Derivatives of phenylaniline, their tautomers and stereoisomers, their mixtures and their salts, pharmaceutical composition with anti-thrombotic and anti antiaggregatory action

 

(57) Abstract:

Describes new derivatives of phenylaniline General formula I, where R means a hydrogen atom, alkyl with 1 or 2 carbon atoms or cyclohexyl, Y is 1,4-piperidyl, their tautomers and stereoisomers, including mixtures thereof, and salts, which can be an active ingredient of pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action. Describes a pharmaceutical composition based formula I. 2 C. p. F.-ly, 1 PL.

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action.

Known derivatives of phenylaniline with biological activity, which can be an active ingredient of pharmaceutical compositions with multilateral action, including antithrombotic and antiaggregatory action (see application EP N 0 381 033, class C 07 C 311/19, A 61 K 31/16, published. 08.08.1990 year).

The task of the invention to provide new derivatives of phenylaniline, which can be a AK The problem is solved proposed derivatives phenylaniline General formula (I)

< / BR>
where R means a hydrogen atom, alkyl with 1 or 2 carbon atoms or cyclohexyl;

Y represents 1,4-piperidinyl,

their tautomers and stereoisomers, including mixtures thereof, and salts.

The new compounds of General formula (I) can be obtained by known methods, for example, by the following method.

The compound of formula (II)

< / BR>
subjected to interaction with the compound of General formula (III)

< / BR>
where R and Y have the above meaning,

or its reactive derivative, and then, if necessary, the radical R is transferred to the hydrogen atom.

As reactive derivatives of compounds of General formula (III) is suitable, for example, acid chlorides, aidenhead, mixed anhydrides with aliphatic or aromatic carboxylic acids, or complex monetary carbonic acid, imidazole and their esters, such as, for example, a complex alkalemia esters, complex akrilovye esters and complex Arakelova esters, such as, for example, methyl ester, complex ethyl ester, complex isopropyl ether complex pentalogy ether complex phenyl ether complex nitrophenyloctyl ether or complex benzyl ether.

Interaction estimationbased, dimethyl sulfoxide, benzene, toluene, chlorobenzene, tetrahydrofuran, pyridine, a mixture of pyridine and dimethylformamide, a mixture of benzene and tetrahydrofuran or dioxane, if necessary in the presence of a dehydrating agent such as, for example, a complex isobutyl ether of Harborview acid, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonate, p-colonelonic, trimethylchlorosilane, sulfuric acid, methanesulfonate, p-toluensulfonate, trichloride phosphorus, phosphoric anhydride, N,N'-dicyclohexylcarbodiimide, a mixture of N, N'- dicyclohexylcarbodiimide and N-hydroxysuccinimide, salt-2-(1H - benzotriazolyl)-1,1,3,3-tetramethyl-Urania, N, N'-carbonyldiimidazole, N,N'-conidiomata or a mixture of triphenylphosphine and tetrachlorophenol, if necessary in the presence of dimethylaminopyridine or 1-hydroxybenzotriazole and/or bases, such as, for example, triethylamine, N-ethyldiethanolamine, pyridine or N-methylmorpholine, expediently at temperatures between -10 and 180oC, preferably at temperatures between 0 and 120oC.

Subsequent translation of the radical R in the hydrogen atom is carried out expediently in the presence of acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, or in the presence of a base, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide in an environment suitable solvent, such as, for example, water, mixtures of water and methanol, a mixture of water and ethanol, a mixture of water and isopropanol, methanol, ethanol, a mixture of water and tetrahydrofuran or a mixture of water and dioxane, at temperatures between -10 and 120oC, for example, at temperatures between room temperature and the boiling temperature of the reaction mixture.

When the above-mentioned reactions of the available reactive group, such as carboxyl, amino - or amidinopropane, during the reaction can be protected customary protective groups, which are removed upon completion of the reaction.

As a protective residue to the carboxyl group can be applied, for example, trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl, as a protective residue to amidinopropane - benzyloxycarbonyl and as a protective residue for an amino group is formyl, acetyl, TRIFLUOROACETYL, etoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, 2,4-dimethoxybenzyl or phthalyl.

