N-phenylamine and n-pyridylamino derivatives, method for their production and containing pharmaceutical compositions

 

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula Iin which X denotes O or S; R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl; R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different; Y represents halogen; R4and R5represent hydrogen; Ar denotes one of the following groups or:T represents hydrogen or (C1-C6)alkyl;
T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;
R6and R7each denotes hydrogen or R6and R7together represent a bond;
Z denotes either (I) the divalent group-chr9-, in which R9denotes a hydrogen atom or (C1-C9)alkyl, or (II) the divalent group is-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-chr12-chr13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,
as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them. These compounds are inhibitors cholesterol-acyltransferase (AST) and can be used in medicine. The technical result is to get new N-phenylamine and N-pyridylamine derivatives possessing valuable bioactive properties. 4 C. and 11 C.p. f-crystals., 9 table.

The invention relates to new N-phenylamine and N-pyridylmethyl derivatives, to methods of producing these compounds, containing their pharmaceutical compositions and to their use as pharmaceuticals, in particular in the treatment of hyperip the courts, responsible for the formation of atherosclerotic plaques that cause various cardiovascular diseases. More specifically, the atherosclerotic plaque is a form of arteriosclerosis characterized by excessive accumulation of lipids, in particular esters of cholesterol in the walls of blood vessels. Recently it was found that the enzyme acyl-COA-cholesterol-acyltransferase (ACAT), responsible for the esterification of cholesterol. In addition, the correlation between increased activity of this enzyme and accumulation of esters of cholesterol in the vessel wall. It is also known that the cholesterol from food in the body, absorbed in the free form and then tarifitsiruetsya putting AST for admission into the bloodstream in the form of lipids very low density lipoproteins (VLDL) and/or in the form of chylomicrons.

Despite the fact that have been identified by some inhibitors of ACAT (see , for example, EP 295637, EP 415413 and EP 497201), development of new ACAT inhibitors with improved therapeutic properties continues.

Attempts have been made to create inhibiting AST products, can prevent the absorption of intestinal cholesterol from food and from bile and vozdeistvovat what about the family of N-phenylamine and N-pyridylamine derivatives and to the discovery of the fact, such products in relation to vascular AST are extremely strong inhibitory activity associated with intensive antihyperlipidaemic effect in animals of different species.

These properties of the compounds according to the invention lead, in particular, the possibility of their use primarily with hyperlipidemia and atherosclerosis.

Compounds according to the invention correspond more specifically to the formula

in which X denotes O, S or CH2,
R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl,
R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different, or a 5-7 membered heteroaryl, containing 1-3 ring heteroatoms selected from O, S and N, which is optionally substituted by one or more radicals Y, which may be the same or different,
Y represents halogen, (C1-C6)alkyl, optionally substituted ar is ascoltami halogen atoms, (C1-C6)allylthiourea, optionally substituted by one or more halogen atoms, (C1-C7)allmenalp, (C1-C3)acyloxy, hydroxyl, nitro-, cyano-, amino-, (C1-C6)alkylamino-, di(C1-C6)alkylamino-, pyrrolidino-, piperidino, morpholino-, (C1-C4)alkylsulfonamides, (C2-C5)alkoxycarbonyl, carboxyl, (C2-C6)alkylsulphonyl, carbarnoyl, (C2-C5)allylcarbamate, di(C2-C5)allylcarbamate or (C1-C6)alkylsulfonyl,
R4and R5that may be the same or different, represent a radical Y or hydrogen,
AG denotes one of the following groups a, b or C:


T1and T2that may be the same or different, represent halogen, (C1-C6)alkoxy, (C1-C6)allylthiourea or (C1-C6)alkyl,
T represents hydrogen or (C1-C6)alkyl,
T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio-, (C6-C12)arylcarbamoyl or -(CH2)p-OR, in which R denotes 1, 2, 3 or 4, and R denotes a (C2-C3)alkyl,
R6and R7each represent hydrogen or
R6and R7together denote a bond,
Z denotes either
(I) the divalent group-chr9-, in which R9denotes hydrogen or (C1-C6)alkyl, or
(II) the divalent group-chr10-chr11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or
(III) a divalent group-chr12-chr13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,
as well as their additive salts with pharmaceutically acceptable acid or base.

Additive salts of these compounds with pharmaceutically acceptable acids and bases are also part of the invention. Examples of these salts are the salts formed with hydrochloric acid, p-toluensulfonate sour estevadeordal acid, phosphoric acid, methanesulfonic acid, tartaric acid and almond acid.

In some cases, the compounds according to the invention are characterized by the presence of one or more chiral centers. It should be noted that each stereoisomer falls under the scope of the invention.

(C1-C6)alkyl represents a linear or branched saturated hydrocarbon radical with 1-6 carbon atoms. Therefore, (C1-C6)alkoxygroup is a group alkyl-O-, and (C1-C6)allylthiourea represents a group of alkyl-S-, alkyl which has the values listed above.

Next, (C3-C8)cycloalkyl denotes a saturated mono - or bicyclic hydrocarbon radical containing 3-8 carbon atoms. Examples are cyclopropyl, cyclohexyl, cyclopentyl and cycloheptyl.

In addition, (C6-C12)aryl denotes a mono - or polycyclic aromatic group containing 6 to 12 carbon atoms, such as phenyl, naphthyl and antril. So, for example, (C6-C12)aristocrata is a radical (C6-C12)aryl-S-.

As examples 5-7-membered heterocycle, containing 1-3 ring heteroatoms, wybranie, pyridazine, pyrimidine and pyrazin.

The halogen atoms are chlorine atoms, bromine, fluorine and iodine.

The term "acyl" refers to alkylcarboxylic radical. So, for example, (C1-C7)alluminare is a (C1-C7)alkylcarboxylic, and (C1-C3)acyloxy is a (C1-C3)alkylcarboxylic.

Among these compounds has 6 subgroups preferred compounds.

The first subgroup comprises compounds of formula I in which Y denotes a halogen atom, (C1-C6)alkyl, (C1-C6)alkoxy or trifluoromethyl.

The second subgroup includes the compounds of formula I, in which
R1and R2which may be identical or different, denote hydrogen, or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl,
R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different,
Y represents halogen,
R4and R5each denotes hydrogen,
AG denotes one of the following groups a, b or C:

1
-C6)alkyl,
T represents hydrogen or (C1-C6)alkyl,
T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)allylthiourea,
R6and R7denote hydrogen or R6and R7together denote a bond,
Z denotes either
(I) the divalent group-chr9-, in which R9denotes hydrogen or (C1-C6)alkyl, or
(II) the divalent group-chr10-chr11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11denote hydrogen.

The third subgroup comprises compounds of formula I in which Z denotes-chr12-chr13-CH2- and the values of R12and R13above.

Among the compounds of the first, second and third subgroups presented above, more preferred are those in which R1and R2denote hydrogen.

