Methanesulfonate (e)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}- 1h-imidazol-5-yl]-2- (2-thienyl)methyl-2-propanolol acid, method thereof, pharmaceutical composition based on it


(57) Abstract:

Methanesulfonate(E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl} -1H-imidazol-5-yl] -2(2-thienyl)methyl-2-propanolol acid (I) is a receptor antagonist of angiotensin II and can be used in the regulation of arterial hypertension caused or aggravated by angiotensin II, and to treat congestive heart failure, renal failure, and glaucoma. The connection I receive the processing of (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl} -1-h-imidazol-5-yl] -2-(2-thienyl)methyl-2-propanolol acid methanesulfonic acid in 2-propanol at 8oC. 3 S. and 2 C.p. f-crystals.

The presented invention relates to new imidazolylalkyl acids, which are receptor antagonists angiotensin II and used in the regulation of arterial hypertension caused or aggravated by angiotensin II, and to treat congestive heart failure, renal failure, and glaucoma. This invention relates also to pharmaceutical compositions containing these compounds, and to methods of using these compounds as antagonists of angiotensin II as antihypertensive agents and agents for the treatment of congestive heart is a, known as angiotensin, due vazopressornye action underlying the etiology of arterial hypertension of the person. Inappropriate activity of renin-angiotensin systems is a key element in the being of hypertension, congestive heart failure and some forms of kidney disorders. In addition to the direct effect on arteries and arterioles, angiotensin AA (AII) is one of the well-known most potent endogenous vasoconstrictor agents, has a stimulating effect on the secretion of aldosterone from the adrenal cortex. Thus, the renin-angiotensin system, thanks to its participation in the management of renal sodium regulation plays an important role in cardiovascular homeostasis.

Violation of the renin-angiotensine system converting enzyme inhibitors such as captopril, is useful in the clinical treatment of hypertension and congestive heart failure (Abrams, W. B., and others, (1984), Federation Proc., 43, 1314). The most direct effect on the inhibition of the renin-angiotensine system should block the action of AII receptor. Undeniable evidence suggests that AII sposob serdeczna failure, cirrhosis and complication of pregnancy (Hollenberg, N. K. (1984), J. Cardiovas. Pharmacol., 6, S 176). In addition, recent studies in animals suggest that inhibition of the renin-angiotensine system can be successful in preventing or slowing the progression of chronic renal failure (Anderson. S. and others (1985), J. Clin. Invest., 76, 612). Also recently filed a Patent application (Patent application southern. Africa N 87/01, 653) argues that AII antagonists are useful as agents that can reduce and regulate elevated intraocular pressure, especially glaucoma, in mammals.

The compounds of this invention inhibit, block and counteract the action of the hormone AII and, therefore, are useful in regulating and mitigating caused by angiotensin hypertension, congestive heart failure, renal failure and other disorders caused by the action of AII. When the reception of the compounds of this invention animals raised blood pressure due to AII, decreases, and other manifestations, based on the action of AII, are minimized and regulated. It can be expected that the compounds of this invention exhibit diuretic is violence, related to the synthesis of antagonists of AII. The following links revealed imidazolone derivatives, which are characterized as having a blocking activity against AII and which are useful as antihypertensive agents.

Furukawa and others, U.S. Pat. USA 4 340 598 describes imidazol-5-yl-acetic acid and imidazole-5-yl-propanoic (propionic) acid. In particular, the inventor notes 1-benzyl-2-n-butyl-5-chloroimidazo-4-acetic acid and 1-benzyl-2-phenyl-5-chloroimidazo-4-propionic acid.

Furukawa and others , U.S. Pat. USA 4 356 040 describes substituted derivatives of imidazol-5-acetic acid. In particular, reveals the connection 1-(2-Chlorobenzyl)-2-n-butyl-4-chloroimidazo-5-acetic acid.

Carini and others in Europe. Pat. 253 310 describe certain imidazolinone acid. Two intermediate compounds described in this patent, represent ethyl-3-[1-(4-nitrobenzyl)-2-butyl-4-chloroimidazo-5-yl] propenoate and ethyl-3 [2-butyl-4-chloro-1-(4-aminobenzyl)imidazol-5-yl]propenoate.

In addition, Wareing in PCT/Heb. Pat. 86/00297 reveals as intermediates certain imidazolidinone. On page 62 of the formula (CX) represents ethyl 3-[1(-4-forfinal)-4-isopropyl-2-FeNi is atarov of angiotensin II, are:

(E)-3-[2-n-butyl-1-{ (4-carboxylate-1-yl)methyl} -1H-imidazol-5-yl]-2-(2-thienyl)methyl-2-Papanova (acrylic) acid and

(E)-3-[2-n-butyl-1-{ (4-carboxylate-1-yl)methyl} -1H-imidazol-5-yl] -2-(2-thienyl)methyl-2-Papanova (acrylic) acid, ethyl ester,

or pharmaceutically acceptable salt of this compound, and

(E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl-1H-imidazol-5-yl/-2-(2-thienyl)methyl-2-Papanova acid methanesulfonate.

The invention also relates to pharmaceutical compositions comprising a pharmaceutical carrier and an effective amount of the foregoing compounds.

This invention also includes methods of counter-receptors of angiotensin II, which consists in receiving the required subject an effective amount of the above compounds. This invention also includes methods of treating hypertension, congestive heart failure, glaucoma, and kidney failure taking these compounds.

The compounds of this invention are obtained in accordance with the methods described herein and are illustrated by examples. Reagents, protective groups and the structure of imidazole and other fragments of the molecule is coordinated with functional groups and protective groups for the imidazole and other parts of the molecule.

Starting material, 2-n-butylimidazole is known (J.Org. Chem., 45: 4038, 1980), or synthesized using known techniques. For example, the imidazole is converted into 2-n-butylimidazole reaction of imidazole with triethylorthoformate and p-toluensulfonate acid with the formation of 1-diethoxypropionate and then the processing of n-butyl lithium with the formation of 2-lithium derivative of Artemida and alkylation of n-butyl iodide in an appropriate solvent, such as tetrahydrofuran (THF).

