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:

Describes 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 12.78, 9.48, 8.99, 8.64, 8.23, 6.39, 6.27, 5.73, 4.01 and 3.96 Specified physical form has favorable properties, suitable for use in the manufacture of a pharmaceutical product useful as an antagonist of AMPA. 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 a variety of neurological disorders. (R) 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.

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 in 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 as a catalyst, and then removing the catalyst by filtration, evaporation of the ethanol, heating the residue 5.7 volume 1:1 mixture of water and ethanol under conditions of reflux distilled and then leaving the resulting solution to cool.

Committed surprisingly, the modification of the process used to obtain form I, using ammonium formate and ballad-methyl-7H-1,3-dioxolo[4,5-h] [2,3] benzodiazepine hereafter referred to as form II. Thus, the form II 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 ammonium 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 II has a powder x-ray with a characteristic d parameters in 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 poluchennymi d parameters in 10,61, 8,83, 6,78, of 5.83, 4,13 and 3.74 This physical form is subject are simultaneously pending patent application (reference N X938C).

Surprisingly it was also found in another physical form, referred to below as the form IV. Initially it was noticed that the shape is formed after form II heated. It was subsequently discovered that the form IV can be obtained directly through modification of the process used to form III, in particular, by increasing the volume ratio of water/ethanol used during crystallization. Thus form IV obtained by recovering (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 8 volumes of a mixture of 5:3 water/ethanol or 7 volumes of a mixture of 4: 3 water/ethanol in terms of dephlegmation, with optional use of seed crystals of form IV, when 70-80oC and leaving the resulting mixture to cool. It was found that the form IV has a powder x-ray with a characteristic d parametrov of the present invention.

It was found that form I has several adverse properties. In particular, it was found that it crystallizes in the form of a thick suspension which is difficult to mix and transport. 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 parameters at 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 of a able who is thermally stable.

Form IV, as found also crystallizes in the form of a mixed suspension, which can be freely filtered and dried. As form III, it has been found that it is also 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 D equipped with CuKa ( = 1,54056 A), the source is 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 0.03omaximum scanning speed 2 stage.

Measurements of differential scanning calorimetry (DSC) was performed on a differential scanning calorimeter the 5oC) to not less than 200oC at a rate of 10oC/min

13C NMR spectra of the cross-polarization/rotation under magic angle (CP/MAS) was obtained using MHz spectrometer Varian unity 400 operating at a carbon frequency 100.577 MHz and equipped with an auxiliary set of solids and Varian probe 5 or 7 mm VT CP/MAS. Typical measurement conditions were as follows: 90 (deg.) proton r.f. a ripple of 5.0 MS, the contact time of 1-2 MS, time repetition ripple 5 s, MAS frequency of 7 kHz, spectral width 50 kHz, 50 MS acquisition. Chemical shifts were related to CH3the group hexamethylbenzene (δ = 17.3 million dollars.) when replacing the sample.

Form I

DSC: Main endotherm at which is 171,5oC minor endotherm at 207,4oC.

XRD: option d - the relative intensity

17,30 - 100

to 12.28 - 34

7,76 - 71

6,57 - 37

5,24 - 35

to 4.81 - 94

4,34 - 30

4,21 - 29

4.09 to 19

3,98 - 14

3,62 - 18

2,85 - 12

Form II

DSC: Endotherm with an 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 x - 37

6,61 - 60

5,25 - 28

5,01 - 94

4,89 - 70

4,75 - 41

what about the found, show endotherm at a temperature in the range from 192 to 195oC.

XRD: Parameters, d is the relative intensity

10,61 - 78

8,83 - 73

8,33 - 15

the 7.85 - 9

6,78 - 100

of 5.83 - 17

5,68 - 6

5,31 - 25

5,11 - 68

4,94 - 62

4,78 - 20

4,55 - 5

to 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 is 203.2oC. was Found that other samples 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

lower than the 5.37 - 44

5,22 - 14

5,18 - 11

5,10 - 15

4,95 - 32

4,89 - 61

4,75 - 12

4,56 - 10

to 4.41 - 29

4,32 - 20

4,01 - 53

3,96 - 35

of 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

is in the solid state are presented in table. 1.

