Derivatives of diazepine, pharmaceutical composition and method of treating arrhythmia

 

(57) Abstract:

The invention relates to medicine, in particular to derivatives of diazepine formula, where the values of the radicals A, R1X, Y, and R4specified in the claims, to a pharmaceutical composition having anti-arrhythmic activity, and to a method of treatment of arrhythmia. Derivatives of diazepine possess antiarrhythmic activity and are safe. 6 C. and 15 C.p. f-crystals, 6 tab., 15 schemes.

The invention relates to a new method of treating arrhythmia by the introduction of compounds of General structural formula I

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The present invention also relates to pharmaceutical compositions containing one or more new compounds as active ingredient, either alone or in combination with one or more anti-arrhythmic means of class I, class II or class IV.

Arrhythmias often occur as complications of cardiac diseases such as myocardial infarction or heart failure. In severe case, arrhythmia develops into ventricular fibrillation and can cause sudden death.

Although currently on the market there are various antiarrhythmic agent, agents, possessing as udoa I in accordance with the classification of Vaughan-Williams, which cause a selective inhibition of the maximum rate of increase (upstroke) peak potential (Vmax), are inadequate in relation to the prevention of ventricular fibrillation. In addition, they have problems from the point of view of security, namely: they cause a depression of cardiac contractility and have a tendency to induce fibrillation due to the suppression of impulses. Blockers beta-adrenergic receptors and calcium antagonists, which belong to class II and class IV, respectively, have the disadvantage that their action or limited to a particular type of arrhythmia, or they are contraindicated, due to its cardio-depressant properties, some patients with cardiovascular disease. However, their security is higher than the safety of antiarrhythmic drugs class I

Antiarrhythmic agent of class III are drugs that cause a selective prolongation of the duration of the peak potential without significant weakening of the Vmax. The number of drugs in this class is limited. It is shown that drugs such as sotalol and amiodarone have the properties of a class III. Sotalol she is timopoetin some sensitive patients. Amiodarone is also strictly limited due to its side effects. It is expected that drugs of this class will be effective for the prevention of ventricular fibrillation. It is believed that the means of class III in its pure form, by definition, do not cause myocardial depression or induce arrhythmias due to the suppression of the peak holding capacity, as shown for antiarrhythmic drugs class I

Compounds suitable for the new method of treatment according to the present invention have structural formula I

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or are pharmaceutically acceptable salts of such compounds, where

A represents a

1) ceanography,

2) peridogram or

3) anthropou, or unsubstituted or substituted-NH2, NHSO2(C1-3-alkyl), C1-3-alkyl or C1-3-alkoxygroup;

X is a

1) = O

2) = S,

3) =N-NH2,

4) =N-OH or

5) =H2;

Y represents a

1) = O

2) =N-CN or

3) =H2;

Z represents a

1) C1-6-alkylene, or a linear or branched chain and either unsubstituted or substituted by phenyl or spiroperidol,

2) C2-4-alkenylsilanes, 0, 1, 2, 3 or 4, and W represents-O-, -S - or-NH,

4) 4-(5-methylisoxazol-3-yl),

5) C3-6- cycloalkyl or

6) simple connection;

p is 0 or 1;

R1represents a

1) phenyl, either unsubstituted or substituted by one or two substituents selected among

a) -NO2b) -Cl, Br, F or I, c) -CF3d) -C1-3-alkyl, e) -C1-3-alkoxygroup, f) -CN, (g) -methylendioxy,

2) C5-7-cycloalkyl,

3)

4) mono - or bicyclic a heterocycle with 5 to 10 ring atoms, of which one or two atoms are sulfur, nitrogen or oxygen, and the remainder are carbon atoms, such as 2-thienyl, 2-furanyl, 2-indolyl, 2-honokalani or 2-(2,3 - dihydrobenzofuranyl),

5) C1-3-alkyl or

6) indan-5-yl;

R2represents a

1) phenyl, either unsubstituted or substituted C1-3- alkoxygroup or 4,4-dimethyloxazole-2-Il,

2) C1-6-alkyl, or linear or branched chain and either unsubstituted or substituted C1-3-alkoxygroup or C1-3-alkoxy-C1-3-alkoxygroup,

3) C5-7-cycloalkyl,

4) 2 - or 3-furyl,

5) 1 methylpiperidin-2-yl or

6) if R2represents phenyl, Hairdryer and a double bond between the nitrogen-4 and carbon-5 is a simple link;

R3represents a

1) hydrogen or

2) C1-3-alkyl, either unsubstituted or substituted by-N(CH3)2-OH, -CF3or

3) -CF3;

R4represents a

1) hydrogen,

2) C1-6-alkyl, in which the chain of carbon atoms may be interrupted by one or two not located adjacent oxygen atoms and which is either unsubstituted or substituted C1-3-alkoxycarbonyl, -OH or or

3) tetrazol-5-yl;

R5represents hydrogen or oxygen, or attached to R2with the formation of patterns

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and the relationship depicted is a

1) a double bond when p is zero, or when p is 1, and R5represents oxygen, or

2) a simple link, when R5is soda hydrogen, or R5connect with R2with the formation of a private structure

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It is implied that the present invention includes a separate diastereomers, when they exist, and their mixtures, and enantiomers and mixtures of enantiomers.

To pharmaceutically acceptable salts of the compounds of formula I include the conventional nontoxic salts or Quaternary ammonium salts of the base, educated soy is conventional non-toxic salts include salts, derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like acids; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, Panova, maleic, ximalayasha, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova acid and similar acids.

Pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the formula I which contain a basic or acidic group, conventional chemical methods. Typically, the salt get in the interaction of the free base or acid with stoichiometric amounts or an excess of the desired salt-forming inorganic or organic acid, or the desired salt-forming base, in a suitable solvent or various combinations of solvents.

One of the embodiments of the present invention are novel compounds suitable for the new method is an oxygen;

R3represents methyl;

R4represents hydrogen; and

R2represents a C1-6-alkyl.

Typical new compounds which are mentioned variant, are compounds having the structure and the substituents listed in table. 1.

Another option compounds suitable for the new method of treatment, are compounds in which

A represents a

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X and Y represent oxygen;

R3represents methyl;

R4represents hydrogen; and

R2represents phenyl.

A group of new compounds within this option are compounds having the structural formula

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in which Z represents a C1-6-alkylen or connection and R1represents phenyl, phenyl, substituted-Cl, -Br, -I, -F, or-CF3or R1represents cyclohexyl.

Typical compounds of this group of compounds are compounds shown in the table. II.

Another group of compounds of this option are compounds with the structural formula

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in which Z represents a C2-4-alkene -alkoxygroup or methylendioxyphenyl.

Typical new compounds of this group are the compounds shown in the table. III.

The third option of compounds suitable for the new method of treatment of the present invention, are compounds in which Z represents-NH-.

Compounds representing this option are the compounds shown in table. IV.

Other typical compounds included in a wide range, but is not included in any of the previously described variants, are compounds presented in table. V.

Representative compounds in which R is equal to 1, is a compound of structural formula

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Representative compounds in which the relationship between the clauses 4 and 5 is a simple relationship, is a compound of structural formula

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Representative compounds in which the link is a simple link and R5attached to R2is a compound of structural formula

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Another embodiment of the present invention is the group of compounds active in the new method of treatment of the present invention, which are novel in themselves. These new compounds are described in the table. VI.

Connect and, required for antiarrhythmic drugs class III, namely: prolongation miocardio peak potential in vitro, without a significant suppression of the Vmaxand prolongation OTc-internal at anesthesiaand dogs.

Such compounds are effective for treatment and prevention of all types of arrhythmias, including ventricular arrhythmia and atrial (supraventricular) arrhythmias. Compounds of the present invention are particularly suitable for combating circulating cardiac arrhythmias and prevention of sudden death due to ventricular fibrillation. These compounds are also effective for treating or preventing the weakening of the pumping function of the heart.

In the new method of treatment of arrhythmia according to the present invention one of the compounds or its pharmaceutically acceptable salt is administered in an amount in the range of from 0.0001 to 20 mg per kg of body weight per day, preferably from 0.001 to 10 mg per kg of body weight per day as a single dose or in 2-4 separate doses.

Such compounds can be administered as the sole active ingredient or in combination with other antiarrhythmic agents or other cardiovascular agents.

Such compounds or their farm is a rule, transdermal, under the tongue or intravenously. It is preferable to introduce them orally, for example in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gum or the like, obtained by methods known in the art. The number of active compound in such therapeutically useful compositions or preparations is such that to get the right dosage.

The activity of the compounds described here as antiarrhythmic drugs, measured by their ability to block 1 Ks 1 and Kr, as shown in the following diagram tests.

Measure external potassium (ion) currents in ventricular myocytes one cavy, using the method of fixation of the cell voltage, is described in detail in other work (Sanguinetti and Jurkiewicz, 1990. Two components of cardias de layed out actifier K+current: differential sensitivity to block by Class III antiarrhythmic agents. J. Gen. Physiol., 96:195-215).

Myocytes secrete enzyme (collagenase and protease) digestion of the heart, perfoirmance on Langendorff (Langandorf) Individual cells are then fixed voltage, using a pipette with a square (1 mm) hole filled with 0.5 M K gluconate, 25 mm KCl, 5 mm K (2) ATP. Cells are then washed in a solution containing nm: 132 NaCl, 4 KCl, 1.2 Mariwana -50 mV. For line voltage changes from -85 to -50 mV in the experiment used depolarization, as well as for transitions to -10 mV (0.5 s) and +50 mV (1.0 c). I [KI] is measured as a peak external current when the line voltage changes. I [Kr] measured as tail currents after depolarization to -10 mV to -50 mV. I [Ks] is measured as a current depending on time of the pulse to +50 mV. Currents measured during the pulse to +50 mV. Currents measured during control and then after entering the medicinal product in two different concentrations.

When applying this test, the compounds described herein have the IC50less than 1000 nm as 1Ks-blockers and/or as 1Kr-blockers.

Compounds suitable for the new method of treatment of the present invention, are either known, or is similar in structure to known compounds and are known as possessing activity SCQ-In-antagonists. See, for example, the U.S. patents 4820834 and 5004741, Evans et. al. Methods of obtaining these compounds are, therefore, obvious to a person skilled in this technical field. Typical schemes 1-15 synthesis used here for these compounds are given in the end of the description.

Example 1.

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(E)-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl - 1H-1,4-benzo(1 ml) are added to a solution of 3(R)-amino - 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it (J. Org. Chem., 1987, 52, 3232-3259) (531 mg, 2.0 mmol) and triethylamine (307 μl, 225 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture is stirred at room temperature for 25 minutes, and remove the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/Et2O (95:5), and the residue is treated with Et2O. the Solid is collected and dried in vacuum at 70oC, get (E)-(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl] -3-phenyl-2 - propenamide in the form of a colorless solid (170 mg, 21%), so pl. 140-142oC []D+86,7(c=0,173, CH2Cl2).

H (CDCl3) 7,70-7,26 (16H, m), 6,63 (1H, d, J 15.6 Hz), of 5.68 (1H, d, J 8,3 Hz) and a 3.50 (3H, s).

Elemental analysis; Calculated for C25H21N3O20,15(C2H5)2O:

C-75,63; H-TO 5.58; N -10,33.

Found: C-75,29; H-To 5.57; N-10,33%.

Using the methodology described above, but replacing (E)-3 - phenyl-2-propenonitrile to the corresponding acid chloride, get the following compounds.

Example 2.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]benzamide

So pl. 224-225oC []D+89,2(C=0,141, CH2Cl2).

Example 3

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First suirvey diastereoisomer

(-)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl] - (TRANS-2-phenyl-1-cyclopropane)carboxamid

So pl. 180-181oC []D-155,8(C=0,434, CH2Cl2)

H (CDCl3) 7,62-7,09 (15H, m), 5,59 (1H, d, J 8.1 Hz), 3,47 (3H, s), 2,52 at 2.45 (1H, m), 1,90-of 1.84 (1H, m), 1,69-of 1.56 (1H, m), and 1.38 - 1,32 (1H, m).

Elemental analysis. Calculated for C26H23N3O20,25 H2O:

C-75,43; H-5,72; N-10,15.

Found: C-75,38; H-5,64; N-9,94%.

Second suirvey diastereoisomer

(+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl] - (TRANS-2-phenyl-1-cyclopropane)carboxamid

So pl. 104-107oC []D+328,2(C=0,098, CH2Cl2)

H (CDCl3) 7,62-7,13 (15H, m), the ceiling of 5.60 (1H, d, J 8,3 Hz), 3,48 (3H, s), 2,59-of 2.54 (1H, m), 1.93 and-of 1.87 (1H, m), 1,62-of 1.56 (1H, m, overlapping with water) and 1,33-1,25 (1H, m).

Elemental analysis. Calculated for C26H23N3O20,50 H2O 0,45 PhCH3:

C-76,13; H-5,95; N-9,14.

Found C-76,10; H-5,94; N-9,17%.

Example 4.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodi the BR> H (CDCl3) to 9.15 (1H, CL), 8,10 (1H, d, J 9.0 Hz), 7,75-7,10 (14H, m), of 5.75 (1H, d, J 9.0 Hz) and a 3.50 (3H, s)

Elemental analysis. Calculated for C25H20N4O2:

C-73,51; H-4,94; N-13,72.

Found: C-73,31; H-4,80; N-13,62%.

Example 5.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]heptanoic

So pl. 49-54oC []D+69,5(C=1,000, MeOH).

Elemental analysis. Calculated for C23H27N3O20,4 H2O:

C-71,81; H-7,28; N-10,92.

Found: C-71,90; H-To 7.09; N-10,85%.

Example 6.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]hexanamide

[]D+72,6(c = 0,920, MeOH)

Elemental analysis. Calculated for C22H25N3O2:

C-72,70; H-6,93; N-TO 11.56.

Found: C-72,44; H-6.75 In; N-11.25 Per Cent.

Example 7.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]pentanone

[]D+68,2(C=1,310, MeOH).

Elemental analysis. Calculated for C21H23N3O20,25 CHCl3:

C-68,21; H-6,26; N-OF 11.26.

Found C-68,2; H-6,29; N-11,17%.

Example 8.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-vinilhlorida (158 μl, 230 mg of 1.81 mmol) and the mixture was stirred at room temperature for 40 minutes. Add 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4 - benzodiazepine-2-he (J. Org. Chem., 1987, 52, 3232-3239) (400 mg and 1.51 mmol) and triethylamine (252 μl, 183 mg, is 1.81 mmol) and the mixture stirred at room temperature for 18 hours. The mixture is then poured into a saturated aqueous solution of sodium bicarbonate (20 ml) and extracted with ethyl acetate (3h20 ml). The combined organic fractions are dried (Na2SO4) and evaporated the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/Et2O (95: 5), and the residue is recrystallized from toluene and hexane, to obtain (+)- N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-phenylpropanamide in the form of a colorless solid (380 mg, 63%). So pl. 179oC []D+100,4(C=0,225, CH2Cl2).

H (CDCl3) a 7.62 EUR 7.57 (2H, m), 7,47-7,21 (13H, m) 5,54 (1H, d, J 8.1 Hz), 3,47 (3H, s), 3,03 (2H, t, J 7.8 Hz) and 2,73-to 2.67 (2H, m).

Elemental analysis. Calculated for C25H23N3O20,15 H2O:

C-75,04; H-BY 5.87; N-10,50.

Found: C-75,06; H-5,78; N-10.55 Percent.

Using the methodology described above, but replacing 3-phenylpropane acid ACC
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(3,4-disorfer)-2-propenamide

So pl. 145-147oC []D+77,8(C=0,126, CH2Cl3).

H (CDCl3) to 7.64-7.25 (14H, m), is 6.61 (1H, d, J 15.6 Hz), the 5.65 (1H, d, J 8.0 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H19N3O2Cl2:

C-64,67; H-4,12; N-9,05.

Found: C-64,57; H-4,25; N-9,01%.

Example 10.

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E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(4-nitrophenyl)-2-propenamide

So pl. 165-166oC []D+80,5(c=0,126, CH2Cl2).

H (CDCl3) compared to 8.26 (1H, d, J 8,8 Hz), 7,74-7,28 (13H, m), 6,76 (1H, d, J 15.6 Hz), to 5.66 (1H, d, J 8.0 Hz) and 3,51 (3H, s).

Elemental analysis. Calculated for C25H19N4O4:

C-68,17; H-4,58; N-12,72.

Found: C-68,25; H With 4.65; N-12,57%.

Example 11.

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E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)-2-propenamide

So pl. 137-139oC []D+66,0(c=0,144, CH2Cl2).

H (CDCl3) 8,02 (1H, d, J 15.6 Hz), 7,73-7,26 (13H, m), of 6.66 (1H, d, J 15.6 Hz), of 5.81 (1H, d, J 8,8 Hz) and of 3.53 (3H, s).

Elemental analysis. Calculated for C25H19Cl2N3O2:
So pl. 133-135oC []D+90,4(c =0,125, CH2Cl2)

H (CDCl3) 7,68-7,19 (15H, m), 6,59 (1H, d, J 15.6 Hz), 5,70 (1H, d, J 8.0 Hz), 3,50 (3H, s) and of 2.38 (3H, s).

Elemental analysis. Calculated for C26H23N3O2:

C-76,26; H-5,66; N-10,26.

Found: C-75,93; H-Of 5.82; N-10,10%.

Example 13.

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E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(4-methoxyphenyl)-2-propenamide

So pl. 129-133oC []D+89,9(C =0,188, CH2Cl2).

H (CDCl3) 7,65-7,24 (14H, m), 6,92 (1H, d, J 8,8 Hz), 6,50 (1H, d, J 15.6 Hz), 5,69 (1H, d, J 8.0 Hz), of 3.84 (3H, s) and a 3.50 (3H, s).

