HRP950125A2 - Imidazodiazepines - Google Patents

Description

The present invention relates to imidazodiazepines of the general formula

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in which means A together with both carbon atoms marked with α and β one of the residues

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Q one of the rest

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R1 and R2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, 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, or together with the nitrogen atom a 5- to 8-membered hetercycle which in this case contains one further heteroatom or a post-condensed benzene ring,

R3 hydrogen and

R4 lower alkyl or

R3 and R4 together are one di- or trimethyl group and

R5 and R6 are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or nitro,

wherein the carbon atom marked with γ, which shows the S-configuration, if R3 is something other than hydrogen, and of which in pharmacy applicable acid addition-salts.

The compounds and salts are new and possess significant pharmacodynamic properties. They can therefore be used for therapeutic purposes, especially for anxiolytic and/or anticonvulsant and/or muscle-relaxing and/or sedative-hypnotic purposes.

The subject of this invention are the mentioned compounds of formula I and their salts as such and as therapeutically effective substances, their production and their application for therapeutic purposes, i.e. the production of appropriate drugs as well as drugs containing one compound of formula I or its salt, and the production of such drugs .

The term "lower" means residues or compounds with up to 7, preferably up to 4 carbon atoms. The term "alkyl" means straight-chain or branched saturated hydrocarbon radicals, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. The term "Alkoxy" refers to alkyl groups bonded through one oxygen atom, such as methoxy and ethoxy. The term "cycloalkyl" means saturated cyclic hydrocarbon residues, such as e.g. cyclopropyl. The terms "alkenyl" and "alkynyl" mean straight-chain or branched hydrocarbon residues, which have one C-C-double- or triple-bond, such as allyl, but-2-enyl, 3-methyl-but-2-enyl, propargyl and the like The term "aryl" in this case means a phenyl radical substituted with halogen, trifluoromethyl, lower alkyl or lower alkoxy. The term "halogen" means fluorine, chlorine and iodine. If R1 and R2 together with the nitrogen atom denote one heterocycle, then these are residues such as 1-pyrrolidinyl, 1-pyrrolinyl, piperidino, 2,6-dimethyl-piperidino, 3,3-dimethyl-piperidino, hexamethyleneimin-1-yl, heptamethyleneimin-1-yl, morpholino, 4-methyl-1-piperazinyl, isoindolin-2-yl and the like.

In formula I, Q means primarily one residue of formula Q2 or formula Q3. R 1 and R 2 mean first and foremost lower alkyl, lower hydroxyalkyl or (C 3 -C 6 )-cycloalkyl-lower alkyl or together with the nitrogen atom piperidino or isoindolin-2-yl. A denotes primarily one residue of the formula A1, where R5 means hydrogen, chlorine, fluorine, trifluoromethyl or lower alkoxy, and R6 hydrogen or fluorine, or one residue of the formula A2. Finally, R3 primarily means hydrogen, and R4 is methyl or together R3 or R4 is dimethylene.

Compounds of formula I, which are given particular preference, are:

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

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

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

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

(S)-1-(5-diallylaminomethyl-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-one;

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

3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-c][1,4]benzodiazepine -6-one;

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

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

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

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-one;

7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazo-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine -6-one;

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

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

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

Further examples of compounds preferred within the scope of the present invention are

(S)-1-(5-diallylaminomethyl-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-one;

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

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

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

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

3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]trieno[2,3-f][1 ,4]diazepin-6-one;

3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-9H,11H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one; and

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

The compounds of the formula mentioned at the beginning and their pharmaceutically acceptable acid addition salts can be produced according to the invention in such a way that

a) one reaction-capable functional derivative of a carboxylic acid of the general formula

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with one amidoxime of the general formula

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or with a hydrazide of the general formula

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in which A, R3 and R4 have the above meaning, and R11 and R21 are each independently lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl- lower alkyl, di-lower alkylamino-lower alkyl or aryl-lower alkyl or together with a nitrogen atom denotes one 5- to 8-membered existing heterocycle, in this case one further heteroatom or one post-condensed benzene ring, reacts or

b) one compound of the general formula

[image]

where A, R3 and R4 have the above meaning and X means a leaving group, reacts in the presence of a base with one isonitrile of the general formula

[image]

wherein Q, R 11 and R 21 have the above meaning, reacts, or

c) one compound of the general formula

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in which A, Q, R3 and R4 have the above meaning and Y means a leaving group, reacts with an amine of the general formula

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wherein R1 and R2 have the above meaning, reacts, or

d) from some compound of the general formula

[image]

in which A, Q, R3 and R4 have the above meaning and R7 means one protecting group, protected lower hydroalkyl, protected amino-lower alkyl or protected lower alkylamino-lower alkyl and R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, protected lower hydroxyalkyl, 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 or aryl -lower alkyl or R7 and R8 together mean one protecting group, which separates the protecting group (n), or

e) a compound of the general formula

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wherein A, Q, R 3 and R 4 have the above meaning and R 12 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower hydroxyalkyl, lower alkoxy-lower alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl- lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkyl-amino-lower alkyl or aryl-lower alkyl, respectively N-alkylated, or

f) a compound of the general formula

[image]

in which A, Q, R3 and R4 and R12 have the above meaning, and R22 means lower alkenyl or lower alkynyl, reducing and if desired

g) convert the compound of general formula I into one pharmaceutically applicable acid addition salt.

According to procedure variant a) by building the oxadiazole residue, compounds of the formula I are prepared, in which R1 and R2 each mean lower alkyl, lower alkenyl, lower alkynyl, 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 one 5- to 8-membered heterocycle, in this case one further heteroatom or one on the condensed benzene ring. In doing so, from compounds of formulas II and IV, residue Q' is formed, from compounds of formulas III and V residue Q2 and from compounds of formulas II and VI or III and VII residue Q3.

As reactive functional derivatives of carboxylic acids of formulas II and III, appropriate imidazoles are used, as appropriate for the purpose, which can be prepared according to already known procedures from the respective free carboxylic acids, e.g. by reaction with 1,1'-carbonyldiimidazole in an inert organic solvent, as N,N-dimethylformamide.

For example, carboxylic acid chlorides, which can be prepared from the corresponding free carboxylic acids using thionyl chloride, can also be used as reactive functional derivatives.

The reaction of a reactive functional derivative of a carboxylic acid of formula II or III with an amidoxime of formula IV or V is recommended to be carried out by heating for several hours at around 70 to 130°C in an inert solvent, such as N,N-dimethylformamide. The intermediately formed non-cyclized condensation product is not purposefully captured, but is spontaneously cyclized under the given reaction conditions.

The reaction of a reactive functional derivative of a carboxylic acid of the formula II or III with a hydrazide of the formula VI or VII is expediently carried out at room temperature in an inert organic solvent, such as N,N-dimethylformamide. The resulting uncyclized condensation product can be captured and cyclized to more, expediently during 1- to several hours of heating with polyphosphoric acid at approx. 100°C.

Also according to procedure variant b), compounds of the formula I are prepared, in which R1 and R2 each stand for themselves, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy-lower alkyl, (C3-C6)-cycloalkyl, (C3-C6 )-cycloalkyl-lower alkyl, di-lower alkylamino-lower alkyl or aryl-lower alkyl or together with a nitrogen atom mean one 5- to 8-membered corresponding heterocycle, in this case one further hetero-atom or one post-condensed benzene ring. In formula VIII, the leaving group marked with X is, for example, an easily cleaving residue of a phosphoric acid derivative, e.g. formula group

-O-PO(ORa)2 or -O-(NRbRc)2

in which Ra means lower alkyl or aryl, and Rb and Rc are each independently lower alkyl, lower alkenyl (as allyl) or aryl or together with the nitrogen atom one associated 5- to 8-membered heterocycle, in this case a further heteroatom (as morpholine ), halogen atom, alkylthio group, aralkylthio group, N-nitrosoalkylamino group, alkoxy group, mercapto group and the like. The reaction of a compound of the general formula VIII with an isonitrile of the formula IX is carried out in an inert solvent, such as dimethylformamide , hexamethylphosphoric acid amide, dimethyl sulfoxide, tetrahydrofuran, or in any other suitable organic solvent and in the presence of a base sufficiently basic to form the isonitrile anion. Suitable bases are alkali metal alkoxides, such as sodium methoxide or potassium tert-butoxide, alkali metal hydrides, such as sodium hydride, alkali metal amides, such as lithium amide or lithium diisopropylamide, butyllithium , tertiary amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5), and the like. The reaction temperature lies expediently between -70°C and around room temperature.

According to the variant of procedure c), compounds of formula I are prepared, in which R1 and R2 have the meaning stated at the beginning. In formula X, the leaving group marked with Y is expediently a halogen atom, primarily a chlorine or bromine atom, or some easily separable sulfonyloxy group, such as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy or the like. Reaction of 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, expediently an organic base, e.g. of a tertiary amine, such as N-ethyldiisopropylamine or the like, whereby the amine of formula XI can be used in excess as an organic base.

According to process variant d), a compound of formula I is obtained, in which R1 is hydrogen, lower hydroxyalkyl, amino-lower alkyl or lower alkylamino-lower alkyl, and R2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower hydroxyalkyl, lower alkyloxy- 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. Suitable protective groups and methods for their removal are known to every expert, whereby of course only such protective groups can be applied, which can be removed by methods, the conditions of which do not affect other structural elements in the compounds of formula XII.

A suitable N-protecting group is, for example, a tert-butoxycarbonyl group (BOC), which can be cleaved off using trifluoroacetic acid.

A suitable O-protecting group is, for example, a tert-butyl group (tert-Bu), which can also be cleaved off using trifluoroacetic acid.

If R7 and R8 mean together one protective group, then the residue –NR7R8 means, for example, one phthalimido group, which can be cleaved using methylamine to form an NH2 group.

According to process variant e), compounds of formula I are obtained, in which at least one of R1 and R2 is different from hydrogen. Suitable alkylating agents and methods for alkylating are known to those skilled in the art. Suitable alkylating agents are particularly appropriate halides, such as propyl bromide, propyl iodide, butyl iodide, allyl bromide, crotyl bromide, 4-bromo-1-butene, 3,3-dimethylallyl bromide, propargyl bromide , cyclopropylethyl bromide, benzyl bromide or α,α'-dibromo-o-xylene (whereby the last NH2 group can be converted into an isoindolin-2-yl group). Alkylation is carried out in the presence of a base, as appropriate for the purpose of an organic base, such as N-ethyl-diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (1,5-5) or the like. Furthermore, alkylation is expediently carried out in an inert solvent, such as N,N-dimethylformamide.

According to procedure variant f) compounds of formula I, where at least one of R1 and R2 means lower alkyl, are obtained from corresponding compounds of formula I, where at least one of R1 and R2 means lower alkenyl or lower alkynyl, i.e. from compounds of formula Ib, and by reducing the C-C double or triple bond. This reduction is appropriately carried out using catalytic hydrogenation, for example in the presence of a palladium catalyst, such as Pd/C. Furthermore, this reduction is carried out in some inert solvent, such as acetic ester.

According to process variant g), the compounds of formula I can be converted into pharmaceutically applicable acid addition salts. Here, not only salts with inorganic but also with organic acids come into play. Examples of such salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methanesulfonates, p-toluenesulfonates, etc. These salts can be prepared by methods already known and known to every expert.

The starting products of the above formulas III, IV, VI and XI belong to generally known groups of compounds, and thus are available to every expert. Also the starting products of formulas II, V, VII and VIII belong to known groups (compare e.g. EP 0 150 040 A2 and EP 0 027 214 A1). The starting products of formula XII can be prepared, for example, in analogy with the previously described methods of variants a) and b). The preparation of the starting product of formulas IX and X will be explained later using reaction schemes 1 to 3 and 4, respectively. In addition, some of the examples described further below contain extensive information regarding the preparation of specific starting products.

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(IXa : Formula IX, in which Q stands for the residue Q')

Reaction scheme 2

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(IXb: formula IX, where Q is the residue Q2)

Reaction scheme 3

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(IXc: formula IX, where Q is the residue Q3)

Reaction scheme 4

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(Xa, Xb and Xc: formula X, where Y is chlorine and Q is the residue Q' or Q2 or Q3)

As mentioned at the beginning, the compounds of formula I are new. They possess valuable pharmacodynamic properties and show only very toxicity. They have as a common feature a pronounced affinity for the central benzodiazepine receptor and, based on their agonistic effect on that receptor, have pronounced anxiolytic, anticonvulsant, muscle-relaxing and sedative-hypnotic properties. They form highly soluble acid addition salts in water and are therefore particularly suitable for the preparation of aqueous injection solutions.

The affinity of compounds of general formula I for central benzodiazepine receptors was determined in vitro according to the method described in Nature 294, 763-765 (1981) and J. Neurochemistry 37, 714-722 (1981). According to this method, the stopping of the binding of tritiated flumacenil to specific benzodiazepine receptors in the rat cortex of each individual test substance is tested. IC50 ("50% inhibiting concentration") denotes the concentration of each test substance, which causes a 50% stoppage of the specific binding of tritiated flumacenil to specific benzodiazepine receptors in the rat cortex.

The sedative/muscle-relaxing properties of the compounds of formula I according to the invention can be understood, for example, from the rotary stick test. Mice weighing 19-21 g are used for this test. Up to 1 hour before the start of the experiment, they have free access to food and drinking water. At least 30 minutes before the experiment, they are brought to the laboratory for experiments. In the rotating rod test, the animals are placed on a horizontally laid, smooth metal rod with a diameter of 3 cm, which rotates at 2 revolutions per minute. First, the animals are given an opportunity of 30 seconds to familiarize themselves with the test situation. Then those animals that managed to stay on the stick for at least 1 min are selected. These animals are given intravenously the preparations being tested, in different doses. In different time intervals, it is then determined whether the animals can stay on the stick for the shortest time (shortest time: 10 sec; from 5 min after administration: 1 min). The dose at which 50% of the animals are able to stand on the stick is determined (ED 50).

The following table shows the results obtained from the previously described experiments with representative representatives of the types of compounds defined by the general formula I.

Table

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A: (S)-8-chloro-1-(5-dipropylaminomethyl-1,2 azeto[2,1-dmidazo[1,5-a][1,4]benzodiazepine-9-one.

B: (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-almidazo[5,1-c] thieno[3,2-e][1,4]diazepin-8-one.

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

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

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

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

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

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-one.

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

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

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-one.

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

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

N: (S)-1-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]midazo[5,1- c]thieno[3,2-e][1,4]diazepin-8-one.

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

P: 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-one.

It is evident from the above table that compounds A to P develop a sedative effect that occurs very quickly and is maintained for a very short time.

The compounds of formula I can be used as sedatives/hypnotics, anticonvulsants, muscle relaxants and anxiolytics based on their agonistic effect on benzodiazepine receptors. They are suitable for example as fast but short-acting hypnotics for pre-oral administration, especially but - in the form of aqueous solutions of their acid addition salts - as injectable short-hypnotics for pre-medication, sedation as well as initial narcosis and maintenance of narcosis; Possibilities of use that are preferred are pre-medication before initial narcosis, basal sedation before diagnostic or surgical procedures with or without local anesthesia, long-term sedation in the intensive care unit, use as an induction agent for inhalation narcosis or as an inducing component for sleep, combined narcosis (including total intravenous anesthesia), etc.

A series of compounds of formula I, including the above compounds A, B, D and E were administered i.v. mice and rats in doses of 32 and 100 mg/kg, without any deaths.

The compounds of formula I and their pharmaceutically acceptable acid addition salts may find use as drugs, e.g. in the form of pharmaceutical preparations. These pharmaceutical preparations can be administered orally, e.g. in the form of tablets, lacquer tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. It can also be administered rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

For the production of pharmaceutical preparations, the compounds of formula I and their pharmaceutically applicable acid addition salts can be processed with pharmaceutically inert, inorganic or organic carriers. Such carriers can be used for tablets, lacquer tablets, dragees and hard-gelatin capsules, for example lactose, corn starch or their derivatives, talc, stearic acid or its salts, etc. For soft-gelatin capsules, they are suitable as carriers for example vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; but due to the property of the active substance in soft-gelatin capsules, carriers are not needed at all. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, inventive sugar, glucose, etc. For aqueous injection solutions of water-soluble acid addition salts of compounds of formula I, auxiliary substances such as alcohols, polyols, glycerin, vegetable oils and the like, but as a rule they are not necessary. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Pharmaceutical preparations may also contain preservatives, solubilizing agents, stabilizing agents, dispersing agents, emulsifying agents, sweeteners, dyes, flavoring agents, salts for changing osmotic pressure, buffers, coating agents or antioxidants. They may also contain other therapeutically valuable substances.

As mentioned at the beginning, medicines, containing one compound of formula I or one of its pharmaceutically applicable acid addition salt and one therapeutically inert excipient, are also the subject of this invention, furthermore also the process for the production of such medicines, which are characterized by the fact that one or more compounds of formula I or their pharmaceutically applicable acid addition-salts and in this case one or more other valuable substances together with one or more therapeutically inert carriers are brought into the galenic administration form.

As mentioned at the beginning, the compounds of formula I and their pharmaceutically applicable acid addition salts can be used according to the invention for therapeutic purposes, especially for anxiolytic and/or anticonvulsant and/or muscle-relaxing and/or sedative-hypnotic purposes. The dosage can vary within wide limits and, of course, should be adapted to individual conditions in each case. In general, with intravenous administration, the daily dose should be approx. 1 mg to 1000 mg.

The subject of the invention is also, as mentioned at the beginning, the use of compounds of formula I and their pharmaceutically applicable acid addition salts for the production of drugs, especially anxiolytic and/or anticonvulsant and/or muscle-relaxing and/or sedative-hypnotic drugs.