The fourth subgroup are compounds of formula I, in which X denotes O or S, a R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl.

Fifth is denotes the group-CH=CH - or-CH= SNSN2.

Usually in a preferred embodiment, AG denotes 2,4-dimethyldi-6-methyl-3-pyridyl, 2-methoxy-4-hexylthio-3-pyridyl or 2,6-diisopropylphenyl.

The sixth subgroup are compounds of formula I, in which X denotes CH2.

Among these compounds, more preferred are those in which AG refers to a group In a or C. it is particularly preferred values for AG are 2,4-dimethyldi-6-methyl-3-pyridyl and 2-methoxy-4-hexylthio-3-pyridyl.

In accordance with the preferred execution of the invention the radical R3preferably represents phenyl which is optionally substituted, pyridyl or thienyl, each of which is optionally substituted, such as, for example, 2-pyridyl or 2-thienyl, which is optionally substituted in the 5-th position.

Compounds according to the invention can be obtained by the reaction of a combination of an acid of formula II

which R1, R2, R3, R4, R5, R6, R7and Z have the values listed in paragraph 1 of the claims, with an aromatic amine of the formula III
Ar-NH2(III)
in which AG has the values listed above.

This method, as well as, preferred is the combination of the acid of formula II with the amine of formula III can be carried out by implementing a simple interface amine of formula III with an activated derivative of the acid of formula II, such as the acid chloride, ester or mixed anhydride of the acid.

In addition, specialists in the art will know that you can perform amination of the following activated acid derivatives: Po-CO-SH, Po-CO-SR, Ro-COSe-Me, RoCO- (OR)2(Po-COO)4Si, Rabout-CO-C(hal)3or Ro-CO-N3where Paboutdoes

hal denotes a halogen atom, and
R denotes (C1-C6)alkyl.

Methods of activation of organic acids in the art known.

Moreover, the reaction mix acid of formula II with the amine III can be performed using any method, which is used in liquid-phase synthesis of peptides. These methods are described, for example, in "Methods of Peptide Synthesis", T. Wieland and N. Determann, Angew. Chem. Interm., the publication in English. Jaz., 2, 358 (1963).

For example, the anhydrides of the acids of formula II can be obtained when exposed SOCl2, oxalicacid, l3or PCl5.

The acid chloride of the acid can also be obtained by exposure of triphenylphosphine in carbon tetrachloride on the acid of formula II.

To obtain bromohydrin acids may be used the corresponding brominated REGO anhydride may be mentioned the impact of bis(2-oxo-3-oxazolidinyl)phosphinic acid on the acid of formula II. In a preferred variant of this reaction, like most of the activation reactions, carried out in the presence of a base. This may serve or pyridine, or Ethylenediamine, or 4-dimethylaminopyridine.

Thus, in accordance with the preferred execution of the invention the compounds of formula I get
- implementation of the following stages (I) and (II):
(I) an acid of formula II is treated with oxalylamino in the presence of dimethylformamide, and then
(II) the compound obtained in stage (I) enter into interaction with the amine of formula III,
or alternatively
- implementation of the following stages (I) and (II):
(I) an acid of formula II is treated with bis(2-oxo-3-oxazolidinyl)phosphinic acid in the presence of a base, and then
(II) the compound obtained in stage (I) enter into interaction with the amine of formula III.

The reaction mix acid II with the amine III can be carried out in accordance with, for example, the following two methods.

Method And
In accordance with this method before the reaction mix with the amine III acid of formula II can activate in the form of a carboxylic acid.

The reaction oxalicacid acid of formula II is carried out in non-polar aprotic solvent such as ug is of dimethylformamide is introduced into a solution of the compounds of formula II, the temperature maintained within the range of 15-25oC, preferably at room temperature. Next, the reaction medium is heated to a temperature in the range of 30-70oWith, for example up to the boiling point of the used solvent. The reaction course is monitored by means of thin layer chromatography (TLC). Then before adding aromatic amine III and bases, such as pyridine or 4-dimethylaminopyridine, the solvent is evaporated and the residue is dissolved in a nonpolar aprotic solvent such as, for example, previously used halogenated hydrogen. This reaction continued for such a period of time whose duration is necessary in the conditions of temperature within the 15-85oC, preferably at room temperature.

Method B
In accordance with this method before the reaction mix with the amine III acid of formula II can activate in the form of a mixed anhydride. In the solution of the acid of formula II in non-polar aprotic solvent such as halogenated hydrocarbon, introducing a weak base, such as triethylamine, after which the reaction medium is heated to a temperature in the range from -10 to 10oWith, preferably in the range from 0 to 5oC. Next add harangues injected into the reaction medium, moreover, the temperature of this latter maintained within the range from -10 to 10o(Preferably in the range from 0 to 5oC). After this base is introduced into the reaction environment in small portions in the form of a solution in non-polar aprotic solvent such as halogenated hydrocarbon.

Next, the resulting compound of formula I is isolated and purified.

Amines of formula III are either directly commercially available products or can be easily obtained from commercially available products.

In the rest of the description provides methods of preparing compounds of formula II.

The compounds of formula II in which Z denotes a group chr9- can be obtained in accordance with reaction scheme a, is provided at the end of the description.

The implementation of the first stage allows you to enter carboxaldehyde functional group.

The compound of formula VIII, in which R1, R2, R3, R4, R5and X have the meanings specified above, enter into interaction with phosphorus oxychloride. In the preferred embodiment, this interaction takes place in a polar aprotic solvent such as dimethylformamide (DMF). The reaction temperature ranges from -20oWith up to the house be monitored using thin-layer chromatography. The resulting aldehyde VII distinguish by conventional method: dilution of the reaction mixture to its introduction into the mixture with ice water, neutralization and subsequent extraction and purification.

The next stage of recovery of the aldehyde functional group to hydroxymethylene functional groups are using any of the methods known in the art, with the only condition that the reaction conditions must be such as not to cause undesirable side reactions. In appropriate cases, the reactive functional groups of the radicals R1, R2, R3, R4and R5protects.

Among the reagents which to this end normally uses, you can call alumoweld lithium, natrojarosite and nutritionrelated. When using natrojarosite, in the preferred embodiment, the reaction is performed in methanol/water at temperatures ranging from -40 to 0oC, more preferably in the range from -25 to -15oC. In this case, the compound obtained also distinguish by a known method.

Further selected so the alcohol of formula VI is converted into the corresponding alkylchloride. This transformation can be performed according to any method with the only usl is stuudy cases, the reactive functional groups of the radicals R1, R2, R3, R4and R5protects.

The known method is the treatment of the alcohol VI thionyl chloride in an inert solvent, such as, for example, aromatic hydrocarbons toluene or benzene type, at a temperature in the range from 15 to 30oC, preferably at room temperature.

For chlorination of compound VI can be used with other reagents, such as PCl5, l3or POCl3.

