Imidazolidine, the way they are received and drug

 

(57) Abstract:

Describes imidazolidine General formula I, where the values of A, Q, R1, R2, R3, R4specified in paragraph 1 of the claims, which have a pronounced anxiolytic, anticonvulsant, muscle-relaxante and sedative-hypnotic properties. They form distinguished by good solubility of the additive, acid salts, and it may be effectively used in the manufacture of aqueous solutions for injection of drugs on the basis of the compounds of formula I. also Describes the method of obtaining the above-mentioned compounds. 3 C. and 24 C.p. f-crystals, 1 PL.

The invention relates to imidazolidine General formula

< / BR>
where A together with the two identified through carbon atoms denotes one of the radicals

< / BR>
Q denotes one of the radicals

< / BR>
R1and R2denote each respectively hydrogen, (lower)alkyl, (lower) alkenyl, (lower)quinil, (lower)hydroxyalkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(lower)alkyl, amino (lower)alkyl, (lower) alkylamino(lower)alkyl, di-(lower)alkylamino (Nissi(lower)alkoxygroup, or R1and R2together with the nitrogen atom to which they are bound, form a 5-8-membered heterocycle, which may optionally contain another heteroatom of oxygen, or 5-8-membered heterocycle containing as the heteroatom nitrogen and linked by condensation with a benzene ring;

R3denotes hydrogen and R4represents (lower)alkyl, or R3and R4both together represent di - or trimethylene group and

R5and R6denote each respectively a hydrogen, halogen, trifluoromethyl, (lower) alkoxy or nitro, and indicated via a carbon atom has the S-configuration, if R3has a value other than hydrogen,

and their pharmaceutically acceptable acid additive salt.

These compounds and their salts are new and possess valuable pharmacological properties. Because of this they can find effective application in therapeutic use, primarily as an anxiolytic and/or anticonvulsant and/or muscle-relaxant and/or sedative-hypnotics.

The object of the present invention are the above compounds of formula I and their salts as such, as well as therape sootvetstvujushij medicines, containing one of the compounds of formula I or its salt, and the manufacture of such drugs.

The definition of "lower" denotes radicals or compounds with the number of carbon atoms and a maximum of 7, preferably a maximum of 4. The term "alkyl" denotes a linear or branched saturated hydrocarbon radicals, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl and tert.-butyl. The term "alkoxy" refers to linked through the oxygen atom of the alkyl group, such as methoxy, ethoxy. The concept of "cycloalkyl" denotes a saturated cyclic hydrocarbon radicals, such as, for example, cyclopropyl. The concept of "alkenyl" and "quinil" refers to linear or branched hydrocarbon radicals containing C-C double or triple bond, such as allyl, but-2-enyl, 3-methyl-but-2-enyl, propargyl, etc., the Term "aryl" in this case denotes substituted by halogen trifluoromethyl, lower alkyl or lower alkoxy phenyl radical. The term "halogen" includes fluorine, chlorine, bromine and iodine. When R1and R2together with the nitrogen atom represent a heterocycle, it is of such radicals, such as 1-pyrrolidinyl, 1-pyrrolidyl, piperidino, 2,6-dimethylpiperidino, 3,3-dimethylpiperidino, the Q in the formula I preferably denotes a radical of the formula Q2or a radical of the formula Q3. R1and R2denote each, respectively, preferably (lower) alkyl, (lower) hydroxyalkyl or (C3-C6) cycloalkyl (lower) alkyl or together with the nitrogen atom represent piperidine or isoindoline-2-yl. A preferably denotes a radical of the formula A1where R5represents hydrogen, chlorine, fluorine, trifluoromethyl or (lower) alkoxy and R6represents hydrogen or fluorine, or a radical of the formula A2. And, finally, R3means is preferably hydrogen and R4preferably methyl, or R3and R4indicate both dimetilan.

Particularly preferred compounds of formula I include:

3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-8 - fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

(S)-8-chloro-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12 - dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-he;

(S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-11,11-dihydro - 8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he;

8-fluoro-5-methyl-3-[5-(piperidine-1-ylmethyl)-1,2,4-oxadiazol-3-yl] - the 15.6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl) shall eazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

(S)-8-chloro-1-[5-(piperidine-1-yl)methyl-1,2,4-oxadiazol-3-yl] -12,12 - dihydro-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-he;

7-fluoro-5-methyl-3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

7-chloro-3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

(S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro - 8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he;

(S)-1-(5-dibutylamino-1,3,4-oxadiazol-2-yl)-11,11 a-dihydro - 8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he;

3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it; and

3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

Other examples of preferred compounds within the present invention are followed by EPIN-9-he;

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl - 12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-he;

3-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-he;

8-fluoro-3-(5-isoindoline-2-ylmethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro - 18H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-he;

3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-he;

3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-7 - trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-it; and

(S)-8-chloro-1-(5-dipropylamino-1,3,4-oxadiazol-2-yl) -12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he.

According to the invention the compounds of formula I, where R denotes one of the radicals Q2or Q3can be obtained by the method lies in the fact that a)

The above compounds of formula I and their pharmaceutically applicable additive salts of the acids can be obtained according to the invention due to the fact that a) reactive functional carboxylic acid derivative of General formula the crystals

< / BR>
where A, R3and R4are specified in paragraph (1 value, a R11and R21denote each respectively aminosidine group, (lower)alkyl, (lower)alkenyl, (lower)quinil, protected hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(lower) alkyl, protected amino(lower)alkyl, protected (lower)alkylamino (lower)alkyl, di(lower)alkylamino(lower)alkyl, phenyl (lower)alkyl, where phenyl may be substituted with halogen, trifluoromethyl, (lower) alkyl or (lower) alkoxygroup, or R11and R21together with the nitrogen atom to which they are bound, form a 5-8-membered heterocycle, which may optionally contain another heteroatom of oxygen, or 5-8-membered heterocycle containing as the heteroatom nitrogen and linked by condensation with a benzene ring, or a protective group and, if necessary, the resulting product conducts the removal of existing protective groups

and, if necessary, the obtained target product of the formula Ia

< / BR>
where A, R3and R4are specified in paragraph 1, the value of Q means Q2or Q3, a R12denotes hydrogen, (lower) alkyl, (lower)Alka/SUB>-C6)cycloalkyl-(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di-(lower)alkylamino(lower)alkyl or phenyl(lower)alkyl, where phenyl may be substituted with halogen, trifluoromethyl, (lower) alkyl or (lower) alkoxygroup, appropriately N-alkylate,

and/or, if necessary, the obtained target product of formula Ib

< / BR>
where A, R3and R4are specified in paragraph 1, the value of Q means Q2or Q3and R12has the above meaning and R22represents (lower) alkenyl or (lower) quinil,

restore, and/or obtained the desired product of formula I is transferred to pharmaceutically acceptable acid additive salt.

The compounds of formula I can also be obtained by a variant of the method

(a) consists in the fact that the reactive functional carboxylic acid derivative of General formula

< / BR>
subjected to interaction with amidoximes General formula

< / BR>
or hydrazide of General formula

< / BR>
where A, R3and R4have the above value, a R11and R21denote each, respectively (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)alkoxy(lower)alkyl,for aryl(lower)alkyl, or together with the nitrogen atom denote a 5-8-membered, another heteroatom of oxygen or 5-8-membered heterocycle containing as the heteroatom nitrogen and linked by condensation with a benzene ring.

In addition, the compounds of formula I can be obtained by methods according to which the (b) compound of General formula

< / BR>
where A, R3and R4have the above meaning and X denotes tsepliaeva group, in the presence of a base is subjected to interaction with isonitriles General formula

< / BR>
where Q, R11and R21have the above significance, or

in connection with the General formula

< / BR>
where A, Q, R3and R4have the above value, a Y indicates tsepliaeva group, is subjected to the interaction with the amine of General formula

< / BR>
where R1and R2have the above significance, or

g) the compound of General formula

< / BR>
where A, Q, R3and R4have the above significance, and R7denotes a protective group, protected (lower) hydroxyalkyl, protected amino (lower) alkyl

or protected (lower)alkylamino(lower)alkyl and R8denotes hydrogen, (lower)alkyl, (lower)alkenyl, (lower)quinil protected(lower) Herkel, protected amino(lower)alkyl, protected (lower)alkylamino (lower)alkyl, di(lower) alkylamino(lower)alkyl or aryl(lower)alkyl, or R7and R8both together represent a protective group, the protective group (n) otscheplaut, or

d) the compound of General formula

< / BR>
where A, Q, R3and R4have the above significance, and R12denotes hydrogen, (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)hydroxyalkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino (lower)alkyl or aryl(lower)alkyl appropriately N-alkylate, or

e) a compound of General formula

< / BR>
where A, Q, R3and R4and R12have the above value, a R22indicates the lowest alkenyl or lower quinil, restore and, if necessary

g) the compound of General formula I translate into pharmaceutically acceptable acid additive salt.

According to the options) method the compounds of formula I, where R1and R2denote each, respectively (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)alkoxy(lower)alkyl, (Cthe Rhyl (lower) alkyl or together with the nitrogen atom represent videopreteen a heterocycle, get as a result of education oxadiazole radical q

However, based on the compounds of formulas II and IV, there is a radical Q1on the basis of compounds of formulas III and V, the radical Q2and, based on the compounds of formulas II and VI, or formula III and VII - radical Q3.

As reactive functional derivatives of carboxylic acids of formulas II and III, it is advisable to use appropriate imidazoline, which can be obtained by known methods from the corresponding free carboxylic acids, for example, interaction with 1,1'-carbonyl diimidazol in an inert organic solvent such as N,N-dimethylformamide.

As reactive functional derivatives can be used, furthermore, for example, carboxylic acid anhydrides, which can be obtained from the corresponding free carboxylic acids with thionyl chloride.

The interaction of reactive functional derivatives of carboxylic acids of the formula II or III with amidoximes formula IV, respectively, of formula V, it is advisable to carry out by heating for 20 several hours at a temperature of about 70-130oCC in an inert solvent is Ansatie preferably not allocated, and spontaneously cyclist under the reaction conditions.

The interaction of reactive functional derivatives of carboxylic acids of the formula II or III with a hydrazide of formula VI, respectively, of formula VII, it is advisable to carry out at room temperature in an inert organic solvent such as N,N-dimethylformamide. The resulting nettlesbey the condensation product may be selected, after which it can be cichlisuite, preferably using polyphosphoric acid by heating for from one to several hours at a temperature of about 100oCC.

According to variant b) method, you also get the compounds of formula I, where R1and R2denote each, respectively (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(lower)alkyl, di(lower)alkylamino(lower)alkyl or aryl (lower)alkyl or together with the nitrogen atom form videopreteen a heterocycle. Denoted by X in the formula VIII leaving group is, for example, easily ottsepleny residue derived phosphoric acid, for example, a group of the formula

-O-PO(ORa)2or-O-PO(NRbRcoCC to room temperature.

According to variant b) of the method are the compounds of formula I, where R is t preferably a halogen atom, mainly chlorine atom or bromine, or represents an easily tsepliaeva sulfonyloxy, such as methanesulfonate, benzosulfimide, p-toluensulfonate, or other similar group. The interaction of the compounds of formula X with an amine of formula XI is carried out in the presence of an inert solvent, such as N, N-dimethylformamide and in the presence of a base, preferably organic bases, for example tertiary amines, such as N-ethyldiethanolamine, or any other, similar, and as the organic base may also serve as an excess of amine of formula XI.

Under option g) method and additional optional stage a) obtain the compounds of formula I, where R1denotes hydrogen, (lower) hydroxyalkyl, amino(lower)alkyl or (lower)alkylamino(lower) alkyl, a R2denotes hydrogen, (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)hydroxyalkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(lower)alkyl, amino(lower)alkyl, (lower) alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl or aryl(lower)alkyl. Appropriate protective groups, as well as METAIRIE group, which can be chipped off using methods that do not have a negative impact on other structural elements in the compounds of formula XII.

As the N-protective group can be used, for example, tert.- butoxycarbonyl group (BOC), which can be split using triperoxonane acid.

As the O-protective group can be used, for example, tert.- butyl group (tBu), to split which you can also use triperoxonane acid.

If R7and R8both together represent a protective group, the radical-NR7R8means, for example, phthalimidopropyl that using methylamine can be split up to NH2group.

Under option d) method and additional optional stage of the way and get the compounds of formula I where at least one of R1and R2has a value other than hydrogen. Appropriate alkylating funds, as well as methods of alkylation, known to every expert. As alkylating means can be used, preferably the corresponding halides, such as propyl bromide, propyliodide, utilidad, allylbromide, brothelbased, 4-bromo-1-butts the latest NH2group can be converted into isoindoline-2-silt group). The alkylation is carried out in the presence of a base, preferably an organic base, such as N-ethyldiethanolamine, 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) or any other similar. Alkylation should be carried out in an inert solvent, such as N, N-dimethylformamide.

Under option e) method and additional optional stage of the way and get the compounds of formula I where at least one of R1and R2represents (lower)alkyl, from corresponding compounds of formula I where at least one of R1and R2represents (lower) alkenyl or (lower) quinil, i.e., from compounds of formula 1b, namely, by restoring the C-C double, triple bond, respectively. This restoration is carried out preferably by catalytic hydrogenation, for example, in the presence of a palladium catalyst such as Pd/C. the reduction is carried out in an inert solvent, such as ethyl acetate.

Under option f) method of the compounds of formula I can be converted into pharmaceutically acceptable acid salt additive. While we are talking about how the salt neorganics, nitrates, citrates, acetates, maleate, succinate, methanesulfonate, p-toluensulfonate, etc., These salts can be obtained by conventional, well-known to every expert methods.

The initial products of the above formula III, IV, VI and XI belong to known classes of compounds and are available so that for each specialist. Starting materials of formulas II, V, VII and VIII also belong to known classes of compounds (see, for example, European application EP 0150040 A2 and EP 0027214 A1). The initial products of formula XII can be obtained, for example, similarly to the above-described options a) and b) of the method. Getting the original products of formulas IX and X is illustrated below in reaction schemes 1-3, 4 respectively. In addition, some of the following examples contain detailed data on obtaining specific source products.

As mentioned above, the compounds of formula I are new. They differ valuable pharmacodynamic properties and have only minor toxicity. Common to them all sign is pronounced affinity to the Central benzodiazepine receptors, and due to its agonistic action on these receptors they obladayuthimi. They form a different very good water-soluble acid additive salt and is therefore perfectly suited for the manufacture of aqueous solutions for injection.

The affinity of compounds of General formula I with respect to the Central benzodiazepine receptors was established in vitro by the method described in Nature 294, 763-765 (1981) and in Journ. Neurochemistry 37, 714-722 (1981). According to this method the inhibition of binding titiraupenga flumazenil with a specific benzodiazepine - receptor was determined in the cerebral cortex of rats, using the respective test substance. IC50("50% inhibitory concentration) refers to such a concentration of the respective test substance that causes 50% inhibition of specific binding titiraupenga flumazenil with specific benzodiazepine receptors in the cerebral cortex of rats.

Sedative/muscle-relaxant properties proposed according to the invention compounds of formula I can be detected, for example, in the test with a spinning rod. In this experiment used mice weighing 19-21, an hour before the start of the experiment the animals had free access to food and water. At least 30 minutes before the start of the experiment their Dostal the horizontal position of a smooth metal rod with a diameter of 3 cm, which rotates at a speed of 2 revolutions/min First animals give 30 seconds of time to ensure that they are familiar with the environment in which an experiment. Then select those animals that are at least within 1 min manages to stay on the rod, then intravenously injected with varying doses of the tested drugs. Then after certain time intervals to detect whether the animals for a minimum period of time to stay on the rod (minimum time: 10 seconds; after 5 min after drug administration: 1 min). In this way determine the dose at which 50% of animals able to stay on the rod (ED50).

In the table (see below) shows the results obtained when carrying out the above-described experiments, where he tested a number of compounds from the group represented by the General formula I.

A: (S)-8-chloro-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-he.

B: (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)- 11.11 is a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e] [1,4]diazepin-8-he.

C: 8-fluoro-5-methyl-3-[5-(piperidine-1-ylmethyl)-1,2,4-oxadiazol-3 - yl)-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

Dx2">

E: (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he.

F: 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

G: 3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-C][1,4]benzodiazepine-6-he.

H: 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-he.

I: (S)-8-chloro-1-[5-(piperidine-1-yl)methyl-1,2,4-oxadiazol-3-yl] - 12,12-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he.

J: 7-fluoro-5-methyl-3-(5-dipropylamino-1,2,4-oxadiazol-3 - yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

K: 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

L: 7-chloro-3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

M: (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11-dihydro - 8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno [3,2-e][1,4]diazepin-8-he.

N: (S)-1-(5-dibutylamino-1,3,4-oxadiazol-2-yl)-11,11 a-dihydro - 8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he.

A: 3-(5-diisopropyl aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

As can be seen from the table above, for compounds A-P is characterized by a very fast appearing and acting only a relatively short time, sedative effectiveness.

Due to its agonistic action on benzodiazepine receptors of the compounds of formula I can be used as sedative-hypnotics, anticonvulsants, muscle-relaxant and anxiolytics. They are suitable for use, for example, as fast, but in a short time, sleeping pills, injected oral, but primarily in the form of aqueous solutions of their acid additive salts as injectable pills quick steps for sedation, sedation, and before the introduction of anesthesia and for the conservation of the anesthesia.

Preferred applications are premedication before the introduction of anaesthesia, General sedation prior to diagnostic or surgical procedure with local anesthesia with or without sedation for an extended period of time during the course of intensive therapy, the use of as inducing means during inhalation anesthesia or as conducive to falling asleep comp the uly I, including the above compounds A, B, D, and E, were injected into mice and rats doses of 32 and 100 mg/kg intravenously, and when this has not been a single case of death of the animals.

The compounds of formula I and their pharmaceutically acceptable acid salt additive can be used as medicines, for example, in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, for example in the form of tablets, lacquered tablets, coated tablets, terdoslavich and megkozeliteni capsules, solutions, emulsions or suspensions. Medications can also be carried out rectally, for example, by in the form of suppositories, or parenterally, for example in the form of solutions for injection.

In the manufacture of pharmaceutical preparations of the compounds of formula I and their pharmaceutically acceptable acid salt additive can be recycled together with an inert pharmaceutical respect, inorganic or organic fillers. As such for tablets, lacquered tablets, coated tablets and terdoslavich capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., For magagalit rdie and liquid polyols, etc.; however, depending on the characteristics of the active substance for megkozeliteni capsules in General, you may not have any fillers. For the manufacture of solutions and syrups as fillers suitable, for example, water, polyols, sucrose, invert sugar, glucose, etc. When receiving water injection solutions of water-soluble acid additive salts of compounds of formula I can be used auxiliary substances, such as alcohols, polyols, glycerol, vegetable oils, etc., but usually this is not necessary. As excipients for suppositories are suitable, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc.

The pharmaceutical preparations may contain, in addition, also preservatives, substances that promote solubility, stabilizers, wetting agents, emulsifiers, chemicals, improves taste, colouring agents, flavouring agents, salts for modifying the osmotic pressure, buffers, coating or antioxidants. They can also contain other therapeutically valuable substances.

Drug, possess agonistic action in relation to benzodiazepine receptors and practie, containing the compound of formula I or its pharmaceutically acceptable acid additive salt and a therapeutically inert fillers are also an object of the present invention. The method of obtaining such drugs is that of one or more compounds of the formula I or their pharmaceutically acceptable acid additive salts and optionally one or more other valuable therapeutic for substances together with one or more therapeutically inert fillers are made herbal preparations.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable acid additive salts can be used according to the invention for therapeutic purposes, namely, primarily as anxiolytic and/or anticonvulsant and/or sedative-hypnotics. The dosage can vary within wide limits, but in each case must, of course, to take into account the individual characteristics of the patient. Typically, intravenous daily dose should be administered in the range from 1 mg to 1000 mg

Finally, the present invention relates as indicated above, to primeneniya funds first of all drugs anxiolytic and/or anticonvulsant, and/or muscle-relaxante, and/or sedative-hypnotic action. Below the invention is explained in more examples, which in no way limit its scope. All temperatures are in degrees Celsius.

Example 1.

and 1.89 g (10 mmol) of BOC-sarcosine was dissolved in 10 ml of N,N-dimethylformamide, treated portions 1.63 g (10 mmol) of 1,1'-carbonyldiimidazole and was stirred for 20 min at 50oCC. After the addition of 3.05 g (10 mmol) of 7-chloro-5,6-dihydro-5-methyl-6 - oxo-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxamidine continued to stir for 7 h at 90oCC. Then the reaction mixture was cooled and poured it into 300 ml of water. The resulting suspension was filtered and the crystals were washed with water and dried. The result has been to 3.16 g (69%) of 7-chloro-5,6-dihydro-5-methyl-3-(5-N-BOC-N-methylaminomethyl-1,2,4 - oxadiazol-3-yl)-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 114-117oC.

b) to 3.09 g (of 6.73 mmol) 7-chloro-5,6-dihydro-5-methyl-3-(5-N-BOC-N-methylaminomethyl-1,2,4-oxadiazol-3-yl)- 4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 2.5 h in 20 ml triperoxonane acid at room temperature. The solution was concentrated, polymacon and was extracted with her four times with methylene chloride. After drying and evaporation of the United organic phase and recrystallization of the residue from ethanol was obtained 1.3 g (54%) of 7-chloro-5,6-dihydro-5-methyl-3- (5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 192-193oC.

Example 2.

a) 4,60 g (16,95 mmol) 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamidine mixed with 3,19 g (18,65 mmol) of Chloroacetic anhydride acid in 25 ml of N,N-dimethylformamide first for 30 min at room temperature and then for 2 h at 105oC. the Reaction mixture was evaporated, the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. After drying over magnesium sulfate the solution was concentrated and the crystalline residue was chromatographically on silica gel with elution by ethyl acetate. The result has been 3.94 g (70%) of 3-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 208-209oC.

b) and 3.3 g (10 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5,6 - dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred in 20 ml of N, N-dimethylformamide with of 5.06 g (50 mmol) of dipropylamine for 4 h at room temperature. Then the reaction mixture upar%) of 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 130-132oC, which was transferred into the hydrochloride with MP 213-215oC.

Example 3.

1.4 g (13.5 mmol) of N,N-dimethylglycine suspended in 20 ml of N,N-dimethylformamide, and treated with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole and stirred first for 1 h at room temperature and then for 1 h at 75oC. was Then added to 3.9 g (12.3 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-1 - carboxamidine and was stirred overnight at 90oC. After concentrating the reaction mixture and chromatography was carried out of the residue on silica gel with elution with methylene chloride and methanol in a ratio of 19/1 and after recrystallization from ethyl acetate received 2,53 g (54%) of (S)-8-chloro-12,12 a-dihydro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it MP 127-129oC, which was transferred into the hydrochloride with MP 178oC.

Example 4.

2.55 g (13.5 mmol) of 1-pyrrolidin-acetic acid was dissolved in 20 ml of N, N-dimethylformamide and treated portions of 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole. After 45 minutes of mixing was added to 3.9 g (12.3 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo-9H,11H-azeto [2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamides ivali for 4 h at 90oC. the Reaction mixture was concentrated. After chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and recrystallization from ethyl acetate and hexane were obtained 1.6 g (32%) of (S)-8-chloro-12,12 a-dihydro-1-[5-(pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-3 - yl] -9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it MP 117-120oC, which was transferred into the hydrochloride.

Example 5.

1.4 g (13.5 mmol) of N,N-dimethylglycine was dissolved in 20 ml of N,N-dimethylformamide and treated portions of 2.6 g (15 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 70oC. was Then added as 4.02 g (15 mmol) of (S)-8-chloro-11,12,13,13-tetrahydro-9-oxo-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After concentration of the solution and chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1,99 g (40%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13 - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 261oC.

Example 6.

3.5 g (10 mmol) of BOC-glycine races the private stirring at 45oC was added 6,35 g (20 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. the Reaction mixture was concentrated; the residue was dissolved in methylene chloride and the solution washed three times with water, then dried over magnesium sulfate and evaporated. By chromatography was carried out of the residue on silica gel with elution by ethyl acetate was obtained 7.5 g (82%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which without further purification was used in the next stage.

b) 7,29 g (16 mmol) of crude (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it was stirred for 2 h in 25 ml triperoxonane acid. The solution was concentrated, the residue was dissolved in water and the aqueous solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and extracted seven times with methylene chloride. After drying and concentrating the United organic phases were received 5,12 g (90%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H - azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with T the foreign Ministry and was treated portions 3.5 g (21.6 mmole) of 1,1'-carbonyldiimidazole. After 10 minutes of stirring at 45oC was added 6,35 g (20 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After concentrating the reaction solution and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was received 7,58 g (80%) of (S)-8-chloro-12,12 a-dihydro-1-[5-(N-BOC-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which without further purification was used in the next stage.

b) 8 g (17 mmol) of (S)-8-chloro-12,12 a-dihydro-1-[5-(N-BOC-N-methyl)-aminomethyl-1,2,4 - oxadiazol-3-yl] -9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred for 2 h in 25 ml triperoxonane acid at room temperature. The solution was concentrated, the residue was dissolved in water and the aqueous solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and extracted seven times with methylene chloride. After drying and evaporation of the United organic phases were received 4.35 g (69%) of (S)-8-chloro-12,12 a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H, 11H - azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 250oC.

Example 8.

oC was added to 3.9 g (12.3 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo-9H, 11H - azeto[2,1-c]imidazo[1,5-a] [1,4] -benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. the Reaction mixture was concentrated. By chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from ethyl acetate were obtained 1.85 g (35%) of (S)-8-chloro-12,12 a-dihydro-1-[5-(morpholine-4-ylmethyl)-1,2,4-oxadiazol-3 - yl] -9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride.

Example 9.

of 1.75 g (17 mmol) of N,N-dimethylglycine was dissolved in 20 ml of N,N-dimethylformamide and treated portions is 3.08 g (15 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 70oC. was Then added as 4.02 g (15 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo [1,5-a] [1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After evaporation of the solution, chromatography was carried out residue on 240 g of silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and crystallization from ethyl acetate were obtained 1.35 g (24%) of (S)-7-fluoro-12,12 a-dihydro-1-[5-(Dima were transferred into the hydrochloride with MP 150-155oC.

Example 10.

a) for 6.81 g (36 mmol) of BOC-sarcosine was dissolved in 30 ml of N,N-dimethylformamide and treated portions of 6.5 g (40 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 40oC. Then was added 9,04 g (15 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After evaporation of the solution and chromatography was carried out of balance on 450 g of silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 8,81 g (65%) of (S)-7-fluoro-12,12 a-dihydro-1-[5-(N-BOC-N-methylaminomethyl)- 1,2,4-oxadiazol-3-yl] -9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which without further purification was used in the next stage.

b) 7,74 g (17 mmol) of (S)-7-fluoro-12,12 a-dihydro-1-[5-(N-BOC-N - methylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred for 2 h in 25 ml triperoxonane acid. The solution was concentrated, the residue was dissolved in water and the solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and extracted seven times with methylene chloride. The result has been 5,12 g (85%) of (S)-7-fluoro-12,12 a-dihydro-1-is that translated into hydrochloride with MP 155-160oC.

Example 11.

of 4.13 g (11,13 mmol) of (S)-8-chloro-12,12 a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl] -9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it, 20 ml of N, N-dimethylformamide, 2 g (13 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (1,5-5) and 1.58 g (13 mmol) allylbromide was stirred for 60 h at room temperature. Then the reaction mixture was purified by chromatography on silica gel with elution with methylene chloride/methanol 19/1. The result has been 2.86 g (62%) of (S)-1-[5-(N-allyl-N-methyl)- aminomethyl-1,2,4-oxadiazol-3-yl] -8-chloro-12,12 a-dihydro-9H, 11H - azeto[2,1-c] imidazo[1,5-a] [1,4] -benzodiazepine-9-it, which was transferred into the hydrochloride with MP 187-192oC.

Example 12.

a) to 8.41 g (48 mmol) of BOC-glycine was dissolved in 30 ml of N,N-dimethylformamide and treated portions of 7.8 g (48 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 10 min at 45oC. Then was added a 12.05 g (40 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After evaporation of the solution, chromatography was carried out of balance on 550 g of silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and Perekrestok[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it MP 147-150oC.

b) and 4.40 g (10 mmol) of (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3 - yl] -7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred for 2 h in 20 ml triperoxonane acid. The solution was concentrated, the residue was dissolved in water and the aqueous solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and extracted seven times with methylene chloride. After drying and evaporation of the United organic phases were received 2,77 g (81%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12 a - dihydro-9H, 11H-azeto [2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it MP 195-198oC, which was transferred into the hydrochloride with MP 275oC.

Example 13. 1.24 g (12 mmol) of N,N-dimethylglycine was dissolved in 20 ml of N, N-dimethylformamide and treated portions 2,43 g (15 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 70oC. was Then added to 3.35 g (10 mmol) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine and was stirred for 3.5 h at 90oC. After evaporation of the solution, chromatography was carried out of the residue on 300 g of silica gel with elution by ethyl acetate/methanol in a ratio of 9/1, cristalli the ol-3-yl] -9H, 11H-azeto [2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it MP 166-169oC, which was transferred into the hydrochloride with MP 223-227oC.

Example 14.

470 mg (1,32 mmole) of (S)-7-fluoro-12,12 a-dihydro-1-(5-methylaminomethyl - 1,2,4-oxadiazol-3-yl)-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-9-she and 750 mg (1,92 mmole) of the hydrochloride of (S)-7-fluoro-12,12 a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3 - yl)-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it, 837 mg (5.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) and 450 mg (3.5 mmole) of allylbromide was stirred in 15 ml of N, N-dimethylformamide first overnight at room temperature, and then for 2.5 hours at 55oC. the Reaction mixture was purified by chromatography was carried out on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. The result has been to 1.15 g (88%) of (S)-1-[5-(N-allyl-N-methyl)- aminomethyl-1,2,4-oxadiazol-3-yl]-7-fluoro-12,12 a-dihydro - 9H,11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 224-226oC.

Example 15

a) to 3.02 g (16 mmol) of BOC-sarcosine was dissolved in 15 ml of N,N-dimethylformamide and treated portions of 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole. After 15 minutes stirring at 50oC was added 5,04 g (15 mmol) of (S)-8-chloro-7-fluoro-12,12 a if 90oC. After concentrating the reaction solution and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was obtained 5.0 g (68%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-1-[5-(N-BOC-N-methyl)-aminomethyl-1,2,4 - oxadiazol-3-yl] -9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which without further purification was used in the next stage.

b) 4.42 g (9 mmol) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-1- [5-(N-BOC-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl] -9H,11H-azeto [2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-9-she was kept in overnight in 20 ml triperoxonane acid. Then, the solution was evaporated, the residue was dissolved in water and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet concentrated ammonia and eight times (for a total of a total of 11 times) were extracted with methylene chloride. After evaporation of the United and dried over magnesium sulfate organic phases were received of 2.97 g (84%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4] benzodiazepine-9-it, which without further purification was used as the source of the product in the following example.

Example 16.

2,95 g (7.6 mmol) of crude (S)-8-chloro-7-fluoro-12,12 a-dihydro-1- (5-methylaminomethyl-1,2,4-oxadiazol-34.0] undec-7-ene (1,5-5) and 1.1 g (9 mmol) of allylbromide was stirred first overnight at room temperature, and then for 6 h at 55oC. the Reaction mixture was purified by chromatography on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. As a result received 1.39 g (42%) of (S)-1-[5-(N-allyl-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl] -8-chloro-7-fluoro - 12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo [1.5 a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 199-203oC.

Example 17.

a) to 3.02 g (16 mmol) of BOC-sarcosine was dissolved in 25 ml of N,N-dimethylformamide and treated portions of 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 60oC. was Then added as 4.02 g (15 mmol) of (S)-8-chloro-11,12,13,13-tetrahydro-9-oxo-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-1-carboxamidine and was stirred overnight at 95oC. After evaporation of the solution and chromatography was carried out of the residue on 300 g of silica gel with elution by ethyl acetate was obtained 3.6 g (49%) of (S)-8-chloro-11,12,13,13-tetrahydro-1-(5-N-BOC-N - methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H-imidazo [1,5-a]pyrrolo[2,1-C] [1,4] benzodiazepine-9-it, which without further purification was used in the next stage.

b) 3.6 g (7.4 mmol) of crude (S)-8-chloro-11,12,13,13 a-tetrahydro-1-(5-N-BOC-N-methylaminomethyl-1,2,4 - oxad is islote at room temperature. The solution was concentrated, the residue was dissolved in water and the aqueous solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and was extracted five times with methylene chloride. After drying and evaporation of the United organic phases were received 2,47 g (87%) of (S)-8-chloro-11,12,13,13 - tetrahydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H-imidazo [1,5-a] pyrrolo[2,1-c][1,4]-benzodiazepine-9-it MP 161-163oC.

Example 18.

2,19 g (5.7 mmol) of (S)-8-chloro-11,12,13,13-tetrahydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] - benzodiazepine-9-it, 20 ml of N,N-dimethylformamide, 1.07 g (7 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (1,5-5) and 850 mg (7 mmol) allylbromide was stirred for 4.5 hours at 60oC. the Reaction mixture was concentrated and the residue was purified by chromatography on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. The result has been 1,32 g (54%) of (S)-1-(5-N-allyl-N-methylaminomethyl-1,2,4-oxadiazol-3-yl)-8 - chloro-11,12,13,13-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride.

Example 19.

a) 7.47 g (16,35 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, 20 oC. After evaporation of the solvent the residue was dissolved in methylene chloride, and the solution was twice washed with water, dried and evaporated. Chromatographytandem residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received of 2.08 g (25%) of (S)-1-(5-N-allyl-N-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8 - chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]- benzodiazepine-9-it, which without further purification was used in the next step.

b) of 2.08 g (4.2 mmole) of crude (S)-1-(5-N-allyl-N-BOC-aminomethyl - 1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4] -benzodiazepine-9-it was stirred for 3/4 hour in 10 ml triperoxonane acid. After evaporation of the reaction mixture the residue was dissolved in methylene chloride, and then the solution was washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. The result was obtained 0.75 g (48%) of (S)-1-(5-allelomimetic-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro - 9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 227-228oC.