The following examples are intended to further clarify this invention, but in no way limit its scope. All temperatures are given in degrees Celsius.

Example 1

a) 1.89 g (10 mmol) of BOC-sarcosine is dissolved in 10 ml of N,N-dimethyl-formamide, 1.63 g (10 mmol) of 1,1'-carbonyl-diimidazole are mixed in portions and stirred for 20' at 50°C. 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-carboxamidoxime, 7 hours at 90°. The reaction mixture is cooled and poured into 300 ml of water. The resulting suspension is filtered, and the crystals are washed with water and dried. 3.16 (69%) 7-chloro-5,6-dihydro-5-methyl-3-(5-N-BOC-N-methylaminomethyl-1,2,4-oxadiazol-3-yl)-4H-imidazo is obtained [1,5-a][1,4]benzodiazepine-6-one m.p. 114-117°.

b) 3.09 g (6.73 mmol) 7-chloro-5,6-dihydro-5-methyl-3-(5-N-BOC-N-methylamino oxadiazol-3-yl)-4H-imidazo[1,5-a ][1,4]benzodiazepine-6-one is stirred for 2.5 hours in 20 ml of trifluoroacetic acid at room temperature. The solution is solidified, after which the residue is dissolved in water and washed twice with methylene chloride. The aqueous phase is basified with 25% ammonia and extracted four times with methylene chloride. After drying in evaporation of the combined organic phases and recrystallization of the residue from methanol, 1.3 g (54%) of 7-chloro-5,6-dihydro-5-methyl-3-(5-methylaminomethyl-1,2,4-oxadiazole-3) is obtained -yl)-4H-imidazo[1,5a][1,4]benzodiazepine-6-one m.p. 192-193°.

Example 2

a) 4.60 g (16.95 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime is mixed with 3.19 g (18.65 mmol ) of hydridachloroacetic acid in 25 ml of N,N-dimethylformamide for 30 minutes at room temperature and 2 hours at 105°. The reaction mixture is evaporated, the residue is dissolved in methylene chloride, and the solution is washed with a saturated solution. After drying over magnesium sulfate, the solution is evaporated and the crystalline residue is chromatographed on silica gel eluting with acetic ester. 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 mp 108-109°.

b) 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-one is mixed in 20 ml of N,N-dimethylformamide with 5.06 g (50 mmol) of dipropylamine for 4 hours at room temperature. The reaction mixture is evaporated, and the residue is chromatographed on silica gel under elution with acetic ester. 3.65 g (92%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one with m.p. 130-132°, which is converted into the hydrochloride with m.p. 213-215°.

Example 3

1.4 g (13.5 mmol) of N,N-dimethylglycine is suspended in 20 ml of N,N-dimethylformamide, mixed with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole and stirred for 1 hour at room temperature and 1 hour at 75° 3.9 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]-benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. Concentration of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride and methanol 19/1 yielded after recrystallization from acetic ester 2.53 g (54%) of (S)-8-chloro-12,12a-dihydro-1-( 5-dimethylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1-c]midazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 127-129°, which is converted into the hydrochloride with m.p. 178°.

Example 4

2.55 g (13.5 mmol) of 1-pyrrolidine-acetic acid is dissolved in 20 ml of N,N-dimethylformamide and mixed with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole in portions. After stirring for 45 minutes, 3.9 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a ][1,4]benzo-diazepine-1-carboxamidoxime and stirred overnight at 90°. 0.2 g of p-toluenesulfonic acid is added and stirred again for 4 hours at 90°. The reaction mixture is solidified. Chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 and recrystallization from ethyl acetate and hexane yields 1.6 g (32%) of (S)-8-chloro-12,12a-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-he with t.t. 117-120°, which is converted 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 mixed in portions with 2.6 g (15 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 30' at 70°. Then 4.02 g (15 mmol) of (S)-S-chloro-11,12,13,13a-tetrahydro-9-oxo-9H4midazo[1,5-a]pyrrolo[2,1-c][1, 4]-benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. Evaporation of the solution and chromatography of the residue on 340 g of silica gel eluting with methylene chloride/methanol 19/1 yielded 1.99 g (40%) of (S)-8-chloro-1-(5-dimethylaminomethyl-1,2,4-oxadiazole-3 -yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 261°.

Example 6

a) 3.5 g (20 mmol) of BOC-glycine is dissolved in 20 ml of N,N-dimethylformamide and mixed in portions with 3.35 g (20 mmol) of 1,1'-carbonyldiimidazole. After stirring for 10 minutes at 45°, 6.35 g (20 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-1-carboxamidoxime and stir overnight at 90°. The reaction mixture is evaporated; the residue is dissolved in methylene chloride, and the solution is washed three times with water, dried over magnesium sulfate and evaporated. Chromatography of the residue on silica gel eluting with acetic ester yields 7.5 g (82%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro- 12,12a-dihydro-9H,11H-azeto(2,1-c)imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used in the next step without further purification.

b) 7.29 g (16 mmol) of crude (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro12,12a-dihydro-9H,11H-azeto(2 ,1-c)imidazo(1,5-a)(1,4)benzodiazepine-9-one is stirred for 2 hours in 25 ml of trifluoroacetic acid. The solution is concentrated, the residue is taken up in water, and the aqueous solution is washed twice with methylene chloride. The aqueous phase is made alkaline with 25% ammonia and extracted seven times with methylene chloride. Drying and evaporation of the organic phase gives 5.12 g (90%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H -azeto[1,5-a][1,4]benzodiazepine-9-one with m.p. 212-214°, which is converted into the hydrochloride with m.p. 252-255°.

Example 7

a) 3.8 g (20 mmol) of BOC-sarcosine is dissolved in 20 ml of N,N-dimethylformamide and mixed in portions with 3.5 g (21.6 mmol) of 1,1'-carbonyldiimidazole. After stirring for 10 minutes at 45°, 6.35 g (20 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[ 1,5-a]-[1,4]benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. By compressing the reaction solution and chromatography of the residue on silica gel eluting with acetic ester, 7.58 g (80%) of (S)-8-chloro-12,12a-dihydro-1-[5-(N-BOC-N) are obtained -methyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is applied in the next stage without further cleaning.

b) 8 g (17 mmol) of crude (S)-8-chloro-12,12a-dihydro-1-[5-(N-BOC-N-methyl)-aminomethyl-1,2,4-oxadiazole-3- yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepin-9-one is stirred for 2 hours in 25 ml of trifluoroacetic acid at room temperature temperature. The solution is concentrated, the residue is dissolved in water, and the aqueous phase is washed twice with methylene chloride. The aqueous phase is basified with 25% ammonia and extracted seven times with methylene chloride. Drying and evaporation of the combined organic phases gives 4.35 g (69%) of (S)-8-chloro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4-ixadiazol-3-yl)-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 250°.

Example 8

1.96 g (13.5 mmol) of 4-morpholinoacetic acid was dissolved in 20 ml of N,N-dimethylformamide and mixed in portions with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole. After stirring for 15 minutes at 80°, 3.9 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]-imidazo[1 ,5-a][1,4]benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. The reaction mixture is solidified. Chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 and recrystallization from acetic ester yields 1.85 g (35%) of (S)-8-chloro-12,12a-dihydro-1-[5-(pyrrolidine) -1-ylmethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is translated into the hydrochloride.

Example 9

1.75 g (17 mmol) of N,N-dimethylglycine was dissolved in 20 ml of N,N-dimethyl formamide and mixed with 3.08 g (15 mmol) of 1,1'-carbonyldiimidazole in portions. After the CO2 evolution stops, the solution is stirred for 30' at 70°. 4.02 g (15 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime and stirred overnight at 90°C. Evaporation of the solution, chromatography of the residue on 240 g of silica gel eluting with methylene chloride/methanol 19/1 and crystallization from acetic acid yielded 1.35 g (24%) of (S)-7-fluoro-12,12a-dihydro-1-[ 5-(Dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with d.p. 187-190°, which is converted into the hydrochloride with m.p. 150-155°.

Example 10

a) 6.81 g (36 mmol) of BOC-sarcosine is dissolved in 30 ml of N,N-dimethyl-formamide and mixed with 6.5 g (40 mmol) of 1,1-carbonyldiimidazole in portions. After the CO2 evolution stops, the solution is stirred for 30' at 40°. Then 9.04 g (15 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1, 4]benzodiazepine-1-carboxamidoxime and stir overnight at 90°. After evaporation of the solution and chromatography of the residue on 450 g of silica gel eluting with methylene chloride/methanol 19/1, 8.81 g (65%) of (S)-7-fluoro-12,12a-dihydro-1-[5-(BOC) are obtained -N-methylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used in the next stage without further cleaning.

b) 7.74 g (17 mmol) of crude (S)-7-fluoro-12,12a-dihydro-1-[5-(N-BOC-N-methylaminomethyl)-1,2,4-oxadiazole-3- yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 2 hours in 25 ml of trifluoroacetic acid. The solution is concentrated, the residue is taken up in water, and the solution is washed twice with methylene chloride. The aqueous phase is basified with 25% ammonia and extracted seven times with methylene chloride. 5.12 g (85%) of (S)-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2, 1–c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 187-190°, which is converted into the hydrochloride with m.p. 155-160°.

Example 11

4.13 g (11.13 mmol) (S)-8-chloro-12,12a-dihydro-1-[5-methylaminomethyl-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 20 ml N,N-dimethylformamide, 2 g (13 mmol) 1,8-diazabicyclo-[5.4.0]-undec-7 -ene(1,5-5) and 1.58 g (13 mmol) of allyl bromide were stirred for 60 hours at room temperature. The reaction mixture is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 2.86 g (62%) of (S)-1-[5-(N-allyl-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-8-chloro-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 187-192°.

Example 12

a) 8.41 g (48 mmol) of BOC-glycine is dissolved in 30 ml of N,N-dimethylformamide and mixed in portions with 7.8 g (48 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 10 minutes at 45°. Then 12.05 g (40 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1, 4]-benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. Evaporation of the solution, chromatography of the residue on 550 g of silica gel eluting with methylene chloride/methanol 19/1 and recrystallization from acetic ester yielded 10.78 g (61%) of (S)-1-[5-(BOC-aminomethyl)-1,2 ,4-oxadiazol-3-yl-7-fluoro-12,12a-dihydro-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 147-150°.

b) 4.40 g (10 mmol) (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,HH- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 2 hours in 20 ml of trifluoroacetic acid. The solution is concentrated, the residue is taken up in water, and the aqueous solution is washed twice with methylene chloride. The aqueous phase is basified with 25% ammonia and extracted seven times with methylene chloride. After drying and evaporation of the organic phase, 2.77 g (81%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H are obtained, 11H-azeto-[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-9-one with m.p. 195-198°, which is converted into the hydrochloride with m.p. 275°.

Example 13

1.24 g (12 mmol) of N,N-dimethylglycine is dissolved in 20 ml of N,N-dimethylformamide and mixed in portions with 2.43 g (15 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 30' at 70°. Then 3.35 g (10 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5- a][1,4]-benzodiazepine-1-carboxamidoxime and stirred for 3.5 hours at 90°. Evaporation of the solution, chromatography of the residue on 300 g of silica gel eluting with ethyl acetate/methanol 9/1 and crystallization from ethyl acetate and hexane give 0.98 g (24%) of (S)-8-chloro-7-fluoro- 12,12a-dihydro-1-[5-(dimethylaminomethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1 ,4]benzodiazepine-9-one with m.p. 166-169°; which is converted into the hydrochloride with m.p. 223-227°.

Example 14

470 mg (1.32 mmol) (S)-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one and 750 mg (1.92 mmol) (S)-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1, 2,4-oxadiazol-3-yl)-9H,11H-azeto[2,1c]imidazo[1,5-a][1,4]benzodiazepine-9-one hydrochloride, 837 mg (5.5 mmol) 1 ,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) and 450 mg (3.5 mmol) of allyl bromide are mixed in 15 ml of N,N-dimethylformamide overnight at room temperature and 2.5 hours at 55° . The reaction mixture is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 1.15 g (88%) of (S)-1-[5-(N-allyl-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-7-fluoro-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 224-226°.

Example 15

a) 3.02 g (16 mmol) of BOC-sarcosine is dissolved in 15 ml of N,N-dimethylformamide and mixed with 2.75 g (17 mmol) of 1,1-carbonyldiimidazole in portions. After stirring for 15 minutes at 50°, 5.04 g (15 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c] were added. imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime and stirred overnight at 90°. Concentration of the reaction solution and chromatography of the residue on silica gel eluting with acetic ester yielded 5.0 g (68% of (S)-8-chloro-7-fluoro-12,12a-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- he, which is applied in the next stage without further cleaning.

b) 4.42 g (9 mmol) (S)-8-chloro-7-fluoro-12,12a-dihydro-1-[5-(N-BOC-N-methyl)-aminomethyl-1,2,4-oxadiazole- 3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one was allowed to stand overnight in 20 ml of trifluoroacetic acid. The solution is evaporated, the residue is dissolved in water, and the solution is washed three times with methylene chloride. The aqueous phase is alkalized with conc. with ammonia and extracted eight times with methylene chloride (ca. 1 l in total). After evaporation of the combined and magnesium sulfate-dried organic phases, 2.97 g (84%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4- oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further purification as the starting product in the next described for example.

Example 16

2.95 g (7.6 mmol) crude (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-9-one, 15 ml N,N-dimethylformamide, 1.4 g (9.4 mmol) 1,8-diazabicyclo[5.4.0 ]undec-7-ene(1,5-5) and 1.1 g (9 mmol) of allyl bromide are mixed overnight at room temperature and for 6 hours at 55°. The reaction mixture is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 1.39 g (42% of (S)-1[5-(N-allyl-N-methyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-8-chloro-7-fluoro-12, 12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with mp 199-203°.

Example 17

a) 3.02 (16 mmol) of BOC-sarcosine is dissolved in 25 ml of N,N-dimethylformamide and mixed with 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole in portions. After the CO2 emission stops, the solution is stirred for 30' at 60°. Then 4.02 g (15 mmol) of (S)-S-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][ 1,4]-benzodiazepine-1-carboxamidoxime and stir overnight at 95°. After evaporation of the solution and chromatography of the residue on 300 g of silica gel under elution with acetic ester, 3.6 g (49%) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-N-BOC) is obtained -N-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H-imidazol(1,5-a)pyrrolo[2,1-c][1,4]benzodiaepin-9-one, which without further cleaning is used in the next step.

b) 3.6 g (7.4 mmol) of crude (S)-8-11,12,13,13a-tetrahydro-1-(5-N-BOC-N-methylaminomethyl-1,2,4-oxadiazole-3- yl)-9H-imidazol[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one is stirred for 1 hour in 25 ml of trifluoroacetic acid at room temperature. The solution is concentrated, the residue is taken up in water and the aqueous solution is washed twice with methylene chloride. The aqueous phase is made alkaline with 25% ammonia and extracted five times with methylene chloride. Drying and evaporation of the combined organic phases gives 2.47 g (87%) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl) )-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one with m.p. 161-163°.

Example 18

2.19 g (5.7 mmol) (S)-8-chloro-11,12,13,13a-tetrahydro-1-(5-methylaminomethyl-1,2,4-oxadiazol-3-yl)-9H4midazol[1,5- a]pyrrolo[2,1-c][1,4]benz 20 ml N,N-dimethylformamide, 1.07 g (7 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene-(1,5 -5) and 850 mg (7 mmol) of allyl bromide are mixed for 4.5 hours at 60°. the reaction mixture is concentrated, and the residue is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 1.32 g (54%) of (S)-1-(5-N-allyl-N-methylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a- tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one, which is converted to the hydrochloride.

Example 19

a) 7.47 g (16.35 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 20 ml of N,N-dimethylformamide, 800 mg of sodium hydride and 4.34 g (36 mmol) of allyl bromide are mixed overnight at 65°. After evaporation of the solvent, the residue is taken up in methylene chloride, after which the solution is washed twice with water, dried and evaporated. Chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yields 2.08 g (25%) of (S)-1-(5-N-allyl-N-BOC-aminomethyl-1,2,4-oxadiazole-3- yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-9-one, which without further purification used in the next stage.

b) 2.08 g (4.2 mmol) of crude (S)-1-(5-N-allyl-N-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro -9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 3/4 hour in 10 ml of trifluoroacetic acid. After evaporating the reaction mixture, the residue is dissolved in methylene chloride, after which the solution is washed with saturated sodium carbonate solution and water, dried over magnesium sulfate and dried. The residue is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 0.75 g (48%) of (S)-1-(5-allylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 227-228°.

Example 20

36.5 g (235 mmol) of diallylglycine were dissolved in 165 ml of N,N-dimethylformamide and mixed with 40.5 g (250 mmol) of 1,1'-carbonyldiimidazole in portions. After stirring for 10 minutes, add 40 g (126 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a ][1,4]benzodiazepine-1-carboxamidoxime and stirred for 1 hour at room temperature and 3.5 hours at 110°. The reaction mixture is concentrated, and the residue is purified by chromatography on silica gel eluting with methylene chloride/octene ester 1/1. 27.1 (45%) (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1c ]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 181-182.5°.

Example 21

2.70 g (7.2 mmol) (S)-1-(5-aminoethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 35 ml N,N-dimethylformamide, 3.39 g (22.2 mmol) 1,8-diazabicyclo[5.4.0.] Undec-7-ene(1,5-5) and 2.61 g (21.6 mmol) of allyl bromide were mixed for 20 hours at room temperature. After evaporation of the reaction mixture, the residue is taken up in methylene chloride, the solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel eluting with methylene chloride/methanol 19/1. Unique fractions with Rf=19 are concentrated. 1.21 g (37%) of (S)-1-(5-allylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepin-9-one, which is converted to the hydrochloride with a decomposition temperature of 190°.