1-substituted naftalina or benzyl group is introduced at the 2-n-butylimidazole known methods, for example, by reaction with substituted nafcillin or benzyl-halide, mesilate or acetate, such as 2-chlorobenzylamino or 4-carbomethoxybiphenyl in an appropriate solvent, such as dimethylformamide (DMF) in the presence of a suitable acid acceptor, such as sodium alkylate, potassium carbonate or sodium or metal hydride, preferably sodium hydride at the reaction temperature of approximately 25oC to 100oC, preferably at 50oC. the Resulting 1-substituted nattily or benzyl-2-n-butylimidazole is hydroxymethylpropane in position 5 product, the aqueous afternova or-benzyl-2-n-butyl-5-hydroxymethylimidazole intermediates.

Or obtained above 5-hydroxymethylimidazole intermediate compounds are obtained by reaction of amidoamine, such as methyl ether of viramidine with dihydroxyacetone in liquid ammonia under pressure with the formation of 2-n-butyl-5-hydroxymethylimidazole. This intermediate compound interacts with acetic anhydride with the formation of 1-acetyl-5-acetoxymethyl-2-n-butylimidazole. Diacetate intermediate compound is represented by N-alkylation, for example, using 2-chlorobenzaldehyde or 4-carbomethoxyamino, and the resulting 1-substituted-2-n-butyl-5-acetoacetotoluidide treated aqueous base, such as 10% sodium hydroxide solution, with the formation of 5-hydroxymethylimidazole intermediates described earlier.

Hydroxymethylene group previously obtained intermediate compound is oxidized to aldehyde by the action of an appropriate reagent, such as anhydrous chromic acid-silica gel in tetrahydrofuran or, preferably, activated manganese dioxide in a suitable solvent, such as benzene or toluene, or preferably methylene chloride at a temperature of 25oC to 140oC, prefer the Il-3-(2-trienyl)-2-phosphonopropionic. Phosphonates are obtained, for example, from trialkylphosphates by alkylation of the corresponding halogen, methylsulfonate or acetate in the presence of an appropriate base such as sodium hydride in a suitable solvent, preferably glyme, at the reaction temperature of approximately 25oC to 110oC, preferably at 55oC, with the formation of the corresponding phosphonate. The interaction of the imidazole-5-carboxyaldehyde with phosphonates is carried out in the presence of a suitable base such as a metal alcoholate, lithium hydride or, preferably, sodium hydride in an appropriate solvent, such as ethanol, methanol, ether, dioxane, tetrahydrofuran or, preferably, glyme, at the reaction temperature of approximately 10oC to 50oC, preferably at 25oC, with the formation of the volatile mixture of TRANS and CIS, for example, (E) and (Z), 1-substituted-2-n-butyl-5-CH=C [(2-thienyl)methyl]-(COO-alkyl)-imidazoles. These isomers are easily separated by chromatographytandem through silica gel in the solvent, preferably hexane/ an ethyl acetate mixtures. The esters are hydrolyzed to the corresponding acid compounds using a base, such as wider, aqueous alcohols or diglyme.

Or 1-substituted-2-n-butylimidazole-5-carboxaldehyde obtained in the following way. The original 2-n-butylimidazole-5-carboxyaldehyde processed by N-alkylating a protective agent, such as chlorocyphidae (IND-C1) in the presence of a base such as potassium carbonate, in an appropriate solvent, such as dimethylformamide, at a temperature of from about 20oC to 50oC, preferably at 25oC, with the formation of the products of N-alkylation (e.g., SIP-derivatization) on the least difficulty nitrogen atom of imidazole nucleus. 1-substituted-naftalina or benzyl group is merged into the imidazole N-alkylation prepared above aldehyde galoidoserebryanykh compounds, such as methyl 4-bromeilles or methyl 4-bromocinnamyl-1-carboxylate at a temperature of approximately 80oC to 125oC, preferably at 100oC. the protecting group at the 3-nitrogen of imidazole ring is removed using basic hydrolysis, for example, when using two-phase mixture of ethyl acetate and aqueous sodium carbonate with the formation of 1-substituted-n-butylimidazole-5-carboxyaldehyde compounds. The compounds of this Odow.

Or, 2-n-butylimidazole original substances interact with trimethylsilyloxy methyl (SEM) chloride with the formation of 1-(trimethylsilyl)-ethoxymethyl-2-n-butylimidazole. The reaction is carried out, for example, in the presence of sodium hydride in a solvent such as dimethylformamide. Derivatives of 5-anti obtained by treatment with lithium, for example, butyllithium in an appropriate solvent, preferably in diethyl ether, followed by treatment litiepodobnogo derived halide tributiloltin, preferably chloride, tri-n-butyanova approximately at a temperature of from -10oC to 35oC, preferably at 25oC. 1-SAM-2-n-butyl-5-tributylammonium connects with ether, unsaturated acid having a residual group in the - position, such as halide or tripterocalyx group, for example, BrCR4=C [(2-thienyl)methyl] (COO-alkyl) in the presence of a phosphine ligand, such as bis(diphenylphosphino)propane or triphenylphosphine and palladium compounds (II), or preferably tetrakis(triphenylphosphine)palladium (O) in the presence of a base or without it - such as tributylamine at a temperature of from 50oC to 150oC, preferably at 120oC. (E) is a W using silica gel. 1-SAM group (E) and (Z) isomers hydrolyzed by acid, for example aqueous hydrochloric acid in a suitable alcoholic solvent such as methanol or ethanol, and 1-unsubstituted imidazole derivatives are converted to 1-t-butoxycarbonyl (t-SIDE) imidazoles, di-t-BUTYLCARBAMATE (Hoppe-Seyler's Z. Physiol. Chem. (1976), 357, 1651). T-SIDE esters alkiliruyutza and hydrolyzed using, for example, 2-chlorobenzaldehyde or 4-carbomethoxyamino in the presence of an appropriate base, preferably of diisopropylethylamine, in a suitable solvent, preferably methylene chloride, forming a 1-substituted imidazole derivatives (esters). (E) and (Z) isomers hydrolyzing in (E) and (Z) acid using the method described above.

