The way to obtain 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5 - trichlorophenyl) pyrimidine or its acid salt additive

 

(57) Abstract:

Usage: in medicinal chemistry. The essence of the invention: 2 ways to obtain 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-pyrimidine or its acid salt additive. a) Reagent I: 1-(2,3,5-trichlorophenyl)-3-alkoxy-Acrylonitrile. Reagent II: N-methylpiperidine or its salt. b) Reagent I: 2-(2,3,5-trichlorophenyl)-3-acetylproline. Reagent II: N-methylpiperidine; the resulting product is isolated in the form of a base or in the form of its acid salt additive. 2 S. p. f-crystals, 1 table.

The present invention relates to a process for the preparation of pyrimidine compounds, which are suitable for the treatment of diseases and disorders of the Central nervous system (CNS), for example, to prevent cerebral ischemic lesions.

Glutamate is an excitatory amino acid that acts as neurotransmitter. However, if its extracellular concentration is high enough, glutamate acts as a powerful neurotoxin that can kill neurons in the Central nervous system (Rothman and Olney (1968) 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 ishem is stroisch 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 EP-A-N21121 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 of the compounds described in this application, 3,5-diamino-6-(2,3-dichlorophenyl)1,2,4-triazine-(lamotrigine) has been shown to inhibit 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).

The authors of the present invention found that, in particular, substituted pyrimidine compound 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-pyrimidine is a potential inhibitor of the release of glutamate. This compound is useful in the treatment of the above-mentioned previously, diseases and disorders of the Central nervous system. The pyrimidine compound is also an inhibitor of the release of aspartate.

The compound has the formula:

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Accordingly, the present invention provides a method for obtaining compounds of fortrel formula II:

< / BR>
where L represents C1C4alkoxy group, or N-methylpiperidine formula III:

< / BR>
or its salt, and produce the compound of formula I in free base or its salt additive acid.

The present invention provides for obtaining compounds of formula I by the reaction of 2-(2,3,5-trichlorophenyl)-3-acetylpiperidine formula IV:

< / BR>
where R10and R11both alkyl or together form a group -(C(R)2)n-, where R is hydrogen or alkyl and n is 2 4, N-methylpiperidine formula III, above.

According to the first method, preferably the reaction of the compounds of formula 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 base, preferably, alkoxide, preferably at the temperature of reflux distilled using sodium ethylate as a base.

The compounds of formula II can be obtained by methods known in the art (JACS, 1951, 73, 3763 3770; JACS, 1952, 74, 1310 1313).

The compounds of formula III, where R1is piperazinil or alkylpiperazine, you can get them in standard ways, for example, when interaction is and the reaction mainly proceeds at room temperature in water.

With the implementation of the second method, it is preferable that the reaction was performed in a nonaqueous solvent, for example ethanol by boiling under reflux, using as the Foundation of the sodium ethylate.

4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine and its pharmaceutically acceptable salt can be used in the treatment or prevention of acute and chronic disorders of the Central nervous system of mammals. Acute conditions include cerebral ischemia, which may occur for different reasons from different cases, including shock, cardiac arrest, postoperative state, neonatal hypoxia and hypoglycemia; and 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.

Compounds of the present invention can be used in the treatment or predator.

Mammal susceptible to or having neurotoxic levels of extracellular glutamate in the Central nervous system, can be treated.

Suitable additive salts of acid compounds of formula I include those formed with both organic and inorganic acids. Typically, these additive salts of the acids are pharmaceutically acceptable. Thus, preferred salts include those derived from hydrochloric, Hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methansulfonate, econsultancy, para-toluenesulfonic acid, benzosulfimide and satynowej acids. These salts can be obtained by the interaction of compounds of formula I in the form of free bases with the corresponding acids.

Although the compounds of formula I can be introduced in the form of pure chemical compounds, preferably incorporated in the pharmaceutical 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 terapevticheskii ingredients of the composition and must not cause harm to 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 single dosage form, and may 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 powdered solid carriers, or both, and then, if necessary, giving the composition the desired shape.