Then chlorinated compound of formula V is treated with a cyanide of an alkali metal (MCN), such as sodium cyanide in a polar solvent such as DMF. Depending on the reactivity of the chloride V the reaction temperature is maintained within the range of from 0 to 50oC. When MCN is a sodium cyanide is usually acceptable temperature within 20-25oC. the resulting compound of formula IV is isolated and purified by a known method.

The compound of formula II in which R9denotes hydrogen, easily obtained from the nitrile IV acid or base treatment. This purpose can be used in the following reaction system:
NaOH/H2O2or aq. NaOH,
H2SO4,
HCOOH/NVG or Hcl,
Asón/F3,
AcOH/HCl.

is lne is acceptable mixture in a ratio of 1/1. In this case, in the preferred embodiment, a mixture of AcOH/HCl acts as a solvent, and temperature are important does not matter and is from 0 to 50oC, preferably from 15 to 25oC.

To obtain compounds of the formula I in which R9 denotes (C1-C6)alkyl, the corresponding compound of formula II in which R9denotes hydrogen, is treated with alkylhalogenide formula R9-X, in which X denotes a halogen atom, a group (C1-C6)alkylsulfonate or (C6-C10)arylsulfonyl, optionally substituted (C1-C6)alkyl, a R9means (C1-C6)alkyl, in the presence of a strong base capable of removing a hydrogen atom in the-position relative to the position of the carboxyl functional group in the compound of formula II (R9denotes H). Such a base is, for example, diisopropylamide lithium (DAL).

In accordance with the preferred option GAVE obtain in situ from n-utility and Diisopropylamine at a temperature in the range from -15 to 5oC, preferably at about 0oC. the Solvent used to get MADE, is a polar aprotic lastly II. The reaction temperature is, for example, from 15 to 35oC, preferably from 20 to 25oC.

When the compound of formula I is a compound, which Z represents the group-chr10-chr11- it can be obtained in accordance with reaction scheme B, is given at the end of the description.

The introduction of a bromine atom in the compound of formula VIII is carried out by exposure to N-bromosuccinimide (N-BS) to the compound of formula VIII dissolved in proton polar solvent, such as dimethylformamide, in the absence of moisture. The reaction is carried out, for example, at room temperature. However, depending on the reactivity of the compounds of formula VIII, the reaction temperature can be varied in the range from 10 to 35oC.

The next stage is to transform the received brominated derivative of the formula IX to the compound of formula X. For this alkylacrylate formula H2C=CH-COOR, in which R denotes a (C1-C6)alkyl, enter into interaction with brominated derivative IX in the presence of palladium acetate, a phosphine and a base. The reaction should be carried out in a polar aprotic solvent such as dimethylformamide.

As a basis you can use Treaty the e PAr'3where AG' in the preferred embodiment, means (C6-C12)aryl, optionally substituted (C1-C6)alkyl. Rag'3represents, for example, triphenylphosphine or trailerteen.

For effective reaction initially introduced in the contact between a compound of formula IX, dissolved in DMF, a base, a phosphine and a palladium acetate, and then the reaction mixture was added to the acrylate of the formula CH2=CH-COOR.

The resulting ester of formula X emit the usual way, after which amyraut by a known method of obtaining the compounds of formula II in which R10and R11together form a bond.

The use of this compound as a starting material makes it easy to get all of the compounds of formula II in which Z represents-chr9-chr10-.

So, for example, obtained by the above method, the acid of formula II

subjected to catalytic hydrogenation. The proper regulation of hydrogenation conditions can receive either a compound of the formula II in which each of R6, R7, R10and R11denotes a hydrogen atom, or a compound of the formula II in which R6and R712-chr13-CH2- can be obtained by Wittig reaction using as the starting material aldehyde of formula VII (scheme A). It is possible, for example, using a system of reagents, including (I) phosphorylated formula ROOC-CH2-CH2-P+A3hal-in which R denotes hydrogen or (C1-C6)alkyl, hal denotes a halogen atom, and the values And select from (C6-C12)aryl, optionally substituted (C1-C6)alkyl, and (II) a base, such as tert-piperonyl alkali metal (tBuOK), alkali metal hydride (NaH) or alkality (C4H9Li). This reaction can be successfully carried out in a polar aprotic solvent such as dimethylformamide or tetrahydrofuran, at a temperature in the range from 0 to 30oC.

Another object of the present invention is a pharmaceutical composition comprising at least one compound of formula I in combination with one or more pharmaceutically acceptable carriers.

As carriers can be used, for example, fillers, diluents, binders, wetting agents, disintegrating agents, surface-Akti the drugs in doses at one time, including tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), etc.

For the preparation of tablets, you can use the media known in the art, for example fillers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and etc., binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc, disintegrating agents such as dried starch, sodium alginate, powdered agar, kelp powder, sodium bicarbonate, calcium carbonate, esters of fatty acids and polyoxyethylenesorbitan, sodium lauryl sulfate, monoglyceride of stearic acid, starch, lactose, etc., inhibitors loosening, such as refined sugar, stearin, cacao butter, hydrogensource oil, etc., accelerators suction, such as Quaternary ammonium base, sodium lauryl sulfate, etc., wetting agents such as glycerin, starch, etc., agents that promote adsorption, such canny talc, salt of stearic acid, powdered boric acid, polyethylene glycol, etc.,

In the case of the manufacture of tablets for this last can, in addition, apply coatings using conventional coating, allowing thus to recycle them into tablets, coated in sugar, tablets coated with gelatin film tablet intersolubility coated tablets film-coated tablets with a two-layer or multilayer coating.

For the preparation of pills can be applied, for example, known carriers, which are usually used in the art, such as fillers, in particular glucose, lactose, starch, cacao butter, hydrogensource vegetable oils, kaolin, talc, etc., binders such as powdered Arabian gum, powdery tragacanth gum, gelatin, ethanol, etc., and leavening agents, such as powdered kelp, agar, etc.,

For the manufacture of suppositories you can apply the well-known carriers, which are widely used in the art, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

In the preparation of drugs for the OSC blood. For the preparation of drugs for injection can also be used carriers that are commonly used in the art, for example water, ethyl alcohol, propylene glycol, ethoxylated isostearoyl alcohol, polioksidony isostearoyl alcohol, esters of fatty acids and polyoxyethylenesorbitan, etc. In this case, to obtain a solution isotonicity in the target pharmaceuticals can add the appropriate quantity of sodium chloride, glucose or glycerin. Moreover, when appropriate, in the target pharmaceuticals can add dissolving agents, buffers, analgesic agents, which are usually used, as well as coloring agents, preservatives, fragrances, additives that improve the sense of taste, sweetening agents and other medicines.

It was found that the compounds according to the invention are effective inhibitors of acyl-coenzyme A. They can be used in the treatment or prevention of hypercholesterolemia, atheromatous arteriosclerosis, and can prevent possible ischemic lesion, such as, for example, myocardial infarction or cerebrovascular disease.