Elemental analysis. Calculated for C26H23N3O3:

C-72,48; H-5,52; N-9,75.

Found: C-72,75; H Is The Ceiling Of 5.60; N-9,36%.

Example 14.

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(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

So pl. 92-95oC []D+90,5(C=0,196, CH2Cl2).

H (CDCl3) 7,62-7,15 (13H, m), 5,52 (1H, d, J 8.1 Hz), 3,47 (3H, s), 3,10 (2H, t, J 7,6 Hz) and $ 2.68 (2H, DD, J of 7.6, 2.8 Hz).

Elemental analysis. Calculated for C25H21Cl2N3O2< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl]-3-(3-chlorophenyl)-2-propene is 15H, m), 6,62 (1H, d, J 15.6 Hz), to 5.66 (1H, d, J 8.1 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H20ClN3O2:

C-69.85 MM; H-4,69; N-9,77.

Found: C-70,20; H Of 4.83; N-9,41%.

Example 16.

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E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2-chlorophenyl)-2-propenamide

So pl. 128-131oC []D+61,7o(C=0,196, CH2Cl2).

H (CDCl3) of 8.06 (1H, d, J 15.6 Hz), 7,65-7,28 (14H, m), 6,62 (1H, d, J 15.6 Hz), of 5.68 (1H, d, J 8,3 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H20ClN3O2< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(2,4-differenl)-2-propenamide

So pl. 121-123oC []D+76,8(C=0,111, CH2Cl2).

H (CDCl3) 7,71 (1H, d, J, or 15.9 Hz), of 7.64-7,24 (11H, m), 6,92-6,84 (2H, m), 6,69 (1H, d, J, or 15.9 Hz), 5,67 (1H, d, J 8.1 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H19F2N3O2< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(4-chlorophenyl)propanamide

So pl. 203-205oC []D+99,2(C=0,300, CH2Cl2).

H (CDCl3) 7,62-7,16 (14H, m), 5,52 (1H, d, J 8.1 Hz), 3,47 (3H, s) to 2.99 (2H, t, J 7.7 Hz) and to 2.67 (2H, t, J 7.7 Hz).

Elemental analysis. Vicis the Example 19.

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E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,6-dichlorophenyl)-2-propenamide

So pl. 121-124oC []D+69,0(C=0,342, CH2Cl2).

H (CDCl3), 7,79 (1H, d, J 16.1 Hz), of 7.64-7,15 (13H, m), is 6.78 (1H, d, J, or 15.8 Hz), 5,69 (1H, d, J 8.1 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H19Cl2N3O2< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-4-(trifluoromethyl)phenyl-2-propenamide

So pl. 133-137oC []D+68,7(C=0,115, CH2Cl2).

H (CDCl3) 7,72-of 7.25 (15H, m), of 6.71 (1H, d, J 15.6 Hz), 5,67 (1H, d, J 8.1 Hz) and 3,51 (3H, s).

Elemental analysis. Calculated for C26H20F3N3O2:

C-67,38; H IS 4.35; N-9,07.

Found: C-67,38; H Is 4.45; N-8,95%.

Example 21.

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(+)-5-Chloro-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl]indole-2-carboxamide

So pl. 160-164oC []D+103,8(c=0,160, CH2Cl2).

H (CDCl3) 9,71 (1H, sh.C), 8,13 (1H, d, J 7.8 Hz), 7.68 per-7,09 (13H, m), of 5.75 (1H, d, J 7.8 Hz) and of 3.53 (3H, s).

Elemental analysis. Calculated for C25H19lN4O20,15 PhCH3:

C-67,84; H-4,49: N-12,15.

Found: C-67,80; H-To 4.41; N-12,07%.

PR is So pl. 200-201oC []D+97,0(=has 0.168, CH2Cl2).

H (CDCl3) 7,60-7,22 (20H, m), to 5.58 (1H, d, J 8.1 Hz), to 5.08 (1H, s) and 3,44 (3H, s).

Elemental analysis. Calculated for C30H25N3O20,15 PhCH3:

C-78,79; H-5,55; N-8,88.

Found: C Unchanged At 78.81; H-5,63; N-9,07%.

Example 23.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-differenl)propanamide

So pl. 79-81oC []D+92,9(c=0,105, CH2Cl2).

H (CDCl3) 7,62-7,56 (3H, m), 7,50-7,19 (8H, m), 6,82 - 6,76 (2H, m), 5,52 (1H, d, J 8.1 Hz), 3,47 (3H, s), a 3.01 (2H, t, J 7,6 Hz) and 2,69 (2H, m).

Elemental analysis. Calculated for C25H21F2N3O2:

C-69,27; H-4,88; N-RS 9.69.

Found C-68,96; H-4,99; N For 9.47%.

Example 24.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2-phenylethanone

So pl. 241-242oC (decomp.), []D+85,5(=strength of 0.159, CH2Cl2).

H (CDCl3) to 7.59-of 7.55 (3H, m), 7,46-7,22 (12H, m), the 5.51 (1H, d, J 8.1 Hz), and 3.72 (2H, s) and 3,44 (3H, s).

Elemental analysis. Calculated for C24H21N3O20,55 H2O:

C-73,28; H-5,66; N IS 10.68.

Found: C-73,25; H Is 5.38; N-10,47%.

Example 25.

< / BR>
(+)-N-[(3R)-2,3-WHOM B>+95,8(c=0,224, CH2Cl2).

H (CDCl3) a 7.62 EUR 7.57 (3H, m), 7,47-7,16 (11H, m), of 5.55 (1H, d, J 8.1 Hz), 3,47 (3H, s), 3,14 (2H, t, J 7.9 Hz), and a 2.75 - 2,69 (2H,m).

Elemental analysis. Calculated for C25H22ClN3O2< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-4-(trifluoromethyl)phenyl propanamide

So pl. 175-176oC []D+86,5(C=0,141, CH2Cl2).

H (CDCl3) a 7.62 rate of 7.54 (5H, m), 7,47-of 7.2 (9H, m), 5,52 (1H, d, J 8.1 Hz), 3,47 (3H, m), is 3.08 (2H, t, J 7,6 Hz) and of 2.72 (2H,m).

Elemental analysis. Calculated for C26H22F3N3O2< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2-4-(trifluoromethyl)phenyl ethanamide

So pl. 224-226oC []D+68,0(C=0,153, CH2Cl2).

H (CDCl3) 7,63-of 7.55 (4H, m), 7,51-7,33 (8H, m), 7,26-of 7.23 (2H, m), the 5.51(1H, d, J 8.1 Hz), of 3.77 (2H, s) and 3.46 (3H, s).

Elemental analysis. Calculated for C25H20F3N3O2:

C-66,51; H-4,47; N-9,31.

Found: C-66,46; H Is 4.36; N-9,10%.

Example 28.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-3-(trifluoromethyl)phenyl propanamide

So pl. 135-136oC []D+78,8(C=0,134, CH2Cl2).

chileno for C26H22F3N3O2:

C-67,09; H-4,46; N-9,03.

Found: C-67,03; H-4,73; N-9.13 Per Cent.

Example 29,

< / BR>
(+)-3-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl]propanamide

So pl. 144,5-145,5oC []D+83,1(C=0,116, CH2Cl2).

H(CDCl3) 7,62-7,56 (3H, m), 7,46-7,21 (7H, m), of 5.55 (1H, d, J 8,3 Hz), 3,48 (3H, s), 2,41-of 2.36 (2H, m), 1.77 in is 1.58 (7H, m), 1,31-of 1.16 (4H,m) and 0.98-of 0.90 (2H, m).

Elemental analysis. Calculated for C25H29N3O2:

C-74,41; H-7,24; N-10,41.

Found: C-74,46; H-7,27; N-Of 10.58%.

Example 30.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-2-(trifluoromethyl)phenyl propanamide

So pl. 110-113oC []D+79,2(c=0,376, CH2Cl2).

H(CDCl3) the 7.65 EUR 7.57 (4H, m), 7,50-7,22 (10H, m), of 5.55 (1H, d, J 8.0 Hz), 3,47 (3H, s), 3,20 (2H, t, J 7.9 Hz) and 2.70 (2H, dt, J 7,9 3,3 Hz).

Elemental analysis. Calculated for C26H22F3N3O2:

C-67,09; H WAS 4.76; N-9,03.

Found: C-66,97; H Was 4.76; N-8,93%.

Example 31.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-3-(4-cyanophenyl)propanamide

So pl. 81-85oC []D+91,0(C = 0,111, CH2Cl2)

H Alize. Calculated for C26H22N4O20,60 H2O0,50PhCH3:

C-73,93; H-5,62; N-OF 11.69.

Found: C-73,98; H-5,61; N-11,71%.

Example 32.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(3-chlorophenyl)propanamide

So pl. 157-159oC []D+90,7(C=0,134, CH2Cl2).

H (CDCl3) a 7.62 EUR 7.57 (3H, m), 7,47-7,12 (11H, m), of 5.53 (1H, d, J 8.1 Hz), 3,47 (3H, s) of 3.00 (2H, t, J 7,3 Hz) and 2,71-of 2.66 (2H, m).

Elemental analysis. Calculated for C25H22ClN3O2< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(2-bromophenyl)-2-propenamide

So pl. 113-116oC []D+44,2(C=0,113, CH2Cl2).

H (CDCl3) 8,03 (1H, d, J 15.6 Hz), of 7.64-7,16 (14H, m), to 6.57 (1H, d, J 15.6 Hz), of 5.68 (1H, d, J 8.1 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H20BrN3O20,30 PhCH3:

C-63,48; H-4,58; N-8,19.

Found: C-63,49; H-To 4.38; N-8,19%.

Example 34

< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(3-bromophenyl)-2-propenamide

So pl. 221-223oC []D+65,5(C=0,206, CH2Cl2).

H (CDCl3) of 7.69 (1H, CL), of 7.64-EUR 7.57 (4H, m), 7,51-7,37 (6H, m), 7,29-7,19 (4H, m), 6,62 (1H, d, J 15.6 Hz), to 5.66 (1H, d, J 8,1
C-63,54; H-4,46; N-8,42.

Found: C-63,50; H-4,39; N-8,42%.

Example 35.

< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(4-itfeel)-2-propenamide

So pl. 137-140oC []D+67,9(C=0,268, CH2Cl2).

H (CDCl3) 7,75-7,72 (2H, m), of 7.64 and 7.36 (8H, m), 7,29-7,16 (5H, m), 6,63 (1H, d, J 15.6 Hz), to 5.66 (1H, d, J 8.1 Hz) and a 3.50 (3H, m).

Elemental analysis. Calculated for C25H20IN3O20,30 PhCH3:

C-59,29; H-4,06, N-7,65.

Found: C-59,29; H-3,90; N-7,40%.

Example 36.

< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(4-bromophenyl)-2-propenamide

So pl. 121-124oC []D+75,6(C=0,201, CH2Cl2).

H (CDCl3) to 7.64-EUR 7.57 (3H, m), 7,55-to 7.35 (11H, m), 7,28-7,24 (1H, m), 6,62 (1H, d, J 15.6 Hz), to 5.66 (1H, d, J 8.1 Hz) and a 3.50 (3H,m).

Elemental analysis. Calculated for C25H20BrN3O2:

C-63,30, H-4,25, N-8,86.

Found: C-63,50, H-4,20, N-8,78%.

Example 37.

< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-4-phenylbutyramide

So pl. 65-74oC []D+77,4(C=0,155, CH2Cl2).

H (CDCl3) 7,62-7,56 (3H, m), 7,46-7,19 (12H, m), of 5.55 (1H, d, J 8.1 Hz), 3,47 (3H, s), a 2.71 (2H, t, J 730H2O:

C-74,91, H-TO 6.19, N-10,08.

Found: C-74,93, H-6,05, N-10,07%.

Example 38.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-5-methyl-3-phenylisoxazol-4-carboxamid

So pl. 123-126oC []D+122,0(C=0,199, CH2Cl2).

H (CDCl3) 7,79-7,76 (2H, m), 7,62-to 7.32 (11H, m), 7,26-7,21 (2H, m), 5,61 (1H, d, J 7.9 Hz), 3,42 (3H, s) and was 2.76 (3H, s).

Elemental analysis. Calculated for C27H22N4O30,40 H2O:

C-70,85; H-5,02; N-12,24.

Found: C-70,84; H-4,91; N-11,92%.

Example 39

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-3-(3-cyanophenyl) propanamide

So pl. 110-112oC []D+84,2(C=0,202, CH2Cl2)

H (CDCl3) 7,63-7,22 (14H, m), the 5.51 (1H, d, J 8.1 Hz), 3,47 (3H, s), 3,06 (2H, t, J 7.8 Hz) and 2,74 of 2.68 (2H, m).

Elemental analysis. Calculated for C26H22N4O20,50 H2O:

C-72,37, H LOWER THAN THE 5.37, N-12,98.

Found: C-72,52, H-5,12, N-12,59%.

Example 40.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 benzodiazepine-3-yl]cyclohexanamine

So pl. 144-146oC []D+72,1(C=1,000, MeOH).

Elemental analysis. Calculated for C24H27N3O20,20 H2O:

C,3-dihydro-1-methyl-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl]butanamide

[]D+57,7(C=0,440, MeOH)

Elemental analysis. Calculated for C26H31N3O2:

C-74,79; H-OF 7.48; N-10,06.

Found: C-74,80; H-7,78; N OF 10.05%

Example 42.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-4-methylpentanoic

So pl. 123-125oC []D+66,8o(C=0,500, MeOH).

Elemental analysis. Calculated for C22H25N3O20,45 H2O:

C-71,12, H-7,03, N-11,31.

Found: C-71,08; H-For 6.81, N-11,42%.

Example 43.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2,3-dihydrobenzofuran-2-carboxamide

To a solution of 3 (R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4 - benzodiazepine-2-it (J. Org. Chem., 1987, 52, 3232-3239) (400 mg, 1.5 mmol), 2,3-dihydrobenzofuran-2-carboxylic acid (274 mg, 1.7 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (583 mg, 3.0 mmol) and 1-hydroxybenzotriazole (479 mg, 3.1 mmol) in DMF (4.5 ml) under stirring and cooling (0oC) add diisopropylethylamine (0.3 ml, 223 mg, 1,72 mmol). The mixture is stirred at room temperature for 18 hours, poured it into aqueous hydrochloric acid (3 M, 12 ml) and extracted with ethyl acetate (3h20 ml). The combined organic fractions Pro is evaporated under reduced pressure. The residue is crystallized from 2-chloro-2-methylpropane/hexane, and receive (+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2,3-dihydrobenzofuran-2-carboxamide in the form of a colorless solid (156 mg, 25%).

So pl. 141-180oC []D+127,1(C = 0,425, CHCl3).

H (CDCl3) (a mixture of diastereoisomers 3:1) 8,44 (1H, m), 7,65-6,91 (13H, m), 5,52 (1H, m), 5,28 (1H, m) and 3.70 is 3.40 (5H, m).

Elemental analysis. Calculated for C25H21N3O30.25 hexane:

C-73,50; H-5,70, N-9,71.

Found: C-74,12, H-5,57, N-9,71%.

Example 44.

(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] -1'-(1,1-dimethylethoxysilane)Spiro(cyclohexane-4,4'- piperidine)-1-carboxamid

Stage A

< / BR>
Diethyl-1-benzylpiperidine-4,4-diacetate

Ethanol (120 ml) cooled on ice, and passed through the ammonia to obtain a saturated solution. Add 1-benzyl-4-piperidone (40,0 g, 211 mmol) and ethylcyanoacrylate (47,8 g, 423 mmol), the reaction vessel sealed and stored at 0oC during the night. Collect solid, wash it with ethanol and ether and dried under vacuum, to obtain yellow solid (68,86 g). This solid (58,86 g) dissolved in a mixture of sulfuric acid (70 ml, the greater part of the water. The residue is distilled azeotrope with ethanol (g ml), then add ethanol (500 ml) and the mixture is refluxed for 20 hours, cooled on ice, and slowly, with vigorous stirring, add sodium carbonate (100 g). The ethanol is evaporated under reduced pressure, add water (800 ml) and the mixture is extracted with methylene chloride (3x400 ml). The combined organic extracts dried (Na2SO4), and evaporated the solvent, receive diethyl-1-benzylpiperidine-4,4-diacetate (37,51 g). A small part of the clear column flash chromatography.

NMR (300 MHz, CDCl3) : of 7.2 to 7.4 (m, 5H), 4,11 (K, J =7,3 Hz, 4H), 3,50 (s, 2H), has 2.56 (s, 4H), 2,4 (m, 4H), to 1.7 (m, 4H), 1,24 (t, J =7,3 Hz, 6H).

Stage B

< / BR>
1-Benzylpiperidine-4,4-diethanol

Under stirring in an argon atmosphere to a cold (-30oC) a suspension of LiAlH4(2.1 g, 55 mol) in ether (400 ml) add a solution of complex diapir (12.2 g, 35 mmol) in ether (25 ml). Add THF (60 ml) and the reaction mixture was allow to warm to room temperature. After re-cooling to 0oC add water (2.2 ml), 1 M NaOH (4.4 ml) and water (5 ml), the reaction mixture was vigorously stirred for 30 minutes, and filtered the solid, which is washed with ether is with 8 g of 1-benzylpiperidine-4,4-diethanol.

So pl. 75-78oC.

NMR (300 MHz, CDCl3) : of 7.2 to 7.4 (m, 5H), and 3.7 (t, J=6,8 Hz, 4H), 3,52 (s, 2H), 2,7 (CL, 2H), 2,43 (m, 4H), of 1.66 (t, J =6,8 Hz, 4H) 1,5 (m, 4H).