Possible subsequent removal of the used protective residue is carried out, for example the acetic acid and water, mixture of tetrahydrofuran and water, or a mixture of dioxane and water, in the presence of acid, such as, for example, triperoxonane acid, hydrochloric acid or sulphuric acid or in the presence of an alkaline base, such as, for example, sodium hydroxide or potassium, or by splitting a simple ester, for example, in the presence of trimethylsilane iodide, at temperatures between 0 and 120oC, preferably at temperatures between 10 and 100oC.

Removing benzyl, methoxybenzylthio or benzyloxycarbonylamino residue is carried out, for example, by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium on coal in the environment of a solvent, such as, for example, methanol, ethanol, complex ethyl ester of acetic acid or glacial acetic acid, if necessary with the addition of acid as hydrochloric acid, at temperatures between 0 and 100oC, preferably at temperatures between 20 and 60oC, at a pressure of hydrogen of 1 to 7 bar, preferably 3 to 5 bar. Removal of 2,4-dimethoxybenzamide residue is preferably carried out in trifluoroacetic acid in the presence of anisole.

Removal of the tert.butyl or tert.butyloxycarbonyl balance exercise suppose the eat processed by trimethylsilanol iodine, if necessary when using a solvent, such as, for example, methylene chloride, dioxane, methanol or ether.

Removing triftoratsetatov residue is preferably carried out by treatment with acid, as a salt, if necessary in the presence of a solvent, such as, for example, acetic acid or methanol, at temperatures between 50 and 120oC or by treatment with sodium lye, if necessary in the presence of a solvent, such as tetrahydrofuran or methanol, at temperatures between 0 and 50oC.

Removing telelavoro residue is preferably carried out in the presence of hydrazine or a primary amine, such as methylamine, ethylamine or n-butylamine in a solvent environment, such as, for example, methanol, ethanol, isopropanol, a mixture of toluene and water, or dioxane, at temperatures between 20 and 50oC.

In addition, the compounds of General formula (I) can be divided into their enantiomers and/or diastereomers. For example, a mixture of CIS-/TRANS-isomers can be divided into separate CIS - and TRANS-isomers, and compounds with at least one active carbon atom on a separate enantiomers.

So, example: the received compounds of General formula (I), existing in the form of the racemates, by well-known methods (see Allinger N. L. and Adiel E. L. in "Topics in Stereochemistry", vol. 6, Wiley Intersience, 1971) - optical antipodes and compounds of General formula (I) with at least two asymmetric carbon atoms on the basis of their physical chemical differences by well-known methods, for example by chromatography and/or fractional crystallization of the diastereomers, which, if they exist in the form of the racemates, can then, as videocasino, divided into enantiomers.

The separation of enantiomers is preferably carried out by column chromatography on chiral phases or by recrystallization from an optically active solvent or by reacting with forming with the racemic compound, salt or derivative as, for example, esters or amides, optically active substance, in particular acid and their activated derivatives or alcohols, and by dividing the thus obtained diastereomeric mixture of salts or a derivative thereof, for example on the basis of different solubilities, and from the pure diastereomeric salts or derivatives, you can release the free antipodes by influencing podkhody or dibenzoyltartaric acid, Vatolina acid, malic acid, mandelic acid, camphoric acid, glutamic acid, aspartic acid or Hinn acid. As the optically active alcohol can be called, for example, (+)- or (-)-menthol, and as optically active etilovogo balance Amidah - for example, (+)- or (-)-methyloxycarbonyl.

In addition, the resulting compounds of formula (I) can translate into their salts, particularly for pharmaceutical use into their physiologically tolerated salts with inorganic or organic acids. As acids can be used such as, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the thus obtained new compounds of formula (I), if the latter contain carboxyl, if desired, then translate into their salts with inorganic or organic bases, particularly for pharmaceutical use into their physiologically tolerated salts. As the bases can be used, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ETANA is known from the literature or can be obtained by known literature methods (see examples).