Pharmacological its the project hepatic ACAT rats
Male Wistar rats weighing 220-250 g were killed by a fracture of the cervical vertebrae was removed liver was homogenized by ultracentrifugation for preparation of microsomal fractions. These microsome assay incubated with14With oleyl-coenzyme And according to the method described in P. J. Gillies and others in Exp. and Mol. Pathol. , 1986, 44, 329-339; lipids were extracted from incubate a mixture of methanol/chloroform and using thin-layer chromatography was identified14C-Reinholdtsen; data is that they reflect the activity of AST. The results were expressed as inhibitory concentration IR50, which is the concentration of compound that inhibits the activity of ASAT by 50%.

So, for example, IR50for compounds 1, 4 and 6 were respectively h-9, H-9and h-9mol/L.

Test B. Determine the absorption of cholesterol in the intestines of rats
The male Wistar rats weighing 230-250 g, starving for 24 h, were co-administered test compound orally and Triton WR 1339 intravenously over 1 h them again oral introduced3H-cholesterol, and after 3 hours they were taken in 1 ml of blood from retroorbital sinus; using 0.1 ml of serum was determined by the radioactivity of the blood, and this figure is characterized visiva the weight of the animal), which characterized the number of compounds inhibiting the absorption of cholesterol in the intestines by 50%.

For example, the values of the ED50for compounds 1, 4 and 6 were respectively equal to 0.005, 0,038 and is 0.023 mg/kg

Test Century Model of hypercholesterolemia
Proposed under item 1 of the claims of the compounds was tested by oral administration to animals of a diet enriched with cholesterol.

In particular, male Wistar rats were fed for 8 days food enriched to 2.5% cholesterol, and gave them within 2 days connection 1. The dose 0,78 mg/kg total cholesterol was reduced by 50%. The effect was manifested mainly in the lipids of very low density lipoproteins (VLDL).

So, for example, rabbits were fed for 15 days with food, enriched with 0.5% cholesterol, and at the same time they were given a connection 1. At the dose of 0.1 mg/kg
total cholesterol was reduced by 70%. The effect was manifested mainly in the lipids of very low density lipoproteins (VLDL).

Below, preferred embodiments of the invention are illustrated in the examples.

I. extraction of aromatic amines of the formula III
When AG denotes 2-(C1-C6)alkoxy-4-n-hexylthio-3-pyridyl, the reaction is carried out, neprimerna
In a 100-ml reactor protected from moisture, in the atmosphere of nitrogen load and 3.72 g (30 mmol) 2-methoxy-3-pyridylamine in the form of a solution in 30 ml of tetrahydrofuran, and then added dropwise at room temperature, add 60 ml (60 mmol) of bis(trimethylsilyl)amide sodium in the form of a 1 M solution in tetrahydrofuran.

After stirring the reaction mixture at room temperature for 20 min in this reaction mixture, which was kept at room temperature, added dropwise 6,54 g (30 mmol) of di-tert-BUTYLCARBAMATE.

After stirring at room temperature for 3 h, the tetrahydrofuran is evaporated. The residue is dissolved in ethyl acetate, washed with water, 0.1 M hydrochloric acid and then with water up until the pH value of the wash liquids are 7. After drying the organic phase over sodium sulfate and evaporating the solvent to obtain a substance in the form of a black oil, which chromatographic on silica gel (eluent: ethyl acetate/hexane in a ratio of 1/3). After evaporation of the solvent in the form of colored amber color oil gain of 6.1 g of substance, i.e., in other words, the output is 90,2%.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in the ratio of 1/2): Rf=0,4.

IR-spectrum:

Stage 2
tert-Butyl(4-n-hexylthio-2-methoxy-3-pyridyl)carbamate
In a reactor protected from moisture, in the atmosphere of nitrogen load 4,48 g (20 mmol) of the compound obtained in the previous phase, in solution in 100 ml of diethyl ether and 9,05 ml (60 mmol) of tetramethylethylenediamine.

After cooling the solution to -70oWith added dropwise to 37.5 ml (60 mmol) of 1.6 M solution of n-utility in hexane. The reaction mixture is stirred at -10oC for 2 h, and then at -70oWith added dropwise 14.1 g (60 mmol) of Vexillology.

After stirring the solution for 12 h at room temperature, the reaction mixture is dissolved in water and extracted with diethyl ether. The organic phase is washed with 0.1 M hydrochloric acid and then with water up until the pH value of the wash liquids are 7, and finally dried over sodium sulfate. After evaporation of the solvent in the form of oils are a substance that chromatographic on silica gel (eluent: ethyl acetate/hexane in a ratio of 1/5). After evaporation of the solvent to obtain 5.6 g of the substance in the form of an oil which crystallized, i.e., in other words, the output is 82,3%. Its melting point is the img src="https://img.russianpatents.com/chr/965.gif">NH=3171, WITH=1720 cm-1.

NMR-spectrum (CDC3): of 0.85 (t, 3H) and 1.3 (m, 4H), of 1.45 (m, 11H), a 1.7-1.8 (m, 2H), 3,0 (t, 2H), 4,25 (s, 3H), 6,7 (d, 1H, J=6,8 Hz), the 7.85 (d, 1H, J=6,8 Hz).

Stage 3
4-n-Hexylthio-2-methoxy-3-aminopyridine
In a 500 ml reactor with intensive stirring mix of 5.6 g (16,45 mmole) of the compound obtained in the previous phase, in the form of a solution in 140 ml of ethyl acetate and 140 ml of 4 M hydrochloric acid solution.

The reaction mixture is left to stand at room temperature for 12 hours Then this reaction mixture is neutralized with sodium bicarbonate (up until the pH value of the wash liquids are 7), then the organic phase is washed with water and dried over sodium sulfate, and then evaporated. Obtained in the form of oil substance chromatographic on silica gel (eluent: dichloromethane). After evaporation of the solvent in the form of oil get 3,63 g of substance, i.e., in other words, the output is of 91.8%.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in the ratio of 1/3): Rf=0,6.

The NMR spectrum (CDCl3): of 0.85 (t, 3H), 1,2-1,3 (m, 4H), to 1.3-1.4 (m, 2H), a 1.5-1.6 (m, 2H), 2,85 (t, 2H), 3,95 (s, 3H), 4,1 (s, 2H), 6,7 (d, 1H, J=6,7 Hz), and 7.4 (d, 1H, J=6,7 Hz).