The compounds of this invention is also obtained by the following method. 1-substituted-2-n-butylimidazole-5-carboxaldehyde obtained as described above, interact with substituted semi-acidic, polufinal derived malonate, such as ethyl-2-carboxy-3-(2-thienyl) propionate, in the presence of a base such as piperidine in a suitable solvent, such as toluene, at a temperature of from 80oC to 110oC, preferably at 100oC. the Resulting 1-Samaa alkaline hydrolysis, as explained above.

Alternatively, the compounds of this invention was prepared as follows. 1-substituted-2-n-butylimidazole-5-carboxaldehyde obtained as described herein above, is treated with lithium derivatives of substituted ethyl or methyl ester. These lithium derivatives are obtained by interaction lithium diisopropylamide in a suitable solvent, preferably tetrahydrofuran, with acid ester, such as ROOC-CH2-CH2-(2-thienyl) with the formation of the lithium derivative, at a temperature of from -78oC to -10oC, preferably at -78oC, which is treated with imidazolecarboxaldehyde. Intermediate - hydroxy-group ether imidazole turns into methylsulfonyl or acetate, methylsulfonyl or, preferably, the acetate, is heated in an appropriate solvent, such as toluene with one or two equivalents of 1,8-diazabicyclo[5,4,0] undec-7-ene at a temperature of from 50 to 110oC, preferably at 80oC with the formation of esters of 3-(imidazol-5-yl)-2-(2-thienyl)methyl-2-propanolol acid. (E) isomer is the predominant olefin isomer. Acid derived from esters according to the above method.

The compounds of this invention in which Seni, in which the group is substituted by CO2C1-C4the alkyl, using basic hydrolysis, such as aqueous sodium or potassium hydroxide in methanol or ethanol, or using acid hydrolysis, such as aqueous hydrochloric acid.

Pharmaceutically acceptable acid additive salts of compounds of formula (I) are formed with the use of appropriate organic or inorganic acids and known methods. For example, the base interacts with the corresponding inorganic or organic acid in mixing with the water solvent, such as ethanol, with separation of salts removal of solvent or miscible with water, the solvent when the acid is soluble therein, such as ethyl ether or chloroform, with immediate separation of the desired salt, or with the release of her removal of solvent. Typical examples of appropriate acids are maleic, fumaric, benzoic, ascorbic, pamoic, succinic, biotranslation, methansulfonate, ethicality, acetic, propionic, tartaric, salicylic, citric, gluconic, bartekova, stearic, palmitic, Takanawa, glycolic, is calculatingly, phosphoric and nitric acid.

Pharmaceutically acceptable basic salt additive compounds of formula (I) in which R8is hydrogen, receive by known methods from organic and inorganic bases, including non-toxic bases of alkaline and alkaline-earth metals, for example, hydroxides of calcium, lithium, sodium and potassium, ammonium hydroxide and a non-toxic organic bases such as triethylamine, butylamine, piperazine, meglumine, choline, diethanolamine and tromethamine.

The activity of antagonists of angiotensin II compounds of the formula (I) is evaluated by means of in vitro and in vivo. Antagonistic activity in vitro is determined by the ability of the compounds to compete with125I-angiotensin II binding receptors of vascular angiotensin II and their ability to withstand compressive response of angiotensin II in the selected aorta of the rabbit. Activity in vivo evaluated the effectiveness of the compounds in the inhibition of Pressor response to exogenous angiotensin II in the conscious rats and in reducing blood pressure in rats that model associated with renal hypertension.


Analysis of binding of labeled ligand predstave artery rats were thermostatically in buffer Tris-with a pM 80125I-angiotensin II in the presence of antagonists of angiotensin II, or without them for 1 hour at 25oC. Temperature control results in the quick filter and coupled receptor125I-angiotensin II, deposited on the filter is determined quantitatively by the count of gamma radiation. The power of the antagonists of angiotensin II is expressed as IC50that is the concentration of antagonist needed to displace 50% of the total in particular linked angiotensin II. Estimated value of the IC50compounds of the invention (E isomers) is approximately from 0.1 nm to 30 mm.

The aorta

The ability of the compounds to antagonize the angiotensin II that causes narrowing of blood vessels, is determined on the rabbit aorta. From the thoracic aorta of a rabbit cut ring segments and suspensions in organ baths containing physiological salt solution. The ring segments are fastened on the metal holders are attached to the measuring displacement sensors associated with the recording device. Cumulative concentration curves corresponding to angiotensin II, are removed in the absence of the antagonist or 30 minutes after incubation with the antagonist. Constants ate concentrations. Approximate values of KBcompounds of the invention (E isomers) values are from 0.1 nm to 0.50 nm.

Inhibition of Pressor response to angiotensin II in the conscious rats

Preparing rats with permanent femoral arterial and venous catheters and gastric tube (Gellai and others, Kidney Int., 15:419, 1979). After two or three days after surgery, rats are placed in a fixture with a device for fixation of the limbs and is under constant surveillance of blood pressure through arterial catheter pressure sensor and record on a multichannel recorder. Change in blood pressure in response to injection of 250 mg/kg of angiotensin II is compared at various time points before admission and after admission compounds intravenously or orally at doses from 0.1 to 300 mg/kg Dose of compound required to create a 50% inhibition of the control response to angiotensin II (IC50), is used as an evaluation of the effectiveness of the compounds.

Activity in the prevention of arterial hypertension

Activity of compounds against hypertension evaluated by their ability to reduce the blood pressure of Asnani the Oh artery (Cangiano and others, J. Pharmacol. Exp. Ther. , 208: 310, 1979). Rats with a bandaged renal artery are obtained by introduction of indwelling catheters as described above. After seven or eight days after ligature of the renal artery, during which the levels of renin in the plasma are the most high, in consciousness rats are placed in a fixture with a device for fixation of the limbs and is continuous values of blood pressure to intravenous or oral administration of the compounds and after their introduction. As assessment of effectiveness is used the dose of a compound required to reduce the value of the blood pressure of 30 mm Hg (IC30).