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 the active ingredient; as a powder or granules; in the form of the ode, 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, optionally with one or more additional ingredients. Molded tablets can be obtained by molding in a suitable device is the active ingredient in svobodnolezhaschaya the form of, 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. Tablets may be such that not need to be coated, in combination may be such as to provide a slow and controlled release of it's active ingredient.

Compositions for parenteral administration 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 to seawat 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, 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 flavors such as sugar and acacia or tragakant, and tablets containing the active ingredient on the basis of gelatin and glycerin or sucrose and acacia.

The preferred composition unit doses contain an effective dose, as will be described later, or the appropriate portion thereof, of the active ingredient.

It should be noted that in addition to these specific ingredients previously, the compositions of the present invention can include other agents conventional practice regarding this type of comp is tabletki or other forms, offered in a discrete form, may contain such quantities of the compounds of formula 1, which is effective at such dosage or in their multiples doses, for example, 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, must depend on its severity and status.

The compounds of formula I can be entered orally or by 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 the program 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; acute conditions to reassure the patient by reducing the daily dose.

The following examples illustrate the present invention.

Reference example 1

Getting hydroiodide N-methylpiperidine

10.8 g of thiourea was dissolved in acetone (250 ml) at 50oC. Add 10 ml iodomethane, and the reaction mixture was stirred at 50oC for 4 hours. After cooling, the solution was diluted with ether (1 l) and filtered salt under the conditions, washed with ether and dried in vacuo get 29,2 g, so pl. 113 - 115oC. 5 g of salt under the conditions dissolve in water, add 30 ml of N-methylpiperazine. The resulting solution is stirred, barbotine nitrogen at room temperature for 24 hours. The solution was concentrated in vacuo. The residue is stirred with ethanol, filtered and dried in vacuum. Get to 4.98 g, So pl. 230 242oC.

Reference example 2

1. Obtain 2,3,5-trichloranisole alcohol

To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50 g), in ethanol (1.0 l) at room temperature add NaBH4(7.0 g) and the resulting mixture perimeter between CHCl3and a saturated solution of NaHCO3. The organic phase is washed with brine, dried over MgSO4, filtered and the solvent is evaporated in vacuo to obtain a solid part. Get 43,0, So pl. 90 93oC.

2. Obtain 2,3,5-trichlorobenzaldehyde

To a solution of alcohol in benzene (400 ml) under nitrogen atmosphere add RVG3(126,58 g), and the 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 (x 3) and the combined benzene extracts are washed with saturated NaHCO3solution in water, dried over MgSO4. Filtered and the solvent is evaporated to obtain a brown liquid which solidifies upon standing to 37.5 g, So pl. 40 - 42oC.

3. Obtain 2,3,5-trichlorophenylacetic

Bromide are suspended in DMF (130 ml) (water) (86,67 ml) at 0oC and portions add KCN (12,99 g). After stirring at 30 35oC for 3 hours, the suspension is diluted with water and extracted with Et2O. the combined ether extracts washed with water, dried over MgSO4, filtered, and the solvent is evaporated in vacuum. After chromatographic processing on silica gel, using the 60 62oC.

Example 1

Getting 4-amino-2-(methylpiperazin-1-ml)-5-(2,3,5-trichlorophenyl)pyrimidinedione

1. Getting 2-(2,3,5-trichlorophenyl)-3-oxo-propionitrile, sodium salt

To a solution of ateleta sodium NaOE (0,803 g of sodium) in ethanol (55 ml) cooled with ice in a nitrogen atmosphere add 1,3,5-Trichloroisocyanuric (see reference example 2). Add ethylformate (5,1 ml), and get the mixture is stirred at room temperature overnight. After stirring for 2.5 hours at 50oC the resulting mixture was cooled and filtered. The resulting filtrate is evaporated and the residue triturated with diethyl ether, filtered and dried (6,82 g).

2. Getting 2-(2,3,5-trichlorophenyl)-3-methoxy-Acrylonitrile

The above solid product is dissolved in DMF (36 ml) and add 2 ml under the conditions. The reactor is pressurized before its contents are stirred for 3 hours at 40oC. Then the solvent is evaporated. The residue is divided between water and ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and the solvent is evaporated upon receipt of the crude product as a red-brown oil that solidifies upon standing (5,04 g).