The second object of the invention is a pharmaceutical composition with anti-thrombotic and anti antiaggregatory action, which in addition one or more inert carriers and/or diluents contains a derivative of phenylaniline the above General formula (I) or its physiologically tolerable salt in an effective amount.

Biological activity of compounds of General formula (I), which are classified as toxic substances investigated, for example, the following manner.

1. Inhibition of binding3H-BIBU 52 with human platelets

In a suspension of human platelets in plasma add3H-BIBU 52 [=(3S, 5S)-5-[(4'-amidino-4-biphenylyl)oxymethyl] -3- [(carboxy)methyl]-2-pyrrolidinone [3-3N-4-biphenylyl] ] , substitute known from the literature ligand125J-fibrinogen (see patent application Germany A-4214245), and incubated with different concentrations of the studied compounds. Free and bound ligands are separated by centrifugation and their number is determined by scintillation. Based on the results of the experiment determine the inhibition of binding 3H-BIBU 52 of the investigated compound.

For the implementation of the experience by puncture anticubital who acidity: 13 mmol). The blood is subjected to centrifugation at 170 x g for 10 minutes. Platelet-rich plasma is removed, and the residual blood for plasma again centrifuged. Platelet-rich plasma was diluted with autologous plasma at a ratio of 1:10, 750 μl of the fluid together with 50 μl of physiological saline, 100 μl of a solution of tested compound, 50 μl of14C-sucrose (3700 Bq) and 50 μl of3H-BIBU 52 (final concentration: 5 nmol) are incubated at room temperature for 20 minutes. To determine nonspecific binding instead of the compounds using 5 ál BIBU 52 (final concentration: 30 Microm). Samples are centrifuged at 10,000 x g for 20 sec, the supernatant removed. 100 μl of this liquid is subjected to measurement to determine the free ligand. Product centrifugation is dissolved in 500 μl of 0.2 N. of sodium hydroxide, to 450 μl of the resulting solution add 2 ml of scintillation fluid and 25 μl of 5 N. hydrochloric acid and measured. Still available in the product centrifugation, the plasma is determined from the contents of the 14C, and the bound ligand - from3H. After subtraction of nonspecific binding compared Akti the target compound inhibits binding3H-BIBU 52 50% (concentration braking KT50).

2. Antithrombine action

Technique

Platelet aggregation is determined by the method of born and Cross (J. Physiol., 170, page 397, 1964) on platelet-rich plasma of healthy people. To delay the clotting of the blood type 3,14% sodium citrate in a volume ratio of 1:10.

Induced collagen aggregation

The decrease in optical density of a suspension of platelets is measured photometrically and register after you add the caller aggregation substance. The rate of aggregation is determined on the basis of the angle of inclination of the density curve. The point of the curve, showing the highest light transmission, calculates the optical density.

The amount of collagen choose more small, but sufficient for irreversible reaction curve. Use commercially available collagen firm Gormonami, , Munich/DE.

Before adding collagen plasma together with a test compound are incubated at a temperature of 37oC for 10 minutes.

On the basis of the curves for concentration and effect determine the effective dose ED50in nmol, i.e., the dose that produces 50% inhibition and the slide action on the interaction between cells or between cells and matrix new compounds of General formula (I) and their physiologically tolerated salts are suitable for the treatment and prevention of diseases, when you have an aggregation of cells of different sizes, or when a certain role is played by the interaction between cells and matrix, for example, for the control and prevention of venous and arterial thrombosis, cerebrosides disease, embolism of the pulmonary artery or its branches, myocardial infarction, arteriosclerosis, osteoporosis and metastasis of tumors or treatment of genetically determined or acquired disorders of interaction between cells or between cells and solid structures. In addition, these compounds are suitable for treatment of when thrombolyse when using fibrinolytic drugs or interventions in the vessels, for example, when the transcutaneous base charges angioplasty of the coronary arteries, as well as for treatment in the event of a state of shock, psoriasis, diabetes and inflammation.