II. Obtaining carboxylic acids of the formula II in which Z represents-chr10-chr11.

1. 3-{Spiro{cyclopentane-1,2'-[4'-(4'-ft N-benzopyran]}
In a reactor protected from moisture, loads of 43.4 g (0,3 mol) of N-bromosuccinimide in the form of a solution in 500 ml of dimethylformamide. In this solution, maintained at room temperature, added dropwise a solution to 70.1 g (0.25 mole) of Spiro{ cyclopentane-1,2'-[4'-(4-forfinal)-2 N-benzopyran]} in 1 l of dimethylformamide. The solution was stirred at room temperature overnight and then poured into 3 l of ice water. The reaction mixture was extracted with diethyl ether. Next, the organic solution washed with water (up until the pH value of the wash liquids are 7) and then dried over sodium sulfate. After evaporation of the solvent, the obtained solid was dispersed in 100 ml of ethanol, incubated at -20oC for 12 h, and then drain the liquid and dried. In this way receive of 68.7 g of the target product, i.e., in other words, the output is 76,5%. The melting point of this product is within 107-109oC (ethanol).

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in the ratio of 2/100): Rf=0,7.

Stage 2
Ethyl-3-{ Spiro{cyclopentane-1,2'-[4'-(4-forfinal)-2 N-3'-benzopyranyl]}} prop-2-ENOAT
In a reactor protected from moisture, load 14.1 g (39,25 mmole) of the compound obtained in the previous study the NML add a solution of 90 ml of triethylamine in 90 ml of dimethylformamide and then the reaction mixture is successively enter the following reagents: 0,72 g (2.3 mmole) three(2-tolyl)phosphine, 0.18 g (0,79 mmole) of palladium acetate, and then at room temperature is added dropwise 19,55 ml (of 180.5 mmole) acrylate.

Then the reaction mixture is refluxed (at 95oC) for 2 hours Then the reaction mixture was poured into a mixture of ice water, then acidified with concentrated hydrochloric acid to pH 1. The precipitate is extracted with methylene chloride, followed by washing the organic solution with water (up until the pH value of the wash liquids are 7), drying over sodium sulfate and evaporation.

In conclusion, the obtained solid was dispersed in 100 ml of ethanol and then drain the liquid. In this way receive a 10.5 g of the target product, i.e., in other words, the output is 70,8%. The melting point of the obtained compound is within 138-140oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 5/95): Rf=0,3.

IR-spectrum:WITH=1715 cm-1.

Stage 3
3-{ Spiro{ cyclopentane-1,2'-[4'-(4-forfinal)-2 N-3'-benzopyranyl] } } prop-2-ANOVA acid
18,92 g (50 mmol) of the compound obtained in the previous stage, poured into 700 ml of ethanol. To this solution was added 75 ml (75 mariwana obtained solid was dispersed in diethyl ether and the liquid drain. The solid material is again dissolved in water and the insoluble fraction is filtered off. The aqueous phase is acidified with hydrochloric acid to pH 1 and then extracted with ethyl acetate. The organic phase is washed with water (up until the pH value of the wash liquids are 7), dried and evaporated. The obtained solid substance is dispersed in the pentane and liquid drain. In this way gain of 17.5 g of the target product, i.e., in other words, the output is 100%. The melting point of this product is within 172-174oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0,46.

IR-spectrum:WITH=1682 cm-1.

NMR-spectrum (Dl3): 1.5 to 2.5 (m, 8H), 5,5-5,8 (d, 1H), of 6.5-7.5 (m, 9H), 10 (s, 1 H).

Elemental analysis data: C22H19FO3to 0.25 mol H2Oh, Mw=354,87.

Calculated, %: C 74,39; H 5,49; N 5,35.

Found, %: C 74,65; H 5,58; N 5,39.

Stage 4
3-{Spiro{cyclopentane-1,2'-[4'-(4-forfinal)-2 N-3'-benzopyranyl]}}propanoic acid
In an autoclave under hydrogen pressure of 100 bar at 60oC for 2 h 30 min stand with stirring, a solution consisting of 7 g (20 mmol) of the acid obtained in the previous phase, 170 ml of tetrahydrofuran and 5 g of Raney Nickel. Pollout liquid. The melting point of the obtained compound is 177oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0,60.

IR-spectrum:CO=1706 cm-1.

2. Other acids of the formula II in which Z represents-chr10-chr11and their respective preceding ethers.

According to the method described above (in section II.1) 3-{Spiro{cyclopentane-1,2'-[4'-(4'-forfinal)-2 N-3'-benzopyranyl] } } propanoic acid, obtained acid of the formula II, are shown in table 1.

In table 1 the word "communication" means that R10and R11together form a bond, a 4-F-C6H4represents a radical of the formula

Table 2 summarizes the intermediate bromides, which are compounds presented in table 1.

III. Obtaining carboxylic acids of the formula II in which Z represents-chr9-.

1. 2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetic acid.

Stage 1
4-Phenyl-2H-3-benzo[b]pernickety aldehyde
3,13 l (40,7 mole) of dimethylformamide in an argon atmosphere loaded into a 6-liter reactor, which protect from moisture. In the reactor, which is maintained at a temperature in the range 0-5oWith dropwise enter 748 ml (8,14 R add 175,28 g (0,814 mole) of 4-phenyl-2H-3-benzo[b]Piran, dissolved in 246 ml of dimethylformamide. At room temperature the solution is stirred for 48 hours Then the reaction mixture was poured into a mixture of ice water, neutralized with concentrated sodium hydroxide solution, the pH value of which exceeds 10, and at room temperature, stirred for 1 h then the reaction mixture is extracted three times with diethyl ether.

Next, the organic solution washed with water and dried over sodium sulfate. After evaporation the product is obtained in the form of oil, which was dispersed in 200 ml of heptane. This solution is left to stand for 1 h at -20oAnd then the formed solid is filtered off and dried. In this way receive 144,5 g of the target product, i.e., in other words, the output is of 75.1%. The melting point of this compound is within 78-80oC.

TLC (silica gel "Kieselgel 60" by the company Merck; CH2With2l/hexane in a ratio of 1/1): Rf=0.5 in.

NMR-spectrum (l3): of 5.15 (s, 2H), 6,9-to 7.5 (m, 9H), to 9.45 (s, 1H).

IR-spectrum:CO=1660 cm-1.

Stage 2
(4-Phenyl-2H-3-benzo[b]pyranyl)methanol
A 20-liter reactor, which supports a nitrogen atmosphere, loads of 302.6 g (1,28 mol) of the compound obtained in the previous article is the temperature, small portions add 53,3 g (1,4088 mole) of sodium borohydride. Upon completion of addition the reaction mixture is stirred for 30 minutes After evaporation of the solvent the residue is dissolved in diethyl ether and the organic solution washed with water up until the pH value of the wash liquids are 7. After evaporation of the solvent the product is obtained in the form of oil, which is crystallized from 200 ml of pentane. After 2 h exposure at -20oWith the liquid from the solid product drain. In this way receive 269,3 g of the target product, i.e., in other words, the output is 88.3 per cent. The melting point of this compound is within 67-68oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0.5 in.

IR-spectrum:CO=3356 cm-1.