Example 20.

36.5 g (235 mmol) of diaola. After a 10-minute stirring was added 40 g (126 mmol) of (S)-8-chloro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidine and stirred first for 1 h at room temperature, and then for 3.5 hours at 110oC. the Reaction mixture was concentrated and the residue was purified by chromatography on silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The result has been 27,1 g (45%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 181-182,5oC.

Example 21.

2.70 g (7.2 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-she, 35 ml of N,N-dimethylformamide, 3,39 g (22,2 mmole) of 1,8-diazabicyclo[5.4.0] -undec-7-ene (1,5-5) and 2,61 g (21.6 mmole) of allylbromide was stirred for 20 h at room temperature. After evaporation of the reaction mixture the residue was dissolved in methylene chloride, the solution washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 300 g of silica gel with elution with methylene chloride/methanol in a ratio of 19/1. Homogeneous fractions with Rf=0,19 con is 9H, 11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with Trasl 190oC.

Example 22.

25.4 g (100 mmol) of (S)-5-chloro-6-fluoro-a 1,10-dihydro-2H-azeto[2,1-C] [1,4] benzodiazepine-4,10(9H)-dione was dissolved in 125 ml of N,N-dimethylformamide was treated at -30oC 4.8 g (110 mmol) of a dispersion of sodium hydride (55-65% in oil, washed n-hexane) and was deprotonirovaniem for 40 minutes at a temperature of from -30oC to -18oC. At -60oC was added a solution of 26,86 g (100 mmol) of acid chloride of diphenyl ether phosphoric acid in 5 ml of N, N-dimethylformamide and stirred for 35 minutes at a temperature of max -45oC. At the same time separately dissolved 12.3 g (110 mmol) of tert.-the butyl potassium in 30 ml of N, N-dimethylformamide and treated at -60oC 12.2 g (107 mmol) of ethyl ether isocyanates acid. Deprotonirovannym ethyl ester isocyanates acid was cooled to -70oC and using chilled with dry ice dropping funnel was added dropwise to the reaction mixture at a temperature of -65 maxoC for 5/4 hours. Then continued to stir for 1 h in a bath of acetone and dry ice, neutralized 12 ml of acetic acid and poured into 500 ml of ice water. After this five times ek is the impact. Chromatography of the residue on 1.5 kg of silica gel with elution by ethyl acetate were obtained 14.4 g (41%) of ethyl-(S)-8-chloro-7-fluoro-12,12 a - dihydro-9-oxo-9H, 11H-azeto[2,1-C] imidazo[1,5-a]-[1,4]- benzodiazepine-1-carboxylate with MP 161-163oC.

b) of 57.3 g (164 mmole) of ethyl-(S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate, 40 ml of ethanol, 60 ml of water and 51.5 ml (206 mmol) of 4H sodium hydroxide was heated for 30 min on the steam bath under reflux. The alcohol evaporated using a rotary evaporator. The remaining aqueous phase was twice washed with methylene chloride and with the help of 51.5 ml (206 mmol) of 4H hydrochloric acid acidified to pH 3-4. The resulting suspension was cooled and filtered, after which the residue was washed with a small amount of ice water and dried. The result has been 47,92 g (91%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H,11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-1-carboxylic acid with MP 225-226oC.

in) 40 g (124 mmole) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo - 9H,11H-azeto[2,1-c] imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylic acid suspended in 190 ml of N,N-dimethylformamide and at room temperature was treated portions 21 g (129,5 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2por the 25oC for approximately 10 min was treated dropwise 30 ml of concentrated ammonia. After 30 minutes stirring the obtained suspension was poured into 700 ml of ice water for 30 min was stirred at room temperature and filtered, after which the crystals were washed with a small amount of water. After drying, got 31,36 g (78%) of (S)-8 - chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide with MP 296-298oC.

g) 33,67 g (105 mmol) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamide suspended in 140 ml of dioxane and 18 ml of pyridine and at a temperature of < 8oC for 30 min was treated dropwise to 22.6 g (107,6 mmol) of anhydride triperoxonane acid. Then was stirred for 2.5 h at 50oC and was poured into 700 ml of water. The suspension was filtered and after drying of the residue was obtained 28,62 g (90%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-C]imidazo[1,5-a] [1,4]-benzodiazepine-1-carbonitrile with MP 225-228oC.

d) 3.1 g (134,8 mmole) of sodium was dissolved in 140 ml of methanol. Then at room temperature was sequentially added 10 g (145 mmol) of hydroxylamine hydrochloride and 28.6 g (94.5 mmole) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-AZE is the temperature, after which it was cooled for 30 min to 0oC, the crystals were filtered off, smokepole them in 50 ml of water and again filtered. The methanol solution was concentrated and then the residue was smokepole in 30 ml of water and the crystals were filtered off. After drying, the United crystallization received 30,94 g (97%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1 - carboxamidine with MP 236-238oC.

e) 17,08 g (97 mmol) of BOC-glycine was dissolved in 165 ml of N,N-dimethylformamide and treated portions of 16.9 g (104 mmole) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 30 min at 50oC. Then was added 30,8 g (91 mmol) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. After evaporation of the solution and chromatography was carried out of balance on 1.5 kg of silica gel with elution with methylene chloride/methanol in a ratio of 19/1 got to 36.8 g (84%) of (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-chloro-7 - fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] -imidazo[1,5-a] [1,4] benzodiazepine-9-it, which without further purification was used in the next stage.

g) to 36.8 g (77.5 mmol) of crude (S)-1-[5-(BOC-aminododecanoic acid was stirred for 2 h at room temperature. Then, the solution was evaporated, the residue was dissolved in water and the aqueous solution washed three times methylene chloride. The aqueous phase was podslushivaet concentrated ammonia and eight times were extracted with methylene chloride (a total of approximately 1 liter). After evaporation of the United and dried over magnesium sulfate organic phases were received of 23.8 g (82%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12 a-dihydro - 9H,11H-azeto[2,1-C]-imidazo[1,5-a][1,4]benzodiazepine-9-it, which without further purification was used as the source of the product in the following example.

Example 23.

26,6 g (71 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8 - chloro-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] -imidazo[1,5-a] [1,4] benzodiazepine-9-she, 400 ml of methylene chloride, 85 ml (496 mmol) of N-ethyldiethanolamine and of 34.5 g (285 mmol) of allylbromide was stirred for 20 h at room temperature. Then the reaction mixture is washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 2 kg of silica gel with elution by ethyl acetate. Homogenous fractions were evaporated and recrystallized from toluene and n-hexane. In this way received 22,34 g (69%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro - 12,12 a-dihydro-9H,Nola) BOC-glycine was dissolved in 30 ml of N,N-dimethylformamide and treated portions 4,08 g (25.2 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 20 min at 50oC. Then was added of 7.36 g (22,2 mmole) of (S)-8-chloro-11,12,13,13 a-tetrahydro-9-oxo-9H - imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidine and was stirred overnight at 90oC. the Reaction mixture was evaporated, the residue was dissolved in methylene chloride and the solution was washed once with water and once with saturated sodium bicarbonate solution. After drying and concentration was obtained of 7.75 g (74%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13 - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] -benzodiazepine-9-it, which without further purification was used in the next stage.

b) of 7.75 g (16.5 mmol) of crude (S)-1-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-8-chloro-11,12,13,13-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-C][1,4] benzodiazepine-9-it was stirred for 1.5 h in 25 ml triperoxonane acid at room temperature. The solution was concentrated, the residue was dissolved in saturated sodium bicarbonate solution and the solution was extracted 10 times with methylene chloride. After drying and evaporation of the United organic phases were received 5.53 g (90%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-OS="ptx2">

Example 25.

2,47 g (6.7 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13-tetrahydro-9H - imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-9-it, 20 ml of N,N-dimethylformamide, 9 ml (60 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (1,5-5) and 10,26 g (54 mmole) benzylbromide was stirred first overnight at room temperature and then for 6 h at 50oC. Then the reaction mixture was concentrated and the residue was purified by chromatography on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. After recrystallization from ethyl acetate and hexane were obtained 2.16 g (58%) of (S)-1-(5-dibenzylamino-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13 - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it MP 107-109oC.

Example 26.

3.0 g (8.1 mmol) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-8-chloro-11,12,13,13-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-9-it, 20 ml of N, N-dimethylformamide, 3 ml (20 mmol) of 1,8-diazabicyclo[5.4.0] - undec-7-ene (1,5-5) and is 6.54 g (54 mmole) allylbromide was stirred overnight at 40oC. Then the reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution washed with water. After drying, the product was purified by chromatography on silica gel with boixader-3-yl)-8-chloro-11,12,13,13-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-9-it, which translated in hydrochloride.

Example 27.

a) of 6.68 g (22 mmole) of (S)-8-chloro-12,12-dihydro-9-oxo-9H, 11H - azeto[2,1-C]-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid was dissolved in 70 ml of N,N-dimethylformamide, treated at 40oC portions of 3.84 g (24 mmole) of 1,1'-carbonyldiimidazole and was stirred for 30 min at this temperature. After the addition 5,78 (26 mmol) phthaloylglycine was stirred first for 2.5 h at 60oC and then for 18 h at 110oC, after which the reaction mixture was concentrated. After chromatography was carried out of the residue on silica gel with elution by ethyl acetate was received 6,01 g (56%) of (S)-8-chloro-12,12 a-dihydro-1-(3-phthalimidomethyl-1,2,4 - oxadiazol-5-yl)-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9 - it MP 189-192oC.

b) 6,01 g (12.3 mmol) of (S)-8-chloro-12,12 a-dihydro-1-(3-phthalimidomethyl - 1,2,4-oxadiazol-5-yl)-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-she was placed in 60 ml of ethanol at 60oC for 30 min was treated dropwise to 120 ml of methylamine (33% in ethanol). The solution was stirred for 2 h at 70oC and then concentrated. After chromatography was carried out of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 8/2 received 4.0 g (91%) of (S)-1-(3-and oC.

Example 28.

5,02 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-she, 75 ml of N, N-dimethylformamide, 21 g (173,8 mmole) of allylbromide and 29.4 g (193 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) was stirred for 60 h at 75oC. Then the solution was concentrated and the residue was purified by chromatography on 350 g of silica gel with elution by ethyl acetate. The result has been of 1.97 g (35%) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine - 9-it, which was transferred into the hydrochloride with MP 190-192oC.

Example 29.

a) of 0.60 g (26 mmol) of sodium was dissolved in 32 ml of methanol. Then at room temperature was added first 1,95 g (28.1 mmol) of hydroxylamine hydrochloride and after 1 h another 5,77 g (346 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile. The suspension was stirred for 3.5 h at 70oC, cooled for 30 min to 0oC and the crystals were filtered off. After drying kristalliset received 6.5 g (100%) (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H,11H - azeto[2,1-c] imidazo[1,5-a]-[1,4]benzodiazepine-1-carboxamidine with MP 248-250oC.

b) 2,32 midsole. After 20 minutes stirring at 50oC was added a 3.01 g (10 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-1-carboxamidine and stirred first for 16 h at 90oC and then for 2 h at 120oC. the Solution was concentrated and the residue was purified by chromatography on 320 g of silica gel with elution by ethyl acetate. The result has been 1.54 g (37%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)- 7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 100-105oC.

Example 30.

a) 8 g (23.7 mmole) of (S)-8-trifluoromethyl-12,12 a-dihydro-9-oxo-9H,11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid was dissolved in 50 ml of N, N-dimethylformamide, treated portions 4,06 g (25 mmol) of 1,1'-carbonyldiimidazole and was stirred for 30 min at 55oC. After the addition of 5.26 g (24 mmole) phthaloylglycine was stirred for 20 h at 105oC. Then the reaction mixture was evaporated and the residue was chromatographically on silica gel with elution by ethyl acetate. The result has been 5.34 g (43%) of (S)-8-trifluoromethyl-12,12 a-dihydro-1-(3-phthalimidomethyl-1,2,4 - oxadiazol-5-yl)-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it MP 24, 1H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it is in 70 ml of ethanol was treated at 60oC for 45 min dropwise 150 ml of methylamine (33% in ethanol). Then, the solution was stirred for 2 h at 70oC and then concentrated. The residue was dissolved in methylene chloride and 30 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 30 ml 4H sodium hydroxide and was extracted five times with methylene chloride. After drying, the United organic solution and evaporation of the solvent was received 3,98 g (100%) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9 - it, which without further purification was used as the source of the product in the following example.

Example 31.

2 g (5.1 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8 - trifluoromethyl-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 30 ml of methylene chloride and 6.2 ml (36 mmol) of N-ethyldiethanolamine and 2.57 g (1.8 mmole) of allylbromide was stirred for 18 h at room temperature. The reaction mixture is washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 300 g of silica gel with elution ethylacetate[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9 - it, which translated into hydrochloride with MP 147-150oC.

Example 32.

of 3.56 g (10 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, 15 ml of methylene chloride, and 8.6 ml (50 mmol) of N-ethyldiethanolamine and 2.64 g (10 mmol), a-dibromo-o-xylene was stirred for 20 h at room temperature. Then the reaction mixture is washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 500 g of silica gel with elution with methylene chloride/methanol in a ratio of 19/1. The result obtained 1.55 g (33%) of (S)-8-chloro-12,12 a-dihydro-1- (5-isoindoline-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto [2,1-C]imidazo[1,5-a]-[1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 218-222oC.

Example 33.

473 mg (1.1 mmol) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)-8 - chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine - 9-it was first made in 10 ml of ethyl acetate in the presence of 20 mg of 5% palladium on coal at room temperature and normal pressure. After removal of the catalyst the solution was concentrated. The result has been 0,42 g (80%) of (S)-8-chloro-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-12,12-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a is) (S)-1-(5-diallyldimethyl-1,2,4 - oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it was first made in 80 ml of ethyl acetate in the presence of 35 mg of 5% palladium on coal at room temperature and normal pressure. After removal of the catalyst the reaction mixture was purified by chromatography on silica gel with elution by ethyl acetate. In this way got to 1.83 g (80%) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride.

Example 35.

a) cooled to -70oC solution to 57.2 g (250 mmol) of N-(tert.-butoxycarbonyl)-3,4-diptiranjan in 500 ml of tetrahydrofuran for 1 h was added dropwise to 400 ml (600 mmol) of tert.-utility (1.5 M in pentane). Then in the yellow suspension in small portions was added 160 g of dry ice was allowed to warm to 0oC, and then was added dropwise to 400 ml of water. Tetrahydrofuran and pentane drove, the aqueous phase is twice washed with simple ether and then concentrated hydrochloric acid was set to pH 1. An acidic aqueous phase was extracted three times with methylene chloride; the organic phase was dried over sodium sulfate, filtered and evaporated. The obtained solid beige color recrystallized from telengard holcatova substances with MP 159,5-160,5oC.

b) In a solution of 100 g (366 mmol) of 2-(tert.-butoxycarbonyl)amino-5,6 - diferential acid in 1.5 l of dry tetrahydrofuran under ice cooling was added dropwise a solution of 108 ml of thionyl chloride in 300 ml of tetrahydrofuran, after which it was stirred for 16 h at room temperature. The brown solution was evaporated and the resulting solid brown were thoroughly stirred with methylene chloride. The resulting powder beige was filtered and dried in high vacuum. The result has been of 56.5 g (77%) of 5,6-debtor-2,4-dihydro-1H-3,1-benzoxazin-2,4-dione in the form of a beige powder with MP > 240oC.

C) a Solution of 19.6 g (98.4 mmol) 5,6-debtor-2,4-dihydro-1H-3,1 - benzoxazin-2,4-dione and 9.95 g (98.4 mmol) L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid was stirred at 120oC for 16 hours Then the brown solution was evaporated and the resulting brown residue was led from ethanol. The result obtained 16 g (68%) of (S)-5,6-debtor-1,2,4,9,10,10 a-hexahydrate[2,1-C] [1,4] benzodiazepine-4,10-dione in the form of colorless needle-like substances with MP > 250oC.

g) a suspension of 2.7 g (62.3 mmole) of NaH (55%, washed in hexane) in 5 ml of dimethylformamide at -30oC and 65 ml of dimethylformamide and stirred for 40 min at -30oC. After cooling to -60oC was added dropwise a solution of 12.1 ml (56.7 mmol) of acid chloride of diphenyl ether phosphoric acid in 3 ml of dimethylformamide, and the additive is carried out so that the temperature did not exceed -45oC. Then continued to stir for 30 minutes at a time with this 7.0 g (62.3 mmole) of tert.-the butyl potassium was dissolved in 20 ml of dimethylformamide and at -60oC was treated with 7 ml (60.6 mmol) of ethyl ether (95%) isocyanurate acid. In the thus obtained solution at -70oC using a dropping funnel cooled to -40oC, was added dropwise the above solution. The resulting viscous solution is dark brown in color and was stirred for 1 h at -60oC and after neutralization with 7 ml of acetic acid at -40oC was poured into 300 ml of ice water, then was extracted five times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The remainder light brown recrystallized from ethanol. The result has been a 8.9 g (47%) of ethyl ester of (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-1-carboxylic acid as colorless IG-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid in 20 ml of ethanol and 30 ml of water was added dropwise to 8.6 ml (34.3 mmole) 4H caustic soda and the mixture was heated for 30 min under reflux. The ethanol is then drove away. The aqueous phase was twice washed with methylene chloride and 4h. hydrochloric acid was established pH 3. After extraction with methylene chloride (total of five times), drying over sodium sulfate, filtration and evaporation was obtained 7.2 g (89%) of (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxylic acid in the form of colorless needle-like substances with MP 218,0-to 219.5oC (decomposition).

(e) a suspension of 7.2 g (23,6 mmole) of (S)-7,8-debtor-9-oxo-12,12 a-dihydro - 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxylic acid in 50 ml of dimethylformamide was added in portions of 4.2 g (26 mmol) of 1,1'-carbonyldiimidazole. The obtained light brown solution was heated for 45 min to 50oC. Then the solution was cooled to room temperature and was added dropwise 6 ml of an aqueous solution of ammonia. After a further 30 minutes of stirring, the reaction mixture was poured into 100 ml of ice water and was extracted seven times with methylene chloride. After drying the organic phase over sodium sulfate, filter-debtor-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxylic acid as a colourless powder with MP 200,5-204,0oC.

g) a suspension of 6.3 g (20.7 mmol) of amide (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-1-carboxylic acid in 30 ml of dioxane and 5 ml of pyridine at a temperature of 5-8 was added dropwise 3 ml of 21.7 mmole) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at 50oC and then poured into 50 ml ice water. After extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation was obtained 4.8 g (81%) of (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile in the form of a colourless powder with MP > 250oC.

C) In a freshly prepared solution of sodium methylate in methanol [750 mg (32,8 mmole) of sodium in 25 ml of methanol] was added 4.7 g (16.4 mmol) of (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H, 11H - azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-1-carbonitrile and 2.7 g (36.1 mmol) of hydroxylamine hydrochloride and stirred for 16 h at room temperature. Then the suspension was evaporated and the residue was distributed between methylene chloride and water. The insoluble component was filtered and dried ve substance together with an insoluble component was chromatographically (silica gel, methylene chloride/methanol 9/1) and the way it was obtained 4.4 g (84%) of (E)- and/or (Z)-(S)-7-fluoro-8-methoxy-12,12 a-dihydro-9-oxo-9H, 11H - azeto[2,1-C] -imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamide in the form of a colorless foamy substance, Rf=0,33 (silica gel, methylene chloride/methanol 9/1).

and In a solution of 2.5 g (14.4 mmol) of BOC-glycine in 25 ml of dimethylformamide was added 2.5 g (15.4 mmol) of 1,1'-carbonyldiimidazole and was stirred for 30 min at 50oC. Then was added 4.3 g (13.5 mmol) of (E)- and/or (Z)-(S)-7-fluoro-8-methoxy-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-C] imidazo [1,5-a][1,4]-benzodiazepine-1-carboxamidine and was stirred for 16 h at 90oC. the thus Obtained brown solution is evaporated in a high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 19/1). The result was obtained 4.1 g (65%) of (S)-1-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12 a-dihydro-9H, 11H-azeto [2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,18 (silica gel, methylene chloride/methanol 19/1).

to a Solution of 4.0 g (8.5 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a] [1,4] - benzodiazepine-9-she's in 10 ml triperoxonane acid was stirred for 2 h at room temperature. Then the yellow solution was evaporated, the residue Rastogi ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The obtained residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). The result was obtained 2.3 g (73%) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a][1,4]benzodiazepine-9-it is in the form of colorless crystals with MP 196-198oC.

Example 36.

In a solution of 800 mg (2,16 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro - 8-methoxy-12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4] -benzodiazepine-9-she in 12 ml of methylene chloride was added 5.1 ml (29.8 mmol) of N-ethyldiethanolamine and of 1.46 ml (17,34 mmol) allylbromide. The reaction mixture was stirred for 20 h at room temperature, then was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was chromatographically (silica gel, methylene chloride/methanol 19/1). In this way received 770 mg (79%) of (S)-1-(5-diallyldimethyl - 1,2,4 - oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12 a-dihydro-9H, 11H - azeto[2,1-C]imidazo[1,5-a][1,4]-benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,37 (silica gel, methylene chloride/methanol 19/1).

Example 37.

In RA the [1,4] -benzodiazepine-9-she in 12 ml of methylene chloride was added 2.55 ml (14.9 mmol) of N-ethyldiethanolamine and 0.73 ml (8,67 mmol) allylbromide. The reaction mixture was stirred for 20 h at room temperature, then was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The obtained residue was chromatographically (silica gel, methylene chloride/methanol 19/1). In this way received 340 mg (35%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol - 3-yl)-7-fluoro-8-methoxy-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a] [1,4]-benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,37 (silica gel, methylene chloride/methanol 19/1), 30 mg of mixed fractions and 120 mg (13%) (S)-1-(5-allelomimetic - 1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12 a-dihydro-9H, 11H - azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,21 (silica gel, methylene chloride/methanol 19/1).

Example 38.

a) In a solution of sodium methylate prepared in the usual manner, 2.0 g (86.9 mmol) of sodium and 85 ml of methanol, in an atmosphere of argon at room temperature was sequentially added 6.2 g (89.2 mmol) of hydroxylamine hydrochloride and 16.3 g (63,6 mmole) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carbonitrile. The reaction mixture was stirred for 24 h at room temperature and then cooled n is microvilli and dried in a vacuum at a temperature of 60oC. the result obtained 12.4 g (67%) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxamide in the form of white crystals with MP 249-250oC (decomposition).

By evaporation of the filtrate and repetition of the above methods gave additional product (2.8 g), which contained another impurity of the original product. This additional product chromatographically on 100 g of silica gel, first with methylene chloride/acetone in a ratio of 9/1, 2/1 and finally with methylene chloride/methanol in a ratio of 9/1, resulting received another 1,72 g of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H - imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamidine. Total yield: 77%.

b) a suspension of 0.4 g (2.2 mmole) of the hydrochloride morpholine-4-yl-acetic acid in 4 ml of DMF was added to 0.38 ml (2.2 mmole) of N-ethyldiethanolamine. Then at room temperature portions was added 390 mg (2.4 mmole) of 1,1'-carbonyldiimidazole, after which the solution for 30 min was stirred at 50oC and then at room temperature was treated 0,58 mg (2.0 mmole) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine - 3-carboxamidine. The reaction mixture was heated for 20 h 90oC. the Solvent was removed in vacuo, the residue was dissolved in 15 ml was filtered and was evaporated. The crude product was purified by chromatography on silica gel (methylene chloride/methanol 19/1). The solvent was removed in vacuo, the residue was dissolved in 5 ml of acetonitrile and the solution was acidified by addition of HCl solution in a simple ether. White crystals were sucked out and recrystallized from acetonitrile. The result was obtained 0.5 g (54%) of hydrochloride (3:5) 8-fluoro-5-methyl-3-(5-morpholine-4-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro - 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 198-205oC (decomposition).

Example 39.

a) of 11.8 g (39.2 mmol) of (S)-7-fluoro-11,12,13,13 a-tetrahydro-9-oxo-9H - imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid was dissolved in 80 ml of N,N-dimethylformamide, portions were processed of 6.71 g (41,4 mmole) of 1,1'-carbonyldiimidazole and was stirred for 20 min at 50oC. After the addition 8,77 g (40 mmol) phthaloylglycine was stirred during the first night at the 100oC and then for 5 h at 120oC. After evaporation of the solvent the residue was dissolved in methylene chloride and then the solution is washed three times with water, dried over magnesium sulfate and concentrated. After chromatography was carried out on silica gel with elution by ethyl acetate were obtained 9.6 g (50%) of (S)-7-fluoro-11,12,13,13 a-tetrahydro-9H-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-is ovali at the next stage.

b) 9.6 g (19.8 mmol) of (S)-7-fluoro-11,12,13,13 a-tetrahydro-9H-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazol[1,5-a] pyrrolo [2,1-C][1,4]benzodiazepine-9-it was dissolved in 130 ml of ethanol and 65oC for 30 min was treated dropwise 130 ml of methylamine (33% in ethanol). The solution was stirred for 2 h at 70oC and then concentrated. The residue was dissolved in methylene chloride and 20 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 20 ml 4H sodium hydroxide and was extracted three times its methylene chloride and five times with ethyl acetate. After drying, the United organic solution and evaporation of the solvent was received of 6.73 g (96%) of (S)-1-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-C][1,4]benzodiazepine-9-it, which without further purification was used as the source of the product in the following example.

Example 40.

4 g (11.3 mmol) of crude (S)-1-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-9-it, 60 ml of methylene chloride, to 13.6 ml (79 mmol) of N-ethyldiethanolamine and 5.63 g (46 mmol) of allylbromide was stirred for 60 h at room temperature. Then the reaction solution was thrice washed research Institute with ethyl acetate. Homogenous fractions were evaporated. In this way received 2,19 g (45%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-7 - fluoro-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]-pyrrolo[2,1-c] [1,4] benzodiazepine-9-it (oil: Rf:0,43; silica gel 60 F254; solvent: ethyl acetate), which was transferred into the hydrochloride.

Example 41.

a) of 6.31 g (21 mmol) of (S)-7-fluoro-9-oxo-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide suspended in 20 ml of dioxane and 3.6 ml of pyridine and at a temperature of 5-10oC was treated dropwise with 3.3 ml of anhydride triperoxonane acid. Then the reaction mixture was stirred over night at room temperature and poured into 150 ml of water. The resulting suspension was filtered and the crystals were dried. The results obtained are 5.36 g (90%) of (S)-7-fluoro-9-oxo - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carbonitrile with MP 254-256oC.

b) 615 mg (26.8 mmol) of sodium was dissolved in 35 ml of methanol. Then at room temperature was sequentially added 2 g (28.8 mmol) of hydroxylamine hydrochloride and 5.3 g (18.8 mmol) of (S)-7-fluoro-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carbonitrile. The suspension was stirred over night at room temperature, Zor-11,12,13,13-tetrahydro-9-oxo - 9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidine with MP 267-268oC.

in) of 2.93 g (15.7 mmol) of BOC-glycine was dissolved in 30 ml of N,N-dimethylformamide and treated portions 2.76 g (17 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 20 min at 55oC. Then was added of 4.95 g (22,2 mmole) of (S)-7-fluoro-11,12,13,13 a-tetrahydro-9-oxo - 9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-1 - carboxamidine and was stirred overnight at 90oC. the Reaction mixture was evaporated and the residue was chromatographically on silica gel with elution with methylene chloride/methanol in a ratio of 19/1. The result has been of 4.45 g (61%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9 - it, which without further purification was used in the next stage.

g) 4.4 g (9.7 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-it was stirred for 1.5 h in 15 ml triperoxonane acid at room temperature. Then the solution was concentrated. The residue was dissolved in saturated sodium bicarbonate solution and was extracted ten times with methylene chloride. After drying and evaporation of the United organic phases were received 2.76 g (80%) of (S)-1-(5-which without further purification was used as the source of the product in the following example.

Example 42.

2,75 g (7.6 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7 - fluoro-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4] benzodiazepine-9-it, 50 ml of methylene chloride, 9 ml (53.3 mmol) of N-ethyldiethanolamine and 3.75 g (31 mmol) of allylbromide was stirred for 96 h at room temperature. Then the reaction mixture is washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically 360 g of silica gel with elution by ethyl acetate. Homogenous fractions were evaporated. In this way received 2,46 g (74%) of (S)-1-(5-diallyldimethyl - 1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H - imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride.

Example 43.

a) 10 g (29.7 mmol) of (S)-8-trifluoromethyl-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid are suspended in 50 ml of N,N-dimethylformamide and at room temperature was treated with portions of 5.1 g (31,2 mmole) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2transparent brown solution was stirred for 20 min at 50oC, cooled and when the temperature is below 15oC for about 15 min, treated dropwise 8 ml koncentrirane the increase was stirred 20 min at room temperature, was filtered and washed with a small amount of water. After drying, got 7.51 g (75%) of (S)-8-trifluoromethyl-12,12 a-dihydro-9-oxo-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide with MP > 300oC.

b) 7.5 g (22.3 mmole) of (S)-8-trifluoromethyl-12,12 a-dihydro-9 - oxo-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxamide suspended in 40 ml of dioxane and 4 ml of pyridine and at a temperature of 7-10oC for 10 min, treated dropwise 3.6 ml of anhydride triperoxonane acid. Then was stirred for 3/4 hour at room temperature and poured into 300 ml of water. The resulting suspension was filtered and the way after drying of the residue was obtained 3.75 g (52%) of (S)-8-trifluoromethyl-12,12 a-dihydro-9-oxo - 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 - carbonitrile with MP 115-119oC.

in) 730 mg (of 31.8 mmole) of sodium was dissolved in 40 ml of methanol. At room temperature was sequentially added 2.37 g (34.1 mmole) of hydroxylamine hydrochloride and 7.1 g (22.3 mmole) of (S)-8-trifluoromethyl-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-1-carbonitrile and was stirred over night at room temperature. After evaporation of the solvent was obtained 7.8 g (100%) (S)-8-trifluoromethyl-12,12 a-dihydro-9 - oxo-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]growing presence,2 g (24 mmole) of BOC-glycine was dissolved in 40 ml of N,N-dimethylformamide and treated portions of 4.05 g (25 mmol) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the solution was stirred for 20 min at 50oC. was Then added to 7.7 g (22 mmole) of (S)-8-trifluoromethyl-12,12 a - dihydro-9-oxo-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxamidine and was stirred over night at a temperature of 90oC. the Reaction mixture was concentrated and the residue was dissolved in methylene chloride. After washing, drying and evaporation of the organic phase was received of 7.82 g (72%) of (S)-1-[5-(N-BOC-aminomethyl)-1,2,4-oxadiazol-3-yl] -8-trifluoromethyl-12,12 a - dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine - 9-it, which without further purification was used in the next stage.

d) of 7.8 g (15.9 mmol) of crude (S)-1-[5-(N-BOC-aminomethyl)-1,2,4 - oxadiazol-3-yl] -8-trifluoromethyl-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] -benzodiazepine-9-she and 30 ml triperoxonane acid was stirred for 1 h at room temperature. Then, the solution was evaporated. The residue was dissolved in water and washed three times with methylene chloride. The aqueous phase was podslushivaet concentrated ammonia and nine times were extracted with ethyl acetate (a total of approximately 1 liter). After evaporation of the United and dried over magnesium sulfate organic phases were received of 4.57 g (73%) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-Ki was used as the source of the product in the following example.

Example 44.

3 g (7.7 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8 - trifluoromethyl-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 50 ml of methylene chloride, to 14.2 ml (72 mmole) of N-ethyldiethanolamine and 5,14 g (3.6 mmole) of allylbromide was stirred first overnight at room temperature, and then for 4 h at 40oC. the Reaction solution was thrice washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographically 390 g of silica gel with elution by ethyl acetate. The result has been a 1.50 g (41%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)- 8-trifluoromethyl-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo [1,5-a] [1,4] benzodiazepine-9-she, who with the help of methanolic hydrochloric acid were transferred into the dihydrochloride.

Example 45.

1.51 g (7.7 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8 - trifluoromethyl-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 15 ml of methylene chloride, 4 ml (23.4 mmole) of N-ethyldiethanolamine and 1.06 g (4 mmole) ,- dibromo-o-xylene was stirred over night at room temperature. The reaction mixture was twice washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 240 g of silica gel with elution of etelaat is indolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 185-188oC.

Example 46.

a) 40,58 g (128,7 mmol) ethyl-(S)-7-fluoro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-1 - carboxylate, 300 ml of ethanol and 32.5 ml (130 mmol) 4H sodium hydroxide was heated for 1.5 hours on the steam bath under reflux. Then the alcohol is evaporated using a rotary evaporator. The aqueous phase was twice washed with methylene chloride and acidified with 32.5 ml (130 mmol) 4H hydrochloric acid to pH 3-4. The resulting suspension was cooled and filtered. The residue after filtration was washed with a small amount of ice water and dried. The result has been 36,67 g (99%) (S)-7-fluoro-12,12 a-dihydro-9 - oxo-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]-benzodiazepine-1 - carboxylic acid with MP 159-160oC.

b) 20 g (69,6 mmol) of (S)-7-fluoro-12,12 a-dihydro-9-oxo-9H,11H-azeto [2,1-c] -imidazo[1,5-a] [1,4]benzodiazepine-1-carboxylic acid was dissolved in 40 ml of N,N-dimethylformamide, treated portions 13 g (80.2 mmol) of 1,1'-carbonyldiimidazole and continued to stir for 10 min at 60oC. After the addition 16.78 in g (76.6 mmol) phthaloylglycine was stirred for 1 h at 90oC, was added 14 ml triperoxonane acid, lly was filtered and washed them with methanol. In this way received 16,74 g (51%) of (S)-7-fluoro-12,12 a-dihydro-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H, 11H-azeto [2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-9-it MP 287-288oC, which without further crystallization was used in the next stage.

in) 10.8 g (23 mmole) of crude (5)-7-fluoro-12,12 a-dihydro-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-she's in 150 ml of ethanol was treated at 60oC for 30 min dropwise 150 ml of methylamine (33% in ethanol). The solution was stirred for 2 h at 70oC and then concentrated. The residue was dissolved in methylene chloride and 30 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 30 ml of 4n. sodium hydroxide and was extracted five times with methylene chloride. After drying, the United organic solution and evaporation of the solvent was obtained 7.5 g (96%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12 a - dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9 - she who is without crystallization used as starting product in the reaction described in the following example.