According to another aspect of the present invention provides a process for the form IV, which includes:

a) interaction of the compounds of formula

< / BR>
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

< / BR>
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 at least 1.1 to 1.0 in.

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.

At the stage (c) the number of volumes of water per volume of ethanol is preferably in the range from 1.15 to 2.0, more preferred is the process based on the derived methylenedioxyphenylacetone. This process includes:

a) providing a quantity of compounds having the formula:

< / BR>
in which R represents methyl,

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

< / BR>
c) interaction of the compounds of formula III with n-nitrobenzaldehyde compound of the formula Aryl. CHO obtaining itomenuage compounds having the formula:

< / BR>
d) the interaction of the compounds of formula IV with an oxidizing agent to obtain compounds of the formula:

< / BR>
e) the interaction of the compounds of formula V with acetic hydrazide with obtaining the compounds of formula:

< / BR>
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 benzo-condensed 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 sectitle the initial stage in the synthesis of compounds of formula I of ketones is chiral phase recovery. Chiral restoration can be carried out with the use of special chemicals or, preferably, with the use of 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, the resulting enantiomer is or (+) stereoisomer of alcohol.

Alternatively, the first 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 biologists who are entrusted yeast from the group Zygosacoharomyces. Other biological agents that can be used include:

Pichia fermentans, Endomycopsis fibuligera, Nematospora coryli; Saccharomyces sp, Candida famata, Saccharomyces pastorianus, Saccharomyces cerevisiae, Saccharomyces uvarum, Candida utilis, Saccharomyces globosus, Kluyveromyces dobzhansk, Kluyvermyces 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, and 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 carbon components. The preferred reagent is p-nitrobenzaldehyde, although you can also use other reagents known to specialists in this field, such as occhialini compound is 7,8-dihydro-7-methyl-5-(4-nitrophenyl)-5H-1,3-dioxolo-benzo[b]Piran.

Dihydrobenzofuran derivative is 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 gerasoulis component is attached to the C5 carbon. The reaction is conveniently carried out in deleverage or aromatic proton solvent, with the preferred hydrazone has a General formula

< / BR>
in which R is CH3, X is acetyl and Aryl is p-nitrophenyl.

The process can be summarized using the following schema.

Scheme I

< / BR>
In scheme (I) 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, kV> (cross stitched polymethacrylates company Rohm and Xaac), HP20 (polystyrene) or SP 207 (commercially available brominated polystyrene firm Mitsubishi). Can also be used with other similar resins.

Scheme II

< / BR>
According to scheme II, 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 second-utility) and enantiomerically pure epoxide. Alternatively, 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 iodide (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 is such treatment.

It was shown that a large variety of physiological functions affected by the influence of excessive or inappropriate stimulation of neurotransmi excitatory 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, amyotrophic 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 IV for the production of medicaments for the treatment of et is arealogicheskii violations mammals, related glutamate dysfunction, such as muscle spasms, convulsions, migraine, urinary incontinence, psychosis, tolerance of drugs and their rejection, 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 IV for the production of drugs for the treatment of these disorders.

The term "effective amount", as used here, refers to the number of form IV, 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. Alternatively, this form may be administered by continuous infusion. Typical daily to the s dose is from about 0.05 mg/kg to 24 mg/kg, more preferably, from about 0.1 to 20 mg/kg

Form IV is usually administered to patients in the form of pharmaceutical compositions. According to another aspect of the present invention provides a pharmaceutical composition, which includes the form IV 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, polyvine the oil. Finished preparations can additionally include lubricating agents, wetting agents, emulsifying and suspendresume agents, 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 forms, and each dose 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, and 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 illustrated/BR> 1 equiv. 3,4-methylenedioxyphenylacetone, 0.45 equiv. dinatriumfosfaatti, of 0.03 equiv. phosphoric acid, 12.5 volumes of HELL-7 resin and 5.8 volumes of water were mixed together and stirred for 15-60 minutes at 20-25oC. was Added 2,27 equiv. glucose is added to the Z. rouxii ATCC 14462 in the amount of 1.5 grams of cell paste per gram of ketone (i.e. 0.375 gram/gram on a dry basis). This mixture was diluted with water to 25 volumes, and then gently stirred at 33-35oC for 8-16 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 EE - 100%.

