 h and cooled. To decompose the excess lithium aluminum hydride to the mixture are added dropwise 1.5 ml of water, then with 2.3 ml of 15% aqueous sodium hydroxide solution and 4.5 ml of water. The mixture is stirred until the formation of granular white precipitate, filtering obtain a clear solution. In vacuum THF evaporated, the residue is dissolved in ether. The desired product is isolated in the form of hydroarsenate and recrystallized from ethyl acetate.

/-(Dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy)-benzoimidazol, hydrocalc, so pl. 126oC (compound 4:1 = connection 1:4).

Example 5. Mix-amino what about formaldehyde (7.2 g, 0,088 mol) is boiled for 4 hours, then add 3.4 ml of concentrated hydrochloric acid and evaporated in vacuum formic acid and an excess of formaldehyde. The residue is dissolved in water and alkalinized (pH > 11) the addition of 25% aqueous sodium hydroxide. The mixture was twice extracted with ether, the desired compound is isolated in the form of hydroarsenate.

-/(Dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy)- benzoimidazol, hydrocalc, so pl. 126oC (compound 5:1 = connection 1:4).

Example 6. The following examples illustrate the separation of racemates in accordance with the invention.

Mix racemic 3-chloro- -/(dimethylamino)methyl/-2- (1-methylethoxy)-benzoimidazol (19,35 g of 0.075 mol) and di-0,0'-para-toluyl-L-tartaric acid (30,3 g of 0.075 mol), the product is crystallized from a mixture of 125 ml of absolute ethanol and 175 ml of water. The mixture was incubated over night at a temperature of 4oC, the precipitation of the salt is separated by filtration and washed with a mixture of alcohol-water 1:1. Product (42,71 g) is recrystallized twice from 50% ethanol, transferred to the base, and then the hydrochloride of (-)-3-chloro- -/(dimethylamino)-methyl/-2-(1-methylethoxy)-benzoimidazol. The output of 6.6, So pl. 99oC. []2D5= -52,4oC (C = 1% in ethanol). (Soy is the second evaporator, the residue is alkalinized 2 M sodium hydroxide solution and extracted with ether. The ether layer is evaporated, receive the product (14.6 g, 0,057 mol), which crystallized from di-0,0'-para-toluyl-D-tartaric acid (21,9 g 0,057 mol) of 195 ml of 50% ethanol. Product three times recrystallized from 50% aqueous ethanol. The resulting product (19.5 g) was transferred to the Foundation, and then converted into hydrochloride (+)-3-chloro- -/(dimethylamino)methyl/-2-(1-methylethoxy)-benzoimidazol. The output of 7.2, So pl. 98oC. []2D5= +50,9oC (C = 1% in ethanol). (Compound 6:2).

Mix racemic -/(dimethylamino)methyl/-3-methoxy-2- (methylethoxy)-benzoimidazol (253,0 g, 1 mol) and di-0,0'-para-toluyl-D-tartaric acid (386,3 g, 1 mol), the product is crystallized from 765 ml of a mixture of ethanol-water (6:4). The mixture is kept for 20 hours at room temperature, after which the temperature is slowly reduced to 10oC. the precipitation of the salt is separated by filtration, washed with a mixture of ethanol-water 1:1 (260 ml), the mixture ethanol-water (260 ml) and dried in vacuum. The resulting product (205 g) is recrystallized twice from a mixture of ethanol-water 6:4, translated in the base receive (+)- -/(dimethylamino)methyl/-3-methoxy-2(1-methylethoxy)-benzoimidazol. Exit 51, So pl. 49,2oC. []2D5= +52othe t to dryness on a rotary evaporator, the residue is alkalinized 2 M sodium hydroxide solution and extracted with ether, the ether layer is evaporated. The selected basis (87 g, 0,343 mol) crystallized from di-0,0'-para-toluyl-L-tartaric acid (132,8 g, 0,343 mol) of 231 ml of a mixture of ethanol-water 6:4. The precipitation of the salt is separated by filtration, washed with a mixture of ethanol-water 1:1 (220 ml) and the mixture ethanol-water 6:4 (220 ml), dried in vacuum. The resulting product (70,3 g) is recrystallized twice from a mixture of ethanol-water 6:4, is transferred to the base, receive (-)- -/(dimethylamino)methyl/-3-methoxy-2-(1-methylethoxy)-benzoimidazol. The output of 17.5, So pl. 49,1oC. []2D5= -52o(C = 1% in ethanol). (Compound 6:4).