For the treatment and prevention of the above diseases new connections used in doses between 0.1 mg and 30 mg per kg of body weight, preferably 1 μg to 15 mg per kg of body weight, in 1 to 4 doses per day. The new compounds of General formula (I) can be converted to known drugs, for example, tablets, pills, capsules, powders, suspensions, solutions, sprays or suppositories, if necessary,mi synthesis of thromboxane substances or their mixture, the serotonin antagonists, antagonists of receptors, alkyl nitrate, for example, trinitrate, substances inhibiting phosphodiesterase, prostacyclines and their analogues, anti-fibrinolytic drugs such as tissue plasminogen activator, PUK, urokinase, streptokinase or inhibiting clotting medications, such as heparin sulfate of dermatan, activated protein C, vitamin K antagonists, hirudin, inhibitors of thrombin or other activated clotting factors, together with one or some of the known inert carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, mixture of water and ethanol, a mixture of water and glycerol with a mixture of water and sorbitol, a mixture of water and glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances, for example, rejected a fat, or their suitable mixtures.

The following examples explain the formation of compounds of formula (I).

Example 1

4-[2-[(Lidinopril)aminocarbonyl] ethyl]-1-[(carboxymethyl]- piperidine x 0,ramida and 1.5 ml of pyridine added 720 mg of the hydrochloride of 4-[2-(chlorocarbonyl)ethyl]-1 - etoxycarbonyl)methyl]piperidine and stirred at 100oC for 80 minutes. The reaction mixture is cooled, mixed with ice water, alkalinized sodium lye and extracted with a simple tert.butyl methyl ether and methylene chloride. The aqueous phase is alkalinized with hydrochloric acid to pH 3 to 4 and evaporated to dryness at a bath temperature of 70oC. the Residue in 100 ml of ethanol is heated to boiling, and after cooling is filtered, then the filtrate concentrated. The evaporation residue is heated with 30 ml of ethanol, then cooled, and the solid is sucked off. The solid is stirred with 15 ml of tetrahydrofuran and 4.5 ml of 1 N. sodium lye. To the mixture was added to 2.75 ml of 1 N. hydrochloric acid, then stirred in an ice bath. The precipitate is washed with water and tetrahydrofuran, and dried in vacuum.

Yield: 144 mg (21% of theory)

Melting point: 283oC (decomp.)

The value of Rf: 0,76 (silica gel to obetovannoi chromatography; eluent: a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6:4)

Rasch.: C 60,77 H 7,32 N 16,67

Calc.: 60,55 7,26 equal to 16.83

Mass spectrum: (M+H)+= 333.

Source hydrochloride 4-[2-(chlorocarbonyl)ethyl]-1 - [(etoxycarbonyl)methyl]-piperidine was prepared as follows.

To of 1.46 g of 4-(2-carboxyethyl)-1-[(etoxycarbonyl)methyl]- put 1.2 g of thionyl chloride and stirred at room temperature for 3 hours. The reaction mixture was concentrated, to the residue twice added toluene, and each time again thicken.

Analogously to example 1 get the following connection:

(1) 1 -[2-[(4-amidinophenoxy)aminocarbonyl] ethyl]-4 - carboxymethyl-piperidine x 2H2O

Melting point: 192 - 200oC (sintering and decomposition)

The value of Rf: 0,77 (silica gel to obetovannoi chromatography; eluent: a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6:4)

Rasch.: C TO 55.42 H 7,66 N 15,21

Calc.: 55,02 7,38 14,95.

Example 2

4-[2-[(Lidinopril)aminocarbonyl] ethyl] -1- [(etoxycarbonyl)methyl]-piperidine x 2,15 HCl x 0.7 H2O

To 625 mg 4-aminobenzamidine and 30 mg 4-dimethylaminopyridine in 5 ml of pyridine added 950 mg of the hydrochloride of 4-[2- (chlorocarbonyl)ethyl]-1-etoxycarbonyl)methyl]piperidine and stirred at 100oC for one hour. Add 2 ml of dimethylformamide and stirred at 100oC for a further 72 minutes. The reaction mixture was concentrated, the residue is stirred twice with simple tert. butyl methyl ether each time, the solvent is decanted and removed. The residue is purified by chromatography on aluminium oxide with ethanol. The product is dissolved in ethanol, slightly alkalinized essential sod: 335 mg (25% of theory)

The value of Rf: 0,35 (aluminium oxide; eluent: a mixture of ethanol and concentrated aqueous ammonia in the ratio 99:1)

Rasch.: C 50,55 H? 7.04 baby mortality N 12,41 Cl 16.88 in

Calc.: 50,02 of 6.96 12,51 17,27

Mass spectrum: (M+H)+= 361.

