Derivatives of pyrimidine, the retrieval method, farmcampsite

 

(57) Abstract:

Disclosed class of substituted phenylpyrimidine compounds of the formula I, where R1represents NH2N-alkylamino, N, N-dialkylamino; R2represents NH2; R3represents trifluoromethyl or CH2X, in which X represents a C1-C6-alkyl, velocci, benzyloxy, hydroxy or halogen; R4and R5each means a halogen; R6- R8each represents hydrogen, and its pharmaceutical acceptable acid additive salts, which are strong inhibitors of excitatory amino acid, glutamate. Such substances are useful in the treatment or prevention of a number of disorders of the Central nervous system, including cerebral ischemic damage and epilepsy. The method of obtaining compounds of formula I based on the interaction of compounds of the formula III: R1C(=NH) NH2with compounds of formula II, V. the Proposed farmcampsite having activity as an inhibitor selection of glutamate, comprising as active ingredient an effective amount of compounds of formula I or its pharmaceutically acceptable salt. 3 S. and 6 C.p. f-crystals, 2 PL.

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Glutamate is an excitatory amino acid that acts as neurotransmitter. However, if its extracellular concentration is high enough, glutamate acts as a strong neurotoxin that can kill neurons in the Central nervous system (Rothman &Olney (1986) Prog. Brain. Res., 63, 69).

Neuroticism action of glutamate is included in a number of diseases and disorders of the Central nervous system, including cerebral ischemic lesions, epilepsy and chronic neurodegenerative disorders such as disease Altmeyer, disorders of the musculoskeletal system and Huntington's chorea (Meldrum Clinical Science (1985) 68, 113-122). In addition, glutamate was included in other neurological disorders, such as manic depression, depression, schizophrenia, neurological syndrome high pressure, chronic pain, trigeminal neuralgia and migraine.

In European patent application N 21121 disclosed group of 3,5-diamino-6-(substituted phenyl)-1,2,4-triazines, which are active in the treatment of CNS diseases, for example in the treatment of epilepsy. One connected the release of excitatory amino acids, glutamate and aspartate (Leach et al. Epilepsia 27, 490-497, 1986, A. A. Miller et al. New anticonvulsant drugs. Ed. Meldrum and Porter, 165-177, 1987).

Some phenylpyrimidine known in the art as having antimalarial activity, see, for example, Brit. J. Pharmacol. 6, 185-200 (1951; JACS, 73, 3763-70 (1951). Other phenylpyrimidine known from Chem. Biol. Pteridines, 463-468 (1982) and Pharmacotherap. Budesinsky, p. 129-141 (1963), ed. Oldrich Hanc.

The authors of the present invention have found that a number of the substituted pyrimidine compounds as defined in formula I, are potential inhibitors of the release of glutamate, these compounds are useful in the treatment of the above-mentioned previously, diseases and disorders of the Central nervous system, which causes the action of glutamate. The pyrimidine compounds of formula I are inhibitors of the release of aspartate.

Thus, in the first aspect of the present invention proposed a pyrimidine of formula I:

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where

R1- NH2N-(alkyl)amino or N,N-di(alkyl)amino;

R2- NH2;

R3is trifluoromethyl or a group CH2X, where

X is hydroxy, C1-C6-alkoxy, phenoxy, benzyloxy or halogen;

R4and R5each halogen;

R6- R8are hydrogen,
Vlada chiral, and note that in these cases the formula I includes both the racemic mixture and the individual enantiomers of such compounds.

In the present invention

R1preferably is amino;

R3preferably is methoxymethyl, trifluoromethyl, benzoyloxymethyl or phenoxymethyl.

Preferably, in the formula I R3was trifluoromethyl or methoxymethyl or R3can be formation, R4preferably chlorine, R5preferably chlorine.

Preferably, the alkyl fragment contained between

1 to 4 carbon atoms.

The most preferred class of compounds of formula I are those in which

R1selected from amino, N,N-dimethylamino and N-ethylamino;

R2is an amino group,

R3choose from cryptomeria, benzyloxyethyl and methoxymethyl,

R4and R5both chlorine.

The compounds of formula I are potent inhibitors of the release of glutamate, show only a weak (i.e. IR50more than 20 microns) or a slight inhibiting effect on the enzyme dihydrotetrazolo.

The compounds of formula I can itausa, caused by the action of glutamate.