Effects on reduction of intraocular pressure achieved in the present invention, can be estimated according to the method described in the work of Watkins and others, J. Ocular Pharmacol., 1 (2): 161-168 (1985).

The compounds of this invention are included in the appropriate dosage forms, such as preparations for injection or active compounds for oral administration, capsules or tablets. Apply solid or liquid pharmaceutical carriers. The solid carriers include starch, lactose, dihydrate calcium sulphate, Terra Alba, sucrose, talc, gelatin, agar, pectin, acacia , eziologicheskie solution and water. Similarly, the carrier or diluent may include any substance, prolonging the selection, such as glycerol monostearate or distearate glycerol alone or in combination with paraffin. The amount of solid carrier may vary within wide limits, but preferably ranges from 25 mg to 1 g per dosage unit. When using a liquid medium, the drug can be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile water for injection, such as an ampoule, or an aqueous or nonaqueous liquid suspension.

For local ophthalmic use, the pharmaceutical compositions are applied in the form of solutions, suspensions, ointments and solid compositions. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and miscible solvents such as lower alcohols or vegetable oil, and water-soluble ophthalmologist acceptable non-toxic polymers, for example, cellulose derivatives such as methylcellulose. The pharmaceutical preparations can also contain non-toxic auxiliary substances such as emulsifying, preserving, moisturizing and a binding agent, such as, naprimuju ingredients such as alkali metal chloride, antioxidants such as sodium metabisulfite and other standard ingredients, such as monolaurate sorbitan.

In addition, as media vehicles for this purpose may be used appropriate eye fillers containing standard phosphate buffer system fillers.

The pharmaceutical preparation may also be in the form of a solid composition. For example, as a carrier of drugs you can use a solid water-soluble polymer. Can be used as a solid water-insoluble compositions, such as compositions prepared from a copolymer of ethylene-vinyl acetate.

The pharmaceutical preparations are prepared using the following standard for chemists, pharmacists techniques, including mixing, granulating and compressing, when necessary for tablet forms, or mixing, filling and dissolving the ingredients, as applicable, to obtain a desired oral, parenteral or local products.

Doses of the compounds of the present invention in pharmaceutical dosage unit form as described above, are effective methoxycinnamate the patient if necessary, counter-receptor of angiotensin II from 1 to 6 times daily orally rectally, topically, by injection, or continuously by infusion. Oral dosage unit for reception by the person preferably contain from 1 to 500 mg of active compound. Preferably, lower doses are used for parenteral administration. The oral intake may also be used with higher dosages, however, provided security and convenience for the patient. Compositions for topical application containing an active compound in amounts of from 0.0001 to 0.1 (wt./vol.%), preferably from 0.0001 to 0.01. As a local unit of dosage for human eye is used the number of active connections from 50 ng to 0.05 mg, preferably from 50 ng to 5 mg.

When the reception of the compounds of the invention in accordance with this invention, is not observed undesired Toxicological effects.

The method of this invention, consisting in the counter of angiotensin II receptors in mammals, including humans, comprises a reception in need of such opposition to the subject an effective amount of the compounds of this invention. The method of this invention, which consists in activity in combating hypertension and in the treatment of congestive heart who widawsky in it subject an effective amount to create a named activity.

Putative equivalents of the compounds of this invention are compounds otherwise corresponding to them, which were introduced substituents in any of the unsubstituted positions of such compounds, provided that such compounds have pharmaceutical utility, characteristic of the compounds of this invention.

The following examples illustrate the preparations of the compounds and pharmaceutical compositions of the present invention. It is assumed that the examples do not limit the scope of the claims of the present invention as defined above and as claimed below.

Example 1

(E)-3-[2-n-Butyl-1-{ (2-chlorophenyl)methyl} -1H-imidazol-5-yl] -2- (2-thienyl)methyl-2-Papanova acid

(i) 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol

The imidazole was transformed into 1-diethoxyaniline derived by the method of Curtis and Brown, J. Org. Chem., (1980), 45, 20. The imidazole (12.8 g, 0.19 mol) and 118.4 g (0.8 mol) triethylorthoformate interacted in the presence of 1 g of p-toluensulfonate acid with the formation of 20.6 (61%), so Kip. 65-70oC (0.1 mm) 1-diethoxyethane imidazole. This product (24.0 g, 0.14 mol) was dissolved in dry tetrahydrofuran (250 ml), cooled to -40oC was added n-utility (0.14 mol, 56.4 ml of 2.5 M solution in hexane) at the same time the operating mixture stirred over night at room temperature. The reaction mixture was divided between ether and 0.3 N hydrochloric acid, and the organic layer was re-extracted with diluted hydrochloric acid. The combined aqueous extracts were kind of balanced out by sodium bicarbonate solution, extracted with methylene chloride, dried over magnesium sulfate and concentrated. Once equilibrium evaporation on a Kugelrohr apparatus gave 14.8 g (85%) 2-n-butylimidazole.

2-n-Butylimidazole (9.7 g, 0.078 mol) was dissolved in methanol (50 ml) and was added dropwise to a solution of sodium methylate (sodium hydride (2.31 g, 0.0934 mol) in methanol (250 ml). After one hour the solution is evaporated until dry and the sodium salt was dissolved in dry dimethylformamide (150 ml) was added 2-Chlorobenzilate (16.3 g, 0.079 mol). The mixture was heated for 17 hours at 50oC in argon atmosphere, poured into ice water and the product was extracted with ethyl acetate. The extract was washed, dried and concentrated, gaining 18.5 g of the crude product, which was subjected to chromatographicaliy over silica gel using a mixture of 2:1 ethyl acetate/hexane, receiving 11.9 g (61%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole in the form of oil. Thin layer chromatography on silica gel with a mixture of 4:1 ethyl acetate/Huck is about 1

A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole (95.5 g, 0.384 mol), 37% formaldehyde (500 ml), sodium acetate (80 g ) and acetic acid (60 ml) was heated to the temperature of reflux distilled over 40 hours in argon atmosphere. The reaction mixture was concentrated in vacuo, and the residue was mixed with 500 ml of 20% sodium hydroxide solution for 4 hours, it was diluted with water and extracted with methylene chloride. The extract was washed, dried and concentrated. The crude product (117 g) was subjected to flash chromatographicaliy over 600 g of silica gel with a gradient of ethyl acetate to 10% methanol in ethyl acetate with the formation of 8.3 g of educt, 24.5 g of a mixture of educt and product and 44 g (41%) of 2-n-butyl-1-(2 - chlorophenyl)-methyl-5-hydroxymethyl-1H-imidazole, so square 86-88oC (from ethyl acetate). Further elution gave bis(4,5-hydroxymethyl) derivative, so pl. 138-140oC (from ethyl acetate).