Stage C

< / BR>
1-tert-Butoxycarbonylamino-4,4-diethanol

Benzylamine (2,07 g, 7.9 mmol) was dissolved in methanol (60 ml), add BOC2O (BOk2O) (1,72 g, 7.9 mmol) and the mixture hydronaut at 345 kPa (50 f/d2) over 10% palladium hydroxide on coal (200 mg) for 18 hours. The reaction mixture was filtered through celite, washed with methanol, and the filtrate evaporated, to obtain 1-tert-butoxycarbonylamino-4,4-diethanol (2.0 g).

NMR (300 MHz, CDCl3) : to 3.7 (m, 4H), 3,3 (m, 6H), of 1.65 (t, J=6,8 Hz, 4H), of 1.41 (s, 9H).

Stage D

< / BR>
Vis(methanesulfonate) 1-tert-butoxycarbonylamino-4,4 - diethanol

Diol (2,41 g, 8.9 mmol) is dissolved in dichloromethane (50 ml), the solution is cooled to -20oC in argon atmosphere, and then add triethylamine (with 3.7 ml, 26 mmol) and methanesulfonamide (1.6 ml, 20 mmol). After 30 minutes the reaction mixture is poured into ice 10% citric acid and extracted with ether (X3). The combined extracts washed with water, saturated solution of NaHCO3and brine, dried (MgSO4), and the solvent is evaporated, receive bis(methanesulfonate) 1-tert-b is,89 (t, J =7,1 Hz, 4H).

Stage E

< / BR>
Diethyl-3-tert-butoxycarbonyl-3-azaspiro[5.5] undecane-9,9 - in primary forms

To a suspension of 60% NaH (2,04 g, 0.51 mmol) in toluene (160 ml) in an argon atmosphere gradually add diethylmalonate (and 3.72 ml, 24,3 mmol). The mixture is cooled to 0oC, and add bis-mesilate 1 (7.0 g, 16.3 mmol) in the form of solids, and the mixture is refluxed for 18 hours. The reaction is quenched with 10% citric acid (100 ml), and the reaction product is extracted with CH2Cl2(G ml). The extracts are dried (Na2SO4), concentrated to oil and chromatographic on the silicon dioxide receive a 3.83 g (60%) of diethyl-3-tert-butoxycarbonyl-3-azaspiro[5.5]undecane-9,9-in primary forms.

1H NMR (CDCl3) : to 1.22 (t, 6H), and 1.4 (s, 9H), 2.0 (m, 4H), to 3.35 (m, 4H), 4,2 (K, 4H).

Stage F

< / BR>
3-tert-Butoxycarbonyl-3-azaspiro[5.5] undecane-9-carboxylic acid

To a solution of complex diapir 2 (of 3.69 g, 0,0093 mol) in THF (50 ml) was added 1 N LiOH (47 ml). The reaction mixture is stirred for 3 days at 25oC, diluted with water (50 ml) and pH adjusted to 2.2 KHSO4. The reaction product is extracted with ethyl acetate (CH ml), dried (Na2SO4) and concentrated to a foam (3.5 g). The solid is melted in a flask at 140oC in those who Chi at 30oC. the Reaction mixture is concentrated by removing THF, diluted with water (20 ml) and washed with diethyl ether (10 ml). Bring the pH to 2.5 with KHSO4and the product is extracted (g ml) ethyl acetate. The extracts are dried (Na2SO4), filtered and concentrated, to obtain 3-tert-butoxycarbonyl-3-azaspiro [5.5] undecane-9-carboxylic acid in the form of foam (2,48 g, 90%).

1NMR (CDCl3casticin.) : 1,45 (s, 9H), 3,4 (m, 4H).

Using the procedure described in example 43, but substituting 2,3-dihydrobenzofuran-2-carboxylic acid to the corresponding acid, receive the following compounds.

Stage G

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl] -1' (1,1-dimethylethoxysilane)Spiro(cyclohexane-4,4-piperidine)-1 - carboxamid

So pl. 135-138oC []D+58,8(C=0,925, CHCl3).

H (CDCl3) to 7.61-of 7.23 (10H, m) 5,54 (1H, d, J 9.0 Hz), 3,47 (3H, s), 3,37 (4H, m), 2,28 (1H, m) and 1,81-1,18 (21H, s). Elemental analysis. Calculated for C32H40N4O4:

C - 70,56; H - 7,40; N - 10,29.

Found: C - 70,21; H - 7,40; N - 10.16 Per Cent.

Example 45.

< / BR>
(+)-N-[3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl]-3-(furan-2-yl)propanamide

So pl. 115-118oC []D+65,8

Elemental analysis. Calculated for C23H21N3O30.3 hexane:

C - 72,07; H - 6,15; N -10,17.

Found: C - 71,78; H - 6,30; N -9,77%.

Example 46.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl]-4-(2-thienyl)butanamide

So pl. 170-180oC []D+63,5o(c = 1,000, MeOH).

Elemental analysis. Calculated for C24H23N3O20,95 H2ABOUT:

C - 66,32; H IS 5.77; N - 9,67.

Found: C - 66,32; H - 5,34, N - 9,40%.

Example 47.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]cyclohexanecarboxylic

So pl. 213-214oC []D+62,4(C =1,000, MeOH).

Elemental analysis. Calculated for C23H24N3O2:

C - 73,77; H - 6,46; N - 11,22.

Found: C - 73,86; H - For 6.81; N - Of 11.15%.

Example 48.

< / BR>
E-(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-3-(3,4-methylenedioxyphenyl)-2-propenamide

So pl. 143-145oC []D+62,3(C = 1,960, MeOH).

Elemental analysis. Calculated for C25H21N3O410H2O 0,20 Et2O:

C - 69,78, H - 5,27, N - 9,46.

Found: C - 69,78; H - 4-hinatainternational

[]D+85,8(c = 0,360, MeOH)

Elemental analysis. Calculated for C25H19N5O2:

C - 69,96; H - 4,90; N - 15,33.

Found: C - 69,95; H - 4,72; N - 15,25%.

Example 50.

(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]- 2-(phenylamino)ndimethylacetamide

Stage AND

< / BR>
N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - 2-bromoacetamide

Add bromoacetamide (165 μl, 383 mg, 1.9 mmol) to a cooled with ice to a solution of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4 - benzodiazepine-2-it (J. Org. Chem., 1987, 52, 3232-3239) (500 mg, 1.88 mmol) and triethylamine (264 μl, 192 mg, 1.9 mmol) in methylene chloride (10 ml), and the mixture is stirred at room temperature for 1 hour. The mixture was washed with water (3x10 ml), dried (MgSO4), and the solvent is evaporated under reduced pressure to obtain N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]- 2-bromoacetamide in the form of a colourless foam (760 mg, 100%).

H (CDCl3) 8,24 (1H, d, J 7.8 Hz), of 7.64-7,24 (9H, m), of 5.48 (1H, d, J 7.8 Hz), 4,00 (2H, m) and a 3.50 (3H, s).

Stage

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2-(phenylamino)ndimethylacetamide

Add aniline (297 μl, 304 mg, 3,26 mmol) to a solution of N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1 for 24 hours. The mixture is cooled, the solid collected and recrystallized from ethanol (20 ml), receive (+)-N-[(3R)-2,3 - dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]-2-(phenylamino) ndimethylacetamide in the form of a colorless solid (500 mg, 81%), so pl. 245-246oC []D+119(C=0,850, CHCl3).

H (CDCl3) compared to 8.26 (1H, d, J 8,3 Hz), 7,63-7,20 (12H, m), for 6.81 (1H, t, J 7,3 Hz), 6,72 (2H, d, J 7,6 Hz) to 5.56 (1H, d, J 8,3 Hz), 3,95 (2H, d, J 1.5 Hz) and 3.45 (3H, s).

Elemental analysis. Calculated for C24H22N4O2:

C - 72,34; H - TO 5.57; N - 14,06.

Found: C - 72,37; H - 5,59; N - 14,32%.

Using the procedure described above but replacing aniline with 2 - Chloroaniline or 4-(trifluoromethyl)aniline, get the following compounds.

Example 51.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl]-2-(2-chlorpheniramine)ndimethylacetamide

So pl. 222-224oC []D+111(c = 0,973, CHCl3).

H (CDCl3) of 8.15 (1H, d, J 8,3 Hz), 7,60-7,16 (12H, m), of 6.71 (2H, m), to 5.57 (1H, d, J 8,3 Hz) to 4.01 (2H, d, J 2.7 Hz) and 3.45 (3H, s).

Elemental analysis. Calculated for C24H21ClN4O2:

C - 66,59; H - 4,89; N - 12,94.

Found: C - 66,40; H - 4,94; N - 12,92%.

Example 52,

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-9(C=0,419, CHCl3).

H (CDCl3) 8,13 (1H, d, J 9.0 Hz), 7,70-of 7.25 (12H, m), 6,72 (2H, d, J 8.7 Hz), the ceiling of 5.60 (1H, d, J 9.0 Hz), of 4.05 (2H, m) and a 3.50 (3H, s).

Elemental analysis. Calculated for C25H21F3N4O20,7 H2O:

C - 62,68; H - 4,71; N - OF 11.69.

Found: C - 72,47; H - 4,32; N - 11,44%.

Example 53

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-2-(phenoxy)ndimethylacetamide

To a suspension of sodium hydride (60% dispersion in mineral oil, 44 mg, 1.1 mmol) in toluene (10 ml) was added phenol (104 mg, 1.1 mmol). When hydrogen evolution ceases, add N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2-bromoacetamide (400 mg, 1.04 million mg), and the mixture is stirred at room temperature for 18 hours. The mixture was washed with water (I ml), dried (MgSO4), and the solvent is evaporated under reduced pressure. The residue is triturated with 2-propanol, the solid is collected and recrystallized from 2-propanol (5 ml), receive (+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl] -2-(phenoxy)ndimethylacetamide in the form of a colorless solid (112 mg, 27%). So pl. 126-128oC []D+81,6(C=0,692, CHCl3).

H (CDCl3) 8,49 (1H, d, J 8.2 Hz), of 7.64-7,01 (14H, m), 5,61 (1H, d, J 8.2 Hz), 4,6 O3:

C - 72,17, H - 5,30, N - 10,52.

Found: C - 71,84; H - 5,25; N - 10,41%.

Using the procedure described above but substituting phenol 2,4-dichlorphenol, thiophenol or 2,4-Dichlorotoluene receive the following compounds.

Example 54

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-2-(2,4-dichlorphenoxy)ndimethylacetamide

So pl. 206oC []D+31,1(C = 0,289, CHCl3).

H (CDCl3) is 8.75 (1H, d, J 9.0 Hz), 7,65-7,20 (11H, m), 6.90 to (1H, d, J 8.7 Hz), the ceiling of 5.60 (1H, d, J 9.0 Hz) and 4.65 (2H, m) and a 3.50 (3H, s).

Elemental analysis. Calculated for C24H19Cl2N3O20,3 H2O:

C - 60,85; H - 4,17, N - 8,87.

Found: C - 60,80; H - 4,04; N - 8,87%.

Example 55.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl]-2-(phenylthio)ndimethylacetamide

[]D+104,9(C = 0,316, CHCl3).

H (CDCl3) and 8.50 (1H, d, J 9.0 Hz), 7,60-7,20 (14H, m), of 5.50 (1H, d, J 9.0 Hz), of 3.75 (2H, m) and 3.45 (3H, s).

Elemental analysis. Calculated for C24H21N3O2:

C - 69,37, H - 5,10, N - 10,11.

Found: C - 68,98, H - Is 5.06, N -9,76%.

Example 56.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl]- 2-(2,4-dichlorophenylthio)ndimethylacetamide

[]D m) and a 3.50 (3H, C).

Elemental analysis. Calculated for C22H19N3O2:

C - TO 59.51; H - 3,95; N - 8,67.

Found: C - 59,32; H - 3,95; N - 8,65%.

Example 57.

< / BR>
(+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(phenylamino)propanamide

It chilled with ice to a solution of 3(R)-amino-1,3-dihydro-1 - methyl-5-phenyl-2H-1,4-benzodiazepine-2-it (J. Org. Chem, 1987, 52, 3232-3239) (5.0 g, 18,8 mmol) and triethylamine (and 2.79 ml, 2,02 mg, 20 mmol) in methylene chloride (85 ml) is added 3-bromo-propionate (2,01 ml, 3,428 g, 20 mmol) and the mixture stirred at room temperature for 18 hours. The mixture was washed with saturated aqueous sodium hydrogen carbonate (85 ml), water (I ml) and saline solution (85 ml), dried (MgSO4), and the solvent is evaporated under reduced pressure. The sample (0.5 g, 1.25 mmol) dissolved in ethanol (25 ml), added aniline (230 μl, 233 mg, 2.5 mmol) and the mixture refluxed for 70 hours. The mixture is cooled, the solid collected and recrystallized from ethanol, to obtain (+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl] -3-(phenylamino)propanamide in the form of a colorless solid.

So pl. 218 to 221oC []D+58,2(C=0,585, CHCl3).

keno for C25H24N4O20,5 EtOH:

C - 71,70, H - 6,25, N - 12,87.

Found: C - 71,42, H Is 5.98, N - 12,84%.

Example 58.

< / BR>
(+)-1-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl]-3- (2, 4-dichlorophenyl)urea

To a solution of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4 - benzodiazepine-2-it (J. Org. Chem., 1987, 52, 3232-3239) (265 mg, 1.0 mmol) in tetrahydrofuran (20 ml) is added 2,4-dichlorophenylisocyanate (188 mg, 1.0 mmol). The mixture is stirred at room temperature for 18 hours, and the solvent is removed under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH (of 99.5:0.5), and the residue is recrystallized from CH2Cl2/hexane, to obtain (+)-1-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl - 1H-1,4-benzodiazepine-3-yl] -3-(2,4-dichlorophenyl)urea as a colorless solid.

So pl. 215 - 217,5oC []D+76,2(C=0,261, CHCl3).

H (CDCl3) 8,10 (1H, d, J 9.9 Hz), 7,65-6,95 (13H, m), of 5.50 (1H, d, J 9.0 Hz) and a 3.50 (3H, s).

Elemental analysis. Calculated for C23H18Cl2N4O20,3 H2O:

C - 60,22; H - 4.09 TO; N - 12,21.

Found: C - 60,28; H - To 3.89; N - 12,10%.

Example 59.

< / BR>
(-)-3-Cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo - 5-phenyl-1H-1,4-benzodiazepine-3-yl]propanamide (0,60 g, 1.5 mmol) in dichloromethane (25 ml) is added 3-chloroperoxybenzoic acid (80%, 0.32 g, 1.5 mmol), and the mixture is stirred at room temperature for 18 hours. Add another 3-chloroperoxybenzoic acid (80%, 0.1 g, 0.5 mmol) and the mixture stirred for 24 hours. The mixture was washed with saturated aqueous sodium hydrogen carbonate (4x25 ml), water (I ml) and brine (25 ml), dried (MgSO4), and remove the solvent under reduced pressure. The residue is recrystallized from a mixture of toluene with hexane (65:35), and receive (-)-3-cyclohexyl-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-4 - oxido-5-phenyl-1H-1,4-benzodiazepine-3-yl]propanamide in the form of colorless prismatic crystals.

So pl. 222-224oC []D-80,7(C=1,15, CHCl3).

H (CDCl3) 7,71-of 7.23 (10H, m), 6,01 (1H, d, J 9.3 Hz), of 3.54 (3H, s), 2,48 (2H, m) and 1.76-0,89 (13H, m).

Elemental analysis. Calculated for C25H29N3O30.5 H2O:

C - 70,06; H - 7,06; N - 9,81.

Found: C - 70,10; H - 6,80; N - 9,79%.

Example 60.

N-[2,3-Dihydro-1-(2-dimethylaminoethyl)-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

Stage AND

< / BR>
2,3-Dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepine-2-he

To the washed geksal-1H-1,4-benzodiazepine-2-he (1,00 g, to 4.23 mmol). Add DMF (10 ml), and the mixture is stirred at room temperature. To the washed hexane to sodium hydride (60% dispersion in mineral oil, 200 mg, 5.0 mmol) in DMF (5 ml) was added the hydrochloride of 2-(dimethylamino)ethylchloride (0.73 g, 5 mmol), and both mixtures are combined. Add potassium iodide (1 crystal), and the mixture was stirred at 110oC for 30 minutes. Evaporated the solvent under reduced pressure, water is added and the mixture extracted with ethyl acetate. The combined organic fractions washed with water (2x), dried (MgSO4), and remove the solvent under reduced pressure, to obtain 2,3-dihydro-1-(2-dimethylaminoethyl)- 5-phenyl - 1H-1,4-benzodiazepine-2-he (1,21 g, 93%).

H (CDCl3) 7,63-7,16 (9H, m), of 4.77 (1H, d, J 10,6 Hz) to 4.41 (1H, m), 3,80 (1H, m), of 3.78 (1H, d, J a 10.6 Hz), 2.49 USD (2H, m) and 2.12 (6H, s).

Stage

< / BR>
2,3-Dihydro-1-(2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl-1H-1,4 - benzodiazepine-2-he

2,3-Dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepine-2-he (1,21 g, 3.9 mmol) dissolved in toluene (20 ml). The mixture is cooled to -78oC, and add tert-piperonyl potassium (1.0 M solution in tert-butanol, 4,72 ml, 4,72 mmol). The mixture was stirred at -78oC for 20 minutes, and then add soliditet (0.63 ml, 0.55 g, 4,72 mmol). The mixture merlivat in an aqueous solution of citric acid (1M, 10 ml). Bring the pH to 5.0 with an aqueous solution of sodium hydroxide and then to 7.0 with a saturated aqueous solution of sodium bicarbonate. The mixture is extracted with ethyl acetate (50 ml) and the organic layer was kept at room temperature. The solid which forms is collected and dried in vacuum, to obtain 2,3 - dihydro-1- (2-dimethylaminoethyl)-3-hydroxyimino - 5-phenyl-1H-1,4-benzodiazepine-2-he (0,876 g, 66%) as a solid.