Acute conditions include cerebral ischemia, which may occur for different reasons from different cases, including shock, cardiac arrest, postoperative state, neonatal hypoxia and hypoglycemia, as well as physical destruction or injury of the spine or brain. Chronic neurodegenerative disorders that can be treated include the illness of Alzheimer, horey Huntington, olivopontocerebellar atrophy, disorders of the locomotor system. Other neurological conditions that can be treated with compounds of formula I include depression, manic depression, schizophrenia, chronic pain, epilepsy, trigeminal neuralgia and migraine.

Treatment or prevention of disorders or diseases of the Central nervous system in mammals, including humans, caused by the action of glutamate, can be carried out by injecting the mammal an effective amount of the compounds of formula I or its pharmaceutically acceptable salt accession acid.

In particular, mammals, tend to have neurotoxic levels of extracellular glutamate in the Central nervous system, there may be non-toxic S="ptx2">

Preferred new compounds of the present invention include the following, and the numbers correspond to the numbers of examples in which they appear.

Example N

1. 2,4-diamino-5-(2,3-dichlorophenyl)-6-cryptomaterial

2. 2,4-diamino-5-(2,3-dichlorophenyl)-6-ethoxymethyleneamino

3-3. 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxyethylpyrrolidine

3-4. 2,4-diamino-5-(2,3-dichlorophenyl)-6-formerpresident

4. 2,4-diamino-5-(2,3-dichlorophenyl)-6-phenoxymethylpenicillin

or their pharmaceutically acceptable salts accession acid.

Suitable pharmaceutically acceptable salts of accession of the acid compounds of formula I include those formed with both organic and inorganic acids.

Thus, preferred salts include those derived from hydrochloric, Hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methansulfonate, econsultancy, para-toluenesulfonic acid, benzosulfimide and isetionate acid. These salts can be obtained by the interaction of compounds as free bases with the corresponding acids.

Although ticheskie composition. Compositions of the present invention include the new compounds of formula I, as defined previously, or their pharmaceutically acceptable salts together with one or more carriers and optionally other therapeutic ingredients. The carrier (s) must be "acceptable" in the sense that it must be compatible with other ingredients of the composition and should not cause harm to the person who makes them.

These compositions include those that are suitable for oral, parenteral (including subcutaneous, intramuscular and intravenous), rectal and surface (including the application to the skin, through the nose or under the tongue) administration, although the most suitable method will depend on the type, condition and extent of disease of the patient. The composition generally can be manufactured in a unit dosage form and can be obtained by any means known to pharmacists. All methods include the stage of the compounds of formula I or its pharmaceutically acceptable salt accession acid ("active ingredient") with the carrier, which consists of one or more accessory ingredients. Typically, the compositions are prepared, carefully mixing the active ingredient with liquid carriers or finely ismale the/P> Compositions of the present invention suitable for oral administration may be presented in discrete form, for example in the form of capsules, pellets or tablets, each contains a certain amount of active ingredient in the form of a powder or granules; as solution or suspension in an aqueous solvent or nonaqueous liquid or in the form of a liquid emulsion of the type oil-in-water or water in oil, the active ingredient may also be presented in the form of balls, electuary or paste.

Tablets can be produced by extrusion or melt optional one or more additional ingredients. Molded tablets can be obtained by molding in a suitable device is the active ingredient in svobodnolezhaschaya form, for example in the form of powder or granules, optionally mixed with a binder, lubricant agent, inert diluent, surface active or dispersing agent. Tablets from the melt can be obtained, melting in the respective device a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated, and the composition may be such as to provide slow and counter the include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buferiruemoi agents, bacteriostatic and dissolved substances, which give the compositions of isotonicity with the blood of the patient, and aqueous and non-aqueous sterile suspensions that can include suspendresume and thickening agents. Such compositions can be in the form of single doses or packings for many doses, for example sealed ampoules and vials, and can be stored in a lyophilized state, which require only the addition of sterile liquid carrier, for example water for injections, immediately prior to use.

Arbitrary injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the previously described types.

Compositions for rectal injection can be prepared as a suppository with the usual carriers, as cocoa butter or polyethylene glycol.

The composition for surface coating, for example in the mouth or under the tongue, include pellet, containing the active ingredient with such flavors as sucrose and acacia or tragakant, and tablets containing the active ingredient on the basis of gelatin and glycerin or sucrose and acacia.

Predpochtitelno active ingredient.