Example 2.

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

The above intermediate compound was dissolved in with 4.64 of abhimanshree and 1.05 equiv. concentrated hydrochloric acid, and the mixture was heated to 55-65oC and stirred for 1 hour. Then replacing the solvent at 250 mm Hg, and the toluene was replaced 12,4 by volume mixture of 93% isopropanol/7% water. Volume during the replacement of the solvent ranges from 11-14 volume and the final volume was about 11 volumes. The mixture was cooled to 0-10oC and stirred for 1 hour. Needle-like crystals of the product were filtered off and were washed 2 times 1,85 volumes of isopropanol and dried under vacuum at 50-60oC. the Yield of the target compound in situ was 95+%, while the output of the selected product was 87-93%. The activity was 99+% EE 100%.

Example 3.

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

3,47 grams 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 1.00 g (S)-(-)propylene oxide in 2 ml of THF, and the solution was mixed for 45 minutes. The solution is then warmed to 23oC for 16 hours. The reaction mixture was poured into 3 M solution of ammonium chloride, and the product otdelalis Florisil and concentrated by rotary evaporation. The residual oil was purified using chromatography on silica gel and loirevalley a mixture of 50:50 hexane and diethyl ether, giving 1.40 g (45%) named in the header of the intermediate product. P chem: +117,2o(C 1.0, CHCl3) TLC Rf= 0,26 (50:50 hexane: ether) IR (CHCl3) 3598, 3012, 2973, 2883, 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: 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 grams of p-nitrobenzaldehyde was added to a solution of 300 grams of the intermediate compounds formed during biokatalizatora recovery example 1 4.45 l of toluene. Dropwise over 15-20 minutes 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 portions of ethanol, and the mixture is stirred for 1 hour. Suspeitos on the filter was rinsed with ethanol, and then were dried in a vacuum oven at 40-60oC, giving 450 g (86%) not quite white solid, which according to the definition presented isomeric mixture of the above in the title optically active intermediate substance. P chem: ()365+ 55o(0.4, CHCl3).

Example 5

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

350 grams 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 minutes to 8,25 l mix 1 standards. hydrochloric acid at 10-15oC. the Resulting precipitate was filtered off and were washed 3 liters 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 6,55 (with, 1H), 6,38 (C. 1H), 5,86 (s, 1H), of 5.83 (s, 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), 6,02 (S., 1H), 3,95 (m, 1H), 2,7 (dim, m, 2H), 1,24 (d, 3H, J = of 6.71 Hz), mass spectrum, m/z (FD, M+) 329.

Analysis for C17H15NO6. 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 liters of saturated sodium bicarbonate, and then 1.5 l of salt solution. 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%) of pure according to HPLC). P chem: Data registry, 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), 6,00, 6,95 (C., 1H, Ar-H), 6,52, 6,50 (C., 1H, Ar-H), 6,06, 6,05 (D., 2H, J = 5 Hz, O2CH2), 2,44 (C., 3H, CH3), a 3.87 (m, 1H, CH), 2,4 - 2,2 (m, 2H, CH2), 1,12, 1,10 (D., 3H. CH3).

13C NMR (CDCl3, 75 MHz) d 209,94 (C), 173,38, 173,43 (C), 149,38, 149,62 (C), 148,31, 148,58 (C), 148,58 (C), 147,90, 148,18 (C), 147,54 (C), 142,5, 143,04 (C), 132,64 (C), 127,53, 127,61 (CH), 123,75, 123,77 (CH), 122,86, 123,27 (C), 112,13, (CH), 110,55 (CH), 108,03, 108,10 (CH), 108,10 (CH), 101,83 (CH2), 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), ()589+ 103,8o(C 1, CHCl3), mass spectrum, m/z (FD, M+) 385.