Analogously to example 2 obtain the following connection:

(1) 4-[2-[(4-amidinophenoxy)aminocarbonyl]ethyl]-1- [(cyclohexyloxycarbonyl)methyl]-piperidine x 2.3 HCl x 2 H2O

Melting point: from 170oC (decomp.)

The value of Rf: of 0.58 (silica gel to obetovannoi chromatography; eluent: a mixture of methanol and 5%-aqueous solution of sodium chloride in the ratio 6:4)

Rasch.: C 51,69 H 7,60 N 10,48 Cl 15,26

Calc.: 51,69 7,46 10,44 15,17.

The following examples illustrate possible medications offer pharmaceutical compositions.

Example 3

Vial with dry sterile substance containing 2.5 mg of active substance per ml

Composition:

The active substance of example 1 to 2.5 mg

Mannitol - 50.0 mg

Water for injection To 1.0 ml

Receive:

The active ingredient and mannitol are dissolved in water. After filling dried by freezing. Dissolution to obtain a ready to use solution is performed using water for injection.

Example 4
E. substance of example 1(1) - 35,0 mg

Mannitol - 100.0 mg

Water for injection Up to 2.0 ml

Receive:

The active ingredient and mannitol are dissolved in water. After filling dried by freezing. Dissolution to obtain a ready to use solution is performed using water for injection.

Example 5

Tablet containing 50 mg of active substance

Composition:

(1) the Active substance of example 1 - 50.0 mg

(2) Lactose - 98,0 mg

(3) Corn starch 50.0 mg

(4) Polyvinylpyrrolidone - 15,0 mg

(5) magnesium Stearate - 2.0 mg - 215,0 mg

Receive:

(1), (2) and (3) are mixed and granularit together with an aqueous solution (4). After drying, the granulate is admixed (5). From this mixture is pressed to tablets with a flat surface and the chamfer on both sides and dividing notch on one side. The tablet diameter 9 mm

Example 6

Tablet containing 350 mg of active substance

Composition:

(1) the Active substance of example 2 - 350,0 mg

(2) Lactose - 136,0 mg

(3) Corn starch - 80.0 mg

(4) Polyvinylpyrrolidone - 30.0 mg

(5) magnesium Stearate 4.0 mg - of 600.0 mg

Receive:

(1), (2) and (3) are mixed and granularit together with an aqueous solution (4). After drying, the granulate is admixed (5). From this mixture pre the tablets of 12 mm

Example 7

Capsules containing 50 mg of active substance

Composition:

(1) the Active substance of example 2 (1) - 50.0 mg

(2) Corn starch, dried - 58,0 mg

(3) Lactose, spray - 50.0 mg

(4) magnesium Stearate - 2.0 mg - 160,0 mg

Receive:

(1) grind together with (3). This mixture with vigorous stirring to the mixture from (2) and (4). The resulting powdery mixture by means of a dosing machine is poured into the push-fit capsules size 3 hard gelatin.

Example 8

Capsules containing 350 mg of active substance

Composition:

(1) the Active substance of example 2 (1) - 350,0 mg

(2) Corn starch, dried - 46,0 mg

(3) Lactose, spray - 30.0 mg

(4) magnesium Stearate 4.0 m - 430,0 mg

Receive:

(1) grind together with (3). This mixture with vigorous stirring to the mixture from (2) and (4). The resulting powdery mixture by means of a dosing machine is poured into the push-fit capsules size 0 hard gelatin.

1. Derivatives of phenylaniline General formula I

< / BR>
where R means a hydrogen atom, alkyl with 1 or 2 carbon atoms or cyclohexyl;

Y represents 1,4-piperidinyl,

their tautomers and stereoisomers, including mixtures thereof, and salts.


 

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