3. Paule (20 ml) is added N-methylpiperidine hydroiodide (of 2.06 g) (see example 1.1). After stirring for another 10 minutes add the compound of example 3,2 (1 g) and the resulting mixture is stirred at the boil under reflux for 4 hours. The resulting mixture was left to stand at room temperature overnight, and then filtered. The obtained filtrate is concentrated and the residue is purified chromatographically on SiO2, elwira CHCl3up to 4% MeOH/CHCl3to obtain the title compound in the form of a free base, 0,89 g, So pl. 162-164oC.

Then 0,805 g of the free base is dissolved in ethanol (35 ml) and cooled in an ice bath. Add methansulfonate (0.21 g) and the reaction mixture stirred at room temperature for 2 hours. Then the solvent is evaporated and the residue triturated with diethyl ether, filtered, dissolved in cold water and dry with wimalaratana to obtain specified in the title salt as solid pale green color, and 0.98 g, So pl. 143-146oC.

1H NMR ( ) (DMSO)-d6: 7,8 (d, 1H), 7,65 (s, 1H), was 7.36 (D. 1H), 6,33 6,23 (Shir. C. 2H), 3,68 (m, 4H), 2,32 (m, 4H), 2.2 s, 3H).

Example 2

Synthesis of 4-amino-2-(4-methylpiperazin-1-yl)-5-2,3,5-trichlorophenyl)pyrimidine

1. Obtaining 1,4-dioxolan-Pro-is-3-oxo-propionitrile (3.00 g 12,07 mm), add ethane-1,2-diol (anhydrous) (18 ml) and Amberlust H15, Xilin (150 ml). The flask is equipped with a trap Dean-stark with a capacitor. The flask contents are heated under reflux for 5 hours. The reaction mixture is cooled to room temperature and add anhydrous MgSO4. The dried organic solution is filtered and washed with toluene. The filtrate is concentrated under reduced pressure to an oil (4.6 g). The oil is a crude product of the desired 1,4-dioxolan-derived 2-(2,3,5-trichlorophenyl)-3-oxo-propionitrile formula:

< / BR>
2. Getting 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of ateleta sodium (1.73 g is 25.50 mm) in absolute ethanol (100 ml) for 15 minutes with stirring at room temperature is added 4-methyl-1-piperazine carboxamide hydroiodide (6.85 g, 25.3 mm). To add the last of the crude product 1,4-dioxolane-derived 2-(2,3,5-trichlorophenyl)3-oxo-propionitrile dissolved in absolute ethanol (25 ml). The resulting mixture was refluxed for 4 hours.

Then the ethanol is evaporated under reduced pressure and the resulting residue is divided into parts between water (200 ml) and ethyl acetate (100 ml). The organic layer odvody (2 x 100 ml) and then dried over MgSO4(anhydrous).

The ethyl acetate is evaporated under reduced pressure to obtain the residue (3.4 g). The rest bring in dichloromethane (100 ml) and extracted with 3% (vol./about.) water methansulfonate (2 x 40 ml) (pH about 2). Connected the aqueous layer washed with dichloromethane (2 x 50 ml) and then cooled with ice water to about 5oC. the pH of the latter is brought to a pH of about 11-12 drip added 2M aqueous NaOH with stirring. The precipitate defend 1 hour and then filtered under vacuum to obtain the desired compound in the form of a solid light green (0,82 g, 18% of the tautomeric mixture).

The 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. The Protocol for testing inhibition activity DEFR is a modification of the method described in Pharmocology, vol 20, p. 561-574, 1971.

The results are shown in the table, with IC50is the concentration of compound that causes 50% inhibition (a) caused by veratrine release of glutamate, and (b
A. Compound of example 1, 150 mg

Lactose 200 mg

Corn starch 50 mg

Polyvinylpyrrolidone 4 mg

Magnesium stearate 4 mg

(The content on the pill)

The drug is mixed with the lactose and starch and graduate with a solution of polyvinylpyrrolidone in water. The obtained granules are dried, mixed with magnesium stearate and compressed to obtain tablets.

