Derivatives of 5-acylamino-1,2,4-thiadiazolo, the method of production thereof and pharmaceutical composition having an affinity for cholecystokinin receptors

 

(57) Abstract:

Describes new derivatives of 5-acylamino-1,2,4-thiadiazolo formula (I) in which Ar denotes an aromatic nitrogen-containing heterocycle selected among chinoline, izochinolina, indolyl, the latter may be substituted on nitrogen by a group W, where W is selected from the group including: (a)-(CH2)nCOR, where n = 1 or 2 and R is a OR1where R1is selected from hydrogen and (C1-C4)-alkyl; b) tetrahydropyranyl in) chain (CH2)3- last carbon atom which is fixed on the phenyl indole nucleus with the formation of 6-membered heterocycle; Z represents a group (a), where a and b denote, X1-X4identical or different, denote a hydrogen atom, a chlorine atom or bromine, (C1-C3)-alkyl group, (C1-C3)-CNS group or triptorelin group; naftalina group, and their pharmaceutically acceptable salts. The compounds have affinity for a biological receptor cholecystokinin. Also described is a method of obtaining derivatives of 5-acylamino-1,2,4-thiadiazolo formula I according to any one of paragraphs. 1-6, consists in the fact that the derivative of 5-amino-thiadiazole of the formula (II) in which Z is specified in p. EET values, specified in paragraph 1 for Ar, or represents the derived Ar, which is reactive under the conditions of acylation centers protected, then, if necessary, removing the protective group from the specified reactive centers of the aromatic nucleus Ar. 2 c. and 6 C.p. f-crystals, 3 PL.

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The present invention relates to 5-acylamino-1,2,4 - thiadiazole, substituted in position 3 of the aromatic group linked through a carbonyl function with aromatic nitrogen-containing heterocycle; these compounds have affinity for a biological receptor cholecystokinin.

Cholecystokinin (CCK) is a polypeptide hormone, which in vivo are several fragments 4-39 amino acids. They have numerous physiological activities, especially the effects on the biliary tract, gastrointestinal tract or on the Central and peripheral nervous system, as described by J. E. Morley in the Life Sciences, 30, 479-493(1982).

Shows 2 types of receptors, a and B, does not exclude the existence of other types or subtypes. Agonists and antagonists of the effects of cholecystokinin on these receptors known; can be called a derivative of 3-amino-benzodiazepinones, J. Med.Chem. 32, 13-16 (1989), or production is depending on the nature of the substituents, are more or less selective receptor type a or B.

Various antagonists and agonists CCK is currently being studied in the clinic for people, especially as regulators of appetite, for the treatment of gastrointestinal disorders, to fight the pain, to reduce anxiety, schizophrenia, or for the elimination of withdrawal symptoms in dependent drug people.

Compounds of the invention, which, depending on their structure, have agonistic or antagonistic activity exerted on cholecystokinin in relation to its receptor type a or B, correspond to the formula (I)

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in which Ar denotes an aromatic nitrogen-containing heterocycle selected among chinoline, izochinolina, benzimidazolyl and indolyl, the latter in some cases substituted on nitrogen by a group W, where W is selected from the group including:

(I) -CO-(C1-C4)-alkyl;

(II) -(CH2)nCOR, where R is indicated OR1or NR1R2and R1and R2identical or not, are chosen from among hydrogen and (C1-C4)- alkyl, and n = 1, 2;

(III) hydroxy, (C1-C4)-alkyl;

(IV) alkoxyalkyl with 2-6 C-atoms;

(V) tetrahydrate education 6-membered heterocycle;

Z represents the group(a)

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where a and b are, independently of one another, denote C, CH or N;

X1-X4identical or different, denote a hydrogen atom, (C1-C4)-alkyl group, (C1-C3)-CNS group, halogen, in particular chlorine or bromine, or trifluoromethyl,

or naftalina group, in some cases substituted (C1-C3)-alkyl group, (C1-C3)-CNS group or halogen atom.

The invention also relates to pharmaceutically acceptable salts of compounds of formula (I).

Of these compounds are preferred those in which at least 3 of the substituents X1-X4represent a hydrogen atom or a (C1-C2)- alkyl group, or (C1-C2)-CNS group, and in particular those selected among methyl or metaxylene groups in positions 2, 4, 6 aromatic nucleus; in addition, it is preferable that Ar meant substituted or substituted indolyl or predominantly substituted or not 2-indolering group.

