The physical form of (r)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro - 8-methyl-7h-1,3 - dioxolo[4,5-h]-[2,3]-benzodiazepine, its preparation and pharmaceutical composition

 

(57) Abstract:

The physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h] -[2,3] -benzodiazepine having a powder x-ray with d parameters when 10.61, 8.83, 6.78, 5.83, and 3.74 4.13 , is a potent and selective antagonist of the AMPA receptor. 3 S. and 1 C.p. f-crystals, 2 tab.

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system.

In the published European patent application N EP-A1-0492485 reveals the connection 1-(4-AMINOPHENYL)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine. This compound is a potent and selective antagonist of excitatory amino acid AMPA receptor and it is believed that it has the ability to treat various neurological disorders. (P) enantiomer of this compound, called hereafter (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h] [2,3]benzodiazepine, is the most powerful enantiomer.

The present invention provides the physical form of (R)-7 - acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h] [2,3]benzodiazepine the receipt of this form, pharmaceutical compositions containing it and methods of its use.

It was found that (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro - 8-methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine is polymorphic.

First, the physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h] [2,3] benzodiazepine, was found to have a melting point of about 168 - 172oC and powder x-ray with a characteristic d parameters at 6.57 and 5.24 This physical form is called here below as form I. It is obtained by using the recovery (R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine in ethanol using hydrogen and palladium on coal as a catalyst, and then removing the catalyst by filtration, evaporation of the ethanol, heating the remainder of 5.7 g volume 1:1 mixture of water and ethanol under conditions of reflux distilled and then leaving the resulting solution to cool.

Quite surprisingly modification of the process used to obtain form I, using ammonium formate and palladium on coal instead of hydrogen and palladium on coal gave a new physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4 is (R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3 - dioxolo[4,5-h] [2,3] benzodiazepine in ethanol using ammonium formate and palladium on coal as a catalyst, then remove the catalyst by filtration, evaporation of the ethanol, heating the residue in 6 volumes of 1:1-mixture of water and ethanol under conditions of reflux distilled and leaving the resulting solution to cool. It was found that the form II has a powder x-ray with a characteristic d parameters when 13.12 and 5.01

Modification of the process used to obtain form II using potassium formate and palladium on coal instead of ammonium formate and palladium on coal, surprisingly gave another physical form, called here below form III. Thus, the form III was obtained by using the recovery (R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h] [2,3] benzodiazepine in ethanol using potassium formate and palladium on coal as a catalyst, and then removing the catalyst by filtration, evaporation of the ethanol, heating the residue in 6 volumes of 1:1-mixture of water and ethanol under conditions of reflux distilled and leaving the resulting solution to cool. It was found that the form III has a powder x-ray with a characteristic d parameters when 10.61, 8.83, 6.78, 5.83, 3.74 4.13 and This physical form is represented as one of the aspects of the present invention.

It was found that form I has several adverse properties. In castnet is to be encoded. It was found that the filtering process is unacceptably long for large-scale production, and the drying of the filtered wet filtercake long. In addition, it was found that form I is thermally unstable and, as it was discovered, becomes a form IV or occasionally in another physical form, called here below form V. it Was found that the shape of the V has a powder x-ray characteristics d options when 6.12, 5.94 and 5.48 Form V shows multiple phase transitions when subjected to differential scanning calorimetry.

It was found that the form II crystallizes in the form of a mixed suspension which can be easily filtered. However, it was found that it dries slowly and retains the crystallization solvent. It was found that, as form I, it is thermally unstable in relation to transformations in form IV.

Form III, as it was discovered, crystallizes in the form capable of stirring the suspension, which can be freely filtered and subjected to drying. It was also found that it is thermally stable.

Form IV, as found also crystallizes in the form of p which is thermally stable.

Each of the forms I, II, III, IV and V was characterized using x-ray diffraction,13C NMR spectroscopy in the solid state and by differential scanning calorimetry. The used techniques and the physical characteristics defined for samples of each form are given below together (only for forms III and IV) with the common intervals obtained by differential scanning calorimetry using a number of different samples.

Picture of x-ray diffraction (XRD) were obtained in the x-ray diffractometer Siemens D5000, equipped with CuKa ( = 1,54056 A) source operating at the capillary load of 50 KV and 40 mA. Data were collected using a Kevex detector in the solid state. Each sample was scanned between 4 and 35o2 with step size increase of 0.03oC and a maximum scanning speed of 2 stage.

Measurements of differential scanning calorimetry (DSC) was performed on a differential scanning calorimeter (Seiko. Samples (2 to 5 mg), sealed in aluminum cups, was heated from ambient temperature (25oC) to not less than 200oC at a rate of 10oC/min

13C NMR spectra poperechna, operating at a carbon frequency 100.577 MHz and equipped with an auxiliary set of solids and Varian probe 5 or 7 mm UT CP/MAS. Typical measurement conditions were as follows: 90 (deg.) proton r.f. ripple 5.0 MS contact time of 1 to 2 MS, time repetition ripple 5 s, MAS frequency of 7 kHz, spectral width 50 kHz, and the time of the acquisition of 50 MS. Chemical shifts were treated with CH3the group hexamethylbenzene (δ = 17.3 million dollars.) when replacing the sample.

Form I

DSC: Main endotherm at 171.5oC minor endotherm at 207.4oC.

XRD:Parameters, d () is the relative intensity

17.30 - 100

12.28 - 34

7.76 - 71

6.57 - 37

5.24 - 35

4.81 - 94

4.34 - 30

4.21 - 29

4.09 - 19

3.98 - 14

3.62 - 18

2.85 - 12

Form II

DSC: Endotherm at 85.2oC, ectotherm when 91.4oC, endotherm at 192.3oC

XRD: Parameters, d is the relative intensity

13.12 - 100

9.72 - 23

6.73 - 37

6.61 - 60

5.25 - 28

5.01 - 94

4.89 - 70

4.75 - 41

4.24 - 28

3.74 - 25

Form III

DSC: the Endotherm for this sample at 194.7oC. Other samples was found to show the endotherm at a temperature in the range from 192 to 195oC.