Example 22

a) 25.4 g (100 mmol) (S)-5-chloro-6-fluoro-1,10a-dihydro-2H-azeto[2,1-c]-[1,4]benzodiazepine-4,10(9H) -dione is dissolved in 125 ml of N,N-dimethylformamide, mixed with 4.8 g (110 mmol) of sodium hydride dispersion (55-65% in oil, washed with n-hexane) at -30° and deprotonated at - 30° to -18° for 40 min. At -60°, a solution of 26.86 g (100 mmol) of diphenyl-ester-chloride-phosphoric acid in 5 ml of N,N-dimethylformamide is added and stirred for 35 min at max. -45°. In the meantime, 12.3 g (110 mmol) of potassium tert-butylate were separately dissolved in 30 ml of N,N-dimethylformamide and mixed with 12.2 g (107 mmol) of ethyl ester-isocyano-acetic acid at -60°. The deprotonated ethyl ester-isocyano-acetic acid is cooled to -70° and using the addition funnel, cooled with dry ice, the reaction mixture is added dropwise at max. -65° within 5/4 hours. In an acetone/dry-ice bath, it is stirred for 1 hour, neutralized with 12 ml of acetic acid and poured into 500 ml of ice-water. It is extracted five times with methylene chloride (total 1.2 1), dried over magnesium sulfate and evaporated to dryness. Chromatography of the residue on 1.5 kg of silica gel eluting with acetic ester gives 14.4 g (41%) of ethyl-(S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate with m.p. 161-163°.

b) 57.3 g (164 mmol) ethyl-(S)-8-chloro-7-fluoro-12,12a-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 4N sodium hydroxide solution are heated for 30 minutes in a steam bath under reflux. The alcohol is evaporated on a rotary evaporator. The remaining aqueous phase is washed twice with methylene chloride and with 51.5 ml (206 mmol) of 4N-hydrochloric acid and acidified to pH 3-4. The obtained suspension is cooled and filtered, and the filter residue is washed with a little ice-water and dried. 47.92 g (91%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a] are obtained [1,4]benzodiazepine-1-carboxylic acids with m.p. 225-226°.

c) 40 g (124 mmol) (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]-imidazo[1,5-a ][1,4]benzodiazepine-1-carboxylic acid is suspended in 190 ml of N,N-dimethylformamide and mixed with 21 g (129.5 mmol) of 1,1-carbonyldiimidazole in portions at room temperature. After the CO2 evolution has stopped, the clear brown solution is stirred for 30 min at 50°, cooled and at a temperature below 25° within approx. For 10 min, it is mixed with 30 ml conc. ammonia. After stirring for 30 minutes, the resulting suspension is poured into 700 ml of ice water, stirred for 30 minutes at room temperature and filtered, after which the crystals are washed with a little water. After drying, 31.36 g (78%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5- a][1,4]benzodiazepine-1-carboxamide with m.p. 296 298°.

d) 33.67 g (105 mmol) (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide is suspended in 140 ml of dioxane and 18 ml of pyridine and at a temperature of <8° it is mixed with 22.6 g (107.6 mmol) of anhydride-trifluoroacetic acid dropwise within 30 min. It is mixed for 2.5 hours at 50° and poured into 700 ml of water. The suspension is filtered and after drying the residue, 28.62 g (90%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo are obtained [1,5-a][1,4]benzodiazepine-1-carbonitrile with m.p. 225-228°.

e) 3.1 g (134.8 mmol) of sodium is dissolved in 140 ml of methanol. At room temperature, 10 g (145 mmol) of hydroxylamine hydrochloride and 28.6 g (94.5 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile. The suspension is stirred overnight at room temperature, cooled to 0° within 30 minutes, the crystals are filtered off, mixed with 50 ml of water and filtered. The methanol solution is concentrated, after which the residue is washed in 30 ml of water, and the crystals are filtered off. By drying the combined crystallisates, 30.94 g of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][ 1,4]benzodiazepine-1-carboxamidoxime with mp 236-238°.

f) 17.08 g (97 mmol) of BOC-glycine is dissolved in 165 ml of N,N-dimethylformamide and mixed in portions with 16.9 g (104 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred at 50° for 30 min. Add 30.8 g (91 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamide oxime and stirred overnight at 90°. Evaporation of the solution and chromatography of the residue on 1.5 kg of silica gel eluting with methylene chloride/methanol 19/1 yielded 36.8 g (84%) of (S)-1-[5-(BOC-aminomethyl)-oxadiazol-3-yl]-8- chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further purification in the next level.

g) 36.8 g (77.5 mmol) of crude (S)-1-[5-(BOC-aminomethyl)-oxadiazol-3-yl]-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one and 90 ml of trifluoroacetic acid are stirred for 2 hours at room temperature. The solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. The aqueous phase is alkalized with conc. with ammonia and extracted eight times with methylene chloride (ca. 11 in total). After evaporation of the combined organic phases and dried over magnesium sulfate, 23.8 g (82%) of (S)-1-(5-aminomethyl)-1,2,4-oxadiazol-3-yl)-8-chloro-7- fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further purification as a starting product for the following described example

Example 23

26.6 g (71 mmol) of crude (S)-1-(5-aminomethyl)-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 400 ml of methylene chloride, 85 ml (496 mmol) of N-ethyldiisopropylamine and 34.5 g (285 mmol) of allyl bromide are mixed 20 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate in steam. The residue is chromatographed on 2 kg of silica gel eluting with acetic ester. The single fractions are evaporated and recrystallized from toluene and n-hexane. 22.34 g (69%) of (S)-1-(5-diallylaminomethyl)-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H are obtained -azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one m.p. 103-104°.

Example 24

a) 4.16 g (23.6 mmol) of BOC-glycine is dissolved in 30 ml of N,N-dimethylformamide and mixed in portions with 4.08 g (25.2 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 20 min at 50°. 7.36 g (22.2 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c]-[ 1,4]benzodiazepine-1-carboxamide oxime and stirred overnight at 90°. The reaction mixture is evaporated, the residue is dissolved in methylene chloride and the solution is washed once with water and once with saturated sodium bicarbonate solution. After drying and compression, 7.75 g (74%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a- tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is used in the next step without further purification.

b) 7.75 g (16.5 mmol) of crude (S)-1-(5-BQC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H -imidazo[1,5-a]pyrrolo[2,1-c]-[1,4]benzodiazepine-9-one is mixed for 1.5 hours in 25 ml of trifluoroacetic acid at room temperature. The solution is concentrated, the residue is concentrated, the residue is collected in saturated sodium bicarbonate solution and the solution is extracted ten times with methylene chloride. By drying and evaporating the combined organic phases, 5.53 g (90%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a- tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is used without further purification as the starting product in the next described example.

Example 25

2.47 g (6.7 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one, 20 ml N,N-dimethylformamide, 9 ml (60 mmol) 1,8-diazabicyclo[5.4.0]undec -7-ene(1,5-5) and 10.26 g (54 mmol) of benzyl bromide were stirred overnight at room temperature and for 6 hours at 50°. The reaction mixture is concentrated and the residue is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. After recrystallization from acetic ester and hexane, 2.16 (58%) (S)-1-(5-dibenzylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a is obtained -tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one with m.p. 107-109°.

Example 26

3.0 g (8.1 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 20 ml N,N-dimethylformamide, 3 ml (20 mmol) 1,8-diazabicyclo[5.4.0]undec-7 -ene(1,5-5) and 6.54 g (54 mmol) of allyl bromide are stirred overnight at 40°. The reaction mixture is concentrated, the residue is dissolved in methylene chloride, and the solution is washed with water. After drying, the product is purified by chromatography on silica gel eluting with methylene chloride/methanol 19/1. 1.8 g (49%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride.

Example 27

a) 6.68 g (22 mmol) (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acid is dissolved in 70 ml of N,N-dimethylformamide, mixed with 3.84 g (24 mmol) of 1,1-carbonyldiimidazole in portions at 40° and stirred for 30 min at that temperature. After the addition of 3.78 g (26 mmol) of phthaloylglycinamidoxime, it is stirred for 2.5 hours at 60° and 18 hours at 110° and the reaction mixture is solidified. Chromatography of the residue on silica gel eluting with acetic ester gives 6.01 g (56%) of (S)-8-chloro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl) )-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one stt. 189-192°.

b) 6.01 g (12.3 mmol) (S)-8-chloro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is placed in 60 ml of ethanol and mixed with 120 ml of methylamine (33% in ethanol) dropwise for 30 min at 60°. The solution is stirred for 2 hours at 70° and then solidified. Chromatography of the residue on silica gel eluting with acetic ester/methanol 8/2 gives 4.0 g (91%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro -12,12a-dihydro-9H,11H-azeto with m.p. 206-208°.

Example 28

502 g (14 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one 75 ml of N,N-dimethylformamide, 21 g (173.8 mmol) of allyl bromide and 29.4 g (193 mmol) of 1,8-diazabicyclo[5.4. 0.]undec-7-ene(1,5-5) is stirred for 60 hours at 75°. The solution is concentrated, and the residue is purified by chromatography on 350 g of silica gel eluting with acetic ester. 1.97 g of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c] midazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 190-192°.

Example 29

a) 0.60 g (26 mmol) of sodium is dissolved in 32 ml of methanol. At room temperature, 1.95 g (28.1 mmol) of hydroxylamine hydrochloride is added, and after 1 hour, 5.77 g (346 mmol) of (S)-7-fluoro-12,12a-dihydro-9-ox6-9H,11H-azeto[2 ,1-c]midazo[1,5-a][1,4]benzodiazepine-1-carbonitrile. The suspension is stirred for 3.5 hours at 70°, cooled for 30 min at 0° and the crystals are filtered. By drying the crystallized, 6.5 g (100%) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1 ,4]benzodiazepine-1-carboxamidedioxime with m.p. 248-250°.

b) 2.32 g (15 mmol) of diallylglycine are dissolved in 15 ml of N,N-dimethylformamide and mixed with 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole. After stirring for 20 minutes at 50°, 3.01 (10 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5 -a][1,4]benzodiazepine-1-carboxamidoxime and stirred for 16 hours at 90° and 2 hours at 120°. The solution is concentrated, and the residue is purified by chromatography on 320 g of silica gel eluting with acetic ester. 1.54 g (37%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 100-105°.

Example 30

a) 8 g (23.7 mmol) (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acid is dissolved in 50 ml of N,N-dimethylformamide, mixed in portions with 4.06 g (25 mmol) of 1,1'-carbonyldiimidazole and stirred for 30 min at 55°. After the addition of 5.26 g (24 mmol) of phthaloylglycinamidoxime, the mixture is stirred for a further 20 hours at 105°. The reaction mixture is evaporated and the residue is chromatographed on silica gel eluting with acetic ester. 5.34 g (43%) of (S)-8-trifluoromethyl-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 243-245°.

b) 5.3 g (10.2 mmol) (S)-8-trifluoromethyl-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 70 ml of ethanol was mixed at 60° for 45 min dropwise with 150 ml of methylamine (33% in ethanol). The solution is stirred for 2 hours at 70° and finally solidified. The residue is dissolved in methylene chloride and 30 ml of 4N hydrochloric acid and the solution is washed three times with methylene chloride. The aqueous phase is basified with 30 ml of 4 N sodium hydroxide solution and extracted five times with methylene chloride. After drying the combined organic solutions and evaporating the solvent, 3.98 g (100%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro- 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further purification as the starting product for the example described below.

Example 31

2 g (5.1 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1 -c]imidazo[1,5-a][1,4]benzodiazepine-9-one 30 ml of methylene chloride, 6.2 ml (36 mmol) of N-ethyldiisopropylamine and 2.57 g (1.8 mmol) of allyl bromide were stirred for 18 hours at room temperature. The reaction solution is washed three times with water, it is dried over magnesium sulfate and evaporated. The residue is chromatographed on 300 g of silica gel eluting with acetic ester. 1.62 g (67%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 147-150°.

Example 32

3.56 g (10 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one 15 ml methylene chloride, 8.6 ml (50 mmol) N-ethyldiisopropylamine and 2.64 g (10 mmol) α,α'-dibromo-o-xylene it is mixed from 20 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 500 g of silica gel eluting with methylene chloride/methanol 19/1. 1.55 g (33%) of (S)-8-chloro-12,12a-dihydro-1-(5-isoindilin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 218-222°.

Example 33

473 mg (1.1 mmol) (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepm-9-one is hydrogenated in 10 ml of acetic ester in the presence of 20 mg of 5% palladium-carbon at room temperature and normal pressure. After separating the catalyst, the solution solidifies. 0.42 g (80%) of (S)-8-chloro-1-(5-di-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride with m.p. 147-153°.

Example 34

2.27 g (5 mmol) (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is hydrogenated in 80 ml of acetic ester in the presence of 35 mg of 5% palladium-carbon at room temperature and normal pressure. After separation of the catalyst, the reaction mixture is purified by chromatography on silica gel eluting with acetic ester to obtain 1.83 g (80%) of (S)-chloro-7-fluoro-12,12a-dihydro-1-(5-dipropylaminomethyl-1,2 ,4oxadiazol-3-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiaepin-9-one, which is converted to the hydrochloride.

Example 35

a) To a solution, cooled to -70°, of 57.2 g (250 mmol) of N-(tert-butoxycarbonyl)-3,4-difluoroanilan in 500 ml of tetrahydrofuran, 400 ml (600 mmol) of tert-butyl-lithium is added dropwise within 1 hour (1.5 M in pentane). 160 g of dry ice is then added to this yellow suspension in small portions, heated to 0° and 400 ml of water added. Tetrahydrofuran and pentane are distilled off, the aqueous phase is washed twice with ether and then with conc. brought to pH=1 with hydrochloric acid. The acidic aqueous phase is extracted three times with methylene chloride; the organic phase is dried over sodium sulfate, filtered and evaporated. The resulting yellowish-gray solid was recrystallized from ethylene chloride to give 52 g (76%) of 2-tert-butoxycarbonyl)amino-5,6-difluorobenzoic acid as colorless needles with m.p. 159.5-160.5°.

b) A solution of 108 ml of thionyl chloride in 300 ml of tetrahydrofuran is added dropwise to a solution of 100 g (366 mmol) of 2-tert-butoxycarbonyl)amino-5,6-difluorobenzoic acid in 1.5 l of dry tetrahydrofuran under ice cooling, after which it is stirred for 16 hours at room temperature. The brown solution is evaporated, and the resulting brown solid is mixed with methylene chloride. The resulting yellowish-gray powder is filtered off and dried in a high vacuum. 56.5 g (77%) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione is obtained as a yellowish-gray powder with m.p. >240°.

c) A solution of 19.6 g (98.4 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 9.95 g (98.4 mmol) of L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid is stirred at 120° for 16 hours. The brown solution is evaporated, and the resulting brown residue is crystallized from ethanol. 16 g (68%) of (S)5,6-difluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1, 4]benzodiazepine-4,10- dione as colorless needles with m.p.>250°.

d) To a suspension of 2.7 g (62.3 mmol) of NaH (55%, washed with hexane) in 5 ml of dimethylformamide, a solution of 13.5 g (56.7 mmol) of (S)-5,6-difluoro 1, 2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione in 65 ml of dimethylformamide and stirred for 40 min at -30°. After cooling to -60°, a solution of 12.1 ml (56.7 mmol) of chloride-ester-diphenyl-phosphoric acid is added dropwise so that the temperature does not rise above -45°. Then it is mixed for another 30 minutes.

During this time, 7.0 g (62.3 mmol) of potassium tert-butylate were dissolved in 20 ml of dimethylformamide and mixed with 7 ml (60.6 mmol) of ethyl ester-isocyano-acetic acid (95%) at -60°. The reaction mixture obtained above is added dropwise to the solution thus obtained at -70° via a poor addition funnel cooled to -40°. The thus obtained dark brown grainy solution is further stirred for 1 hour at -60° and after neutralization with 7 ml of acetic acid at -40° it is poured into 300 ml of ice-water and then extracted five times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The resulting light brown residue is recrystallized from ethanol. 8.9 (47%) ethyl ester (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a ][1,4]benzodiazepine-1-carboxylic acids as colorless needles with m.p. 233.5-235.5°.

e) Suspension of 8.8 g (26.4 mmol) ethyl ester (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1, 8.6 ml (34.3 mmol) of 4N sodium hydroxide solution is added dropwise to 5-a][1,4]benzodiazepine-1-carboxylic acid in 20 ml of ethanol and 30 ml of water, and the mixture is heated at reflux for 30 minutes. Then the ethanol is distilled off. The aqueous phase is washed twice with methylene chloride and brought to pH=3 with 4 N hydrochloric acid. Extraction, filtration and evaporation gave 7.2 g (89%) of (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5 -a][1,4]benzodiazepine-1-carboxylic acid as colorless needles with m.p. 218.0-219.5° (exp.).

f) Suspension of 7.2 g (23.6 mmol) (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] 4.2 g (26 mmol) of 1,1'-carbonyldiimidazole is added in portions to [1,4]benzodiazepine-1-carboxylic acid in 50 ml of dimethylformamide. The resulting light-brown solution is heated for 45 minutes at 50°. Then the solution is cooled to room temperature and 6 ml of aqueous ammonia solution is added dropwise. After further stirring for 30 minutes, the reaction mixture is poured into 100 ml of ice-water and extracted with methylene chloride seven times. Drying of the organic phase over sodium sulfate, filtration, evaporation and further chromatography (silica gel, methylene chloride/methanol 19:1) yielded 7.0 g (97%) of (S)-7,8-difluoro-9-oxo-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid as a colorless powder with mp 200.5-204.0°.

g) A suspension of 6.3 g (20.7 mmol) of amide-(S)-7,8-difluoro-9-oxo-12,12a-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 is added dropwise at 5-8° to 3 ml (21.7 mmol) of trifluoroacetic anhydride. The obtained yellowish-gray solution is heated at 50° and then poured into 50 ml of ice-water. Extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation gave 4.8 g (81%) of (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile as a powder with m.p. >250°.

h) 4.7 g (16.4 mmol) (S)-7,8-difluoro-9-oxo-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid and 2.7 g (36.1 mmol) of hydroxylamine hydrochloride and stirred for 16 hours at room temperature . The suspension is then evaporated and the residue partitioned between methylene chloride and water. The insoluble part is filtered off and dried under high vacuum. The organic phase is dried over sodium sulfate, filtered and evaporated. The resulting foam is chromatographed together with the insoluble part (silica gel, methylene chloride/methanol 9/1), and 4.4 g (84%) of (E)- and/or (Z)-(S)-7-fluoro-8-methoxy are obtained. -12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime as a colorless foam, Rf=0.33 (silica gel , methylene chloride/methanol 9:1).

i) 2.5 g (15.4 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 2.5 g (14.4 mmol) of BOC-glycine in 25 ml of dimethylformamide and stirred for 30 minutes at 50°. Then 4.3 g (13.5 mmol) of (E)- and/or (Z)-(S)-7-fluoro-8-methoxy-12,12a-dihydro-9-oxo-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime and stirred for 16 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 4.1 (65%) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H is obtained -azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.18 (silica gel, methylene chloride/methanol 19:1).

k) A solution of 4.0 g (8.5 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro- 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 10 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 5 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried over sodium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 2.3 g (73%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as colorless crystals with m.p. 196-198°.