The compounds of formula (I) can be obtained by condensation of aminothiadiazole formula (II)

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with acid or reactive acid derivative is investing features are protected. Suitable derivatives of the acids can be called the acid chlorides and acid anhydrides, in some cases mixed, or activated esters commonly used in the synthesis of peptides.

Some compounds of formula (II) is known; it is possible to refer, for example, in European patent A-455 356, or patents Germany 842 346 or 955 684, which explains their receipt by the impact of the thiocyanate of an alkali metal to the corresponding N-halogenation. Other compounds of formula (II) are new and are obtained by known methods. They can be obtained, for example, by exposure to liquid ammonia at 5-chlorothiazole usually substituted in position 3 and received by the impact of trichlorocarbanilide on appropriately substituted amidin. Amidine get when using known methods from the corresponding NITRILES of the formula (III): Z-C=N (III), or oxime, which can be restored to amidine hydrogen in the presence of a catalyst, or from complex aminoether, which is treated with NH4Cl.

The conditions in all of these reactions are well known to the specialist.

When NITRILES (not for sale, they can be obtained by exposure of the reagent Lawesson to the appropriate perve method of condensation with the amine can be referenced in European patent A-432 040 and patent Germany 3 907 390.

Compounds of the invention displace audirovannyj cholecystokinin or iodirovannoye biological fragments of their receptor type a or B.

The affinity for the receptor type And was studied in vitro in the homogenate of rat pancreas in relation to iodirovannoye CCK 8 S according to the method described especially in Endocrinology, 109, 1746 (1981); in these conditions are described in the following examples, the products have Cl50in the range of 10-8M - 10-10M

The affinity for the receptor type B was studied by the method described in J. Neurochem. , 37, 443 (1981), the homogenate of cerebral cortex of the Guinea pig, and connection examples are Cl50order 10-7M

Finally, to determine whether the connection agonists or antagonists of receptors of type a, the expert knows that he can study the effect of compounds on the secretion of amylase pancreatic acini (acini) rats according to the method described especially in J. Biol. Chem. 254 (12), 5321-5327 (1979); under these conditions, the agonist stimulates the secretion of amylase, whereas the antagonist reduces the secretion caused by a fragment of CCK 8S. Of the compounds of formula (I) those for which located in position 2 X1means OCH3and X2and X3regardless ASS="ptx2">

In accordance with their ability to displace cholecystokinin of its receptor a or B, the compounds of the invention preferably can be used for the treatment or prevention of diseases involving cholecystokinin or its fragments.

When these compounds are antagonists of CCK, you can use them against ulcers, pancreatic cancer and cancer of the spleen, pancreatitis, hyperinsulinemia, syndrome, irritable colon, or in the case of psychosis, anxiety, Parkinson's disease, to reduce slow dyskinesias, as regulators of appetite or in the treatment of pain or against withdrawal from dependent drug people.

When these compounds are agonists of CCK receptor type a, they are used as anoreksigena or even psychosis treatment, to improve memory or as antishock funds.

Pharmaceutical compositions which contain as an active beginning at least one compound of formula (I) or one of its pharmaceutically acceptable salts, are another subject of the invention.

In the pharmaceutical compositions of the present invention for ora is the detailed introduction, effective the beginning of the above formula (I) or their possible salts can be produced in single doses, mixed with classical pharmaceutical basics, animals and people for the prevention or treatment of the above disorders or diseases. The appropriate unit forms of introduction include oral forms such as tablets, gelatin capsules with the medicine, powders, granules and oral solutions or suspensions; sublingual, oral, intratracheal, intranasal forms of administration; subcutaneous, intramuscular or intravenous forms of administration and rectal forms of administration. For topical application it is possible to use the compounds according to the invention in creams, lipsticks or lotions.

When preparing a solid composition in the form of tablets, the principal active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or similar substances.

Tablets can be coated by a shell of sucrose-derived cellulose, or other suitable material, or can be treated so that they have a prolonged or delayed activity and that they are freed continuous is given by mixing the active ingredient with a diluent and introducing the resulting mixture into soft or hard gelatin capsules.

The drug is in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, preferably low-calorie, vehicle, methyl paraben or propyl paraben as antiseptics, as well as with the agent, gives taste and the color.