XRD: Print the>5.68 - 6

5.31 - 25

5.11 - 68

4.94 - 62

4.78 - 20

4.55 - 5

4.41 - 25

4.13 - 71

4.07 - 19

3.90 - 24

3.74 - 40

3.53 - 16

3.42 - 18

3.37 - 26

3.28 - 11

3.21 - 30

3.02 - 5

2.85 - 7

2.78 - 6

Form IV

DSC: the Endotherm of this sample when 203.2oC. was Found that other show endotherm at a temperature in the range from 201 to 207oC.

XRD: Parameters, d is the relative intensity

12.78 - 100

9.48 - 29

8.99 - 17

8.64 - 23

8.23 - 59

6.53 - 58

6.39 - 13

6.27 - 20

5.73 - 33

5.37 - 44

5.22 - 14

5.18 - 11

5.10 - 15

4.95 - 32

4.89 - 61

4.75 - 12

4.56 - 10

4.41 - 29

4.32 - 20

4.01 - 53

3.96 - 35

3.77 - 22

3.59 - 31

3.39 - 15

3.11 - 19

Form V

DSC: Endotherm at 170.6oC, ectotherm when 177.3oC, endotherm at 206.2oC.

XRD: Parameters, d is the relative intensity

17.37 - 51

12.29 - 21

7.75 - 29

6.79 - 32

6.12 - 13

5.94 - 14

5.48 - 15

5.34 - 24

4.89 - 82

4.33 - 100

4.26 - 50

4.08 - 34

4.02 - 20

3.65 - 21

2.86 - 13

These chemical shifts13C NMR in solution and in the solid state (forms I-V) are given in table. 1.

According to another aspect of the present is rmula

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where MS represents methanesulfonyl, R is methyl, X is acetyl and aryl is p-nitrophenyl, with caustic soda to obtain the compounds of formula I

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in which R is methyl, X is acetyl, and aryl is p-nitrophenyl,

b) recovering the n-nitroaniline group in the compound of formula I in aniline group using potassium formate in the presence of palladium on charcoal as a catalyst for obtaining the compounds of formula I, in which aryl is p-AMINOPHENYL, and

c) crystallization of the compounds of formula I, in which aryl is p-AMINOPHENYL, from a mixture of water and ethanol, in which the number of volumes of water per volume of ethanol is less than 1.1 to 1.0.

If you are using the seed crystal form III, stage (c) it is possible to use a higher volume ratio of water to ethanol.

Stage (a) of the process is conveniently carried out at a temperature in the range from 0 to 100oC. Suitable solvents include alkanols, such as methanol or ethanol, and ethers, such as tetrahydrofuran.

The compound of General formula VII may be obtained by using multi-stage process based on the derived methylenedioxyphenylacetone. This process includes:

b) asymmetric reduction of compound of formula II with obtaining compounds having the formula

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c) interaction of the compounds of formula III with p-nitrobenzaldehyde with getting itomenuage compounds having the formula

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d) the interaction of the compounds of formula IV with an oxidizing agent to obtain compounds of formula

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e) the interaction of the compounds of formula V with acetic hydrazide with obtaining the compounds of formula

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and (f) the interaction of the compounds of formula VI with methanesulfonanilide and tertiary amine to form compounds of formula VII.

The preferred process includes early chiral restoration of the ketone to the alcohol. In the multistage process is added to the deputies for circuit benzododecinium Pyrenophora rings before hydrazine powered reagent is introduced to the opening of the ring and add the required nitrogen components. Finally, the secondary ring is closed by adding a strong base, and the connection is restored and formed the desired connection.

Most preferably the initial stage in the synthesis of compounds of formula I of ketones is chiral phase vosstanovleniya using biological agents, described below. Establishing the stereochemistry at an early stage in this process is favorable and allows the later stages be carried out at a relatively enantiomerically pure material. This increases both productivity and enantiomeric purity.

The first stage of this process involves chiral restoration 3,4-methylenedioxyphenylacetone with obtaining virtually enantiomerically pure alcohol derived from 1,2-methylenedioxybenzene. Preferably formed enantiomer is S or (+) stereoisomer of alcohol.

Alternative initial stage may include a combination of a halide derivative of 1,2-methylenedioxybenzene with enantiomerically enriched epoxide. This also results in obtaining highly enantiomerically enriched alcohol-derived 1,2-methylenedioxybenzene.

The material used for holding chiral restoration at the initial stage, can be either chemical or preferably the biological. In the case of biological agents preferred agents are regenerating enzymes, and most preferred are yeast from the group Zygosaccharomyces. Friend , Candida famata, Saccharomyces pastorianus, Saccharomyces cerevisiae, Saccharomyces uvarum, Candida utilis, Saccharomyces globosus, Kluyveromyces dobzhansk, Kluyveromyces lactis, Candida albicans, Baker's yeast, Zygosaccharomyces rouxii, Lactobacillus acidophilus, Aureobasidium pullulans, Mortierella isabellina, Rhizopus oryzae, Kloeckeva javanica, Hanseniaspora valbyensis, Octosporomyces octospori, Candida guilliermondi; Candida parapsilosis, Candida tropicalis, Torulopsis taboadae, Torulopsis ethanolitolerans, Torulopsis ptarmiganii, Torulopsis sonorensis, Trigonopsis variabilis, Torulopsis enokii, Torulopsis methanothermo, SAF instant yeast, inact. yeast ashland, Candida boidinii, Candida blankii and yeast Red Star.

The desired intermediate compound formed in the initial stage, is alcohol-substituted derivative of 1,2-methylenedioxybenzene, with the most preferred derivative is (S)-alpha-methyl-1,3-benzodioxol-5-ethanol.

The desired intermediate compound formed in the initial stage, and then is subjected to reaction Pictet-Spengler, which provides convergent fusion or condensation benzodiazepine carbohydrate components. The preferred reagent is p-nitrobenzaldehyde, although you can also use other reagents known to specialists in this field, such as acetals. The preferred compounds are dihydrobenzofuranyl, with the most preferred connection avcnue then oxidized at C-5 position, giving gemcitabine derivative of General formula

< / BR>
Preferred oxidizing agents include potassium permanganate, DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) or others, and the most preferred agent is sodium hydroxide, and mix with air.

C-5-hemiketal then undergoes reaction with acetic hydrazide in the presence of acid to obtain hydrazono intermediate connection. At this stage benzopyrrole ring is revealed, so hydrazine powered component is attached to the C5 carbon. The reaction is conveniently carried out in deleverage or aromatic proton solvent, and the hydrazone has a General formula

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in which R is CH3, X is acetyl and aryl is p-nitrophenyl.