Example 36

Solutions of 800 mg (2.16 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 12 ml of methylene chloride is added to 5.1 ml (29.8 mmol) of N-ethyldiisopropylamine in 1.46 ml (17.34 mmol) of allyl bromide. The reaction solution is stirred for 20 hours at room temperature, then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 770 mg (79%) of (S)-1-(5-diallyl-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H are obtained, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a colorless foam, Rf=0.37 (silica gel, methylene chloride/methanol 19:1).

Example 37

Solutions of 800 mg (2.16 mmol) (S)-2-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H- 2.55 ml (14.9 mmol) of N-ethyldiisopropylamine and 0.73 ml (8.67 mmol) of allyl bromide are added to azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 12 ml of methylene chloride. The reaction solution is stirred for 20 hours at room temperature, then diluted with methylene chloride and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 340 mg (35%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.37 (silica gel, methylene chloride/methanol 19:1), 30 mg of the mixed fraction and 120 mg (13%) (S)-1-(5-allylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-8-methoxy-12,12a-dihydro-9H,11H-azeto[2 ,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.21 (silica gel, methylene chloride/methanol 19:1).

Example 38

a) To the sodium methylate solution, which is prepared in the usual way from 2.0 g (86.9 mmol) of sodium and 85 ml of methanol, 6.2 g (89.2 mmol) of hydroxylamine hydrochloride and 16.3 g (63.6 mmol) of 8-fluorine are added one after another. -5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonyl. The reaction mixture was stirred for 24 hours at room temperature and then cooled in an ice bath. The crushed crystals are filtered off and mixed with 35 ml of water. The white crystals are filtered off and dried in a vacuum at 60°. 12.4 g (67 %) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime are obtained as white crystals with d.p. 249-250° (exp.).

By evaporating the filtrate and repeating the procedure described above, an additional product (2.8 g) contaminated with the output product is obtained. This is chromatographed on 100 g of silica gel first with methylene chloride/acetone 9:1, 2:1 and finally with methylene chloride/methanol 9:1, whereby a further 1.72 g of 8-fluoro-5,6-dihydro-5-methyl- 6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime. Overall utilization: 77%.

b) 0.38 ml (2.2 mmol) of N-ethyldiisopropylamine is added to a suspension of 0.4 g (2.2 mmol) of hydrochloride-morpholin-4-yl-acetic acid in 4 ml of DMF. At room temperature, 390 mg (2.4 mmol) of 1,1'-carbonyldiimidazole is added in portions, after which the solution is stirred for 30 min. stirred at 50° and then mixed at room temperature with 0.58 g (2.0 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4 ]benzodiazepine-3-carboxamidoxime. The reaction mixture is heated to 90° for 20 hours. The solvent is removed in vacuo, the residue is taken up in 15 ml of water, and the solution is extracted several times with ethyl acetate. The combined extracts are dried over sodium sulfate, filtered and evaporated. The crude material is purified by chromatography on silica gel (methylene chloride/methanol 19:1). The solvent is removed in vacuo, the residue is dissolved in 5 ml of acetonitrile, and the solution is acidified by the addition of ethereal HCl solution. The white crystals are suction filtered and recrystallized from acetonitrile. 0.5 g (54%) of 8-fluoro-5-methyl-3-(5-morpholin-4-ylmethyl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine is obtained -6-one-hydrochloride (3:5) with m.p. 198-205° (exp.).

Example 39

a) 11.8 g (39.2 mmol) (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo pyrrolo[2,1-c][1,4]benzodiazepine- 1-carboxylic acid is dissolved in 80 ml of N,N-dimethylformamide, mixed in portions with 6.71 g (41.4 mmol) of 1,1-carbonyldiimidazole and stirred for 20 min at 50°. After the addition of 8.77 g (40 mmol) of phthaloylglycinamidoxime, it is stirred overnight at 100° and for 5 hours at 120°. After evaporation of the solvent, the residue is dissolved in methylene chloride, after which the solution is washed three times with water, dried over magnesium sulfate and dried. Chromatography on silica gel eluting with acetic ester yielded 9.6 g (50%) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9H-1-(3-phthalimidomethyl-1,2,4- oxadiazol-5-yl)-imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-9-one with m.p. 258-260°, which is applied in the next stage without further cleaning.

b) 9.6 g (19.8 mmol) (S)-7-fluoro-11,12,13,13a-tetrahydro-9H-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazo[ 1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-9-one dissolves in 130 ml of ethanol and at 65° within 30 min. dropwise mixed with 130 ml of methylamine (33% in ethanol). The solution is stirred for 2 hours at 70° and finally solidifies. The residue is dissolved in methylene chloride and 20 ml of 4N hydrochloric acid, and the solution is washed three times with methylene chloride. The aqueous phase is made alkaline with 20 ml of 4 N sodium hydroxide solution and extracted three times with methylene chloride and five times with ethyl acetate. After drying the combined organic solutions and evaporating the solvent, 6.73 g (96% of 9 (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-11,12,13, 13a-tetrahydro-9H-imidazo[1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is used without further purification as the starting 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-one, 60 ml of methylene chloride, 13.6 ml (79 mmol) of N-ethyldiisopropylamine and 5.63 g (46 mmol) of allyl bromide were mixed for 60 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 360 g of silica gel eluting with ethyl acetate. The resulting fractions are combined. 2.19 g (45%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-9-one (oil: Rf: 0.43; silica gel 60 F254; flow agent: acetic ester), which is converted to the hydrochloride.

Example 41

a) 6.31 (21 mmol) (S)-7-fluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]-pyrrolo[2,1-c][1 ,4]benzodiazepine-1-carboxamide is suspended in 20 ml of dioxane and 3.6 ml of pyridine and mixed with 3.3 ml of trifluoroacetic anhydride at 5° to 10°. The reaction mixture is stirred overnight at room temperature and poured into 150 ml of water. The resulting suspension is filtered, and the crystals are dried. 5.36 g (90%) of (S)-7-fluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1 ,4]benzodiazepine-1-carbonitrile with m.p. 254-256°.

b) 615 mg (26.8 mmol) of sodium are dissolved in 35 ml of methanol. At room temperature, 2 g (28.8 mmol) of hydroxylamine hydrochloride and 5.3 g (18.8 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1, 5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile. The suspension is stirred overnight at room temperature, cooled to 0° for 30 min and the crystals are filtered. After drying, 4.97 (84%) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo[2,1-c] is obtained. [1,4]benzodiazepine-1-carboxamidoxime with m.p. 267-268°.

c) 2.93 g (15.7 mmol) of BOC-glycine is dissolved in 30 ml of N,N-dimethylformamide and mixed in portions with 2.76 g (17 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 20 min at 55°. Then 4.95 g (22.2 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo[2,1-c] are added [1,4]benzodiazepine-1-carboxamidoxime and stir overnight at 90°. The reaction mixture is evaporated, and the residue is chromatographed on silica gel, eluting with methylene chloride/methanol 19/1. 4.45 g (61%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is used in the next step without further purification.

d) 4.4 g (9.7 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro- 9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one is stirred for 1.5 hours in 15 ml of trifluoroacetic acid at room temperature. The solution solidifies. The residue is taken up in a saturated sodium bicarbonate solution and extracted ten times with methylene chloride. By drying and evaporating the combined organic phases, 2.76 g (80%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a- tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one which is used without further purification as the starting product in the next described example.

Example 42

2.75 g (7.6 mmol) of crude (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 50 ml of methylene chloride, 9 ml (53.3 mmol) of N-ethyldiisopropylamine and 3.75 g (31 mmol) of allyl bromide were stirred for 96 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 360 g of silica gel eluting with ethyl acetate. Uniform fractions are paired. 2.46 g (76%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]-pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride.

Example 43

a) 10 g (29.7 mmol) (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acid is suspended in 50 ml of N,N-dimethylformamide and mixed with 5.1 g (31.2 mmol) of 1,1'-carbonyldiimidazole in portions at room temperature. After the CO2 evolution has stopped, the clear brown solution is stirred for 20 min at 50°, cooled and at a temperature below 15, mixed by adding dropwise within approx. 15' with 8 ml conc. ammonia. After stirring for 40 minutes, the obtained suspension is poured into 300 ml of ice-water, after which it is stirred for 20 minutes at room temperature, filtered and washed again with a little water. After drying, 7.51 g (75%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]midazo[1,5-a][1 ,4]benzodiazepine-1-carboxamide sat.t. >300°.

b) 7.5 g (22.3 mmol) (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamide is suspended in 40 ml of dioxane and 4 ml of pyridine and at 7 to 10° within 10 min it is mixed with 3.6 ml of anhydride-trifluoroacetic acid. It is mixed for 3/4 hours at room temperature and poured into 300 ml of water. The obtained suspension is filtered and after drying the residues, 3.75 g (52%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-1-carboxamidoxime, which is used in the next step without further purification.

c) 730 mg (31.8 mmol) of sodium are dissolved in 40 ml of methanol. At room temperature, 2.37 g (34.1 mmol) of hydroxylamine hydrochloride and 7.1 g (22.3 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c ]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile and stirred overnight at room temperature. Evaporation of the solvent gives 7.8 g (100%) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1 ,4]benzodiazepine-1-carboxamidoxime, which is used in the next step without further purification.

d) 4.2 (24 mmol) of BOC-glycine is dissolved in 40 ml of N,N-dimethylformamide and mixed in portions with 4.05 g (25 mmol) of 11'-carbonyldiimidazole. After the CO2 evolution stops, the solution is stirred for 20 min at 50°. Then 7.7 g (22 mmol) of (S)-8-trifluoromethyl-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][ 1,4]benzodiazepine-1-carboxamidoxime and stir overnight at 90°. The reaction mixture was concentrated, and the residue was dissolved in methylene chloride. Washing, drying and evaporation of the organic phase yielded 7.82 g (72%) of (S)-1-[5-(N-BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-trifluoromethyl-12 ,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used in the next step without further purification.

e) 7.8 g (15.9 mmol) of crude (S)-1-[5-(N-BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-trifluoromethyl-12,12a-dihydro-9H ,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one and 30 ml of trifluoroacetic acid are stirred for 1 hour at room temperature. The solution is evaporated. The residue is dissolved in water and washed three times with methylene chloride. Aqueous phases are alkalized with conc. with ammonia and extract nine times with acetic ester (total 11). Evaporation of the combined organic phases dried over magnesium sulfate yields 4.57 g (73%) of (S)-1-(5-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-trifluoromethyl-12,12a -dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further purification as the starting product in the next described example.

Example 44

3 g (7.7 mmol) of crude (S)-1-(5-aminomethyl)-1,2,4-oxadiazol-3-yl]-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2, 1-c]midazo[1,5-a][1,4]benzodiazepine-9-one, 50 ml of methylene chloride, 14.2 g (72 mmol) of N-ethyldiisopropylamine and 5.14 g (3.6 mmol) of allyl bromide are stirred overnight at room temperature. and 4 hours at 40°. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 390 g of silica gel eluting with acetic ester. 1.50 g (41%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the dihydrochloride with methanolic hydrochloric acid.

Example 45

1.51 g (7.7 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 15 ml methylene chloride, 4 ml (23.4 mmol N-ethyldiisopropylamine and 1.06 g (4 mmol) α,α'-dibromo-o-xylene are stirred overnight at room temperature. The reaction solution is washed twice with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 240 g of silica gel eluting with acetic ester/hexane/triethylamine 17/2/1. This gives 0.5 g (26%) (S)-8-trifluoromethyl-12,12a-dihydro-1-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with mp 185-188°.

Example 46

a) 40.58 g (128.7 mmol) ethyl-(S)-7-fluoro-12,12a-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) of 4N-sodium alkali are heated for 1.5 hours on a steam bath under reflux. The alcohol is evaporated on a rotary evaporator. The aqueous phase is washed twice with methylene chloride and acidified with 32.5 ml (130 mmol) of 4N hydrochloric acid to pH 3-4. The resulting suspension is cooled and filtered. The residue on the filter is washed with a little ice water and dried. 36.67 g (99%) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acids with m.p. 159-160°.

b) 20g (69.6 mmol) of crude (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acid is dissolved in 40 ml of N,N-dimethylfonnamide, mixed in portions with 13 g (80.2 mmol) of 1,1'-carbonyldiimidazole and stirred further for 10 min at 60°. After the addition of 16.78 g (76.6 mmol) of phthaloyl-glycine-amidoxime, it is stirred for 1 hour at 90°, 14 ml of trifluoroacetic acid is added and stirred for another 18 hours at 85°. The resulting suspension is cooled, the crystals are filtered off with methanol. 16.74 g (51%) of (S)-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with mp 287-288°, which is used in the next step without further crystallization.

c) 10.8 g (23 mmol) of crude (S)-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2 ,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is mixed dropwise with 150 ml of methylamine (33% in ethanol) in 150 ml of ethanol at 60° within 30 min. The solution is stirred for 2 hours at 70° and then evaporated. The residue is taken up in methylene chloride and 30 ml of 4N hydrochloric acid, and the solution is washed three times with methylene chloride. The aqueous phase is basified with 30 ml of 4N sodium hydroxide solution and extracted five times with methylene chloride. After drying the combined organic solutions and evaporating the solvent, 7.5 g (96%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is used without further crystallization as the starting product in the next described example.

Example 47

10.35 g (30.4 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1 -c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 100 ml of N,N-dimethylformamide, 13 ml (76 mmol) of ethyldiisopropylamine and 7.72 g (63.8 mmol) of allyl bromide are stirred for 3 hours at room temperature temperature. After evaporation of the reaction mixture, the residue is purified by chromatography on silica gel eluting with acetic ester. Recrystallization from ethyl acetate and hexane yielded 8.11 g (63%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-7-fluoro-12,12a-dihydro-9H ,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 188-190°.

Example 48

a) Under argon, 0.92 g (5.3 mmol) of BOC-glycine is dissolved in 7 ml of N,N-dimethylformamide and mixed with 0.9 g (5.6 mmol) of 1,1'-carbonyldiimidazole in portions at room temperature. After the CO2 evolution stopped, the mixture was stirred for another 30 min at room temperature and then mixed 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-carboxamidoxime, It is heated for 18 hours at 90°, cooled to room temperature and diluted with 50 ml of water, during which the product crystallizes. The product is filtered off with suction and dissolved in methylene chloride, and the solution is dried with sodium sulfate. Evaporation in a vacuum gives 1.25 g of white foam.

The aqueous filtrate is extracted several times, and the extracts are dried with sodium sulfate, filtered and evaporated, whereby a further 0.95 g of solid is obtained. This is taken up in 10 ml of water and mixed, during which the further product is separated. The precipitated material is filtered off, dissolved in methylene chloride, dried with sodium sulfate, filtered and evaporated. Once again 0.47 of crude product is obtained.

The combined crude products (1.72 g) were crystallized from 7 ml of acetic acid. 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 m.p. 170-172°.

b) Under argon, 0.64 g (1.5 mmol) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo Dissolve [1,5-a][1,4]benzodiazepine-6-one in 1.5 ml of trifluoroacetic acid and stir for 1 hour at room temperature. The solvent is evaporated in a vacuum, and the residue is dissolved in 10 ml of water. The solution is extracted with methylene chloride, and the aqueous phase is basified with conc. with ammonia and extracted several times with methylene chloride. The combined organic extracts are dried with sodium sulfate, filtered and evaporated. The slightly pink colored crystals obtained are heated in 10 ml of methanol, after which they are filtered through Celite and the filtrate is evaporated. The residue is recrystallized from 9 ml of acetonitrile/methanolic hydrochloric acid 2:1. 0.30 g (50%) 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-one hydrochloride (1:1:9 with m.p. 264-266° (dec.).