Powders or granules, dispersible in water, may contain the active ingredient mixed with dispersing agents or wetting, or suspendresume agents, for example, polyvinylpyrrolidone, just as with sweetening matter or improving the taste substances.

For rectal injection resort to candles, which are prepared with binders, melting at rectal temperature, for example, cocoa butter or polyethylene glycols.

For parenteral administration using aqueous suspensions, isotonic saline solutions or sterile and injectisome solutions which contain pharmacologically acceptable dispersant and/or wetting, such as propylene glycol or butyleneglycol.

The active principle can also be produced in the form of microcapsules, in some cases with one or more bases or additives.

The comp is acceptable salts, can contain other existing start that may be suitable for treatment of the above disorders or diseases.

Input dose depend on the nature and significance of the disease, connections, and route of administration. They are usually 20-100 mg per day for adult oral and 3-10 mg in the form of injections.

Below are examples of sample compounds of the invention.

Example 1. 2-[3-(2-Chlorophenyl)-1,2,4-thiadiazolyl-5-amino - carbonyl]indol-1-acetic acid and its methyl ester.

Formula (I):

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where P=H or CH3-.

a) 2-Chlorobenzamidine.

To 200 ml saturated with gaseous florodora methanol added 56 g of 2-chlorobenzonitrile at a temperature of about 0oC. the Mixture is maintained at +5oC overnight (in the refrigerator). Then the reaction mixture is evaporated without heating, the residue is treated with 200 ml of anhydrous methanol. The solution is cooled to a temperature of about 0oC and put gaseous ammonia until alkaline pH-values. Reaction medium was heated for 3 hours. After evaporation to dryness, 2-chlorobenzamidine purified by column chromatography on silicon dioxide b) 5-Chloro-3-(2-chlorophenyl)-1,2,4-thiadiazole.

To a cooled to -10oC a mixture of 37 g of 2-chlorobenzamidine-bromhidrosis in 160 ml of dichloromethane was added dropwise 36 g trichloromethylsulfuryl-chloride, dissolved in 160 ml of dichloromethane. After stirring for 30 minutes on Wednesday, keeping the temperature -10oC, was added dropwise 65 ml of aqueous 50% NaOH solution. The solution is left to stand to raise to room temperature and stirred for 2 hours. In the reaction medium, water is added and decanted. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness.

C) 5-Amino-3-(2-chlorophenyl)-1,2,4-thiadiazole.

In the autoclave obtained in the previous stage, the crystals are suspended in 100 ml of methanol and cooled add a large excess of liquid ammonia. Leave the temperature to rise to room temperature and stirred for 24 hours, before concentrating to dryness. The target product was then purified by column chromatography on silica (eluting agent: dichloromethane/hexane = 80/20).

So pl. 136oC. the Total yield of stages b) and C) is 61%.

g) (Methyl)-2-[3-(2-chlorophenyl)-1,2,4-thiadiazolyl-5 - aminocarbonyl]-indol-1-acetate.

3.6 ml of Pyridine are dissolved in 40 ml of dichloromethane and to ablaut 3 g of 1-(methoxycarbonylmethyl)- indolyl-2-carboxylic acid. Stirred for 30 minutes at the same temperature, then added in several portions of 2.4 g of 5-amino-3- (2-chlorophenyl)-1,2,4-thiadiazole. Leave the temperature of the reaction mixture to rise to room temperature and stirred for 18 hours. The reaction medium is washed with water, the solution is decanted, the organic phase is dried over sodium sulfate and evaporated to dryness. The product was then purified by column chromatography on silica [eluting agent: dichloromethane/methanol = 95/5], and then recrystallized from diisopropyl ether.

So pl. 197oC. Yield 69%.

d) 2-[3-(2-Chlorophenyl)-1,2,4-thiadiazolyl-5-aminocarbonyl] - indol-1-acetic acid.

1 g (Methyl)-2-[3-(2-chlorophenyl)-1,2,4-thiadiazolyl-5 - aminocarbonyl]-indol-1-acetate are suspended in 20 ml of methanol and, at room temperature, add 7 ml of 1 N. aqueous solution of NaOH. The mixture is stirred for 3 hours at room temperature; reaction medium concentrate; add water and brought to pH = 3 by adding KHSO4. Allocate sediment.

So pl. 255oC. Yield 92%.

Example 2. 2-[3-(2,4,6-Trimethoxyphenyl)-1,2,4-thiadiazolyl-5 - aminocarbonyl]indol-1-acetic acid and its methyl ester.