Example 7. The method of producing tablets 20 mg

I Typical loading for 1000 tablets:

Active connection 70 mesh*- a 20 g

Lactose, Ph. Nord - 210 g

Starch (Amylum maidis), Ph. Nord - 75 g

II Kollidon 25 B. A. S. F. - 3.5 grams

Purified water - q.s.

III Talc, Ph. Nord - 15 g

Magnesium stearate, Ph. Nord - 1.5 grams

The weight of 1000 tablets - 325

The weight of one tablet is 325 mg

*Standard mesh in accordance with the international system, the cipher DIN 4189/1968.

Punch: 10.5 mm diameter, flat cut, edges bevelled.

Carefully mix the sifted substances is t in a furnace at a maximum temperature of 40oC, then repeat sifting through a sieve No. 10. Add substances III and mix thoroughly. Pressed tablets with a gross weight of approximately 325 mg.

Example 8. Suspension for injection 20 mg/ml:

Active connection, 100 mesh. 20 mg

Sodium chloride 8 mg

Carboxymethylcellulose 1 mg

Benzyl alcohol - 1 mg

Distilled water to a volume of 1 ml

Example 9

Oral suspension 5 mg/ml:

Active connection, 100 mesh. 5 mg

Sorbitol - 600 mg

Flavoring - q.s.

Dye - q.s.

Water up to a volume of 1 ml

Example 10

Candles on 25 mg:

Active connection - 25 mg

Cocoa butter - q.s.

Example 11 2% ointment:

Active connection - 2 g

Triethanolamine - 1 g

Glycerin - 7 g

Cetyl alcohol - 2.5 grams

Lanolin - 2.5 grams

Stearic acid - a 20 g

Monooleate sorbitol, 0.5 g

Sodium hydroxide and 0.2 g

Methyl-para-aminobenzoate - 0.3 grams

Propyl-para-aminobenzoate - 0.1 g

Ethanol - 0.9 grams

Water to weight - 100 g

Example 12. Capsules 10 mg:

The active compound, 10 mg

Magnesium stearate 2 mg

Talc - 188 mg

Substances are mixed and the mixture is filled capsules.

Example 13. 15
Chloride of sodium 4 mg

Methyl-para-aminobenzoate - 0.7 mg

Propyl-para-aminobenzoate - 0.3 mg

Substances dissolved in distilled water, the solution is poured into bubbles and lyophilizers.

Example 14. Solution for injection 20 mg/ml:

Water-soluble active compound 20 mg

Ascorbic acid - 1 mg

Sodium bisulfite 1 mg

Chloride of sodium 6 mg

Methyl-para-aminobenzoate - 0.7 mg

Propyl-para-aminobenzoate - 0.3 mg

Distilled water to a volume of 1 ml

In examples 7-14, which relate to compositions, the active compounds are compounds covered by the above General formula (I) or their acid additive salts with pharmaceutically acceptable inorganic or organic acids. Water-soluble active compounds are acid additive salts or salts with pharmaceutically acceptable inorganic or organic cation. It should also be noted that the compositions can be used two or more active compounds of the present invention, and, if necessary, they can be used in combination with other pharmacologically active agents.

Compounds of the invention so the CA body. However, it should be understood that the number of input connections will be determined by a physician taking into account the specific circumstances, including the condition being treated, the chosen route of administration, age, weight and response of the particular patient and the severity of symptoms. Thus, the spacing of the doses in no way limit the scope of the present invention. As used in this description, the term "pharmaceutical composition" covers the composition and ingredients for both human and veterinary use.

The following pharmacological data illustrate the activity of a number of potent and selective compounds in comparison with the classical substance that stimulates adrenoceptor, phenylpropanolamine.

Effect on isolated urethra and the portal vein of the rabbit. Female rabbit weighing 2.5-3.0 kg kill and bleed. Remove the urethra and the portal vein and put them in jars for bodies containing oxygenated Krebs solution at a temperature of 37oC. Use two rings of the urethra (4 mm wide) and two transverse strips of the portal vein. After a time of 60 min equilibration establish basic natyageet appliance Grass polygraph, mod.7.

To help achieve reductions using a submaximal concentration of noradrenaline (610-5M).

The compounds add (ESD & retail) (12 concentrations) to achieve maximum response. The results presented in the table.