Example 47.

10,35 g (30.4 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl) -7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazolone was stirred for 3 h at room temperature. After evaporation of the reaction mixture the residue was purified by chromatography on silica gel with elution of ethyl acetate. By recrystallization from ethyl acetate and hexane were obtained 8,11 g (63%) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)-7-fluoro - 12,12 a-dihydro - 9H, 11H-azeto[2,1-C]-imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 188-190oC.

Example 48.

a) In an argon atmosphere was dissolved 0,92 g (5.3 mmol) of BOC-glycine in 7 ml of N,N-dimethylformamide and at room temperature was treated with portions of 0.9 g (5.6 mmol) of 1,1'-carbonyldiimidazole. After the formation of the CO2the mixture was stirred for 30 min at room temperature, then was treated with 1.44 g (5.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxamidine. Then for 18 h was heated to 90oC, cooled to room temperature and diluted with 50 ml water and the product precipitated in the form of crystals. The product was aspirated and was dissolved in methylene chloride, after which the solution was dried over sodium sulfate. After evaporation in vacuum was obtained 1.25 g of a white foamy substance.

The aqueous filtrate was extracted several times with methylene chloride and the extract was dried over all water and thoroughly mixed, and there were a further selection of product. Precipitated precipitated substance was filtered, dissolved in methylene chloride, dried with sodium sulfate, filtered and evaporated. In the re-received of 0.47 g of crude product.

United raw foods (1,72 g) was led with 7 ml of ethyl acetate. In this way got to 1.23 g (58%) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 170-172oC.

b) In an argon atmosphere was dissolved 0.64 g (1.5 mmole) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it in 1.5 ml triperoxonane acid for 1 h and was stirred at room temperature. The solvent is then evaporated in vacuum and the residue was dissolved in 10 ml of water. The solution was extracted with methylene chloride and the aqueous phase was podslushivaet concentrated ammonia solution and was extracted several times with methylene chloride. The combined organic extracts were dried over sodium sulfate, filtered and evaporated. The obtained crystals, slightly colored in pink, was heated in 10 ml of methanol, then filtered through celite and the filtrate was evaporated. The residue was recrystallized from 9 m is isomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-6-she (1:1,9) with MP 264-266oC (decomposition).

Example 49.

In argon atmosphere, the suspension of 0.49 g (1.5 mmole) of the hydrochloride(1:1,9) 3-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-6-it in 8 ml of methylene chloride was treated with 1.8 ml (10.5 mmol) of N-ethyldiethanolamine and 0.51 ml (6.0 mmol) of allylbromide and was stirred for 42 h in an argon atmosphere at room temperature. Then the solution is washed three times with 10 ml water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 50 g of silica gel (ethyl acetate), and then the eluate was evaporated, and the residue was dissolved in 5 ml of methanol. This solution was acidified with hydrochloric acid in a simple ether and the solvent was removed in vacuum. The residue was dissolved in 4 ml of methanol and then filtered through celite, cooled to 0oC and diluted with 8 ml of a simple ester. This was accompanied by the slow precipitation of white crystals, which were filtered off. In this way received 345 mg (50%) of the hydrochloride(2:3) 3-[5-(diallyldimethyl-1,2,4-oxadiazol-3-yl] -8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 133-140oC (decomposition).

Example 50.

In the atmosphere of argon, a suspension of the 0,49 g (1.5 mmole) of 3-(5-aminomethyl - 1,2,4-OK the,77 ml (4.5 mmole) of N-ethyldiethanolamine value (0.475) and g (1.8 mmole) ,-dibromo-o-xylene and stirred for 7 h in an argon atmosphere at room temperature. Then the solution once washed with 10 ml water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 40 g of silica gel (methylene chloride/acetone in a ratio of 4/1 first, then 2/1), after which the eluate was evaporated and the residue was dissolved in 3 ml of methanol. Then the solution was acidified with hydrochloric acid in a simple ether and the solvent was removed in vacuum. The residue was dissolved in 3 ml of methanol, after which the solution was cooled to approximately 0oC and diluted drops 3 ml of a simple ester. This was accompanied by the slow precipitation of white crystals, which were filtered off. The result obtained 190 mg (26%) of hydrochloride (2:3) 8-fluoro-3-(5-isoindoline-2-ylmethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]- [1,4] benzodiazepine-6-one with MP 177-184oC (decomposition).

Example 51.

1.85 g (5 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it, 20 ml of N,N-dimethylformamide, 3.4 ml (20 mmol) of N-ethyldiethanolamine and 1.45 g (5.5 mmol) ,- dibromo-o-xylene was stirred at room temperature overnight. After concentrating the reaction solution, the residue was chromatographically 430 g of silica gel with elution by ethyl acetate/the 4-oxadiazol-5-yl)-9H-imidazo[1,5-a] pyrrolo [2,1-C][1,4]benzodiazepine-9-it, which translated into hydrochloride with MP 165-170oC.

Example 52.

5 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro - 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4] benzodiazepine-9-it, 50 ml of methylene chloride, 12 ml (70 mmol) of N-ethyldiethanolamine and 3.7 g (14 mmol) ,-dibromo-o-xylene was stirred for 72 h at room temperature. Then the reaction solution was thrice washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 70 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 7/3. The result was obtained 4.0 g (62%) of (S)-8-chloro-12,12 a-dihydro-1- (3-isoindoline-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H, 11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 170-175oC.

Example 53.

a) In an argon atmosphere of 2.75 g (10.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl - 6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid are suspended in 20 ml of N,N-dimethylformamide and then at room temperature portions were added 1,95 g (12.0 mmol) of 1,1'-carbonyldiimidazole. After gassing the reaction mixture was stirred for 30 min at 50oC, then cooled to room temperature and was treated to 2.41 g (11.0 Malalai 40 ml of a simple ester, then the precipitated crystals were filtered and dried in vacuum. The result has been 2,88 g (63%) of 8-fluoro-5,6-dihydro-5 - methyl - 3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4] benzodiazepine-6-one with MP 273-276oC.

b) of 10.1 g (22 mmole) of 8-fluoro-5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4 - oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was heated in 220 ml of ethanol to 65oC, then for 100 min was added dropwise 150 ml of a 33% solution of methylamine in ethanol. After completion of addition the solution was continued to be heated for 17 h and then cooled in an ice bath, and this was accompanied by the precipitation of white crystals. These crystals were filtered off and dried in vacuum. After recrystallization from ethanol was obtained 3,05 g of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5,6 - dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 208-217oC. 2.5 g of product was obtained by chromatography on silica gel with methylene chloride/methanol first in a ratio of 19/1 and then 9/1. The total yield amounted to 5.55 g (77%).

Example 54.

In an argon atmosphere 492 mg (1.5 mmole) of 3-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 8 ml of methylene chloride was treated with 1.8 ml (10.5 mmol) of N-atii temperature. Solution once washed with 10 ml water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 40 g of silica gel (ethyl acetate), the eluate was evaporated and the residue was dissolved in 5 ml of methanol. Then the solution was acidified with hydrochloric acid in a simple ether and the solvent was removed in vacuum. The residue was dissolved in 5 ml of methanol and the solution was cooled to about 0oC and diluted with 18 ml of a simple ester. This resulted in the slow precipitation of white crystals, which were filtered off. The way it was obtained 270 mg (40%) hydrochloride(1: 1) 3-(3-diallyldimethyl-1,2,4 - oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 181-185oC (decomposition).

Example 55.

In an argon atmosphere 492 mg (1.5 mmole) of 3-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 8 ml of methylene chloride was treated with 1.3 ml (7.5 mmol) of N-ethyldiethanolamine and 0.42 ml (3.6 mmole) of 3,3-dimethylacrylamide and within 2 hours was stirred in an argon atmosphere at room temperature. The solution was evaporated and the crude product was purified by chromatography on 40 g of silica gel (ethyl acetate). Then the eluate was evaporated and the residue was dissolved in 3 ml of methanol. Races the and. The solution was cooled to about 0oC and the white crystals were filtered off. The result was obtained 220 mg (29%) hydrochloride(1: 1) 3-[3-[bis-(3-methylbut-2-enyl)-aminomethyl]-1,2,4 - oxadiazol-5-yl] -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 181-184oC (decomposition).

Example 56.

In an argon atmosphere 492 mg (1.5 mmole) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5,6-dihydro-5-methyl - 4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 8 ml of methylene chloride was treated with 1.3 ml (7.5 mmol) of N-ethyldiethanolamine and 0.42 ml (3.6 mmole) of 3,3-dimethylacrylamide and within 2 hours was stirred in an argon atmosphere at room temperature. The solution was evaporated and the crude product was purified by chromatography on 40 g of silica gel (ethyl acetate). Then the eluate was evaporated and the residue was dissolved in 3 ml of methanol. The solution was acidified with hydrochloric acid in a simple ether and was evaporated, then the residue was dissolved in 10 ml of ethyl acetate. Then, the solution was heated for 30 min under reflux and cooled to about 0oC, whereupon white crystals were filtered off. In this way received 315 mg (40%) hydrochloride(2:3) 3-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl] -1,2,4-oxadiazol-3-yl] -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 144-148oC for 3 h Brown solution was evaporated and the resulting brown residue was led from ethanol. The result obtained 15.2 g (43%) of (S)-6,7-dihydroiso[1,2-a]thieno[3,2-e][1,4]diazepin-5,9(4H,5aH)-dione as colorless crystals with MP 274oC.

b) a suspension of 1.92 g (44 mmole) of NaH (55%, washing with hexane) in 5 ml of dimethylformamide at a temperature of -30oC was added dropwise a solution 8,32 g (40 mmol) of (S)-6,7-dihydroiso[1,2-a] thieno[3,2-e] [1,4]diazepin-5,9(4H, 5aH)-dione in 45 ml of dimethylformamide and the mixture for 40 min was stirred at -30oC. After cooling to -60oC in this mixture was added dropwise a solution compared to 8.26 ml (40 mmol) of acid chloride of diphenyl ether phosphoric acid in 3 ml of dimethylformamide so that the temperature did not exceed -45oC. Then continued to stir for another 30 minutes

Simultaneously, the prepared solution to 4.92 g (44 mmole) of tert.-the butyl potassium in 20 ml of dimethylformamide, treated at a temperature of -60oC of 4.7 ml (42.8 mmole) ethyl ester (95%) isocyanurate acid. In th was added dropwise the above reaction mixture. The obtained viscous solution dark brown color was stirred for 1 h at -60oC and after neutralization 4.8 ml of acetic acid at -40oC was poured into 300 ml of ice water, then was extracted five times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The obtained light brown residue was recrystallized from ethanol. The result has been to 8.12 g (67%) of ethyl ester of (S)-8-oxo-11.11 is a-dihydro-8H, 10H-azeto [1,2-a] -imidazo[5,1-c] thieno[3,2-e] [1,4] diazepin-1-carboxylic acid as colorless crystals with MP 188-191oC.

C) In a suspension of 13.5 g (44.5 mmole) ethyl ester of (S)-8-oxo - 11.11 is a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in 10 ml of ethanol and 16 ml of water was added dropwise to 13.9 ml (55.6 mmol) 4H caustic soda. The mixture was heated for 30 minutes under reflux and then ethanol drove away. The aqueous phase was twice washed with methylene chloride and 4H hydrochloric acid was established pH 3. The resulting residue was filtered and washed first with water, ethanol and then diethyl ether. The way it was obtained 10.8 g (88%) of (S)-8-oxo - 11.11 is a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in the form of be is,10H - azeto[1,2-a] imidazo[5,1-c] thieno[3,2-e][1,4]diazepin-1-carboxylic acid in 70 ml portions of dimethylformamide was added of 7.65 g (47 mmol) 1,1'-carbonyldiimidazole. The resulting solution was light brown color was heated for 45 min to a temperature of 50oC. Then the solution was cooled to room temperature and was added dropwise into him 10.9 ml of an aqueous solution of ammonia. After a further 30 minutes of stirring, the reaction mixture was poured into 100 ml ice water and the precipitate was filtered and washed first with water, ethanol, and then a simple ether. After drying at 70oC/10 Torr received 11,0 g (89%) of amide (S)-8-oxo-11.11 is a - dihydro-8H,10H-azeto[1,2-a] -imidazo[5,1-C] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid as colorless crystals with MP > 250oC.

d) suspension 11,05 g (40.2 mmol) of amide (S)-8-oxo-11.11 is a-dihydro - 8H, 10H-azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e] [1,4] diazepin-1-carboxylic acid in 55 ml of dioxane and 7 ml of pyridine at a temperature of 5-8oC was added dropwise of 5.75 ml (41,3 mmole) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at 50oC and then poured into 50 ml ice water. After extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation was received light brown residue, which was chromatographically (silica gel, methylene chloride/methanol 10/1). As a result, what about the powder with MP 211 - 213oC.

(e) In a freshly prepared solution of sodium methylate in methanol [1,08 g (47 mmol) of sodium in 50 ml of methanol] was added 8.44 grams (32,9 mmole) of (S)-8-oxo-11.11 is a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c]thieno [3,2-e][1,4]diazepin-1-carbonitrile and of 3.48 g (50.5 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred for 48 h at room temperature. Then the suspension was evaporated and treated with 100 ml of water. The precipitate was filtered and dried in high vacuum. The way it was received with 7.8 g (82%) of (E)- and/or (Z)-(S)-1-(amino-gidroksilaminami)- 11.11 is a-dihydro-8H,10H-azeto[1,2-a] -imidazo[5,1-c] thieno [3,2-e] [1,4]diazepin-8-it is in the form of colorless powder, MP 195-198oC.

g) In a solution of 5.17 g (29.4 mmol) of BOC-glycine in 55 ml of dimethylformamide was added 5,12 g (31.5 mmole) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. was Then added to 7.95 g (27.5 mmol) of (E)- and/or (Z)-(S)-1-(amino-hydroxyimino-methyl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-it was stirred for 15 h at a temperature of 90oC. the Obtained brown solution was evaporated under high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 10/1). The result pin-8-it is in the form of a colorless foamy substance, Rf=0,48 (silica gel, methylene chloride/methanol 10/1).

C) a Solution of 11.6 g (27 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H - azeto [1,2-a] imidazo[5,1-C]thieno[3,2-e] [1,4]diazepin-8-she's in 20 ml triperoxonane acid was stirred for 2 h at room temperature. The yellow solution was evaporated, the residue was dissolved in water and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase was podslushivaet 10 ml of an aqueous solution of ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol 9/1). In this way received 5.0 g (56%) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo [5,1-c] thieno[3,2-e] [1,4] diazepin-8-it is in the form of colorless crystals with MP 235-238oC.

Example 58.

In a solution of 1.2 g (3.65 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 20 ml of methylene chloride was added to 4.4 ml (25.2 mmol) of N-ethyldiethanolamine and 1.77m (14,65 mmol) allylbromide and the mixture was stirred for 48 h at room temperature. Then the reaction solution was diluted with methylene chloride and three times the current was chromatographically (silica gel, methylene chloride/methanol 19/1). In the way it was received 980 mg (65%) of (S)-1-(5-diallyldimethyl-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,52 (silica gel, methylene chloride/methanol in a ratio of 10/1).

Example 59.

1.6 g (2.3 mmole) of (S)-1-(3-diallyldimethyl-1,2,4 - oxadiazol-5-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was first made in 80 ml of ethyl acetate in the presence of 50 mg of 5% palladium/coal at room temperature and normal pressure. After separation of the catalyst residue was purified by chromatography on silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1 and crystallization from ethyl acetate and hexane. The result has been 0.71 g (44%) of (S)-8-chloro-12,12 a-dihydro-1-(3-di-n-propyl - aminomethyl-1,2,4-oxadiazol-5-yl)-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 179-181oC.

Example 60.

a) 13,46 g (50 mmol) (S)-12,12 a-dihydro-9-oxo-9H,11H-azeto[2,1-C] imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylic acid was dissolved in 40 ml of N, N-dimethylformamide, portions was treated with 10 g (61,7 mmole) of 1,1'-carbonyldiimidazole and was stirred teeenie 2 hours at a temperature of 85oC. Then was added 10 ml triperoxonane acid and continued to stir overnight at 85oC. Then the reaction mixture was cooled to 10oC and the crystals were filtered off. After recrystallization from methanol has been 9,16 g (40%) (S)-12,12 a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-9-it MP 290-292oC.

b) 9 g (19.9 mmol) of (S)-12,12 a-dihydro-1-(3-phthalimidomethyl-1,2,4 - oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]- benzodiazepine-9-it was stirred in 20 ml of ethanol and 65 ml of methylamine (33%) in ethanol for 2 h at a temperature of 70oC. Then the solution was concentrated and the residue is thoroughly stirred with 70 ml of methylene chloride. The resulting suspension was filtered. After drying of the residue was obtained (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which without further purification was used as starting product in the reaction described in the following example.

Example 61.

4,72 g (14.6 mmol) of crude (S)-1-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-9-she, 70 ml of methylene chloride, 6 ml (35 mmol) of N-ethyldiethanolamine and of 3.53 g (29.2 mmol) was allylboration on 180 g of silica gel with elution by ethyl acetate. After concentration of the homogeneous fractions were obtained (S)-1-(3-diallyldimethyl-1,2,4 - oxadiazol - 5-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo [1,5-a][1,4]benzodiazepine-9-he that was transferred into the hydrochloride with MP 147-150oC.

Example 62.

1.78 g (5 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, 40 ml ethylthiourea, and 8.6 ml (50 mmol) of N-ethyldiethanolamine and 9,10 g (60 mmol) of bromelicola was stirred overnight at a temperature of 75oC. Then the reaction mixture was evaporated. The residue was chromatographically on 200 g of silica gel with elution by ethyl acetate. The result was obtained 0.7 g (30%) of (S)-1-[5-(bis-cyclopropylmethyl)-aminomethyl - 1,2,4-oxadiazol-3-yl]-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo [1,5-a][1,4]benzodiazepine-9-it MP 96-99oC, which was transferred into the hydrochloride.

Example 63.

a) a suspension of 4.9 g (35.2 mmol) of potassium carbonate in 40 ml of dimethylformamide at room temperature was added 2.6 g (37.7 mmol) of hydroxylamine hydrochloride. Then was added dropwise a solution of 7.2 g (25.2 mmol) of (S)-7,8-debtor-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a]-[1,4] benzodiazepine-1-carbonitrile in 100 ml of dimethylformamide and mixed in accordance with the chloride and water and the aqueous phase was extracted four times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. By subsequent chromatography (silica gel, methylene chloride/methanol 9/1) received 3 g (37%) of (E) - and/or (Z)-(S)-1-(aminohydrocinnamic)-7,8-debtor-12,12 a - dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine - 9-it is in the form of colorless powder, MP > 250oC.

b) a solution of 4.5 g (14.1 mmol) of BOC-glycine in 30 ml of dimethylformamide was added 2.7 g (16.9 mmol) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. Then it was added 4.5 g (14.1 mmol) of (E)- and/or (Z)-(S)-1-(aminohydrocinnamic)-7,8-debtor-12,12 a-dihydro-9H, 11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred for 16 h at 90oC. the resulting brown solution was evaporated under high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 19/1). The result was obtained 4.9 g (76%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-debtor-12,12 a - dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,21 (silica gel, methylene chloride/methanol 19/1).

C) a Solution of 330 mg (0.72 mmole) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-debtor-12,12 a-dihydro-9H, 11H-azeto[2,1-c] is the temperature. Then the yellow solution was evaporated, the residue was dissolved in water and the aqueous phase is washed three times with methylene chloride. Next, the aqueous phase was podslushivaet 2 ml of an aqueous solution of ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting residue was led from methylene chloride/simple ether. In this way received 190 mg (73%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol - 3-yl)-7,8-debtor-12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo [1,5-a] [1,4] benzodiazepine-9-it is in the form of powder beige color with MP 240oC (decomposition).

Example 64.

In a solution of 800 mg (2,23 mmole) of (S)-2-(5-aminomethyl-1,2,4-oxadiazol-3-yl) -7,8-debtor-12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-she's in 60 ml of methylene chloride was added 1.9 ml (11.2 mmol) of N-ethyldiethanolamine and 710 mg (2.7 mmole) ,-dibromo-ortho - xylene and the mixture was stirred for 20 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol 19/1). The result was obtained 130 mg (12%) (S)-1-(5-isoindoline-2-ylmethyl-1,2,4-oxadiazol-3-Rf=0,15 (silica gel, methylene chloride/methanol 19/1).

Example 65.

In a solution of 800 mg (2,23 mmole) of (S)-1-(5 - aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-debtor-12,12 a-dihydro-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-she's in 60 ml of methylene chloride was added to 2.6 ml (15.4 mmol) of N-ethyldiethanolamine and 1 ml (8,93 mmol) of 3,3-dimethylacrylamide and the mixture was stirred for 20 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol 19/1). The result was 300 mg (27%) of (S)-1-[5-[bis-(3-methylbut-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl] -7,8-debtor-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,19 (silica gel, methylene chloride/methanol 19/1).

Example 66.

In a solution of 700 mg (1,95 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-debtor-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-she's in 40 ml of methylene chloride was added to 2.3 ml (13.5 mmol) of N-ethyldiethanolamine and of 0.66 ml (7.8 mmol) of allylbromide and the mixture was stirred for 20 h at room temperature. Satiata magnesium, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol 19/1). In this way received 400 mg (46%) of (S)-1-(5-diallylamine)-1,2,4-oxadiazol-3-yl]-7,8-debtor - 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4] benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,17 (silica gel, methylene chloride/methanol 19/1).

Example 67.

4 g (11.2 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro - 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 50 ml of methylene chloride, 7.3 ml (42,6 mmole) of N-ethyldiethanolamine and 3 ml (approximately 24.6 mmole) of brothelbased was stirred for 7 h at room temperature. Then the reaction mixture is washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 200 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The way it was obtained 2.4 g (46%) of (S)-1-[3-bis-(but-2-enyl)- aminomethyl-1,2,4-oxadiazol-5-yl]-8-chloro-12,12 a-dihydro-9H,11H - azeto[2,1-C]imidazo[1,5-a]-[1,4]benzodiazepine-9-it is in the form 4/1 E/Z-mixture, which was transferred into the hydrochloride with MP 109-113oC.

Example 68.

5 g (14 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-o is stirred for 2 h at room temperature. Then the reaction solution was thrice washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 190 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The result has been 3.25 g (47%) of (S)-1-[3-bis-(3-methyl-but-2-enyl)aminomethyl - 1,2,4-oxadiazol-5-yl] -8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 188-189oC.

Example 69.

4 g (11.2 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5 - yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 25 ml of N,N-dimethylformamide, 7.5 ml (43,7 mmole) of N-ethyldiethanolamine and 2.9 ml (28 mmol) 4-bromo-1-butene was stirred for 25 hours at a temperature of 80oC. Then the reaction mixture was evaporated, the residue was dissolved in methylene chloride, the solution washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 160 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The way it was obtained 2.8 g (53%) of (S)-1-{ 3-[bis-(but-3 - enyl)aminomethyl] -1,2,4-oxadiazol-5-yl} -8-chloro-12,12 a-dihydro - 9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 115-120oC.

Example 70.oC. Then the reaction solution was evaporated, the residue was dissolved in methylene chloride, the solution washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 110 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The result was obtained 2.3 g (38%) of (S)-1-[3-(bis - cyclopropanemethylamine)-1,2,4-oxadiazol-5-yl]-8-chloro-12,12 a - dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4] benzodiazepine-9 - it, which was transferred into the hydrochloride with MP 155-160oC.

Example 71.

3.7 g (10 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8 - chloro-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it, 30 ml of N,N-dimethylformamide, 4,27 ml (25 mmol) of N-ethyldiethanolamine and of 2.38 g (20 mmol) of propargylamine was stirred for 1 h at room temperature. After concentrating the reaction solution, the residue was chromatographically 430 g of silica gel with elution by ethyl acetate/methanol in a ratio of 9/1. Homogeneous fractions with smaller Rfwas evaporated. In this way they obtained 1.19 g (29%) of (S)-8-chloro-11,12,13,13 a-tetrahydro-1-(3-probabilitiy in hydrochloride with MP 189-192oC.

Example 72.

a) 6,35 g (20 mmol) of (S)-8-chloro-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid was dissolved in 30 ml of N,N-dimethylformamide, treated portions 3.57 g (41,4 mmole) of 1,1'-carbonyldiimidazole and was stirred for 20 minutes at a temperature of 50oC. After the addition which 9.22 g (42 mmole) phthaloylglycine was stirred overnight at 90oC, was added 1 ml triperoxonane acid and continued to stir for 20 h at a temperature of 110oC. the resulting suspension was cooled and the crystals were filtered off. As a result, received a grade of 5.74 g (57%) of (S)-8-chloro-11,12,13,13 a-tetrahydro-9H-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a] pyrrolo [2,1-C][1,4]benzodiazepine-9-it MP 275-277oC.

b) 54,25 g (108,3 mmol) of (S)-8-chloro-11,12,13,13 a-tetrahydro-9H-1- (3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazo[1,5-a] pyrrolo [2,1-C] [1,4] benzodiazepine-9-it is within 1.5 h was mixed with 280 ml of methylamine (33%) in ethanol at a temperature of 75oC. Then the solution was concentrated, the residue was dissolved in methylene chloride and 115 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 115 ml 4H sodium hydroxide and was extracted six times with methylene chloride. is trihydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it, which without further purification was used as starting product in the reaction described in the following example.

Example 73.

3.7 g (10 mmol) of crude (S)-1-(3-aminomethyl - 1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13 a-tetrahydro-9H - imidazo[1,5-a] pyrrolo[2,1-C][1,4]benzodiazepine-9-it, 30 ml of methylene chloride, 4.3 ml (25 mmol) of N-ethyldiethanolamine and 2.3 ml (20 mmol) of 3,3-dimethylacrylamide was stirred for 3 h at room temperature. The reaction solution was chromatographically on 250 g of silica gel with elution with acetic ether. The result has been 2,44 g (48%) of (S)-1-[3-bis-(3-methyl-but-2 - enyl)aminomethyl-1,2,4-oxadiazol-5-yl] -8-chloro-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-9 - it, which was transferred into the hydrochloride with MP 137-140oC.

Example 74.

1 g (2.2 mmole) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5 - yl)-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was first made in 5 ml of methanol in the presence of 22 mg of 5% Pd/C at room temperature and normal pressure. After separation of the catalyst residue was purified by chromatography on silica gel with elution by ethyl acetate/hexane/triethylamine in the ratio 17/2/1. In this way received of 0.53 g (56%) of (S)-7-Faso: Rf0,36; silica gel 60 F254; solvent system: ethyl acetate/hexane/triethylamine 17/2/1), which was transferred into the hydrochloride.

Example 75.

In an argon atmosphere 328 mg (1.0 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5,6-dihydro - 5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 6 ml of methylene chloride was treated with 1.2 ml (7.0 mmol) of N-ethyldiethanolamine and 0.65 ml (6.0 mmol) of propargylamine (80% in toluene) and the mixture was stirred for 19 h in an argon atmosphere at room temperature. Then the solution was washed with 10 ml water and evaporated and the crude product was purified by chromatography on 15 g of silica gel (methylene chloride/acetone 9/1). Eluate was evaporated and the residue was dissolved in 5 ml of methanol. Then the solution was acidified with 5 ml of hydrochloric acid in a simple ether and the white crystals were filtered off. In this way received 200 mg (45%) hydrochloride(4:5) 3-[3-[bis-(prop-2-inyl)-aminomethyl] -1,2,4 - oxadiazol-5-yl] -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 186-189oC (decomposition).

Example 76.

To a solution of 660 mg (2 mmole) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-11,11-dihydro-8H, 10H-azeto[1,2-a] imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 20 ml of dimethylformamide was added 2.5 g of potassium carbonate and of 0.48 ml (4.1 mmole) of dimethyl the Ali and the filtrate was distributed between methylene chloride and water. The aqueous phase was extracted three times with methylene chloride; the combined organic phases were dried over sodium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 300/10/1) and as a result received 650 mg (70%) of (S)-1-[5-[bis-(3 - methyl-but-2 - enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl] -11,11-dihydro-8H, 10H - azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e] [1,4] diazepin-8-it is in the form of a colorless foamy substance, Rf= 0,16 (silica gel, methylene chloride/methanol/aqueous ammonia 300/10/1).

Example 77.

To a solution of 660 mg (2 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3 - yl)-11,11-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno [3,2-e][1,4]diazepin-8-she's in 20 ml of dimethylformamide was added 2.5 g of potassium carbonate and 0.55 g (2.1 mmole) ,-dibromo-o-xylene and the mixture was stirred for 12 h at room temperature. Then the reaction solution was filtered and the filtrate was distributed between methylene chloride and water. The aqueous phase was extracted three times with methylene chloride; the combined organic phases were dried over sodium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 300/10/1) and as a result received 535 mg (62%) of (S)-1-[5-(isoindoline-2-ylmethyl)- 1,2,4 is the first substance, Rf=0,12 (silica gel, methylene chloride/methanol/aqueous ammonia 300/10/1).

Example 78.

a) In the solution 11,88 g (41,2 mmole) of (S)-10,11,12,12 a-tetrahydro - 8-oxo-8H-imidazo[5,1-C]pyrrolo[1,2-a]thieno[3,2-e] [1,4]diazepin-1-carboxylic acid (see European patent application EP 0059390 A1) in 65 ml of dimethylformamide at room temperature in one portion was added 6,98 g (43 mmole) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. Then also at one time was added 9.2 grams (41,9 mmole) phthaloylglycine and the mixture was stirred for 15 h at a temperature of 110oC. the Dimethylformamide is evaporated in a high vacuum and the resulting residue was treated with 150 ml of water. After extraction with methylene chloride (twice), dried over sodium sulfate, filtration and evaporation was obtained residue reddish color, which was then chromatographically (silica gel, methylene chloride/methanol 20/1). The result has been to 7.3 g (38%) (S)-2-[5-(8-oxo-10,11,12,12-tetrahydro-8H-imidazo [5,1-c] pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin-1-yl)-1,2,4 - oxadiazol-3-ylmethyl]-1,3-dihydroindol-1,3-dione in the form of colorless crystals with MP 248-250oC.

b) In the solution 7,28 g (15.4 mmol) (S)-2-[5-(8-oxo-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo [1,2-a] thieno[3,2-e] [1,4] Diaz is ina (33% in ethanol) at a temperature of 70oC and stirred for 2 h at 70oC. Then the reaction mixture was evaporated and the residue was chromatographically (silica gel, methylene chloride/methanol 20/1). In this way received 4,36 g (83%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)- 10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno [3,2-e][1,4]diazepin-8-it is in the form of colorless crystals with MP 156-158oC.

Example 79.

In a solution of 685 mg (2 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5 - yl)-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno [3,2-e] [1,4] diazepin-8-she's in 20 ml of methylene chloride was added 2.4 ml (13.8 mmol) of N-ethyldiethanolamine and 0.67 ml (8 mmol) of allylbromide and the mixture was stirred for 20 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 200/10/1). The result obtained 693 mg (82%) of (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12 a - tetrahydro-8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,32 (silica gel, methylene chloride/methanol/aqueous ammonia 200/10/1).

Example 80.

oC (decomposition).

Example 81.

a) of 2.45 g (14 mmol) of BOC-glycine was dissolved in 20 ml of N,N-dimethylformamide, after which the mixture was treated with portions 2,43 g (15 mmol) of 1,1'-carbonyldiimidazole and was stirred for 20 minutes at a temperature of 50oC. After the addition of 3.8 g (12.4 mmol) of 7-chloro-5,6-dihydro-5 - methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3 - carboxamidine continued to stir overnight at a temperature of 90oC. the Reaction mixture concentrate and crystallization of the residue from ethyl acetate and hexane were obtained 5,33 g (96%) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H - imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 144-146oC.

b) 7,03 g (16.4 mmol) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7 - chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6 - it was stirred for 1 h in 30 ml triperoxonane acid at room temperature. Then the solution was concentrated, the residue was dissolved in water and the solution was twice washed with methylene chloride. The aqueous phase was podslushivaet 25% ammonia and extracted seven times with methylene chloride. After drying and evaporation of the United organic phases were obtained 4.5 g (79%) of 3-(5-aminomethyl)-1,2,4 - oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it, which without further purification was used as starting product in the reaction described in the following example.

Example 82.

1.5 g (4.4 mmole) of 3-(5-aminomethyl)-1,2,4-oxadiazol-3-yl)-7-chloro-5,6 - dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, 20 ml of N,N-dimethylformamide, 2.10 ml (12 mmol) of N-ethyldiethanolamine and of 1.16 g (9.6 mmol) of allylbromide was stirred for 4 h at room temperature. Then the reaction mixture was evaporated and the residue was chromatographically on 250 g of silica gel with elution by ethyl acetate. Homogenous fractions were evaporated. In this way received 1.54 g (82%) of 3-(5-diallylamine)-1,2,4-oxadiazol-3-yl)-7 - x is.