Formula (I): is hydroxylaminopurine in 100 ml of ethanol at a temperature of approximately 15oTo add a solution of ateleta sodium obtained by dissolving 4.3 g of sodium in 100 ml of ethanol. On Wednesday introduced 12 g of 2,4,6-trimethoxybenzoyl, then, before evaporation to dryness, refluxed for 41 hours. The crystals are washed with water and dichloromethane.

So pl. 205oC. Yield 71%.

b) 2,4,6-Trimethoxybenzamide.

In the autoclave, 3.4 g of 2,4,6-trimethoxybenzamide dissolved in 120 ml of methanol/dichloromethane/acetic acid [2:2:1 by volume)] and hydronaut under pressure 2106PA in the presence of 1 g of Raney Nickel. After hydrogenation for 2 hours, the catalyst was separated and concentrated to dryness.

C) 5-Chloro-3-(2,4,6-trimethoxyphenyl)-1,2,4-thiadiazole.

Obtained in the previous stage resin dissolved in 20 ml of dichloromethane, cooled to -10oC and added dropwise 2.8 ml trichlorocarbanilide dissolved in 20 ml of dichloromethane.

The reaction medium is stirred for 30 minutes at -10oC, was added dropwise 5 ml of aqueous 30% NaOH solution and then stirred for 2 hours at room temperature, after which the reaction medium, water is added; after decanting, the organic phase is washed with water, dried over sodium sulfate and evaporated, DOI stage, the crystals are suspended in 100 ml of methanol and cooled add a large excess of liquid ammonia. The mixture is left to rise to room temperature and stirred for 18 hours, then evaporated to dryness. To the residue was added 100 ml of aqueous 2n. hydrochloric acid; the precipitate is filtered off, washed with water, then with acetone.

So pl. 215oC (hydrochloride). The output of all three stages of 41%.

d) (Methyl)-2-[3-(2,4,6-trimethoxyphenyl)-1,2,4 - thiadiazolyl-5-aminocarbonyl]indol-1-acetate.

1.5 ml of Pyridine was dissolved in 20 ml dichloromethane and at a temperature of about -5oC add 0,34 ml of thionyl chloride. Leave on for 30 minutes at -5oC and portions add 1 g of 1-(methoxycarbonylmethyl)-indolyl-2-carboxylic acid. The mixture is stirred for 30 minutes at the same temperature, then added in several portions 1.24 g of 5-amino-3-(2,4,6-trimethoxyphenyl)- 1,2,4-thiadiazole-hydrochloride; leave to stand for increasing the temperature up to room temperature and the mixture is stirred for 18 hours. The reaction medium is washed with water. After decanting, the organic phase is dried over sodium sulfate and evaporated to dryness. The target product was then purified by column chromatography on silica (eluting agent: dichloromethane/methanol = 95:5) and crystallized from diisopropyl ether.

So pl. acid.

0.7 g (Methyl)-2-[3-(2,4,6-trimethoxyphenyl)-1,2,4-thiadiazolyl - 5-aminocarbonyl] indol-1-acetate are suspended in 15 ml of methanol and, at room temperature, added to 4.4 ml of aqueous 1N. NaOH solution. The solution was stirred at room temperature for 3 hours. The reaction medium is evaporated. Add water and bring the pH to 3 by adding KHS04. The formed precipitate was separated.

So pl. 260oC. Yield 65%.

Example 3. 2-[3-(2,6-Dimethoxy-4-were)-1,2,4-thiadiazolyl-5 - aminocarbonyl]-indol-1-acetic acid and its methyl ester.

Formula (I):

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where P=H or CH3.

(a) 2,6-Dimethoxy-4-methyl-benzoic acid.

To 200 ml of tetrahydrofuran, add 104 ml of a 1.6 M solution of n-utility in hexane, then at a temperature of 0-5oC was added dropwise 25 ml of 3,5-dimethoxy-toluene. Stirred at 5oC for 1.5 hours, then for 30 minutes in the reaction medium is injected excess gaseous CO2. The mixture is introduced into 200 ml of water of 0.5 n HCl solution and the aqueous phase extracted with ethyl acetate. The remainder of the concentrate and chromatographic on a column of silica (eluting agent: dichloromethane/methanol = 93/7).