Note that in addition to these specific ingredients previously compositions of the present invention can include other agents conventional practice regarding this type of compositions, such as compositions for oral administration may include flavouring agents or perfumes.

Tablets or other forms proposed in discrete form, may contain such quantities of the compounds of formula I which is effective at such dosage or in their multiples doses, as a single dose can be from 5 to 500 mg, and typically from 10 to 250 mg.

The compounds of formula I are preferably used for the treatment of disorders and diseases of the Central nervous system by oral administration or by injection (intraparenchymally or subcutaneous). The exact number of input connections depend on the treating physician. However, the prescribed dose should depend on a number of factors, including the age and gender of the patient, an accurate diagnosis and extent of disease to be treated. For example, when treating a patient with epilepsy interval doses should be, apparently, is significantly lower than in the treatment of a patient after a stroke to relieve cerebral ischemic lesions. Similarly, the route of administration, apparently,injection in doses of from 0.1 to 30 mg/kg / day. The range of doses for adults are usually from 8 to 2400 mg/day and preferably from 35 to 1050 mg/day. Some compounds of formula I are compounds long-term actions, and may be important to take in the first day of the initial dose of from 70 to 2400 mg, and then to reduce the dose in the next days to 20-1200 mg

Connection with a long-term effect is particularly important clinically, because they are easier to work with. In chronic situations, you can enter them without injections, and thus to minimize medical intervention, and also in acute conditions to reassure the patient, reducing the daily dose. On the contrary, these high-speed connections allow for clinical monitoring of pharmacological action of the compounds with a high accuracy, since such compounds are removed from the Central nervous system quickly.

Compounds of the present invention can be obtained in any manner known for analogous compounds (see JACS vol 73 (1951) 3763-70).

In the present invention proposed a method of obtaining a pyrimidine of the formula I or its pharmaceutically acceptable salt accession acid by the interaction of the compounds of formula II:

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where

R3to R8have indicated p

where

R1has these values,

highlighting the compound of formula I in free base or its pharmaceutically acceptable salt accession acid and, optionally, converting the base into its pharmaceutically acceptable salt accession acid or other pyrimidine of the formula I or its pharmaceutically acceptable salt accession acid.

If the product of the above process R3is a group CH2OR, where R is alkyl, this product can be turned into a CH2X interaction with HX (X is halogen), for example, acetic acid. Then you can convert it into vermeil processing, for example, cesium fluoride (CsF).

In another embodiment, a group of CH2OR you can deaccelerate to obtain the corresponding alcohol, for example, Me3SiI, and his next turn in vermeil using the TRIFLUORIDE diethylaminoethyl (DAST).

In the embodiment specified: (A) a compound of formula II, where R3the group CH2OR, in which R represents a C1-C6-alkyl, are subjected to interaction with the compound of the formula III, receiving a pyrimidine of formula I, where R3- this group CH2OR;

B) thus obtained pyrimidine separated and d is thus the pyrimidine is subjected to interaction with the TRIFLUORIDE diethylaminoethyl, receiving a pyrimidine of formula I, where R3- vermeil.

Note that you can do other interconversion, as clearly professionals, in accordance with standard methodology.

Examples of suitable tseplyaesh groups (L) include C1-4-alkoxy, halogen, aniline, morpholine, C1-4-alkylamino, benzylamino or alkylthio.

Preferably the reaction of the compounds of formulas II and III lead in nonaqueous solvents, for example in alkanol, for example in ethanol, at elevated temperatures (for example, between 50 and 110oC) at the base, preferably arkancide, preferably at the boiling point under reflux, using as the Foundation of the sodium ethylate.

The compounds of formula II can be obtained by methods known in the art (JACS, 1951, 73, 3763-3770), such as the interaction of the compounds of formula IV:

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where

Y is cyano, R4-R8defined above,

with diazomethane or with alkylation (JACS 1952, 74, 1310-1313), or by condensation with the amine.

The compound of formula IV can be obtained by a method known in this field

(JACS, 1951, 73, 3763-70).

In the present invention proposed a method of obtaining a pyrimidine of forcena, and R10and R11are alkyl or together form -(C(R)2)n- where n has a value from 2 to 4 and R is H or alkyl,

with the compound of the formula III. More preferably, R is amino.

Preferably the reaction is conducted in non-aqueous solvent, for example ethanol, boiling under reflux, using as the Foundation of the sodium ethylate.