The process can be summarized using the following schema.

In scheme I (see end of description) the initial stage of the process involves the addition of biological agents, most preferably Zygosaccharomyces rouxii, for recovery of the ketone to the desired alcohol. To prevent the death of the body and for the adsorption is carried alcohol as soon as it is formed, the reaction mixture may be added a suitable amount of an adsorbent resin such ka is hydrated polystyrene company "Mitsubishi"). Can also be used with other similar resins.

According to scheme II (see end of description) the initial stage of the process involves the interaction arylhalides derivative, such as 4-bromo-1,2- (methylenedioxy)benzene, hydrocarbon compound of an alkali metal (preferred Deut. utility) and enantiomerically pure epoxide. Alternative aryl halides can turn into a Grignard reagent by reaction with magnesium, then subjected to reaction with enantiomerically pure epoxide in the presence of copper oxide (1) as catalyst. Preferred (S)-(-)-propylene oxide. And according to the scheme I and scheme II the aim is to establish the stereochemistry C8 atom of the benzodiazepine ring as soon as possible. According to the observations it was noted that both schemes achieve this goal, and are formed enantiomerically enriched (EE) alcohols with a purity of 98%.

It is known that (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro - 8-methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine is a selective antagonist of AMPA receptor. Thus, according to another aspect of the present invention provides the use of form III for the production of medicaments for blocking AMPA receptor in a mammal requiring such LeCroy or inappropriate stimulation of the excitatory neurotransmission amino acids. It is believed that (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h] [2,3] benzodiazepine has the ability to treat a variety of neurological disorders in mammals that are associated with this condition include acute neurological disorders such as cerebral insufficiency as a consequence of surgery using cardiopulmonary bypass and organ transplantation, stroke, cerebral ischemia, spinal cord injury, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. It is believed that this compound has the ability to treat many chronic neurological disorders such as Alzheimer's disease, Huntington's chorea, amiotroficheskii lateral sclerosis, dementia caused by AIDS, ocular damage and retinopathy, idiopathic or caused by drugs Parkinson's disease. The present invention also provides the use of form II for the production of medicaments for the treatment of these disorders.

It is believed that this compound has the ability to treat many other neurological disorders mammals that are associated with glutaminase and rejection of them, anxiety or fear, emesis, brain edema, chronic pain, and late or late dyskinesia. This compound is also useful as an analgesic agent. Therefore, the present invention also provides the use of form III for the production of drugs for the treatment of these disorders.

The term "effective amount", as used here, refers to the number of form III, which is able to block the receptor for the excitatory amino acid AMPA. The specific dose of a compound that is assigned to receive according to this invention will of course depend on the particular circumstances, including appointed by the Union, the assignment method, the particular condition being treated, and similar factors. This form may be administered using a variety of methods, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular or intranasal ways. This alternative form may be administered by continuous infusion. A typical daily dose contains from about 0.01 to 30 mg/kg of active compound of the present invention. The preferred daily dose is from about 0.05 to 24 mg/kg, more predic compositions. According to another aspect of the present invention provides a pharmaceutical composition, which includes the form III and a pharmaceutically acceptable diluent or carrier.

In the manufacture of the compositions of the present invention the active ingredient is usually mixed with a carrier, or diluted by a carrier, or is introduced into the carrier, which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier, excipient or medium for the active ingredient. The composition can be in the form of, for example, tablets, pills, powders, elixirs, Sasha, those capsules, suspensions, aerosols, soft and hard gelatin capsules and sterile packaged powders.

Some examples of suitable carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methylcellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Prepared pre is Genty, preservative or preservative agents, sweetening agents or flavoring or flavoring agents. Compositions of the invention can be formed in such a way as to ensure rapid, delayed or detained, or delayed release of the active ingredient after the appointment of the patient using procedures well known in the art.

The composition preferably formed in the form of a unit dosage form, each dosage contains from about 5 to 5000 mg, more preferably from about 25 to 3000 mg of the active ingredient. The most preferred unit dosage forms contain from about 100 to 2000 mg of active ingredient. The term "unit dosage form" refers to physically discrete unit suitable as a single dose for humans and other mammals, each unit contains a defined quantity of active material calculated so as to produce the desired therapeutic effect, in combination with a suitable pharmaceutical carrier. The following examples illustrate the invention.

Example 1

Synthesis of (S)-alpha-methyl-1,3-benzodioxol-5-ethanol

1 EQ. 3,4-methylendioxyphenyl the e and stirred for 15 60 minutes at 20 - 25oC. was Added 2,27 EQ. glucose and added Z. rouxii ATCC 14462 in the amount of 1.5 g of cell paste per 1 g of the ketone (i.e. 0.375 g/g on a dry basis). This mixture was diluted with water to 25 volumes, and then gently stirred at 33 - 35oC for 8 to 16 hours the Mixture was filtered through a stainless steel sieve of 100 mesh (about 150 microns), and resin, which was retained by the sieve were washed with 25 volumes of water, divided into 4 portions. The product, which was adsorbiroval on the resin, then decarbonators with resin 25 volumes of acetone. A solution of the product in acetone was then otprivilsya to dryness under vacuum, giving specified in the header of the intermediate compound in the form of a yellow oil of medium viscosity. The output was 97-100%, while the output of the selected product was 85-90%. The activity was 80-95% and 100%.

Example 2

Synthesis of (5RS,7S)-7,8-dihydro-7-methyl-5-(4-nitrophenyl)-5H-1,4 - dioxolo-[4,5-G][2]benzopyran

The above intermediate compound was dissolved in with 4.64 volume of toluene, filtered through hyflo and was filtered 1.55 volume of toluene. Was added to 1.05 EQ. p-nitrobenzaldehyde and 1.05 EQ. concentrated hydrochloric acid, and the mixture was heated to 55-65oC and stirred For 1 h the water. Volume during the replacement of the solvent varies from 11 to 14 volumes, and the final volume was about 11 volumes. The mixture was cooled to 0-10oC and stirred for 1 h, needle-like crystals of the product were filtered off and were washed 2 times 1.85 volume of isopropanol and dried under vacuum at 50-60oC. the Yield of the target compound "in situ" was 95+%, while the selected product - 87-93%. The activity was 99+% and 100%.