Example 83.

a) to 38.8 g (133 mmole) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H - imidazo[1,5-a] -[1,4]benzodiazepine-3-carboxylic acid was dissolved in 200 ml of N,N-dimethylformamide, treated portions of 23.7 g (146 mmol) of 1,1'-carbonyldiimidazole and was stirred for 20 minutes at a temperature of 70oC. After the addition 43,73 g (199,5 mmol) phthaloylglycine was stirred for 1 h at a temperature of 90oC, was added 1.5 ml triperoxonane acid and continued to stir for another 3 hours at a temperature of 120oC. the resulting suspension was concentrated to half its volume and cooled, after which the precipitated crystals were filtered. The result has been to 35.3 g (56%) of 7-chloro-5,6-dihydro-5-methyl-3- (3-phthalimidomethyl-1,2,4-oxadiazol - 5-yl)-4H - imidazo[1,5-a]-[1,4]benzodiazepine-6-one with MP 237-239oC.

b) of 35.1 g (74 mmole) of 7-chloro-5,6-dihydro-5-methyl-3-(3-phthalimidomethyl - 1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 3 h with 190 ml of methylamine (33% in ethanol) and 100 ml of ethanol at a temperature of 80oC. Then the solution was concentrated, the residue was dissolved in methylene chloride and 100 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 105 ml 4H caustic soda and six times extra is whether 18,14 g (71%) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H - imidazo[1,5-a] [1,4] benzodiazepine-6-it, which without further purification was used as starting product in the reaction described in the following example.

Example 84.

of 5.17 g (15 mmol) of crude 3-(3-aminomethyl)-1,2,4-oxadiazol-5-yl)-7 - chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-she, 45 ml of N, N-dimethylformamide, and 6.5 ml (37.5 mmol) of N-ethyldiethanolamine and 3,63 g (30 mmol) of allylbromide was stirred for 1 h at room temperature. Then the reaction solution was evaporated and the residue was chromatographically on 250 g of silica gel with elution by ethyl acetate. Homogeneous fractions with a large value of Rfwas evaporated. The result has been 4,84 g (76%) of 3-(3-diallylamine) -1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it, which is translated in hydrochlorid with MP 125-130oC.

Example 85.

3,44 g (10 mmol) 3-(3-diallylamine)-1,2,4-oxadiazol-5-yl)-7 - chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, 30 ml of N, N-dimethylformamide, and 3.7 ml (22 mmole) of N-ethyldiethanolamine and 2.9 g (11 mmol) ,- dibromo-o-xylene was stirred for 6 h at room temperature. After evaporation of the solvent the residue was chromatographically 230 g of silica gel with elution by ethyl acetate. Odnorodnymi-4H-imidazo[1,5-a] [1,4]-benzodiazepine-6-it, which translated into hydrochloride with MP 180-184oC.

Example 86.

a) 15 g (of 5.83 mmol) 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid was dissolved in 100 ml of N,N-dimethylformamide, treated portions of 11.3 g (7 mmol) of 1,1'-carbonyldiimidazole and was stirred for 20 minutes at a temperature of 70oC. After the addition of 19.2 g (8.75 mmol) phthaloylglycine was stirred for 3 hours at a temperature of 80oC, was added 5 ml triperoxonane acid and stirred overnight at 110oC. Then the reaction mixture was concentrated and the residue was chromatographically on 200 g of silica gel with elution by ethyl acetate. The result obtained 13 g (50%) of 5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo [1,5-a][1,4]benzodiazepine-6-one with MP 239-240oC.

b) 13 g (29.5 mmol) 5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo [1,5-a] [1,4]benzodiazepine-6-it was stirred for 3 h with 90 ml of methylamine (33% in ethanol) and 40 ml of ethanol at a temperature of 80oC. Then the solution was concentrated, the residue was dissolved in methylene chloride and 53 ml 4H hydrochloric acid and the solution washed three times with methylene chloride. The aqueous phase was podslushivaet 55 ml 4H caustic soda and six were alocale 9 g (100%) 3-(3-aminomethyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H - imidazo[1,5-a]-[1,4]benzodiazepine-6-one with MP 183-185oC, which was used without further purification as the starting product in the reaction described in the following example.

Example 87.

of 3.10 g (10 mmol) of crude 3-(3-aminomethyl)-1,2,4-oxadiazol-5-yl)-5,6 - dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, 20 ml of N,N-dimethylformamide, and 3.7 ml (22 mmole) of N-ethyldiethanolamine and of 1.81 g (15 mmol) of allylbromide was stirred for 1.5 h at room temperature. After evaporation of the solvent the residue was chromatographically on 220 g of silica gel with elution by ethyl acetate. The result has been 0,86 g (22%) of 3-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-it, which was transferred into the hydrochloride with MP 203-205oC.

Example 88.

1.85 g (5 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9 - it, 20 ml of N,N-dimethylformamide, and 2.14 ml (12.5 mmol) of N-ethyldiethanolamine and 0.97 ml (10 mmol) of propyliodide was stirred overnight at a temperature of 80oC. After evaporation of the solvent the residue was chromatographically 210 g of silica gel with elution by ethyl acetate. In this way received 0,81 g (36%) of (S)-8-chloro-11,12,13,13 a-tetrahydro-1-(3-dipropylamino 155-158oC.

Example 89.

of 5.17 g (15 mmol) of 3-(3-aminomethyl)-1,2,4-oxadiazol-5-yl)-7-chloro-5,6 - dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-she, 45 ml of N,N-dimethylformamide, and 6.5 ml (37.5 mmol) of N-ethyldiethanolamine and 3,63 g (30 mmol) of allylbromide was stirred for 1 h at room temperature. Then the reaction mixture was evaporated and the residue was chromatographically on 250 g of silica gel with elution by ethyl acetate. Homogeneous fractions with a smaller value of Rfwas evaporated. The result has been 0,344 g (6%) 3-(3-allelomimetic-1,2,4-oxadiazol-5 - yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 171-174oC.

Example 90.

1.5 g (4,65 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, 20 ml of N, N-dimethylformamide and 2.8 ml (16.3 mmol) of N-ethyldiethanolamine and 1.1 ml (10.7 mmol) of bromelicola was stirred for 18 hours at a temperature of 80oC. Then the reaction mixture was evaporated, the residue was dissolved in methylene chloride, the solution washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 110 g of silica gel with elution with methylene chloride/ethylacetate-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 174-176oC.

Example 91.

1.28 g (4.1 mmole) of 3-(3-aminomethyl-1,2,4 - oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo [1,5-a] [1,4]benzodiazepine-6-it, 25 ml of N,N-dimethylformamide, 2 ml (11.7 mmol) of N-ethyldiethanolamine and 1.19 g (4.5 mmole) ,-dibromo-o-xylene was stirred for 4 h at room temperature. After evaporation of the solvent the residue was chromatographically on 180 g of silica gel with elution by ethyl acetate. Homogenous fractions were evaporated. The result has been 0.39 g (23%) of 5,6-dihydro-3-(3-isoindoline-2-ylmethyl - 1,2,4-oxadiazol-5-yl)-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 155-160oC.

Example 92. 3,44 g (10 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo [1,5-a][1,4]benzodiazepine-6-it, 20 ml of N,N-dimethylformamide, a 4.3 ml (25 mmol) of N-ethyldiethanolamine and 2,98 g (20 mmol) of 3,3-dimethylacrylamide was stirred for 1.5 h at room temperature. Then the reaction mixture was evaporated and the residue was chromatographically 215 g of silica gel with elution by ethyl acetate. The result was obtained 1.8 g(37%) 3-{3-[bis- (3-methylbut-2-enyl)aminomethyl]-1,2,4-oxadiazol-5-yl}-7-chloro-5,6 - is ptx2">

Example 93.

1.5 g (4,65 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)- 12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-it, 20 ml of N, N-dimethylformamide, 2.4 ml (13.9 mmol) of N-ethyldiethanolamine and 1.3 g (4.9 mmole) ,- dibromo-o-xylene was stirred for 1 h at room temperature. Then the reaction mixture was evaporated, the residue was dissolved in methylene chloride and was chromatographically it on 50 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 1/1. The way it was obtained 1.2 g (61%) (S)-12,12 a - dihydro-1-(3-isoindoline-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H - azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 210-213oC.

Example 94.

5 g (15.5 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9 - it, 50 ml of N, N-dimethylformamide, 8 ml (46.5 mmol) of N-ethyldiethanolamine and 4 ml of 32.5 mmole) of 3,3-dimethylacrylamide was stirred for 2 h at room temperature. Then the reaction solution was evaporated, the residue was dissolved in methylene chloride, the solution washed three times with water, dried over magnesium sulfate and evaporated. The residue was chromatographically on 130 g of silica gel with elution with methylene chloride/etelaat,12a-dihydro - 9H, 11H-azeto[2,1 - C]imidazo[1,5-a][1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 119-122oC.

Example 95.

1.5 g (3.7 mmole) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was first made into 50 ml of ethyl acetate in the presence of 50 mg of 5% palladium on coal at room temperature and normal pressure. After separation of the catalyst residue was purified by chromatography on silica gel with elution by ethyl acetate/methylene chloride in a ratio of 1/1. The way it was obtained 0.9 g (59%) (S)-12,12-dihydro-1-(3-dipropylamino - 1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 185-187oC.

Example 96.

a) 10 g (31,09 mmole) of (S)-8-chloro-7-fluoro-12,12 a-dihydro-9-oxo-9H,11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid was dissolved in 100 ml of N-dimethylformamide, treated portions 6,05 g (37.3 mmol) of 1,1'-carbonyldiimidazole and was stirred for 1 h at room temperature. After the addition of 6.8 g (31,09 mmole) phthaloylglycine was stirred over night at room temperature, was added 10 ml triperoxonane acid and stirred overnight at a temperature of 90 was obtained 8,55 g (54%) of (S)-8-chloro-7-fluoro - 12,12 a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)- 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4] benzodiazepine-9-it MP 292-294oC.

b) 16 g (31,85 mmole) of (S)-8-chloro-7-fluoro-12,12 a - dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-she was treated with 100 ml of methylamine (33% in ethanol). The solution was stirred for 1 h at a temperature of 70oC and then cooled. The resulting suspension was filtered and crystallized was partially dissolved in 10 ml of methylene chloride. After filtration and evaporation of the filtrate received 11,7 g (99%) (S)-1-(3-aminomethyl-1,2,4-oxadiazol - 5-yl)-8-chloro-7-fluoro-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which without further purification was used as starting product in the reaction described in the following example.

Example 97.

11,7 g (31,2 mmole) of crude (S)-1-(3-aminomethyl-l,2,4-oxadiazol-5-yl)- 8-chloro-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, 100 ml of methylene chloride, 6,04 g (50 mmol) of allylbromide and 7.75 g (60 mmol) of N-ethyldiethanolamine was stirred over night at room temperature. Then the solution was concentrated and the residue was purified by chromatography on 500 g of silica gel with elution by ethyl acetate. After recrystallization from methanol was received with 5.3 g (47%) of (S)-1-(3-dial is 139-140oC, which was transferred into the hydrochloride with MP 127oC.

Example 98.

In argon atmosphere, the suspension 328 g (1.0 mmol) 3-(3-aminomethyl - 1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-6-it in 5 ml of methylene chloride was treated to 0.38 ml (2,2 mole) of N-ethyldiethanolamine and 317 mg (1.2 mmole) ,-dibromo-o-xylene and stirred for 5 h in an argon atmosphere at room temperature. Then the solution once washed with 5 ml of water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 30 g of silica gel (methylene chloride/acetone first in a ratio of 4/1, and then 2/1). Eluate was evaporated and the residue was dissolved in 2.5 ml of methanol. Then the solution was acidified with hydrochloric acid in a simple ether and the solvent was removed in vacuum. The residue was dissolved in 6 ml of hot methanol; then was cooled to about 0oC and white crystals were isolated by suction. The result was obtained 150 mg (32%) of hydrochloride (1: 1) 8-fluoro-3-(3-isoindoline-2-ylmethyl-1,2,4 - oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 229-233oC (decomposition).

Example 99.

a) a Solution of 28.8 g (144,6 mmole) of 5,6-debtor-2,4-dihydro - 1H-3,1-benzoxazin-2,4-dione and 16.7 g (144,6 MoE 16 PM Then the brown solution was evaporated and the resulting brown residue was led from ethanol. In this way received 30 g (82%) of (S)-6,7-debtor-2,3,5,10,11,11 a-hexahydro-1H-pyrrolo[2,1-C] [1,4]benzodiazepine-5,11-dione in the form of colorless crystals with MP > 250oC.

b) a suspension of 5.7 g (130 mmol) NaH (55%, washing with hexane) in 10 ml of dimethylformamide at -30oC was added dropwise a solution to 29.8 g (118,2 mmol) of (S)-6,7-debtor-2,3,5,10,11,11 a - hexahydro-1H-pyrrolo[2,1-C][1,4]benzodiazepine-5,11-dione in 140 ml of dimethylformamide and stirred for 40 min at -30oC. After cooling to -60oC was added dropwise a solution of 25.2 ml (118,2 mmol) of acid chloride of diphenyl ether phosphoric acid in 50 ml of dimethylformamide so that the temperature did not exceed -45oC. Then continued to stir for another 30 minutes

Simultaneously dissolved 14.6 g (130 mmol) of tert.-the butyl potassium in 50 ml of dimethylformamide and at a temperature of -60oC was treated with 14.5 ml (126,4 mmol) of ethyl ether isocyanurate acid (95%). Cooked this way the solution at -70oC using chilled to -40oC a dropping funnel was added the above mixture. The obtained viscous lastcase acid at -40oC was poured into 400 ml of ice water, then was extracted five times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The resulting light brown residue was chromatographically (silica gel, ethyl acetate). The result obtained 22 g (54%) of ethyl ester of (S)-7,8-debtor-9-oxo-11,12,13,13 a-tetrahydro-9H - imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid as colorless crystals with MP 199-200oC.

C) In a suspension of 22.1 g (63,6 mmole) ethyl ester of (S)-7,8-debtor-9 - oxo-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylic acid in 55 ml of ethanol and 90 ml of water was added dropwise to 20.7 ml (82,7 mmole) 4H caustic soda and within 45 minutes was heated under reflux. The ethanol is then drove away. The aqueous phase was twice washed with methylene chloride and 4H hydrochloric acid was established pH 3. After extraction with methylene chloride (five times), drying over sodium sulfate, filtration and evaporation was obtained 20 g (98%) of ethyl ester of (S)-7,8-debtor-9-oxo - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxylic acid as colorless crystals with MP 214,5-215,5oC (decomposition).

g) a suspension of 11 g (34.5 mmole) of (S)-7,8-ditto the amide portions was added to 6.1 g (37.9 mmol) of 1,1'-carbonyldiimidazole. The obtained light brown solution was heated for 45 min to a temperature of 50oC. Then the solution was cooled to room temperature and was added dropwise 12 ml of an aqueous solution of ammonia. After stirring for 30 min the reaction mixture was poured into 150 ml of ice water and was extracted seven times with methylene chloride. After drying the organic phase over sodium sulfate, filtration and evaporation was obtained a colorless residue, which was thoroughly stirred with methylene chloride. After drying in high vacuum was obtained 9.8 g of the amide (S)-7,8-debtor-9-oxo-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-c] [1,4] benzodiazepine-1-carboxylic acid with MP 221-224oC.

d) a suspension of 10.9 g (a 34.2 mmole) amide (S)-7,8-debtor-9-oxo - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carboxylic acid in 50 ml of dioxane and 10 ml of pyridine at a temperature of 5-8oC was added dropwise with 5.2 ml (37.7 mmol) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at 50oC and then poured into 50 ml ice water. After extraction with methylene chloride (seven times), drying over sodium sulfate, filtration and evaporation and recrystallization from ethanol was obtained is colorless crystals with MP > 250oC.

(e) a suspension of 5.4 g (br93.1 mmole) of potassium carbonate in 150 ml of dimethylformamide at room temperature was added 2.9 g (a 41.9 mmole) of hydroxylamine hydrochloride. Then was added dropwise a solution of 8.9 g (28 mmol) of (S)-7,8-debtor-9-oxo-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carbonitrile in 100 ml of dimethylformamide and stirred for 60 h at room temperature. The obtained yellow suspension was evaporated, the residue was distributed between methylene chloride and water and the aqueous phase was extracted four times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. Subsequent chromatography (silica gel, methylene chloride/methanol 9/1) was obtained 2.4 g (37%) of (E)- and/or (Z)-(S)-7,8-debtor-9-oxo-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine - 1-carboxamide in the form of a colorless foamy substance, Rf=0.1 (silica gel, methylene chloride/methanol 9/1).

g) In a solution of 2.2 g (12.5 mmol) of BOC-glycine in 70 ml of dimethylformamide was added 2.2 g (13.7 mmol) of 1,1'-carbonyldiimidazole and was stirred for 30 min at a temperature of 50oC. Then was added 3.8 g (11.4 mmol) of (E)- and/or (Z)-(S)-7,8-debtor-9-oxo-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazep the Wali in high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 19/1). In this way received 4,2 g (78%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-debtor - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-9-it is in the form of a pale yellow foamy substance, Rf= 0,22 (silica gel, methylene chloride/methanol 19/1).

C) a Solution of 3.3 g (7 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol - 3-yl)-7,8-debtor-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-C] [1,4] benzodiazepine-9-she's in 20 ml triperoxonane acid was stirred for 2 h at room temperature. Then the yellow solution was evaporated, the residue was dissolved in water and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase was podslushivaet 2 ml of an aqueous solution of ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 100/10/0,1). As a result received 2 g (77%) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-7,8-debtor-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4] benzodiazepine-9-it is in the form of powder beige color with MP 218-220oC (decomposition).

Example 100.

To a solution of 650 mg (1,76 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol - 3-yl)-7,8-debtor-11,12,13,13 fileisopen and 0.6 ml (7.0 mmol) of allylbromide and was stirred for 20 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was twice chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/0,1). As a result received 625 mg (78%) of (S)-1-[5-(diallylamine)-1,2,4 - oxadiazol-3-yl] -7,8-debtor-11,1,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,45 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/0,01).

Example 101.

To a solution of 650 mg (1,76 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol - 3-yl)-7,8-debtor-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4] benzodiazepine-9-she's in 40 ml of methylene chloride was added to 2.1 ml (10.5 mmol) of N-ethyldiethanolamine and 0.8 ml (7.0 mmol) of dimethylacrylamide and was stirred for 20 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was twice chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/0,1). As a result received 589 mg (66%) of (S)-1-[5-[bis-(3-methylbut-2-enyl)-aminomethyl] -1,2,4 - ox is about substance, Rfor =0.51 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/0,1).

Example 102.

2 g (5,95 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro - 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4]benzodiazepine - 9-it, 30 ml of N,N-dimethylformamide, 3,1 ml (17.8 mmol) of N-ethyldiethanolamine and 1.1 ml (13.1 mmol) of allylbromide was stirred for 1.5 h at room temperature. Then the reaction mixture was chromatographically on 250 g of silica gel with elution with methylene chloride/ethyl acetate 7/3. As a result received 2 g (81%) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13 a - tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 175-177oC.

Example 103.

2 g (6.2 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, 30 ml of N,N-dimethylformamide, and 3.7 ml (21,7 mmole) of N-ethyldiethanolamine and 1.6 ml (14.3 mmol) of 1-iodobutane was stirred first for 6 h at room temperature, and then another 1.5 hours at a temperature of 80oC. the Reaction mixture was evaporated and the residue was chromatographically on 180 g of silica gel with elution with methylene chloride/ethyl acetate in a ratio of 7/3. After concentration of the homogeneous - 1,4]benzodiazepine-9-it, which was transferred into the hydrochloride.

Example 104.

2 g (6,44 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro - 5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, 20 ml of N,N-dimethylformamide, and 3.3 ml (19.3 mmol) of N-ethyldiethanolamine and 1.65 ml (13.5 mmol) of 3,3-dimethylacrylamide was stirred for 2 h at room temperature. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed with water, dried and concentrated. After chromatography on 220 g of silica gel with elution by metilenhloride/ethyl acetate in a ratio of 1/1 was obtained 1.9 g (69%) of 3-[3-bis-(3-methyl-but-2-enyl)aminomethyl-1,2,4-oxadiazol-5-yl] -5,6-dihydro-5 - methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, which was transferred into the hydrochloride.

Example 105.

2 g (6,44 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro - 5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, 20 ml of N,N-dimethylformamide, and 3.8 ml (22.5 mmole) of N-ethyldiethanolamine and 1.6 ml (14.8 mmol) of bromelicola was stirred for 4 hours at a temperature of 80oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed with water, dried and concentrated. After chromatography on 220 g of silica gel with elwer the-oxadiazol-5-yl]-5,6-dihydro-5 - methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, which translated into hydrochloride with MP 170-174oC.

Example 106.

a) a Suspension of 5.8 g (at 0.020 mole) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo - 4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxamidine in 60 ml of dimethylformamide was treated with 3.9 g (is 0.023 mole) of Chloroacetic anhydride acid. The obtained yellow solution was stirred for 1.5 h at 100 ° oC, and then out completely remove the solvents. The oily product was led from acetonitrile and filtered. The mother liquor was concentrated, the residue was chromatographically on silica gel using the solvent system dichloromethane/methanol in the ratio of 97/3 and received an additional portion of the product was recrystallized from acetonitrile. In this way received a total of 4.05 g (59%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 245-247oC.

b) a Suspension of 1.5 g (0,0043 mole) of 3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-she's in 15 ml of dimethylformamide was treated with 1.6 g (0,022 mol) of diethylamine. After stirring for 16 h at room temperature, the obtained solution is completely udaljala in a ratio of 9/1. The result has been to 1.33 g (81%) of 3-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 172-174oC.

in) of 1.30 g (0,0034 mole) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol - 3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she's in 20 ml of ethanol was treated 0,79 ml (0,0037 mole) 4,78 H hydrochloric acid in ethanol. After addition of 100 ml of simple ether precipitated crystals. As a result received 1.28 g (90%) of the hydrochloride(1:1) 3-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 220-223oC (decomposition).

Example 107.

a) a Suspension of 1.30 g (0,0037 mole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she's in 15 ml of dimethylformamide was treated with 2.4 g is 0.019 mole) of dibutylamine. After stirring for 65 hours at room temperature of the resulting orange solution is fully solvent was removed. The residue was chromatographically on silica gel using the solvent system dichloromethane/methanol in a ratio of 19/1. The product was recrystallized from methanol/simple ether and the way it was obtained 1.27 g (77%) of 3-(5-debutylation with MP 137 - 140oC.

b) of 1.17 g (0,0027 mole) of 3-(5-dibutylamino-1,2,4-oxadiazol-3-yl)-8 - fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she's in 30 ml of ethanol was treated with 0.65 ml (0,0031 mole) of 3.7 H hydrochloric acid in ethanol. Then from the solution fully solvent was removed and the residue was recrystallized from acetone. The result obtained 0.87 g (69%) hydrochloride(1:1) 3-(5-dibutylamino-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it is in the form of white crystals with MP 183-185oC.

Example 108.

a) a Suspension of 1.50 g (0,0043 mole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she's in 15 ml of dimethylformamide was treated with 1.5 g (0,022 mol) of pyrrolidine. After stirring for 65 hours at room temperature of the resulting yellow-orange solution is completely solvent was removed. The residue was chromatographically on silica gel using the solvent system dichloromethane/methanol in a ratio of 19/1. The product was recrystallized from methanol/simple ether. In this way received 1.35 g (82%) of 8-fluoro-5-methyl-3-(5-pyrrolidin-1 - ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a] -[1,4] benzodiazepine-6-it is in the form of white crystals with MP 158-160oC.

oC (decomposition).

Example 109.

a) a suspension of 7.0 g (23 mmole) of ethyl ester of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 70 ml of ethanol was added 13 ml of hydrazine hydrate and the mixture was heated for 3 h under reflux. After cooling to 0oC the obtained crystals were filtered off and the result has been to 6.43 g (96%) hydrazide 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxylic acid in the form of colorless needle-like substances with MP 288-290oC.

b) a Solution of 4.46 g (a 21.75 mmole) of N-phthaloylglycine in 35 ml of dimethylformamide was treated at room temperature 3,66 g (22,6 mmole) of 1,1'-carbonyldiimidazole and then was heated to 50oC. After 30 min, cooled to room temperature, was added to 6.43 g (22,15 mm is whether within 12 h at room temperature. Next, the resulting suspension was filtered and the resulting colorless powder was washed with ethanol and diethyl ether. The way it was obtained 10.2 g (98%) of N'-(2,3-dioxo-2,3-dihydro-1H-isoindole-2-ylacetic)- hydrazide 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid with MP > 280oC.

C) a Solution of 6.0 g (12.6 mmol) of N'-(2,3-dioxo-2,3-dihydro-1H-isoindole-2-ylacetic)-hydrazide 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]-[1,4] benzodiazepine-3-carboxylic acid in 38 g of polyphosphoric acid was stirred for 1.5 h at 100oC. After cooling to room temperature the mixture under vigorous stirring was poured into 300 ml of ice water, after which was added solid sodium carbonate to pH 8. After extraction with methylene chloride and chromatography was carried out (silica gel, methylene chloride/methanol 20/1) was obtained 4.9 g(85%) 2-[5-(8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-3-yl)-1,3,4-oxadiazol-2 - ylmethyl] -2,3-dihydro-1H-isoindole-1,3-dione as a colourless powder with MP > 250oC.

g) a suspension of 4.9 g (10.7 mmol) of 2-[5- (8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-yl)-1,3,4-oxadiazol-2-ylmethyl]-2,3-dihydro-1H-isoindole-1,3-dione in 100 ml of ethanol was added dropwise at 70OK was filtered hot and the resulting yellow powder was washed with ethanol, while the powder does not become colorless. The result was obtained 2.6 g (80%) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-c] [1,4]benzodiazepine-6-it is in the form of a colourless powder with MP 227-231oC.

Example 110.

In the solution 0,656 g (2,0 mol) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-8 - fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-c] [1,4] benzodiazepine-6-she's in 15 ml of dimethylformamide was added 3.5 ml of N-ethyldiethanolamine and 1.1 ml (12 mmol) of 1-bromopropane, after which it was stirred for 12 hours at a temperature of 70oC. Then the dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride; the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 20/1) received 0,450 g (55%) of 3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5-c]-[1,4]benzodiazepine-6-it is in the form of a colorless foamy substance, Rf=0,48 (silica gel, ethyl acetate/methanol 20/1).

Example 111.

In the solution 0,500 g (1.52 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 15 ml dimethylformamid is the temperature value 70oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice extracted with methylene chloride and the organic phase was dried over sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 20/1) received 0,350 g (55%) of (S)-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H - azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e][1,4]diazepin - 8-it is in the form of a colorless foamy substance, Rf=0,44 (silica gel, ethyl acetate/methanol 20/1).

Example 112.

1.04 g (3 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, 0.64 g (7.5 mmol) of piperidine and 10 ml of N, N-dimethylformamide was stirred for 4 h at room temperature. Then the reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution was podslushivaet 4H sodium hydroxide. Then, the solution once washed with a saturated solution of sodium chloride, dried using magnesium sulfate and evaporated. After chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 9/1 received 0,89 g (75%) of 8-fluoro-5-methyl-3-[5-(piperidine-1-ylmethyl)- 1,2,4-oxadiazol-3-yl] -5, b-dihydro-4H-and the ptx2">

Example 113.

Suspension 4.77 g (13.7 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 70 ml of dimethylformamide was treated with 5.6 ml (41,0 mmol) dipropylamine. After stirring for 18 h at room temperature the resulting solution was concentrated and the residue was dissolved in 70 ml of water. Then the crystals were filtered off, washed with 10 ml of water and dried at a temperature of 60oC in vacuum. The residue was chromatographically on 100 g of silica gel using the solvent system dichloromethane/acetone in a ratio of 2/1. The result has been 4,19 g of white crystals. The crystals are recrystallized twice from ethyl acetate and, after drying at 60oC/0.03 mbar received 2,77 g (49%) of 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 153-154oC.

Example 114.

In the solution of the 0,600 g (1.75 mmole) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12 a-tetrahydro-8H - imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepin-8-she's in 30 ml of methylene chloride was added 2.4 ml (13.8 mmol) of N-ethyldiethanolamine and 0.97 ml (8 mmol) of allylbromide, after which it was stirred for 12 hours at a temperature of 70oC. Then reactal with methylene chloride, and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 20/1) received 0,580 g (78%) of (S)-1-(5-diallyldimethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12 a - tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,56 (silica gel, ethyl acetate/methanol 20/1).

Example 115.

In the solution 0,443 g (1.3 mmole) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2 - yl)-10,11,12,12-tetrahydro-8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno [3,2-e] [1,4]diazepin-8-she's in 30 ml of methylene chloride was added 2 ml (11.5 mmol) of N-ethyldiethanolamine and 0.3 ml (2,61 mmole) of dimethylacrylamide, after which it was stirred for 12 hours at a temperature of 70oC. Then the reaction mixture was diluted with methylene chloride and washed 2H solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 10/1) received 0,190 g (30%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl] -1,3,4-oxadiazol-2-yl]- 10,11,12,12 a-tetradehydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno-[3,2-e] [1,4] diazepin-8-it is in the form of a colorless foamy substance, Rf= 0,50 (silica gel, atlatl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e] [1,4]diazepin-8-she's in 30 ml of methylene chloride was added 2 ml (11.5 mmol) of N-ethyldiethanolamine and 0.97 ml (8 mmol) of allylbromide, after which it was stirred for 12 hours at a temperature of 70oC. Then the reaction mixture was diluted with methylene chloride and washed 2H solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 20/1) received 0,476 g (77%) of (S)-1-[5-diallyldimethyl-1,3,4-oxadiazol-2-yl] -11,11 a - dihydro-8H, 10H-azeto[1,2-a]-imidazo[5,1-C] thieno[3,2-e] [1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf= 0,36 (silica gel, ethyl acetate/methanol 20/1).

Example 117.

In the solution 0,426 g (1.3 mmole) of (S)-1-(5-aminomethyl-1,3,4 - oxadiazol-2-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 30 ml of methylene chloride was added 2 ml (11.5 mmol) of N-ethyldiethanolamine and 0.3 ml (2,61 mmole) of dimethylacrylamide, after which it was stirred for 12 hours at a temperature of 70oC. the Reaction solution was diluted with methylene chloride and washed 2H solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic zitat/methanol 40/1) received 0,270 g (44%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)- aminomethyl]-1,3,4-oxadiazol-2-yl]-11,11 a-dihydro-8H,10H-azeto [1,2-a] imidazo[5,1-c] thieno[3,2-e] [1,4] diazepin-8-it is in the form of a colorless foamy substance, Rf=0,24 (silica gel, ethyl acetate/methanol 40/1).

Example 118.

In the solution 0,550 g (1.68 mmole) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2 - yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e] [1,4]diazepin-8-she's in 30 ml of dimethylformamide was added 3 ml (17,25 mmol) of N-ethyldiethanolamine and 0.8 ml (8.8 mmol) of propyl bromide, after which it was stirred for 12 hours at a temperature of 70oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,300 g (43%) of (S)-1-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-11,11 a-dihydro-8H,10H - azeto[1,2-a]imidazo[5,1-c] thieno[3,2-e] [1,4] diazepin-8-it is in the form of a colorless foamy substance, Rf= 0,28 (silica gel, ethyl acetate/methanol 20/1).

Example 119.

In the solution 0,300 g (of 0.87 mmole) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)- 10,11,12,12-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno [3,2-e] [1,4] diazepin-8-she's in 20 ml of dimethylformamide was added 1.5 ml (8.6 mmol) of N-ethyldiethanolamine and 0.4 ml (4.4 mmole) of propyl bromide, after which it was stirred for 12 h at temperance sodium. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 20/1) received 0,140 g (38%) of (S)-1-(5-dipropylamino-1,3,4 - oxadiazol-2-yl)-10,11,12,12-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,28 (silica gel, ethyl acetate/methanol 20/1).

Example 120.

In the solution 0,656 g (2.0 mmole) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-c] [1,4]benzodiazepine-6-she's in 15 ml of dimethylformamide was added 3.5 ml of N-ethyldiethanolamine and 1.29 ml (12 mmol) of 1-bromobutane, after which it was stirred for 12 hours at a temperature of 70oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,470 g (53%) of 3-(5-dibutylamino-1,3,4 - oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is the form of a colorless foamy substance, Rf=0,66 (silica gel, ethyl acetate/IU is, 1H-azeto[2,1-C]imidazo[1,5-a] [1,4]diazepin-1-carboxylic acid in 70 ml of ethanol was added 13 ml of hydrazine hydrate and the mixture was heated for 3 h under reflux. After cooling to 0oC the obtained crystals were filtered off and the result was obtained 3.6 g (96%) hydrazide (S)-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]diazepin-1-carboxylic acid in the form of colorless needle-like substances with MP 246-248oC.

b) a Solution of 5 g (17,64 mmole) hydrazide (S)-12,12-dihydro-9-oxo - 9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid and 3.06 g (19,41 mmol) ethyl ester of chloroacetonitrile in 40 ml of dimethylformamide and 10 ml of ethanol was stirred for 12 h at a temperature of 90oC. the solvent is Then evaporated and the residue was distributed between methylene chloride and water. The aqueous phase is once washed then with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. After chromatography was carried out of the residue (silica gel, methylene chloride/methanol 93/3) received 3,26 g (55%) of (S)-1-(5-chloromethyl-1,3,4 - oxadiazol-2-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,5 (methylene chloride/methanol 10/1).

in Rasta in 10 ml of dimethylformamide was added to 0.94 ml (73 mmole) of dipropylamine, then was stirred for 12 h at room temperature. The dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, methylene chloride/methanol 95/5) got to 0.900 g (65%) of (S)-1-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it is in the form of a colorless foamy substance, Rf=0,46 (silica gel, methylene chloride/methanol 95/5).