B. Injection (I)

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

Composition for intravenous injection (II)

The active ingredient 0.20 g

Sterile besprovannyk phosphate buffer (pHO) to 10 ml

The compound of example 1 in the form of a salt is dissolved in most of the phosphate buffer at 35 40oC, then brought to the desired volume, and filtered through a sterile micropore filter into sterile 10 ml glass vials (type 1), which is closed with sterile tubes and sealed.

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

C. Composition for capsules

Composition for capsules A

Composition A can be obtained by mixing the ingredients and filling two-part hard as Patrickemailguard 25

(d) magnesium Stearate 2

Total 420

Composition for capsules B, mg/capsule:

(a) Active ingredient 250

(b) the Macrogel 4000 BP 350

Total 600

Capsules can be manufactured by melting the Macrogel 4000 BP, dispersive active ingredient in the melt and filling gelatin capsules consisting of two parts.

Composition for capsules B (capsules with regulatory release), mg/capsule

(a) Active ingredient 250

(b) Microcrystalline cellulose 125

(c) Lactose B. P. 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 ethylcellulose (d) as a control release membrane, and filled into hard gelatin capsules consisting of two parts.

The composition of the syrup

The active ingredient 0,2500 g

Solution of sorbitol 1,5000 g

Glycerin 1,0000 g

Sodium benzoate 0,0050

Flavoring agent of 0.0125 ml

Purified water to 5.0 ml

Sodium benzoate is dissolved in a portion of purified water and add a solution of sorbitol. Add active Noah water.

Composition suppositories, mg/suppository

Active ingredient (63 μm)*250

Hard fat, BP (Witepsol H15 Dynamit Nobel) 1770

Total 2020

*The active ingredient used in the form of a powder in which at least 90% of the particles are of 63 μm or less.

One-fifth of the Witepsol H15 is melted in a vessel with a steam jacket at 45oC maximum. The active ingredient is passed through a 200 μm sieve and add to the melted base, using a Silverson with a cutting head, until a homogeneous dispersion. Maintaining the temperature of the mixture 45oC 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 to 40oC 2,02 g aliquot mixture is filled into suitable plastic moulds and the suppositories allowed to cool to room temperature.

1. The way to obtain 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5 - trichlorophenyl)-pyrimidine or its acid salt additive, characterized in that 1-(2,3,5-trichlorophenyl)-3-alkoxy-Acrylonitrile of the formula II

< / BR>
where L1-C4- alkoxygroup,

experience is methylpiperazin-1-yl)-5-(2,3,5 - trichlorophenyl)-pyrimidine in the form of free base or in the form of its acid salt additive.

2. The way to obtain 4-amino-2-(4-methylpiperazin-1-yl)-5- (2,3,5-trichlorophenyl)pyrimidine, wherein the 2-(2,3,5-trichlorophenyl)-3-acetal-propionitrile formula IV

< / BR>
where R10and R11both alkyl or together form a group (C(R)2)n-, where R is hydrogen or alkyl and n is 2 to 4, is subjected to reaction with N-methylpiperazine formula III

e

 

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FIELD: organic chemistry, chemical technology.

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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SUBSTANCE: invention describes a method for preparing 1,3-oxathiolan nucleosides or a method for preparing derivatives of 1,3-oxathiolanyl-5-one that involve effective methods for formation of 1,3-oxathiolan ring followed by condensation of 1,3-oxathiolan with pyrimidine or purine base. Using indicated methods these compounds can be synthesized as separate enantiomers with high selectivity.

EFFECT: improved preparing methods.

27 cl, 3 dwg, 16 ex

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SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

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SUBSTANCE: method involves applying eradicative anti-helicobacterial therapy comprising Omeprazol administration at a dose of 20 mg twice a day and Ximedone at a dose of 500 mg twice a day in 12 days long course.

EFFECT: enhanced effectiveness of eradication; reduced adverse side effects risk.

FIELD: organic chemistry, medicine, pharmacy, pharmacotherapy.