Stage 3
3-(Chloromethyl)-4-phenyl-2H-3-benzo[b]Piran
In a 6-liter reactor, which supports a nitrogen atmosphere and which protects against moisture, download 269,3 g (1,13 mol) of the compound obtained in the previous phase, in the form of a solution in 2.7 l of toluene. In this solution, maintained at room temperature, added dropwise 165 ml (2,16 mole) of thionyl chloride. The reaction mixture gradually becomes dark of Krasnopillya the residue is dissolved in diethyl ether. The organic solution is washed with water until until the pH value of the wash liquids are 7, and then dried over sodium sulfate. After evaporation of the solvent in the form of oil get 291,2 g of the product, i.e., in other words, the output is 100%.

Stage 4
2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetonitrile
In a 6-liter reactor, which supports a nitrogen atmosphere and which protects against moisture, upload to 58.2 g (1,186 mole) of sodium cyanide in the form of a suspension of 1.36 l of dimethyl sulfoxide. In this solution, maintained at room temperature, added dropwise 291,2 g (1,13 mol) of the compound obtained in the previous phase, in the form of a solution in 1.2 l of dimethyl sulfoxide. Upon completion of addition the reaction mixture is stirred for 48 hours the Solution is poured into a mixture of ice water. The resulting residue extracted three times with methylene chloride. The solution is washed with water and then dried over sodium sulfate. After evaporation of the solvent in the form of oil getting 262 g of substance. This oil is dissolved in a mixture of methylene chloride/heptane 1/1 and chromatographic on silica gel. After evaporation of the solvent in the form of oil get 196,7 g of the product, i.e., in other words, the output is 70,5%.

TLC (silica gel "Kiese the Mr spectrum (CDCl3): 3,1 (s, 2H), 5,0 (s, 2H), of 6.65 (dd, 1H), 6,8 (dd, 1H), 6,9 (dd, 1H), 7,15-to 7.3 (m, 3H), 7,4-7,6 (m, 3H).

Stage 5
2-(4-Phenyl-2H-3-benzo[b]pyranyl)acetic acid
A 2-liter reactor for 3 h refluxed 56.7 g (0,229 mol) of the compound obtained in the previous phase, in the form of a solution in a mixture of 300 ml of acetic acid and 300 ml of concentrated hydrochloric acid. After cooling and maturation for 12 h at room temperature, a precipitate may form. After draining and washing with water the precipitate solubilizer in methylene chloride. The organic phase is washed with water (up until the pH value of the wash liquids are 7), dried over sodium sulfate and evaporated. The obtained solid product was dispersed in pentane, and then drain the liquid. This way obtain 54 g of the target product, i.e., in other words, the output is 88%. The melting point of this compound is within 147-149oC.

IR-spectrum:CN=1721 cm-1.

NMR-spectrum (Dl3): 3,1 (s, 2H), and 4.8 (s, 2H), of 6.6 to 7.3 (m, 10H).

2. Other compounds of formula II in which Z represents-chr9-.

According to the method described above for 2-(4-phenyl-2H-3-benzo[b] pyranyl)acetic acid, receive connection x in tables 4-7.

More specifically, these compounds were obtained from the appropriate reagents according to the same method as in stage 1 above, section III.1.

More specifically, these compounds were obtained from the appropriate reagents according to the same method as in stage 2 above, section III.1.

More specifically, these compounds were obtained from the appropriate reagents according to the same method as in stage 3 above, section III.1.

More specifically, these compounds were obtained from the appropriate reagents according to the same method as in stage 4 of the above section III.1.

EXAMPLE 1
N-(2,4-Dimethyldi-6-methyl-3-pyridyl)-2-(4-phenyl-2H-3-benzo[b] pyranyl)ndimethylacetamide
A 2-liter reactor protected from moisture, load 45 g (0,169 mole) of 2-(4-phenyl-2H-3-benzo[b] pyranyl)acetic acid and 23.5 ml (0,169 mole) of triethylamine in solution in 338 ml of methylene chloride. In this solution, which is maintained at a temperature in the range 0-5oWith small amounts injected 43,02 g (0,169 mol) of acid chloride of bis(2-oxo-3-oxazolidinyl)phosphinic acid, followed by stirring the reaction mixture for 1 h Then one portion add 33,84 g (0,169 mole) of 2,4-dimethyldi-6-methyl-3-pyridylamino. Then in this solution, which is maintained at temps 68 ml of methylene chloride. The reaction mixture is gradually solubilizers and stirred at room temperature for 12 hours After adding water and methylene chloride precipitate is filtered off and discarded. Upholding the reaction mixture is allowed the opportunity to be separated and then the organic phase is washed with water, then with a solution of hydrochloric acid and finally with water until until the pH value of the wash liquids are 7. After drying over sodium sulfate the organic phase is evaporated. The obtained solid substance for 30 min was dispersed in 300 ml of ethanol, and then the liquid drain. In this way get up to 52 g (wet) of the target product. Further, this product is recrystallized from 4.5 litres of ethanol for 12 h, incubated at -20oC. After draining the obtained solid product is dried in a ventilated drying Cabinet for 2 h 30 min at 50-55oWith and then for 20 h at 95oC. Thus obtain 30.5 g of the target compound, i.e., in other words, the output is 40.2%. The melting point of this compound is within 201-203oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0,51.

IR-spectrum:NH=3198, WITH=1661 cm-1.

25H24N2O2S2Mw=448,5.

Calculated, %: C 66,94; H 5,39; N 6,25; S 14,29.

Found, %: C 66,65; H Of 5.34; N 6,23; S 14,07.

EXAMPLE 2
N-(2,4-Dimethyldi-6-methyl-3-pyridyl)-3-(4-phenyl-2H-3-benzo[b] pyranyl)prop-2-ename
In a 250-ml reactor protected from moisture, load 1 g (3,59 mmole) 3-(4-phenyl-2H-3-benzo[b]pyranyl)prop-2-ene acid in solution in 30 ml of methylene chloride and added to the reactor drop of dimethylformamide. In this solution, which is kept at room temperature, poured dropwise to 0.39 ml (3,76 mmole) of oxalicacid. Next, the reaction mixture was refluxed for 1 h After evaporation of the solvent, the reaction mixture was dissolved in 20 ml of methylene chloride. Then the solution is poured into the mixture, which is maintained at a temperature in the range 0-5oWith and which includes 0.75 g (3,76 mmole) 2,4-dimethyldi-6-methyl-3-pyridylamino, 2.2 ml of pyridine and 30 ml of methylene chloride. The resulting reaction mixture at room temperature and stirred for 12 h After the addition of water and subsequent upholding the organic phase is separated, washed with 2 N. hydrochloric acid and then with water up until the pH value of the wash liquids are 7. After drying over sodium sulfate akim by obtain 1.1 g of the target product in its raw state. This product is recrystallized from 140 ml of ethanol for 12 h, incubated at -20oC), after which the liquid drain and the product is dried. The result of 0.77 g of the target compound, i.e., in other words, output is to 46.7%. The melting point of this compound is within 225-227oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0,59.