So pl. 232-234oC.

H (d6-DMSO) 10,90 (1H, s), 7,72-of 7.25 (9H, m), and 4.40 (1H, m), 3,80 (1H, m) of 2.50 (2H, m) and 1.85 (6H, s).

Stage C

< / BR>
3-Amino-2,3-Dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4 - benzodiazepine-2-he

To a mixture of 2,3-dihydro-1-(2-dimethylaminoethyl)-3-hydroxyimino-5-phenyl - 1H-1,4-benzodiazepine-2-it (0,91 g, 2.7 mmol) and triethylamine (of 0.56 ml, 0,41 g, 4.0 mmol) in THF (30 ml) is added utilizationa (320 μl, 287 mg, 4.0 mmol). The mixture is refluxed for 7 hours, again add utilizationa (167 ál, 150 mg, 2.1 mmol) and the mixture is refluxed for 12 hours. The mixture is cooled, remove the solvent under reduced pressure, and add ethyl acetate (75 ml) and water (25 ml). The organic phase is washed with water (4x25 ml), dried (MgSO4) and evaporated under reduced pressure. The remainder R is (a) within 4.5 hours. Then add again palladium-on-coal (10%, 100 mg) and the mixture shaken with hydrogen (345 kPa) for 1.5 hours. The mixture is filtered, and removed solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH and get 3-amino-2, 3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4-benzodiazepine-2-he (180 mg, 17%).

H (CDCl3) 7,75-7,17 (9H, m), of 4.45 (1H, s), and 4.40 (1H, m), 3,82 (1H, m), 2,47 (4H, m) and of 2.08 (6H, s).

Stage E

< / BR>
N-[2,3-Dihydro-1-(2-dimethylaminoethyl)-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

To a mixture of 3-amino-2,3-dihydro-1-(2-dimethylaminoethyl)-5-phenyl-1H-1,4 - benzodiazepine-2-she (180 mg, 0.6 mmol), 3-(2,4-dichlorophenyl)propanoic acid (131 mg, 0.6 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (115 mg, 0.6 mmol) and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) in DMF (15 ml) is added

the triethylamine up until pH becomes equal to 9.0. The mixture is stirred at room temperature for 72 hours. Evaporated the solvent under reduced pressure, and add ethyl acetate. The mixture is washed with water, saturated aqueous sodium bicarbonate and water, dried (MgSO4) and evaporated under reduced pressure. The residue is triturated with ACET is azepin-3-yl] -3-(2,4-dichlorophenyl)-propanamide in the form of solids. So pl. 199-201oC.

H (CDCl3) 7,60-7,15 (13H, m), of 5.50 (1H, d, J 8.0 Hz), and 4.40 (1H, m), 3,80 (1H, m), 3,10 (2H, t, J 7.5 Hz), 2,70 (2H, d, J 7.5 Hz), 2.40 a (2H, m) and was 2.05 (6H, s).

Elemental analysis. Calculated for C28H28N4O2:

C - 64,25, H - 5,39, N - 10,70.

Found: C - 64,23, H 5.40, Is N - 10,61%.

Example 61.

< / BR>
Hydrochloride (+)-3(R)-{ N-[3-(4-chlorophenyl)prop-1-EN-3-yl]-amino}-1,3-dihydro - 1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it

A mixture of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it (J. Org. Chem. , 1987, 52, 3232-3239) (265 mg, 1 mmol), E-1-chloro-4-(3-chloro-1-propenyl)benzene (281 mg, 1.5 mmol), potassium carbonate (276 mg, 2 mmol) and potassium iodide (25 mg, 0.15 mmol) in acetonitrile (2 ml) is refluxed for 4 hours. The mixture is cooled and poured into ethyl acetate (10 ml) and water (5 ml). The layers separated, and the aqueous layer was extracted with ethyl acetate (5 ml). The combined organic fractions washed with brine, dried (Na2SO4), and remove the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira with EtOAc-hexane (65: 35 with an increase to 100:0). The first compound, which eluted, suspended in ethanol (1 ml), and add ethanol solution of HCl (6M, of 0.11 ml). The mixture premesis the STV and dried in vacuum, receive hydrochloride (+)-3(R)-{ N, N-bis[1-(4-chlorophenyl)propen-3-yl] -amino}-1,3-dihydro-1-methyl - 5-phenyl-2H-1,4-benzodiazepine-2-she (235 mg, 39%) as a yellowish brown solid. So pl. 138-145oC []D+9,2o(C = 0,500, MeOH).

H (d6-DMSO) to 11.2 (1H, CL), to 7.77-7,31 (17H, m), 6,85 (2H, BL), is 6.54 (2H, m), 5,20 (1H, CL), 4,60-4,00 (4H, m) and 3.46 (3H, s).

Elemental analysis. Calculated for C34H29Cl2N3O HCl 0,10 EtOH:

C - 67,60; H - 5,08; N - 6,92.

Found: C - 67,60; H - To 5.03; N - 7,03%.

A second connection, which elute, suspended in ethanol (0.5 ml), and add ethanol solution of HCl (6M, a 0.035 ml). The mixture is stirred, and then remove the solvent under reduced pressure. The residue is triturated with ether, the solid collected and dried in vacuum, to obtain hydrochloride of (+)-3(R)-{ N-[3-(4-chlorophenyl)-propene - 3-yl] -amino} -1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-she (56 mg, 12%) as a yellow solid. So pl. 156-162oC []D+35(C = 0,100, MeOH).

H (d6-DMSO) to 10.3 (1H, CL), and 10.0 (1H, CL), 7,79-7,34 (13H, m), is 6.78 (1H, d, J, or 15.9 Hz), 6,40 (1H, dt, Jd15,9, Jt9.0 Hz), 5,13 (1H, s), of 4.00 (2H, m) and 3.46 (3H, s).

Elemental analysis. Calculated for C25H22ClN3O HCl 0,10 EtOH 0,40 H2O:

C - 65,20, H - 5,30, N - 9,05.

panel) benzene, 1-(2-bromoethoxy)-4-nitrobenzene or the methanesulfonate of 4-chlorobenzophenone, get the following compounds.

Example 62.

< / BR>
Hydrochloride (+)-3(S)-{ N, N-bis[2-(4-nitrophenoxy)ethyl] -amino}-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it

So pl. 126-145oC []D+5,0(100, CHCl3).

H (d6-DMSO) to 8.20 (4H, d, J 9,2 Hz), 7,75 and 7.36 (9H, m), was 7.08 (4H, d, J 9,2 Hz), the 4.90 (1H, CL), 4,50 (4H, CL), 4,30-of 3.60 (5H, BL) and to 3.34 (3H, s).

Elemental analysis. Calculated for C32H29N5O7HCl 0,15 EtOH:

C - 60,71; H - 4,87; N - 10,96.

Found: C - 60,70; H - 4,87; N - 10,70%.

Example 63.

< / BR>
Hydrochloride (+)-3(R)-{ N-[3-(4-nitrophenoxy)ethyl] -amino} -1,3-dihydro - 1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it

So pl. 154-160oC []D+84,6(0,500, MeOH).

H (d6-DMSO) to 10.2 (1H, CL), of 8.25 (2H, d, J 9.0 Hz), 7,83-7,41 (9H, m), to 7.09 (2H, d, J 9.0 Hz), to 5.21 (1H, s), of 4.57 (2H, m), 3,70 (2H, m), 3,47 (3H, s) and 3.40 (1H, m).

Elemental analysis. Calculated for C24H22N4O4HCl 0,15 EtOH 0,20 H2O:

C - 61,13; H - 5,13; N -11,74.

Found: C - 61,12; H To 4.92; N - 11,64%.

Example 64.

< / BR>
Hydrochloride (+)-3(R)-{ N-[3-(4-chlorophenyl)prop-1-yl] -amino}-1,3 - dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it

So pl. 167-168oC []D20,8(C=0,500, MeOH).

H (d6-Diz. Calculated for C25H24ClN3O HCl:

C - 66,08; H - 5,55; N - 9,25.

Found: C - 65,81; H - 5,49; N - Of 9.30%.

Example 65.

< / BR>
(+)-Phenylmethyl-N-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H - benzodiazepine-3-yl]carbamate

A mixture of (+)-phenylmethyl-N-[(3R)-2,3-dihydro-1-methyl-5 - phenyl-2-oxo-1H-1,4-benzodiazepine-3-yl] carbamate (4.0 g, 10 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide (4.5 g, 11 mmol) in toluene (100 ml) is refluxed for 75 minutes. The mixture is cooled, and reduce the volume to 30 ml by evaporation under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira mixture with EtOAc-hexane (75: 25), receive (+)-phenylmethyl-N-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4 - benzodiazepine-3-yl] carbamate in the form of solids. So pl. 128 - 131oC. []D+22,5(C=0,656, CHCl3).

H (CDCl3) the 7.65 7,26 (15H, m), of 5.50 (1H, d, J 8,8 Hz), 5,14 (2H, s) and 3,86 (3H, s).

Elemental analysis. Calculated for C24H21N3O2S 0,25 H2O:

C - 68,63; H - 5,16; N - 10,01.

Found: C - 68,28, H - To 5.21; N - 10,06%.

Using the procedure described above but substituting (+)-phenylmethyl - N-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-oxo-1H-1,4-benzodiazepine-3-yl] carbamate for phenyl">

Example 66.

< / BR>
Phenylmethyl-N-[2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepine-3-yl] carbamate

H (d6-DMSO) 10,85 (1H, CL), 8,42 (1H, d, J 8.6 Hz), 7,65-7,10 (14H, m), 5,10 (2H, s) and of 5.05 (1H, d, J 8.6 Hz).

Example 67.

< / BR>
3-Cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4 - benzodiazepine-3-yl)propanamide

The hydrogen bromide at room temperature is passed through a solution of (+)-phenylmethyl-N-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H-1,4 - benzodiazepine-3-yl] carbamate (0.9 g, 2.1 mmol), acetic acid (5 ml) and dichloromethane (5 ml). After 2 hours the solvent is evaporated under reduced pressure, add air, collect the solid and dry it in a vacuum. Sample (of 0.58 g, 1.8 mmol) suspended in THF (10 ml), add triethylamine (of 0.24 ml, 0.18 g, 1.8 mmol), and the mixture is stirred at room temperature for 3 hours. In a separate flask, to a solution cyclohexylpropionic acid (0.33 ml, of 0.30 g, 1.9 mmol) and DMF (1 drop) in THF (10 ml) add oxalicacid (0,20 ml, 0.29 grams, 2.3 mmol) and the mixture stirred at room temperature for 3 hours. Combine both mixtures and add triethylamine (0,32 ml of 0.23 g, 2.3 mmol) and the mixture stirred at room temperature for 2.5 hours. The solvent is removed under reduced pressure, relax the one solution of sodium bicarbonate, water (2x) and brine, dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2with MeOH (of 99.5:0.5), and the residue is recrystallized from EtOAc hexane, get 3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo - 1H-1,4-benzodiazepine-3-yl)propanamide in the form of a solid substance.

So pl. 219-221oC.

H (CDCl3) to 7.95 (1H, sm, J 8.6 Hz), 7,65-7,30 (9H, m) 5,72 (1H, d, J 8.6 Hz), a 3.87 (3H, s) to 2.41 (2H, t, J 7,6 Hz) and 1,80-0,85 (13H, m).

Elemental analysis. Calculated for C25H29N3OS 0,25 H2O:

C - 70,81; H - 7,01; N - TO 9.91.

Found: C - 70,80; H - 6,91; N - 9,95%.

Using the procedure described above but substituting (+)-phenylmethyl-N-[(3R)-2,3-dihydro-1-methyl-5-phenyl-2-thioxo-1H - 1,4-benzodiazepine-3-yl]carbamate to phenylmethyl-N-[2,3-dihydro-5-phenyl - 2-thioxo-1H-1,4-benzodiazepine-3-yl] carbamate and cyclohexylpropionic acid to the corresponding acid, receive the following compounds.

Example 68.

< / BR>
3-Cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepine-3-yl)propanamide

So pl. 113-119oC

H (CDCl3) 9,8 (1H, CL), 7,75-of 7.25 (10H, m), of 5.75 (1H, d, J 8.1 Hz), is 2.41 (2H, m) 1,80-0,85 (13H, m).

Eliminiating: C - 62,88; H - 5,70; N - 9,12%.

Example 69.

< / BR>
3-Cyclohexyl-N-(2,3-dihydro-2-hydrazino-5-phenyl-1H-1,4-benzodiazepine - 3-yl)propanamide

To a solution of 3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-2-thioxo - 1H-1,4-benzodiazepine-3-yl)propanamide (120 mg, 0.25 mmol) in methanol (3 ml) is added hydrazine (53 μl, 56 mg, 1.8 mmol). The mixture is stirred at room temperature for 3 hours, and the solvent is removed under reduced pressure. Add ethyl acetate and the mixture washed with water and brine, dried (Na2SO4), and remove the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH (of 99.5: 0.5, and increasing to 98:2), and get 3-cyclohexyl-N-(2,3-dihydro-2-hydrazono-5-phenyl - 1H-1,4-benzodiazepine-3-yl)propanamide in the form of foam.

H (CDCl3) 7,55-7,00 (11H, m), of 5.75 (1H, d, J 7,6 Hz), 3,50 (2H, CL), is 2.37 (2H, t, J 8.0 Hz) and 1,80-0,85 (13H, m).

Elemental analysis. Calculated for C24H29N5O 0,8 CH3OH 0,15 CH2Cl2:

C - 67,82; H - 7,41; N - 15,85.

Found: C - 67,79; H - 7,46; N - Of 16.05%.

Example 70.

< / BR>
(E)- and (Z)-3-Cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5-phenyl-1H-1,4 - benzodiazepine-3-yl)propanamide

A mixture of 3-cyclohexyl-N-(2,3-dihydro-1-tag) and triethylamine (280 μl, 203 mg, 2 mmol) in methanol (15 ml) with THF (15 ml) was stirred at room temperature for 3 hours. Remove the solvent under reduced pressure, and the residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH (98:2). The residue is recrystallized from ethyl acetate. The first isomer, which crystallizes, is recrystallized from ethyl acetate, and get (E)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino-5 - phenyl-1H-1,4-benzodiazepine-3-yl) propanamide in the form of solids. So pl. 196oC.

H (d6-DMSO) 12,20 (1H, s), of 9.00 (1H, d, J 8.0 Hz), 7,70-7,30 (10H, m), the 5.45 (1H, d, J 8.0 Hz), 2,30 (2H, m) or 1.80-0.75 in (13H, m).

The second isomer, which crystallizes, is recrystallized from methanol, and obtain (Z)-3-cyclohexyl-N-(2,3-dihydro-2-hydroxyimino - 5-phenyl-1H-1,4-benzodiazepine-3-yl)propanamide in the form of solids. So pl. 219oC.

H (d6-DMSO) for 9.95 (1H, s), of 8.95 (1H, s), is 8.75 (1H, d, 8.0 Hz), 7.50-7,00 (9H, m), 5,70 (1H, d, J 8.0 Hz), of 2.25 (2H, m) and 1.75-0.75 in (13H, m).

Elemental analysis. Calculated for C24H28N4O2:

C - 71,26; H - 6,98; N - 13,85.

Found: C - 70,89; H - 6,99; N - 13,55%.

Example 71.

< / BR>
3-Cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine - 3-yl)propanamide

With the-1,4-benzodiazepine - 3-yl)propanamide (200 mg, 0.5 mmol) in ethanol (20 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is filtered, and the solvent is removed under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH (of 99.75:0.25 in), and get 3-cyclohexyl-N-(2,3-dihydro-1-methyl-5-phenyl-1H-1, 4-benzodiazepine-3-yl)propanamide in the form of foam.

H (CDCl3) 7,60-6,80 (9H, m), 6,37 (1H, sm, J 7 and 6.6 Hz), of 5.53 (1H, m), of 3.60 (2H, m), 2,77 (3H, s), of 2.21 (2H, t, J 8.0 Hz) and 1.85-0,80 (13H, m).

Elemental analysis. Calculated for C25H31N3O 0,2 CH2Cl2:

C - 74,45; H - 7,79; N - 10,34.

Found: C - 74,68; H - 7,87; N - 10,23%.

Example 72.

1-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e] -1,4-diazepin-3-yl)- 3-(3-were)urea

Stage AND

< / BR>
(2-Amino-3-thienyl)phenylmethane

To a heated (33oC) a mixture of oxopentanenitrile (18.6 g, 128 mmol) and 1,2-dition-2,5-diol (9,8 g, 64 mmol) in ethanol (120 ml), add triethylamine (6.8 ml, 4.94 g, 49 mmol) and the mixture stirred at 50oC for 18 hours. The mixture is cooled, and the solvent is evaporated under reduced pressure. Add dichloromethane, the mixture is washed with aqueous hydrochloric acid (0.5 M), aqueous solution of sodium hydroxide (1M) and saliva from acetonitrile (150 ml), and get (2-amino-3-thienyl)phenylmethanone as an orange solid (5.7 g, 44%).

H (CDCl3) 7,70-to 7.35 (5H, m), to 6.95 (2H, CL), of 6.90 (1H, d, J 6.3 Hz) and x 6.15 (1H, d, J 6.3 Hz).

Stage

< / BR>
2,3-Dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-he

A solution of 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetylchloride (8.6 g, 38 mmol) in dichloromethane (20 ml) is gradually added to a cooled (0oC) a mixture of (2-amino-3-thienyl)phenylmethanone (6.8 g, 33 mmol), pyridine (6,34 ml, 6.20 g, 78 mmol) and 4-dimethylaminopyridine (0,79 g, 6.5 mmol) in dichloromethane (130 ml). The mixture was stirred at 0oC for 30 minutes, diluted with dichloromethane (80 ml) and washed with aqueous hydrochloric acid (1M), saturated aqueous sodium bicarbonate and saline. The mixture is dried (Na2SO4) and the solvent is evaporated under reduced pressure. The residue is triturated with ethanol, the solid is collected and dried under vacuum, to obtain N-(3-benzaiten-2-yl)-1,3-dihydro-1,3 - dioxo-2H-isoindole-2-ndimethylacetamide in the form of a solid (9.8 g, 76%).