Example 3

Alternative synthesis of (S)-alpha-methyl-1,3-benzodioxol-5-ethanol

3,47 g of 4 bromo-1,2-(methylenedioxy)benzene was dissolved in 100 ml of tetrahydrofuran at -78oC, then added to 13.9 ml of 1.3 M sec.utility in cyclohexane for consumption helgaleena less than 30 minutes With a syringe was added to 1.00 g ( )-(-)propylene oxide in 2 ml of THF, and the solution was mixed for 45 minutes the Solution is then heated to 23oC for 16 h, the Reaction mixture was poured into 3 M solution of ammonium chloride, and the product was separated by extraction with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered through Florisil and concentrated by rotary evaporation. The residual oil was purified using chromatography on silica gel and OCTA. P chem: + 117,2o(c and 1.0, CHCl3), TLC Rf= 0,26 (50:50 hexane:ether) IR (CHCl3) 3598, 3012, 2973, 2887, 1490, 1249, 1041 cm-1,13C NMR (CDCl3d 147,75, 146,19, 132,26, 122,27, 109,68, 108,30, mass spectrum, m/z (FD, M+) 180.

Analysis for C10H12O3< / BR>
Calculated, %: C 66,65; H of 6.71

Found, %: C 66,42; H 6,66

Example 4

Alternative synthesis of (5RS, 7S)-7,8-dihydro-7-methyl-5-(4-nitrophenyl)- 5H-1,3-dioxolo-[4,5-G][2]benzopyran

244 g of p-nitrobenzaldehyde was added to a solution of 300 g of the intermediate compounds formed during biokatalizatora recovery example 1 4.45 l of toluene. Dropwise over 15-20 min was added KZT 166.5 ml of concentrated hydrochloric acid, and the resulting mixture was heated to 60oC for 2.5 hours the Mixture was cooled to room temperature and concentrated by rotary evaporation. Was added 3 l of ethanol, and the mixture was concentrated to a solid. Added another 3-l portion of ethanol, and the mixture is stirred for 1 h, the Suspension was cooled overnight and the crystalline product was separated by filtration under vacuum. The filter cake was rinsed with ethanol, and then dried in a vacuum oven at 40-60oC, giving 450 g (86%) above in the title optically active intermediate substance. P chem: +55o(c 0,4, CHCl3).

Example 5

Synthesis of (5RS, 7S)-7,8-dihydro-7-methyl-5-(nitrophenyl)-5H-1,3 - dioxolo[4,5-G][2]benzopyran-5-ol

350 g of isomeric intermediate compound from example 4 was added to a solution of 731 ml of dimethyl sulfoxide and 2923 ml of dimethylformamide. The mixture was cooled to 8-12oC, and after the mixture was passed compressed air. Added 117,5 ml of 50% aqueous sodium hydroxide in the form of one portion and the resulting mixture stirred for 4.5 hours, the Reaction mixture was added with a straw for 30-60 min to 8,25 l mix 1 N. hydrochloric acid at 10-15oC. the Resulting precipitate was filtered off and were washed 3 l of water, and then subjected to air drying to constant weight (384 g). Wet sediment was transferred in example 6 without further drying. P chem: Data were recorded on 3:1 isomeric mixture. TLC Rf= 0,19 (75:25 hexane: ethyl acetate), IR (CHCl3) 3605, 3590, 3015, 3000, 2960, 2910, 1608, 1522, 1484, 1352, 1240, 1042 cm-1.

1H NMR (CDCl3, 300 MHz) d (main isomer) is 8.16 (d, 2H, J = 6.9 Hz), 7,73 (D., 2H, J = 6.9 Hz), 6,55 (S., 1H), 6,38 (S., 1H) 5,86 (S., 1H), of 5.83 (SD , 1H), to 4.38 (m , 1H), 2,70 (m, 2H), 1.39 in (D., 3H, J = 6.3 Hz), d (minor isomer) of 8.27 (D. , 2H, J = 8,9 Hz), of 7.90 (D., 2H, J = 8.6 Hz), 6.87 in (S., 1H), 6.73 x (S., 1H), 6,03 (S., 1H), H15NO6< / BR>
Calculated, %: C 62,01; H 4,59; N 4,25

Found, %: C 62,22; H 4,79; N 4,29

Example 6

Synthesis of (S)-acetic acid-[[6-(2-hydroxypropyl)-1,3-benzodioxol - 5-yl](4-nitrophenyl)methylene]hydrazide

To 350 g wet filtercake from example 5 in 2300 ml of ethanol was added to 94.5 g of acetic hydrazide and 1 ml of concentrated hydrochloric acid. The resulting solution was heated to the temperature of reflux distilled for 2.5 hours the Mixture was cooled to room temperature and concentrated to a yellow foam by rotary evaporation. The concentrate was dissolved in 4.9 l of ethyl acetate and was washed with 1.5 l of saturated sodium bicarbonate, then 1.5 liters of saline. The organic phase was dried over sodium sulfate, filtered and concentrated, giving 373 g of a yellow foam (91%). This material was identified as a 1:1 inseparable mixture of isomers named the title compound (97% pure according to HPLC). P chem: Data were recorded on a 1: 1 isomeric mixture. So pl. 167,8-169,7oC, TLC Rf= 0,55 (ethyl acetate), IR (CHCl3) 3590, 3485, 3310, 1694, 1673, 1520, 1485, 1346 cm-1.

1H NMR (CDCl3, 300 MHz) d 8,64, 8,50 (C., 1H, NH), 8,18 (D., 2H, Ar-H), 7,74, 7,71 (D., 2H, J = 8, Ar-H), 6,99, 6,95 (C., 1H, Ar-H), 6,52, 6,50 (C., 1H, Ar-H), 6,06, 6,05 (D., 2H, J = 5, O22), 67,51, 68,08 (CH), 42,37, 42,97 (CH2), 23,48, 23,83 (CH3), 23,48, 23,83 (CH3), 20,47, 20,55 (CH3), +103,8o(c 1, CHCl3), mass spectrum, m/z (FD, M+) 385.