In the following examples, the present invention abbreviations and symbols chemical compounds in compliance with generally accepted among specialists and have the following meanings:

DMF - dimethylformamide

Et2O - diethyl ether

NaOEt-tilt sodium

EtOH - ethanol

AcOH - acetic acid

MeOH - methanol

DMSO - dimethyl sulfoxide

DME - dimethoxyethan

Et2N - triethylamine

Example 1. Obtaining 2,4-diamino-5-(2,3-dichlorophenyl)-6 - cryptomaterial.

1. Obtain 2,3-amyl-metacresol.

To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 mg) in 800 ml of ethanol at room temperature is added NaBH4(8,54 g) and the resulting mixture is stirred for 1.5 hours. The reaction is quenched with water and the solvent is evaporated in a vacuum to the separation balance between CHCl3and feast upon foretell evaporated in vacuo to yield a white solid product, 48.38 per g, So melting 87-87,5oC.

2. Obtain 2,3-dichlorobenzamide.

To a solution of alcohol in benzene (500 ml) under nitrogen atmosphere add PBr3(167,8 g) and the resulting mixture was stirred at 55-60oC for 3.5 hours. After cooling the mixture was poured on crushed ice (2 l) and emit benzene layer. The aqueous phase is washed with benzene (x3) and the combined benzene extracts are washed with saturated NaHCO3solution and water, dried over MgSO4, filtered and the solvent is evaporated, leaving a brown liquid, which solidifies upon standing. Get 37,53 g, So pl. 31-32oC.

3. Obtain 2,3-dichlorobenzonitrile.

Bromide are suspended in DMCO (155 ml)/water (105 ml) at 0oC and KCN (20,24 g) added in portions. After stirring at 30-35oC for 2 hours, the suspension is diluted with water and extracted with Et2O. the combined ether extracts washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo to obtain a solid product is white, 27,52 g, so pl. 64-67oC.

4. Getting 2-(2,3-dichlorophenyl)-4,4,4-Cryptor-3-oxo - butyronitrile.

To a solution of NaOEt (from 1.48 g of Na) in EtOH (25 ml) at room temperature while boiling under reflux for 5 hours. After cooling, the solvent is removed in vacuo, and the residue is dissolved in water. The aqueous phase is washed with Et2O (merge), acidified with sulfuric acid and extracted with Et2O. the combined extracts Et2O washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo to obtain oil. His triturated c petroleum ether, filtered off the solid part and dried. Get 9,56, So pl. 74-75oC.

5. Getting 2-(2,3-dichlorophenyl)-4,4,4-Cryptor-3 - methoxybutyl-2-isonitrile.

To a solution of triptoreline in Et2O (90 ml) at room temperature add diazomethane (from 19,35 g Diazald) in Et2O (180 ml) and the resulting mixture left to stand at room temperature overnight. Then the excess diazomethane removed in vacuum in AcOH and the residue is dissolved in Et2O, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo to obtain a brown solid, 6,44,

6. Obtaining 2,4-diamino-5-(2,3-dichlorophenyl)-6 - cryptomaterial.

To a solution of the above enol ether in ethanol (37 ml) was added guanidine hydrochloride (1.92 g), and then a solution of NaOEt (from 540 mg, Na) in EtOH (90 ml) and the resulting mixture paramesh the config filtrate is evaporated to dryness in a vacuum. After chromatography was carried out on silica gel with elution CHCl3up to 2% MeOH-CHCl3get the target product which is triturated with Et2O and dried in vacuo to obtain 673 mg, So pl. 218-219oC.

7. 2,4-diamino-5-(2,3-dichlorophenyl)-6-cryptomaterial-methansulfonate.

To a suspension of the free base (100 mg) in ethanol add methansulfonate (30 mg) and the resulting clear solution was stirred at room temperature for 2 hours. This solution is evaporated to dryness and the remaining solid part triturated with ether, filtered and dried in vacuum, 107 mg, So pl. 253-256oC.

8. 2,4-diamino-5-(2,3-dichlorophenyl)-6 - triftormetilfullerenov.

To a solution of free base (150 mg) in methanol add an ethereal solution of hydrogen chloride. After mixing, the solvent is evaporated to dryness and the resulting solid triturated with ether, filtered and dried in vacuum, 160 mg. So pl. 233-236oC.