Effect on urethral and blood pressure have shot rabbits. Rabbits weighing 2.5-3.0 kg analiziruyut using pentobarbitone (initially 40 mg/kg per hour). For measuring urethral pressure in the urethra catheter (Dog cath N 6), which is fixed at the point of maximum pressure. Basic urethral pressure is approximately 10 cm of water.article Blood pressure is measured via a catheter (PP50) introduced into the femoral artery. The compounds are administered intravenously through a catheter in the femoral vein. Throughout the experiment a constant deep level of anesthesia is maintained by continuous intravenous infusion pentobarbitone. To establish the baseline (standard) response initially carried out by three successive injections of noradrenaline (0,025 mg/kg intravenously). Repeated intravenous injections of different doses of the same investigational compounds provorny compounds have a very high selectivity towards the urethra in relation to their effect on blood vessels and blood pressure. In other pharmacological experiments (not described here) also shows that the claimed compounds do not affect or have minimal effect on other organs, such as, for example, bladder, Central nervous system, intestines, sperm duct, etc.

Data concerning toxicity, the compounds of example 4, in particular the indicator LD50for mice and rats is in the range of 300-400 mg/kg, metric MTD (maximum tolerant or portable dose for dogs is 20 mg/kg (main problems wore gastrointestinal in nature, i.e., vomiting and diarrhea).

1. Derivatives - (tertiary aminomethyl) benzoimidazole General formula (I)

< / BR>
where R1- lower alkoxy, lower alkenylacyl, lower alkanity, lower alkylthio;

R2halogen, lower alkyl, lower alkoxy, nitro, lower alkylthio, lower alkenylacyl, lower alkanity, trifluoromethyl;

R3and R4- lower alkyl or together with the nitrogen atom form a saturated 5 - or 6-membered ring possibly containing a second heteroatom oxygen,

and their physiologically acceptable salts.

2. Connection on p. 1, wherein R1- C1- C5-altio, trifluoromethyl, nitro, R3and R4- C1- C5-alkyl, or together with the nitrogen atom form a saturated 5 - or 6-membered heterocycle.

3. Connection on p. 1 selected from the group comprising - [(dimethylamino)methyl] -2-(1-methylethoxy)-3-methyl - benzene-methanol, 3-chloro-- [(dimethylamino)methyl] -2-ethoxy-benzoimidazol, - [(diethylamino)methyl] -3-methoxy-2-(1 - methylethoxy)-benzoimidazol, - [(dimethylamino)methyl]-3 - methoxy-2-(1-methylethoxy)benzoylmethyl, - [(dimethylamino)methyl] -3-methoxy-2-(2-propenyloxy) -benzoimidazol, 3-methoxy-2-(1-methylethoxy) -- pyrrolidinone-benzoimidazol, 3-methoxy-2-(2-propenyloxy) -- pyrrolidinone-benzoimidazol, 3-chloro-2-(1-methylethoxy) -- pyrrolidinone - benzoimidazol, 3-chloro -- [(dimethylamino)methyl]-2-(1-methylethoxy)-benzoimidazol, 3-chloro -- [(N-ethyl-N - methylamino)methyl] -2-(1 - methylethoxy)-benzoimidazol, 3-chloro -- [(diethylamino)methyl] -2- (1-methylethoxy)-benzenethiol, - [(dimethylamino)methyl]-2-( 1-methylethoxy)-3-nitro - benzene-methanol, 3-chloro -- [(dimethylamino)methyl]-2-(1-metalicity)-benzoimidazol, - [(dimethylamino)methyl] -3-methoxy-2-(1-metalicity)-benzoimidazol, 3-chloro -- [(dimethylamino)methyl]-2 -(methylthio)-benzoimidazol, - [(dimethylamino)methyl]-3-methoxy-2- (methylthio)-benzoimidazol, - [(dimethylamino)methyl]-physiologically acceptable salt.

4. Compounds according to any one of paragraphs.1 to 3 that controls urination.

5. Pharmaceutical composition that controls urination, comprising an active agent and a carrier, wherein the active means it has a connection on p. 1 in an effective amount.

 

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FIELD: medicine, anesthesiology, resuscitation.

SUBSTANCE: one should perform puncturing of epidural space at Th12-L1 level. Through the lumen of puncture needle one should introduce catheter to move it cranially at the depth of 3 cm. After that one should inject 10 ml 05%-marcaine solution to perform repeated injections per 5.0 ml every 4 h during 1-8 d. The effect is achieved due to unloading minor cycle of circulation.

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2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

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19 cl, 4 tbl, 4 ex

FIELD: medicine, endocrinology.

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28 cl, 3 dwg, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: improved preparing methods, valuable medicinal properties of compositions.

18 cl, 14 tbl, 78 ex

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8 cl, 2 dwg, 3 ex, 3 tbl

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6 cl, 5 tbl, 19 ex

FIELD: medicine.

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1 tbl

FIELD: organic chemistry, medicine.

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13 cl, 2 tbl, 43 ex

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2 ex

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