So pl. 178oC. Yield the methane and to the solution was added dropwise to 6.7 ml of oxalicacid, maintaining the temperature of 10oC. the Mixture is left for 4 hours at room temperature, then evaporated to dryness; the residue is poured onto 100 ml of liquid ammonia and the mixture is left at 20oC for 18 hours in an autoclave. After evaporation to dryness, the residue is poured onto a mixture of water with ethyl acetate and the desired product is extracted in the organic phase. The product was then purified by column chromatography on silica (eluting agent: dichloromethane/methanol = 9:1).

So pl. 201oC. The Yield Was 73%.

C) 2,6-Dimethoxy-4-methylbenzonitrile.

3 g of Amide are suspended in 60 ml of toluene and added 3.7 g of reagent Lawesson, after which the mixture is heated at 90oC for 1.5 hours. The reaction medium is evaporated to dryness and the residue treated with ethyl acetate; the organic solution is washed with aqueous solution of NaOH, dried and concentrated. The residue is purified by column chromatography on silica (eluting agent: dichloromethane/toluene = 1:1).

So pl. 122oC. Yield 92%.

g) 2,6-Dimethoxy-4-methylbenzamide.

To a solution of 2.6 g videolooking benzonitrile in 30 ml of ethanol is added to 2.2 g of hydroxylamine-hydrochloride, then of 1.34 g of NaOH in the form of tablets. Boil reverse 1H. HCl solution and washed with ethyl acetate; by adding aqueous 1N. NaOH solution and the pH of the solution was adjusted to 5 and then amidoxime-hydrochloride extracted with ethyl acetate.

So pl. 140oC. A Yield Of 75%.

d) 5-Amino-3-(2,6-dimethoxy-4-were)-1,2,4-thiadiazole.

In the autoclave injected 3.2 g of 2,6-dimethoxy-4-methyl-benzamidoxime in the form of a solution in 50 ml of methanol and add 400 mg of Raney Nickel; hydronaut at 20oC under pressure 1,4106PA of hydrogen for 12 hours. The catalyst is filtered off on a layer of talc and methanol, the filtrate is evaporated to dryness. The remaining yellow oil is dissolved in 50 ml of dichloromethane and 20oC add 2,84 g trichloromethylsulfuryl-chloride, and then, if -10oC, was added dropwise 20 ml of a solution of 3 g of NaOH in 20 ml of water. After adding leave the temperature of the reaction mixture to rise to 20oC and the mixture is stirred for 3 hours. After the reaction mixture is extracted with dichloromethane target product. This oil is dissolved in a mixture of 40 ml of methanol and 10 ml of dichloromethane and, after cooling, is introduced into the autoclave containing 200 ml of liquid ammonia; after incubation for 12 hours at room temperature, the residue is concentrated and treated it the Noah chromatography on silica (eluting agent: dichloromethane/methanol = 96/4).

So pl. 117oC. Yield total 58%.

(e) (Methyl)-2-[3-(2,6-dimethoxy-4-were)-1,2,4 - thiadiazolyl-5-aminocarbonyl]indol-1-acetate.

Inject 1 ml of pyridine in 10 ml of dichloromethane at 0oC, then 0.25 ml of thionyl chloride; after 30 minutes in the reaction medium portions add 0.2 g of acid chloride of 1-/methoxy-carbonylmethyl/indolyl-2-carboxylic acid, is then added dropwise 0.8 g of 5-amino-3-/2,6-dimethoxy-4-were/-1,2,4-thiadiazole in the form of a solution in 10 ml of dichloromethane. The reaction mixture is left for 5 hours at 20oC, then type in one volume of water. Separated from the mixture of the organic phase, dried and solvent is evaporated. The obtained yellow oil purified by column chromatography on silica (eluting agent: dichloromethane/diethyl ether 95/5). The product is recrystallized from isopropanol.

So pl. 122oC. Yield 65%.

g) 2-[3-(2,6-Dimethoxy-4-were)-1,2,4-thiadiazolyl-5 - aminocarbonyl] -indol-1-acetic acid.

0.35 g videolooking difficult methyl ester is introduced into 5 ml of methanol, and then injected 1.5 ml aqueous 1N. NaOH solution. After stirring for 6 hours the methanol is evaporated, the residue is poured onto 50 ml of water, and the medium is acidified with water is comfort. The product is obtained as yellow crystals.

So pl. 235oC. Yield 82%.