Example 2. Obtaining 2,4-diamino-5-(2,3-dichlorophenyl)-6-ethoxymethyleneamino.

1. Getting 2-(2,3-dichlorophenyl)-4-methoxy-3-oxo - butyronitrile.

To stir boiling under reflux the solution dissolved in 20 ml of DMA for 5 minutes. After 5 hours, you receive the precipitate (sodium salt of the product). The resulting mixture was cooled and filtered, the resulting filtrate is evaporated to dryness in vacuo and the residue is divided between ether and water (the ether phase is drained). The aqueous residue acidified with 2 N. H2SO4and extracted with ether (x2). The combined extracts Et2O washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a yellow solid (a). The above sodium salt is dissolved in water and the solution is extracted with ether and poured. The aqueous solution acidified with 2 N. H2SO4and extracted with ether. The ether solutions are washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a solid product is white (b).

The above products (a and b) are combined to obtain 10.4 g, which is used without further purification. On TLC single spot (19:1 CH2Cl2:MeOH), Rf0,35.

2. Getting 2-(2,3-dichlorophenyl (3,4-dimethoxy-2-isonitrile.

To a stirred solution of the above nitrile (9.4 g) in ether is added in portions diazomethane (0,4 - 0,45 M) in the air. First, there is intense foaming, and after further adding immediate is for 3 hours and evaporated in vacuum in AcOH to obtain the enol ether.

3. Obtaining 2,4-diamino-5-(2,3-dichlorophenyl)-6 - ethoxymethyleneamino.

To a solution of NaOEt (from 0,92 g of Na) in EtOH (40 ml) was added guanidine hydrochloride (3,44 g). Add the above solution of enol ester in EtOH (30 ml) and the resulting mixture is refluxed for about 3 hours. After cooling, the solvent is evaporated in vacuum and the residue treated with 5 N. NaOH (50 ml). The red solution is filtered, dissolved in AcOH (20 ml), diluted with 40 ml of water, treated with charcoal and filtered. The obtained filtrate (yellow solution) alkalinized 2 N. NaOH and the white precipitate is filtered off, dried and recrystallized from EtOH. Get 4,39, So melting 237 - 240oC.

Example 3. Obtaining 2,4-diamino-5-(2,3-dichlorophenyl)-6-formerpresident.

1. 2,4-diamino-5-(2,3-dichlorophenyl)-6-(diethoxylate)-pyrimidine.

To stir while boiling under reflux a solution of NaOEt (1,38 g of sodium in 25 ml of ethanol is added over 5 minutes to a mixture of ethyldiazoacetate (13,21 g, 75 mmol) and (example 1.3) 2,3-dichlorobenzonitrile (9.3 g, 50 mmol) in dry dimethoxyethane (20 ml). After 4 hours, cooled and evaporated in vacuum. The residue is divided between water (100 ml) and ether (100 ml) and the ether phase is drained, ITIL (13,47 g), which is used without further purification.

To a stirred solution of the above acetonitrile in ether (100 ml), cooled on ice, add portions solution diazomethane (approximately 3 g) in ether. After 2 hours the solution is evaporated in a vacuum to obtain the target enol ether in the form of oil, which is used without further purification.

To a solution of NaOEt (from 1.4 g of sodium) in ethanol (50 ml) was added guanidine hydrochloride (4.8 g, 50 mmol). Add a solution of the above enol ether in ethanol (20 ml) and the resulting mixture is refluxed for 4 hours, cooled and concentrated in vacuo to about 30 ml, and dilute with water to produce a dark purple solid, which was filtered, dissolved in CH2Cl2, washed with water, dried over magnesium sulfate and evaporated in vacuum. The residue is triturated with 50 ml of ethanol and filtered, obtaining the target product (8,4 g), which is used without further purification (so pl. 214 - 217oC).

2. 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine-6-carboxaldehyde.

A mixture of the above acetal (7 g) and 0.4 M HCl (150 ml) is refluxed under stirring for 1 hour, cooling the left of the product (6.2 g), which is used without further purification.

3. 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxyethylpyrrolidine.

To a stirred solution of the above aldehyde (2.8 g, 10 mmol) in a mixture of dimethoxyethane (15 ml) and ethanol (15 ml) is added in portions sodium borohydride (110 mg, 3 mmole). After 30 minutes the solution is treated with water (50 ml) and add a few drops of acetic acid to destroy the remnants of the borohydride. After extraction with dichloromethane (2 x 50 ml), washed with water and the extract is dried over magnesium sulfate. After evaporation of the solvent receive solid pink color, which is triturated with ether, filtered and dried (1.6 g). After recrystallization from methanol (50 ml) to obtain the target product in the form of fine colorless crystals, 0,65, So pl. 173 - 176oC.