Example 122.

To a solution of 4 g (12,18 mmol) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2 - yl)-11,11-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e] [1,4]diazepin-8-she's in 100 ml of dimethylformamide was added to 17.4 ml (100 mmol) of N-ethyldiethanolamine and 7,87 ml (73 mmole) butylbromide, and then was stirred for 12 hours at a temperature of 70oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography was carried out (silica gel, ethyl acetate/methanol 10/1) 4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,4 (silica gel, ethyl acetate/methanol 10/1).

Example 123.

a) a Solution of 5 g (17,28 mmol) hydrazide 8-fluoro-5,6-dihydro-5-methyl-6 - oxo-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid are 2.87 g (18,16 mmol) ethyl ester of chloroacetonitrile in 40 ml of dimethylformamide and 10 ml of ethanol was stirred for 12 h at a temperature of 90oC. the Solvent is evaporated and the residue was distributed between methylene chloride and water. The aqueous phase is once washed then with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. After chromatography was carried out of the residue (silica gel, methylene chloride/methanol 93/3) received 3,66 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol - 2-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it is in the form of colorless crystals with MP 260-262oCC (decomposition).

b) a solution of 2 g (5.8 mmol) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl) -8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it in 50 ml of dimethylformamide was added 1.0 ml (12.7 mmol) of Propylamine, after which it was stirred for 12 hours at a temperature of 55oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is twice the pre chromatography was carried out (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1) received 1.40 g (65%) of (S)-1-(5-propylaminoethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5,6-dihydro-5 - methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it is in the form of a colorless foamy substance, Rf=0,49 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 124.

a) Suspension of 3.06 g (which 9.22 mmol) hydrazide (S)-8-chloro-9-oxo-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carboxylic acid in 30 ml of N,N-dimethylformamide was treated with 1.97 g (0,0115 mole) of Chloroacetic anhydride acid. The obtained yellow solution was stirred for 1.5 h at room temperature and then out completely remove the solvents. The residue is suspended in a simple ether and was filtered by suction. The obtained crystals beige (3.75 g, MP 262 to 264oC (decomposition)) was treated with 27 ml of methanesulfonate and 3 g of phosphoric anhydride, after which it was stirred for 65 h at room temperature. Orange-brown solution was poured into 150 ml of ice water, podslushivaet aqueous solution of sodium hydroxide and was extracted with methylene chloride. The crystalline product was chromatographically on silica gel in ethyl acetate as eluent. The result has been 2,03 g (56%) of (S)-8-chloro-1-(5-christelow; MP 230-232oC and []2D0= +104,5oC (DMF, C=1%).

b) a Suspension of 1.30 g (3.33 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,3,4 - oxadiazol-2-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-9-it in 10 ml of N,N-dimethylformamide was treated with 1.7 g (of 0.017 mole) of dipropylamine. After stirring during the first 20 h at room temperature and then for 4 h at 80oC from the resulting solution were completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether. In this way they obtained 1.27 g (85%) of (S)-8-chloro-1-(5-dipropylamino-1,3,4-oxadiazol-2 - yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4]benzodiazepine-9-it is in the form of white crystals; MP 158-160oC and []2D0= +48,8oC (CH2Cl2with=1%).

in) 1.27 g (2,79 mmole) of (S)-8-chloro-1-(5-dipropylamino-1,3,4 - oxadiazol-2-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-9-she's in 30 ml of ethanol was treated 0,83 ml (of 3.07 mmole) of 3.7 H hydrochloric acid in ethanol. After stirring for 15 min at 0oC the solution was treated dropwise 150 ml of simple ether and the resulting white, susp the-1,3,4-oxadiazol-2-yl)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it is in the form of white crystals; MP 204-206oC and []2D0= -43,6oC (H2O, s= 1%).

Example 125.

(a) In suspension vs. 5.47 g (0,00162 mole) of the ethyl ester of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid in 55 ml of ethanol was added to 9.15 ml of hydrazine hydrate and the mixture was heated for 18 h under reflux. After cooling to 0oC the obtained crystals were filtered off and as a result received 3.28 g (63%) hydrazide 7-chloro-8-fluoro-5-methyl - 6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3 - carboxylic acid as white crystals with MP 308-310oC.

b) a Suspension of 0.50 g (0,00154 mole) of the hydrazide 7-chloro-8-fluoro-5-methyl-6 - oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid in 5 ml of N, N-dimethylformamide was treated with 0.33 g (0,00193 mole) of Chloroacetic anhydride acid. The resulting solution was stirred for 1.5 h at room temperature, resulting in the obtained suspension. Then was cooled to 0oC, was treated with 40 ml of simple ether and was filtered by suction. The obtained white crystals (0,643 g, MP 264-266oC (decomposition)) was treated with 4.5 ml of methansulfonate and 0.5 g of phosphoric anhydride, after which the mixture was heated and the solution was stirred during the course ivali aqueous solution of sodium hydroxide and was extracted with methylene chloride. The crystalline product was chromatographically on silica gel with ethyl acetate as eluent. In the received rate of 0.193 g (33%) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-8-fluoro - 5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 234-236oC.

C) a Suspension rate of 0.193 g (of 0.51 mmole) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 2 ml of N,N-dimethylformamide was treated with 0.26 g (to 2.55 mmole) of dipropylamine. After stirring for 17 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether/n-hexane at a temperature of 0oC. as a result received 0,094 g (41%) of 7-chloro-3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it is in the form of white crystals with MP 128-130oC.

g) 0,094 g (of 0.21 mmole) of 7-chloro-3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 10 ml of ethanol was treated 0,062 ml (0,23 mmole) of 3.7 H hydrochloric acid in ethanol. After paramasivan in 20 ml simple ether and was filtered by suction. The result was obtained 0.84 g (83%) of hydrochloride (1:1) 7-chloro-3-(5-dipropylamino - 1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepine-6-it is in the form of white crystals with MP 152-154oC.

Example 126.

a) 4.4 g (14.1 mmol) (12.3 mmol) of the hydrazide of (S)-8-chloro-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid was stirred over night in 30 ml of N,N-dimethylformamide with 2.65 g (15.5 mmol) of Chloroacetic anhydride acid at room temperature. After evaporation of the solvent the residue was stirred for 48 h with 20 ml of 10% aqueous solution of phosphoric anhydride in methansulfonate at room temperature. Then the reaction mixture was treated with ice, podslushivaet concentrated sodium hydroxide and was extracted four times with methylene chloride by shaking. After drying the organic phase over magnesium sulfate and evaporation of solvent received 3,39 g (60%) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it MP 185-189oC.

b) 1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred over the weekend with 1.12 g (11 mm the residue was dissolved in methylene chloride and the solution was twice washed with water and dried over magnesium sulfate. After evaporation of the solvent and crystallization of the residue from ethyl acetate and hexane were obtained 2.15 g (98%) of (S)-8-chloro-1-(5-dipropylamino-1,3,4-oxadiazol-2-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it MP 134-136oC, which was transferred into the hydrochloride with MP 235-237oC.

Example 127.

a) 9.4 g (34.7 mmol) of the hydrazide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid for 3 h and stirred in 75 ml of N,N-dimethylformamide from 27.1 g (41.5 mmole) of Chloroacetic anhydride acid at room temperature. After evaporation of the solvent the residue during the night was stirred with 75 ml of 10% aqueous solution of phosphoric anhydride in methansulfonate at room temperature. Then the reaction mixture was treated with ice, podslushivaet concentrated sodium hydroxide and was extracted four times with methylene chloride by shaking. After drying the organic phase over magnesium sulfate, evaporation of solvent and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was obtained 6.9 g (61%) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 221-222oC.

b) 0.33 g (1 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl) and 5 ml of N,N-dimethylformamide at room temperature. After evaporation of the solvent and chromatography was carried out of the residue on silica gel with elution by ethyl acetate/ethanol in a ratio of 9/1 was obtained 0.31 g (84%) of 3-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 235-238oC.

Example 128.

a) 50 g (156,4 mmol) ethyl-7-chloro-5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate was stirred for 6 h with 90 ml of 1.85 mmole) of hydrazine hydrate and 500 ml of ethanol at boiling point. After cooling to -10oC, filter the suspension on the suction and drying kristalliset received 51.9 g (100%) hydrazide 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid MP 287oC.

b) and 15.3 g (50 mmol) of hydrazide 7-chloro-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid was stirred over night in 160 ml of N,N-dimethylformamide with 9,41 g (55 mmol) of Chloroacetic anhydride acid at room temperature. After evaporation of the solvent the residue over the weekend was stirred with 100 ml of 10% aqueous solution of phosphoric anhydride in methansulfonate at room temperature. Then the reaction mixture obrabatyvaniyu. After drying the organic phase over magnesium sulfate, evaporation of solvent and chromatography was carried out of the residue on silica gel with elution by ethyl acetate were obtained 9.7 g (53%) of 7-chloro-3-(5-chloromethyl - 1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]-benzodiazepine-6-one with MP 201-203oC.

in) of 1.09 g (3 mmole) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 1.5 g (11.6 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was received 1,09 g (79%) of 7-chloro-3-(5-dibutylamino-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 105-108oC.

Example 129.

1,09 g (3 mmole) of 7-chloro-3-(5-dibutylamino-1,3,4-oxadiazol-2-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 1 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was received 1,17 g (91%) of 7-chloro-3-(5-dipropyl hydrochloride with MP 188-195oC.

Example 130.

1,09 g (3.0 mmole) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred overnight with 1 g (13.7 mmol) of diethylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation reaktsionnoi mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate/ethanol in a ratio of 9/1 was obtained 1.18 g (98%) of 7-chloro-3-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it, which was transferred into the hydrochloride with MP 188-195oC.

Example 131.

10 g (30.3 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 7 h with 10.1 g (100 mmol) of dipropylamine and 70 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from ethyl acetate received 7,42 g (62%) of 3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 126-127oC, which was transferred into the hydrochloride with MP 208-210oC.

Example 132.

oC. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was given to 0.72 g (85%) of 3-(5-dibutylamino-1,3,4 - oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it, which was transferred into the hydrochloride with MP 211-213oC.

Example 133.

1.64 g (5 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred over night from 1.62 g (12.5 mmol) of diisobutylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate was received 1.63 g (77%) of 3-(5-diisobutylamine - 1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 138-140oC, which was transferred into the hydrochloride with MP 177-180oC.

Example 134.

1,09 g (3.0 mmole) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-6-it was stirred over night with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution by ethyl acetate, polain-6-it MP 181-182oC, which was transferred into the hydrochloride with MP 161-163oC.

Example 135.

1.64 g (5.0 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred over night with 1.07 g (12.5 mmol) of piperidine and 40 ml of dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from acetic acid ethyl ester was obtained 1.3 g (68%) of 5-methyl-3-[5-(piperidine-1-yl)methyl-1,3,4-oxadiazol-2-yl] -5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 160-162oC, which was transferred into the hydrochloride with MP 255-257oC.

Example 136.

1.64 g (5.0 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 3 ml (21 mmol) of Diisopropylamine and 30 ml of N,N-dimethylformamide at a temperature of 70oC. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from ethyl acetate received 1,32 g (67%) of 3-(5-diisopropylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [EP 137.

1.64 g (5.0 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred for nights of 2.26 g (17.5 mmol) debtor.-of butylamine and 25 ml of N,N-dimethylformamide at a temperature of 75oC. After evaporation of the reaction mixture and chromatography was carried out of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from ethyl acetate were obtained 1.35 g (64%) of 3-(5-diver. -butylaminoethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 80-83oC, which was transferred into the hydrochloride (amorphous).

Example 138.

To a solution of 340 mg (1.0 mmol) of (S)-1-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-C]pyrrolo [1,2-a]thieno[3,2-e][1,4] diazepin-8-she's in 15 ml of methylene chloride was added to 0.87 ml (5.0 mmol) of N-ethyldiethanolamine and 0.17 ml (2.1 mmole) of allylbromide and the mixture was stirred for 12 h at room temperature. Then the reaction mixture was diluted with methylene chloride and washed three times with water. The organic phase was dried over magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 250/10/1). The result obtained 280 mg (66%) of (S)--she Rf=0,41 (silica gel, ethyl acetate).

Example 139.

In a solution of 756 mg (2.0 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11 a-dihydro - 8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 20 ml of methylene chloride was added 2.4 ml (13.8 mmol) of N-ethyldiethanolamine and 0.67 ml (8.0 mmol) of allylbromide and the mixture was stirred for 20 h at room temperature. Then the solution was diluted with methylene chloride and washed three times with water. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1). As a result received 645 mg (79%) of (S)-1-(5-diallyldimethyl-1,2,4 - oxadiazol-5-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-C] thieno [3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,52 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1).

Example 140.

In a solution of 453 mg (1.2 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-C]thieno[3,2-e] [1,4]diazepin-8-she's in 20 ml of methylene chloride was added 1.5 ml (8.6 mmol) of N-ethyldiethanolamine and 0.28 ml (2.4 mmole) of dimethylacrylamide and the mixture was stirred for 20 h at room temperature. Then the reaction RNA, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1). As a result received 240 mg (43%) of (S)-1-[3-bis-[3-methylbut-2-enyl)-aminomethyl]-1,2,4 - oxadiazol-5-yl]-11,11 a-dihydro-8H,10H-azeto[1,2-a] imidazo [5,1-C]thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,55 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1).

Example 141.

Into a solution of 600 mg (1.9 mmole) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-she's in 20 ml of dimethylformamide was added 4 ml (8.6 mmol) of N-ethyldiethanolamine and 1.1 ml (12 mmol) of 1-bromopropane and the mixture was stirred for 12 hours at a temperature of 70oC. Then the reaction mixture was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1). The result is received 410 mg (54%) of (S)-1-(3-dipropylamino-1,2,4-oxadiazol-5-yl)-11,11 a-dihydro-8H,10H - azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4] diazepin-8-it is in the form bescoto is.

To a solution of 340 mg (1.0 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol - 3-yl)-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno [3,2-e] [1,4] diazepin-8-it in 10 ml of dimethylformamide was added 1,74 ml (10 mmol) of N-ethyldiethanolamine and 0.55 ml (6 mmol) of 1-bromopropane and the mixture was stirred for 12 hours at a temperature of 70oC. Then the reaction solution was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 240/10/1). The result has been 162 mg (38%) of (S)-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-10,11,12,12 a-tetrahydro-8H-imidazo [5,1-C] pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepin-8-it, Rf= 0,26 (silica gel, ethyl acetate/methanol 40/1).

Example 143.

In a solution of 1.5 g (4,74 mmole) 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-it in 40 ml of dimethylformamide was added 7 ml (23 mmole) of N-ethyldiethanolamine and 0.9 ml (9.9 mmol) of 1-bromopropane, and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, after which Ottorino. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 250/10/1). The result has been 930 mg (49%) of 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] thieno[2,3-f] [1,4] diazepin-6-it MP 128,5-130,0oC.

Example 144.

In a solution of 0.6 g (1.9 mmole) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)- 5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-6-she's in 20 ml of dimethylformamide was added 4 ml (23.4 mmole) of N-ethyldiethanolamine and 1.1 ml (12 mmol) of 1-bromopropane and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction mixture was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, ethyl acetate/methanol 25/1). As a result received 440 mg (57%) of 3-(3-dipropylamino-1,2,4-oxadiazol-5-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f]- [1,4]diazepin-6-it is in the form of a colorless foamy substance, Rf=0,34 (silica gel, ethyl acetate/methanol 25/1).

P] thieno[2,3-f] [1,4]diazepin-4 - it in 50 ml of dimethylformamide was added 7.5 ml (43.6 mmole) of N-ethyldiethanolamine and 2.3 ml (25.3 mmol) of 1-bromopropane and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). As a result received 250 mg (10%) 7-(5-dipropylamino-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f]- [1,4]diazepin-4-it is in the form of a colorless foamy substance, Rf= 0,46 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 146.

To a solution of 2.0 g (6.3 mmol) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a]thieno[3,2-f][1,4]diazepin-4-it in 50 ml of dimethylformamide was added to 3.75 ml (to 21.8 mmole) of N-ethyldiethanolamine and 1.15 ml (12.7 mmol) of 1-bromopropane and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographical the 2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4]- diazepin-4-it is in the form of a colorless foamy substance, Rf= 0,31 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 147.

In a solution of 1.0 g (3,16 mmole) of 7- (5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] thieno[3,2-f][1,4]diazepin-4-she's in 30 ml of dimethylformamide was added to 3.7 ml (to 21.8 mmol) of N-ethyldiethanolamine and 1.4 ml (12.6 mmol) of 1-bromobutane and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). As a result received 290 mg (22%) 7-(5-dibutylamino-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]- diazepin-4-it is in the form of a colorless foamy substance, Rf= 0,37 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 148.

In a solution of 1.0 g (3,16 mmole) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4]diazepin-4-she's in 30 ml of dimethylformamide was added to 1.85 ml (10.9 mmol) of N-ethyldiethanolamine and 0.7 ml (6.3 in Aravali, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). As a result received 290 mg (25%) 7-(5-butylaminoethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a]thieno[3,2-f][1,4]-diazepin-4-it is in the form of a colorless foamy substance, Rf= 0,37 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 149.

In a solution of 1.0 g (3,16 mmole) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a]thieno[3,2-f][1,4]diazepin-4-she's in 30 ml of dimethylformamide was added to 3.75 ml (to 21.8 mmol) of N-ethyldiethanolamine and 0.94 ml (12.6 mmol) of 1-brometea and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia is ieno[3,2-f][1,4]-diazepin-4-it is in the form of a colorless foamy substance, Rf= 0,56 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 150.

In a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-6-she's in 20 ml of dimethylformamide was added 2.35 ml (13.6 mmol) of N-ethyldiethanolamine and 1.1 ml (10.2 mmol) of butylbromide and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). As a result received 265 mg (36%) of 3-(5-dibutylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-6-it is in the form of a colorless foamy substance, Rf= 0,73 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 151.

In a solution of 0.54 g (1.7 mmol) of 3-(5-aminomethyl - 1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-6-she's in 20 ml of dimethylformamide was added 2.35 ml (13.6 mmol) of N-ethyldiethanolamine and from 0.76 ml (who was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). As a result received 301 mg (47%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]- diazepin-6-it is in the form of a colorless foamy substance, Rf= 0,66 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 152.

In the solution 0,500 g (1.52 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl) -11,11 a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e] [1,4]diazepin-8-she's in 15 ml of dimethylformamide was added to 0.87 ml of N-ethyldiethanolamine and 0.28 ml (3 mmole) of 1-bromopropane, after which it was stirred for 12 hours at a temperature of 70oC. the Dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was extracted twice with methylene chloride and the organic phase was dried over sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,324 g (57%) of (S)-1-(5 - propylaminoethyl substances, Rf= 0,24 (silica gel, ethyl acetate/methanol 20/1).

Example 153.

In a solution of 0.54 g (1.7 mmole) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-she's in 20 ml of dimethylformamide was added at 1.17 ml (6.8 mmol) of N-ethyldiethanolamine and 0.55 ml (5.1 mmol) of butylbromide and the mixture was stirred for 1 h at a temperature of 70oC. Then the reaction solution was evaporated, then the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase is washed three times with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1). The result obtained 310 mg (47%) of 3-(5-butylaminoethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a]thieno[2,3-f] [1,4]-diazepin-6-it is in the form of a colorless foamy substance, Rf=0,73 (silica gel, methylene chloride/methanol/aqueous ammonia 110/10/1).

Example 154.

a) a Freshly prepared solution of sodium methylate in methanol (53,46 g (2,32 mole) of sodium in 1 liter of methanol) was added dropwise over 10 min to a suspension 141,4 g (2,32 mole) of hydroxylamine hydrochloride in 1.2 l of methanol, after which peret processed portions 433 g (2,32 mole) of phthalimidomethyl (see Ber. 55, 2961 (1921)) so that the temperature did not exceed 40oC. the Suspension was stirred overnight, filtered and the obtained crystals were dried at 60oC/10 Torr. In this way received 475 g (E and/or Z)-N'-hydroxy-1,3-dioxo-2 - azaindolizines in the form of colorless crystals with MP 192-195 (in Russian)oC.

b) a suspension of 50 g (228 mmol) of (E and/or Z)-N'-hydroxy-1,3-dioxo-2-azaindolizines in 1 l of dimethylformamide portions were added 40 g (228 mmol) of Chloroacetic anhydride of the acid, and then was stirred for 2 h at room temperature. Then for 20 h was heated to 100oC, after which the brown solution was evaporated and distributed between methylene chloride and water. The aqueous phase is repeatedly washed with methylene chloride. The organic phase was dried with magnesium sulfate, filtered and evaporated. The residue was first chromatographically (silica gel, methylene chloride/ethyl acetate 20/1), and then was led from methylene chloride/diethyl ether. The result obtained 36 g (57%) of 2-(5-chloromethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3 - dione with a MP of 96.5-98oC.

C) In a solution of 36 g (130 mmol) of 2-(5-chloromethyl-1,2,4-oxadiazol-3 - ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in 300 ml of methylene chloride at room atoi temperature. The yellow solution was washed with a saturated solution of sodium bicarbonate, dried with sodium sulfate, filtered and evaporated. The resulting residue was chromatographically (silica gel, methylene chloride/aqueous ammonia 19/1). The result obtained 38 g (85%) of 2-(5-dipropylamino - 1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in the form of oil beige, Rf=0,12 (silica gel, methylene chloride/aqueous ammonia 19/1).

g) In a solution of 38 g (111 mmol) of 2-(5-dipropylamino-1,2,4-oxadiazol-3-ylmethyl)-2,3 - dihydro-1H-isoindole-1,3-dione in 300 ml of ethanol was added dropwise to 400 ml of methylamine (33% in ethanol). Then was stirred for 1.5 h at a temperature of 70oC and evaporated. The residue is thoroughly stirred in methylene chloride and filtered. The filtrate was concentrated and chromatographically (silica gel, methylene chloride/methanol 19/1). The result has been 15.6 g (66%) (3-aminomethyl-1,2,4-oxadiazol-5-ylmethyl)-dipropylamine in the form of a yellow oil, Rf=0,25 (silica gel, methylene chloride/methanol 9/1).

d) a Solution of 15.6 g (of 73.5 mmole) of (3-aminomethyl-1,2,4-oxadiazol-5 - ylmethyl)-dipropylamine in 100 ml of methyl ester of formic acid was heated for 7 hours under reflux. Then, the solution was evaporated and the residue chromakeyer-3-ylmethyl)-formamide, Rf=0,28 (silica gel, methylene chloride/methanol 19/1).

(e) In a solution of 2.4 g (10 mmol) of N-(5-dipropylamino-1,2,4-oxadiazol-3-ylmethyl)-formamide in 25 ml of methylene chloride and 4.3 ml (30 mmol) of Diisopropylamine at a temperature of 0oC was added dropwise to 0.92 ml (10 mmol) of phosphorus oxychloride in 5 ml of methylene chloride and was stirred for 45 min at 0oC. Then the solution was poured into ice water and was extracted twice with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and evaporated. Obtained 5-(dipropylamino-1,2,4-oxadiazol-3-ylmethyl)isocyanide without further purification used in the reaction described below in paragraph (g).

g) a Solution of 7.23 g (42,75 mmole) 6H-thieno[2,3-d][1,3]oxazin - 4,6(7H)-dione (see Journ. Chem. Res. (M), 1986, 1459) and 1.99 g (24,75 mmole) L-azetidine-2-carboxylic acid in 30 ml of dimethylformamide and 6 ml of acetic acid was stirred at a temperature of 120oC for 16 hours Then the brown solution was evaporated and the resulting brown residue was led from ethanol. In this way received 3,74 g (42%) (S)-7,7 a-dihydroiso[1,2-a]thieno[2,3-e][1,4]diazepin of 4.8(6H,9H)-dione in the form of colorless needle-like substances with MP 272-274oC.

C) In a suspension of 0.45 g (10.3 mmol) NaH (55%, flushing Gex is routeto[1,2-a]thieno[2,3-e][1,4]diazepin of 4.8(6H,9H)-dione in 20 ml of dimethylformamide, then was stirred for 40 min at -30oC. After cooling to -60oC was added dropwise a solution of 2 ml (9.3 mmol) of acid chloride of diphenyl ether phosphoric acid so that the temperature did not exceed -45oC. continued to stir for another 30 minutes

Simultaneously, prepare a solution of 1.2 g (10.3 mmol) of tert. -butyl potassium in 20 ml of dimethylformamide, treated at a temperature of -60oC 2.2 g (10 mmol) 5-(dipropylamino-1,2,4-oxadiazol-3 - ylmethyl)isocyanide in 20 ml of dimethylformamide. Cooked this way the solution at -70oC through cooled to -40oC addition funnel was added dropwise the above solution. The obtained viscous solution dark brown continued to stir for 1 h at -60oC and after neutralization with 10 ml of acetic acid at -40oC was poured into ice water, then was extracted three times with methylene chloride. The combined organic phases were dried with sodium sulfate, filtered and evaporated. After chromatography of the residue (silica gel, ethyl acetate/methanol 20/1) received 0,370 g (10%) (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H,10H - azeto[1,2-and the tat/methanol 20/1).

Example 155.

To a suspension of 0.45 g (10.3 mmol) NaH (55%, washing with hexane) in 10 ml of N, N-dimethylformamide at a temperature of -30oC was added dropwise a solution of 1.94 g (9.3 mmol) of 6-fluoro-3,4-dihydro-4-methyl-2H-1,4 - benzodiazepine-2,5-(1H)-dione (see European patent application EP-A 0027214) in 20 ml of N,N-dimethylformamide, after which it was stirred for 40 min at -30oC. After cooling to -60oC was added dropwise a solution of 2 ml (9.3 mmol) of acid chloride of diphenyl ether phosphoric acid in 5 ml of N,N-dimethylformamide so that the temperature did not exceed -45oC. continued to stir for 30 minutes at a time with this prepared solution of 1.2 g (10.3 mmol) of tert. -butyl potassium in 20 ml of N,N-dimethylformamide, at a temperature of -60oC was treated with 2.2 g (10 mmol) 5-(dipropylamino-1,2,4-oxadiazol-3-ylmethyl)-isocyanide in 20 ml of N,N-dimethylformamide. Cooked this way the solution at -70oC through cooled to -40oC addition funnel was added dropwise the above mixture. The resulting viscous solution is dark brown in color and was stirred for 1 h at -60oC and after neutralization with 10 ml of acetic acid at -40oC was poured into ice sadria, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) got to 0.480 g (12%) 7-fluoro-5-methyl-3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of a colorless foamy substance, Rf= 0,26 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1).

Example 156.

a) a Solution of 10 g (55.2 mmol) 5-fluoro-2H-3,1-benzoxazin - 2,4(1H)-dione and to 5.66 g (55.2 mmol) of L-azetidine-2-carboxylic acid in 75 ml of dimethylformamide and 15 ml of acetic acid was stirred at a temperature of 120oC for 16 hours Then the brown solution was evaporated and the resulting brown residue was led from ethanol. As a result received 6 g (42%) of (S)-5-fluoro-1,2,4,9,10,10 a-hexahydrate[2,1-C] [1,4] benzodiazepine - 4,10-dione in the form of needle-shaped substances beige color with MP 232-233,5oC.

b) a suspension of 0.45 g (10.3 mmol) NaH (55%, washing with hexane) in 10 ml of dimethylformamide at a temperature of -30oC was added dropwise a solution of 2.05 g (9.3 mmol) of (S)-5-fluoro-1,2,4,9,10,10 a-hexahydrate[2,1-C] [1,4] benzodiazepine-4,10-dione in 20 ml of dimethylformamide and stirred for 40 min at 30oC. After cooling to -60oC was added dropwise a solution of 2 ml (9.3 mmol) of acid chloride of di is>
C. Then continued to stir for 30 minutes at a time with this prepared solution of 1.2 g (10.3 mmol) of tert.-the butyl potassium in 20 ml of dimethylformamide, at a temperature of -60oC was treated with 2.2 g (10 mmol) 5-(dipropylamino-1,2,4-oxadiazol-3-ylmethyl)-isocyanide in 20 ml of dimethylformamide. Cooked this way the solution at -70oC through cooled to -40oC addition funnel was added dropwise the above mixture. The resulting viscous solution is dark brown in color and was stirred for 1 h at -60oC and after neutralization with 10 ml of acetic acid at -40oC was poured into ice water, then was extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,360 g (9%) (S)-8-fluoro-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine - 9-it is in the form of a colorless foamy substance, Rf=0,28 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1).

Example 157.

To a suspension of 0.45 g (10.3 mmol) NaH (55%, washing with hexane) in 10 ml of dimethylformamide in temp is diazepin-4,10 - dione in 20 ml of N,N-dimethylformamide and stirred for 40 min at -30oC. After cooling to -60oC was added dropwise a solution of 2 ml (9.3 mmol) of acid chloride of diphenyl ether phosphoric acid in 5 ml of N, N-dimethylformamide so that the temperature did not exceed -45oC. Then continued to stir for 30 minutes at a time with this prepared solution of 1.2 g (10.3 mmol) of tert.-the butyl potassium in 20 ml of N,N-dimethylformamide, at a temperature of -60oC was treated with 2.2 g (10 mmol) 5-(dipropylamino-1,2,4 - oxadiazol-3-ylmethyl)-isocyanide in 20 ml of N,N-dimethylformamide. Cooked this way the solution at -70oC through cooled to -40oC addition funnel was added dropwise the above mixture. The resulting viscous solution is dark brown in color and was stirred for 1 h at -60oC and after neutralization with 10 ml of acetic acid at -40oC was poured into ice water, then was extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,380 g (9%) (S)-7,8-debtor-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] -[1,4] benzodiazepine-9-it is in the form boe Example 158.

a) a solution of 2.8 g (9,68 mmol) of (E)- and/or (Z)-(S)-1-(aminohydrocinnamic)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c] thieno[3,2-e][1,4]diazepin-8-she's in 25 ml of N,N-dimethylformamide was added to 1.9 g (11.1 mmol) of Chloroacetic anhydride acid and was stirred for 1.5 h at room temperature. Then was heated for 2 h to 105oC. the Solution was evaporated and the residue was distributed between 2H sodium hydroxide and methylene chloride. The aqueous phase was then washed with methylene chloride and the organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was led from methylene chloride/ethanol. The result was obtained 2.4 g (71%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11 a - dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e] [1,4] diazepin-8-it is in the form of powder beige color with MP 210-213oC.

b) a suspension of 400 mg (1.15 mmole) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H,10H-azeto[1,2-a]imidazo [5,1-C]thieno[3,2-e][1,4] diazepin-8-it in 10 ml of N,N-dimethylformamide was added to 0.36 ml (3.45 mmole) of diethylamine and was stirred for 12 h at room temperature. Then, the solution was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was extracted with methylene chloride, and organicheskimim/methanol 10/1). In this way received 410 mg (92%) of (S)-1-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo [5,1-C] thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,31 (silica gel, ethyl acetate/methanol 10/1).

Example 159.

To a suspension of 400 mg (1.15 mmole) of (S)-1-(5-chloromethyl - 1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c] thieno[3,2-e][1,4] diazepin-8-it in 10 ml of N,N-dimethylformamide was added 0.6 ml (3.45 mmol) of dibutylamine and was stirred for 12 h at room temperature. Then, the solution was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was extracted with methylene chloride and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographically (silica gel, methyl acetate/methanol 10/1). In this way received 425 mg (84%) of (S)-1-(5-dibutylamino-1,2,4-oxadiazol-3-yl)-11,11-dihydro - 8H, 10H-azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,31 (silica gel, methyl acetate/methanol 10/1).

Example 160.

To a suspension of 400 mg (1.15 mmole) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-it in 10 ml of N,N-dimethylfuran was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was extracted with methylene chloride and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographically (silica gel, methyl acetate/methanol 15/1). In this way received 375 mg (82%) of (S)-l-(5-piperidine-1-ylmethyl-1,2,4 - oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-C] thieno [3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,22 (silica gel, methyl acetate/methanol 15/1).

Example 161.

a) In the solution 18,92 g (68,48 mmol) of (E)- and/or (Z)-3-(aminohydrocinnamic)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4] diazepin-6-it in 250 ml of N,N-dimethylformamide was added 13,44 g (78.5 mmol) of Chloroacetic anhydride acid and was stirred for 1.5 h at room temperature. Then for 2 h was heated to a temperature of 105oC. the Solution was evaporated and the residue was distributed between 2H sodium hydroxide and methylene chloride. The aqueous phase was then washed with methylene chloride and the organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was led from methylene chloride/ethanol. The result obtained 18 g (78%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] thieno[2,3-f] [1,4]diazepin-6-it is in the form of powder beige with whom idazo[1,5-a] thieno[2,3-f][1,4]diazepin-6-she's in 30 ml of N, N-dimethylformamide was added to 0.73 ml (9 mmol) of Propylamine and was stirred for 12 h at room temperature. The solution was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was extracted with methylene chloride and the organic phase was dried, filtered and evaporated. The residue was chromatographically (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1). In this way received 0,86 g (80%) of (S)-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-11,11 a-dihydro-8H, 10H - azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,38 (silica gel, methylene chloride/methanol/aqueous ammonia 140/10/1).

Example 162.

0,93 g (3.0 mmole) of 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred over night with 0.51 g (3.0 mmole) of benzylbromide and 0.52 g (4.0 mmole) of N-ethyldiethanolamine in 10 ml of methylene chloride at room temperature. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate/methanol 6/1 received 3-(3-benzylamino - 1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-he that was transferred into the hydrochloride (0.25 g; 17%) with MP 195-198oC.

oC. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 3-{ 3-[bis-(Penta-4-enyl)aminomethyl] -1,2,4-oxadiazol-5-yl} -5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-he that was transferred into the hydrochloride (0.55 g; 38%) with MP 167-169oC.