IR-spectrum:NH=3253, WITH=1652 cm-1.

The NMR spectrum (CDCl3): 2,35 (s, 3H), and 2.4 (s, 3H), of 2.45 (s, 3H), 4,7 (s, 1H), 5,0 (s, 1H), 5,9-5,95 (d, 1H), and 6.25 (s, 1H), return of 6.58 (d, 1H), 6,62-to 6.80 (m, 2H), at 6.84-6.87 in (d, 1H), 7,05-7,17 (m, 3H), 7.3 to 7.4 (m, 4H).

Elemental analysis data: C26H24N2O2S2Mw=460,62.

Calculated, %: C 67,80; H 5,25; N Between 6.08; S 13,92;
Found, %: C 67,54; H 5,25; N 6,15; S 14,15.

Using the appropriate reagents according to method described in example 1 were obtained compounds of the following examples 3-5.

With regard to compounds of the following examples 6-15, they were received using the appropriate reagents according to method described in example 2.

These compounds are summarized in tables 8 and 9, in which the word "communication" means that R6and R7accordingly, R10and R11together form a bond.

P, Agregat of 3.1 ml (22 mmole) of Diisopropylamine in the form of a solution in 20 ml of tetrahydrofuran, and then to this solution, maintained at 0oWith that added dropwise of 13.75 ml (22 mmole) of 1.6 M solution of n-utility in hexane. After stirring the reaction mixture at 0oC for 15 min in this solution, maintained at 0oWith that added dropwise 2.66 g (10 mmol) of 2-(4-phenyl-2H-3-benzo[b]pyranyl)acetic acid. The reaction mixture was stirred at 0oC for 2 h, after which this solution, maintained at a temperature of 0oWith that pour out of 1.18 ml (11 mmol) of 1-bromobutane. The reaction mixture was stirred at room temperature for 72 h After the addition of water and 2 M hydrochloric acid, the reaction mixture was extracted with diethyl ether. After washing with water the organic phase is dried and then evaporated. Obtained in the form of oil product chromatographic on silica gel (eluent: methylene chloride). After evaporation of the solvent the obtained crystals dispersed in pentane, and then the liquid drain. This way obtain 1.7 g of the target compound, i.e., in other words, the output is 52,8%. The melting point of this compound is within 117-119oC.

TC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane is-6-methyl-3-pyridyl)-4-(4-phenyl-2H-3-benzo[b] pyranyl)but-3-ename
Stage 1
4-(4-Phenyl-2H-3-benzo[b]pyranyl)but-3-EN-1-OIC acid
In a reactor protected from moisture, load of 1.9 g (0,008 mole) of 4-phenyl-2H-3-benzo[b] pernikcharacteristics and 3.5 g (0,0084 mole) of 1-carboxypropylbetaine in suspension in 20 ml of tetrahydrofuran. In this suspension for 1 h at 0oTo add a solution of 1.9 g (0,0176 mole) of tert-butoxide potassium in 10 ml of tetrahydrofuran. The reaction mixture for 30 min stirred at a temperature in the range 0-5oC and then for 1 h at room temperature. Next, the reaction mixture was poured into a mixture of ice water followed by extraction with diethyl ether. The aqueous phase is acidified with concentrated hydrochloric acid (at pH 2). After extraction of the aqueous phase with ethyl acetate the organic phase is dried over sodium sulfate and evaporated. The result is 2 g of solid, which is dissolved in a mixture of methylene chloride/ethyl acetate in a ratio of 9/1 and chromatographic on silica gel. After evaporation of the solvent to obtain 0.7 g of a solid substance, i.e., in other words, the output is of 29.9%.

Thin layer chromatography (silica gel "Kieselgel 60" by the company Merck; AcOEt/CH2Cl2/MeOH in a ratio of 45/45/10): Rf=0.65 is.

IR-spectrum:CO2N=1718 in terms mentioned in example 1, using 4-(4-phenyl-2H-3-benzo[b] pyranyl)but-3-EN-1-OIC acid and 2,4-dimethyldi-6-methyl-3-pyridylamino, tPL204-206oC.

TLC (silica gel "Kieselgel 60" by the company Merck; AcOEt/hexane in a ratio of 1/1): Rf=0,6.

IR-spectrum:NH=3203 cm-1,WITH=1651 cm-1.

NMR-spectrum (Dl3): of 2.4 (s, 3H), by 2.55 (s, 6H), 2,9-3,2 (m, 2H), of 5.05-of 5.15 (m, 2H), 5,9 (m, 1H), and 6.3 (d, 1H), 6,6-7,5 (m, 11H).

The study below for this application showed that LS 3519 has antihyperlipidemic effect and is more active than the compounds LR 12 and LR 44, cited in EP 0585913 B1 on page 146 line 22-24, respectively.

In addition, LS 3519 shows less toxicity compared with the compounds of the prior art.




Data pharmacological tests.

Inhibition of adsorption of cholesterol in vivo (rat):
DE 50 (mg/kg): LS 3519 5; LR 12 45; LR 44 39. LS 3519 is 7 to 8 times more active compared to LR 12 and LR 44, respectively.

Toxicity in the Guinea pig adrenal (comparative studies).

The polarity of the adrenal glands is the main sign of the Histopathological study showed the effect on the adrenal Guinea pig for all three compounds. However, the defeat was evident at 10 mg/μm in the case of compounds LR 12 and LR 44, while in the case of LS 3519 they are only noticeable at 100 μg/kg Thus, LS 3519 approximately 10 times less toxic in comparison with the toxicity of the substances of the prior art.

I conducted or oversaw the experiments for testing the inhibition of the absorption of cholesterol in accordance with the methods described in claims according to the original application. Further, I declare that all statements made here are based on my knowledge, are true. They are all based on information and data that are truthful. If it is determined that these convictions made on the basis of knowledge that is intentionally false, it can lead to punishment me by fine or his imprisonment or both under section 1001 of the document 18, United States Code. In addition, such knowingly false statements may jeopardize the validity of the application or any patent issued on its basis.


Claims

1. The compound of the formula I

in which X denotes O or S;
R1and R2that is>)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;
R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;
Y represents halogen;
R4and R5represent hydrogen;
Ar denotes one of the following groups or With:

T represents hydrogen or (C1-C6)alkyl;
T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;
R6and R7each denotes hydrogen or R6and R7together represent a bond;
Z denotes either (I) the divalent group-R9-, in which R9denotes a hydrogen atom or (C1-C6)alkyl, or (II) the divalent group-chr10-chr11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-chr is N=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,
as well as its additive salts with pharmaceutically acceptable acid or base.

2. Connection on p. 1, characterized in that
R1and R2which may be identical or different, denote hydrogen or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;
R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;
Y represents halogen;
R4and R5each denotes a hydrogen atom;
AG denotes one of the following groups or With:

T represents hydrogen or (C1-C6)alkyl;
T3and T4that may be the same or different, each denotes a (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)allylthiourea;
R6and R7each denotes hydrogen or R6and R7together denote a bond,
Z denotes either (I) the divalent group-chr9- in which in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11denote hydrogen.