4. 2,4-diamino-5-(2,3-dichlorophenyl)-6-formerpresident.

To a stirred suspension of 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxyethylpyrrolidine (185 mg, 1 mmol) in dry dichloromethane (25 ml) under nitrogen atmosphere at -70oC, is added dropwise TRIFLUORIDE diethylaminoethyl (263 μl, 2 mmole). The obtained mixture is allowed to warm to 0oC and maintain this temperature for 4 hours. After cooling to -70o the scrap and dried over magnesium sulfate. After concentrating receive a colorless resin (0.2 g). After chromatography was carried out on silica gel with elution of 0.01:1:19 Et3N:MeOH:CH2Cl2get the target product which is triturated with CCl4and dried in vacuum, get 111 mg, so melting 224 - 226oC.

Example 4. 2,4-diamino-5-(2,3-dichlorophenyl)-6-phenoxymethylpenicillin.

To a stirred solution of NaOEt (from 1,38 g of sodium) in ethanol (70 ml) at boiling under reflux add 10 minutes to a mixture of 2,3-dichlorobenzonitrile (9.3 g) and ethylenoxide (13.5 g) in dry dimethoxyethane (50 ml). After stirring while boiling under reflux for 3 hours the mixture is cooled, filtered and the solvent is evaporated in vacuum. The residue is dissolved in water, washed with ether (merge), acidified with 2 N. hydrochloric acid and extracted with dichloromethane. The combined extracts washed with brine, dried over magnesium sulfate and evaporated in vacuum, obtaining a yellow-brown solid product (8 g), which is used without further purification.

To a suspension of the crude allocationally (8 g) and 150 ml of ether is added in portions excess solution diazomethane in the air. After stirring for 1 hour at further purification.

To a solution of Etisalat sodium (0,63 g of sodium) in ethanol (29 ml) at room temperature add guanidine hydrochloride (2,39 g). After 15 minutes, add a solution of the above enol ether in ethanol (25 ml) and the resulting mixture is stirred at the boil under reflux for 4 hours. After cooling, the solvent is evaporated in vacuum. The residue is suspended in 2 N. NaOH (75 ml), filtered, washed with water, dried in air and recrystallized from ethanol to obtain the target product as a colorless solid product, 3,82, So melting at 211 213oC.

Preferred among the compounds of formula (I) are pyrimidines of the above examples and their pharmaceutically acceptable salts accession acid.

These compounds have the following two-dimensional structure:

Example 1

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Example 2

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Table1H NMR (see table. 1).

Pharmacological activity

Inhibition of release of glutamate and DHFR inhibition of rat liver

The compounds of formula (I) were tested for their efficiency caused by veratrine glutamate release from slices of rat brain according to the Protocol described in Epilepsia 27(5):490 - 497, 1986. Proto - 574, 1971.

The results are shown in table 2, and the IC50is the concentration of compound that causes 50% inhibition (a) caused by veratrine release of glutamate, and (b) activity of the enzyme DHFR (DIHYDROFOLATE REDUCTASE).

The example of the pharmaceutical composition

A: Injections

Salt of the compounds of formula I is dissolved in sterile water for injection.

In the following examples as an active connection, you can use any compound of formula (I) or its pharmaceutical salt.

B: Composition for capsules

Composition for capsules A

Composition A can be obtained by mixing the ingredients and filling two-part hard gelatin capsules with the mixture.

Composition for capsules And mg/capsule

(a) Active ingredient 250

(b) Lactose C. R. - 143

(c) Patrickemailguard - 25

(d) magnesium Stearate - 2

Total - 420

Composition for capsules In mg/capsule

(a) Active ingredient 250

(b) the Macrogel VR - 350

Total - 600

Capsules can be manufactured by melting the macrogel 4000BP, dispersive active ingredient in the melt and filling gelatin capsules consisting of two parts is gradient - 250

(b) Microcrystalline cellulose - 125

(c) Lactose C. R. - 125

(d) Ethylcellulose - 13

Total - 513

Composition for capsules controlled release can be obtained, extragere mixed ingredients (a) to (c) using the extruder, giving them a spherical shape and drying the extrudate. The dried tablets covered with atillasoy (d) as a control release membrane and filled into hard gelatin capsules consisting of two parts.