Analysis for C19H19N3O6< / BR>
Calculated, %: C 59,22; H equal to 4.97; N 10,90

Found, %: C 58,99; H 5,04; N IS 10.68

Example 7

Synthesis of (S)-acetic acid-[[6-[2-[(methylsulphonyl)oxo]propyl]- 1,3-benzodioxol-5-yl](4-nitrophenyl)methylene]hydrazide

340 g of the intermediate compound of example 6 was dissolved in 2380 ml of methylene chloride. The solution was cooled to 0 - (-10oC), and added 187 ml of triethylamine. Then was added to 78.2 ml methanesulfonanilide, and the resulting mixture was mixed for 15-30 minutes was Added 510 ml of water. The separated organic phase was washed 460 ml of 1 n hydrochloric acid, and then 500 ml of saline solution. Methylenchloride the solution was heated to 35-45oC, 90 min was added 4760 ml of hexane. The mixture was slowly cooled to room temperature, and then cooled further to 0-5oC. the Product was separated by filtration and dried in vakuumnaya. P chem: Data were recorded on 3:1 isomeric mixture. So pl. 150,5-152,5oC, TLC Rf= 0,80 and 0.73 (ethyl acetate), IR (CHCl3) 1696, 1520, 1486, 1346, 1175, 1041, 923 cm-1,1H NMR (CDCl3, 300 MHz) d 8,44 (s, 1H, NH), 8,20 (D., 2H, J = 8,8 Hz, Ar-H), 7,73 (D., 2H, J = 8.6 Hz), 6,94 (D., 1H, J = 2.7 Hz, Ar-H), 6,57 (D., 1H, 2.6 Hz, Ar-H), between 6.08 (D., J = 5.4 Hz), of 4.77 (m, 1H, CH), 2,90 (C., 3H, SCH3the chief), 2,83 (C., 3H, SCH3minor), 2,66-to 2.57 (m , 2H, CH2), 1,30 (D., 3H, CH3minor), 1,26 (D., 3H, CH3the chief), mass spectrum, m/z (FD, M+) 385.

Analysis for C20H21N3O8S

Calculated, %: C 51,83; H of 4.57; N 9,07; S 6,92

Found, %: C 52,05; H a 4.53; N 8,84; S OF 6.96

Example 8

Synthesis of (R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H - 1,3-dioxolo[4,5-h][2,3]benzodiazepine

325 g of the intermediate of example 7 was dissolved in 3174 ml of methanol. To the stirred solution was added to 38.1 ml of a 50% aqueous solution of caustic soda. The resulting mixture was mixed for 4 hours To the mixture was added 6348 ml of water, and the contents were mixed for 3 h, after which the resulting precipitate was separated by vacuum filtration. The material was dried in a vacuum oven at 45-55oC, giving 255 g (97%) named in the title compound, which was on the 97.6% of net% of the ethanol, which was heated to the temperature of reflux distilled. The resulting mixture was cooled to room temperature and the precipitate was separated by vacuum filtration. Extracts were dried in a vacuum oven at 45-55oC, giving 199 g (90%) named in the title compound, which was 100% purity, according to the analysis of HPLC.

Example 9

The synthesis of form IV (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8 - methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine

To 5 g of the intermediate compound of example 8 in 50 ml of ethanol was added 0.5 g of 10% Pd/C, moistened with water. Stir the suspension was treated with a solution of 4 g of potassium formate in 4 ml of water. The resulting mixture was stirred for 2.5 h and then filtered over hyflo. The filtrate was concentrated to 10-20 ml by distillation, and was slowly added 22 ml of water to be reheated (78oC) solution. The resulting mixture was heated to 90oC and then slowly cooled to room temperature. The product was separated by vacuum filtration and were washed 10-29 ml of water. Separated solid substance was dried under vacuum at 50oC, giving of 4.17 g (93%) specified in the header end of the connection, which had 100% purity, according to installcheck, turned out to be a form IV.

Example 10

Synthesis of (5RS, 7S)-7,8-dihydro-7-methyl-5-(4-nitrophenyl)-5H-1,3-dioxolo[4,5-G] [2]benzopyran-5-ol.

15 g of the intermediate compound of example 4 (obtained by the reaction of the ketone restore using Z. rouxii) was dissolved in a solution of 75 ml of dimethyl sulfoxide and 75 ml of dimethylformamide. The solution was cooled to 7-9oC, and then Aeronavale 40% oxygen in nitrogen. Added a 7.62 g of 50% sodium hydroxide in water, and the resulting mixture stirred for 4-5 hours the Reaction was terminated, and maintaining the temperature = 12oC was added 120 ml of toluene, followed by addition of a mixture of 45 ml and 10 ml of hydrochloric acid. The phases were separated and the organic layer was washed with 75 ml of 10% water solution of sodium thiosulfate. The organic layer containing specified in the header of the intermediate compound, was postponed to the next stage.

Example 11

Synthesis of (S)-acetic acid-[[6-(2-hydroxypropyl)-1,3-benzodioxol-5-yl](4-nitrophenyl) methylene]hydrazide

To the toluene solution of the intermediate of example 10 was added 4.26 deaths g of acetic hydrazide and 0.01 volume of hydrochloric acid. The resulting mixture was heated to reflux distilled in tiomnoi distillation to 1 volume. The concentrate was diluted 105 ml of methylene chloride and was washed 50-55 ml each of saturated sodium bicarbonate solution and saline. The organic solution was dried over magnesium sulfate (0.25 weight. %) and filtered through sediment hiflo. The filter was propulsively 1 volume of methylene chloride. The combined organic phase containing specified in the header of the intermediate compound, was postponed to the next stage.

Example 12

Synthesis of (S)-acetic acid-[[6-[2-[(methylsulphonyl)oxy] propyl]-1,3-benzodioxol-5-yl](4-nitrophenyl)methylene]hydrazide

Methylenechloride solution containing the intermediate compound of example 11, was cooled to 0 - (-5oC), and added 10 ml of triethylamine. Was slowly added to 4.1 ml of methanesulfonanilide to maintain the reaction temperature = 0oC. To the resulting solution were added 1.5 volume of water. The organic phase was separated and was washed with 2.5 volumes of 1 N. hydrochloric acid. The organic phase was separated and concentrated to half the original volume by means of an atmospheric distillation. The product was precipitated by adding to the solution at 45oC dropwise heptane (2:1 volume of heptane to organic concentrate). Stir the mixture ahmadalamer filtration and were washed with 3 volumes of 4:1 mixture of heptane:methylene chloride. Then were dried in a vacuum oven at 45-50oC. was 17,43 g named in the header of the intermediate product (78%) in the form of optically active isomeric mixture of the hydrazone, which was 97.7 percent pure, according to the analysis of HPLC.