A mixture of N-(3-benzaiten-2-yl)-1,3-dihydro-1,3-dioxo-2H - isoindole-2-ndimethylacetamide (10,9 g, 28 mmol) and hydrazine (1.9 ml, of 1.94 g, 60 mmol) in THF (500 ml) is refluxed for 4 hours. The mixture is cooled, filtre, and the mixture is extracted with ethyl acetate. The combined organic fractions washed with brine, dried (Na2SO4), and the solvent is removed under reduced pressure. Add acetic acid (300 ml) and the mixture refluxed for 15 minutes. The mixture is cooled, and removed the solvent under reduced pressure. Add saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The combined organic fractions washed with brine, dried (Na2SO4), and the solvent is evaporated under reduced pressure, to obtain 2,3-dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-it is in the form of foam (3.5 g, 52%).

H (CDCl3) of 9.75 (1H, CL), of 7.90-7,30 (5H, m), 6.87 in (1H, d, J 6.0 Hz), PC 6.82 (1H, d, J 6.0 Hz) and 4.45 (2H, s).

Stage C

< / BR>
2,3-Dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-he

Add sodium hydride (60% dispersion in mineral oil, 757 mg, 11.3 mmol) to a cooled (0oC) a solution of 2,3-dihydro-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-it (2,61 g to 10.8 mmol) in DMF (7 ml). Add DMF (10 ml) and the mixture stirred for 30 minutes. Add a solution of iodomethane (of 0.67 ml of 1.53 g to 10.8 mmol) in ether (20 ml), and the mixture is stirred for 1 hour. The mixture was poured into water and extracted with what arevut the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH (95:5), and receive 2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-he (1.5 g, 54%).

H (CDCl3) to 7.67-to 7.35 (5H, m), 7,00 (1H, d, J 6.0 Hz), 6,85 (1H, d, J 6.0 Hz), of 4.45 (2H, CL) and a 3.50 (3H, s).

Stage D

< / BR>
3-Amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e]-1,4-diazepin-2-he

Dissolve 2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e] -1,4-diazepin - 2-he (1.5 g, 5.8 mmol) in toluene (30 ml). The mixture is cooled to -10oC, and add tert-piperonyl potassium (1.7 g, 15.1 mmol). The mixture was stirred at -10oC for 15 minutes, and then add soliditet (1.0 ml, 0.87 g, 7.4 mmol). The mixture was stirred at -10oC for 1 hour, then give her the opportunity to come to room temperature, and poured the mixture into water (50 ml) and acetic acid (3 ml). The mixture is extracted with ethyl acetate, and the combined organic fractions washed with brine, dried (Na2SO4), and remove the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira EtOAc hexane, and receive 2,3-dihydro-1-methyl-3-hydroxyimino-5-phenyl-1H-thieno [2,3-e]-1,4-diazepin-2-he (0,80 g, 48%).

2,3-Dihydro-1-methyl-3-hydroxyimino-5-phenyl-1H-thieno [2, 3-is tmosphere hydrogen (345 kPa) for 5 days, adding portions of 10 g of Raney Nickel. The mixture is filtered, and removed solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira CH2Cl2/MeOH, and get 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e] -1,4 - diazepin-2-he (248 mg, 33%).

H (CDCl3) 7,50-7,30 (5H, m), 7,05 (1H, d, J 6.0 Hz), 6,85 (1H, d, J 6.0 Hz), of 4.57 (1H, s), 3,55 (3H, s) and 1.70 (2H, CL).

Stage E

< / BR>
1-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e] -1,4 - diazepin-3-yl)-3-(3-were)urea

To a solution of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno [2,3-e]-1,4-diazepin-2-she (124 mg, 0.46 mmol) in tetrahydrofuran (5 ml) is added 3-methylphenylhydrazine (60 μl, 62 mg, 0.46 mmol). The mixture is stirred at room temperature for 2 hours, and remove the solvent under reduced pressure. The residue is crystallized from EtOAc (4 ml), and get 1-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H - thieno[2,3-e] -1,4-diazepin-3-yl)-3-(3-were) urea as a solid (94 mg, 50%).

So pl. 128-130oC.

H (CDCl3) to 8.70 (1H, s), the 7.65 6.75 in (12H, m), of 5.55 (1H, d, J 9.0 Hz), 3,55 (3H, s) and is 2.30 (3H, s).

Elemental analysis. Calculated for C22H20N4O2S 0,25 H2O:

C - 64,62; H - 4,99; N - 13,70.

Found: C - 64,68; H - 4,96; N - 13,70%.


To a mixture of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-thieno[2,3-e] -1,4-diazepin-2-she (82 mg, 0.3 mmol), cyclohexylpropionic acid (52 μl, 47 mg, 0.3 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (58 mg, 0.3 mmol) and 1-hydroxybenzotriazole (42 mg, 0.3 mmol) in DMF (1.5 ml) is added triethylamine (75 μl, 54 mg, 0.54 mmol). The mixture is stirred at room temperature for 18 hours, and add ethyl acetate (60 ml). The mixture was washed with aqueous citric acid (10%), saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira mixture with EtOAc-hexane, and get 3-cyclohexyl-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-thieno[2,3-e] -1,4 - diazepin-3-yl)propanamide in the form of a solid (56 mg, 46%). So pl. 189-190oC.

H (CDCl3) the 7.65 6,85 (8H, m), the 5.65 (1H, d, J 8.0 Hz), 3,55 (3H, s), is 2.40 (2H, t, J 7.0 Hz) and 1,80-0,85 (13H, m).

Elemental analysis. Calculated for C23H27N3O2S 0,5 H2O:

C - OF 66.00; H - 6,74; N - 10,04.

Found: C - 66,25; H - 6,76; N - 9,83%.

Example 74.

< / BR>
3-Cyclohexyl-N-(5-cyclohexyl-2,3-dihydro-2-oxo-1H-1,4 - benzodiazepine-3-yl)propanamide

ora hydrogen bromide in acetic acid (30%, 0.5 ml). After 2 hours add the ether, the solid collected and dried in vacuum. Add THF (3 ml) and triethylamine (0,45 μl, 33 mg, 0.32 mmol) and the mixture stirred at room temperature for 3 hours. In a separate flask, to a solution cyclohexylpropionic acid (61 μl, 56 mg, 0.36 mmol) and DMF (1 drop) in THF (2 ml) add oxalicacid (38 μl, 56 mg, 0.44 mmol), and the mixture is stirred at room temperature for 3 hours. Combine both mixtures and add triethylamine (61 μl, 44 mg, 0.44 mmol), and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated under reduced pressure, and add ethyl acetate. The mixture was washed with water (2x), saturated aqueous sodium bicarbonate, water and brine, dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is recrystallized from isopropyl alcohol, and get 3-cyclohexyl-N-(5-cyclohexyl-2,3-dihydro-2-oxo-1H - 1,4-benzodiazepine-3-yl)propanamide in the form of solids. So pl. 133-138oC.

H (CDCl3) a 7.85 (1H, CL), a 7.62 to 6.95 (5H, m), of 5.40 (1H, d, J 8.7 Hz), 2,77 (1H, m), 2,34 (2H, m) and 2,05-0,75 (23H, m).

Elemental analysis. Calculated for C24H33N3O20,7 C3H7OH:

C - 71,64; H - 8,89; N - 9,60.

Nile-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

Stage A

To a mixture of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine - 2-it (J. Org. Chem., 1987, 52, 3232-3239) (3,98 g, 15.0 mmol) of concentrated sulfuric acid (15 ml), cooled in a bath with ice, add dropwise a solution of potassium nitrate (2,12 g, 21,0 mmol) in concentrated sulfuric acid (6 ml). The mixture is stirred under cooling for 2 hours and then stirred at ambient temperature for 1.5 hours. Add ice (80 g) and the mixture is alkalinized with concentrated ammonium hydroxide to pH 9. The resulting mixture is extracted with ethyl acetate (CH ml). The combined organic fractions washed with brine, dried (Na2SO4), and remove the solvent under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira with chloroform-methanol (97: 3). A substance that elute, then purified column flash chromatography on silica gel, elwira the ethyl acetate with methanol (95:5). A substance that elute, stirred in n-butyl chloride (30 ml), and the solvent is evaporated under reduced pressure, get an inseparable mixture of 3(R)-amino-1,3-dihydro-1-methyl-7 - nitro-5-phenyl-2H-1,4-benzodiazepine-2-it 3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-(2-nitrophenyl)-2H-1,4-b is inania) 8,43 (1H, DD, J 9.3 Hz), 8,23 (1H, d, J 3 Hz), to 7.59 (2H, m), 7,52 (2H, m), 7,44 (2H, m), 4,47 (1H, s); of 3.53 (3H, s), and to 2.42 (2H, CL); (dinitrosobenzene) 8,49 (1H, DD, J 9.3 Hz), 8,42 (1H, m), 8,18 (1H, d, J 3 Hz), 8,01 (1H, m), to 7.67 (1H, t, J 6 Hz), 7,6 to 7.4 (2H, m) to 4.52 (1H, s), of 3.56 (3H, s), and to 2.42 (2H, CL).

Stage B

A solution of 3-(2,4-dichlorophenyl)propionic acid (482 mg, 2.2 mmol), DMF (of 0.017 ml, 0.22 mmol) and thionyl chloride (0,24 ml, 3.3 mmol) in chloroform (2.5 ml) is refluxed for 1 hour. The solvent is evaporated under reduced pressure, and the obtained 3-(2,4-dichlorophenyl)propionate (520 mg, 100%). To a solution of a mixture of 3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-phenyl-2H-1,4 - benzodiazepine-2-it 3(R)-amino-1,3-dihydro-1-methyl-7-nitro-5-(2 - nitrophenyl)-2H-1,4-benzodiazepine-2-she (3:1) (621 mg, 2 mmol) and triethylamine (0,305 ml, 2.2 mmol) in methylene chloride (10 ml) add a solution of 3-(2,4-dichlorophenyl)propionitrile (520 mg, 2.2 mmol) in methylene chloride (15 ml). The mixture is stirred for 30 minutes, the solvent was partially removed under reduced pressure, and the reaction mixture is purified column flash chromatography on silica gel, elwira the methylene chloride with ether (90:10), and receive a mixture of (+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-phenyl-1H-1,4-benzodiazepine - 3-yl] -3-(2,4-dichlorophenyl)propanamide and (+)-N-[(3R)-2,3-dihydro-1-methyl - 7-nitro-2-oxo-5-(2-nitrophenyl)-1H-1,">

H (CDCl3) (mononitrotoluene) to 8.45 (1H, DD, J 9.3 Hz), of 8.25 (1H, d, J 3 Hz), 7,54 (3H, m), 7,45 (2H, m), 7,38 (1H, d, J 2 Hz), 7.26-7.18 in (4H, m), of 5.50 (1H, d, J 8 Hz), 3,52 (3H, s), 3,10 (2H, m), and 2.70 (2H, m); (dinitrosobenzene) 8,51 (1H, DD, J 9.3 Hz), 8,40 (1H, m), 8,21 (1H, d, J 3 Hz), 7,98 (1H, m), 7,68 (1H, t, J 6 Hz), 7,60 (1H, m), 7,44 (1H, m), 7,26-to 7.15 (4H, m), 5,52 (1H, d, J 8 Hz), 3,55 (3H, s), 3,10 (2H, m), and 2.70 (2H, m).

Stage C

To a solution of a mixture of (+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3-yl] -3-(2,4-dichlorophenyl)propanamide and (+)-N-[(3R)-2,3-dihydro-1-methyl-7-nitro-2-oxo-5-(2-nitrophenyl)-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide (3:1) (770 mg, 1.5 mmol) in acetic acid (6 ml) is added dropwise, parts, within 1.5 hours a solution of 15% chloride titanium (III) in 20-30% hydrochloric acid (7.8 ml, 9.0 mmol). The resulting solution is stirred for 30 minutes, alkalinized with 20% sodium hydroxide solution (pH 9), diluted with water (80 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic fractions washed with brine, dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira the ethyl acetate with hexane (75:25, ascending to 100:0). The first connection, which elute, crystallized from ethyl acetate is(413 mg, 57%) as a pale yellow solid. So pl. 179-180oC []D+60,2(C=0,500, CHCl3).

H (CDCl3) 7,60 (2H, d, J 7 Hz), 7,49 and 7.36 (5H, m), 7,24 (1H, d, J 9 Hz), 7,17 (2H, m), of 6.99 (1H, DD, J 9.3 Hz), only 6.64 (1H, d, J 3 Hz), 5,54 (1H, d, J 8 Hz), 4.80 to a 3.50 (2H, CL), 3,39 (3H, s) to 3.09 (2H, t, J 8 Hz) and $ 2.68 (2H, dt, Jd3, Jt8 Hz).

Elemental analysis. Calculated for C25H22Cl2N4O2:

C - 62,38; H - BR4.61; N - 11,64.

Found: C - 62,58; H - To 4.68; N -11,65%.

A second connection, which elute, crystallized from ethyl acetate, and receive (+)-N-(3R)-7-amino-2,3-dihydro-1-methyl-2-oxo-5- (2-AMINOPHENYL)-1H-1,4-benzodiazepine-3-yl] -3-(2,4-dichlorophenyl)propanamide (114 mg, 15%) as a pale yellow solid. So pl. 188-189oC []D+50,0(C=0,100, MeOH).

H (CDCl3) of 7.36 (2H, m), 7,25 (1H, d, J 9 Hz), to 7.15 (3H, m), 7,00 (1H, m), to 6.88 (2H, m), 6,79 (1H, m), 6,60 (1H, CL), 5,52 (1H, d, J 8 Hz), 4,10-2,80 (4H, CL), 3,40 (3H, m), 3.09 (2H, t, J 8 Hz) and 2,69 (2H, m).

Elemental analysis. Calculated for C25H23Cl2N5O20,05 EtOAc:

C - 60,43; H - 4,71; N - 13,99.

Found: C - 60,79; H - 4,74; N - 13,83%.

Example 76.

< / BR>
(+)-N - [(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-7-methanesulfonamido-1H-1,4 - benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

To the solution is b) and pyridine (0,065 ml, 0.80 mol) in methylene chloride (1.6 ml) add methanesulfonanilide (0,040 ml, 0.52 mmol). The resulting solution is stirred for 2 hours. The solution is diluted with ethyl acetate (12 ml), washed with 1N HCl, water, saturated sodium bicarbonate solution, water and brine, dried (Na2SO4) and the solvent evaporated under reduced pressure. The residue is dissolved in warm toluene, treated with charcoal and filtered. The filtrate is diluted with hexane, the mixture is cooled and the resulting precipitate collected and dried in vacuum. Receive (+)-N-[(3R) -2,3-dihydro-1-methyl-2-oxo-5-phenyl-7-methanesulfonamido-1H-1,4-benzodiazepine - 3-yl]-3-(2,4-dichlorophenyl)propanamide (152 mg, 68%) as a white solid. So pl. 138-148oC. []D+111,6(C=0,500, CHCl3).

H (CDCl3) 7,55-to 7.32 (9H, m), 7,24 (2H, DD, J 10,2 Hz), 7,17 (1H, DD, J 9,2 Hz), 7,05 (1H, d, J 3 Hz), 5,49 (1H, d, J 8 Hz), to 3.41 (3H, s), is 3.08 (2H, t, J 8 Hz), of 2.97 (3H, s) and of 2.97 (3H, s) and a 2.71 (2H, dt, Jd3, Jt8 Hz).

Elemental analysis. Calculated for C26H24Cl2N4O4S:

C - 55,82; H - 4,32; N - 10,01.

Found: C - 56,12; H - 4,47; N - 9,89%.

Example 77.

< / BR>
The hydrochloride of N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4, 3-e]-1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl) - Rev.-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin-2-it (J. Med. Chem., 1965, 8, 722-724) (1,63 r, 6.5 mmol) in toluene (32 ml) in an argon atmosphere add tert-piperonyl potassium (1,83 g, 16.3 mmol). The resulting violet suspension is stirred for 15 minutes at -20oC, and add soliditet (1,05 ml, 7.8 mmol). The mixture is stirred at -20oC for 30 minutes, then pour in a mixture of water (50 ml), acetic acid (3 ml) and ethyl acetate (65 ml). The mixture is stirred to dissolve all solids, and the layers separated. The aqueous layer was extracted with ethyl acetate (65 ml). The combined organic fractions washed with saturated sodium bicarbonate solution and saline (20 ml each), dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is triturated with cold toluene, and the solid is collected and dried under vacuum. Receive 2,3-dihydro-3-hydroxyimino-1 - methyl-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin-2-he (1.22 g, 67%) as a yellow solid. So pl. p.223-224oC.

H (CDCl3) of 8.92 (1H, CL), 8,73 (1H, d, J 7 Hz), to 8.62 (1H, s), 7,80 (2H, DD, J 7,1 Hz), to 7.59 (1H, m), of 7.48 (2H, m), 7,26 (1H, d, J 7 Hz) and a 3.50 (3H, s).