Analysis for C19H19N3O6: 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 grams of the intermediate 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. Added 510 ml of water. The separated organic phase was washed with 35 45oC, and 90 minutes were added 4760 ml of hexane. The mixture was slowly cooled to room temperature, and then cooled further to 0 to 5oC. the Product was separated by filtration and dried in a vacuum oven at 40 - 50oC, giving 356,2 grams (87%) of the isomeric mixture named the title compound as a yellow solid. P chem: Data registered by 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, J = 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), of 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 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 50% solution of causti stirred for 3 hours, then the resulting precipitate was separated by vacuum filtration. The material was dried in a vacuum oven at 45 - 55oC, giving 255 grams (97%) named in the title compound, which was on the 97.6% pure % area HPLC. 221 grams of the dried material was further purified by re-suspension in 1105 ml of ethanol 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 grams (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 grams of the intermediate of example 8 in 50 ml of ethanol was added 0.5 grams of 10% Pd/C, moistened with water. Stir the suspension was treated with a solution of 4 grams of potassium formate in 4 ml of water. The resulting mixture was mixed for 2.5 hours and then filtered on hyflo. The filtrate was concentrated to 10 to 20 ml by distillation, and was slowly added 22 ml of water to be reheated (78oC, giving 4.17 grams (93%) specified in the header end of the connection, which had 100% purity according to HPLC analysis.

()365= -303,7 (C = 1, methanol).

It was later found that the product was crystalline, was 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 grams of 50% sodium hydroxide in water, and the resulting mixture was mixed for 3 to 4 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 of water 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 the specified header Prohm is a lot-[[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 grams of acetic hydrazide and 0.01 volume of hydrochloric acid. The resulting mixture was heated to reflux distilled for 3.5 hours with removal of water using traps Dean-stark. The reaction mixture was concentrated by vacuum 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 wt.%) 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 to -5oC, was 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 is removals 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 was cooled to 20 to 25oC for 1 hour, then cooled to 0 to -5oC for 1 to 2 hours. The precipitate was separated by vacuum filtration and were washed with 3 volumes of 4:1 mixture of heptane : methylene chloride, then dried in a vacuum oven at 45 - 50oC. was 17.43 grams named in the header of the intermediate product (78%) in the form of optically active isomeric mixture of the hydrazone, which was 97,7% 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 grams of the intermediate of example 12 was suspendibility in 175 ml of ethanol. To stir the mixture was added 1.7 grams of powdered sodium hydroxide. The resulting mixture was mixed for 1 hour. To the mixture was added 68 ml of water, and the contents were mixed for 1 hour, 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 78oC, yielding 12.2 g (86%) Nazvanov
(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)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepine

1.05 g (S)-acetic acid-[[6-[2-(hydroxy)propyl]-1,3-benzodioxol-5-yl] (4-nitrophenyl)methylene] hydrazide and 0.78 grams of triphenylphosphine in 70 ml of tetrahydrofuran was cooled to 0oC. dropwise over 15 minutes was added 0.57 gram of diethylazodicarboxylate in 5 ml of tetrahydrofuran. The resulting mixture was mixed for 2 hours, then heated to room temperature within 2 hours. The mixture was transferred into a separating funnel, and the solution was filtered 1 standards. 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 30 m is ltoi 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%), which had a purity of 98.3% according to HPLC analysis activity.

Examples 16 to 18

0.5 ml suspension of frozen yeast containing the microorganism, specified in table 1, was added to 50 ml Solodovnikova medium in 250 ml flask. After shaking for 48 hours 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 will not be 10 grams/liter, along with 1 ml of 10% glucose. Culture tuberous and shake for 24 hours, then analyzed by HPLC for the presence of a chiral alcohol of the intermediate product of example 1.

The results are presented in table. 2.

Example 19

The synthesis of form 1 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 is shown, the source 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 night, giving of 31.6 g of the pure product. Another recrystallization using the same conditions gave 28,7 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 II (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-digit the use 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 mixture of 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 crystals contained 5,0% ethanol (GC) and 4.2% water (KF). Analysis using XRD, SS and DSC indicated that formed form II polymorph.