Example 164.

3.4 g (10 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-6-it was stirred over the weekend with 2.7 g (20 mmol) 4-bromo-1-butene and 2.7 g (23 mmole) of N-ethyldiethanolamine in 30 ml of N, N-dimethylformamide at a temperature of 70oC. After evaporation of the solvent and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and after recrystallization from ethyl acetate received 0,61 g(13,5%) 3-{3-[bis-(but-3-enyl)-aminomethyl] - 1,2,4-oxadiazol-5-yl} -7-chloro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 143-145oC, which was transferred into the hydrochloride with MP 145-150oC.

Example 165.

a) a suspension of 17 g (64.6 mmole) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4]diazepin-7-carboxylic acid (see European patent application EP 00285837 A1) in 100 ml of N,N-dimethylformamide portions was added to 11.5 g (71 mmol) of 1,1'-carbonylbis and to room temperature and was added dropwise 20 ml of an aqueous solution of ammonia. After stirring for 30 min the reaction mixture was poured into 100 ml ice water and the precipitate was filtered and washed first with water, ethanol, and then a simple ether. After drying at 70oC/10 Torr received 15 g (89%) of amide 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4] diazepin-7-carboxylic acid as colorless crystals with MP > 250oC.

b) a suspension of 15 g (57.2 mmol) of amide 5-methyl-4-oxo-5,6-dihydro - 4H-imidazo[1,5-a] thieno[3,2-f] [1,4] diazepin-7-carboxylic acid in 80 ml of dioxane and 20 ml of pyridine at a temperature of 5-8oC was added dropwise to 8.7 ml (62.9 mmole) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at a temperature of 50oC, then poured into 220 ml of ice water. The precipitate was filtered. After drying at 70oC/10 Torr received 12,70 g (91%) of the nitrile 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4]diazepin-7 - carboxylic acid as a white powder with MP 197-200oC.

C) In a freshly prepared solution of sodium methylate in methanol (1.1 g (49.9 mmol) of sodium in 200 ml of methanol) was added 8.7 g (35.6 mmol) of the nitrile 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f] [1,4]diazepin-7-carboxylic colmerauer. Then the suspension was evaporated and the residue was treated with 100 ml of water. The precipitate was filtered and dried in high vacuum. The result has been of 7.70 g (78%) of (E)- and/or (Z)-7-(aminohydrocinnamic)- -5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4]diazepin-4 - it is in the form of colorless powder, MP 216-217oC.

g) In a solution of 5.40 g (30.5 mmol) of BOC-glycine in 150 ml of N,N-dimethylformamide was added to 5.40 g (a 33.3 mmole) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. Then was added of 7.70 g (7,58 mmol) of (E)- and/or (Z)-7-(aminohydrocinnamic)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno [3,2-f][1,4]diazepin-4-it was stirred for 15 h at a temperature of 90oC. the Obtained brown solution was evaporated under high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 19/1). In this way received of 8.40 g (73%) of 7-(5-BOC-aminomethyl-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno[3,2-f] [1,4] diazepin-4-it is in the form of a colorless foamy substance, Rf=0,35 (silica gel, methylene chloride/methanol 19/1).

d) a Solution of 8.40 g (20.2 mmol) of 7-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f] [1,4]diazepin-4-it in 50 ml triperoxide in water and the aqueous phase is washed three times with methylene chloride. Next, the water phase was podslushivaet 10 ml of an aqueous solution of ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting residue was led from methylene chloride/ethanol. As a result received 5 g (78%) of 7-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] thieno[3,2-f] [1,4] diazepin-4-it is in the form of powder beige color with MP 181-183oC.

Example 166.

2,98 g (a 9.25 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred for 60 h with 3.2 g (25 mmol) of N-ethyldiethanolamine and 2.5 g (18.5 mmol) of 4-bromo-1-butene in 20 ml of N,N-dimethylformamide at a temperature of 75oC. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate was received of 0.62 g (15%) of (S)-1-{3-[bis-(but-3-enyl)aminomethyl] -1,2,4-oxadiazol-5-yl} -12,12 a-dihydro-9H,11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 80-87oC.

Example 167.

1.5 g (4.5 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 24 h in 10 ml of benzylamine at room temperature the/methanol 19/1 and crystallization from acetic ether and hexane were obtained 1.3 g (71%) of 3-(5-benzylamino-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 88-92oC, which was transferred into the hydrochloride with MP 178-182oC.

Example 168.

1.8 g (4 mmole) of (S)-1-(3-diallyldimethyl-1,2,4-oxadiazol-5-yl)- 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it was dissolved in 50 ml of methanol and was first made in the presence of 60 mg of 5% palladium on coal at normal pressure and room temperature. Then the catalyst was separated and the solution was evaporated. After chromatography of the residue on silica gel with elution with methylene chloride/methanol in the ratio of 19.5/0.5 received 1 g (60%) of (S)-1-(3-dipropylamino-1,2,4-oxadiazol-5-yl)- 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 198-201oC. Ro 48-6686.

Example 169.

1.5 g (4.5 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 2 h at 1.1 ml (14 mmol) of pyrrolidine and 30 ml of N,N-dimethylformamide at a temperature of 80oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 was obtained 1.4 g (84%) of 5-methyl-3-[5-(pyrrolidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]- 5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-she, who translated l-5-yl)-8-chloro - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred for 2.5 h with 0.8 ml (9.7 mmol) of ethyliodide and 2.5 ml (14.7 mmol) of N-ethyldiethanolamine in 30 ml of N,N-dimethylformamide at a temperature of 80oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in the ratio of 19.5/0.5 obtained 0.8 g (46%) of (S)-8-chloro-1-(3-diethylaminomethyl-1,2,4-oxadiazol-5-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 169-171oC.

Example 171.

1.5 g (4.5 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 20 h in 1 ml (14 mmol) of 3-pyrroline and 30 ml of N,N-dimethylformamide at a temperature of 80oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 was obtained 0.2 g (12%) 5-methyl-3-[5-(3-pyrrolin-1-yl)methyl-1,2,4-oxadiazol-3-yl] -5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it, which was transferred into the hydrochloride with MP 215-220oC.

Example 172.

1.7 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 2 h with 5 ml (7.2 mmol) of cyclopropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and washed the lisali of the residue from ethyl acetate and hexane were obtained 1,17 g (65%) of 3-(5-cyclopropylmethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 176-178oC, which was transferred into the hydrochloride.

Example 173.

2.2 g (6.3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred with 20 ml (183 mmole) of benzylmethylamine first overnight at room temperature and then for 1 h at 70oC. After evaporation of the reaction mixture, the residue was chromatographically on silica gel with elution by ethyl acetate. After crystallization from ethyl acetate received 1,80 g(66%) 3-[5-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-3-yl] -8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 161-162oC, which was transferred into the hydrochloride.

Example 174.

a) 4.1 g (10 mmol) 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was dissolved in 15 ml of N, N-dimethylformamide and deprotonirovaniem of 0.44 g (10 mmol) of a dispersion of sodium hydride (55% in oil). After the addition of 1.7 g (10 mmol) of propyliodide was stirred over night at room temperature. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate and, after crystallization from ethyl acetate were received of 2.46 g (54%) of 3-(5-N-BOC-N-propylaminoethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-nometer-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred overnight with 30 ml of 3H hydrochloric acid in methanol at room temperature. The resulting suspension was diluted simple ether, cooled to 0oC and was filtered by suction. The result has been 1,99 g (77%) of 5-methyl-3-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it is in the form of the hydrochloride with MP 248-250oC.

Example 175.

a) of 10.5 g (60 mmol) of BOC-glycine was dissolved in 50 ml of N,N-dimethylformamide, treated portions 9,73 g (60 mmol) of 1,1'-carbonyldiimidazole and was stirred for 20 minutes at a temperature of 55oC. After the addition of 15.5 g (57.1 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3 - carboxamidine continued to stir overnight at a temperature of 90oC. Then the reaction mixture was concentrated, the residue was dissolved in methylene chloride and the solution washed three times with water. After drying the solution, evaporation of the solvent and crystallization of the residue from ethanol was obtained with 20.4 g (87%) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 108-113oC.

b) 15.9 g (38.7 mmol) of 3-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 3 h in 40 ml triperoxonane acid at room temperature. Then the solution concentrado phase was extracted three times with methylene chloride and six times with ethyl acetate. After drying and evaporation of the United organic phase and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 2,03 g (17%) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 192-195 (in Russian)oC.

Example 176.

a) 192,4 g (714,6 mmol) of (S)-9-oxo-12,12 a-dihydro - 9H,11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-1-carboxylic acid suspended in 900 ml of N, N-dimethylformamide at room temperature was treated with 116 g (715 mmol) of 1,1'-carbonyldiimidazole and was stirred for 30 min at a temperature of 50oC. and Then for 30 min at a temperature of 25-30oC was added dropwise 173 ml of 25% aqueous ammonia. After 30 minutes of stirring, the reaction mixture was concentrated and the residue was dissolved in 500 ml of alcohol. After addition of 250 ml of simple ether was cooled to 0oC and crystallized was filtered by suction and dried. The result has been 133,6 g (69%) of (S)-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a] [1,4] benzodiazepine-1-carboxamide with MP 228-230oC.

b) 78 g (290 mmol) of (S)-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamide suspended in 380 ml of dioxane and 68 ml of pyridine and at a temperature of 0oat a temperature of 50oC the reaction mixture was poured into 2 l of ice water, the crystals were filtered by suction, washed with water and dried. As a result received 60 g (82%) of (S)-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo [1,5-a]-[1,4]benzodiazepine-1-carbonitrile with MP 232-234oC.

C) to 64.7 g (258 mmol) of (S)-9-oxo-12,12 a-dihydro-9H,11H - azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile for 2.5 h was heated under reflux with of 52.8 g (497 mmol) of sodium carbonate and 42,36 g (608 mmol) of hydroxylamine hydrochloride in 1.5 l of ethanol and 300 ml of water. Then the alcohol is evaporated, and the resulting suspension was cooled to 0oC. the Crystals were filtered by suction, washed with water and dried. The way it was received and 68.5 g (93%) of (S)-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine with Trasl 216oC.

g) of 34.5 g (122 mmole) of (S)-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamidine mixed with 23 g (140 mmol) of Chloroacetic anhydride acid in 200 ml of N,N-dimethylformamide first overnight at room temperature and then for 2 h at 110oC. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. Organicheskoi with methylene chloride/methanol in a ratio of 19/1. The result obtained 24 g (58%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it MP 205-207oC.

d) 1.4 g (4 mmole) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred for 1 h with 5.2 g (90 mmol) of Propylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1.07 g (73%) of (S)-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 177.

a) of 36.4 g (205 mmol) of BOC-glycine was dissolved in 300 ml of N,N-dimethylformamide and treated portions 35,8 g (220 mmol) of 1,1'-carbonyldiimidazole. The solution was stirred for 30 min at a temperature of 50oC, was added 54,7 g (194 mmole) of (S)-9-oxo-12,12 a-dihydro - 9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4] benzodiazepine-1-carboxamidine and was stirred over night at a temperature of 90oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed with water, dried over magnesium sulfate and konzentrieren-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it is in the form of a white foamy substance which without further purification was used in the next step.

b) 25 g (59.3 mmol) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl) -12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred overnight with 60 ml of 3H hydrochloric acid in methanol at room temperature. After evaporation of the solvent the residue was dissolved in water and the solution was extracted three times with methylene chloride. The aqueous phase was podslushivaet concentrated ammonia and seven times were extracted with methylene chloride by shaking. After drying the organic phase over magnesium sulfate and evaporation of the solvent was received of 16.9 g (88%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it MP 211-214oC.

Example 178.

6,9 g (21,4 mmole) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it was mixed with the 7.65 g (45 mmol) of propyliodide in 80 ml of 1,3-dimethyl-3,4,5,6 - tetrahydro-2(1H)-pyrimidinone and 6.5 g (50 mmol) N-ethyldiethanolamine first overnight at a temperature of 80oC and then for 2 hours at a temperature of 100oC. After upar is%) (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] -imidazo [1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 208-210oC.

Example 179.

1,96 g (4.1 mmole) of (S)-1-(5-diallyldimethyl-1,2,4 - oxadiazol-3-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-C][1,4]benzodiazepine-9-it was dissolved in 25 ml ethyl acetate and was first made in the presence of 37 mg of 5% palladium on coal at normal pressure and room temperature. Then the catalyst was separated and the solution was evaporated. After chromatography of the residue on silica gel with elution by ethyl acetate was received 1,49 g (83%) of (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 222-225oC.

Example 180.

A suspension of 11.9 g (0,0394 mol) of (S)-8-chloro-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide in a mixture of 85 ml of dioxane and 6.8 ml of pyridine was treated at a temperature of 0oC with 7.1 ml (0,051 mole) of anhydride triperoxonane acid. Then the suspension was stirred for 3 h at 50oC, cooled and poured into ice-cold water. After stirring for 1.5 h, the suspension was filtered by suction. The result was obtained 11.2 g (100%) (S)-8-chloro-9-oxo-12,12 a-dihydr the s).

b) 178,7 g (628 mmol) of (S)-8-chloro-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-c] imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile and 65.5 g (941 mmol) of hydroxylamine hydrochloride was added to a solution of 17.3 g (753 mmole) of sodium and 1.5 l of methanol. The reaction mixture was stirred over night at room temperature, then diluted with 1 l of water. The resulting suspension was filtered by suction and the crystals were dried. The result has been 169,7 g (85%) of (S)-8-chloro-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] - [1,4]benzodiazepine-1-carboxamidine with Trasl 269oC.

in) and 31.7 g (100 mmol) of (S)-8-chloro-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-c] -imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine suspended in 200 ml of N,N-dimethylformamide and treated 18,8 g (110 mmol) of Chloroacetic anhydride acid. Then the reaction mixture was heated for 2 h to a temperature of 105oC and evaporated. After chromatography of the residue on silica gel with elution by chloroform/methanol in a ratio of 9/1 received 27.9 g (74%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9 - it MP 211-212oC.

g) 3,76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazep is mperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with ethyl acetate was obtained 4.4 g (95%) of (S)-1-(5-N-benzyl-N-methylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 213-215oC.

Example 181.

3,76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred overnight with 2 g (20 mmol) of isopropylethylene and 20 ml of N, N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/ethanol in a ratio of 9/1 was obtained 3.4 g (90%) of (S)-8-chloro-1-(5-N-isopropyl-N-methylaminomethyl-1,2,4 - oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo [1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 198-203oC.

Example 182.

3,76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred over night with 2,19 g (30 mmol) of diethylamine and 30 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel p is xavator-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] - imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 218-220oC.

Example 183.

a) of 9.8 g (32 mmole) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide was stirred in 60 ml of N,N-dimethylformamide with 7 g (41 mmol) of Chloroacetic anhydride acid during the first 1 h at room temperature and then for 4 h at 105oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution washed with saturated sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate was received 6,63 g (65%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5 - a][1,4]benzodiazepine-6-it.

b) of 1.09 g (3 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6 - it was stirred for 4.5 h of 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received of 1.16 g (90%) of 7-chloro-3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5 - methyl-5,6-dihydro-4H-imida the ptx2">

a) 4.4 g (10 mmol) 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3 - yl)-7-chloro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1.4] benzodiazepine-6-it was deprotonirovaniem in 15 ml of N,N-dimethylformamide at a temperature from 0oC to room temperature with the help of 0.44 g of a dispersion of sodium hydride (55% in oil). Then was added 1.7 g (10 mmol) of propyliodide and the reaction mixture continued to stir for 5 h at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received 2.50 g (51%) of 7-chloro-5-methyl-3-(6-N-BOC-N-propylaminoethyl-1,2,4 - oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]- benzodiazepine-6-it is in the form of a white foamy substance which without further purification was further processed.

b) 2.5 g (5.1 mmol) of 7-chloro-5-methyl-3-(6-N-BOC-N - propylaminoethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 3 h with 10 ml of 3H hydrochloric acid in methanol at room temperature. The resulting suspension was cooled to 0oC and filtered by suction. After recrystallization from methanol has been 0,94 g (41%) of the hydrochloride of 7-chloro-5-methyl-3-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with Trasl 235oC.

oC.

Example 186.

3,76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred overnight with 5 g (39 mmol) of dibutylamine and 25 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate were obtained 4.3 g (92%) of (S)-8-chloro-1- (5-dibutylamino-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 120-125oC.

Example 187.

3,76 g (10 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred overnight with 5 g (58 mmol) of piperidine and 25 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with ALWIL-3-yl] -12,12 a-dihydro-9H, 11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it MP 177-179oC, which was transferred into the hydrochloride.

Example 188.

0,94 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9 - it was stirred for 4 h with 2 g (20 mmol) of hexamethylenimine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate were obtained 1.01 g (92%) of (S)-8-chloro-1-[5-(hexamethyleneimino-1-yl)methyl-1,2,4 - oxadiazol-3-yl] -12,12 a-dihydro-9H,11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 189.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro - 9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred overnight with 1.5 g (13.3 mmol) heptamethylnonane and 15 ml of N, N-di-methylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 1.2 g (88%) of (S)-8-chloro-1-[5-(heptamethylnonane-1-yl)methyl-1,2,4 - oxadiazol-3-yl] -12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo [1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

the azo[1,5-a][1,4]benzodiazepine-9-it was stirred over night with 3 g (26.5 mmol) of methylcyclohexylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 19/1 received 0,79 g (69%) of (S)-8-chloro-1-(5-N-cyclohexyl-N-methylaminomethyl - 1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 191.

0,94 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred overnight with 2 g (23 mmole) of tert.-butylmethylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 9/1 received 0,81 g (75%) of (S)-1-(5-N-tert.-butyl-N-methylaminomethyl - 1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 192.

0,94 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred overnight with 2 g (27 mmol) of tert.-of butylamine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chrome-(5-tert.-butylaminoethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12 a-dihydro - 9H,11H-azeto[2,1-C] -imidazo[1,5-a] [1,4] benzodiazepine-9-it, which translated into hydrochloride (amorph.).

Example 193.

0,94 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred for 5 h with 2 g (19.8 mmol) of Diisopropylamine and 15 ml of N, N-dimethylformamide at a temperature of 80oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received 0,81 g (73%) of (S)-8-chloro-1-(5-diisopropylaminomethyl-1,2,4 - oxadiazol-3-yl)-12,12-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 194.

1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it was stirred for 2 h with 1.5 g (15 mmol) of diethanolamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 9/1 received 1,89 g (85%) of (S)-8-chloro-1-(5-diethanolamine-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c] -imidazo[1,5-a][1,4]benzodiazepine - 9-it MP 173-175oC, which was transferred into the hydrochloride.

Example 195.

a) 10.1 mamita. At temperatures from -40oC to -20oC poritsali added to 45.8 g (208 mmol) of (S)-6-fluoro-1,2,4,9,10,10 a-hexahydrate[2,1-C] [1,4] benzodiazepine - 4,10-dione and deprotonirovaniem for 1 h at temperatures from -40oC to -20oC. Then was cooled to -60oC was sequentially added a solution of 59 g (219 mmol) of diphenylchlorophosphine in 10 ml of N,N-dimethylformamide and 24.9 g (220 mmol) isocyanurate ether and then was added dropwise a solution of 24.5 g (218 mmol) of tert. -butyl potassium in 50 ml of N,N-dimethylformamide at a temperature of from -60oC to -55oC. Then the reaction mixture was allowed to warm to room temperature, neutralized her 7 ml of acetic acid, and then poured into 600 ml of ice water. Then ten times were extracted with methylene chloride, the combined organic phases four times washed with water and dried over magnesium sulfate. After evaporation of the solvent and crystallization of the residue from methylene chloride was received of 13.6 g of white crystals. After chromatography of the mother liquor on silica gel with elution by ethyl acetate were additionally compared with 10.9 g (total yield was 62%) of ethyl-(S)-7-fluoro-12,12 a-dihydro-9-oxo - 9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxylate with MP 226-227 of theoC.

b) 40,58 g (128,7 mmole ml (130 mmol) 4H sodium hydroxide was heated under reflux for 1.5 h on a steam bath. Then the alcohol is evaporated using a rotary evaporator. The aqueous phase was twice washed with methylene chloride and acidified with 32.5 ml (130 mmol) 4H hydrochloric acid to pH 3-4. The resulting suspension was cooled and filtered by suction. The filtrate was washed with a small amount of ice water and dried. In this way received 36,67 g (99%) (S)-7-fluoro-9-oxo - 12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]- benzodiazepine-1-carboxylic acid with MP 159-160oC.

in) 100 g (348 mmol) of (S)-7-fluoro-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid suspended in 600 ml of N,N-dimethylformamide and treated 64,1 g (395 mmol) of 1,1'-carbonyldiimidazole. After 30 minutes stirring at 50oC was added dropwise at a temperature of 13-20oC 80 ml of 25% aqueous ammonia and the mixture was stirred for 30 min and then poured it into 2 l of water. After filtering the resulting suspension by suction and drying of the crystals received 52.7 g (76%) of amide (S)-7-fluoro-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo [1,5-a][1,4]benzodiazepine-1-carboxylic acid with MP p.223-224oC.

g) of 75.6 g (264 mmole) amide (S)-7-fluoro-9-oxo-12,12 a-dihydro-9H,11H - azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid suspended in 340 ml of dioxane and 45 ml of pyridine and temperance the mixture was stirred over night at room temperature and was poured into 2 l of water. After filtering the resulting suspension by suction and drying of the crystals was obtained 45,65 g (64%) of (S)-7-fluoro-9-oxo-12,12 a - dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1 - carbonitrile, which without further purification was used in the reaction in the next step.

d) of 4.2 g (180 mmol) of sodium was dissolved in 225 ml of methanol. Then added 13,55 g (195 mmol) of hydroxylamine hydrochloride and 40 g (149 mmol) of (S)-7-fluoro-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile and the reaction mixture was stirred over night at boiling point. Next, the suspension was cooled to 5oC and filtered by suction. The crystals were washed with water and dried. The result has been of 38.9 g (87%) of (S)-7-fluoro-9-oxo-12,12 a - dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4] -benzodiazepine - 1-carboxamidine, which without further purification was used in the reaction in the next step.

e) 15.9 g (52,8 mmole) of (S)-7-fluoro-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-c] -imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidine mixed with to 9.93 g (58 mmol) of Chloroacetic anhydride acid and 50 ml of N,N-dimethylformamide first for 0.5 h at room temperature and then for 2 h at 105oC. After evaporation of the reaction mixture the residue was dissolved in mailinator magnesium, evaporation of the solvent and chromatography of the residue on silica gel with elution with acetic ether was obtained 11 g (58%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4] benzodiazepine-9-it.

W) 1.8 g (5 mmol) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it was stirred overnight with 2 g (20 mmol) of dipropylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate were obtained 1.8 g (85%) of (S)-1-(5-dipropylamino-1,2,4-oxadiazol - 3-yl)-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 196.

1.8 g (5 moles) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4] benzodiazepine-9-it was stirred for 2 h with 2 g (34 mmole) of Propylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the solvent and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 9/1 was obtained 1.4 g (73%) of (S)-7-fluoro-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-CLASS="ptx2">

0,99 g (3.0 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred over night with 1.2 g (16 mmol) of diethylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 9/1 was obtained 0.9 g (81%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)- 5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 153-154oC, which was transferred into the hydrochloride.

Example 198.

0,99 g (3.0 mmole) of 3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 2 g (16 mmol) of dibutylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received 0,82 g (65%) of 3-(5-dibutylamino-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6 - it, which was transferred into the hydrochloride with MP 105-110oC.

Example 199.

1,15 g (3.5 mmole) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred over night with 0.73 MESI and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1,23 g (93%) of (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-C] imidazo[1,5-a] [1,4] benzodiazepine-9-it, which was transferred into the hydrochloride with MP 209-211oC.

Example 200.

1,15 g (3.5 mmole) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9 - it was stirred over night with 1.29 g (10 mmol) of dibutylamine in 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 1.04 g (68%) of (S)-1-(5-dibutylamino-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro - 9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 201.

a) 30 g (106.7 mmol) of (S)-5-bromo-1,10 a-dihydro-2H - azeto[2,1-C][1,4] benzodiazepine-4,10(9H)-dione was dissolved in 50 ml of N,N-dimethylformamide was treated at -20oC 5.6 g (128 mmol) of a dispersion of sodium hydride (55% in oil, washing with hexane) and was deprotonirovaniem for 30 min at a temperature of from -30oC to -20oC. Then at -60oC was added a solution of 43 g (160 mmol) of acid chloride of diphenyl ether phosphoric acid in 25 ml of dimethylformamide and stirred for 35 minutes at a temperature of max -45oC. Simultaneously in these separately prigotovit>C 12,1 g (107 mmol) of ethyl ether isocyanurate acid. This deprotonirovannym ethyl ester isocyanurates acid was added dropwise into the reaction mixture at a temperature of -65 maxoC for 1.25 hours and Then continued to stir for 1 h at bath (acetone-dry ice), neutralized with 10 ml of acetic acid and poured into 500 ml of ice water. Next was extracted five times with methylene chloride (a total of 1.2 l), dried over magnesium sulfate and evaporated to dryness. By recrystallization of the residue from ethanol and simple broadcast received 23.7 g (49%) of ethyl-(S)-8-bromo-9-oxo - 12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxylate with MP 184-185oC.

b) 21.8 g (57.9 mmol) of ethyl-(S)-8-bromo-9-oxo-12,12 a-dihydro - 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate for 15 min was heated under reflux with 17 ml 4H sodium hydroxide and 200 ml of ethanol. Then at room temperature was added 17 ml 4H hydrochloric acid and 250 ml of water. The alcohol evaporated and the suspension was cooled to 0oC. After filtering off by suction and drying of the crystals were obtained of 19.8 g (98%) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo [1,5-a][1,4]benzodiazepine-1-carboxylic acid with MP 178-180oC.

in) of 19.8 g (56,9 mmole ml of N,N-dimethylformamide, was treated at room temperature of 10.1 g (62,6 mmole) of 1,1'-carbonyldiimidazole and was stirred for 30 min at 70oCC. Then at a temperature of 25-30oC was added dropwise 50 ml of 25% aqueous ammonia. The reaction mixture was diluted with 50 ml water and cooled to 0oC, after which crystallized was filtered by suction and dried. The result has been 133,6 g (69%) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide with MP 314-317oC.

g) a Suspension of 19 g (54,7 mmole) of (S)-8-bromo-9-oxo-12,12 a-dihydro - 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 - carboxamide in a mixture of 100 ml of dioxane and 15 ml of pyridine was treated at a temperature of 7oC to 10oC 15 ml of anhydride triperoxonane acid. The suspension was stirred for 1 h at room temperature and poured into 600 ml of water. After 1 h the suspension was filtered by suction. In this way got to 13.1 g (72%) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile with MP 133-136oC.

d) 13 g (39.5 mmol) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H,11H-azeto [2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile was mixed with 7.5 g (71 mmol) of sodium carbonate and 5.7 g (82 mmole) of hydroxylamine hydrochloride in 200 ml of ethanol and 40 ml of water CH the suspension was filtered by suction and the crystals were dried. The result has been 7,33 g (51%) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidine with MP 265-266oC.

f) 7 g (19.3 mmol) of (S)-8-bromo-9-oxo-12,12 a-dihydro-9H, 11H-azeto [2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidine was mixed with 3.8 g (22,2 mmole) of Chloroacetic anhydride acid in 50 ml of N,N-dimethylformamide first for 1 h at room temperature and then for 2 h at 105oC. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated. After recrystallization of the residue from methanol was received with 5.3 g (65%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro - 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9 - it MP 210 - 211oC.

W) 1.26 g (3.0 mmole) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred for 5 h from 0.44 g (6 mmol) of diethylamine and 10 ml of N, N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1,14 g (na, which translated into hydrochloride with MP 206-209oC.

Example 202.

a) a Suspension of 12.8 g (35.4 mmol) of (S)-8-bromo-9-oxo-11,12,13,13-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide in a mixture of 50 ml of dioxane and 7 ml of pyridine was treated at a temperature of from 7 to 10oC 6,5 ml of anhydride triperoxonane acid. Then the suspension was stirred for 2.5 h at room temperature and was poured into 200 ml of water. After 1 h the suspension was filtered by suction. The result has been to 12.1 g (100%) (S)-8-bromo-9-oxo-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-C][1,4]- benzodiazepine-1-carbonitrile with MP 253-254oC.

b) 12 g (35 mmol) of (S)-8-bromo-9-oxo-11,12,13,13 a-tetrahydro-9H - imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carbonitrile was stirred for 2 h with 9.6 g (94 mmole) of sodium bicarbonate and 7.3 g (105 mmol) of hydroxylamine hydrochloride in 170 ml of ethanol and 40 ml of water at boiling point. After evaporation of the alcohol the resulting suspension was cooled and crystallised was filtered by suction and dried. The result obtained 11.4 g (86%) of (S)-8-bromo-9-oxo-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-c] [1,4]-benzodiazepine-1-carboxamidine with MP 235-237oC.

in) of 11.5 g (30.6 mmol) of (S)-8-bromo-9-oxo-11,12,13,13 a-tetrahydro-9H - isney acid in 60 ml of N,N-dimethylformamide first for 1 h at room temperature, and then for 3 h at 105oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. After drying the organic phase over magnesium sulfate, evaporation of solvent and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 10.2 g (76%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-9-it MP 242-244oC.

g) 1.3 g (3.0 mmole) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it was stirred for 5 h 1,02 g (10 mmol) of dipropylamine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of the solvent and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1,41 g (94%) of (S)-8-bromo-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]pyrrolo [2,1-C][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 203.

a) 6,24 g (18.2 mmol) of (S)-8-chloro-7-fluoro-9-oxo-12,12 a-dihydro-9H,11H - azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidine mixed with 3,43 g (20 mmol) of anhydride is an increase of 2.5 h at 105oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1.88 g (26%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro - 12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-9-it MP 214-217oC.

b) 1 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12 a-dihydro - 9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred over night from 0.98 g (7.5 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received of 0.44 g (36%) of (S)-8-chloro-1-(5 - dibutylamino-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12 a-dihydro - 9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 204.

0.88 g (2.5 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7 - fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred overnight with 0.5 g (6.8 mmol) of diethylamine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution washed with water. After drying, organicheskoi-3-yl)-7-fluoro-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 205.

1.19 g (3.0 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7 - trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 5 h 1,02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution washed with water. After drying the organic phase over magnesium sulfate and evaporation of solvent received 1,33 g (96%) of 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5 - methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 216-218oC.

Example 206.

a) 7 g (10.6 mmol) of 5-methyl-6-oxo-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxamide was stirred in 50 ml of N, N-dimethylformamide with of 4.05 g (23.7 mmole) of Chloroacetic anhydride acid during the first 2 h at room temperature and then for 2 h at 105oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate were obtained for 7.12 g (87%) of 3-(5-chloromethyl - 1,2,4-oxadiazol-3-yl) -5-methyl-7-trifluoromethyl - 5,6 is sedesol-3-yl)- 5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred over night with 5.3 g (90 mmol) of Propylamine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution washed with water. After drying the organic phase over magnesium sulfate and evaporation of the solvent was obtained 0.84 g (67%) of 5-methyl-3-(5-propylaminoethyl-1,2,4 - oxadiazol-3-yl)-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it, which was transferred into the hydrochloride with MP 234-237oC.

Example 207.

24,9 g (74,1 mmole) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a] -[1,4]benzodiazepine-3-carboxylic acid are suspended in 100 ml of N,N-dimethylformamide at room temperature was treated with 14.3 g (89 mmol) of 1,1'-carbonyldiimidazole and was stirred for 30 min at 70oC. Then was added dropwise at a temperature of 25-30oC 50 ml of 25% aqueous ammonia. The reaction mixture was diluted with 200 ml of water and cooled to 0oC, after which crystallized was filtered by suction and dried. The result has been to 21.6 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-3-carboxamide with MP 278-279oC.

b) a Suspension of 21.5 g (64.1 mmole) of 7-bromo-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in a mixture of 100 ml of dioxane and 15 ml of pyridine was treated at a temperature of from 7 to 10oC 15 ml anhydride, trifter the 1 h the suspension was filtered by suction. In this way received 17.8 g (88%) of 7-bromo-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile with MP 226-228oC.

in) 17,85 g (56.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carbonitrile mixed with 10.3 g (97,7 mmol) of sodium carbonate and 8 g (115.1 mmol) of hydroxylamine hydrochloride in 300 ml of ethanol and 60 ml of water for 1 h at a temperature of 50oC and for 20 min at 75oC. After dilution with 50 ml water, the suspension was filtered by suction and the crystals were dried. The result has been 16,95 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamidine with MP 265-266oC.

g) of 16.9 g (48.3 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamidine mixed with 9.5 g (55.5 mmol) of Chloroacetic anhydride acid in 100 ml of N,N-dimethylformamide first for 1 h at room temperature and then for 3 h at 105oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. After drying the organic phase over magnesium sulfate, evaporation of solvent and chromatography of the residue on silica gel with elution with methylene chloride/methane is]benzodiazepine-6-one with MP 242-244oC.

d) 2,04 g (5 mmol) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5 - methyl-5, b-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-it was stirred for 4 hours with 1.5 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received of 1.61 g (68%) of 7-bromo-3-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-it, which was transferred into the hydrochloride with MP 135-145oC.

Example 208.

2.1 g (5 mmol) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred for 2 h with 1.52 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate and recrystallization from ethyl acetate were obtained 1.2 g (50%) of (S)-8-bromo-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-12,12 a-dihydro-9H,11H - azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it MP 122-124oC, which was transferred into the hydrochloride with MP 196-198oC.

Example 209.