Example 49

Under argon, a suspension of 0.49 g (1.5 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidzo[1 ,5-a][1,4]benzodiazepine-6-one hydrochloride in 8 ml of methylene chloride is mixed with 1.8 ml (10.5 mmol) of N-ethyl-diisopropylamine and 0.51 ml (60 mmol) of allyl bromide and stirred for 42 hours under argon at room temperature . The solution is washed three times with water, dried with sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on 50 g of silica gel (acetic ester), after which the eluate is evaporated and the residue is taken up in 5 ml of methanol. The solution is acidified with ethereal hydrochloric acid, the solvent is removed in vacuo. The residue is dissolved in 4 ml of methanol, after which it is filtered through Celite, cooled to room temperature. 0° and dilute with 8 ml of ether. In the process, white crystals are slowly secreted, which are filtered. 345 mg (50%) of 3-[5-(diallyl-aminomethyl-)1,2,4-oxadiazol-3-yl]-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (2:3) with m.p. 133-140° (exp.).

Example 50

Under argon, a suspension of 0.49 g (1.5 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidzo[1 ,5-a][1,4]benzodiazepine-6-one in 8 ml of methylene chloride is mixed with 0.77 ml (4.5 mmol) of N-ethyldiisopropylamine and 0.475 g (1.8 mmol) of α,α'-dibromo-o-xylene and mixed under with argon for 7 hours at room temperature. The solution is washed once with water, dried with sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on 40 g of silica gel (methylene chloride/acetone 4:1, then 2:1), after which the eluate is evaporated, and the residue is taken up in 3 ml of methanol. The solution is acidified with ethereal hydrochloric acid, and the solvent is removed in vacuo. The residue is dissolved in 3 ml of methanol, after which the solution is cooled to approx. 0° and dilute by adding 3 ml of ether. In the process, white crystals slowly settle out, which are filtered off. 190 mg (26%) of 8-fluoro-3-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidzo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (2:3) with m.p. 177-184° (exp.)

Example 51

1.85 g (5 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 20 ml of N,N-dimethylformamide, 3.4 ml (20 mmol) of N-ethyldiisopropyl-amine and 1.45 g (5.5 mmol ) α,α'-dibromo-o-xylene is stirred overnight at room temperature. After evaporation of the reaction solution, the residue is chromatographed on 430 g of silica gel eluting with acetic ester/methanol 9/1. 0.74 g (31%) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)- 9H-Imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one which is converted to the hydrochloride with m.p. 165-170°.

Example 52

5 g (14 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 50 ml methylene chloride, 12 ml (70 mmol) N-ethyldiisopropylamine and 3.7 g (14 mmol) α,α'-dibromo-o- xylene is stirred for 72 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 70 g of silica gel eluting with methylene chloride/acetic ester 7/3. 4.0 (62%) (S)-8-chloro-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H-11H-azeto is obtained [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 170-175°.

Example 53

a) Under argon, 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 is suspended in 20 ml of N,N-dimethylformamide and at room temperature 1.95 g (12.0 mmol) of 1,1'-carbonyldiimidazole is added in portions. After gas evolution stops, the reaction mixture is stirred for another 30 min at 50°, then cooled to room temperature and mixed with 2.41 g (11.0 mmol) of phthaloylglycinamidoxime. The mixture is heated for 18 hours at 90°, cooled in an ice bath and diluted with 40 ml of ether, after which the separated crystals are filtered off and dried in a vacuum. 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, 273-276°.

b) 10.1 g (22 mmol) 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 is heated to 65° in 220 ml of ethanol, after which 150 ml of 33% ethanolic methylamine solution is added dropwise over a period of 100 minutes. After the addition is complete, the solution is further heated and then cooled in an ice bath, during which white crystals are separated. These are filtered and dried in a vacuum. After recrystallization from ethanol, 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 m.p. 208-217°. A further 2.5 g of product were obtained by chromatography on silica gel with methylene chloride/methanol 19:1, then 9:1. Total yield: 5.55 g (77%).

Example 54

Under argon, 492 mg (1.5 mmol) 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 in 8 ml of methylene chloride was mixed with 1.8 ml (10.5 mmol) of N-ethyldiisopropylamine and 0.51 ml (6.0 mmol) of allyl bromide and stirred under argon for 24 hours at room temperature. The solution is washed once with 10 ml of water, dried with sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on 40 g of silica gel (acetic ester), the eluate is evaporated, and the residue is taken up in 5 ml of methanol. The solution is removed under vacuum. The residue is dissolved in 5 ml of methanol, and the solution is cooled to approx. 0° and dilute with 18 ml of ether. White crystals are slowly secreted, which are filtered off. 270 mg (40%) of the hydrochloride 3-(3-diallylaminomethyl)-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1, 5-a][1,4]benzodiazepine-6-one (1:1) with m.p. 181-185° (dec.).

Example 55

Under argon, 492 mg (1.5 mmol) 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 in 8 ml of methylene chloride was mixed with 1.3 ml (7.5 mmol) of N-ethyldiisopropylamine in 0.42 ml (3.6 mmol) of 3,3-dimethylallyl bromide and stirred for 2 hours under argon at room temperature . The solution is evaporated, and the crude product is chromatographed on 40 g of silica gel (acetic ester). The eluate is evaporated, and the residue is taken up in 3 ml of methanol. The solution is acidified with ethereal hydrochloric acid and evaporated, after which the residue is taken up in 10 ml of acetic acid. The solution is cooled to approx. 0°, and the white crystals are filtered off. 220 mg (29%) of 3-[3-[bis-(3methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-5-yl]-8-fluoro-5-methyl-5 is obtained, 6-Dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) with m.p. 181-184° (exp.).

Example 56

Under argon, 492 mg (1.5 mmol) of 3-(5-aminomethyl)-1,2,4-oxadiazol-3-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1, Mix 5-a][1,4]benzodiazepine-6-one in 8 ml of methylene chloride with 1.3 ml (7.5 mmol) of N-ethyldiisopropylamine and 0.42 ml (3.6 mmol) of 3,3-dimethylallyl bromide and stir for 2 hours under argon at room temperature . The solution is evaporated and the crude product is purified by chromatography on 40 g of silica gel (acetic ester). The eluate is evaporated, and the residue is taken up in 3 ml of methanol. The solution is acidified with ethereal hydrochloric acid and evaporated, after which the residue is taken up in 10 ml of acetic ester. The solution takes 30 min. heat on the return cooler, cool to approx. 0°, after which the white crystals are filtered off. 315 mg (40%) of 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 hydrochloride (2.3) with m.p. 144-148° (exp.)

Example 57

a) A solution of 26.9 g (171 mmol) 2H-thieno-[3,2-d][1,3]oxazin-2,4(1H)-dione (EP 27214) and 16.1 g (171 mmol) L-azetidine -2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid is mixed for 3 hours at 120°. The brown solution is evaporated, and the resulting brown residue is crystallized from ethanol. 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione are obtained as colorless crystals with m.p. 274°.

b) A solution of 8.32 g (40 mmol) (S)-6,7-dihydroaceto[1,2 -a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione in 45 ml of dimethylfonnamide, and the mixture was stirred for 40 minutes at -30°. After cooling to the ester-chloride-phosphoric acid in 3 ml of dimethylformamide, it is added dropwise so that the temperature does not exceed -45°. Then it is mixed for another 30 minutes.

In the meantime, 4.92 g (44 mmol) of potassium tert-butylate are dissolved in 20 ml of dimethylformamide and mixed with 4.7 ml (42.8 mmol) of ethyl ester-isocyano-acetic acid (95%) at -60°. The above reaction mixture is added to the solution obtained in this way at -70° via the addition funnel cooled to -40°. The obtained dark-brown grainy solution is stirred for 1 hour at -60° and after neutralization with 4.8 ml of acetic acid at -40° it is poured into 300 ml of ice water, after which it is extracted five times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The resulting light brown residue is recrystallized from ethanol. 8.12 g (67%) of ethyl ester (S)-8-oxo-11,11a-dihydro-8H,10H-aceto[1,2-a]imidazo[5,1-c]thieno[3,2 -e][1,4]diazepine-1carboxylic acids as colorless crystals with m.p. 188-191°.

c) Suspension of 13.5 g (44.5 mmol) ethyl ester (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]midazo[5,1-c]thieno[3 ,2-e][1,4]diazepine-1-carboxylic acid in 10 ml of ethanol and 16 ml of water is added dropwise to 13.9 ml (55.6 mmol) of 4N sodium hydroxide solution. The mixture is heated for 30 min. on the return cooler, and then the ethanol is distilled off. The aqueous phase is washed twice with methylene chloride and brought to pH=3 using 4 N hydrochloric acid. The resulting precipitate is filtered off and washed with water, ethanol and finally with diethyl ether. 10.8 g (88%) of (S)-S-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]midazo[5,1-c]thieno[3,2-e] are obtained [1,4]diazepine-1-carboxylic acid as a colorless powder with m.p. 260° (exp.).

d) Suspension of 12.43 g (45 mmol) (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2- e][1,4]diazepine-1-carboxylic acid in 70 ml of dimethylformamide is added in portions of 7.65 g (47 mmol) of 1,1'-carbonyldiimidazoal. The resulting light brown solution is heated for 45 minutes at 50°. Then the solution is cooled to room temperature and 10.9 ml of aqueous ammonia solution is added dropwise. After further stirring for 30 minutes, the reaction mixture is poured into 100 ml of ice water, and the resulting precipitate is filtered off and washed with water, ethanol and finally with ether. After drying at 70°/10 torr, 11.0 g (89%) of amide (S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c ]thieno[3,2-e][1,4]diazepine-1-carboxylic acids as colorless crystals with m.p. >250°.

e) A suspension of 11.05 g (40.2 mmol) of amide-(S)-8-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3, 2-e][1,4]diazepine-1-carboxylic acid in 55 ml of dioxane and 7 ml of pyridine is added dropwise at 5-8° with 5.75 ml (41.3 mmol) of trifluoroacetic anhydride. The obtained yellowish-gray solution is stirred for 2.5 hours at 50° and then poured into 50 ml of ice water. Extraction with methylene chloride (four times), drying over sodium sulfate, filtration and evaporation gave a light brown residue, which was chromatographed (silica gel, methylene chloride/methanol (10:1). 8.5 g (82%) (S) were obtained. -S-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carbonitrile as white powder with m.p. 211-213°.

f) 8.44 g (32.9 mmol) (S)-8-oxo-11,11a-dihydro-8H,10H- is added to a freshly prepared solution of sodium methylate in methanol (from 1.08 g (47 mmol) sodium in 50 ml methanol) azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carbonitrile and 3.48 g (50.5 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred 48 hours at room temperature. The suspension is then evaporated and mixed with 100 ml of water. The precipitate obtained is filtered off and dried under high vacuum. 7.8 g (82%) of (E)-i/or azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one are obtained as colorless powder with tt. 195-198°.

g) 5.12 g (31.5 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 5.17 g (29.4 mmol) of BOC-glycine and 55 ml of dimethylformamide and the mixture is stirred for 30 min at 50°. Then 7.95 g (27.5 mmol) of E)-i/or (Z)-(S)-1-(amino-hydroxyimino-methyl)-11,11a-dihydro-8H,10H-azeto[1,2-a ]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one and stirred for 15 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 10:1). 11.6 g (98%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2- a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.48 (silica gel, methylene chloride/methanol 10:1).

h) A solution of 11.6 g (27 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1, 2-a]imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. The yellow liquid is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 10 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried over sodium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 9:1). 5.0 g (56%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] is obtained midazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one, as colorless crystals with m.p. 235-238°.

Example 58

Solutions of 1.2 g (3.65 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one 4.4 ml (25.2 mmol) of N-ethyldiisopropylamine and 1.77 ml (14.65 mmol) of allyl bromide were added to 20 ml of methylene chloride and the mixture is stirred for 48 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). Thus, 980 mg (65%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a ]midazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one, as a colorless foam, Rf=0.52 (silica gel, methylene chloride/methanol 10:1).

Example 59

1.6 g (2.3 mmol) (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8 chloro-12,12a-dihydro-9H,11H-azeto[2,1-c ]imidazo[1,5-a][1,4]benzodiazepine-9-one is hydrogenated in 80 ml of acetic ester in the presence of 50 mg of 5% palladium-carbon at room temperature and normal pressure. After removal of the catalyst, the residue is purified by chromatography on silica gel under elution with methylene chloride/acetic ester 1/1 and crystallization from acetic ester and hexane. 0.71 g (44%) of (S)-8-chloro-12,12a-dihydro-1-(3-di-n-propyl-aminomethyl-1,2,4-oxadiazol-5-yl)-9H is obtained, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 179-181°.

Example 60

a) 13.46 (50 mmol) (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1 -carboxylic acid is dissolved in 40 ml of N,N-dimethylformamide, mixed in portions with 10 g (61.7 mmol) of 1,1'-carbonyldiimidazole and stirred for 30 min. at 55°. After the addition of 12.06 g (55 mmol) of phthaloylglycinamidoxime, it is stirred for 2 hours at 85°. Add 10 ml of trifluoroacetic acid and continue stirring overnight at 85°. The reaction mixture is cooled to 10°, and the crystals are filtered off. After recrystallization from methanol, 9.16 g (40%) of (S)-12,12a-dihydro-1-(3-phthalylimidomethyl-1,2,4-oxazol-5-yl)-9H,11H-azeto[2, 1-c]-Imidazo[1,5-a][1,4]-benzodiazepine-9-one, mp 290-292°.

b) 9 g (19.9 mmol) (S)-12,12a-dihydro-1-(3-phthalylimidomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c] imidazo[1,5-a][1,4]-benzodiazepine-9-one, is mixed in 20 ml of ethanol and 65 ml of methylamine (33%-tan) in ethanol for 2 hours at 70°. The solution is concentrated, and the residue is mixed with 70 ml of methylene chloride. The resulting suspension is filtered. After drying the filter residue, (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]-benzodiazepine-9-one, which without further crystallization is used as the starting product in the next described example.

Example 61

4.72 g (14.6 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo [1,5-a][1,4]-benzodiazepine-9-one, 70 ml of methylene chloride, 6 ml (35 mmol) of N-ethyldiisopropylamine and 3.53 g (29.2 mmol) of allyl bromide were stirred for 60 hours at room temperature. The reaction mixture is evaporated, and the residue is chromatographed on 180 g of silica gel eluting with acetic ester. By compressing the obtained fractions, (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[ 1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 147-150°.

Example 62

a) 2.6 g (37.7 mmol) of hydroxylamine hydrochloride is added to a suspension of 4.9 g (35.2 mmol) of potassium carbonate in 40 ml of dimethylformamide at room temperature. Then a solution of 7.2 g (25.2 mmol) (S)-7,8-difluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a ][1,4]benzodiazepine-1-carbonitrile in 100 ml of dimethylformamide and stirred for 60 hours at room temperature. The resulting yellow suspension is evaporated, the residue is partitioned between methylene chloride and water and the aqueous phase is extracted four times with methylene chloride. The organic phases are dried over sodium sulfate, filtered and evaporated. Subsequent chromatography (silica gel, methylene chloride/methanol 9:1) afforded 3 g (37%) of (E)- and/or (Z)-(S)-1-(amino-hydroxylimino-methyl)-7, 8-difluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless powder with m.p. >250°.

b) 2.7 g (16.9 mmol) of 1,1'-carbonyldiimidazole was added to a solution of 4.5 g (14.1 mmol) of BOC-glycine in 30 ml of dimethylformamide, and the mixture was stirred for 30 min at 50°. Then 4.5 g (14.1 mmol) of (E)-i/ili(Z)-(S)-1-(amino-hydroxylimino-methyl)-7,8-difluoro-12,12a-dihydro-9H,11H- azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-9-one and stirred for 16 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 4.9 g (76%) of (S)-1-(5-BOC-aminomethyl-1,2,4) are obtained. -oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]benzodiazepine-9-one as a colorless foam, Rf =0.21 (silica gel, methylene chloride/methanol 19:1).

c) A solution of 330 mg (0.72 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a dihydro-9H,11H -azeto[2,1-c]imidazo[1,5-a]benzodiazepine-9-one in 2 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 2 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried over sodium sulfate, filtered and evaporated. The obtained residue is crystallized from methylene chloride/ether. 190 mg (73%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a yellowish-gray powder with m.p. 240° (exp.).

Example 64

Solutions of 800 mg (2.23 mmol) (S)-2-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is added to 60 ml of methylene chloride, 1.9 ml (11.2 mmol) of N-ethyldiisopropylamine and 710 mg (2.7 mmol) of α,α' -dibromo-ortho-xylene and the mixture is stirred for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 130 mg (12%) of (S)-1-(5-(isoindol-2-ylmethyl)-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro- 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a colorless foam, Rf=0..15 (silica gel, methylene chloride/methanol 19:1 ).

Example 65

Solutions of 800 mg (2.23 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 60 ml of methylene chloride is added 2.6 ml (15.4 mmol) of N-ethyldiisopropylamine and 1 ml (8.93 mmol) of 3,3- of dimethylallyl bromide and the mixture was stirred for 20 hours at room temperature. The reaction solution is diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 300 mg (27%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-7 is obtained, 8-difluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a colorless foam, Rf=0.19 (silica gel , methylene chloride/methanol 19:1).

Example 66

Solutions of 700 mg (1.95 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 40 ml of methylene chloride is added to 2.3 ml (13.5 mmol) of N-ethyl-diisopropyl-amine in 0.66 ml (7.8 mmol) of allyl bromide and the mixture is stirred for 20 hours at room temperature. The reaction solution is diluted with methylene chloride and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 400 mg (46%) of (S)-1-[5-(diallylamino-methyl)-1,2,4-oxadiazol-3-yl]-7,8-difluoro-12,12a-dihydro-9H are obtained, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a colorless foam, Rf=0.17 (silica gel, methylene chloride/methanol 19:1).

Example 67

4 g (11.2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 50 ml of methylene chloride, 7.3 ml (42.6 mmol) of N-ethyldiisopoopylamine in 3 ml (24.6 mmol) of crotyl bromide are stirred for 7 hours at room temperature temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 200 g of silica gel eluting with methylene chloride/acetic ester 1/1. 2.4 g (46%) of (S)-1-[3-bis-(but-2-enyl)-aminomethyl-1,2,4-oxadiazol-5-yl]-8-chloro-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a 4/1 E/Z mixture, which is converted to the hydrochloride with m.p. 109-113°.