Stage B

A mixture of 2,3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin-2-it (1.77 g, 6.3 mmol) and freshly prepared Raney Nickel (3.2 g) in the MCA is Uchenie 4 hours. The mixture is filtered through an auxiliary filter substance, and the filtrate evaporated under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira methanol chloroform and acetic acid (5:95:1, ascending to 10:90:1). A substance that elute, stirred with chloroform (30 ml) and potassium carbonate (0.3 g) and water (0.2 ml) for 5 minutes. The mixture is dried (Na2SO4), and the solvent is removed under reduced pressure to obtain 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido [4,3-e]-1,4-diazepin-2-he (276 g, 16%) as a yellow solid. So pl. 109-123oC.

H (CDCl3) 8,72 (1H, d, J 6 Hz), 8,58 (1H, s), to 7.61 (2H, m), 7,51 (1H, m), the 7.43 (2H, m), 7,26 (1H, m), 4,47 (1H, s), 3,50 (3H, s) and 2.1 (2H, sh.C).

The mass spectrum of the cm.authorised: Teoret. mass for C15H14N4O (M+1): 267,124586. Measured mass (M+1): 267,123654.

Stage C

The solution dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylene chloride (0.17 ml) are added to a solution of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin-2-she (93 mg, 0.35 mmol) and 3-(2,4-dichlorophenyl)propionic acid (83 mg, 0.38 mmol) in tetrahydrofuran (0.5 ml) in an argon atmosphere. The resulting mixture is stirred for 5 hours, filtered, and the filtrate UPrev is the ROI methanol chloroform and acetic acid (5:95:1). The purified substance is stirred with chloroform (5 ml), potassium carbonate (0.1 g) and water (2 drops) for 5 minutes. The mixture is dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is suspended in ethanol (2 ml), and added ethanolic HCl solution (6,8 M, 0,147 ml). The mixture is stirred, the resulting precipitate is collected and dried in vacuum. Receive hydrochloride N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H - pyrido[4,3-e] -1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide (32 mg, 18%) as a white solid. So pl. 218-219oC.

H (d6-DMSO) 9,38 (1H, d, J 8 Hz), 8,86 (1H, CL), 8,59 (1H, CL), 7,79 (1H, d, J 6 Hz), 7,56 (3H, m), 7,51 (2H, m), 7,39 (2H, m), 7,25 (1H, m), 7,16 (1H, m), lower than the 5.37 (1H, d, J 8 Hz), 3,44 (3H, s) to 2.94 (2H, t, J 7 Hz) and 2.64 (2H, t, J 7 Hz).

Elemental analysis. Calculated for C24H20Cl2N4O2HCl:

C - 57,22; H - 4,20; N - 11,12.

Found: C - 56,87; H - 4,18; N - 11,09%.

Example 78.

< / BR>
N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin - 3-yl)-3-(cyclohexyl)propanamide

The solution dicyclohexylcarbodiimide (87 mg, 0.42 mmol) in methylene chloride (0.17 ml) are added to a solution of 3-amino-2,3-dihydro-1-methyl-5 - phenyl-1H-pyrido[4,3-e] -1,4-diazepin-2-she (93 mg, 0.35 mmol) and cyclohexylpropionic acid (0,065 ml, 0.38 mmol) in which trout, and the filtrate evaporated under reduced pressure. The residue is purified by preparative pascolini chromatography on silica gel, elwira methanol chloroform and acetic acid (5:95:1). The purified substance is stirred with chloroform (5 ml), potassium carbonate (0.1 g) and water (2 drops) for 5 minutes. The mixture is dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is crystallized from toluene, and get N-(2,3 - dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e]-1,4-diazepin-3 - yl)-3-(cyclohexyl)propanamide in the form of a white crystalline solid. So pl. 170-173oC.

H (CDCl3) is 8.75 (1H, d, J 6 Hz), 8,71 (1H, s), 7,58 (2H, m), 7,52 (1H, m), 7,45 (2H, m), 7,31 (1H, d, J 6 Hz), 7,21 (1H, d, J 8 Hz), 5,54 (1H, d, J 8 Hz), 3,51 (3H, s), 2,39 (2H, m) of 1.73 (4H, m), and 1.63 (3H, m), a 1.75-1,12 (4H, m), and 0.94 (2H, m).

Elemental analysis. Calculated for C24H28N4O20,10 PhCH3:

C - 71,70; H - 7,02; N - 13,54.

Found: C - 71,78; H - 7,01; N - 13,57%.

Using the procedure described above but replacing cyclohexylpropionic acid 3-(4-triptoreline)propionic acid, receive the following connection.

Example 79.

< / BR>
N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[4,3-e] -1,4-diazepin-3-yl)-3-(4-triptoreline)propanamide

Elemental analysis. Calculated for C25H21F3N4O20,20 PhCH3:

C - 65,39; H - 4,70; N - TO 11.56.

Found: C - 65,69; H With 4.64; N - 11,95%.

Example 80.

< / BR>
N-(2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-pyrido[3,4-e] -1,4-diazepin - 3-yl)-3-(2,4-dichlorophenyl)propanamide

Stage A

To a solution of 2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[3,4-e]- 1,4-diazepin-2-she Can. J. Chem., 1987, 65, 1158-1161) (1,43 g, 5.7 mmol) in toluene (28 ml), cooled to -20oC (ice bath with methanol), in the atmosphere of argon added tert-piperonyl potassium (1,59 g of 14.2 mmol). The resulting violet suspension is stirred for 15 minutes at -20oC, and add soliditet (0,92 ml, 6.8 mmol). The mixture is stirred at -20oC for 30 minutes and then poured into a mixture of water (25 ml), acetic acid (2.5 ml) and ethyl acetate (55 ml). The mixture is stirred to dissolve all solids, and the layers separated. The aqueous layer was extracted with ethyl acetate (2 x 55 ml). The combined organic fractions washed with saturated sodium bicarbonate solution and saline (each 20 ml), dried (Na2SO4), and the solvent is evaporated under reduced of davleniya-1-methyl-5-phenyl-1H - pyrido[3,4-e] -1,4-diazepin-2-he (1.60 g, 100%) as a tan foam.

H (CDCl3) 8,77 (1H, s), and 8.50 (1H, d, J 4 Hz), 7,81 (2H, DD, J 8, 1 Hz), 7,60 (1H, m), 7,49 (3H,m), 7,32 (1H, d, J 5 Hz) and 3,55 (3H, s).

Stage B

A solution of chloride dihydrate tin (11) (and 3.72 g, 16.5 mmol) in concentrated hydrochloric acid (11 ml) is added dropwise to 2, 3-dihydro-3-hydroxyimino-1-methyl-5-phenyl-1H-pyrido[3,4-e] -1,4-diazepin-2-ONU (1.54 g, 5.5 mmol), cooled in a bath with ice. The resulting solution was stirred at ambient temperature for 3 hours. The solution was diluted with water (20 ml), alkalinized with concentrated ammonium hydroxide (18 ml) and extracted with ether (4 x 75 ml). The combined organic fractions washed with brine (30 ml), dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is purified column flash chromatography on silica gel, elwira methanol chloroform and acetic acid (5:95:1 increasing to 10:90:1). The substance eluted, stirred with chloroform (20 ml) and potassium carbonate (0.3 g) and water (2 drops) for 5 minutes. The mixture is dried (Na2SO4), and the solvent is evaporated under reduced pressure. The residue is stirred with hexane, and the resulting solid is collected, the tion. So pl. 94-118oC.

H (CDCl3) 8,79 (1H, s), 8,48 (1H, d, J 5 Hz), a 7.62 (2H, DD, J 8, 1 Hz), 4,47 (1H, s), 3,55 (3H, s), 2.2 (2H, CL).

Elemental analysis. Calculated for C15H14N4O 0,25(C2H5)2O:

C - 67,46; H OF 5.84; N - 19,67.

Found: C - 67,28; H - 5,66; N -19,53%.

The mass spectrum of the cm. authorised: Teoret. mass for C15H14N4O (M+1): 267,124586. Measured mass (M+1): 267,123093.

Stage C

The solution oxalicacid (0,023 ml, 0.26 mmol) in methylene chloride (0.2 ml) is added dropwise to a solution of 3-(2,4-dichlorophenyl)propionic acid (48 mg, 0.22 mmol) and DMF (1 drop) in methylene chloride (0.5 ml), cooled in a bath with ice. The resulting solution is stirred for 1 hour while cooling. The solvent is evaporated under reduced pressure, and the obtained 3-(2,4-dichlorophenyl)propionate (52 mg, 100%). To a solution of 3-amino-2,3-dihydro-1-methyl-5-phenyl-1H-pyrido[3,4-e] -1,4-diazepin-2-she (53 mg, 0.20 mmol) and pyridine (0,021 ml, 0.22 mmol) in methylene chloride (3 ml) add a solution of 3-(2,4-dichlorophenyl)propionitrile (52 mg, 0.22 mmol) in methylene chloride (0.5 ml). The mixture is stirred for 1 hour, the solvent was partially evaporated under reduced pressure, and the reaction mixture is purified column flash chromatography on si is jut of toluene with hexane, and get N-(2,3-dihydro-1-methyl-2-oxo - 5-phenyl-1H-pyrido[3,4-e] -1,4-diazepin-3-yl)-3-(2,4-dichlorophenyl)propanamide (38 mg, 38%) as a white solid crystalline substances. So pl. 220-221oC.

H (CDCl3) 8,81 (1H, s), charged 8.52 (1H, d, J 5 Hz), 7,56 (2H, DD, J 7.2 Hz), 7,51 (1H, m), 7,44 (2H, d, J 6 Hz), 7,40 (1H, m), 7,27 (2H, m), 7,18 (2H, DD, J 8, 2 Hz), of 5.48 (1H, d, J 8 Hz), 3,55 (3H, s), 3,10 (2H, t, J 7 Hz) and a 2.71 (2H, dt, Jd2, Jt8 Hz).

Elemental analysis. Calculated for C24H20Cl2N4O20,25 PhCH3:

C - 63,06; H - TO 4.52; N - 11,43.

Found: C - 63,03; H - 4,48; N - 11.25 Per Cent.

Example 81.

N-[2,3-Dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepine-3-yl] - 3-(2,4-dichlorophenyl)propanamide

Stage A

< / BR>
To a solution of the benzodiazepine (1.0 g, 5.3 mmol) in THF (20 ml) at - 78oC in an argon atmosphere, added 60% NaH (2,52 g, 6.3 mmol), BOC-anhydride (1.27 g, 5.8 mmol) and the mixture stirred at - 78oC for 0.5 hours. Then reaction mixture was allow to warm to 25oC and stirred for 2 hours before to repay the reaction in the cold aq. NH4Cl (10%) and to carry out the extraction of the reaction product with ethyl acetate (3 x 50 ml). Concentration of the dried (Na2SO4) extracts gives an oil which is passed through dioxide , ,95 (sm, 1H), 4,80 (sm, 1H), 7,20 (m, 1H), 7,30 (K, 1H), 7,60 (t, 1H), 7,92 (d, 1H).

Stage B

< / BR>
To a solution of BOC-benzodiazepine (4.0 g, of 13.8 mmol) in THF (80 ml) in an argon atmosphere, to quickly add a solution of isopropylacrylamide (2.0 M) in THF (7,66 ml of 15.3 mmol). The reaction mixture is stirred for 0.5 hour, quenched reaction in aq. NH4Cl (50 ml) and extracted with ethyl acetate (CH ml). The organic extracts are concentrated and chromatographic on silica (1:1, EtOAc/hexane). Obtain 1.55 g (34%) of the reaction product.

1H NMR (CDCl3) : to 1.14 (d, 3H), 1,19 (d, 3H), of 1.40 (s, 9H), of 3.13 (s, 3H), of 3.2 to 3.8 (m, 3H), of 5.45 (SHS, 1H), 7,28 (dt, 1H), of 7.48 (dt, 1H), 7,56 (dt, 1H), 7,72 (doctor d, 1H).

Stage C

< / BR>
To a solution of Isopropylamine (1.55 g) in ethyl acetate at 0oWith add anhydrous gaseous HCl for 90 minutes. The reaction mixture was then concentrated under vacuum, and get a solid substance, which was dissolved in H2O (40 ml) and adjusted pH to 11.0 1N LiOH. After 30 minutes exposure at a pH of 11.0 pH adjusted to 7.0 1N HCl, and the reaction product is extracted with ethyl acetate. The organic extracts are dried (Na2SO4), filtered and concentrated receive solid (1.22 g, 100%).

1H NMR (CDCl3) : of 0.95 (d, 3H), of 1.30 (d, 3H), and 3.16 (septet, 1H), on 3.36 (s, 3H), 3,60 (d, 1H), 4,60 (d, method, described in example 80, step A.

Stage E

The oxime (2 g) dissolved in acetic acid (150 ml) and add 10% Pd/C (1 g). The mixture is rapidly stirred in an atmosphere of hydrogen for 90 min or until completion of the reaction by WEHR. The reaction mixture is filtered, washed catalyst with methylene chloride (200 ml) and the filtrates concentrated in vacuo to an oil. The oil is dissolved in a saturated aqueous solution of sodium bicarbonate (100 ml), and the reaction product is extracted with ethyl acetate (3 x 150 ml). Concentration of the dried (Na2SO4) extracts gives 2,60 g (97%) of the substance.

Stage F

Amin enter into reaction with 3-(2,4-dichlorophenyl)propionic acid as described in example 43, and get N-(2,3-dihydro-1-methyl-2 - oxo-5-isopropyl-1H-1,4-benzodiazepine-3-yl)-3-(2,4-dichlorophenyl)propanamide.

1H NMR (CDCl3) : to 0.92 (d, 3H), of 1.25 (d, 3H), 2,65 (dt, 2H), 3,05 (t, 2H), 3.15 in (septet, 1H), 3,40 (s, 3H), 5,38 (d, 1H), 7.0 and about 7.6 (m, 8H).

The following connections get the same way described in example 81, using instead of isopropylacrylamide the corresponding Grignard reagent.

Example 82

N-[2,3-Dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepin-3-yl] - 3-cyclohexylpropionic. So pl. 164-165oC.

CHN: Elemental N - 11,32.

Example 83

N-[2,3-Dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepine-3-yl] - 3-(4-triptoreline)propanamide. So pl. 187-188oC.

1H NMR (CDCl3) : to 0.92 (d, 3H), of 1.25 (d, 3H), of 2.66 (dt, 2H), 3.04 from (t, 2H), 3.15 in (septet, 1H), 3,40 (s, 3H), 5,38 (d, 1H), 7,14 (sm, 1H), 7,25-to 7.6 (m, 8H).

Using the methods described in example 80, but replacing stage E on the way to recovery, described below, receive the following compounds.

< / BR>
To a solution of oxime (1.28 g, 0,0048 mol) in H2O (130 ml) and THF (65 ml) add dithionite sodium (Na2S2O4) (13,0 g 0,075 mol). The mixture is stirred for 2 hours, then diluted with saturated aqueous sodium bicarbonate (50 ml), and extracted the product with ethyl acetate (CH ml). The organic extracts are combined, dried over Na2SO4filter and concentrate, and get the oil (~1.0 g). Oil chromatographic on silica, using ethyl acetate and then 10% methanol in methylene chloride, and get the pure amine (0,778 g, 64%).

1H NMR (DMSO) : of 3.32 (s, 3H), 4,30 (s, 1H), only 6.64 (d, d, 1H), 6,76 (d, 1H), 7,35 (dt, 1H), 7,58-7,74 (m, 3H), 7,88 (m, 1H).

Example 84

N-[2,3-Dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benzodiazepine-3-yl] - 3-cyclohexylpropionic. So pl. 168-169oC.

Found: C - 70,15; H IS 6.67; N - AT 10.64.

Example 85.

N-[2,3-Dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benzodiazepine-3-yl] - 3-(4-triptoreline)propanamide. So pl. 155-157oC.

CHN: Elemental analysis. Calculated for C24H20N3O3F3:

C - 63,29; H - 4,432; N - 9,23.

Found: C - 63,22; H - Of 4.44; N - 9,07.

Example 86.

N-[2,3-Dihydro-1-methyl-2-oxo-5-(2-furanyl)-1H-1,4-benzodiazepine-3-yl] - 3-(2,4-dichlorophenyl)propanamide. So pl. 132-133oC.

CHN: elemental analysis. Calculated for C23H19N3O3Cl2:

C - THEY ACCOUNTED FOR 60,54; H - 4,20; N - OF 9.21.

Found: C - 60,62; H - 4,07; N - 9,07.

Example 87.

N-[2,3-Dihydro-1-methyl-2-oxo-5-(3-furanyl)-1H-1,4-benzodiazepine-3-yl] - 3-cyclohexylpropionic. So pl. 199-200oC.

1H NMR (CDCl3) : 0,9-1,8 (BL, 3H), of 2.38 (t, 2H), 3,42 (s, 3H), 5,55 (sm, 1H), 6.90 to (s, 1H), 7,2-to 7.77 (m, 7H).

Example 88.

N-[2,3-Dihydro-1-methyl-2-oxo-5-(3-furanyl)-1H-1,4-benzodiazepine-3-yl] - 3-(4-triptoreline)propanamide. So pl. 213-214oC.

1H NMR (CDCl3) : a 2.71 (dt, 2H), 3,05 (t, 2H), 3,42 (s, 3H), 5,72 (d, 1H), 6,82 (SHS, 1H), of 7.2 to 7.7 (m, 11H).

Example 89.

N-[2,3-Dihydro-1-methyl-2-oxo-5-[2'-(4,4-dimethyl-2-oxazolyl)phenyl] - 1H-1,4-benzodiazepine-3-yl]-3-(2,4-dichloropheny/SUP>C.

CHN: Elemental analysis. Calculated for C30H28N4O3Cl2:

C - 63,95; H - 5,01; N - 9,94.

Found: C - 63,70; H - 5,01; N - 9,96.

Example 90.