The composition of the syrup - g/ml

Active ingredient - 0,2500 g

Solution of sorbitol - 1,5000 g

Glycerin - 1,0000 g

Sodium benzoate - 0,0050

Flavoring agent - 0.0125 g

Purified water to 5.0 ml

Sodium benzoate is dissolved in a portion of purified water and add a solution of sorbitol. Add the active ingredient and dissolve. The resulting solution was mixed with glycerol, and then brought to the desired volume of purified water.

Composition suppositories mg/suppository

Active ingredient (63 μm)x- 250

Hard fat, BP (Witepsol H15 - Dynamit Nobel) - 1770

Total - 2020

xThe active ingredient used in the form of a powder in which at least 90% of the particles have a diameter of 63 μm or less.

oC add the remaining Witepsol H15 to the suspension, which is stirred to ensure a homogeneous mixture. Then the entire suspension is passed through a stainless steel sieve of 250 μm and with continuous stirring, allowed to cool down to 40oC. At a temperature of 38 - 40oC 2,02 g aliquot of the mixture is filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.

1. The pyrimidine of the General formula I

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where R1represents NH2N-alkylamino; N,N-dialkylamino;

R2represents NH2;

R3represents trifluoromethyl or CH2X, in which X represents a C1-C6-alkoxy, phenoxy, benzyloxy, hydroxy or halogen;

R4and R5each means a halogen;

R6-R8each represents hydrogen,

and its pharmaceutical acceptable acid additive salt.

2. Connection on p. 1, in which R3is vermeil.

3. Connection on p. 1, in which R4and R5each represents chlorine.

4. Connection on p. 1, in which R1/SUB> selected from the group comprising trifluoromethyl, benzyloxyethyl and methoxymethyl; R4and R5each represents chlorine.

5. Connection on p. 1, selected from the group including

2,4-diamino-5-(2,3-dichlorophenyl)-6-cryptomaterial;

2,4-diamino-5-(2,3-dichlorophenyl)-6-ethoxymethyleneamino,

2,4-diamino-5-(2,3-dichlorophenyl)-6-formerpresident,

2,4-diamino-5-(2,3-dichlorophenyl)-6-phenoxymethylpenicillin,

2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxyethylpyrrolidine and their pharmaceutically acceptable acid additive salt.

6. A method of producing a pyrimidine of formula I, the value of which is defined in paragraph 1, or its pharmaceutically acceptable acid salt additive, wherein interact the compounds of formula II or V:

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where R3-R8take the values defined in paragraph 1;

R10and R11both represent alkyl or together form a group -(C(R)2)n-, in which R represents hydrogen or alkyl and n takes the value of integers from 2 to 4;

L represents a group to delete;

Y represents a cyano,

with the compound of the formula III

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where R1accepts values, the acid additive salt and optional turn the base in the acid additive salt or other pyrimidine of the formula I or its pharmaceutically acceptable acid additive salt.

7. The method according to p. 6, wherein L is C1-C4-alkoxy.

8. Pharmaceutical composition having activity as an inhibitor selection of glutamate and including an active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains an effective amount of a pyrimidine of the formula I or its pharmaceutically acceptable acid salt additive as defined in any of paragraphs.1 - 5.

9. The compound according to any one of paragraphs.1 to 5, with inhibiting the release of glutamate activity.

Priority signs and items:

07.12.88 - p. 1, where the pyrimidine of formula I has a value of R3that represents trifluoromethyl, and p. 3;

18.08.89 - p. 2;

07.12.88 - p. 4, where the pyrimidine of formula I has a value of R1= NH2and R3- trifluoromethyl;

14.04.89 - if the value of R1= NH2and R3- methoxymethyl;

07.12.88 - p. 5 - 2,4-diamino-5-(2,3-dichlorophenyl)-6-triptorelin;

14.04.89 - p. 5 - 2,4-diamino-5-(2,3-dichlorophenyl)-6-ethoxymethyleneamino;

18.08.89 - p. 5 - 2,4-diamino-5-(2,3-dichlorophenyl)-6-formatieren and 2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxyethylpyrrolidine;

07.12.88 - p. 6 formula I on PP.1 - 5.

 

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SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

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