Example 68

5 g (14 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 50 ml of methylene chloride, 9.1 ml (53.2 mmol) of N-ethyldiisopropylamine and 3.8 ml (30.8 mmol) of 3,3-dimethylallyl bromide are stirred for 2 hours at room temperature. The reaction solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 190 g of silica gel eluting with methylene chloride/acetic ester 1/1. 3.25 g (47%) of (S)-1-[3-bis-(3-methyl-but-2-enyl)-amino-methyl]-1,2,4-oxadiazol-5-yl]-8 are obtained -chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepin-9-one, which is converted to the hydrochloride with U . 188-189°.

Example 69

4 g (11.2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 25 ml of N,N-dimethylformamide, 7.5 ml (43.7 mol) of N-ethyldiisopropylamine and 2.9 ml (28 mmol) of 4-bromo-1 -butene is stirred for 25 hours at 80°. The reaction solution is evaporated, the residue is dissolved in methylene chloride, the solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 160 g of silica gel eluting with methylene chloride/acetic ester 1/1. 2.8 g (53%) of (S)-1-{3-[bis-(but-3-enyl)-amino-methyl]-1,2,4-oxadiazol-5-yl}-8-chloro- 12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepin-9-one, which is converted to the hydrochloride with m.p. 115-120°.

Example 70

4.6 g (12.9 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2, 1-c]midazo[1,5-a][1,4]benzodiazepine-9-one, 25 ml of N,N-dimethylformamide, 8.6 ml (50.3 mmol) of N-ethyldiisopropylamine and 3.4 ml (32.2 mmol) of bromine -methylcyclopropane is stirred for 18 hours at 80°. The reaction solution is evaporated, the residue is dissolved in methylene chloride, the solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 110 g of silica gel eluting with methylene chloride/acetic ester 1/1. 2.3 g (38%) of (S)-1-[3-(bis-cyclopropylmethyl-aminomethyl)-1,2,4-oxadiazol-5-yl]-8-chloro-12,12a-dihydro-9H are obtained, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 155-160°.

Example 71

3.7 g (10 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 30 ml of N,N-dimethylformamide, 4.27 ml (25 mmol) of N-ethyldiisopropylamine and 2.38 (20 mmol) of propargyl bromide are mixed for 1 hour at room temperature. After evaporation of the reaction solution, the residue is chromatographed on 430 g of silica gel eluting with acetic ester/methanol 9/1. Uniform fractions with lower Rf are combined. 1.19 g (29%) of (S)-8-chloro-11,12,13,13a-tetrahydro-1-(3-propargylamino-methyl-1,2,4-oxadiazol-5-yl)-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]b with m.p. 144-145°, which is converted into the hydrochloride with m.p. 189-192°.

Example 72

a) 6.35 g (20 mmol) (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1 ,4]benzodiazepine-1-carboxylic acid is dissolved in 30 ml of N,N-dimethylformamide, mixed in portions with 3.57 g (41.4 mmol) of 1,1'-carbonyldiimidazole and stirred for 20 min at 50°. After the addition of 9.22 g (42 mmol) of phthaloylglilinamidoxime, it is stirred overnight at 90°, 1 ml of trifluoroacetic acid is added and stirred for a further 20 hours at 110°. The obtained suspension is cooled and the crystals are filtered off. 5.74 g (57%) of (S)-8-chloro-11,12,13,13a-tetrahydro-9H-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one with m.p. 275-277°.

b) 54.25 g (108.3 mmol) (S)-8-chloro-11,12,13,13a-tetrahydro-9H-1-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one is mixed for 1.5 hours with 280 ml of methylamine (33% alcohol) in ethanol at 75°. The solution is concentrated, the residue is taken up in methylene chloride and 115 ml of 4 N hydrochloric acid and the solution is washed three times with methylene chloride. The aqueous phase is basified with 115 ml of 4 N sodium hydroxide solution and extracted six times with methylene chloride. After drying the combined organic solutions and evaporating the solvent, 35.4 g (88%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13, 13a-tetrahydro-9H-imidazo-[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is used without further purification as the starting product in the next described example.

Example 73

3.7 g (10 mmol) of crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 30 ml of methylene chloride, 4.3 ml (25 mmol) of N-ethyldiisopropylamine and 2.3 ml (20 mmol) of 3,3-dimethylallyl bromide are mixed for 3 hours at room temperature. The reaction solution is chromatographed on 250 g of silica gel eluting with acetic ester. 2.44 g (48%) of (S)-1-[3-bis-(3-methyl-but-2-enyl)aminomethyl-1,2,4-oxadiazol-5-yl]-8-chloro-11 are obtained ,12,13,13a-tetrahydro-9H-imidazol[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 137-140°.

Example 74

1 g (2.2 mmol) (S)-1-(3-diallylaminomethyl)-1,2,4-oxadiazol-5--yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is hydrogenated in 5 ml of methanol in the presence of 22 mg of 5% palladium-carbon at room temperature and normal pressure. After removal of the catalyst, the residue is purified by chromatography on silica gel eluting with acetic ester/hexane/triethylamine 17/2/1. 0.53 g (56%) of (S)-7-fluoro-12,12a-dihydro-1-(3-di-n-propylaminomethyl-1,2,4-oxadiazol-5-yl)-9H,11H- azeto[2,1-c]imidazo[1,5-a]benzodiazepine-9-one (oil: Rf: 0.36; silica gel 60 F254. Flow agent: acetic ester/hexane/triethylamine 17/2/1), which converted to hydrochloride.

Example 75

Under argon, 328 mg (1.0 mmol) 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 in 6 ml of methylene chloride was mixed with 1.2 ml (7.0 mmol) of N-ethyldiisopropylamine in 0.65 ml (6.0 mmol) of propargyl bromide (80% in toluene) and the mixture was stirred for 19 hours under argon at room temperature. The solution is washed with 10 ml of water and evaporated, and the crude product is purified by chromatography on 15 g of silica gel (methylene/acetone 9:1). The eluates were evaporated, and the residue was taken up in 5 ml of methanol. The solution is acidified with 5 ml ether-hydrochloric acid, and the white crystals are filtered off. 200 mg (45%) of 343-[bis-(prop-24nyl)-aminomethyl]-1,2,4-oxadiazol-5-yl]-8-fluoro-5-methyl-5,6-dihydro-4H are obtained -imidazo[1,5-a][1,4]benzodiazepine-6-one hydrochloride (4:5) with m.p. 186-189° (exp.).

Example 76

Solutions of 660 mg (2 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one is added to 20 ml of dimethylformamide, 2.5 g of potassium carbonate and 0.48 ml (4.1 mmol) of dimethylallyl bromide and the mixture is stirred for 12 hours at room temperature. The reaction solution is then filtered, and the filtrate is partitioned between methylene chloride and water. The aqueous phase is again extracted three times with methylene chloride; the combined organic phases are then dried over sodium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 300:10:1) and 650 mg (70%) of (S)-14bis-( 3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1 -c]thieno[3,2-e][1,4]-diazepin-8-one as a colorless foam, Rf=0.16 (silica gel, methylene chloride/methanol/aqueous-ammonia 300:10:1).

Example 77

Solutions of 660 mg (2 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one 2.5 g of potassium carbonate and 0.55 g (2.1 mmol) of α,α'- dibromo-o-xylene and the mixture was stirred for 12 hours at room temperature. The reaction solution is then filtered, and the filtrate is partitioned between methylene chloride and water. The aqueous phase is re-extracted three times with methylene chloride; the combined organic phases are then dried over sodium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous-ammonia 300:10:1), and 535 mg (62%) of (S)-1-[5-(isoindolin-2-ylmethyl)-1,2 ,4-oxadiazol-3-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]- diazepin-8-one, as a colorless foam, Rf=0.12 (silica gel, methylene chloride/methanol/aqueous-ammonia 300:10:1).

Example 78

a) Solutions of 11.88 g (41.2 mmol) (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[ 3,2-e][1,4]diazepine-1-carboxylic acid (EP 59390 A1) in 65 ml of dimethylformamide, 6.98 g (43 mmol) of 1,1-carbonyldiimidazole were added at room temperature all at once, and the mixture was stirred for 30 minutes at 50°. Then 9.2 g (41.9 mmol) of phthaloylglycinamidoxime were added all at once, and the mixture was stirred for 15 hours at 110°. Dimethylformamide is evaporated under high vacuum, and the obtained residue is mixed with 150 ml of water. After extraction with methylene chloride (twice), drying over sodium sulfate, filtering and evaporation, a reddish residue is obtained, which is then chromatographed (silica gel, methylene chloride/methanol 20:1). 7.3 g (38%) of (S)-2-[5-(8-oxo-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1, 2-a]thieno[3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-yl-methyl]-1,3-dione, as colorless crystals with m.p. .248-250°.

b) Solutions of 7.28 g (15.4 mmol) (S)-2-[5-(8-oxo-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[ 1,2-a]thieno[3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-yl-methyl]-1,3-dihydro-isoindole-1 ,3-dione in 100 ml of ethanol, 100 ml of methylamine (33% in ethanol) is added dropwise at 70° and stirred for another two hours at 70°. The reaction mixture is evaporated and the residue is chromatographed (silica gel, methylene chloride/methanol 20:1). 4.36 g (83%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as colorless crystals with m.p. 156-158°.

Example 79

Solutions of 685 mg (2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one 2.4 ml (13.8 mmol) of N-ethyldiisopropylamine and 0.67 ml (8 mmol) are added to 20 ml of methylene chloride of allyl bromide, and the mixture was stirred for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 200:20:1). 693 mg (82%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.32 (silica gel, methylene chloride/methanol/aqueous ammonia 200:10:1) .

Example 80

Under argon, 328 mg (1.0 mmol) 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-one in 6 ml of methylene chloride was mixed with 0.51 ml (3.0 mmol) of N-ethyldiisopropylamine and 0.27 ml (2.5 mmol) of propargyl bromide (80% in toluene), and the mixture was stirred for 22 hours under argon at room temperature. 0.09 ml of propargyl bromide (80% in toluene) and 0.05 ml of N-ethyldiisopropylamine were added once more, and the mixture was stirred for a further 74 hours at room temperature. The reaction mixture is washed with 10 ml, dried with sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on 50 g of silica gel (acetic ester). The eluates are evaporated, and the residue is taken up in 5 ml of methanol. The solution is acidified with 5 ml of ethereal hydrochloric acid and evaporated, the residue is taken up in 5 ml of methanol/ether 3:2. The white crystals are filtered off and dried. 87 mg (20%) of 3-[5-[bis-(prop-2-ynyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-5-methyl-5 are obtained, 6-Dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1 with m.p. 175-177° (dec.).

Example 81

a) 2.45 g (14 mmol) of BOC-glycine is dissolved in 20 ml of N,N-dimethylformamide, after which the mixture is mixed in portions with 2.43 g (15 mmol) of 1,1'-carbonyldiimidazole and stirred for 20 min at 50 °. 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-carboxamidoxime, further stirring overnight at 90°. The reaction mixture is solidified; the residue is dissolved in methylene chloride and washed three times with water. After drying the solution, evaporation of the solvent and crystallization of the residue from acetic ester and hexane, 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 m.p. 144-146°.

b) 7.03 g (16.4 mmol) 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 is stirred for 1 hour in 30 ml of trifluoroacetic acid at room temperature. The solution is concentrated, the residue is taken up in water and the solution is washed twice with methylene chloride. The aqueous phase is made alkaline with 25% ammonia and extracted seven times with methylene chloride. After drying and evaporation of the combined phases, 4.5 (79%) 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo is obtained [1,5-a][1,4]benzodiazepine-6-one, which is used without further purification as the starting product in the next described example.

Example 82

1.5 g (4.4 mmol) 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-one, 20 ml of N,N-dimethylformamide, 2.10 ml (12 mmol) of N-ethyldiisopropylamine and 1.16 g (9.6 mmol) of allyl bromide were stirred for 4 hours at room temperature. The reaction solution is evaporated, and the residue is chromatographed on 250 ml of silica gel eluting with acetic ester. Uniform fractions are paired. 1.54 g (82%) of 3-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 126-130°.

Example 83

a) 38.8 g (133 mmol) of 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid is dissolved in 200 ml of N,N-dimethyl-formamide, mixed in portions with 23.7 g (146 mmol) of 1,1'-carbonyl-diimidazole and stirred for 20 min at 70°. After the addition of 43.73 g (199.5 mmol) of phthaloylglycinamidoxime, it is stirred for 1 hour at 90°, 1.5 ml of trifluoroacetic acid is added and stirred overnight at 90° and for 3 hours at 120°. The resulting suspension is compressed to half its volume and cooled, and the secreted crystals are filtered off. 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 m.p. 237-239°.

b) 35.1 (74 mmol) 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 is mixed for 3 hours with 190 ml of methylamine (33% in ethanol) and 100 ml of ethanol at 80°. The solution is concentrated, the residue is taken up in methylene chloride and 100 ml of 4 N hydrochloric acid and the solution is washed three times with methylene chloride. The aqueous phase is basified with 105 ml of 4 N sodium hydroxide solution and extracted six times with methylene chloride. After drying the combined organic solutions and evaporating the solvent, 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-one, which is used without further purification as the starting product in the following example.

Example 84

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-one, 45 ml of N,N-dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred for 1 hour at room temperature. The reaction solution is evaporated and the residue is chromatographed on 250 g of silica gel eluting with acetic ester. Uniform fractions with a higher Rf-value are combined. 4.84 g (76%) of 3-(3-diallyl-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1, 5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 125-130°.

Example 85

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-one, 30 ml of N,N-dimethylformamide, 3.7 ml (22 mmol) of N-ethyldiisopropylamine, 12.9 g (11 mmol) of α,α'-dibromo-o-xylene are stirred for 6 hours at room temperature temperature. After evaporation of the solvent, the residue is chromatographed on 230 g of silica gel eluting with acetic ester. Uniform fractions are paired. 1.56 g (35%) of 7-chloro-5,6-dihydro-3-(3-isoindolin-2-yl-methyl-1,2,4-oxadiazol-5-yl)-5-methyl-4H- imidazo[1,5-a][1,4]benzodiazepine-6-one which is converted to the hydrochloride with m.p. 180-184°.

Example 86

a) 15 g (5.83 mmol) of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxylic acid is dissolved in 100 ml N,N dimethylformamide, mixed in portions with 11.3 g (7 mmol) of 1,1'-carbonyldiimidazole and stirred for 20 min at 70°. After the addition of 19.2 (8.75 mmol) phthaloylglycinamidoxime, it is stirred for 3 hours at 80°, 5 ml of trifluoroacetic acid is added and stirred overnight at 110°. The reaction mixture is concentrated, and the residue is chromatographed on 200 g of silica gel eluting with acetic ester. 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 m.p. 239-240°.

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-one is mixed for 3 hours with 90 ml of methylamine (33% in ethanol) and 40 ml of ethanol at 80°. The solution is concentrated, the residue is taken up in methylene chloride and 53 ml of 4 N hydrochloric acid and the solution is washed three times with methylene chloride. The aqueous phase is made alkaline with 55 ml of 4 N sodium hydroxide solution and extracted six times with methylene chloride. After drying the combined organic solutions and evaporating the solvent, 9 g (100%) of (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 m.p. 183-185°, which is used without further purification as the starting product in the next described example.

Example 87

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-one, 20 ml of N,N dimethylformamide, 3.7 ml (22 mmol) of N-ethyldiisopropylamine and 1.81 g (15 mmol) of allyl bromide are mixed for 1.5 hours at room temperature. After evaporation of the solvent, the residue is chromatographed on 220 g of silica gel eluting with acetic ester. 0.86 g (22%) of 3-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one, which is converted into the hydrochloride with m.p. 203-205°.

Example 88

1.85 g (5 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11?12?13513a--tetrahydro-9H-imidazo[1,5 -a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 20 ml of N,N dimethylformamide, 2.14 ml (12.5 mmol) of N-ethyldiisopropylamine and 0.97 ml (10 mmol) of propyl iodide are mixed overnight at 80°. After evaporation of the solvent, the residue is chromatographed on 210 g of silica gel eluting with acetic ester. 0.81 g (36%) of (S)-S-chloro-11,12,13,13a-tetrahydro-1-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-9H-imidazo[ 5,1-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 155-158°.

Example 89

5.17 g (15 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-one, 45 ml of N,N dimethylformamide, 6.5 ml (37.5 mmol) of N-ethyldiisopropylamine and 3.63 g (30 mmol) of allyl bromide were stirred for 1 hour at room temperature. The reaction solution is evaporated, and the residue is chromatographed on 250 g of silica gel eluting with acetic ester. Uniform fractions with lower Rf-values are combined. 3-(3-allyl-aminomethyl-1,2,4-oxadiazol-5-yl)-7-chloro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][ 1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 171-174°.

Example 90

1.5 g (4.65 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 5,1-a][1,4]benzodiazepine-9-one, 20 ml of N,N dimethylformamide, 2.8 ml (16.3 mmol) of N-ethyldiisopropylamine and 1.1 ml (10.7 mmol) of bromo-methylcyclopropane are mixed for 18 hours at 80° . The reaction solution is evaporated, the residue is dissolved in methylene chloride, the resulting solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 110 g of silica gel eluted with methylene chloride/octene ester 1/1. 1 g (49%) of (S)-1-[3-(bis-cyclopropylmethyl)-aminomethyl-1,2,4-oxadiazol-5-yl]-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[5,1-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 174-176°.