1.88 g (5 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4 - oxadiazol(2-methoxyethyl)amine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of the solvent, the reaction mixture was dissolved in 4H caustic soda, and then was extracted three times with methylene chloride. After drying the organic phase over magnesium sulfate and evaporation of the solvent was obtained 2.2 g (93%) of (S)-8-chloro-1-[5-di-(2-methoxyethyl)aminomethyl-1,2,4-oxadiazol-3 - yl]-12,12 a-dihydro-9H,11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 188-190oC.

Example 210.

0,94 g (2.5 mmole) of (S)-8-chloro-1-(5 - chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred overnight with 1 g (17 mmol) of Propylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 9/1 got to 0.92 g (92%) of (S)-8-chloro-1-(5-propylaminoethyl-1,2,4-oxadiazol-3 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C]imidazo[1,5-a] [1,4]benzodiazepine-9-it MP 237-239oC, which was transferred into the hydrochloride.

Example 211.

1.5 g (4.5 mmole) of 3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 0.5 g (4.4 mmole) heptamethyl residue on silica gel with elution by ethyl acetate was obtained 0.2 g(12%) 3-[5-(heptamethylnonane-1-yl)methyl-1,2,4 - oxadiazol-3-yl] -5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it, which translated into hydrochloride with MP 246-248oC.

Example 212.

0.7 g (2.1 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred overnight with 0.5 g (5 mmol) of hexamethylenimine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate received 0.76 g(90%) 3-[5-(hexamethyleneimino-1-yl)methyl-1,2,4 - oxadiazol-3-yl] -5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 158-159oC, which was transferred into the hydrochloride.

Example 213.

1.13 g (3.0 mmole) of (S)-8-chloro-1- (5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred overnight with 5 ml (25 mmol) of dicyclohexylamine and 7 ml of N, N-dimethylformamide at a temperature of 65oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 0.8 g (51%) of (S)-8-chloro-1- (5-dicyclohexylamine-1,2,4-oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H - azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 155-185oC.

Example 214.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-hlne 4 h 2 g (17 mmol) of 2,6-dimethylpiperidine and 15 ml of N, N-dimethylformamide at a temperature of 70oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/methanol in a ratio of 9/1 received 0,83 g (61%) of (S)-8 - chloro-1-[5-(2,6-dimethylpiperidin-1-yl)methyl-1,2,4-oxadiazol-3 - yl]-12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 233-236oC.

Example 215.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-it was stirred overnight with 2 g (12.7 mmol) of diphenhydamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate were obtained 1.01 g (68%) of (S)-8-chloro-1-(5-dipentylester-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H,11H-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 216.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred overnight with 2 g (17.7 mmol) of 3,3-dimethylpiperidine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of reactionbetween-1 - yl)methyl-1,2,4-oxadiazol-3-yl] -12,12 a-dihydro-9H, 11H-azeto [2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph. ).

Example 217.

a) of 9.8 g (32,1 mmole) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a]-[1,4]benzodiazepine-3-carboxamidine was mixed with 7 g (41 mmol) of Chloroacetic anhydride acid in 60 ml of N,N-dimethylformamide first for 1 h at room temperature and then for 4 h at 105oC. After evaporation of the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with a saturated solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and concentrated and the residue was chromatographically on silica gel with elution by ethyl acetate. The result has been 6,63 g (57%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 208-210oC.

b) 1.6 g (4.4 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred for 4.5 hours with 1.1 g (15 mmol) of diethylamine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 received 1.50 g (85%) of 7-chloro-3-(5-diet hydrochloride with MP 250-252oC.

Example 218.

1.6 g (4.4 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it was stirred for 48 h with 3.6 ml (21 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received of 1.23 g (61%) of 7-chloro-3-(5 - dibutylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 140-142oC, which was transferred into the hydrochloride with MP 184-187oC.

Example 219.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred over night with 1.7 g (9 mmol) of digoxigenin and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was received 0,89 g (56%) of (S)-8-chloro-1-(5-vexillological-1,2,4-oxadiazol-3-yl) -12,12 a-dihydro-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride (amorph.).

Example 220.

1,15 g (3.5 mmole) of 3-(5-chloromethyl - 1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/ethanol in a ratio of 9/1 received 1,32 g(92%) 3-[5-(3,3-dimethylpiperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl] -5 - methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4]benzodiazepine-6-one with MP 167-168oC, which was transferred into the hydrochloride.

Example 221.

1,15 g (3.5 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 1 h with 1 g (11.7 mmol) of piperidine and 10 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate/ethanol in a ratio of 9/1 received 0,98 g (74%) of 5-methyl-3-[5-(piperidine-1-yl)methyl-1,2,4-oxadiazol-3-yl] - 5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 167-168oC, which was transferred into the hydrochloride.

Example 222.

1.3 g (3.6 mmol) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred over night with 1.6 ml (8.9 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution of ethyl the benzodiazepine-6-one with MP 158-160oC, which was transferred into the hydrochloride with MP 125-128oC.

Example 223.

1.13 g (3.0 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3 - yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it was stirred over night with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N, N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate were obtained 1.07 g (76%) of (S)-8-chloro-1-(5-diisobutylamine-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-it, which was transferred into the hydrochloride with MP 125-140oC.

Example 224.

72 g (212 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 16 h in 150 ml of 1.06 mole) of Diisopropylamine and 300 ml of N,N-dimethylformamide at a temperature of 80oC. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution was twice extracted with 100 ml 2H hydrochloric acid. Acidic phase was podslushivaet concentrated sodium hydroxide and was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated. After chromatography of the residue on silica gel with elution si is of 51.6 g (61%) of 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol - 3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 117-119oC.

Example 225.

1 g (3.0 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)- 5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred over night in 3 ml (17 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution by ethyl acetate was obtained 1.2 g (94%) of 3-(5-diisobutylamine-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 170-172oC, which was transferred into the hydrochloride with MP 200-202oC.

Example 226.

of 1.65 g (5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was stirred for 24 h in 3 ml (17.5 mmol) of di-sec.-of butylamine and 25 ml of N,N-dimethylformamide at a temperature of 75oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution with methylene chloride/methanol in a ratio of 19/1 and crystallization from ethyl acetate were received of 1.23 g (58%) of 3-(5-diver.-butylaminoethyl - 1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-one with MP 155-157oC, which was transferred into the hydrochloride with MP 133-140oC.

Example 227.

1,82 g (5 mmol) 7-x is giving night with 3 ml (21.3 mmole) of Diisopropylamine and 20 ml of N,N-dimethylformamide at a temperature of 80oC. After evaporation of the reaction mixture and chromatography of the residue on silica gel with elution using the system cyclohexane/simple ether/isopropanol/ammonia ratio 15/15/5/0,5 received 1,41 g (66%) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3 - yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6 - one with MP 58-63oC, which was transferred into the hydrochloride with MP 230-231oC.

Example 228.

3,30 g (10 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it was stirred for 2.5 h with 3 g (50 mmol) of Isopropylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the solvent the residue was dissolved in methylene chloride and the solution washed twice with water. The organic phase was dried over magnesium sulfate and concentrated. By recrystallization of the residue from ethyl acetate received 2,37 g (67%) of 3-(5-isopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 142-144oC, which was transferred into the hydrochloride with MP 252-254oC.

Example 229.

a) Suspension 7,07 g (21.3 mmole) of (S)-8-chloro-9-oxo-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine - 1-carboxamide in 50 ml of N,N-dimethylferrocene 2 hours at a temperature of 105oC and then out completely remove the solvents. The oily product was chromatographically on silica gel using the solvent system methylene chloride/methanol in a ratio of 9/1, then the obtained oily product was recrystallized from ethyl acetate/simple ether. The mother liquor was concentrated, the residue was re chromatographically on silica gel with acetonitrile as eluent

and received an additional portion of the product was recrystallized from ethyl acetate/simple ether. As a result, received a total of 6,27 g (75%) of (S)-8-chloro-1-(5-chloromethyl - 1,2,4-oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a] pyrrolo(2,1-C] [1,4] benzodiazepine-9-it is in the form of white crystals; MP 184-186oC and []2D0= +36,1oC (MeOH, C=1%).

b) a Suspension of 1.85 g (4,74 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13-tetrahydro-9H-imidazo[1,5-a]pyrrolo [2,1-C][1,4] benzodiazepine-9-she's in 30 ml of N,N-dimethylformamide was treated with 1.73 g (23.7 mmole) of diethylamine. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in a ratio of 19/1. T pyrrolo[2,1-c] [1,4]benzodiazepine-9-it is in the form of a light yellow oil. From simple ether was recrystallized sample and the results obtained white crystals; MP 151-153oC and []2D0= +35,5oC (MeOH, C=1%).

in) 0.84 g (a 1.96 mmole) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4]benzodiazepine-9-it in 10 ml of ethanol was treated 0,41 ml (1,96 mmole) 4,78 H of a solution of hydrochloric acid in ethanol. After 10 minutes of mixing at room temperature of the resulting solution were completely removed solvents. The residue was recrystallized from ethanol/simple ether. In this way received 0,70 g (77%) of hydrochloride (1:1) (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it is in the form of white crystals; MP 205-207oC and []2D0= +25,2oC (MeOH, C=1%).

Example 230.

a) a Suspension of 1.85 g (4,74 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-C] [1,4] benzodiazepine-9-she's in 30 ml of N,N-dimethylformamide was treated to 2.40 g (23.7 mmole) of dipropylamine. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silicagel-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C][1,4]benzodiazepine-9 - it is in the form of a light yellow oil; []2D0= +29,3oC (MeOH, C=1%).

b) of 1.93 g (4,24 mmole) of (S)-8-chloro-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-C][1,4] benzodiazepine-9-she's in 20 ml of ethanol was treated to 0.88 ml (4.2 mmole) 4,78 H of a solution of hydrochloric acid in ethanol. After 10 minutes of mixing at room temperature of the resulting solution were completely removed solvents. The residue was recrystallized from ethanol/simple ether. As a result received 1.42 g (68%) of hydrochloride (1:1) (S)-8-chloro-1- (5-dipropylamino-1,2,4-oxadiazol-3-yl)-11,12,13,13 a-tetrahydro - 9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4] benzodiazepine-9-it is in the form of white crystals; MP 183-185oC and []2D0= +24,4oC (MeOH, C=1%).

Example 231.

a) a Suspension of 1.85 g (4,74 mmole) of (S)-8-chloro-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-C] [1,4]benzodiazepine-9-she's in 30 ml of N,N-dimethylformamide was treated with a 3.06 g (23.7 mmole) dibutylamine. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in a ratio of 19/1. In this way received 2.15 g (EPIN-9-it is in the form of a light yellow oil; []2D0= +28,7oC (MeOH, C=1%).

b) a 2.01 g (4,16 mmole) of (S)-8-chloro-1-(5-dibutylamino-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-C] [1,4]benzodiazepine-9-she's in 20 ml of ethanol was treated 1,12 ml (4,14 mmole) 3,70 H of a solution of hydrochloric acid in ethanol. After 10 minutes of mixing at room temperature of the resulting solution were completely removed solvents. The residue was recrystallized from ethanol/simple ether. The result has been 1,99 g (92%) of hydrochloride (1:1) (S)-8-chloro-1- (5-dibutylamino-1,2,4-oxadiazol-3-yl)-11,12,13,13-tetrahydro - 9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it is in the form of white crystals: MP 163-165oC and []2D0= +23,2oC (MeOH, C=1%).

Example 232.

a) 0.66 g (1.9 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol - 3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was dissolved in 20 ml of N, N-dimethylformamide. Then for 1 h at room temperature gave a weak stream of gaseous ethylamine, and the reaction temperature was increased to 36oC. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using esto beige which then was dissolved in ordinary air. In this way received 0.40 g (59%) of 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of beige crystals; MP 166-168oC.

b) of 0.37 g (1,04 mmole) 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 6 ml of ethanol was treated at 0.31 ml (1,14 mmole) 3,70 H of a solution of hydrochloric acid in ethanol. After addition of 20 ml of ethyl acetate at 0oC fell crystals. The result has been 0,30 g (73%) of the hydrochloride(1:1) 3-(5-ethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-it; MP 250-252oC (decomposition).

Example 233.

a) to 19.8 g (0,0639 mole) of 7-chloro-8-fluoro-5-methyl-6 - oxo-5,6-dihydro-4H - imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid are suspended in 100 ml of N, N-dimethylformamide in the processing of argon and at room temperature was treated with portions of 10.9 g (0,0671 mole) of 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2the beige suspension was stirred for 30 min at 50oC, cooled and when the temperature is below the 25oC for about 10 min bury 20 ml of 25% aqueous ammonia. After a 15-minutes is giving 30 min at room temperature and filtered, then the crystals were washed with a total of 200 ml of water. After drying, got to 14.4 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide in the form of beige crystals with a MP 292-294oC.

b) of 14.4 g (0,0466 mole) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamide suspended in 60 ml of dioxane and 8 ml of pyridine and at a temperature of 8oC for 10 min was added dropwise 10.3 g (0,049 mole) of anhydride triperoxonane acid. Then was stirred for 3 h at 50oC and poured into 400 ml of water. Then it was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate was concentrated. The residue was dissolved in 300 ml of hot ethyl acetate, the solution was filtered by suction on 100 g of silica gel, the silica gel was washed with 200 ml of ethyl acetate and the filtrate was evaporated. In this way received 12 g (89%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] - [1,4]benzodiazepine-3-carbonitrile in the form of crystals, slightly colored yellow in color, MP 221-223oC.

b) 1.0 g (0,0432 mole) of sodium was dissolved in 60 ml of methanol. Then at room temperature was sequentially added cent to 8.85 g (0,0304 mole) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]funeral 67 h at room temperature, then the residue was smokepole in 100 ml of water and the crystals were filtered off.

After drying kristalliset received 8,2 g (83%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamide in the form of white crystals with MP 228-231oC.

The aqueous phase was extracted with ethyl acetate, dried over magnesium sulfate, was filtered and concentrated, receiving 0.95 g (10%) of additional product with MP 225-228oC.

g) a Suspension of 7.0 g (0,0216 mole) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxamidine in 70 ml of N,N-dimethylformamide was treated to 4.38 g (0,0256 mole) of Chloroacetic anhydride acid. The obtained yellow solution was stirred for 2 hours at a temperature of 100oC, and then out completely remove the solvents. The oily product was dissolved in 300 ml of acetonitrile, and the solution was treated with activated charcoal, boiled with reflux condenser and hot filtered through 100 g of silica gel; then, the silica gel was washed with 200 ml of acetonitrile and the filtrate was evaporated. Crystal foamy substance suspended in 100 ml of simple ether and was filtered by suction. From the mother liquor was further identified the target issue for lighting the-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of a white-yellowish crystals with a MP 215-218oC.

d) a Suspension of 1.30 g (3.4 mmole) of 7-chloro-3-(5-chloromethyl - 1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5-a][1,4]benzodiazepine-6-it in 13 ml of N,N-dimethylformamide was treated with 1.24 g (of 0.017 mole) of diethylamine. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether/n-hexane. The result was obtained 1.3 g (91%) of 7-chloro-3-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 140-144oC (decomposition).

e) 1.28 g (a 3.06 mmole) of 7-chloro-3-(5-diethylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-she's in 20 ml of ethanol was treated of 0.91 ml (3,36 mmole) of 3.7 H of a solution of hydrochloric acid in ethanol. After 10 minutes of stirring at room temperature the obtained white suspension was treated with 100 ml of simple ether and was filtered by suction. In this way received 1,31 g (94%) of hydrochloride (1:1) 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl - 5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodi is the Zia of 1.30 g (3.4 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 13 ml of N,N-dimethylformamide was treated 1,72 g (of 0.017 mole) of dipropylamine. After stirring for 16 h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether/n-hexane. The result has been 1,32 g (87%) of 7-chloro-3-(5-dipropylamino - 1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 143-146oC (decomposition).

b) of 1.25 g (2.8 mmole) of 7-chloro-3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-she's in 20 ml of ethanol was treated 0,84 ml (of 3.07 mmole) of 3.7 H of a solution of hydrochloric acid in ethanol. After 30 minutes stirring at 0oC the solution was treated with 100 ml of simple ether and the resulting white suspension was filtered by suction. The result obtained 1.13 g (84%) of hydrochloride (1:1) 7-chloro-3-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 209-211oC (decomposition).

Example 235.

a) a Suspension of 1.30 g (3.4 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a][1,4]benzod h at room temperature, the obtained solution was completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether/n-hexane. As a result received 1.39 g (95%) of 7-chloro-8-fluoro-5-methyl-3-(5-piperidine-1 - ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 210-212oC (decomposition).

b) of 1.37 g (3,18 mmole) of 7-chloro-8-fluoro-5-methyl-3- (5-piperidine-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-6-it was dissolved hot in 50 ml of ethanol and at a temperature of 40oC was treated with 0.95 ml (3.5 mmole) of 3.7 H of a solution of hydrochloric acid in ethanol. After 30 minutes stirring at 0oC the solution was concentrated to a volume of 20 ml, after which it was treated with 100 ml of a simple ester. The obtained white suspension was filtered by suction. The result has been of 1.30 g (88%) of hydrochloride (1: 1) 7-chloro-8-fluoro-5-methyl-3-(5-piperidine-1 - ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 240-243oC (decomposition).

Example 236.

a) a Suspension of 1.20 g (3,14 mmole) of 7-chloro-3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she 20 the temperature value 80oC from the resulting solution were completely removed solvents. The residue was chromatographically on silica gel using the solvent system methylene chloride/methanol in the ratio 39/1. The product was recrystallized from simple ether/n-hexane. The result was obtained 0.84 g (60%) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4] -benzodiazepine-6-it is in the form of white crystals with MP 153-156oC.

b) of 0.82 g (of 1.84 mmole) of 7-chloro-3-(5-diisopropylaminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it was dissolved in hot form in 20 ml ethanol at 0oC was treated with 0.55 ml (2,02 mmole) of 3.7 H of a solution of hydrochloric acid in ethanol. After 30 minutes stirring at 0oC the solution was concentrated. The product was recrystallized from a hot mixture of acetonitrile/ethyl acetate. In this way received 0.74 g (83%) of hydrochloride (1:1) 7-chloro-3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals with MP 206-210oC (decomposition).

Example 237.

a) a suspension of 13.8 g (50,3 mmol) amide 7-fluoro-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic it is aplan of 7.7 ml (55,3 mmol) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at a temperature of 50oC and then poured into 220 ml of ice water. The precipitate was filtered. After drying at 70oC/10 Torr received 11 g (85%) of the nitrile 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid as a white powder with MP > 250oC.

b) In a freshly prepared solution of sodium methylate in methanol (0.27 g (11.7 mmol) of sodium in 50 ml of methanol) was added 2 g (7.8 mmol) of the nitrile 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid and 1.1 g (15.6 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred for 16 h at room temperature. Then the suspension was evaporated and treated with 100 ml of water. The precipitate was filtered and dried in high vacuum. As a result received 2 g (89%) of (E)- and/or (Z)-3-(aminohydrocinnamic)-7 - fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of a colorless foamy substance, Rf=0,25 (silica gel, methylene chloride/methanol 9/1).

C) a solution of 1.8 g (6.2 mmol) of (E)- and/or (Z)-3-(amino-gidroksilaminami)-7-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 50 ml of N,N-dimethylformamide was added Agrawal within 2 h to a temperature of 105oC. the Solution was evaporated and the residue was distributed between 2H sodium hydroxide and methylene chloride. Then the aqueous phase is washed with methylene chloride and the organic phase was dried with magnesium sulfate, filtered and evaporated. The resulting residue was led from methylene chloride/methanol. The result has been a 1.75 g (81%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H - imidazo[1,5, a] [1,4]benzodiazepine-6-it is in the form of powder beige color with MP 205,5-206,5oC.

g) a suspension of 1.7 g (4.9 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7 - fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5,a][1,4]benzodiazepine-6-it in 40 ml of N, N-dimethylformamide was added 1 ml (12.2 mmol) of Propylamine and was stirred for 12 h at room temperature. Then, the solution was evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous solution was extracted with methylene chloride and the organic phase was dried over magnesium sulfate, filtered and evaporated. The residue was chromatographically (silica gel, ethyl acetate/methanol 9/1). In this way got to 1.21 g (67%) of 3-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6 - dihydro-4H-imidazo[1,5, a] [1,4] benzodiazepine-6-it, Rf=0,22 (silica gel, ethyl acetate/methanol 4/1).

Example 238.

oC.

Example 239.

In argon atmosphere, the suspension of 0.49 g (1.5 mmole) of 3-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 8 ml of N,N-dimethylformamide was treated 0,41 ml (4.5 mmole) of N-propyl bromide and 1.04 g (7.5 mmol) of potassium carbonate and stirred for 73 h in an argon atmosphere at room temperature. Then the solution was filtered and the filtrate was evaporated, getting a yellowish oil. The crude product was purified by chromatography on 50 g of silica gel (methylene chloride/acetone 9/1, 4/1, 2/1, and then methylene chloride/methanol 19/1). The eluate was evaporated. The mod is in the form of crystals. The solvent is again evaporated and the residue was heated in 30 ml of ethyl acetate. Then cooled in an ice bath and the precipitated crystals were sucked out. After drying in vacuum received 315 mg (51%) of the hydrochloride(1:1) 3-[5-propylaminoethyl)-1,2,4-oxadiazol-3-yl] -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine - 6-one with MP 144-148oC (decomposition).

Example 240.

a) In a freshly prepared solution of sodium methylate in methanol (230 mg (10.0 mmol) of sodium in 10 ml of methanol) in an argon atmosphere was added 0,79 g (11.4 mmol) of hydroxylamine hydrochloride and 2.0 g (7.6 mmol) of (S)-9-oxo-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-1-carbonitrile and was stirred for 90 hours at room temperature. Then the suspension was evaporated and the residue was dissolved in 30 ml of water. Any insoluble components were sucked out. The aqueous phase was saturated with sodium chloride and at the same time there was a further loss of product in the form of crystals. This product was aspirated and together with the previously obtained product was dried in vacuum. The result has been 2.15 g (95%) of (E)- and/or (Z)-(S)-1-(aminohydrocinnamic)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-C][1,4]-benzodiazepine-9 - it MP 253-254oC (decomposition, methanol/diethyl ether).

b) what C][1,4]-benzodiazepine-9-she's in 11 ml of dimethylformamide in an argon atmosphere was added 1.1 g (6.5 mmol) of Chloroacetic anhydride acid and was stirred for 30 min at a temperature of approximately 25oC, and then heated for 1 h to 110oC. Then, the solution was evaporated under high vacuum and the brown residue was dissolved in 20 ml of methylene chloride. The solution is washed three times with 10 ml of saturated solution of sodium bicarbonate and the solvent was removed in vacuum. The crude product was chromatographically on 100 g of silica gel (methylene chloride/acetone first in a ratio of 9/1, and then 4/1). In this way received 1.45 g (72%) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-c][1,4]benzodiazepine-9-it is in the form of colorless crystals with MP 205-206oC (acetonitrile).

C) a Solution of 711 mg (2.0 mmole) of (S)-1- (5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-it in 10 ml of N,N-dimethylformamide was treated of 0.82 ml (6.0 mmol) of dipropylamine and in argon atmosphere was stirred for 2 h at room temperature. Then, the solution was evaporated, the residue is thoroughly stirred in 10 ml of water and the crystals were filtered off. The crude product was chromatographically on 30 g of silica gel (methylene chloride/acetone first in a ratio of 9/1, and then 4/1). As a result received 840 mg of (S)-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-c] [1,4]benzodiazepine-9-it, notarizationarticle received 685 mg (73%) of hydrochloride (1:1) (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3 - yl)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it MP 137-140oC (decomposition).

Example 241.

A solution of 710 mg (2.0 mmole) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it in 10 ml of N,N-dimethylformamide was treated with 0.5 ml (6.0 mmol) of Propylamine and in argon atmosphere was stirred for 2 h at room temperature. Then, the solution was evaporated, the residue is thoroughly stirred in 5 ml of water and the crystals were filtered off. Additionally, the crude product was obtained by extraction of the aqueous phase with methylene chloride. United fractions of the crude product (0.65 g) was chromatographically on 25 g of silica gel (methylene chloride/methanol 2%, 5%, 10%). The result obtained 540 mg of (S)-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13 a - tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it, which was dissolved in 5 ml of acetonitrile, then with a solution of hydrochloric acid in a simple ether was transferred into the hydrochloride. By recrystallization from acetonitrile received 560 mg (62%) of hydrochloride (1: 2) (S)-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl) -11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4] benzodiazepine-9-it MP 169-173oC (decomposition).

Example 242.

A solution of 710 mg (2.0 mmole) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 to face the s) N, N, N'-tri-methylethylenediamine and in argon atmosphere was stirred for 2 h at room temperature. Then, the solution was evaporated, the residue was dissolved in 10 ml of water. The solution was saturated with sodium chloride and was extracted several times with methylene chloride. The United extracts were dried over sodium sulfate, filtered and evaporated, receiving of 0.85 g of foamy yellowish substance. The crude product was chromatographically on 30 g of silica gel (methylene chloride/acetone 9/1, methylene chloride/methanol 9/1, 4/1 and finally methylene chloride/methanol/triethylamine 80/19/1). The result was obtained 0.64 mg (76%) of (S)-1-[5-[methyl-(2-dimethylaminoethyl)-aminomethyl] - 1,2,4-oxadiazol-3-yl]-11,12,13,13 a-tetrahydro-9H - imidazo[1,5-a]pyrrolo[2,1-C][1,4]benzodiazepine-9-it. The crude product was dissolved in 10 ml of acetonitrile and filtered through celite. It was further acidified with hydrochloric acid in a simple ether and was evaporated. The residue was led from 15 ml of hot acetonitrile. In this way received 690 mg (65%) of hydrochloride (1:3) (S)-1-[5-[methyl- (2-dimethylaminoethyl)-aminomethyl] -1,2,4-oxadiazol-3-yl] -11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-C] [1,4]benzodiazepine-9-it MP 198-200oC (decomposition).

Example 243.

The solution 711 mg (2.0 mmole) of (S)-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-mmol) dibutylamine and in argon atmosphere was stirred for 3 h at room temperature. Then, the solution was evaporated, the residue is thoroughly stirred in 10 ml of water and the crystals were sucked out. The crude product was dissolved in methylene chloride, the solution was dried using sodium sulfate, after which he chromatographically on 30 g of silica gel (methylene chloride/acetone first in a ratio of 9/1, and then 4/1). The result obtained 0.73 g (S)-1-(5-dibutylamino-1,2,4 - oxadiazol-3-yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo [2,1-C][1,4]benzodiazepine-9-it, which in 10 ml of acetonitrile using hydrochloric acid in a simple ether was transferred into the hydrochloride. By crystallization from hot ethyl acetate was obtained 0.75 g (77%) of hydrochloride (1:1) (S)-1-(5-dibutylamino-1,2,4-oxadiazol-3 - yl)-11,12,13,13 a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c] [1,4]benzodiazepine-9-it MP 115-123oC (decomposition).

Example 244.

a) a suspension of 6.9 g (21.6 mmole) ethyl ester of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3 - carboxylic acid in 5 ml of ethanol and 7 ml of water was added dropwise to 5.4 ml 5H sodium hydroxide and heated under reflux for 30 minutes the Solution is hot filtered, concentrated to a volume of about 6 ml and acidified 5.5 ml 5H hydrochloric acid. The product was sucked out. The result obtained 4.7 g (75%) of 8-chloro-5-methyl-6-oxo-5,C (decomposition).

b) a suspension of 4.7 g (16.0 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 25 ml of N,N-dimethylformamide portions was added 2.7 g (16.8 mmol) of 1,1'-carbonyldiimidazole. After the formation of CO2the solution was heated for 45 min to 60oC. Then it was cooled to room temperature and was added dropwise to 3.9 ml of concentrated aqueous ammonia. After a further 90-minute stirring, the reaction mixture was poured into 90 ml of ice water and was stirred for 1 h White crystals was aspirated and washed with a small amount of water. After drying in high vacuum was received of 3.84 g (83%) of amide 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylic acid MP 275-277oC.

C) In the suspension and 3.72 g (12.8 mmol) of amide 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-3 - carboxylic acid in 17 ml of dioxane and 2 ml of pyridine at a temperature of < 8oC was added dropwise of 1.85 ml (13.4 mmol) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 4 h at a temperature of 50-60oC, then cooled and treated with 80 ml of water. White crystals were pumped out and dried in high vacuum. the de colorless crystals with MP 272-275oC.

g) In a solution of sodium methylate (prepared from 342 mg (14.8 mmol) of sodium and 14 ml of methanol) portions was added 1.1 g (15.8 mmol) of hydroxylamine hydrochloride and 2,90 g (10.6 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carbonitrile and was stirred for 18 h at room temperature. The obtained yellow suspension was cooled in an ice bath and was sucked out. Then the crude product is suspended in 10 ml of water, again was aspirated and dried in high vacuum. The result was obtained 2.9 g (89%) of (E)- and/or (Z)-3-(aminohydrocinnamic)-8-chloro - 5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6 - one with MP 266-270oC (acetonitrile/DMF).

d) suspension of 0.90 g (2.9 mmole) of (E)- and/or (Z)-3-(amino-gidroksilaminami)-8-chloro-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 9 ml of dimethylformamide was added in an argon atmosphere 0.55 g (3.2 mmole) of Chloroacetic anhydride acid and was stirred for 1 h at a temperature of about 25oC, and then heated for 1 h to 110oC. the Solution was evaporated under high vacuum and the brown residue was dissolved in 50 ml of methylene chloride. The solution is washed three times with 10 ml of saturated solution of sodium bicarbonate and the solvent was removed in vacuum. Raw prometal-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-it is in the form of almost colorless crystals with MP 229oC (acetonitrile).

e) a Solution of 370 mg (1,01 mmole) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-it in 5 ml of N,N-dimethylformamide was treated at 0.42 ml (3,03 mmole) of dipropylamine and stirred in an argon atmosphere for 2 h at room temperature. Then, the solution was evaporated and the residue is thoroughly stirred in 10 ml of water. White crystals were filtered off. The product was chromatographically on 20 g of silica gel (ethyl acetate/hexane 1/1, then ethyl acetate). As a result received 259 mg of 8-chloro-3- (5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] [1,4]benzodiazepine-6-she, who with the help of hydrochloric acid in a simple ether was transferred into the hydrochloride. By recrystallization from acetonitrile received 268 mg (54%) of hydrochloride (1:1,6) 8-chloro-1-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 180-192oC (decomposition).

Example 245.

A solution of 278 mg (from 0.76 mmole) of 8-chloro-3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it in 5 ml of N, N-dimethylformamide was treated to 0.39 ml (2.3 mmole) of dibutylamine and stirred in an argon atmosphere for 1.5 h at room temperature. Then ABC was dried with sodium sulfate, filtered and evaporated. The crude product was chromatographically on 20 g of silica gel (methylene chloride/acetone 4/1). As a result received 250 mg of 8-chloro-3-(5-dibutylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-she, who with the help of hydrochloric acid in a simple ether was transferred into the hydrochloride. By crystallization from acetonitrile received 151 mg (39%) of hydrochloride (1:1,3) 8-chloro-1-(5-dibutylamino-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 165-175oC (decomposition).

Example 246.

A solution of 200 mg (0.54 mmole) of 8-chloro-3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in 4 ml of N, N-dimethylformamide was treated with 0.17 ml (1.65 mmole) of diethylamine and stirred in an argon atmosphere for 1.5 h at room temperature. Then, the solution was evaporated and the residue is thoroughly stirred in 10 ml of water. The crystals were sucked out, the filtrate once were extracted with ethyl acetate and the extract was evaporated. United fractions crude product was chromatographically on 20 g of silica gel (methylene chloride/acetone 4/1, 2/1). As a result received 124 mg of 8-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is tion of acetonitrile received 108 mg (42%) of hydrochloride (1:1,9) 8-chloro-1-(5-diethylaminomethyl - 1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one with MP 191-205oC (decomposition).

Example 247.

A solution of 200 mg (0.54 mmole) of 8-chloro-3-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-it is in 4 ml of N, N-dimethylformamide was treated 0,136 ml (1.65 mmole) of Propylamine and stirred in an argon atmosphere for 1.5 h at room temperature. Then, the solution was evaporated and the residue is thoroughly stirred in 10 ml of water. The aqueous phase was extracted with methylene chloride and combined extracts washed twice with water, dried over sodium sulfate, filtered and evaporated. United fractions crude product was chromatographically on 30 g of silica gel (ethyl acetate, methylene chloride/methanol 9/1). The result has been 126 mg of 8-chloro-3-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a][1,4] benzodiazepine-6-it is in the form of foamy substance in acetonitrile using hydrochloric acid in a simple ether was transferred into the hydrochloride. By crystallization from hot acetonitrile received 102 mg (42%) of hydrochloride (1: 1,8) 8-chloro-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with MP 230-240oC (decomposition).

Example 248.

Suspension 695 mg (2.0 mmole) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-N,N,N'-trimethyl-Ethylenediamine. After stirring for 2 h at room temperature the solution was concentrated and the residue was dissolved in 70 ml of water. The crystals were filtered off and treated with 20 ml of saturated saline, then was extracted four times with ethyl acetate and three times with methylene chloride. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from acetonitrile. In this way received 460 mg(56%) 3-[5-[methyl-(2-dimethylaminoethyl)-aminomethyl] -1,2,4-oxadiazol-3-yl] -8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4]benzodiazepine-6-it is in the form of white crystals. The crystals were dissolved in acetonitrile and the solution was acidified with hydrochloric acid in a simple ether. After crystallization from hot acetonitrile received 408 mg (40%) hydrochloride(1:2,5) 3-[5-[methyl-(2-dimethylaminoethyl)-aminomethyl] -1,2,4-oxadiazol-3-yl] - 8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine - 6-it is in the form of white crystals with MP 217-222oC (decomposition).