Method 2

A mixture of methyl ester hydrochloride of viramidine (250 g, 1.66 mol) and dihydroxyacetone (150 g, 0.83 mol) dissolved in liquid ammonia, was left overnight at room temperature in high-pressure apparatus, and then was heated for 4 hours at 65oC at 375 psi (at 26.36 kg/cm2). The ammonia was evaporated, and the residue was dissolved in meta is the PR decantation in a hot kind of solid ammonium chloride. This procedure was repeated and the combined the combined acetonitrile extracts were treated with activated charcoal, filtered hot and the filtrate was concentrated in vacuum with the formation of dark oil - 2-n-butyl-5-hydroxymethylimidazole (253 g, 1.63 mol, 98%).

This crude alcohol (253 g) was treated with acetic anhydride (400 ml) at -15oC, then gave him to warm with stirring to room temperature and then further stirred for 19 hours. The acetic anhydride was evaporated under reduced pressure, the residue was dissolved in methylene chloride and washed the organic phase with 5% sodium bicarbonate solution and water. The extract was dried over sodium sulfate and concentrated, obtaining 323 g (83%) of 1-acetyl-4-acetoxymethyl-2-n-butylimidazole.

The diacetate was subjected to N-alkylation according to the following procedure. To a solution of anhydride teplovoi acid (trifloromethyl) (120 ml, 0.71 mol) in methylene chloride (200 ml) at -78oC in argon atmosphere was added a solution of diisopropylethylamine (128 ml, 0.73 mol) and 2-chlorbenzoyl alcohol (104 g, 0.75 mol) in methylene chloride (350 ml) for 20 minutes. After additional stirring for 20 minutes at -78oC this solution is then wzaimouwazhenia 20 minutes. The mixture is then stirred for 18 hours at room temperature and the solvents evaporated. The remaining 2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole was used without purification for the hydrolysis of the acetate groups.

A solution of the crude 2-n-butyl-5-acetoxymethyl-1-(2-chlorophenyl)methyl-1H-imidazole (250 g) in methanol (200 ml) was treated 10% sodium hydroxide solution (700 ml) and the mixture was heated on the steam bath for 4 hours. After cooling, was added methylene chloride, the organic phase was separated, washed with water, dried and concentrated. The residue was dissolved in ether, cooled and strawley with the formation of the crude product. Recrystallization from ethyl acetate gave 176 g of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole, so square 86-88oC. This substance was in all respects identical to the product obtained by method 1.

(iii) 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde

A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl - 1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 ml) was added to a suspension of activated manganese dioxide (27 g) in methylene chloride (325 ml). The suspension was mixed at room temperature for 17 hours. Solid substances is m mix 6: 4 hexane/ethyl acetate, giving 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde in the form of oil. NMR and IR coincided with the structure.

(iv) (E)-3-[2-n-butyl-1-{ (2-chlorophenyl)methyl}-1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-Papanova acid

How A

(a) trimethyl 3-(2-thienyl)-2-phosphonopropionic

To a solution of 2-thiophenemethyl (2.28 g, 0.02 mol) in carbon tetrachloride (25 ml) was added triphenylphosphine (6.81 g, 0.026 mol) and the solution was subjected to delegirovano for 3 hours. The cooled reaction mixture was diluted with hexane (60 ml), was memoratives and filtered. The concentrated filtrate (4.6 g) was subjected to flash chromatographicaliy over silica gel using mixtures of hexane/ethyl acetate 7:3, forming a 2-chloromethylstyrene (1.52 g, 57%) as oil.

A suspension of sodium hydride (0,271 g, 11.3 mmol) in dry glyme (40 ml) in an argon atmosphere was treated dropwise with trimethylphosphate (1.87 g, 10.3 mmol) in glyme (5 ml). The resulting mixture was stirred at room temperature for 1.5 hours. Then were added 2-chloromethylstyrene (1.5 g, 11.3 mmol) and the mixture stirred at 65oC for 18 hours. The reaction mixture was separated between water and ethyl acetate and the organic layer was rinsed with water and the solution harestock over silica gel using a mixture of ethyl acetate/hexane 4:1, forming 800 mg (28%) trimethyl 3-(2-thienyl)-2 - phosphonopropionic.

(b) methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H - imidazol-5-yl]-2-(2-thienyl)methyl-2-propenoate

To a suspension of sodium hydride (69 mg, 2.87 mmol) in glyme (5 ml) is added dropwise a solution of trimethyl 3-(2-thienyl)-2-phosphonopropionic in glyme (3 ml) in an argon atmosphere. When gas evolution ceased, the mixture is heated to 50oC for 15 minutes. Add a solution of 2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-carboxaldehyde (0.53 g, 1.98 mmol) in glyme (3 ml) and the mixture is stirred at 60-65oC for 5 hours. The cooled reaction mixture was separated between water and ethyl acetate and the organic layer was washed with water, dried, concentrated and subjected to flash chromatographicaliy over silica gel with formation of 336 mg (41%) of methyl (E)-3-[2-n-butyl - 1-[(2-chlorophenyl)-methyl] -1H-imidazol-5-yl] -2-(2-thienyl)methyl-2 - propenoate in the form of an oil, NMR, which coincides with the TRANS or E form of the olefin.