Example 91

1.28 g (4.1 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one, 25 ml of N,N dimethylformamide, 2 ml (11.7 mmol) of N-ethyldiisopropylamine and 1.19 g (4.5 mmol) of α,α'-dibromo-o-xylene were mixed for 4 hours at room temperature. After evaporation of the solvent, the residue is chromatographed on 180 g of silica gel eluting with acetic ester. Identical fractions are paired. 0.39 g (23%) of 5,6-dihydro-3-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-5-methyl-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 155-160°.

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-one, 20 ml of N,N dimethylformamide, 4.3 ml (25 mmol) of N-ethyldiisopropylamine and 2.98 g (20 mmol) of 3,3-dimethylallyl bromide are mixed for 1.5 hours at room temperature. The reaction solution is evaporated, and the residue is chromatographed on 215 g of silica gel eluting with acetic ester. 1.8 g (37%) of 3-{3-[bis-(3-methyl-but-2-enyl)aminomethyl]-1,2,4-oxadiazol-5-yl}-7-chloro-5,6 -dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzo-diazepin-6-one, which is converted to the hydrochloride with m.p. 139-142°.

Example 93

1.5 g (4.65 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto-[2,1-c]imidazo [1,5-a][1,4]benzodiazepine-9-one, 20 ml N,N dimethylformamide, 2.4 ml (13.9 mmol) N-ethyldiisopropylamine and 1.3 g (4.9 mmol) α,α'-dibromo-o- xylene is stirred for 1 hour at room temperature. The reaction solution is evaporated, and the residue is dissolved in methylene chloride and chromatographed on 50 g of silica gel eluting with methylene chloride/octene ester 1/1. 1.2 g (61%) of (S)-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2, 1-c]midazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 210-213°.

Example 94

5 g (15.5 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto-[2,1-c]imidazo [1,5-a][1,4]benzodiazepine-9-one, 50 ml of N,N dimethylformamide, 8 ml (4.65 mmol) of N-ethyldiisopropylamine and 4 ml (32.5 mmol) of 3,3-dimethylallylbromide were stirred for 2 hours at room temperature. The reaction solution is evaporated, the residue is dissolved in methylene chloride, the solution is washed three times with water, dried over magnesium sulfate and evaporated. The residue is chromatographed on 130 g of silica gel eluting with methylene chloride/acetic ester 1/1. 3.3 g (46%) of (S)-1-[3-bis-(3-methyl-but-2-enyl)-aminomethyl-1,2,4-oxadiazol-5-yl]-12,12a- dihydro-9H,11H-azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 119-122°.

Example 95

1.5 g (3.7 mmol) (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]midazo[ 1,5-a][1,4]benzodiazepine-9-one is hydrogenated in 50 ml of acetic acid in the presence of 50 mg of 5% palladium-carbon at room temperature and normal pressure. After removing the catalyst, the residue is purified by chromatography on silica gel eluting with acetic ester/methylene chloride 1/1. 0.9 g (59%) of (S)-12,12a-dihydro-1-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto-[2,1-c ]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 185-287°.

Example 96

a) 10 g (31.09 mmol) (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto-[2,1-c]imidazo[1,5-a ][1,4]benzodiazepine-1-carboxylic acid is dissolved in 100 ml of N,N dimethylformamide, mixed in portions with 6.05 g (37.3 mmol) of 1,1'-carbonyldiimidazole and stirred for 1 hour at room temperature. After the addition of 6.8 g (31.09 mmol) of phthaloylglycinamidoxime, it is stirred overnight at room temperature, 10 ml of trifluoroacetic acid is added and stirred overnight at 90°. After evaporation of the solvent, the residue is crystallized from methylene chloride and methanol. 8.55 g (54%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxdiazol-5-yl)-9H,11H- azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 292-294°.

b) 16 g (31.85 mmol) (S)-8-chloro-7-fluoro-12,12a-dihydro-1-(3-phthalimidomethyl-1,2,4-oxdiazol-5-yl)-9H,11H- azeto-[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, is mixed with 100 ml of methylamine (33% in ethanol). The solution is stirred for 1 hour at 70° and then cooled. The resulting suspension is filtered, and the crystallisate is partially dissolved in 100 ml of methylene chloride. Filtration and evaporation of the filtrate yielded 11.7 g (99%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro- 9H,11H-aze which is used without further purification in the next described example.

Example 97

11.7 g (31.2 mmol) crude (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, 100 ml of methylene chloride, 6.04 g (50 mmol) of allyl bromide and 7.75 g (60 mmol) of N-ethyldiisopropylamine are mixed over overnight at room temperature. The solution is concentrated, and the residue is purified by chromatography on 500 g of silica gel eluting with acetic ester. After recrystallization from methanol, 5.3 g (47%) of (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-7-fluoro-12,12a-dihydro- 9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one m.p. 139-140°, which is converted into the hydrochloride with m.p. 127°.

Example 98

Under argon, a suspension of 328 mg (1.0 mmol) of 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-one in 5 ml of methylene chloride is mixed with 0.38 ml (2.2 mmol) of N-ethyldiisopropylamine and 317 mg (1.2 mmol) of α,α'-dibromo-o-xylene and mixed under argon for 5 hours at room temperature. The solution is washed once with 5 ml of water, dried with sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on 30 g of silica gel (methylene chloride/acetone 4:1, then 2:1). The eluates are evaporated, and the residue is taken up in 2.5 ml of methanol. The solution is acidified with ethereal hydrochloric acid, and the solvent is removed in vacuo. The residue was taken up in 6 ml of hot methanol; then cool to approx. 0°, and the white crystals are isolated by suction. 15.0 mg (32%) of 8-fluoro-3-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) with m.p. 229-233° (exp.).

Example 99

a) A solution of 28.8 g (144.6 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 16.7 g (144.6 mmol) of L-proline in 110 ml of dimethylformamide and 20 ml of acetic acid is mixed at 120° for 16 hours. The brown solution is evaporated, and the resulting brown residue is crystallized from alcohol. 30 g (82%) of (S)-6,7-difluoro-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5 are obtained ,11-dione as colorless crystals with m.p. >250°.

b) A solution of 29.8 g (118.2 mmol) (S)-6,7-difluoro-2,3 ,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione in 140 ml of dimethylformamide and stirred for 40 min at -30°. After cooling to -60°, a solution of 25.2 ml (118.2 mmol) of diphenyl ester chloride-phosphoric acid in 50 ml of dimethylformamide is added dropwise so that the temperature does not rise above -45°. Then it is mixed for another 30 minutes.

In the meantime, 14.6 g (130 mmol) of potassium tert-butylate are dissolved in 50 ml of dimethylformamide and mixed with 14.5 ml (126.4 mmol) of ethyl ester of isocyanoacetic acid (95%) at -60°. The reaction mixture obtained above is added dropwise to the resulting solution at -70° via a dropwise addition funnel cooled to -40°. The resulting dark brown grainy solution is stirred at -60° for another hour, and after neutralization with 20 ml of acetic acid at -40°, it is poured into 400 ml of ice water, after which it is extracted five times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and evaporated. The resulting light brown residue is chromatographed (silica gel, acetic ester). 22 g (54%) of ethyl ester (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1 -c][1,4]benzodiazepine-1-carboxylic acids as colorless crystals with m.p. 199-200°.

c) Suspension of 22.1 g (63.6 mmol) ethyl ester (S)-7,8-difluoro-9-oxo-11,12,13,13a-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 is added dropwise to 20.7 ml (82.7 mmol) of 4N sodium hydroxide solution and heated for 45 minutes at reflux. Then the ethanol is distilled off. The aqueous phase is washed twice with methylene chloride and brought to pH=3 with 4 N hydrochloric acid. Extraction with methylene chloride (five times), drying with sodium sulfate, filtration and evaporation gave 20 g (98%) of (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H -imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acids as colorless crystals with m.p. 214.5-215.5° (exp.).

d) Suspension of 11 g (34.5 mmol) (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1- 6.1 g (37.9 mmol) of 1,1'-carbonyldiimidazole is added in portions to c][1,4]benzodiazepine-1-carboxylic acid in 80 ml of dimethylformamide. The resulting light brown solution is heated to 50° for 45 minutes. The solution is then cooled to room temperature and 12 ml of aqueous ammonia solution is added dropwise. After further stirring for 30 minutes, the reaction mixture was poured into 150 ml of ice-water and extracted with methylene chloride seven times. Drying of the organic phases with sodium sulfate, filtration and evaporation gave a colorless residue, which was diluted with methylene chloride. After drying under high vacuum, 9.8 g of amide (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1- c][1,4]benzodiazepine-1-carboxylic acids with m.p. 221-224°.

e) A suspension of 10.9 g (34.2 mmol) of amide-(S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2, 5.2 ml (37.7 mmol) of trifluoroacetic anhydride is added dropwise to 1-c][1,4]benzodiazepine-1-carboxylic acid in 50 ml of dioxane and 10 ml of pyridine at 5-8°. The resulting yellowish-gray solution is stirred for 2.5 hours at 50°, and then poured into ice-water. Extraction with methylene chloride (seven times), drying with sodium sulfate, filtration and evaporation yielded after recrystallization from ethanol 8.5 g (83%) of (S)-7,8-difluoro-9-oxo-11,12,13,13a -tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile as colorless crystals with m.p. >250°.

f) At room temperature, 2.9 g (41.9 mmol) of hydroxylamine hydrochloride is added to a suspension of 5.4 g (93.1 mmol) of potassium carbonate in 150 ml of dimethylformamide. Then a solution of 8.9 g (28 mmol) (S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1 -c][1,4]benzodiazepine-1-carbonitrile in 100 ml of dimethylformamide and stirred for 60 hours at room temperature. The resulting yellow suspension is evaporated, the residue is partitioned between methylene chloride and water, and the aqueous phase is dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 9:1) gave 2.4 g (37%) of (E)- and/or (Z)-(S)-7,8-difluoro-9-oxo- 11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime as a colorless foam, Rf=0.1 (silica gel, methylene chloride/ methanol 9:1).

g) 2.2 g (13.7 mmol) of 1,1-carbonyldiimidazole is added to a solution of 2.2 g (12.5 mmol) of BOC-glycine in 70 ml of dimethylformamide and stirred for 30 min at 50°. Then 3.8 g (11.4 mmol) of E)- and/or (Z)-(S)-7,8-difluoro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5 -a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime and stirred for 16 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 4.2 g (78%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a-tetrahydro- 9H-Imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as light yellow foam, Rf=0.22 (silica gel, methylene chloride/methanol 19:1).

h) A solution of 3.3 g (7 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a- tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 20 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 2 ml of ammonia solution and extracted six times with methylene chloride. The organic phases are dried with sodium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:0.1). 2 g (77%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as a yellowish-gray powder with m.p. 218-220° (exp.).

Example 100

Solutions of 650 mg (1.76 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 40 ml of methylene chloride, add 2.1 ml (10.5 mmol) of N-ethyldiisopropylamine and 0.6 ml (7 mmol) of allyl bromide and stir for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phase is dried with magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed twice (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:0.1). 625 mg (78%) of (S)-1-[5-(diallylaminomethyl)-1,2,4-oxadiazol-3-yl]-7,8-difluoro-11,12,13,13a-tetrahydro- 9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.45 (silica gel, methylene chloride/methanol/aqueous-ammonia 140:10 :0.1).

Example 101

Solutions of 650 mg (1.76 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7,8-difluoro-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 40 ml of methylene chloride was added to 2.1 ml (10.5 mmol) of N-ethyldiisopropylamine in 0.8 ml (7 mmol) of dimethylallyl bromide and stir for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried with magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed twice (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:0.1). 589 mg (66%) of (S)-1-[5-[bis-(3-methyl-butyl-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-11 are obtained, 12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.51 (silica gel, methylene chloride/methanol/ aqueous ammonia 140:10:0.1).

Example 102

2 g (5.95 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, 30 ml of N,N-dimethylformamide, 3.1 ml (17.8 mmol) of N-ethyldiisopropylamine and 1.1 ml (13.1 mmol) of allyl bromide are mixed 1.5 hours at room temperature. The reaction solution is chromatographed on 250 g of silica gel eluting with methylene chloride/octene ester 7/3. 2 g (81%) of (S)-1-(3-diallylaminomethyl)-1,2,4-oxadiazol-3-yl)-8-chloro-11,12,13,13a-tetrahydro-9H-imidazo are obtained [1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 175-177°.

Example 103

2 g (6.2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-9-one5 30 ml of N,N-dimethylformamide, 3.7 ml (12.7 mmol) of N-ethyldiisopropylamine and 1.6 ml (14.3 mmol) of 1-iodo-butane were stirred for 6 hours at room temperature and 1.5 hours at 80°. The reaction mixture is evaporated, and the residue is chromatographed on 180 g of silica gel eluting with methylene chloride/octene ester 7/3. By evaporation of the obtained fractions, 1.6 g (50%) of (S)-1-(3-di-butylaminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2 ,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to 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-one, 20 ml of N,N-dimethylformamide, 3.3 ml (19.3 mmol) of N-ethyldiisopropylamine and 1.65 ml (13.5 mmol) of 3,3-dimethylallylbromide were stirred for 2 hours at room temperature. After evaporation of the solvent, the residue is dissolved in methylene chloride, the solution is washed with water, dried and evaporated. Chromatography on 220 g of silica gel eluting with methylene chloride/octene ester 1/1 yields 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-one? which is translated 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-one, 20 ml of N,N-dimethylformamide, 3.8 ml (22.5 mmol) of N-ethyldiisopropylamine and 1.6 ml (14.8 mmol) of bromo-methylcyclopropane are stirred for 4 hours at 80°. After evaporation of the solvent, the residue is dissolved in methylene chloride, the solution is washed with water, dried and set. Chromatography on 220 g of silica gel eluting with methylene chloride/octene ester 1/1 yields 1.3 g (48%) of 343-(bis-cyclopropylmethylaminomethyl)-1,2,4-oxadiazol-5-yl-5,6-dihydro- 5-Methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 170-174°.

Example 106

a) Suspension of 5.8 g (0.020 mol) 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxima in 60 ml of dimethylformamide is mixed with 3.9 g (0.023 mol) of chloroacetic anhydride. The resulting yellow solution is stirred for 1.5 hours at 100° and then completely freed from the solvent. The oily product is crystallized from acetonitrile and filtered off. The mother liquor is concentrated, the residue is chromatographed over silica gel with dichloromethane/methanol 97:3 as eluant, and the obtained additional portion of the product is recrystallized from acetone. 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-one as white crystals; d.p. 245-247°.

b) Suspension of 1.5 g (0.0043 mol) 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-one in 15 ml of dimethylformamide was mixed with 1.6 g (0.022 mol) of diethylamine. After 16 hours of stirring at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with dichloromethane/methanol 9:1 as eluent. 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-one as white crystals; d.p. 172-174°.

c) 1.30 g (0.0034 mol) 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-one in 20 ml of ethanol was mixed with 0.79 ml (0.0037 mol) of 4.78 N ethanolic hydrochloric acid. After the addition of 100 ml of ether, crystals are separated. 1.28 g (90%) 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-one hydrochloride (1:1 as white crystals; m.p. 220-223° (dec.).

Example 107

a) Suspension of 1.30 g (0.0037 mol) 3-(5-chloro-methyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H- imidazo[1,5-a][1,4]benzodiazepine-6-one in 15 ml of dimethylformamide was mixed with 2.4 g (0.019 mol) of dibutylamine. After 65 hours of stirring at room temperature, the resulting orange solution is completely free of solvent. The residue is chromatographed over silica gel with dichloromethane/methanol 19:1 as eluant. The product is recrystallized from methanol/ether, and 1.27 g (77%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro -4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, as white crystals; d.p. 137-140°.

b) 117 g (0.0027 mol) 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one in 30 ml of ethanol was mixed with 0.65 ml (0.0031 mol) of 3.7 N ethanolic hydrochloric acid. The solution is completely freed from the solvent, and the rest is recrystallized from acetone. 0.87 g (69%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one (1:1), as white crystals; tt. 183-185°.

Example 108

a) Suspension of 1.50 g (0.0043 mol) 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-one 15 ml of dimethylformamide was mixed with 1.5 g (0.022 mol) of pyrroline. After 65 hours of stirring at room temperature, the resulting yellow-orange solution is completely free of solvent. The residue is chromatographed over silica gel with dichloromethane/methanol 19:1 as eluent. The product is recrystallized from methanol/ether. 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-one, as white crystals; d.p. 158-160°.

b) 1.32 g (0.0035 mol) 8-fluoro-5-methyl-3-(5-pyrrolidin-1-ylmethyl-1,294-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one is dissolved in 50 ml of hot ethanol. At room temperature, 0.8 ml (0.0038 mol) of 4.78 N ethanolic hydrochloric acid is added. The solution is set to a volume of approx. 20 ml, whereupon crystallization begins. Add 80 ml of ether, filter and obtain 1.38 g (96%) of 8-fluoro-5-methyl-3-(5-pyrrolidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5 hydrochloride, 6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one (1:1) as white crystals; d.p. 243-245° (exp.).