Example 13

Synthesis of (R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)- 7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine

of 17.5 g of the intermediate of example 12 was suspendibility in 175 ml of ethanol. To stir the mixture was added 1.7 g of powdered sodium hydroxide. The resulting mixture was mixed for 1 hour To the mixture was added 88 ml of water, and the contents were mixed for 1 h, after which the resulting precipitate was separated by vacuum filtration and were washed 175 ml of water. The substance was dried in a vacuum oven at 70oC, yielding 12.2 g (86%) named in the title compound, which was of 99.9% purity, according to the analysis of HPLC.

Example 14

(R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3 - dioxolo[4,5-h] [2,3]-benzodiazepine

When using the product of example 13 was obtained target compound using the experimental procedure, the same as described in example 9.

Example 15

(R[2-(hydroxy)propyl]-1,3-benzodioxol-5-yl] (4-nitrophenyl) methylene]hydrazide and 0.78 g of triphenylphosphine in 70 ml of tetrahydrofuran was cooled to 0oC. dropwise over 15 min was added 0,57 g diethylazodicarboxylate in 5 ml of tetrahydrofuran. The resulting mixture was mixed for 2 h, then was warmed up to room temperature for 2 hours the Mixture was transferred into a separating funnel, and the solution was filtered 1 N. HCl, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The residue was elyuirovaniya through silicagel column (1:1 ethyl acetate: hexane). The fractions containing the desired compound were concentrated to a yellow oil which hardened on standing. A yellow crystalline substance was suspendibility in 30 ml of methylene chloride and hexane (3:7) at 0oC. the Precipitate was removed by filtration, and the filtrate was concentrated to a yellow foam. The residue was suspenderbelt in 10 ml of ethanol is heated to the temperature of reflux distilled, then slowly cooled to room temperature. The precipitate was collected by filtration and dried in a vacuum oven at 60oC, yielding 0.51 g (50%) named the title product (100% EE), which had a purity of 98.3% according to HPLC analysis activity.

Example 16-18

0.5 ml suspension of frozen yeast containing microorg is their 48 h with 1.0 ml of the culture is added to an additional 50 ml of medium and shaken for 48 hours Added 3,4-methylenedioxyphenylacetone up until the final concentration is 10 g/l, along with 1 ml of 10% glucose. Cultures are incubated and shake for 24 h, and then analyzed by HPLC for the presence of a chiral alcohol of the intermediate product of example 1.

Example 19

The synthesis of form I of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine

(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo [4,5-h] [2,3]benzodiazepine (38,93 g) was gidrirovaniya in 730 ml (19 volumes) 2B-3 ethanol using 7,79 g 10% palladium on coal and under 1 ATM of hydrogen. When HPLC analysis showed that the starting material was slashdowns, the catalyst was removed by filtration, and the filtrate was evaporated, giving of 38.7 g of crude product. The crude product was dissolved in 220 ml (5.7 volume) 1:1 mixture of water: ethanol with heating to boiling. The mixture was left to cool, and the product was precipitated at a temperature close to the room. The resulting dense, poorly peremeshivajutsa the suspension was mixed at room temperature, and then cooled in an ice-water bath. A solid substance was separated by filtration and dried in a vacuum oven at 55oC during the 8.7 g (80%) of product after drying under vacuum for 3 days at 65oC and 3 days at room temperature. The product was dried very slowly, and at this point the sample was still 1.6% ethanol. Analysis using x-ray diffraction (XRD), NMR in the solid state (SS NMR) and differential scanning calorimetry (DSC) indicated that formed polymorphic form I.

Example 20

The synthesis of form 11 (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8 - methyl-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine

(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3 - dioxolo[4,5-h][2,3]benzodiazepine (8,63 g) was gidrirovaniya in 170 ml (19 volumes) 2B-3 ethanol using 0,86 g 10% palladium on coal and 4.59 g of ammonium carbonate in 5 ml of water as the source of hydrogen transport. When HPLC analysis indicated that starting material was slashdowns, the catalyst was removed by filtration, and the filtrate was evaporated, giving 8,19 g crude product. The crude product was dissolved in 50 ml (6.0 volume) 1:1 water:ethanol while heating to a boil. The mixture was left to cool to room temperature, and then cooled in a bath of a mixture of ice and water. A solid substance was separated by filtration and dried in a vacuum oven at 60oC during the night, giving 7,41 g (93%) of the pure product. Large crystalluria.

Example 21

The synthesis of form III (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine

(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3 - dioxolo[4,5-h] [2,3]benzodiazepine (2,04 g) was gidrirovaniya in 20 ml (10 volumes) 2B-3 ethanol using 0.20 g of 10% palladium on coal and 1.47 g of potassium formate in 4 ml of water as the source of hydrogen transport. When HPLC analysis showed that the starting material was slashdowns, the catalyst was removed by filtration, and the filtrate was evaporated, giving 2,09 g crude product. The crude product was dissolved in 12 ml (6.0 volume) 1:1 mixture of water:ethanol while heating to a boil. The mixture was left to cool and was setrulevalue crystals of form II at about 40oC. After reaching room temperature, the mixture was cooled in a bath of a mixture of ice and water. A solid substance was separated by filtration and dried in a vacuum oven at 50oC for 24 h, giving 1.45 g (77%) of the pure product. The analysis showed 0.05% ethanol (GC) and 0.75% water (KF). Despite the use of seed crystals of form II polymorph, XRD, SS NMR and DS showed that emerged form III polymorph.

Example 22

The synthesis of form IV (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3]Ben who was little more than 250 ml (10 volumes) 2B-3 ethanol using 2.0 g of 10% palladium on coal and 18.9 g of potassium formate in 20 ml of water as the source of hydrogen transport. When HPLC analysis showed that the starting material was slashdowns, the catalyst was removed by filtration. The filtrate was concentrated by distillation until such time as there was about 70 ml (3 volume) ethanol. To the solution at reflux distilled water was added (93 ml, 4 volume). The mixture was left to cool and was setrulevalue crystalline product of example 9 at 80oC. the Resulting suspension was left to cool to room temperature and mixed for the night. A solid substance was separated by filtration and dried in a vacuum oven at 50oC for 24 h, giving 19,8 g (85%) of the pure product. The analysis showed no detectable levels of ethanol (GC) and 1.0% water (KF).