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 and 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 hours, 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 and DSC showed that the formed shape 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]benzodiazepine

(R)-7-acetyl-8,9-dihydro-8-methyl-5-(4-nitrophenyl)-7H-1,3-dioxolo[4,5-h] [2,3]benzodiazepin of 25.2 g) was gidrirovaniya 250 ml (10 volumes) 2B-3 ethanol using 2.0 g of 10% palladium on coal and 18.0 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 ohlajdat were dried in a vacuum oven at 50oC for 24 hours, giving 19,8 g (85%) of the pure product. The analysis showed non-detectable levels of ethanol (GC) and 1.0% water (KF).

XRD, SS 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 ml of 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 g). The resulting mixture was cooled to -50oC, was slowly added a solution of (S)-(-)-propylene oxide in 3 ml of tetrahydrofuran 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 active ingredient 1 mg 10 mg 50 mg 100 mg

Starch 444,5 mg 435,8 mg 396,2 mg 346,6 mg

Silicone fluid 4,49 mg 4,22 mg of 3.84 mg to 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-2, 3-dioxolo[4,5-h] [2,3] benzodiazepine having a powder x-ray with d parameters in 12.78, 9.48, 8.99, 8.64, 8.23, 6.39, 6.27, 5.73, 4.01 and 3.96 .

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

< / BR>
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

< / 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 is (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, having the properties of a selective antagonist of AMPA receptor, characterized in that it contains the physical form of the compounds having the powder x-ray with d parameters in 12.78, 9.48, 8.99, 8.64, 8.23, 6.39, 6.27, 5.73, 4.01 and 3.96

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 under item 1, useful for the production of medicaments for use as an antagonist of the AMPA receptor.

 

Same patents:

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-

The invention relates to new derivatives dipyridodiazepinone possessing biological activity, and more particularly to 2-heteroaryl-5,11-dihydro-6H-dipyrido[3,2-b: 2', 3'-e] [1,4] diazepin-6-Onam, their pharmaceutically acceptable salts and pharmaceutical composition having inhibitory activity against reverse transcriptase of HIV-1

The invention relates to a method for producing a dosage form of carbamazepine for oral dosage forms with delayed release of active substances

The invention relates to new trehlitrovy complexes, processes for their preparation and their use as pharmaceuticals, in particular for the treatment of cancer
The invention relates to medical practice

The invention relates to a new benzodiazepine derivative of the formula I given in the text of the description, which are useful as medicines, which have an antagonistic effect against gastrin and/or CCK receptor-and their reception, where R1refers to a group-CH2CH(OH)(CH2)aR4or ketone group,- CH2CO(CH2)aR5where a = 0 or 1; R4- C1-C7-alkyl straight or branched chain or C3-C8-cycloalkyl; R5- C1-C8-alkyl, C3-C8-cycloalkyl,3-C8-cycloalkyl-C1-C8-alkyl, C1-C8-alkyl-C3-C8-cycloalkyl, pyrrolidyl, possibly substituted C1-C8-acyl, carbamoyl,1-C8-alkylamino-C1-C8-alkyl, or adamantylidene; R2is phenyl, substituted C1-C8-alkyl, C1-C8-alkoxyl, nitro, cyano, amino, halogen, C1-C8-alkylaminocarbonyl, di-(C1-C8-alkylaminocarbonyl, carboxy, C1-C8-allmineral, carboxyhemoglobin, carboxy(C1-C8)alkyl, or pyridylethyl, possibly substituted C1-C8-alkyl; R3- peloid in the 7-position of the benzodiazepine ring; W is hydrogen or C1-C8the alkyl in the 8-position of the benzodiazepine ring, or its pharmaceutically acceptable salt

The invention relates to medicine and can be used to prevent or reduce the intensity of side effects and complications of dialysis used to treat patients with renal insufficiency

The invention relates to new derivatives benzazepine, which are used as antagonists Organisatorische, to their pharmaceutically acceptable salts, to pharmaceutical compositions containing these compounds as active ingredients and intermediate products for the synthesis of these compounds

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

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: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

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