(c) (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-Papanova acid

A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H - imidazol-5-yl] -2-(2-thienyl)methyl-2-propenoate (336 mg, 0.783 mmol) in ethanol (10 ml) was treated 10% solution of hydro is I a solid residue. The mixture was diluted with water, cooled and filtered, forming 309 mg of a solid product. Crystallization from ethyl acetate gave 195 mg (60%) of (E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl] -1H-imidazol-5-yl]-2-(2 - thienyl)methyl-2-propanolol acid, so pl. 177-179oC.

Method B

(a) methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol - 5-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate

To a solution of Diisopropylamine (1.96 g, 0.0194 mol) in dry tetrahydrofuran (40 ml) maintained at a temperature of -78oC in an argon atmosphere, was added n-utility (7.3 ml, 0.0183 mol 2.5 M solution in toluene) and the mixture was mixed for 10 minutes. Then was added methyl 3-(2-thienyl)propanoate (2.83 g, 0.0166 mol) in tetrahydrofuran (2 ml) and the mixture stirred for 30 minutes at -78oC. was Added a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H - imidazol-5-carboxaldehyde (3 g, 0.0111 mol) in tetrahydrofuran (4 ml) and the resulting mixture stirred at -78oC for 30 minutes. The reaction mixture was divided between a saturated solution of ammonium chloride and ether, the organic extract was washed with a solution of calcium chloride, dried over anhydrous magnesium sulfate and concentrated to education 6.67 g of the crude product. This product has been til 3-[2-n-butyl-1-(2-chlorophenyl)- methyl-1H-imidazol-5-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate.

(b) methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl) methyl-1H-imidazol-5-yl]-2-(2-thienyl)methylpropanoate

A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol - 5-yl]-3-hydroxy-2-(2-thienyl)-methylpropanoate (4.03 g, 9.02 mmol) in methylene chloride (100 ml) interacted with 4-dimethylaminopyridine (0.386 g, 3.16 mmol). Then stir the mixture was added dropwise acetic anhydride (8.5 ml, 9.02 mmol). The mixture is stirred for 18 hours, water was added (35 ml), the mixture was mixed for 1 hour and then was diluted with ether and saturated sodium bicarbonate solution. The ether layer was washed with a solution of calcium chloride, was dried with anhydrous magnesium sulfate and evaporated, giving the titled 3-acetoxy derivative in the form of oil (4.37 g, 99%).

(c) methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)-methyl}-1H-imidazol - 5-yl]-2-(2-thienyl)methyl-2-propenoate

A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H - imidazol-5-yl] -2-(2-thienyl)-methylpropanoate (4.36 g, 8.92 mmol) in dry toluene (80 ml) interacted with 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (3.2 ml, 21.4 mmol) and the resulting solution was heated for 3 hours at 80oC in argon atmosphere. The solvent was evaporated, the residue was ground into powder with ether and was added activated trees is togethereven over silica gel using mixtures of hexane/ethyl acetate 65:35, getting 2.89 g (76%) of methyl (E)-3-[2-n-butyl-1-[(2-chlorophenyl)methyl]-1H-imidazol-5-yl]- 2-(2-thienyl)-methyl-2-propenoate, NMR which TLC (50% ethyl acetate in hexane on silica gel) were identical to the product obtained by method A.

(d) (E)-3-[2-n-butyl-1-{ (2-chlorophenyl)methyl} -1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-Papanova acid

Basic hydrolysis of this ester (2.88 g, 6.71 mmol) according to method A (iii) gave 2.59 g (93%) of (E)-3-[2-n-butyl-1-[(2 - chlorophenyl)methyl] -1H-imidazol-5-yl]-2-(2-thienyl) methyl-2-propanolol acid, so pl. 175-177oC, which was identical to the product obtained in method A.

Example 2

(E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl} -1H-imidazol-5-yl] - 2-(2-thienyl)methyl-2-Papanova acid

(i) By the method of example (I) [(ii) Method 2, (iii) and (iv) How B] using 4-carbomethoxyamino alcohol instead of 2-chlorobenzylamino alcohol were received on the connection, so pl. 250-253oC.

(ii) Obtaining monoethanolamine

Titled connection, 3600 g, was added to 2-propanol (54 l) in a 20-gallon (75.707 l-th) lined glass reactor. The mixed suspension was cooled to approximately 8oC. To a thoroughly stirred suspension was rapidly added methansulfonate (2448 g). Source ectothermy approximately 11oC. over the next three minutes began to stand out a thin white solid precipitate. The suspension is stirred for 5.5 hours at a temperature of 3oC and the solid was collected by centrifugation. After washing 10 l of 2-propanol the product was dried in vacuum at 45oC to a constant weight 4.21 kg (yield 94%, not prepared for analysis).

The crude product (4.20 kg) in solid form was added to 12.6 l of stirred glacial acetic acid in 10-gallon (37.85 liter) lined glass reactor. Pasty mixture was heated up to 80oC, forming a homogeneous solution. The solution was filtered in the form of heat passing through the filter, and the reactor and line filter were washed an additional portion of (4.2 l) acetic acid. The combined solution of acetic acid were mixed at slow cooling to 25oC in a separate 10-gallon (37.85 liter) lined glass reactor. The selection of sediment began approximately at 45oC. After 2.5 hours, the suspension was diluted 42 l of ethyl acetate, was added in two equal portions to the time interval between additions. For complete precipitation, the suspension was mixed for a further 18 hours. The solid product was what SUP>oC output amounted to 3.80 kg of product, so pl. 251-252oC (90.4%, not prepared for analysis).