N-[2,3,4,5-Tetrahydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepine - 3-yl]-3-cyclohexylpropionic

< / BR>
A solution of N-[2,3-dihydro-1-methyl-2-oxo-5-isopropyl-1H-1,4 - benzodiazepine-3-yl] -3-cyclohexylpropionate (50 mg) in methanol (10 ml) containing 10% Pd/C (50 mg) is stirred in hydrogen atmosphere (1 ATM) for 18 hours. Filtering the reaction mixture, concentration and crystallization from diethyl ether to give 21 mg of N-[2,3,4,5-tetrahydro-1-methyl-2-oxo-5-isopropyl-1H-1,4-benzodiazepine-3-yl]- 3-cyclohexylpropionic.

CHN: Elemental analysis. Calculated for C22H33N3O2:

C - 71,12; H - 8,95; N - 11,31.

Found: C - 70,98; H - 8,97; N - Of 11.15.

So pl. 114-115oC.

Example 91.

N-[2,3-Dihydro-1-methyl-2-oxo-5-methyl-1H-1,4-benzodiazepine-3-yl] -3- (2,4-dichlorophenyl)propanamide

Stage A

< / BR>
To CBZ-benzodiazepine (250 mg, 0,776 mmol) in toluene (25 ml) by boiling under reflux is added dropwise a solution of DMF-dimethylacetal (1,09 ml) in toluene (10 ml). The reaction mixture is boiled with reverse holodilny compound (124 mg).

1H NMR (CDCl3) : 2,50 (s, 3H), 3,42 (s, 3H), 5,12-5,20 (m, 3H), 6,62 (d, 1H), 7,25-6.4 (m, 7H), 7.5 to about 7.6 (m, 2H).

Stage

< / BR>
CBZ-amine-N-methylamide (190 mg) is treated with 30% HBr/AcOH (0.8 ml) for 1 hour at room temperature. The reaction mixture was poured into ether (10 ml) at 0oC, and filtered the solid. The solid is dissolved in 10% aqueous NaOH (5 ml) and CH2Cl2(10 ml), the organic layer separated, dried (Na2SO4), filtered and concentrated, receive oil (172 mg, 110%).

1H NMR (CDCl3) : to 2.42 (s, 3H), 3,05 (CL, 2H), 3,40 (s, 3H), and 4.40 (s, 1H), 7,2-7,6 (m, 4H).

Stage C

< / BR>
N-[2,3-Dihydro-1-methyl-2-oxo-5-methyl-1H-1,4-benzodiazepine-3-yl] - 3-(2,4-dichlorophenyl)propanamide get a manner similar to the method previously described in example 43.

So pl. 194-195oC.

CHN: Elemental analysis. Calculated for C20H19N3O2Cl2:

C - 59,42; H - 4,74; N - ACCOUNTED FOR 10.39.

Found: C - 59,50; H - 4,74; N - 10,44.

1H NMR (CDCl3) : 2,49 (CL, 3H), 2,65 (dt, 2H), 3,05 (t, 2H), 3,42 (s, 3H), to 5.35 (d, 1H), a 7.1 to 7.6 (m, 8H).

Example 92.

N-[2,3-Dihydro-1-methyl-2-oxo-[4,5-a] -(1-oxo-1,3-dihydro - 2H-isoindole)-1H-1,4-benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

< / BR>
To a solution of N-[2,3-dihydro-1-methyl-2-is inflorida gradually add methyltrichlorosilane (22 ml, 0,198 mmol). After stirring for 5 minutes add borohydride sodium (7,6 mg, 0.20 mmol) in absolute ethanol (0.5 ml) and the reaction mixture is stirred for 30 minutes, the reaction product is extracted with ethyl acetate and purified column chromatography on silica (60% ethyl acetate in hexane), and receive 30 mg of N-[2,3-dihydro-1-methyl-2-oxo-[4,5-a] -(1-oxo-1,3-dihydro-2H-isoindole)-1H-1,4-benzodiazepine-3-yl]-3-(2,4 - dichlorophenyl)propanamide.

1H NMR (CDCl3) : 2,70 (m, 2H), 3,12 (t, 2H), 3,55 (s, 3H), of 5.68 (s, 1H), 5,90 (d, 1H), 6,85 (DD, 1H), 7,05 (sm, 1H), and 7.1-7.5 (m, 9H), a 7.85 (d, 1H).

M - n-M+1- 494.

Example 93.

< / BR>
3R-(+)-3-(phenylthio)-N-[2,3-dihydro-1-methyl-2-oxo-5 - phenyl-1H-1,4-benzodiazepine-3-yl]propanamide

To a solution of 3-bromopropionic acid (1.0 g, 6.5 mmol) in DMF (20 ml) was added with stirring K2CO3(1/8 g, 13 mmol) and thiophenol (0,72 g, 6.5 mmol). The mixture is heated at 50oC for 1 hour. The mixture is then diluted with 200 ml of H2Oh and extracted with CH ml EtOAc. The combined organic extracts washed with 100 ml of H2O and dried over Na2SO4. The mixture is evaporated, and obtain 1.52 g of colorless oil, to be exact - 1.18 g, taking into account the residual DMF by NMR.

The above oil is dissolved in 30 ml of Amphizoa (1.73 g, 12.8 mmol). This mixture is stirred for 5 minutes at room temperature. Then add 3R-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine - 2-he (0.66 g, 2.6 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture is diluted with 200 ml of H2Oh and extracted with CH ml of ethyl acetate. The combined organic fractions washed with h ml H2Oh, dried over Na2SO4and evaporated. The remainder chromatographic on the silicon dioxide, elwira 2% MeOH in CHCl3. Collected pure fractions evaporated. After evaporation of the diethyl ether obtain 770 mg of a white foam.

Elemental analysis. Calculated for C25H23N3O2S 0.05 hexane:

C - 70,04; H - 5,51; N - RS 9.69.

Found: C - 69,91; H - Of 5.40; N - 9,78%.

Example 94.

< / BR>
3R-(+)-5-(Methylthio)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]propanamide

To a water solution of K2CO3(from 0.76 g, 5.5 mmol) is added 5-bromopentanoate acid and thiametoxam sodium. The mixture is stirred at room temperature overnight. The reaction mixture is diluted with 50 ml of H2O and acidified with 6N HCl to pH 0. Extracted with ethyl acetate h ml Dried over Na2SO4, evaporated and get 0,55 shall propyl)-3-ethylcarbodiimide (1,30 g, 6.8 mmol) and the hydrate of 1-hydroxybenzotriazole (0,92 g, 6.8 mmol). Then add 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H - 1,4-benzodiazepine-2-he of 0.85 g, 3.4 mmol) and the reaction mixture stirred at room temperature overnight. The reaction mixture is diluted with 100 ml of H2Oh and extracted with CH ml of ethyl acetate. The combined organic fractions washed with brine, dried over Na2SO4, evaporated, and receives a yellow oil. The remainder chromatographic on the silicon dioxide, elwira a mixture of EtOAc:hexane (50:50). Pure fractions are collected and the gain of 1.33 g of colorless oil, 0.4 g of which chromatographic on the silicon dioxide, elwira 2% MeOH in CH2Cl2. Pure fractions are collected and evaporated from ethyl ether and hexane, and get a white powder. So pl. 61-65oC.

Elemental analysis. Calculated for C22H25N3O2S 0,35 H2O:

C - 65,76; H - 6,45; N - 10,46.

Found: C - 65,81; H - 6,21; N - 10,57%.

Example 95.

< / BR>
N-Cyano-N'-cyclohexylmethyl-N ' -(1,3-dihydro-1-methyl-2 - oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)guanidine

A solution of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine - 2-it (1 g, 3.7 mmol) in acetonitrile (20 ml) is treated with diphenylcarbonate (0.9 g, 3.7 to the min (0.84 g, 7.4 mmol) and the reaction mixture stirred at room temperature for two hours. The reaction mixture was poured into 100 ml of 0.1 N HCl, and extracted with a mixture of three portions of ethyl acetate (100 ml). The organic layers are combined and washed once with saturated sodium bicarbonate solution (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel, elwira 50% ethyl acetate in hexane, and get 0,875 g of the reaction product. A sample crystallized from ethyl acetate.

So pl. 158-161oC.

Elemental analysis. Calculated for C25H28N6O:

C - 70,07; H - 6,59; N - 19,61.

Found: C - 70,05; H - 6,59; N - 19,64%.

Example 96.

< / BR>
The dihydrochloride of N-(1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepine - 3-yl)-4-(4-Chlorobenzyl)-4-piperazinecarboxamide

Stage A. Obtain N-tert-butoxycarbonyl-4-(4-Chlorobenzyl)-4 - piperidinecarboxylic acid

A solution of N-BOC-of utilisedictated (51,4 g, 200 mmol) in THF (1 l) at -60oC is treated with a solution liebestraume-silylamine (220 ml of 1N solution in THF, 220 mmol). After stirring at -60oC for 5 minutes, add a solution of 4-chlorobenzylchloride (33,8 g is THF (800 ml) is removed by evaporation under reduced pressure. The residue is poured into 1 l of 1N HCl and extracted with two portions (800 ml) ethyl acetate. The organic layers are combined and washed once with saturated sodium bicarbonate solution (500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel, elwira 10-20% ethyl acetate in hexane, and receive ester, which is used directly. Thus obtained substance was dissolved in THF (100 ml) and isopropyl alcohol (100 ml) and treated with 350 ml of 10N NaOH. The mixture is refluxed for 30 hours. The reaction mixture is cooled to room temperature and poured into a mixture of crushed ice (2 l), 6N HCl (500 ml) and saturated solution of potassium hydrosulfate (1 liter). The mixture is extracted with two portions (1 l) of ethyl acetate. The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 52 g of the reaction product.

So pl. 179-180oC.

1H NMR (CDCl3) : 7,26 (d, J = 8 Hz, 2H), 7,03 (d, J = 8 Hz, 2H), 3,98 (m, 2H), from 3.0 to 2.8 (m, 2H), 2,84 (s, 2H), 2,10-2,00 (m, 2H), 1,55-of 1.40 (m, 2H), 1,45 (s, 9H).

Stage Century. Getting dihydrochloride N-(1,3-dihydro-1-methyl-2-oxo - 5-phenyl-2H-1,4-benzodiazepine-3-yl)-4-(4-Chlorobenzyl)-4 - piperidine is 48 g, 4,18 mmol), 3-(R)-amino-1, 3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-it (1 g, 3.7 mmol), hydroxybenzotriazole (1,17 g, 8,66 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,49 g of 7.70 mmol), diisopropylethylamine (0,53 g of 4.13 mmol) and DMF (10 ml), stirred at room temperature for 18 hours. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate (4x50 ml). The organic layers are combined and washed once with saturated sodium bicarbonate solution (50 ml), once with saturated sodium chloride solution (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The remainder chromatographic on silica gel, elwira 25-50% ethyl acetate in hexane, and gain of 2.34 g of amide, which is directly used. Thus obtained substance was dissolved in ethyl acetate (50 ml) and the reaction mixture within 5 minutes miss HCl (gas). The reaction mixture was concentrated under reduced pressure, and the residue is recrystallized from ethyl acetate, to obtain 1.13 g of the reaction product in the form of a pale yellow solid.

So pl. 190-195oC.

Elemental analysis. Calculated for C29H29ClN4O42HCl:

C - 60,68; H - 5,44; N - 9,76.

Nai is pecocet substituted on the N-SIDE is utilipath, get the following connection.

Example 97.

< / BR>
Hydrochloride isomer A + hydrochloride isomer of N-(1,3-dihydro-1-methyl - 2-oxo-5-phenyl-2H-1,4-benzodiazepine-3-yl)-3-(4-Chlorobenzyl)-3 - piperidinecarboxylic

Isomer A

So pl. 205-210oC.

Elemental analysis. Calculated for C29H28ClN4O2HCl 0,5 CH3CH2OH 0,8 H2O:

C - 62,67; H - 6,07; N - 9,75.

Found: C - 62,69; H - 5,94; N - 9,42%

Isomer B

So pl. 200-205oC.

Elemental analysis. Calculated for C29H28ClN4O2HCl of 0.1 CH3CH2OH 1,6 H2O:

C - 61,39; H - 5,96; N - 9,74.

Found: C - 61,39; H - 5,66; N - 9,56%.

Example 98.

< / BR>
(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-N-(ethoxycarbonylmethyl)propanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-he (5.0 g, 18,8 mmol) in acetonitrile (100 ml) is mixed with ethylbromoacetate (2,1 ml of 18.8 mmol) and this mixture is suspended sodium bicarbonate (4.0 g). The mixture is stirred and refluxed for 2 hours. After that the reaction mixture is cooled to room temperature, diluted with 150 ml of water and extracted with ethyl acetate (CH ml). Organic is E. The resulting oil chromatographic on the silicon dioxide at a ratio of ethyl acetate and hexane 1:3, and get monoalkylamines product (2.38 g, 39%) as well as the source of 1,4-benzodiazepine-2-he balkrishna substance. To a solution of 3-cyclohexylpropionic acid (1.0 g, 6,40 mmol) in methylene chloride (30 ml) add axuiliary high (0.56 ml, 6,40 mmol) and catalytic amount of N,N-dimethylformamide (2 drops). After 0.5 hours, add a solution of acetate (2.25 g, 6,40 mmol) in methylene chloride (10 ml) and the reaction mixture stirred for 0.25 hour. Then the reaction mixture is diluted with methylene chloride (150 ml) and add saturated aqueous solution of sodium bicarbonate (150 ml). The water part is again shaken out with methylene chloride (CH ml) and the combined organic phases, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and get a foam which is crystallized from ether. Obtain 2.0 g (64%) of the reaction product.

So pl. 120-122oC []D+0,63(s=0,79, MeOH).

Elemental analysis. Calculated for C29H35N3O4:

C - OBU, essentially the same, which is described above, except that ethylbromoacetate replace ethylbromoacetate.

Example 99.

< / BR>
3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-N-(ethoxycarbonylmethyl)propanamide

So pl. 103-105oC []D00,0;=0,85; MeOH.

Elemental analysis. Calculated for C31H39N3O40,40 mol. H2O:

C - IS 70.94; H - TO 7.64; N - 8,01.

Found: C - 70,91; H - 7,44; N - 8,12%

Example 100.

< / BR>
N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - N-[2-(2-methoxyethoxy)ethyl]hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-he (to 1.33 g, 5.0 mmol) in N,N-dimethylformamide (30 ml) is mixed with 1-bromo-2-(2-methoxyethoxy)ethane (1.35 ml, 5.0 mmol) and triethylamine (1.0 ml). The mixture is stirred and refluxed for 4 hours. After that the reaction mixture is cooled to room temperature, diluted with 150 ml of water and extracted with ethyl acetate (CH ml). The organic layers are combined, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate automatic substance. To a solution of monoalkylamines substances (1.2 g, with 3.27 mmol) in methylene chloride (20 ml) add hexanoate (0,96 ml of 3.27 mmol) and the reaction mixture stirred for 0.25 hour. Then the reaction mixture is diluted with methylene chloride (150 ml), and added a saturated aqueous solution of sodium bicarbonate (150 ml). The water part is again shaken out with methylene chloride (CH ml) and the combined organic phases, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and get the oil, giving 580 mg (38%) of the reaction product.

[]D00,0;=0,27, MeOH.

Elemental analysis. Calculated for C27H35N3O40,80 mol. H2O:

C - 67,56; H - 7,69; N IS 8.75.

Found: C - 67,56; H - 7,39; N Cent To 8.85%.

Example 101.

< / BR>
(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - N-(5-hydroxyphenyl)hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-he (to 1.33 g, 5.0 mmol) in acetonitrile (40 ml) is mixed with 5 - chloropentane-1-I (and 0.61 g, 5.0 mmol) and this mixture is suspended sodium bicarbonate (2.0 g). The mixture is stirred and curatory, diluted with 100 ml of water and extracted with ethyl acetate (CH ml). The organic layers are combined, dried over magnesium sulfate, filtered on a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on the silicon dioxide at a ratio of methanol and chloroform 1:49, and get monoalkylamines product (1.1 g, 62%) as well as the source of 1,4-benzodiazepine-2-he balkrishna substance. To a solution of monoalkylamines substances (0.50 g, of 1.42 mmol) in methylene chloride (30 ml) add hexanoate (0,20 ml of 1.42 mmol) and the reaction mixture stirred for 0.25 hour. Then the reaction mixture is diluted with methylene chloride (100 ml), and added a saturated aqueous solution of sodium bicarbonate (100 ml). The aqueous portion extracted with methylene chloride (CH ml) and the combined organic phases, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and get the foam, giving 360 mg (64%) of the reaction product. Foam, []D+at 8.36(c = 0,61, MeOH).

Elemental analysis. Calculated for C27H35N3O20,25 mol. H2O:

C - 71, the Il-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - N-(ethoxycarbonylmethyl)hexanamide

3-(R)-Amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-he (to 1.33 g, 5.0 mmol) in acetonitrile (40 ml) is mixed with ethyl-6-bromhexinum (0,89 ml, 5.0 mmol) and this mixture is suspended sodium bicarbonate (2.0 g). The mixture is stirred and refluxed for 10 hours. After that the reaction mixture is cooled to room temperature, diluted with 100 ml of water and extracted with ethyl acetate (CH ml). The organic layers are combined, dried over magnesium sulfate, filtered on a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on the silicon dioxide at a ratio of methanol and chloroform 1: 49, and get monoalkylamines product (0.56 g, 28%) as well as the source of 1,4-benzodiazepine-2-he balkrishna substance. To a solution of monoalkylamines substances (0.56 g, 1.37 mmol) in methylene chloride (20 ml) add hexanoate (to 0.19 ml, 1.37 mmol) and the reaction mixture stirred for 0.25 hour. Then the reaction mixture is diluted with methylene chloride (100 ml), and added a saturated aqueous solution of sodium bicarbonate (100 ml). The water part is again shaken out with methylene chloride (CH ml) and the combined organic phases, dried over sulfa the slo chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and get the foam, giving 0.40 g (58%) of the reaction product.