SUBSTANCE: method involves administration in mammal the effective dose of 6-hydroxy-8-[4[4-(2-pyrimidinyl)piperazinyl]butyl]-8-azaspiro[4,5]-7,9-dione or its pharmaceutically acceptable salt of acid addition or its hydrate. Method expands arsenal of medicinal agents used for suppression of fear sensation.

EFFECT: valuable properties of agent.

3 tbl, 6 dwg, 4 ex

FIELD: medicine, narcology.

SUBSTANCE: invention relates to hepatoprotective and anti-encephalopathic agent used for reducing alcoholic intoxication. Invention comprises components based on succinic, fumaric, glutamic acids and, additionally, at least one vitamin of B group. Agent can comprise additionally vegetable extracts or their mixture, L-carnitine, glycine, L-arginine, taurine and/or their mixture, methylsulfonylmethane, dihydroquercitin, dimethylsulfoxide or their mixture, nicotinamide or nicotinic acid or their mixture, energy source and sweetening agent. Also, invention proposes a method for reducing alcoholic intoxication, prophylaxis and removing withdrawal syndrome, liver protection, among them, in non-alcoholic intoxication and protection against encephalopathy. Invention provides described effects without qualifying medical control.

EFFECT: valuable medicinal properties of agent.

16 cl, 3 tbl

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention describes bicyclical nitrogen-containing heterocycles of the general formula (I): , wherein R1 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, pyridyl, naphthyl, furyl-(C1-C4)-alkyl, phenyl optionally substituted with di-(C1-C7)-alkylamino-(C1-C7)-group, halogen atom, (C1-C7)-alkoxy-group or hydroxy-(C1-C7)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group, amino-(C1-C7)-alkyl, amino-group or di-(C1-C7)-alkylamino-(C1-C7)-alkoxy-group; R2 means (C1-C7)-alkyl, (C3-C7)-cycloalkyl, furyl-(C1-C4)-alkyl, pyridyl or its N-oxide; phenyl optionally substituted with halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, hydroxy-group or trifluoromethyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxy-group; R3 means hydrogen atom, (C1-C7)-alkyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (C3-C7)-cycloalkenyl, pyridyl-(C1-C4)-alkyl, naphthyl, phenyl optionally substituted with phthalimido-(C1-C4)-alkyl, amino-(C1-C7)-alkyl, hydroxy-(C1-C7)-alkyl, (C1-C7)-alkylamino-(C1-C7)-alkyl, di-(C1-C7)-alkylamino-(C1-C7)-alkyl, morpholino-(C1-C4)-alkyl or piperazinyl-(C1-C4)-alkyl, or phenyl-(C1-C7)-alkyl optionally substituted with (C1-C7)-alkoxycarbonyl or carboxy-group. Also, invention relates to pharmaceutically acceptable salts of compounds of the formula (I) as a base with acids or pharmaceutically acceptable salts of compounds of the formula (I) as acid with bases, and pharmaceutical composition based on thereof. Compounds described above show inhibitory activity with respect to tyrosine kinase and can be used in treatment or prophylaxis of inflammatory, immunological, oncological, bronchopulmonary, dermatological and cardiovascular diseases, for treatment of asthma, disorders in the central nervous system or complications associated with diabetes mellitus, or for prophylaxis against transplant rejection after surgery transplantation.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 tbl, 92 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a pharmaceutical composition eliciting hepatoprotective effect. The base of pharmaceutical composition comprises adducts of orotic acid with amino acids or amines as an active substance. The composition comprises effective amount of active substance and special additives in the following ratio of active substance and special additives, wt.-%: active substance, 0.05-40.0; special additives, 60.0-99.95. As special additives the composition comprises starch, mixture of vitamins, lactose, aerosil, talc, stearates, polyvinylpyrrolidone, solid confectionary fat, Tween-80, polyethylene glycol, glycerol, citric acid, benzoic acid, sodium benzoate, correcting dye-substances. Compositions are made as tablets, capsules, lozenges, suppositories, syrups. Also, invention proposes a medicinal agent comprising above said pharmaceutical composition. Invention provides high pharmaco-therapeutical effect with fitness period 2 years, not less.

EFFECT: improved and valuable pharmaceutical properties of composition.

9 cl, 6 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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