Example 3

(E)-3-[2-n-Butyl-1-{ (2-chlorophenyl)methyl} -1H-imidazol-5-yl-2-(4 - pyridyl)methyl-2-Papanova acid

(i) methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl] -3 - hydroxy-2-(4-pyridyl)methylpropanoate

To a solution of Diisopropylamine (3.58 ml, 25.6 mmol) in dried tetrahydrofuran (50 ml), late harvested at -78oC in an argon atmosphere, was added n-utility (10.2 ml, 26.6 mmol 2.5 M solution in toluene) and the mixture was mixed for 10 minutes. Then was added methyl 3-(4-pyridyl)propanoate (4.22 g, 25.6 mmol) (obtained by the interaction of 4-pyridinecarboxamide with trimethylphosphate in the presence of sodium hydride in etilenglikolevye ether with subsequent catalytic hydrogenation of the double bond of 10% palladium on carbon in an ethyl acetate solution (98%) at a pressure of 3 atmospheres hydrogen with the formation of a saturated ether) in tetrahydrofuran (40 ml) and this mixture was mixed for 30 minutes at -78oC. was Added a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde (5.9 g, 21.3 mmol) in tetrahydrofuran (10 ml) and stirring at -78oC was continued for 30 minutes. Reactionbetween calcium chloride, were dried over magnesium sulfate, concentrated and subjected to flash chromatographicaliy through silica gel using 5% methanol in ethyl acetate, forming 3.32 g (30%) of methyl 3-[2-n-butyl-1-(2-chlorophenyl)-methyl-1H-imidazol-5-yl] -3-hydroxy - 2-(4-pyridyl)methyl-propanoate. TLC on silica gel using 5% methanol in ethyl acetate reveals a homogeneous product with Rf0.79.

(ii) methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H - imidazol-5-yl]-2-(4-pyridyl)propanoate

A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5 - yl]-3-hydroxy-2-(4-pyridyl)methylpropanoate (3.32 g, 7.5 mmol) in methylene chloride (50 ml), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7:1 ml, 75 mmol) were mixed at room temperature for 18 hours. Water was added (5 ml), the mixture was mixed for 2 hours and then was diluted with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and calcium chloride, dried and concentrated, forming 4 g of the crude titled product. TLC on silica gel using 5% methanol in ethyl acetate detects mainly the material of one sample with Rf0.86. The source material was not detected. This material is l] -2-(4-pyridyl)methyl-2-propenoate

A mixture of methyl 3-acetoxy-3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl] -2- (4-pyridyl)-propenoate (7.5 mmol), toluene (50 ml) and 1,8-diaza-bicyclo[5,4,0]-undec-7-ene (DBU) (3.4 ml, 22.5 mmol) was heated at 90oC for 18 hours in an argon atmosphere. The cooled mixture was diluted with ether, and washed with a solution of calcium chloride, dried and concentrated to 3.1 g (97%) of the titled compound. NMR showed that the main product was TRANS or E isomer.

(iv) (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]- 2-(4-pyridyl)-methyl-2-Papanova acid

A solution of methyl (E)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H - imidazol-5-yl] -2-(4-pyridyl)-methyl-2-propenoate (3.1 g, 7.3 mmol) in ethanol (16 ml) interacted with 10% sodium hydroxide solution and the mixture is stirred for 18 hours at 25oC. the Solution was concentrated in vacuo, water was added, the pH was brought to 6.5 and the resulting solid was filtered, washed with water and was led from methanol/ether to obtain 0.48 g of (E)-3-[2-n-butyl-1-{ (2-chlorophenyl)-methyl} -1H-imidazol-5-yl] -2-(4 - pyridyl)methyl-2-propanolol acid, so pl. 178-182oC (d).

Example 4.

(E)-3-[2-n-Butyl-1-{ (4-carboxylate-1-yl)methyl} -1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-propanol remesiana to a solution of 2-n-butyl-4-hydroxymethylimidazole (100.78 g, 0.652 mol) in 500 ml of absolute ethanol. After 20 minutes the solution was heated at 40-45oC for 45 minutes, diluted with 2.5 liters of water and rapidly cooled. The crystalline product was collected by filtration, washed with water and dried to obtain 174.5 g (95%) of crystalline substances, so pl. 166-166.5oC.

(ii) 2-n-butyl-4-itimidate-5-carboxyaldehyde

Stir the mixture 174.1 g (of 0.62 mol) of 2-n-butyl-5-hydroxymethyl-4-itimidate and 360 g (4.14 mol) of manganese dioxide in 3 liters of methylene chloride was boiled for 24 hours under reflux using a trap to remove water. The hot reaction mixture was filtered through Celitewhich was then washed 4.5 liters of boiling methylene chloride. The United filtrates were concentrated until dry, the residue was dissolved twice in 150 ml of methanol and the solution was concentrated until dry. The residue was dissolved in 130 ml of methanol and rapidly cooled. After the implementation of crystallization was slowly added to 700 ml of water. The mixture is rapidly cooled, the solid was collected by filtration and were washed with water, forming 145.2 g (84%) of product, so pl. 104-105oC.

(iii) methyl 4-[(2-n-butyl-5-formyl-4-iodine-1H-imidazol-1 - yl)methyl]naphthalene-1-the ol-5-carboxyaldehyde and 65.68 g (0.235 mol) of methyl 4-bromethalin-1-carboxylate (E. A. Dixon, A. Fischer, and F. P. Robinson, Can. J. Chem., 59, 2629, (1981)) in 600 ml of dimethylformamide was mixed for 5 hours in an argon atmosphere at 70oC. was further added 6.56 g (0.0235 mol) bromatologia ether and the suspension was mixed for another 15 hours at 70oC. the Reaction mixture was poured into water and the formed solid substance was collected by filtration, rinsed with water and several times were pulverized with 250 ml of boiling methanol, forming 86.8 g (85%) of a solid substance, so pl. 177.5-179oC.

(iv) methyl 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl] naphthalene-1-carboxylate

A suspension of 40.0 g (83.9 mmol) of methyl 4-[(2-n-butyl-5-formyl-4-iodine-1H-imidazol-1-yl)methyl] -naphthalene-1 - carboxylate, 9.07 g (92.4 mmol) of potassium acetate and 6.0 g of 10% palladium on coal in 1.2 liters of ethyl acetate was subjected to hydrogenation for 2 hours. The solid was removed by filtration and addition was added 8.0 g of 10% palladium on coal and 9.01 g (92.4 mmol) of potassium acetate. After hydrogenation the reaction mixture for 2 hours, the solids were removed by filtration, and the solution was concentrated to approximately 1/3 volume. An ethyl acetate solution was washed with an aqueous solution of sodium carbonate, dried over magnesium sulfate and concentrated in vacuum with the formation of oil, what's crystals, so pl. 95.5 - 97oC.