Analysis of the XRD SS NMR and DSC indicated that formed the shape of the IV polymorph.

Example 23

Alternative synthesis of (S)-alpha-methyl-1,3-benzodioxol-5-ethanol

To a suspension of magnesium turnings (17 g) in 50 ml of tetrahydrofuran was added dropwise a solution of 5-bromo-1,3-benzodioxole (93,6 g). After complete addition, the mixture was diluted with 250 tetrahydrofuran, and the resulting mixture stirred over night. 13 ml (0,78 M) was transferred into a round bottom flask containing copper iodide (1) (0,12 is hydrofuran, and then stirred for 10 minutes the Mixture was diluted with ether. Separated organic phase was washed with water and brine. Water wash water was extracted with ether (2×) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. The residue was purified using chromatography on silica gel (50% ether in pentane) to give 1.66 g of the desired product (91%). Analysis of chiral HPLC showed that the optical purity was 98.3% of.

Example 24

Pharmaceutical finished formulation form:

the active ingredient is 1; 10; 50; 100 mg;

starch, respectively 444,5; 435,8; 396,2; 346,6 mg;

silicone fluid, respectively 4,49; 4,22; 3,84; 3,36 mg.

The ingredients were mixed and filled into hard gelatin capsules of size 0 to a weight content of 450 mg.

1. The physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h] [2,3]-benzodiazepine having a powder x-ray with d parameters in 10,61, 8,83, 6,78, of 5.83, 4,13 and 3.74

2. The method of obtaining the physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h][2,3]-benzodiazepine stated in paragraph 1, which includes a) the interaction of the compounds of formula VII
caustic soda to obtain the compounds of formula I

< / BR>
in which R is methyl;

X is acetyl and Aryl is p-nitrophenyl,

C) the restoration of p-nitroaniline group in the compound of formula I in aniline group using potassium formate in the presence of palladium on charcoal as a catalyst for obtaining the compounds of formula I, in which Aryl is p-AMINOPHENYL, and (C) crystallization of the compounds of formula I, in which Aryl is p-AMINOPHENYL, from a mixture of water and ethanol, in which the number of volumes of water per volume of ethanol is less than 1.1 to 1.0.

3. Pharmaceutical composition having the properties of a selective antagonist of AMPA-receptor, which comprises (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3 dioxolo-[4,5-h][2,3]-benzodiazepine and a pharmaceutically acceptable diluent or carrier, characterized in that it contains the physical form of the compounds having the powder x-ray with d parameters in 10,61, 8,83, 6,78, of 5.83, 4,13 and 3.74

4. The physical form of (R)-7-acetyl-5-(4-AMINOPHENYL)-8,9-dihydro-8-methyl-7H-1,3-dioxolo [4,5-h] [2,3]-benzodiazepine having a powder x-ray d-parameters when 10,61, 8,83, 6,78, of 5.83, 4,13 and 3.74 under item 1, useful for the production of medicaments for use as an antagonist of the AMPA receptor.

 

Same patents:

The invention relates to a new physical form derivatives of dihydro-2,3-benzodiazepine, useful as pharmaceutical agents in the treatment of disorders of the nervous system

The invention relates to novel condensed derivative indana formula I

< / BR>
in which A represents an optionally substituted benzene ring, naphthalene ring or benzene ring condensed with the lowest alkylenedioxy; ring B represents an optionally substituted benzene, Y = -N= CR or CR=N-

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: medicine, neurology.

SUBSTANCE: method involves carrying out the standard vascular and nootropic therapy. Diazepam is administrated under EEG control with the infusion rate that is calculated by the following formula: y = 0.0015x - 0.025 wherein y is the rate of diazepam administration, mg/h; x is an average EEG amplitude, mcV. Method provides enhancing the effectiveness of treatment of patients. Invention can be used for treatment of patients in critical severe period of ischemic insult.

EFFECT: enhanced effectiveness of treatment.

2 tbl, 1 dwg, 1 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of dihydrobenzo[b][1,4]diazepine-2-one. Invention describes derivatives of dihydrobenzo[b][1,4]diazepine-2-one of the general formula (I): wherein X means a simple bond or ethynediyl group wherein if X means a simple bond then R1 means cyano-group, halogen atom, lower alkyl, (C1-C3)-cycloalkyl, (lower)-alkoxyl, fluoro-(lower)-alkyl or it means pyrrole-1-yl that may be free or substituted with 1-3 substitutes taken among the group consisting of fluorine, chlorine atom, cyano-group, -(CH2)1-4-hydroxyl group, fluoro-(lower)-alkyl, lower alkyl, -(CH2)n-(lower)-alkoxyl, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'', hydroxy-(lower)-alkoxyl and -(CH2)n-COR'R'', or it means free phenyl or phenyl substituted with one or two substitutes taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, fluoro-(lower)-alkoxyl and cyano-group; if X means ethynediyl group then R1 means free phenyl or phenyl substituted with 1-3 substituted taken among the group consisting of halogen atom, lower alkyl, fluoro-(lower)-alkyl, (C3-C6)-cycloalkyl, (lower)-alkoxyl and fluoro-(lower)-alkoxyl; R2 means -NR'R'', fluoro-(lower)-alkoxyl or 3-oxopiperazin-1-yl, pyrrolidin-1-yl, or piperidin-1-yl wherein their rings are substituted optionally with R''; R' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl or 2-(lower)-alkoxy-(lower)-alkyl; R'' means hydrogen atom, lower alkyl, (C3-C6)-cycloalkyl, fluoro-(lower)-alkyl, 2-(lower)-alkoxy-(lower)-alkyl, -(CH2)2-4-di-(lower)-alkylamino-group, -(CH2)2-4-morpholinyl, -(CH2)2-4-pyrrolidinyl, -(CH2)2-4-piperidinyl or 3-hydroxy-(lower)-alkyl; Y means -CH= or =N-; R3 means halogen atom, lower alkyl, fluoro-(lower)-alkyl, (lower)-alkoxyl, cyano-group, -(CH2)n-C(O)OR'', -(CH2)1-4-NR'R'' or it means optionally substituted 5-membered aromatic heterocycle that can be substituted with halogen atom, fluoro-(lower)-alkyl, fluoro-(lower)-alkoxyl, cyano-group, -(CH2)n-NR'R'', -(CH2)n-C(O)OR'', -(CH2)n-C(O)NR'R'', -(CH2)n-SO2NR'R'', -(CH2)n-C(NH2)=NR'', hydroxyl, (lower)-alkoxyl, (lower)-alkylthio-group or lower alkyl that is optionally substituted with fluorine atom, hydroxyl, (lower)-alkoxyl, cyano-group or carbamoyloxy-group; n means 0, 1, 2, 3 or 4, and their pharmaceutically acceptable additive salts. Also, invention describes a medicinal agent as antagonist of mGlu receptors of group II based on compounds of the formula (I). Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 496 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.

EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

FIELD: oncology.

SUBSTANCE: method comprises administering to an animal, requiring this treatment, in a synergetic mode, therapeutically effective amount of (i) agent selected from group including cytotoxic agents and cytostatic agents and (ii) compound of formula I (given in description) or pharmaceutically acceptable salt thereof. Method provides synergic antitumor effect when using diminished doses of one or both active ingredients, prevents or slows development of multidrug resistance of tumor while ensuring destruction of both proliferative and non-proliferative tumor cells.

EFFECT: enabled use of reduced doses of drugs.

7 cl, 23 dwg, 6 tbl, 25 ex

FIELD: medicine, endoscopy.

SUBSTANCE: one should study psychosomatic state according to questionnaire mentioned in the description followed by calculation of the points obtained. Based upon these data one should calculate the coefficient of symptoms' expressibility C = ∑/n, where ∑ - the sum of points obtained after filling in the questionnaire, n - the quantity of symptoms groups. And at C≥1.5 before endoscopic trial one should prescribe individual therapeutic course of preparations of sedative group. And at C<1.5 before endoscopic trial it is necessary to prescribe standard psychotherapeutic conversation due to paying attention upon reasons that cause dangerous fear at carrying out endoscopic trial. The innovation suggested decreases psychoemotional loadings.

EFFECT: higher efficiency.

2 ex

FIELD: pharmaceutical technology, pharmacy.

SUBSTANCE: method involves addition sugar-alcohol and/or saccharide showing melting point by 5°C lower or above as compared with the first mentioned sugar-alcohol and/or saccharide to sugar-alcohol and/or saccharide followed by combined treatment of prepared powder by pressing and heating. Invention allows preparing medicinal compositions decomposing in mouth cavity rapidly being without water and showing light using owing to the presence of sufficient strength in preparing, transport in usual using. Method involves mixing, pressing and heating components that represent two or more sugar-alcohol and/or saccharide and active component wherein difference between melting points of one among two or more indicated sugar-alcohol and/or saccharide that shows the higher content and any remaining indicated two or more sugar-alcohol and/or saccharide is 5°C or above. Invention provides preparing strength rapidly soluble tablets.

EFFECT: improved preparing method, improved pharmaceutical properties of composition.

30 cl, 12 tbl, 28 ex

FIELD: medicine.

SUBSTANCE: method involves introducing Nooclerine solution at a peroral dose of 5 ml 40 min before surgical intervention with Benzodiazepine series tranquilizer.

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

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new biologically active benzoxazine compounds and describes derivatives of benzoxazine of the following structure: wherein X1 and X2 are taken independently among hydrogen atom (H), -OR4, -CH2OR4; or X1 and X2 taken in common represent -O-CR

52
O- or -O-CR52
CR52
O-, or -O-CR52
=CR52
O-; Z represents oxygen atom (O) or sulfur atom (S); each R1 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R2 represents independently hydrogen atom (H) or (C1-C6)-alkyl, (C1-C3)-fluoroalkyl; each R4 represents independently hydrogen atom (H) or (C1-C6)-alkyl; each R5 represents hydrogen atom (H) or (C1-C6)-alkyl; n = 2, 3 or 4. Also, invention describes a method for preparing compound by cl. 1 with enantiomeric excess above 80% and relates to pharmaceutical composition for enhancing the synaptic response mediated by AMPA-receptors based on compounds by cl. 1. Pharmaceutical composition is useful for treatment of schizophrenia, schizophrenia-like behavior or depression in humans in necessary for carrying out such treatment based on compounds by cl. 1 wherein this pharmaceutical composition is useful for the memory improvement and comprising compound by cl. 1. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

107 cl, 2 dwg, 2 tbl, 10 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to nootropic, cerebroprotective medicinal agents as tablets. Tablet of a medicinal agent comprises thiotriazoline and piracetam as active components and accessory components used for formation of core and applying an envelope on it. Invention provides elevating rate and power of a medicinal agent effect on the brain blood supply, expanding spectrum of its pharmacological effect and excludes negative adverse effects.

EFFECT: improved and valuable medicinal properties of agent.

6 tbl

FIELD: pharmacology.

SUBSTANCE: one should apply glycosaminoglycanes at average molecular weight being 2400 D to prepare pharmaceutical composition for treating senile feeble-mindedness and neurological cerebral lesions induced due to sudden attack or trauma. The innovation suggested increases the number of medicinal preparations of necessary indication.

EFFECT: higher efficiency of application.

7 cl, 2 dwg, 8 tbl

FIELD: organic chemistry, biochemistry, biology.

SUBSTANCE: invention relates to a pharmaceutical composition eliciting the inhibitory effect on activity of serine protease (caspase-3) in the form of tablet, capsule or injections placed into acceptable package, to a method for its preparing and a method for treatment of diseases associated with enhanced activation of apoptosis. The composition comprises compound 2,3-dihydro-1H-benzo[g]pteridine-4-one of the general formula (1) (1)

or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: in the suggested composition one should apply heptapeptide of Met-Glu-His-Phe-Pro-Gly-Pro sequence (heptapeptide A) for treating ischemic insult due to introducing 2 drops of compositions into each nasal canal 5-6 times daily for 10 d at disease of average severity degree, and in case of severe degree - per 3 drops of the present composition into each nasal canal 7 times daily for 10 d. The present innovation provides increased efficiency at decreased concentration of heptapeptide without any side effects.

EFFECT: higher efficiency of therapy.

2 cl, 6 dwg, 8 ex, 5 tbl

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