3. The compound according to any one of the preceding paragraphs, wherein each of R1and R2denotes hydrogen.

4. Connection on p. 1, characterized in that Z represents the group-chr12-chr13-CH2-, in which R12and R13have the values listed in paragraph 1.

5. The compound according to any one of paragraphs.1-4, characterized in that X denotes O or S, a R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl.

6. The compound according to any one of paragraphs.1-4, characterized in that X denotes O or S, and Z is chosen from: (I) -CH = CH - and (II) -CH = CH-CH2-.

7. The compound according to any one of paragraphs.1-6, characterized in that the value of the AG is selected from 2,4-dimethyldi-6-methyl-3-pyridyl, 2-methoxy-4-hexylthio-3-pyridyl and 2,6-diisopropylphenyl.

8. Connection on p. 7, characterized in that the AG denotes one of the groups b or C, preferably 2,4-dimethyldi-6-methyl-3-pyridyl or 2-methoxy-4-hexylthio-3-pyridyl.

9. The method of obtaining the compounds of formula I according to any one of paragraphs.1-8, characterized in that conduct the reaction mix acid of the formula II

10. The method according to p. 9, characterized in that the reaction of a combination of compounds of formula II with the amine III includes: (I) activation of the acid of formula II by obtaining the acid chloride, ester or mixed anhydride of the acid, and (II) the interaction of the amine of formula III with the compound obtained in stage (I).

11. The method according to any of paragraphs.9 and 10, characterized in that it comprises: (I) processing of the acid of formula II bis(2-oxo-3-oxazolidinyl)phosphinic acid in the presence of a base, and then (II) the interaction of the amine of formula III with the compound obtained in stage (I).

12. The method according to any of paragraphs.9-11, characterized in that it comprises: (I) processing of the acid of formula II oxalylamino in the presence of dimethylformamide, and then (II) the interaction of the amine of formula III with the compound obtained in stage (I).

13. The pharmaceutical composition exhibiting gipolipedimecescoe and antiatherosclerotic effect and comprising at least one compound according to any one of paragraphs. 1-8 in combination with one or more pharmaceutically acceptable carriers.

14. The medicinal substance, manifesting gipolipedimecescoe and anteaters the Oia according to any one of paragraphs.1-8, mixed with pharmaceutically acceptable filler.

15. The compound of formula I under item 1

in which X denotes O;
R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;
R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;
Y represents halogen;
R4and R5denotes hydrogen;
AG indicates

T represents hydrogen or (C1-C6)alkyl;
T3and T4which may be identical or different, denote a (C1-C6)allylthiourea;
R6and R7each denotes hydrogen or R6and R7together represent a bond;
Z denotes either (I) the divalent group-chr9-, in which R9denotes hydrogen or (C1-C6)alkyl, or (II) the divalent group-R10-R11-, in which R10and R11together obraznicie, have the values specified above for R9or (III) a divalent group-chr12-chr13-CH2-, in which R12and R13together they form a bond, Z represents-CH= CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,
as well as its additive salts with pharmaceutically acceptable acid or base.

 

Same patents:

The invention relates to derivatives of 2-(arylvinyl)aminoimidazole formula I, where R1denotes a group of formula (A), (B) or (C), a R2, R3, R4, R5, R6and X are such as defined in the claims

The invention relates to benzodiapines General formula I, their derivatives and analogues

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to new derivatives of azetidine and pyrrolidine General formula

< / BR>
where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

The invention relates to derivatives of 4-mercaptopyridine formulae of the following classes of i), ii) and iii), represented by the following formula:

< / BR>
where X1means N; C1-6alkoxyl1-6alkyl; C1-6alkoxyl1-6alkylsulphonyl; And means phenyl, naphthyl; X2means H, phenyl, phenyl WITH1-6alkyl; X3means N; C1-6alkyl; X4means1-6alkylsulfanyl, carbarnoyl;

< / BR>
where X5means-C(O)-C1-4alkyl-Phenyl; -C(O)-C1-6alkyl; -C(O)-C1-4alkylpyridine, and Ph and pyridyl optionally substituted C1-4the alkyl, C1-4alkoxy, C1-4alkalosis1-4by alkyl; a represents naphthyl; R3selected from the group comprising H; HE; NO2; -(CH2)nCOOR8where n is 0 to 3 and R8represents H, C1-4alkyl, C2-4alkenyl; -CONR9R10where R9and R10independently represent H, C1-4alkyl, C2-4alkenyl, -CON(R11OR12where R11and R12independently represent H, C1-4alkyl and C2-4alkenyl; a group of formula II: -CONR13-CHR14-COOR17where R13made the>alkyl; p is 0 to 3, and R3may be the same or different;

< / BR>
where X6has any value defined above for X5in ii); X7is Ph, optionally substituted by substituent (substituents), selected from the group comprising FROM1-4alkoxy; a represents Ph or naphthyl; R3and R such as defined above, or its N-oxide, MES, ester, pharmaceutically acceptable salt

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

The invention relates to new derivatives of 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine F.-ly (I), where Ar is a group of the formula (Ar-1) or (Ar-2), where R1is a halogen, R2represents hydrogen or lower alkyl, R3represents hydrogen, lower alkyl or lower alkanoyl, R4represents hydrogen or lower alkyl, R5and R6are the same or different and represent hydrogen or lower alkyl, n is 1, 2 or 3, And represents a group of formula (a-1), (a-2) or (a-3): -Z-N(Q1)(Q2) (A-1), where Z represents-CO -, - CS-or-SO2-, Q1and Q2are the same or different and represent hydrogen, lower alkyl, cycloalkyl, unsubstituted or substituted phenyl or phenyl(lower alkyl), or Q1and Q2together with the nitrogen atom form a pyrolidine, piperidine, hexahydroazepin, morpholino, thiomorpholine or pieperazinove ring; -CO-R7(A-2), where R7represents hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, substituted lower alkyl; -(CH2)p-CH(R8)-COR9(A-3), where p has a value 0, 1, 2, 3, 4 5; R8represents hydrogen or lower alkyl; R9is

The invention relates to the field of organic chemistry and relates to compounds of formula (I) and their pharmaceutically acceptable salts and difficult ether derivatives

< / BR>
where Ar represents a phenyl group which may be optionally substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and triptorelin groups having antifungal activity

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to an improved process for the preparation of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione used as antifibrillatory and antiarrhythmic agent, the General formula

< / BR>
incorporating the following stages: a) interaction 1- [[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-2,4-imidazolidinedione formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and their mixtures, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione 4-methylpiperazine education 1-[[[5-(4-chlorophenyl)-2-furanyl] the methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

< / BR>
where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

< / BR>
with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichloro is tons of potash, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II
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