(v) methyl (E)-3-[2-n-butyl-1-{ (4-carbomethoxy-naphthas-1-yl)methyl} -1H - imidazol-5-yl]-2(2-thienyl)methyl-2-propenoate

Titled compound was obtained from 25.0 g of methyl 4-[(2-butyl - 5-formyl-1H-imidazol-1-yl)methyl] naphthalene-1-carboxylate sequential procedures of example 3 with the formation of 22.12 g (56%) of product in the form of a hydrochloric salt, so pl. 217-218oC.

(vi) (E)-3-[[2-n-butyl-1-{(4-carboxylate-1-yl)methyl}-1H - imidazol-5-yl] -2-(2-thienyl)methylpropenoate acid

Pasta containing 14.46 g (26.14 mmol) of methyl (E)-3-[2-n-butyl-1-{(4-carbomethoxy-1-yl)methyl} -1H - imidazol-5-yl] -2-(2-thienyl)methyl-2-propenoate, 8.38 g (2.09 mmol) of potassium hydroxide, in a mixture of 165 ml of ethanol and 85 ml of water was mixed for 18 hours at room temperature. Concentration in vacuo and diluted with water gave 400 ml of a clear solution. When bringing the pH to 4.03 hydrochloric acid crystals were obtained, which upon recrystallization from methanol formed 9.89 g (80%) of colorless crystals, so pl. 218-219oC as a partial hydrate.

Example 5

(E)-3-[2-n-butyl-1-{ (4-carboxylate-1-yl)methyl} -1H-imidazol-5 - yl]-2-[(2-thienyl)methyl]-2-Papanova acid

Ethyl ester

A solution of 5.0 g (14.27 mol) of methyl 4-is containing a series of 2.0 g (50 mmol) of sodium hydroxide in 30 ml of water. After stirring for 18 hours at 25oC the reaction mixture was concentrated in vacuum, diluted with water to 50 ml, the pH was brought to 3.15 with 12N hydrochloric acid. Filtering bistroomrade mixture gave 4.71 g of white crystals, so pl. 183-184oC. Recrystallization from ethyl acetate gave another crystalline form, so pl. 134-135oC.

To a solution containing 27.2 g (0.119 mol) of ethyl 2-carboxy-3-(2-thienyl)propionate 250 ml of benzene, was added 4.71 g (14 mmol) of the above, aldehydo-acid, 3.58 g (42 mmol) of piperidine and 10 ml of pyridine and the solution was boiled under reflux for 18 h using a trap to remove water. Then volatiles were removed using a vacuum, was added toluene, and the volatiles were again removed. The residue was treated 2.5% sodium bicarbonate solution and hexane, which caused the separation of the oil. Add ethyl acetate gave two phases. The aqueous phase was filtered, the pH was brought 12N hydrochloric acid to 3.86 and was extracted with ethyl acetate. This an ethyl acetate solution was dried over magnesium sulfate and concentrated in vacuum forming resin which is dissolved in ether and then padillas broadcasting is UP>oC, razmeshayushihsya at 176oC (cleaners containing hydrochloride salt).

Example 6

Oral dosage form for oral way active compounds of the formula (I) is produced by screening, mixing, and filling into hard gelatin capsules the ingredients in the proportions, for example, is shown below:

Ingredients - Number

Methanesulfonate (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H - imidazol-5-yl]-2-(2-thienyl)methyl-2-propanolol acid 100 mg

magnesium stearate 10 mg

lactose 100 mg

Example 7

Sucrose, the dihydrate of calcium sulfate and orally active compounds of the formula (I) are mixed and granulated with 10% gelatin solution. The wet granules are sifted, dried, mixed with the starch, talc and stearic acid and compacted into tablets.

Ingredients - Number

(E)-3-[2-n-butyl-1-{ (4-carboxy-naphthas-1-yl)-methyl} -1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-Papanova acid 75 mg

The calcium sulfate dihydrate 100 mg

Sucrose - 15 mg

Starch - 8 mg

Talc 4 mg

Stearic acid - 2 mg

Example 8

(E)-3-[2-n-butyl-1-{ (4-carboxy-naphthas-1-yl)methyl}-1H-imidazol-5 - yl]-2-(2-thienyl)methyl-2-Papanova acid, ethyl ester, 50 mg, disperse the/P> Example 9

Local ophthalmic solution for using compounds of formula (I) is made by mixing sterile ingredients in proportions, for example, is shown below.

Ingredients Quantity (mg/ml)

(E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl} -1H-imidazol-5-yl] -2-(2-thienyl)methyl-2-Papanova acid methanesulfonate - 1.0

Dibasic sodium phosphate - 10.4

Monobasic sodium phosphate - 2.4

Chlorbutanol - 5.0

Hydroxypropylmethylcellulose - 5.0

Sterilized water is sufficient to 1.0 ml

of 1.0 N sodium hydroxide is sufficient to pH 7.4

It is clear that the invention is not limited to illustrated above realizations, and the following claims shall retain the right as illustrated implementation, and all modifications included in the scope of the claims.

1. Methanesulfonate (E)-3-[2-n-butyl-1-{ (4-carboxyphenyl)methyl}-1H-imidazol-5-yl]-2(2-thienyl)methyl-2-propanolol acid.

2. Connection on p. 1, which has active antagonist of angiotensin II.

3. Pharmaceutical composition having activity antagonist of angiotensin II, wherein as the active ingredient in soda is the teachings of the connection on p. 1, characterized in that the handle (E)-3-[2-n-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl] -2(2-thienyl)methyl-2-propanolol acid in 2-propanol methanesulfonate acid at approximately the 8oC.

5. Connection on p. 1 having antihypertensive activity.


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The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

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< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,


R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

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< / BR>

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