Example 249.

a) 59.3 g (0,3 mol) of anhydride 5-chlorosalicylic and 30.3 g (0,3 mol) of (S)-azetidin-2-carboxylic acid are suspended in 400 ml of N,N-dimethylformamide/acetic acid 5/1, and was heated in an oil bath in an argon atmosphere for 64 hours before the temperature 87-90ooC (decomposition).

b) of 23.6 g (0.1 mol) of (S)-6-chloro-1,2,4,9,10,10 a-hexahydrate[2,1-C] [1,4] benzodiazepine-4,10-dione in 300 ml of THF/DMPU 5/1 in an argon atmosphere at a temperature of about -75oC was added dropwise into a solution of LDA (diisopropylamide lithium) (prepared in the usual manner from 16 ml of 0.11 mol) of Diisopropylamine in 200 ml of THF and 69 ml of a 1.6 M solution of n-utility in hexane). Continued to stir for 40 minutes At a temperature of about -75oC was added dropwise 23 ml of 0.11 mol) of acid chloride of diphenyl ether phosphoric acid and was stirred for 35 min at -75oC. Simultaneously, separately prepare another solution of LDA as described above (100 ml THF). In this solution at a temperature of about -75oC was added dropwise a solution of 12.0 ml of 0.11 mol) of ethyl ether isocyanurate acid in 20 ml THF/DMPU 1/1. Deprotonirovannym ethyl ester isocyanurates acid through klaeden plan in the above-described reaction mixture. Then continued to stir for 2 h in a bath (acetone-dry ice) was added at a temperature of < -60oC 100 ml of 20% aqueous solution of ammonium chloride and poured into 800 ml of ice water. Next was extracted three times with 200 ml of methylene chloride, dried with sodium sulfate and evaporated. The brown oil was dissolved in 300 ml of ethyl acetate, and then was slowly added 300 ml of n-hexane. The crystals were filtered off. Additional product was obtained by chromatography of the mother liquor on 300 g of silica gel (methylene chloride/acetone 9/1). After drying in vacuum received 17.8 g (54%) of ethyl ester of (S)-7-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo [1,5-a][1,4]benzodiazepine-1-carboxylic acid with MP 190-194oC (ethyl acetate).

in) of 20.8 g (of 62.8 mmol) of ethyl ester of (S)-7-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-1-carboxylic acid in 250 ml of ethanol and 75 ml (75 mmol) 1H sodium hydroxide was heated for 30 min under reflux. Then the alcohol is evaporated in a rotary evaporator. The residue was dissolved in 250 ml of water and acidified 1H hydrochloric acid. The crystals were sucked out, washed with water and dried in vacuum. The result obtained 18.2 g (96%) of (S)-7-chloro-12,12 a-dihydro-9-oxo - 9H,11H-azeto[2,1-c] imidazo[1,5-a][1,-dihydro-9-oxo-9H,11H-azeto [2,1-c] imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid suspended in 15 ml of N,N-dimethylformamide and at room temperature was treated with portions of 1.78 g (11.0 mmol) 1,1'-carbonyldiimidazole. After the reaction, the removal of CO2transparent brown solution was stirred for 30 min at a temperature of 50oC, cooled it, and at a temperature below the 25oC for about 10 min, treated dropwise 2.5 ml of concentrated ammonia. After 30 minutes stirring the obtained suspension was evaporated and the residue is thoroughly stirred with 30 ml of water. White crystals were pumped out and dried in vacuum. The way it was obtained 2.8 g (92%) of (S)-7-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide with MP 251-253oC.

d) of 2.38 g (a 7.85 mmol) of (S)-7-chloro-12,12 a-dihydro-9-oxo-9H,11H-azeto [2,1-c] imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide suspended in 15 ml of dioxane and 1.4 ml of pyridine and at a temperature of approximately 10oC was added dropwise 1.2 ml (of 8.25 mmol) of anhydride triperoxonane acid. Then was stirred for 45 min at room temperature and re-added of 0.26 ml of pyridine and 0.11 ml of anhydride triperoxonane acid. The reaction mixture was stirred for 30 minutes then the solvent was removed in vacuum and the residue is thoroughly stirred with 30 ml of water. The crude product was chromatographically on 50 g of silica gel (methylene chloride/acetone 9/1). Product imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile with MP 258-261oC.

(e) In a solution of sodium methylate (prepared from 1,49 g (64.7 mmol) of sodium and 67 ml of methanol) portions was added 4.5 g (65.1 mmol) of hydroxylamine hydrochloride and 12,35 g (43,3 mol) of (S)-7-chloro-12,12 a-dihydro-9-oxo-9H, 11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-1-carbonitrile and was stirred for 108 h at room temperature. Then the crystals were sucked out, was stirred in 40 ml of water for 30 min, re was aspirated and dried in high vacuum. The result obtained 13.3 g (96%) of (E)- and/or (Z)-1-(amino-gidroksilaminami)-7-chloro-12,12 a-dihydro - 9H, 11H-azeto[2, l-C]imidazo[1,5-a][1,4]benzodiazepine-9-it MP 282-283oC (decomposition).

g) a suspension of 1.59 g (5.0 mmol) of (E)- and/or (Z)-1-(amino-gidroksilaminami)-7-chloro-12,12 a-dihydro - 9H, 11H-azeto[2,1-c] imidazo[1,5-a] [1,4] benzodiazepine-9-it in 10 ml of N,N-dimethylformamide in an argon atmosphere was added 1.0 ml (5.75 mmol) of Chloroacetic anhydride acid and was stirred for 1 h at a temperature of about 25oC, then for 1 h was heated to 110oC. the Solution was evaporated under high vacuum and the resulting brown residue was dissolved in 120 ml of methylene chloride. The solution is washed three times with 20 ml of saturated solution of sodium bicarbonate and the solvent was removed in vacuum. The crude product is in a high vacuum received 1.47 g (78%) of (S)-7-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12 a - dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9 - it is in the form of colorless crystals with MP 238-241oC (acetonitrile).

C) a Suspension of 1.13 g (3.0 mmole) of (S)-7-chloro-1-(5-chloromethyl-1,2,4 - oxadiazol-3-yl)-12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo [1,5-a][1,4]benzodiazepine-9-she's in 15 ml of N,N-dimethylformamide was treated to 0.74 ml (9.0 mmol) of Propylamine and stirred in an argon atmosphere for 3 h at room temperature. Then, the solution was evaporated, the residue was dissolved in 20 ml of water and the aqueous phase was extracted with methylene chloride. The United extracts were twice washed with water, dried with sodium sulfate, filtered and evaporated. The crude product was chromatographically on 30 g of silica gel (methylene chloride/acetone first in a ratio of 4/1, 2/1 and then finally methylene chloride/methanol 9/1). In this way received 840 mg of (S)-7-chloro-1-(5-propylaminoethyl-1,2,4 - oxadiazol-3-yl)-12,12 a-dihydro-9H, 11H-azeto[2,1-C] -imidazo [1,5-a][1,4]benzodiazepine-9-it, which in acetonitrile in the presence of fumaric acid were transferred into fumarate. By recrystallization from acetonitrile received 588 mg (35%) fumarata (1:1,4) (S)-7-chloro-1-(5-propylaminoethyl-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H, 11H-azeto[2,1-C] imidazo[1,5-a] [1,4]benzodiazepine-9-it MP 135-140oC (decomposition).

Example 250.oC (decomposition).

Example 251.

a) a suspension of 22 g (76 mmol) of (S)-10,11,12,12 a-tetrahydro-8-oxo-8H - imidazo[5,1-C] pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin-1-carboxylic acid (see European patent application EP 059390 A1) in 100 ml portions of dimethylformamide was added of 12.33 g (76 mmol) of 1,1'-carbonyldiimidazole. The resulting light brown solution was heated for 45 min to 50oC. Then the solution was cooled to room temperature and was added dropwise in 14 ml of an aqueous solution of ammonia. After another 30 min reallamarodom, and then a simple ether. After drying at 70oC/10 Torr was obtained 20 g (91%) of amide (S)-10,11,12,12 a-tetrahydro-8-oxo - 8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-1 - carboxylic acid as colorless crystals with MP 222-223oC.

b) suspension 8,98 g (31,1 mmole) amide (S)-10,11,12,12 a - tetrahydro-8-oxo-8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in 50 ml of dioxane and 5.4 ml of pyridine at a temperature of 5-8oC was added dropwise of 4.44 ml (31.9 per mmole) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at 50oC, then poured it into 220 ml of ice water. The precipitate was filtered. After drying at 70oC/10 Torr received of 6.78 g (80%) nitrile (S)-10,11,12,12 a-tetrahydro-8-oxo-8H-imidazo [5,1-c] pyrrolo[1,2-a] thieno[3,2-e] [1,4] diazepin-1-carboxylic acid as a white powder with MP 249-251oC.

C) In a freshly prepared solution of sodium methylate in methanol (1.55 g (67 mmol) of sodium in 70 ml of methanol) was added 12.7 g (47 mmol) of the nitrile (S)-10,11,12,12 a-tetrahydro-8-oxo-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid and 5 g (72.2 mmole) of hydroxylamine hydrochloride, after which the mixture was stirred for 48 h at room tunervision vacuum. The result has been 9,46 g (66%) of (E)- and/or (Z)-(S)-1-(amino-gidroksilaminami)- 10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo [1,2-a] thieno[3,2-e][1,4] diazepin-8-it is in the form of a colourless powder with MP 106-108oC.

g) In a solution of 1.42 g (8.07 mmol) of BOC-glycine in 13 ml of dimethylformamide was added 1.40 g (8,04 mmol) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. Then was added 2.30 g (7,58 mmol) of (E)- and/or (Z)-(S)-1-(aminohydrocinnamic)- 10,11,12,12 a-tetrahydro-8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno [3,2-e][1,4]diazepin-8-it was stirred for 15 h at a temperature of 90oC. the Obtained brown solution was evaporated under high vacuum and the resulting brown residue was chromatographically on silica gel (methylene chloride/methanol 10/1). The result has been a 1.50 g (44%) of (S)-1-(5-BOC-aminomethyl-1,2,4 - oxadiazol-3-yl)-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-C] pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,62 (silica gel, methylene chloride/methanol 10/1).

d) a Solution of 1.50 g (3.4 mmole) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12 a - tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e][1,4] -diazepin-8-it in 6 ml triperoxonane acid was stirred for 2 h at room temperature. the alley aqueous phase was podslushivaet 10 ml of an aqueous solution of ammonia and was extracted six times with methylene chloride. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting residue was chromatographically on silica gel (methylene chloride/methanol 9/1). As a result received 850 mg (73%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno [3,2-e][1,4]diazepin-8-it is in the form of a colorless foamy substance, Rf=0,25 (silica gel, methylene chloride/methanol 9/1).

Example 252.

a) In the solution to 5.13 g (18.6 mmol) of (S)-11,11-dihydro-9-oxo-9H,10H-azeto[1,2-a] imidazo[5,1-C] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in 30 ml of dimethylformamide at room temperature in one step added 3,15 g (19.4 mmol) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at 50oC. Then also at one time was added to 4.16 g (18.9 mmol) phthaloylglycine and the mixture was stirred for 15 h at a temperature of 110oC. the Dimethylformamide is evaporated in a high vacuum and the resulting residue was mixed with 150 ml of water. After extraction with methylene chloride (twice), dried with sodium sulfate, filtration and evaporation was obtained residue reddish color, which is then chrome, 0H-azeto[1,2-a] imidazo[5,1-C] thieno [3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-ylmethyl] - 2,3-dihydro-1H-isoindole-1,3-dione in the form of light brown crystals with MP 155-157oC.

b) a solution of 2.4 g (5,23 mmol) (S)-2-[5-(8-oxo-11.11 is a-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c] thieno [3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-ylmethyl]-2,3 - dihydro-1H-isoindole-1,3-dione in 40 ml of ethanol was added dropwise 30 ml of methylamine (33% in ethanol) if 70oC and stirred at this temperature for 2 hours Then the reaction mixture was evaporated and the residue was chromatographically (silica gel, methylene chloride/methanol 20/1). The result has been to 1.60 g (93%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-1,11-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-it is in the form of colorless crystals with MP 227oC (decomposition).

Example 253.

a) a suspension of 8.8 g (33,4 mmole) of 5-methyl-6-oxo-5,6-dihydro - 4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid (see European patent application EP 0150040 A2) in 80 ml portions of dimethylformamide was added to 5.66 g (34,9 mmole) of 1,1'-carbonyldiimidazole. The obtained light brown solution was heated for 45 min to 50oC. Then the solution was cooled to room temperature and was added dropwise into it to 8.1 ml of an aqueous solution amigaanywhere successively with water, ethanol and simple ether. After drying at 70oC/10 Torr was obtained 7.6 g (86%) of amide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid as colorless crystals with MP 294-296oC.

b) a suspension of the 7.43 g (28.3 mmol) of amide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3 - carboxylic acid in 40 ml of dioxane and 5 ml of pyridine at a temperature of 5-8oC was added dropwise of 4.05 ml (29 mmol) of anhydride triperoxonane acid. The resulting solution was beige was stirred for 2.5 h at 50oC, then poured into 220 ml of ice water. The precipitate was filtered. After drying at 70oC/10 Torr was obtained 5.6 g (81%) of the nitrile 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f] [1,4] diazepin-3-carboxylic acid as a white powder with MP 206-208oC.

C) In a freshly prepared solution of sodium methylate in methanol (0.74 g (32,3 mmole) of sodium in 40 ml of methanol) was added 5,54 g (22,7 mmole) nitrile 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid and 2.5 g (36.1 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred for 48 h at room temperature. Then the suspension was evaporated and mixed with 100 ml of water. The way hydroxyimino)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno [2,3-f] [1,4]diazepin-6-it is in the form of a colourless powder with MP 248-250oC.

g) In a solution of 3.85 g (of 21.9 mmole) of BOC-glycine in 45 ml of dimethylformamide was added 3,82 g (23.5 mmole) of 1,1'-carbonyldiimidazole and the mixture was stirred for 30 min at a temperature of 50oC. Then was added 5.7 g (20,56 mmol) of (E)- and/or (Z)-3-(aminohydrocinnamic)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-6-it was stirred for 15 h at a temperature of 90oC. the resulting brown solution was evaporated under high vacuum and the resulting brown residue was chromatographically (silica gel, methylene chloride/methanol 10/1). The way it was obtained 7.2 g (84%) is not quite pure 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-it is in the form of a colorless foamy substance, Rf=0,28 (silica gel, methylene chloride/methanol 10/1).

d) a Solution of 7.2 g (17.2 mmol) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro - 4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-she's in 15 ml triperoxonane acid was stirred for 2 h at room temperature. Then the yellow solution was evaporated, the residue was dissolved in water and the aqueous phase is washed three times with methylene chloride. Next, the aqueous phase was podslushivaet 10 ml of an aqueous solution of ammonia and was extracted six times with was methylthiotetrazole (silica gel, methylene chloride/methanol 10/1). The result was obtained 3.2 g (58%) of 3-(5-aminomethyl-1,2,4 - oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] thieno [2,3-f][1,4]diazepin-6-it is in the form of colorless crystals with MP 202-204oC.

Example 254.

a) In a solution of at 5.27 g (20 mmol) 5-methyl-6-oxo-5,6-dihydro-4H - imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid in 50 ml of dimethylformamide at room temperature in one step added 3,39 g (20 mmol) of 1,1-carbonyldiimidazole and the mixture was stirred for 30 min at 50oC. Then also at one time was added to 4.47 × g (20 mmol) phthaloylglycine and the mixture was stirred for 15 h at a temperature of 110oC. the Dimethylformamide is evaporated in a high vacuum and the resulting residue was mixed with 150 ml of water. After extraction with methylene chloride (twice), dried with sodium sulfate, filtration and evaporation was obtained residue reddish color, which was then chromatographically (silica gel, methylene chloride/methanol 20/1). After recrystallization from acetonitrile received is 4.21 g (47%) of 5-(5-methyl-6-oxo-5,6-dihydro - 4H - imidazo[1,5-a]thieno[2,3-f][1,4]desain-3-ylmethyl)-2,3 - dihydro-1H-isoindole-1,3-dione in the form of light brown crystals with MP 245-246oC.

b) In a solution of 4.2 g (9,41 mmol of ethanol was added dropwise at 70oC 50 ml of methylamine (33% in ethanol) and stirred at this temperature for 2 hours the Reaction mixture was cooled and the resulting crystals were filtered off. The result was obtained 1.2 g (40%) 3-(3-aminomethyl-1,2,4-oxadiazol - 5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f] [1,4]diazepin-6-it is in the form of colorless crystals with MP 203oC (decomposition).

Example 255.

a) a suspension of 4.0 g (12.6 mmol) of ethyl ester of (S)-10,11,12,12 a-tetrahydro-8-oxo-8H-imidazo[5,1-C] pyrrolo[1,2-a] thieno [3,2-e][1,4]diazepin-1-carboxylic acid in 40 ml of ethanol was added 8 ml of hydrazine hydrate and the mixture was heated for 3 h under reflux. After cooling to 0oC the obtained crystals were filtered off and the way it was obtained 3.6 g (94%) hydrazide (S)-10,11,12,12 a-tetrahydro-8-oxo-8H-imidazo [5,1-C] pyrrolo[1,2-a] thieno[3,2-e][1,4]diazepin-1 - carboxylic acid in the form of colorless needle-like substances with MP > 260oC.

b) a Solution of 1.0 g (4.9 mmole) of N-phthaloylglycine in 8 ml of dimethylformamide was treated at room temperature 0,83 g (5,11 mmol) of 1,1'-carbonyldiimidazole and then was heated to 50oC. After 30 min, cooled to room temperature, was added 1.5 g (5 mmol) hydrazide (S)-10,11,12,12 a-tetrahydro-8-oxo-8H-imidazo [5,1-C] Pyrrhus the obtained suspension was filtered and the resulting colorless powder was washed with ethanol and diethyl ether. The result was obtained 2.2 g (100%) of the hydrazide of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindole-2 - ylacetic)-8-oxo-10,11,12,12 a-tetrahydro-8H-imidazo[5,1-c] pyrrolo[1,2-a] thieno[3,2-e][1,4] diazepin-1-carboxylic acid with MP > 260oC.

C) a Solution of 10 g (20.4 mmol) of the hydrazide of (S)-N'-(1,3 - dioxo-2,3-dihydro-1H-isoindole-2-ylacetic)-8-oxo-10,11,12,12 a - tetrahydro-8H-imidazo[5,1-C] pyrrolo[1,2-a]thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in 90 g of polyphosphoric acid was stirred for 1.5 h at 100oC. After cooling to room temperature the mixture under vigorous stirring was poured into 300 ml of ice water, after which was added solid sodium carbonate to pH 8. After extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20/1) received 7.5 g (78%) (S)-2-[5-(8-oxo-10,11,12,12 a-tetrahydro-8H-imidazo [5,1-C] pyrrolo[1,2-a] thieno[3,2-e] [1,4]diazepin-1-yl)-1,3,4 - oxadiazol-2-ylmethyl] -2,3-dihydro-1H-isoindole-1,3-dione as a colourless powder with MP > 250oC.

g) a suspension of 2.5 g (5.3 mmol) (S)-2-[5-(8-oxo-10,11,12,12 a-tetrahydro-8H-imidazo [5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-1-yl)-1,3,4 - oxadiazol-2-ylmethyl] -2,3-dihydro-1H-isoindole-1,3-dione in 30 ml of ethanol at 70oC was added dropwise 30 ml of methylamine (33% in ethanol) and stirred at this color was washed with ethanol, until it became colorless. The result has been to 1.23 g (68%) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12 a-tetrahydro-8H - imidazo[5,1-c] pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-it is in the form of a colourless powder with MP 214-216oC.

Example 256.

a) a suspension of 6.0 g (19.8 mmol) of ethyl ester of (S)-8-oxo-of 11.11 - dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-1 - carboxylic acid in 50 ml of ethanol was added 10 ml of hydrazine hydrate and the mixture was heated for 3 h under reflux. After cooling to 0oC the obtained crystals were filtered off and the result was obtained 5.6 g (98%) of the hydrazide of (S)-8-oxo-of 11.11-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno [3,2-e] [1,4] diazepin-1-carboxylic acid in the form of colorless needle-like substances with MP 260-263oC.

b) a Solution of 5.8 g (19 mmol) of N-phthaloylglycine in 30 ml of dimethylformamide was treated at room temperature, 3.2 g (19,75 mmol) of 1,1'-carbonyldiimidazole and then heated to a temperature of 50oC. After 30 min, cooled to room temperature, was added 5.6 g (quintiles these figures were 19.63 mmol) hydrazide (S)-8-oxo-11.11 is a-dihydro-8H, 10H-azeto [1,2-a]imidazo[5,1-c]thieno[3,2-e]-[1,4]diazepin-1-carboxylic acid and was stirred for 12 h at room temperature. The resulting suspension f (96%) of the hydrazide of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindole - 2-ylacetic)-8-oxo-11.11 is a-dihydro-8H, 10H-azeto[1,2-a]imidazo [5,1-C]thieno[3,2-e]-[1,4]diazepin-1-carboxylic acid with MP > 260oC.

C) a Solution of 8.5 g (16.8 mmol) of the hydrazide of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindole-2 - ylacetic)-8-oxo-11.11 is a-dihydro-8H,10H-azeto[1,2-a]imidazo [5,1-C] thieno[3,2-e] [1,4]diazepin-1-carboxylic acid in 70 g of polyphosphoric acid was stirred for 1.5 h at 100 ° oC. After cooling to room temperature the mixture under vigorous stirring was poured into 300 ml of ice water, after which was added solid sodium carbonate to obtain a pH of 8. After extraction with methylene chloride and chromatography on silica gel (methylene chloride/methanol 20/1) was obtained 6.8 g (88%) (S)-2-[5-(8-oxo-of 11.11-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno [3,2-e][1,4]diazepin-1-yl)-1,3,4-oxadiazol-2-ylmethyl]-2,3 - dihydro-1H-isoindole-1,3-dione as a colourless powder with MP > 250oC.

g) a suspension of 2.5 g (5.4 mmol) (S)-2-[5-(8-oxo-of 11.11-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-c] thieno [3,2-e][1,4]diazepin-1-yl)-1,3,4-oxadiazol-2-ylmethyl] -2,3-dihydro-1H - isoindole-1,3-dione in 30 ml of ethanol at 70oC was added dropwise 30 ml of methylamine (33% in ethanol) and stirred at this temperature for 1 h the precipitate was filtered hot and the obtained powder Zheltova the l-1,3,4-oxadiazol-2-yl)-11,11 - dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c] thieno[3,2-e] [1,4]diazepin-8-it is in the form of colorless powder, MP 233-235oC.

Example 257.

a) a suspension of 7.0 g (24 mmole) ethyl ester 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid in 70 ml of ethanol was added 13 ml of hydrazine hydrate and the mixture was heated for 3 h under reflux. After cooling to 0oC the obtained crystals were filtered off and the way it was obtained 6.5 g (97%) of the hydrazide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f] [1,4]diazepin-3-carboxylic acid in the form of colorless needle-like substances with MP > 260oC.

b) a Solution 4,74 g (23,12 mmole) of N-phthaloylglycine in 35 ml of dimethylformamide was treated at room temperature of 3.9 g (24,07 mmole) of 1,1'-carbonyldiimidazole and then was heated to 50oC. After 30 min, cooled to room temperature, was added 6,53 g of the hydrazide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4]diazepin-3-carboxylic acid and was stirred for 12 h at room temperature. The resulting suspension was filtered and the resulting colorless powder was washed with ethanol and diethyl ether. The result obtained 10.4 g (97%) of the hydrazide of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindole-2-ylacetic)-5-methyl-6-oxo-5,6 - dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-carboxylic acid with MP > 260ooC. After cooling to room temperature with vigorous stirring the mixture was poured into 300 ml of ice water, after which was added solid sodium carbonate to obtain a pH=8. After extraction with methylene chloride and chromatography on silica gel (methylene chloride/methanol 20/1) was obtained 4.3 g (89%) (S)-2-[5-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno [2,3-f][1,4]diazepin-3-yl)-1,3,4-oxadiazol-2-ylmethyl] -2,3-dihydro - 1H-isoindole-1,3-dione as a colourless powder with MP 262 to 264oC.

g) a suspension of 4.3 g (5.3 mmol) (S)-2-[5-(5-methyl-6 - oxo-5,6-dihydro-4H-imidazo[1,5-a] thieno[2,3-f] [1,4] diazepin-3 - yl)-1,3,4-oxadiazol - 2-ylmethyl] -2,3-dihydro-1H-isoindole-1,3-dione in 100 ml of ethanol at 70oC was added dropwise 60 ml of methylamine (33% in ethanol) and stirred at this temperature for 1 h the precipitate was filtered hot and the resulting yellow powder was washed with ethanol until it became colorless. The result was obtained 2.7 g (88%) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] thieno[2,3-f][1,4]diazepin-6-it is in the form of a colourless powder with MP 217-219oC.

Example 258.

In the solution 0,632 g (2 mmole) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H - imidazo[1,5-a]Ola) propyl bromide, then was stirred for 12 hours at a temperature of 70oC. Then the dimethylformamide is evaporated and the residue was distributed between methylene chloride and 2H with a solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 20/1) received 0,395 g (49%) of 3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-5 - methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6 - it is in the form of a colorless foamy substance, Rf=0,33 (silica gel, ethyl acetate/methanol 20/1).

Example 259.

In the solution of 0,500 g (1,58 mmole) 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 - dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-it in 40 ml of methylene chloride was added 2 ml (11.5 mmol) of N-ethyldiethanolamine and 0.97 ml (8 mmol) of allylbromide, after which it was stirred for 12 hours at a temperature of 70oC. Then the reaction mixture was diluted with methylene chloride and washed 2H solution of sodium carbonate. The aqueous phase was twice washed with methylene chloride and the organic phase was dried with sodium sulfate, filtered and evaporated. After chromatography (silica gel, ethyl acetate/methanol 10/1) received 0,510 g (81%) of 3-(5-diallyldimethyl-1,3,4 STV, Rf=0,54 (silica gel, ethyl acetate/methanol 10/1).

Example A.

(S)-8-chloro-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)- 12,12 a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-9-he, 3-(5-dipropylamino-1,2,4 - oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]- [1,4]benzodiazepine-6-one or any other compound of the above as particularly preferred, can be used as active substances for the preparation of injection solution of the following composition:

the active substance of 1 mg

1H. HCl - 20 ál

acetic acid - 0.5 mg

NaCl - 8 mg

phenol, 10 mg

1H. NaOH - q.s. at pH 5

H2O - q.s. up to 1 mly

1. Imidazolidine General formula

< / BR>
where A together with the two identified through carbon atoms denotes one of the radicals

< / BR>
Q denotes one of the radicals

< / BR>
R1and R2denote each respectively hydrogen, (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)hydroxyalkyl, (lower)alkoxy (lower)alkyl, (C3- C6)cycloalkyl, (C3- C6)cycloalkyl(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di-(lower)alkylamino(lower)alkyl or phenyl(lower)alkyl, where SUP>2together with the nitrogen atom to which they are bound, form a 5-8-membered heterocycle, which may optionally contain another heteroatom of oxygen, or 5-8-membered heterocycle containing as the heteroatom nitrogen and linked by condensation with a benzene ring;

R3denotes hydrogen and R4represents (lower)alkyl, or R3and R4both together represent di - or trimethylene group, and R5and R6denote each respectively a hydrogen, halogen, trifluoromethyl (lower)alkoxy or nitro, and indicated via a carbon atom has the S-configuration, if R3has a value other than hydrogen, and their pharmaceutically acceptable kislotoupornye salt.

2. Connection on p. 1, where Q denotes the radical of Q2.

3. Connection on p. 1, where Q denotes the radical of Q3.

4. Join one of the PP.1 to 3, where R1and R2denote each, respectively (lower)alkyl, (lower)hydroxyalkyl or (C3- C6)cycloalkyl(lower)alkyl or together with the nitrogen atom represent piperidine or isoindoline-2-yl.

5. Join one of the PP.1 to 4, where A denotes the radical of A1or A2, R5the seat is 6. Join one of the PP.1 - 5, where R3denotes hydrogen and R4denotes methyl, or R3and R4indicate both dimetilan.

7. Connection on p. 1, representing 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a] [1,4] benzodiazepine-6-he.

8. Connection on p. 1, which represents the (S)-8-chloro-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-12,12-dihydro-N, 11N-azeto[2,1-c] imidazo[1,5-a][1,4]benzodiazepine-9-he.

9. Connection on p. 1, which represents the (S)-1-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-11,11-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C] thieno[3,2-e][1,4]diazepin-8-he.

10. Connection on p. 1, representing 8-fluoro-5-methyl-3-[5-piperidine-1-ylmethyl)-1,2,4-oxadiazol-3-yl] -5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-he.

11. Connection on p. 1, which represents the (S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12-dihydro-N, 11N-azeto[2,1-C] imidazo[1,5-a][1,4]benzodiazepine-9-he.

12. Connection on p. 1, representing 3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he.

13. Connection on p. 1, representing 3-(5-dipropylamino-1,3,4-oxadiazol the future of the 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-he.

15. Connection on p. 1, which represents the (S)-8-chloro-1-[5-(piperidine-1-yl)methyl-1,2,4-oxadiazol-3-yl] -12,12-dihydro-N, 11N-azeto[2,1-C]imidazo[1,5-a][1,4]-benzodiazepine-9-he.

16. Connection on p. 1, representing 7-fluoro-5-methyl-3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-he.

17. Connection on p. 1, representing 7-chloro-3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4] benzodiazepine-6-he.

18. Connection on p. 1, representing 7-chloro-3-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-he.

19. Connection on p. 1, which represents the (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he.

20. Connection on p. 1, which represents the(S)-1-(5-dibutylamino-1,3,4-oxadiazol-2-yl)-11,11-dihydro-8H, 10H-azeto[1,2-a] imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he.

21. Connection on p. 1, representing 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-he.

22. Connection on p. 1, representing 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-PI, including

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12-dihydro-N,11N-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he;

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12-dihydro-N,11N-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he;

3-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he;

8-fluoro-3-(5-isoindoline-2-ylmethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he

(S)-1-(5-diallyldimethyl-1,2,4-oxadiazol-3-yl)-11,11-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-C]thieno[3,2-e][1,4]diazepin-8-he.

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

3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-he;

3-(5-dipropylamino-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-he

(S)-8-chloro-1-(5-dipropylamino-1,3,4-oxadiazol-2-yl)-12,12-dihydro-N,11N-azeto[2,1-C]imidazo[1,5-a][1,4]benzodiazepine-9-he.

25. Drug, possess agonistic action in relation to benzodiazepine receptors and showing anxiolytic and/or anticonvulsant, and/or muscle-relaxant, and/or sedations inert fillers, characterized in that, as an active ingredient the product contains the connection PP.1-24.

26. Method of producing compounds of the formula I according to one of paragraphs.1-24, where Q denotes one of the radicals Q2or Q3, characterized in that the reactive functional carboxylic acid derivative of General formula III

< / BR>
subjected to interaction with amidoximes General formula V

< / BR>
or hydrazide of General formula VII

< / BR>
where A, R3and R4are specified in paragraph (1 value, and R11and R21denote each respectively aminosidine group, (lower)alkyl, (lower)alkenyl, (lower)quinil, protected hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl(lower)alkyl, protected amino(lower)alkyl, protected (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, phenyl(lower)alkyl, where phenyl may be substituted with halogen, trifluoromethyl, (lower)alkyl or (lower)alkoxygroup, or R11and R21together with the nitrogen atom to which they are bound, form a 5-8-membered heterocycle, which may optionally contain another heteroatom of oxygen, or 5-8-membered heterocycle, a second group,

and, if necessary, the resulting product conducts the removal of existing protective groups, and, if necessary, the obtained target product of the formula Ia

< / BR>
where A, R3and R4are specified in paragraph (1 value,

Q means Q2or Q3,

R12denotes hydrogen, (lower)alkyl, (lower)alkenyl, (lower)quinil, (lower)hydroxyalkyl, (lower)alkoxy(lower)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl or phenyl(lower)alkyl, where phenyl may be substituted with halogen, trifluoromethyl, (lower)alkyl or (lower)alkoxygroup, appropriately N-alkylate,

and/or, if necessary, the obtained target product of formula Ib

< / BR>
where A, R3and R4are specified in paragraph (1 value,

Q means Q2or Q3,

R12has the above meaning;

R22represents (lower)alkenyl or (lower)quinil,

restore and/or obtained the desired product of formula I is transferred to pharmaceutically acceptable acid additive salt.

27. Connection at one PM.1-24, obladayuschee, and/or muscle-relaxant, and/or sedative-hypnotic effects.

Priority signs:

16.03.94 - PP.1, 2, 4-14, 23, and 25-27;

03.01.95 - PP.3, 15-22 and 24.

 

Same patents:

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, is omposition based on them

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to new imidazolidinedione intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures

The invention relates to compounds and their pharmaceutically acceptable salts, having the ability to inhibit matrix metalloprotease, in particular interstitial collagenase, and therefore suitable for the treatment of painful conditions in mammals, facilitated by the inhibition of such matrix metalloprotease

The invention relates to a new protected bicyclic to amidines formula I, where a is chosen from the group

-CR1R2-CR3R4-CR5R6-; -CR1R2-CR3R4-CR5R6-CR7R8< / BR>
or

-CR1R2-CR3R4-CR5R6-CR7R8-CR9R10,

where the substituents in And respectively numbered, starting from a nitrogen atom;

In choosing from the group of CR11R12-CR13R14-, -CR11R12-CR15R16-CR17R18-CR13R14;

R1and R14respectively independently of one another denote hydrogen, C1-C4-alkyl;

R15-R18respectively independently of one another denote hydrogen, C1-C4-alkyl, or at least one of R15-R18means amino, C1-C4-alkylamino-, or substituted amino group or C1-C4-alkylaminocarbonyl C1-C4-alkyl;

and the way they are received
The invention relates to medical practice

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

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