Example 4. N-[3-(2,6-Dimethoxy-4-were)-1,2,4-thiadiazole-5-yl] -1-(2-Tetra-hydroporini)-indolyl-2-carboxamide.

Formula (I):

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1.8 ml of Pyridine is introduced into 20 ml of dichloromethane. Bring the mixture to 0oC and add back of 0.36 ml of thionyl chloride. 30 minutes later portions impose 1.2 g of acid chloride of 1-(2-tetrahydropyranyl)- indolyl-2-carboxylic acid, is then added dropwise 1.2 g of 5-amino-3- (2,6-dimethoxy-4-were)-1,2,4-thiadiazole in the form of a solution in 10 ml of dichloromethane. After 3 hours of incubation at -20oC, in the reaction medium is injected the same volume of water and the aqueous phase is extracted with dichloromethane. The organic phases are then dried and concentrated. The residue is purified by column chromatography on silica (eluting agent: dichloromethane/methanol = 99/1).

So pl. 142oC. Yield 80%.

Example 5. N-[3-(2-Chlorophenyl)-1,2,4-thiadiazole-5-yl]-1-(2 - tetrahydropyranyl)-indolyl-2-carboxamide.

Formula (I):

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Get as in example 4 from 5-amino-3-(2-chlorophenyl)-1,2,6,4 - thiadiazole, which melts at 136oC.

So pl. 182oC. Yield 90%.

Example 6. N-[3-(2,6-Dimethoxy-4-methylphen astonaut in 25 ml of methanol and add 0.8 ml of aqueous 6N. HCl solution. Refluxed for 6 hours, then the solvent is evaporated, the target product is extracted from the water environment dichloromethane.

So pl. 247oC. Yield 94%.

Example 7. N-[3-(2-Chlorophenyl)-1,2,4-thiadiazole-5-yl] - indol-2-carboxamide.

Formula (I):

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Get as in example 6, from the compound of example 5.

So pl. 291oC. Yield 86%.

Example 8. N-[3-(2-Chlorophenyl)-1,2,4-thiadiazole-5-yl] chinolin-2-carboxamide.

Formula (I):

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The target compound obtained using the method of example 1 and on the basis of the corresponding carboxylic acid.

So pl. 214oC. Yield 85%.

Example 9. N-[3-(2-Chlorophenyl)-1,2,4-thiadiazole-5-yl] [5,6-dihydro-(/4H/- pyrrol-/3,2,1-ij/chinolin)]-2-carboxamide.

Formula (I):

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Using the method of example 1 and on the basis of the corresponding carboxylic acids get the target connection.

So pl. 195oC. Yield 79%.

Acting according to the preceding examples 1-9, get the compounds of formula (I) of examples 10-21 listed in the following table.1. The intermediate 5-amino-1,2,4-thiadiazole P1-P4, leading to the compounds of examples 10-21, are listed in table.2.

the used test method in vitro, described in the journal European Journal of Pharmacology, 232 (1993).

Testing new compounds were carried out in terms of their impact on communication cholecystokinin with its receptors.

The first test relates to the CCK receptor type a, which defined the relationship with cholecystokinin CCK receptor type a membrane preparation of rat pancreas using 40 μg protein/tube membranes of the pancreas and 40 RM radiochango CCK. After incubation at 25oC for 40 min incubation mixture was applied to the incubation buffer in a volume of 1 ml, chilled with ice, with the addition of 0.5% BSA were placed in microcentrifuge and centrifuged at 10 000 g for 5 minutes. The supernatant was removed and radioactivity was determined the lower part of the gamma-scintillation counter.

To determine the effects of the compounds on receptor CCK measured the relation between cholecystokinin with its receptor in the absence and in the presence of the compounds taken in a concentration of 0.5 nm. The results were analyzed using repeated nonlinear regression. Each point represented the average of triple measurements, and the line was determined by regression analysis.

Second ispytannye using 300 μg protein/tube membranes of the cerebral cortex and 25 RM radiochango ligand. After 90 min incubation at 25oC the reaction was stopped and identified a connection with CCK, as described above for CCK receptor type A.

The results are given in table. 3, in which the indicator IC50means the concentration that inhibits 50% due CCK with its receptors.