So pl. 59-65oC []D+52,7(c=0,48, MeOH)

Elemental analysis. Calculated for C30H39O40,20 mol. CH2Cl2:

C - 69,4; H - 7,6; N - 8,04.

Found: C - 69,44; H - To 7.68; N - 7,71%.

The following connection receive the same manner described above except that ethyl-6-bromhexina replace ethylbromoacetate.

Example 103.

< / BR>
(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - N-(ethoxycarbonylmethyl)hexanamide

Foam, []D+2,04(C=0,98; MeOH).

Elemental analysis. Calculated for C26H31N3O4:

C - 69,47; H - 6,95; N - 9,35.

Found: C - 69,41; H - 7,03; N - 9,26%.

Example 104.

< / BR>
(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl]-N-(hydroxymethyl)propanamide

(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4 - benzodiazepine-3-yl] propanamide (2.0 g, 5.0 mmol) dissolved in tetrahydrofuran (30 ml), cool the solution to 0oC, and add methylaniline (3M, 2.0 ml). After 0.25 hour add paraformaldehyde (0.15 g, 10 mmol) and the mixture allow to warm to room temperment sodium (150 ml). The water part is again shaken out with ethyl acetate (CH ml) and the combined organic phases, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and get the foam (0,80 g, 37%).

Foam, []D+124(C=0,69; MeOH).

Elemental analysis. Calculated for C26H31N3O3:

C - 72,03; H - 7,21; N - RS 9.69.

Found: C - 71,66; H - 7,08; N - 9,78%.

The following connection get the same way described above, but on the basis of (+)-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]hexanamide.

Example 105.

< / BR>
(+)-N-[2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl] - N-(hydroxymethyl)hexanamide

So pl. 154-156oC []D+190,8(=to 0.24, MeOH).

Elemental analysis. Calculated for C23H27N3O30,30 mol. H2O:

C - 69,26; H - 6,97; N -10,53.

Found: C - 69,29; H - For 6.81; N -10,6%.

Example 106.

< / BR>
(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H - 1,4-benzodiazepine-3-yl]-N-(tetrazolyl)propanamide

(+)-3-Cyclohexyl-N-[2,3-dihydro-1-methyl-2-the ml) together with tetrazole (0.33 g, 4.7 mmol), and then add N, N-diisopropylchlorophosphoramidite (1.07 g, 3.1 mmol). After 2 hours the mixture is diluted with methylene chloride (150 ml) and extracted with saturated aqueous sodium hydrogen carbonate (g ml).

The organic layers are combined, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic twice on silica with a mixture of ethyl acetate hexane (1:1), and receive two structural isomer - isomer And (65 mg, 9%) and isomer B (56 mg, 7.5 per cent).

Isomer A

So pl. 96-98oC []D+188,9(=to 0.19, MeOH).

Elemental analysis. Calculated for C27H31N7O20,30 mol. TFA (TFA):

C - 63,78; H - 6,07; N - 18,86.

Found: C, Or 63.7; H - 6,12; N - 18,76%.

Isomer B

So pl. 92-95oC []D+81,3(c=0,31, MeOH).

Elemental analysis. Calculated for C27H31N7O20,35 mol. TFK:

C - 63,31; H - 6,01; N - 18,66.

Found: C - 63,35; H - Of 6.02; N - 18,74%.

Example 107.

< / BR>
3R-(+)-3-(Benzyloxycarbonylamino)-2,3-dihydro-1-methyl-2-oxo-5 - phenyl-1H-1,4-benzodiazepine

To a solution of 3-(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine - 2-she (2.0 g, allow to warm to room temperature. The reaction mixture is diluted with methylene chloride (150 ml) and extracted with saturated aqueous sodium hydrogen carbonate (150 ml). The aqueous portion extracted with methylene chloride (CH ml) and the combined organic phases, dried over magnesium sulfate, filtered through a gravity filter, and remove solvent under vacuum. The resulting oil chromatographic on silica with a mixture of ethyl acetate hexane (1:1), and receive a white foam (3.0 g, 99.7 per cent).

[]D+57,5(C=1,17, MeOH).

Elemental analysis. Calculated for C24H20N3O30,70 mol. H2O 0,15 mol. CHCl3:

C - 67,62; H - IS 5.06; N - 9,8.

Found: C - 67,6; H - 5,02; N Is 9.75%.

The following compounds get essentially as described in example 81.

Example 108.

N-[2,3-Dihydro-1-methyl-2-oxo-5-ethyl-1H-1,4-benzodiazepine-3-yl] -3- (2,4-dichlorophenyl)propanamide

So pl. 156-158oC.

CHN: Elemental analysis. Calculated for C21H21Cl2N3O20.5 H2O:

C - 59,02; H - 5,19; N - 9,83.

Found: C - 58,99; H - 4,89; N - 9,88%.

Example 109.

N-[2,3-Dihydro-1-methyl-2-oxo-5-tert-butyl-1H-1,4-benzodiazepine-3-yl] - 3-(2,4-dichlorophenyl)propanamide

So H2O:

C - 60,18; H - 5,80; N - 9,16.

Found: C - 60,17; H - And 5.30; N - Of 9.30%.

Example 110.

N-[2,3-Dihydro-1-methyl-2-oxo-[4'-(4,4-dimethyl-2-oxazolyl)phenyl] - 1H-1,4-benzodiazepine-3-yl]-3-(2,4-dichlorophenyl)propanamide

So pl. 188-190oC.

CHN: Elemental analysis. Calculated for C30H28Cl2N4O3:

C - 63,95; H - 5,01; N - 9,94.

Found: C - 63,96; H - 5,02; N - 10,08%.

Example 111.

N-[2,3-Dihydro-1-methyl-2-oxo-5-(4-methoxyphenyl)-1H-1,4-benzodiazepine - 3-yl]-3-(2,4-dichlorophenyl)propanamide

So pl. 188-189oC.

CHN: Elemental analysis. Calculated for C26H23Cl2N3O30,45 H2O:

C - 62,91; H - 4,67; N - OF 8.47.

Found: C - 61,89; H - 4,78; N - 8,33%.

1. A method of treating arrhythmia, characterized in that it comprises the administration to a patient in need of such treatment, an effective amount of a compound of structural formula I

< / BR>
its individual diastereoisomers, enantiomers and mixtures thereof, or its pharmaceutically acceptable salt,

where a represents ceanography, peridogram or anthropo, or unsubstituted or substituted-NH2, -NHSO2, (C1-3-alkyl), C1-3-alkyl or C1-3-alkoxygroup;

X prawley a C1-6-alkylene, or a linear or branched chain and either unsubstituted or substituted by phenyl or spiroperidol, C2-4-albaniles, or a linear or branched chain; -(CH2)m-W-(CH2)nwhere m and n are equal, independently, 0, 1, 2, 3 or 4, and W represents-O-, -S - or-NH, 4-(5-methylisoxazol-3-yl), C3-6-cycloalkyl or a simple bond;

p = 0 or 1;

R1represents phenyl, either unsubstituted or substituted by one or two substituents selected from Cl, Br, F, I, -CF3; C5-7-cycloalkyl,

< / BR>
mono - or bicyclic a heterocycle with 5 to 10 ring atoms, of which one or two atoms are sulfur, nitrogen or oxygen, and the remainder are carbon atoms, such as 2-thienyl, 2-furanyl, 2-indolyl, 2-honokalani or 2-(2,3-dihydrobenzofuranyl); methyl or indan-5-yl;

R2represents phenyl, either unsubstituted or substituted C1-3-alkoxygroup or 4,4-dimethyloxazole-2-yl, C1-6-alkyl, or linear or branched chain and either unsubstituted or substituted C1-3-alkoxygroup or C1-3-alkoxygroup, C5-7-cycloalkyl, 2 - or 3-furyl, 1-methylpiperidin-2-yl, or if R2is onilne group, and the double bond between the nitrogen-4 and carbon-5 is a simple link;

R3represents hydrogen or C1-3-alkyl, either unsubstituted or substituted by-N(CH3)2, -OH, -CF3or-CF3;

R4represents hydrogen, C1-6-alkyl, in which the chain of carbon atoms may be interrupted by one or two not located near the oxygen atoms, and which is either unsubstituted or substituted C1-3-alkoxycarbonyl, -OH or or tetrazol-5-yl; and

R5represents hydrogen or oxygen, or attached to R2with the formation of partial patterns

< / BR>
and the relationship depicted represents a double bond when R = 0, or when p = 1, and R5represents oxygen, or a simple link, when R5represents hydrogen, or R5connect with R2with the formation of partial patterns

< / BR>
2. The method of treatment under item 1, characterized in that a represents anthropo; X and Y represents oxygen; R3represents methyl; R4represents hydrogen; and R2represents a C1-6-alkyl.

3. The method according to p. 2, characterized in that the compound is chosen among logical;

R2represents methyl, ethyl, tert.butyl; isopropyl, with the proviso that when R1represents 2,4-dichlorophenyl, R2represents methyl, ethyl, isopropyl or tert.butyl; when R1is a 4-triptoreline, R2represents isopropyl; when R1represents cyclohexyl, R2represents isopropyl.

4. The method of treatment under item 1, characterized in that a represents anthropo; X and Y represent oxygen; R3represents methyl; R4represents hydrogen and R2represents phenyl.

5. The method according to p. 4, characterized in that the compound is a compound of the formula

< / BR>
in which Z represents a C1-6-alkylen or bond, and R1represents phenyl, phenyl, substituted-Cl, -Br, -I, -F or-CF3or R1represents cyclohexyl.

6. The method according to p. 5, where the compounds are selected from compounds of General formula

< / BR>
where Z is a simple bond or a group-CH2-, -(CH2)2-, -(CH2)3-;

R1represents 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-differenl, 2-chlorophenyl, 4-trif is that when Z is a group -(CH2)2-, R1represents 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-differenl, 2-chlorophenyl, 4-triptoreline, 3-triptoreline, 2-triptoreline, cyclohexyl, phenyl, 3-chlorophenyl, 2-thienyl; when Z represents a group-CH2-, R1is a 4-triptoreline, cyclohexyl or phenyl; when Z represents a group -(CH2)3-, R1represents a cyclohexyl or phenyl; when Z is a simple bond, R1represents cyclohexyl.

7. The method according to p. 4, wherein the compound has the structural formula

< / BR>
where Z represents a C2-4-albaniles and R1represents phenyl or phenyl substituted-Cl, -Br, -F, -I, -CF3.

8. The method according to p. 7, characterized in that the compound is chosen among compounds of the formula

< / BR>
where Z represents a group: -CH=CH - or

R1represents 2,4-dichlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-differenl, 2,6-dichlorophenyl, 4-triptoreline, 2-bromophenyl, 4-iopener, 4-bromophenyl, phenyl, 3,4-dichlorophenyl, 3-bromophenyl; provided that when Z represents a group R1represents phenyl.

9. The method according to p. 1, otlichay compounds of the formula

< / BR>
where a represents a benzo or lianoglou;

R1represents 2,4-dichlorophenyl, 3-were, methylcyclohexyl, 5-indanyl;

R2represents phenyl, 2-piperidyl;

R3is a 2-hydroxypropyl, methyl, n-propyl;

Y represents oxygen or a group =N-CN, provided that when R1represents 2,4-dichlorophenyl, And is a benzo, R2represents phenyl, R3represents methyl, Y represents oxygen; when R1is methylcyclohexyl, And is a benzo, R2represents phenyl, R3represents methyl, Y represents a group =N-CN; when R1represents a 5-indanyl, And is a benzo, R2represents phenyl, R3is a 2-hydroxypropyl, Y represents oxygen; And when is ceanography, R1is a 3-were, R2represents phenyl, R3represents methyl, Y represents oxygen.

11. Derivatives of diazepine General formula

< / BR>
where a represents a benzo or peridogram;

R4urali;

Y represents oxygen or H2;

-Z-R1represents (1,1-dimethylethoxysilane)Spiro (cyclohexane)-4,4'-piperidinyl, 5-methyl-3-phenyloxazolyl, pentyl, honokalani, diphenylmethyl, phenylthiomethyl, vinylcyclopropyl, (2,4-dichlorophenylthio)methyl, (2,4-dichlorophenyl)ethyl, cyclohexylethyl, (4 nitrophenoxy)methyl, (4-chlorophenyl)ethyl; with the proviso that when a represents a benzo, R4represents hydrogen, X represents oxygen, Y represents oxygen,- Z-R1represents (1,1-dimethylethoxysilane)-Spiro(cyclohexane)-4,4'-piperidinyl, phenylthiomethyl, vinylcyclopropyl, (2,4-dichlorophenylthio)methyl, 5-methyl-3-phenyloxazolyl, pentyl, honokalani, diphenylmethyl; when a represents peridogram, R4represents hydrogen, X represents oxygen, Y represents oxygen,- Z-R1represents (2,4-dichlorophenyl)ethyl or cyclohexylethyl; when R4represents the group a represents a benzo, X represents oxygen, Y represents H2-Z-R1represents a group (4 nitrophenoxy)methyl; when a represents a benzo, R4represents hydrogen, X represents the sludge; when a represents a benzo, R4represents hydrogen, Y represents oxygen, -Z-R1is cyclohexylethyl, X represents a group =N-OH in the E - and Z-configuration.

12. Pharmaceutical composition having anti-arrhythmic activity, containing a pharmaceutically acceptable carrier and an effective amount of the compounds under item 11.

13. Derivatives of diazepine General formula

< / BR>
where Z represents a C1-6-alkylen or bond, and R1represents phenyl, phenyl, substituted-Cl, -Br, -I, -F, -CN or - CF3, cyclohexyl or 2-thienyl.

14 Connection on p. 13, where Z is a simple bond or a group: -CH2-, -(CH2)2-, -(CH2)3-, R1represents 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-differenl, 2-chlorophenyl, 4-triptoreline, 3-triptoreline, 2-triptoreline, cyclohexyl, phenyl, 4-cyanophenyl, 3-chlorophenyl, 3-cyanophenyl, 2-thienyl, provided that when Z is a group -(CH2)2-, R1represents 2,4-dichlorophenyl, 4-chlorophenyl, 2,4-differenl, 2-chlorophenyl, 4-triptoreline, 3-triptoreline, 2-triptoreline, cyclohexyl, phenyl, 4-cyanophenyl, the em a 4-triptoreline, cyclohexyl or phenyl; when Z represents a group -(CH2)3, R1represents a cyclohexyl or phenyl; when Z is a simple bond, R1represents cyclohexyl.

15. Connection on p. 14 General formula

< / BR>
16. Derivatives of diazepine General formula

< / BR>
where Z represents a C2-4-albaniles and R1represents phenyl, phenyl, substituted-Cl, -Br, -F, -I, -CF3C1-3-alkyl, C1-3-alkoxygroup, nitrogroup or methylendioxyphenyl, provided that Z is not-CH= CH-, when R1represents phenyl.

17. Connection on p. 16, where Z represents a group: -CH=CH -, or R1is a 4-nitrophenyl, 2,4-dichlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,4-differenl, 2,6-dichlorophenyl, 4-triptoreline, 2-bromophenyl, 4-iopener, 4-bromophenyl, phenyl, 3,4-dichlorophenyl, 4-were, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 3-bromophenyl; provided that when Z represents a group R1represents phenyl.

18. Connection on p. 17 General formula

< / BR>
19. Connection on p. 17 General formula

< / BR>
20. Derivatives of diazepine General formula

< / BR>
where R1represents phenyl, which>or C5-7-cycloalkyl; and

R2represents a C1-6-alkyl or their pharmaceutically acceptable salts.

21. Connection on p. 20, where R1represents 2,4-dichlorophenyl, 4-triptoreline, cyclohexyl; R2represents methyl, ethyl, tert. butyl, isopropyl, with the proviso that when R1represents 2,4-dichlorophenyl, R2represents methyl, ethyl, isopropyl or tert.butyl; when R1is a 4-triptoreline, R2represents isopropyl; when R1represents cyclohexyl, R2represents isopropyl.

 

Same patents:

The invention relates to derivatives of 3-acylamino-5-phenyl-1,4-benzodiazepine-2-it, and to their salts, retrieval method and intermediate products for their production

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 new derivatives of 1,4-benzodiazepine General formula I, where R1is bromine, R2-CH3O NHNH2, R3-H, halogen, has a selective anxiolytic activity predominantly activating component

The invention relates to ortho-substituted heterocyclyl-benzoyl-guanidine formula (I)

< / BR>
where R1denotes A, CF3CH2F, CHF2C2F5, CN, NO2, Gal, CCH, or-X-R4;

R2and R3each, independently of one another, denote H, Gal A, -X-R4, CN, NO2, CF3CH2F, CHF2C2F5CH2CF3, -SOn-R6, -SO2NR4R5Ph or OPh;

R4denotes H, a, cycloalkyl with 5-7 C atoms, cycloalkenyl with 6-8 C atoms, CF3CH2F, CHF2CH2CF3Ph or-CH2-Ph;

R5denotes H or A, or, however,

R4and R5together also denote alkylene with 4-5 C atoms, and one CH2the group may also be replaced by O, S, NH, N-A or N-CH2-Ph;

R6denotes A or Ph;

Het denotes a dual core, saturated, unsaturated or aromatic heterocycle with 1 to 4 N, O and/or S atoms, linked via N or C, which is unsubstituted or may be substituted by one, two or three times with Gal, CF3, A, -X-R4, CN, NO2and/or carbonyl oxygen;

A stands for Ala is atno replaced with A, OA, NR4R5, Gal or CF3phenyl;

"n" is 1 or 2; and

Gal denotes fluorine, chlorine, bromine or iodine,

and their physiologically acceptable salts
The invention relates to medicine, cardiology

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension and hypertensive crisis

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

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.

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