To illustrate the compositions proposed several possible formulations:

Example formulations for tablets, mg:

The active compound of formula I - 5

Lactose - 60

Polyvinylpyrrolidone - 5

Microcrystalline cellulose - 25

Sodium salt of carboxymethyl amylum - 4

Magnesium stearate - 1

An example recipe for gelatin capsules size n1, mg:

The active compound of formula I - 50

Magnesium stearate - 10

Lactose - 140

Sample preparation for injection, mg:

The active compound of formula I - 10

Inositol - 100

Benzyl alcohol - 20

1. Derivatives of 5-acylamino-1, 2, 4-thiadiazole formula (I)

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in which Ar is an aromatic nitrogen-containing heterocycle selected among chinoline, izochinolina, indolyl, the latter may be substituted on nitrogen by a group W, where W is selected from the group including: (a) -(CH2)nCOR, where n = 1 or 2, R denotes a OR1where Rposledni carbon atom which is fixed on the phenyl indole nucleus with the formation of 6-membered heterocycle;

Z represents the group (a)

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where A and B imply C;

X1- X4identical or different, denote a hydrogen atom, a chlorine atom or bromine, (C1- C3)-alkyl group, (C1- C3)-CNS group or triptorelin group;

naftalina group

and their pharmaceutically acceptable salts.

2. The compounds of formula (I) under item 1, in which Ar is an aromatic nitrogen-containing heterocycle selected from hineline, izochinolina, indolyl, and specified indole group may be substituted on nitrogen by a group of CH2OR, in which R denotes a OR1where R1is hydrogen or (C1- C4)-alkyl; tetrahydropyranyl or a group -(CH2)3- last carbon atom which is fixed on the phenyl indole nucleus with the formation of 6-membered cycle; Z represents a group (a)

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where A and B imply C;

X1- X4the same or different, is hydrogen, (C1- C3)-alkyl, (C1- C3-alkoxy, Cl, Br or trifluoromethyl,

and their pharmaceutically acceptable salts.

3. The compounds of formula (I) under item 1, in which at least 3 of the groups X1- X4identical or different, denote a hydrogen atom, or (C1- C1
X2and X3are in positions 2, 4 or 6 of the aromatic nucleus and denote methyl or methoxy group.

5. The compounds of formula (I) according to any one of paragraphs.1 to 3, in which A denotes a 2-indolering group, in some cases substituted on nitrogen by a group W, where W is selected from the group including: (a) -(CH2)nCOR, where n = 1 or 2, R denotes a OR1and R1selected from hydrogen and (C1- C4)-alkyl; b) tetrahydropyranyl in) chain -(CH2)3- last carbon atom which is fixed on the phenyl indole nucleus with the formation of 6-membered heterocycle.

6. The compounds of formula (I) under item 1, in which X1located in position 2, means a methoxy group, and X2and X3independently of one another denote methyl or methoxy group.

7. The method of obtaining derivatives of 5-acylamino-1,2,4-thiadiazolo formula I according to any one of paragraphs.1 - 6, characterized in that the derivative of 5-amino-thiadiazole of the formula (II)

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in which Z is specified in paragraph 1 value,

enter into interaction with a reactive derivative of the acid of the formula Ar COOH, in which Ar' has the values specified in paragraph 1 for Ar, or represents the derived Ar, in which reacciones reactive centers of the aromatic nucleus Ar.

8. Pharmaceutical composition having an affinity for cholecystokinin receptors containing the active principle and a pharmaceutically acceptable additive, characterized in that the active agent it contains derivatives of 5-ALLO-1,2,4-thiadiazolo formula I

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where the radicals Ar and Z have the values listed in paragraph 1,

in an effective amount.

 

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The invention relates to new derivatives of 2-amino-4-phenylthiazole and their salts, and method of production thereof and to pharmaceutical compositions based on them

The invention relates to new derivatives of 2-benzothiazole of the formula I, where one of the substituents R1and R2the hydroxy - group, while the other denotes hydrogen, or its pharmaceutically acceptable salt accession acid

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to pharmacy - suppositories with vasodilator and antispasmodic effect

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to the field of pharmacy and for the preparation of soft medicinal forms, including ointments buttonboy

The invention relates to a series of new derivatives of 1-biphenylether imidazole having hypotensive activity and are therefore intended for the treatment and prevention of hypertension, including heart disease and circulatory system

The invention relates to pyrazole derivative of the General formula I

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in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;

R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

The invention relates to medicine and can be used in the treatment of stress lesions of the nervous system in combustionengines, traumatic, neurological and surgical hospitals
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