Example 109

a) Suspension of 7.0 g (23 mmol) ethyl ester 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3- of carbonic acid in 70 ml of ethanol, 13 ml of hydrazine hydrate is added, and the mixture is heated for 3 hours at a reflux condenser. After cooling to 0°, the obtained crystals are filtered off and 6.43 g (96%) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-3-hydrazide-carboxylic acids as colorless needles with m.p. 288-290°.

b) A solution of 4.46 g (21.75 mmol) of N-phthaloylglycine in 35 ml of dimethylformamide was mixed at room temperature with 3.66 g (22.6 mmol) of 1,1'-carbonyldiimidazole and then heated to 50°. After 30 minutes, it is cooled to room temperature, 6.43 g (22.15 mmol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4] hydrazide is added. of benzodiazepine-3-carboxylic acid and stirred for 12 hours at room temperature. The obtained suspension is filtered, and the obtained colorless powder is washed with ethanol and diethyl ether. 10.2 g (98%) of N'-(2,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl-hydrazide 8-fluoro-5-methyl-6-oxo-5,6-dihydro -4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acids with tt>280°.

c) A solution of 6.0 g (12.6 mmol) N'-(2,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl-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 is stirred for 1.5 hours at 100°. After cooling to room temperature, the mixture is poured under good stirring at 300 ml of ice water, after which solid sodium carbonate is added until pH = 8. Extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20:1) gave 4.9 g (85%) 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 as colorless powder with m.p. >250°.

d) Suspension 4.9 g (10.7 mmol) 245-(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 is added dropwise at 70° to 60 ml of methylamine (33% in ethanol) and mixed one hour at 70 The obtained precipitate is filtered while hot, and the obtained yellowish powder is washed until it is colorless. 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-one as a colorless powder with m.p. 227-231°.

Example 110

Solutions of 0.656 g (2.0 mmol) 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one is added to 15 ml of dimethylformamide, 3.5 ml of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of 1-bromo-propane, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride; the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol) 20:1) gave 0.450 g (55%) of 3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl -5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as a colorless foam, Rf=0.48 (silica gel, ethyl ester-acetic acid/methanol 20:1).

Example 111

Solutions of 0.500 g (1.52 mmol) (S)-1-(5-aminomethyl-1?254-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[ 5,1-c]thieno[3,2-e][1,4]diazepin-8-one, 1.74 ml of N-ethyldiisopropylamine and 0.55 ml (6 mmol) of 1-bromo-propane are added to 15 ml of dimethylformamide and mixed for 12 hours at 70°. The dimethylformamide is evaporated and the residue partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is extracted twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.350 g (55%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11, 11a-dihydro-8H,10H-azeto[1,2-a]midazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.44 { silica gel, acetic acid ethyl ester/methanol) 20:1).

Example 112

1.04 g (3.0 mmol) 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-one, 0.64 g (7.5 mmol) of piperidine and 10 ml of N,N-dimethylformamide were stirred for 4 hours at room temperature. The reaction mixture is concentrated, the residue is dissolved in methylene chloride, and the solution is basified with 4 N sodium hydroxide solution. The solution is washed once with saturated sodium chloride solution, dried with magnesium sulfate and evaporated. Chromatography of the residue on silica gel eluting with methylene chloride/methanol 9/1 yields 0.89 g (75%) of 8-fluoro-5-methyl-3-[5-(piperidin-1-yl-methyl)-1,2,4- oxadiazol-3-yl]-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with mp 182-184°, which is converted to the hydrochloride with d.p. 254-256°.

Example 113

Suspension of 4.77 g (13.7 mmol) 3-(5-chloromethyl-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one in 70 ml of dimethylformamide was mixed with 5.6 ml (41.0 mmol) of dipropylamine. After 18:00. after mixing at room temperature, the resulting solution is solidified, and the residue is taken up in 70 ml of water. The crystals are filtered off with 10 ml of water and dried in a vacuum at 60°. The residue is chromatographed over 100 g of silica gel with dichloromethane/acetone 2:1 as eluent. 4.19 g of white crystals are obtained. These are recrystallized twice from acetic ester, whereby after drying at 60°/0.03 mbar, 2.77 g (49%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro -5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as white crystals with m.p. 153-154°.

Example 114

Solutions of 0.600 g (1.75 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]-thieno[3,2-e][1,4]diazepin-8-ol 2.4 ml (13.8 mmol) of N-ethyldiisopropylamine and 0.97 ml (8 mmol ) of allyl bromide, after which it is stirred for 12 hours at 70°. The reaction solution is diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.580 g (78%) of (S)-1-(5-diallylaminomethyl-1,3,4-oxadiazol-2-yl)-10, 11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]-thieno[3,2-e][1,4]diazepin-8-one as colorless foam, Rf =0.56 (silica gel, ethyl ester-acetic acid/methanol 20:1).

Example 115

Solutions of 0.443 g (1.3 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one 2.0 ml (11.5 mmol) of N-ethyldiisopropylamine and 0.3 ml (2.61 mmol) are added to 30 ml of methylene chloride of dimethylallyl bromide, after which it is stirred for 12 hours at 70°. The reaction mixture is diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 10:1) gave 0.190 g (30%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl] -1,3,4-oxadiazol-2-yl]-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e] [1,4]diazepin-8-one as a colorless foam, Rf=0.50 (silica gel, ethyl ester-acetic acid/methanol 10:1).

Example 116

Solutions of 0.500 g (1.52 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one, 2 ml (11.5 mmol) of N-ethyldiisopropylamine and 0.97 ml (8 mmol) of allyl bromide are added to 30 ml of methylene chloride, after which it is stirred for 12 hours at 70°. The reaction solution is diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.476g (77%) of (S)-1-[5-diallylaminomethyl-1,3,4-oxadiazol-2-yl-11,11a -dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.36 (silica gel, acetic acid ethyl ester/methanol 20:1).

Example 117

Solutions of 0.426 g (1.3 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one 2 ml (11.5 mmol) of N-ethylisopropylamine and 0.3 ml (2.61 mmol) of dimethylallyl bromide are added to 30 ml of methylene chloride, after which it is stirred for 12 hours at 70°. The reaction solution is diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 40:1) gave 0.270 g (44%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl]- 1,3,4-oxadiazol-2-yl-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4 ]diazepin-8-one as a colorless foam, Rf=0.24 (silica gel, ethyl ester-acetic acid/methanol 40:1).

Example 118

Solutions of 0.550 g (1.68 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] 3 ml (17.25 mmol) of N-ethylisopropylamine and 0.8 ml (8.8 mmol) of propyl bromide are added to imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 30 ml of dimethylformamide, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.300 g (43%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11, 11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.28 ( silica gel, acetic acid ethyl ester/methanol 20: l).

Example 119

Solutions of 0.300 g (0.87 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one 1.5 ml (8.6 mmol) of N-ethyldiisopropylamine and 0.4 ml (4.4 mmol) are added to 20 ml of dimethylformamide of propyl bromide, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.140 g (38 %) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-10, 11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf= 0.28 (silica gel, ethyl ester-acetic acid/methanol 20:1).

Example 120

Solutions of 0.656 g (2.0 mmol) 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one is added to 15 ml of dimethylformamide, 3.5 ml of N-ethyldiisopropylamine and 1.29 ml (12 mmol) of 1-bromo-butane, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.470 g (53 %) of 3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5- methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as colorless foam, Rf=0.66 (silica gel, ethyl ester-acetic acid/methanol 20:1) .

Example 121

a) Solutions of 7.0 g (23.54 mmol) ethyl ester (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1, 4]diazepine-1-carboxylic acid in 70 ml of ethanol, 13 ml of hydrazine hydrate is added and the mixture is stirred for 3 hours at reflux. After cooling to 0°, the crystals are filtered off and 3.6 g (96%) of hydrazide (S)-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5 -a][1,4]diazepine-1-carboxylic acids form colorless needles with m.p. 246-248°.

b) Solutions of 5 g (17.64 mmol) of hydrazide (S)-12,12a-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) of ethyl ester of chloroacetimidic acid in 40 ml of dimethylformamide and 10 ml of ethanol are mixed for 12 hours at 90°. The solvent is evaporated and the residue is partitioned between methylene chloride and water. The aqueous phase is washed once with methylene chloride. The organic phases are dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93:3) gave 3.26 g (55%) of (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.5 (methylene chloride/methanol 10:1).

c) Solutions of 1.17 g (3.42 mmol) (S)-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one 0.94 ml (73 mmol) of dipropylamine is added to 10 ml of dimethylformamide, after which it is stirred for 12 hours at room temperature. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, methylene chloride/methanol 95 : 5) gave 0.900 g (65%) of (S)-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H ,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.46 (silica gel, methylene chloride/methanol 95 : 5).

Example 122

Solutions of 4 g (12.18 mmol) (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one 17.4 ml (100 mmol) of N-ethyldiisopropylamine and 7.87 ml (73 mmol) of butyl bromide are added to 100 ml of dimethylformamide, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 10:1) gave 2.1 g (39%) of (S)-1-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-11, 11a-dihydro-8H,10H-aceto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.4 ( silica gel, acetic acid ethyl ester/methanol 10 : 1).

Example 123

a) a solution of (17.28 mmol) hydrazide 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 2.87 g (18.16 mmol) ethyl ester of chloroacetimidic acid in 40 ml of dimethylformamide and 10 ml of ethanol was stirred for 12 hours. The solution is evaporated, and the residue is partitioned between methylene chloride and water. The aqueous phase is washed once more with methylene chloride and water. The organic phase is dried with magnesium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol 93 : 3) gave 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-one as colorless crystals with m.p. 260-262° (exp.).

b) Solutions of 2 g (5.8 mmol) (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-one 1.0 ml (12.7 mmol) of propylamine is added to 50 ml of dimethylformamide, after which it is stirred for 12 hours at 55°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride and the organic phase is dried with sodium sulfate, filtered and evaporated. Chromatography of the residue (silica gel, methylene chloride/methanol/aqueous-ammonia 140 : 10 :1) gave 1.40 g (65%) of (S)-1-(5-propylaminomethyl-1,3,4-oxadiazol-2-yl)- 8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as a colorless foam, Rf=0.49 (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1).

Example 124

a) Suspension of 3.06 g (9.22 mmol) hydrazide (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c ][1,4]benzodiazepine-1-carboxylic acid in 30 ml of N,N-dimethylformamide was mixed with 1.97 g (0.0115 mol) of chloroacetic anhydride. The resulting yellow solution was stirred for 1.5 hours at room temperature and then the solvent was completely removed. The residue is suspended in ether and filtered off (Nutsche). The resulting yellowish-gray crystals (3.75 g, m.p. 262-264°C (m.p.)) were mixed with 27 ml of methanesulfonic acid and 3 g of phosphorus pentoxide, after which it was further stirred for 65 hours at room temperature. The orange-brown solution is poured into 150 ml of ice water, basified with aqueous sodium hydroxide solution and extracted with methylene chloride. The crystalline product is chromatographed over silica gel with acetic ester as eluant. 2.03 g (56%) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H4midazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as white crystals; d.p. 230-232° and [α]D20= +104.5° (DMF, c=1%).

b) Suspension of 1.30 g (3.33 mmol) (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 10 ml of N,N-dimethylformamide was mixed with 1.7 g (0.017 mol) of dipropylamine. After stirring for 20 hours at room temperature and 4 hours at 80°C, the resulting solution is completely freed from the solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether. 1.27 g (85%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as white crystals; d.p. 158-160° and [α]D20=+48.8° (CH2Cl2, c=1%).

c) 1.27 g (2.79 mmol) (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 30 ml of ethanol was mixed with 0.83 ml (3.07 mmol) of 3.7 N ethanolic hydrochloric acid. After stirring for 15 minutes at 0°, the solution was added dropwise with 150 ml of ether, and the resulting white suspension was filtered off (Nutsche). 1.27 g (93%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one hydrochloride (1:1) as white crystals; d.p. 204-206° [α]D20=-43.6° (H2O, c=1%).

Example 125

a) Suspension of 5.47 g (0.00162 mol) ethyl ester 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4] of benzodiazepine-3-carboxylic acid in 55 ml of ethanol, 9.15 ml of hydrazine hydrate is added and the mixture is heated for 18 hours at reflux. After cooling to 0°, the obtained crystals are filtered off and 3.28 g (63%) of the hydrazide 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a ][1,4]benzodiazepine-3-carboxylic acids as white crystals; d.p. 308-

310°.

b) Suspension of 0.50 g (0.00154 mol) hydrazide 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine- of 3-carboxylic acid in 5 ml of N,N-dimethylformamide was mixed with 0.33 g (0.00193 mol) of chloroacetic anhydride. The obtained solution is stirred for 1.5 hours at room temperature, during which a suspension is formed. It is cooled to 0°, mixed with 40 ml of ether and filtered (Nutsche). The resulting white crystals (0.643 g, m.p. 264-266° (m.p.)) are mixed with 4.5 ml of methanesulfonic acid and 0.5 g of phosphorus pentoxide, after which the mixture is heated and the solution is further stirred for 1 hour at room temperature. The yellow solution is poured into 75 ml of ice water, after which it is made alkaline with sodium hydroxide solution and extracted with methylene chloride. The crystalline product is chromatographed over silica gel with acetic ester as eluent. 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-one as white crystals; d.p. 234-236°.

c) Suspension of 0.193 (0.51 mmol) 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-one in 2 ml of N,N-dimethylformamide was mixed with 0.26 g (2.55 mmol) of dipropylamine. After 5 p.m. stirring at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether/n-hexane at 0°. 0.094 g (41%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one as white crystals; d.p. 128-130°.

d) 0.094 g (0.21 mmol) 7-chloro-3-(5-dipropylaminomethyl-1?3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazep in 10 ml of ethanol was mixed with 0.062 ml (0.23 mmol) of 3.7 N ethanolic hydrochloric acid. After stirring for 30 min at 0°, the solution is completely freed from the solvent, after which the residue is suspended in 20 ml of ether and filtered (Nutsche). 0.84 g (83%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) as white crystals; d.p. 152-154°.

Example 126

a) 4,4 (14.1 mmol) (12.3 mmol) hydrazide (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5- a][1,4]benzodiazepine-1-carboxylic acid is mixed overnight in 30 ml of N,N-dimethylformamide with 2.65 g (15.5 mmol) of chloroacetic anhydride at room temperature. After evaporation of the solvent, the residue is mixed for 48 hours with 20 ml of a 10% solution of phosphorus pentoxide in methanesulfonic acid at room temperature. The reaction mixture was mixed with ice, with conc. alkalize with sodium-alkali and mix four times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent, 3.39 g (60%) of (S)-S-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 185-189°.

b) 1.88 g (5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one was mixed with 1.12 g (11 mmol) of dipropylamine and 10 ml of N,N-dimethylformamide at room temperature over the weekend. After evaporation of the reaction mixture, the residue is dissolved in methylene chloride and the solution is washed twice with water and dried over magnesium sulfate. After evaporation of the solvent and crystallization of the residue from acetic ester and hexane, 2.15 g (98%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12 are obtained ,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is converted to the hydrochloride with a melting point of 235-237°.

Example 127

a) 9.4 g (34.7 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid hydrazide was stirred for 3 hours in 75 ml of N,N-dimethylformamide with 27.1 g (41.5 mmol) of hydride-chloro-acetic acid at room temperature. After evaporation of the solvent, the residue is mixed overnight with 75 ml of a 10% solution of phosphorus pentoxide in methanesulfonic acid at room temperature. The reaction mixture is mixed with ice, basified with conc. sodium-alkali and extract four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporating the solvent and chromatography of the residue on silica gel eluting with acetic ester, 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-9-one with m.p. 221 -222°.

b) 0.33 g (1 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one is stirred overnight with 2 ml (2 mmol) of diethylamine and 5 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/ethanol 9/1, 0.31 g (84%) of 3-(5-diethylaminomethyl-13,4-oxadiazol-2-yl)-5-methyl is obtained -5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 235-238°.

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]-benzo-diazepine-3-carboxylate is mixed for 6 hours with 90 ml (1.85 mol) of hydrazine hydrate and 500 ml of ethanol at the boiling point. By cooling to -10°, filtering (Nutsche) suspension and drying the crystallized, 51.9 g (1 00%) of 7-chloro-5 hydrazide is obtained -methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid with m.p. 287°.

b) 15.3 g (50 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid hydrazide is stirred overnight in 160 ml of N,N-dimethylformamide with 9.41 g (55 mmol) of chloroacetic anhydride at room temperature. After evaporation of the solvent, the residue is mixed over the weekend with 100 ml of a 10% solution of phosphorus pentoxide in methane-sulfonic acid at room temperature. The reaction mixture is mixed with ice, basified with conc. with sodium lye and four times with methylene chloride. By drying the organic phase over magnesium sulfate, evaporating the solvent and chromatography of the residue on silica gel eluting with ethyl acetate, 9.7 g (53%) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazole-2- yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 201-203°.

c) 1.09 g (3 mmol) 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 is mixed 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 of the residue on silica gel eluting with acetic ester, 1.09 g (79%) of 7-chloro-3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl is obtained. -5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 105-108°.

Example 129

1.09 (3 mmol) 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][ 1,4l-benzodiazepine-6-one is 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 of the residue on silica gel eluting with acetic ester, 1.17 g (91%) of 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl is obtained -5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 188-195°.

Example 130

1.09 (3 mmol) 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 was stirred overnight with 1 g (13.7 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 eluting with ethyl acetate/ethanol 9/1, 1.18 g (98%) of 7-chloro-3-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl) are obtained )-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 188-195°.

Example 131

10 g (30.3 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one is stirred for 7 hours with 10.1 g (100 mmol) of diethylamine and 70 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/ethanol 19/1, 7.42 g (62%) of 3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl) are obtained after recrystallization from acetic ester )-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 126-127°, which is converted into the hydrochloride with m.p. 208-210°.

Example 132

0.66 g (2 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one is mixed overnight with 1.2 g (9.3 mmol) of dibuylamine and 10 ml of N,N-dimethylformamide at 75°. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester, 0.72 g (85%) of 3-(5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 -dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one, which is converted to the hydrochloride with mp 211-213°.

Example 133

1.64 g (5 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one is mixed overnight with 1.62 g (12.5 mmol) of diisobuylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester, 1.63 g (77%) of 3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6 -dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 138-140°, which is converted into the hydrochloride with m.p. 177-180°.

Example 134

1.09 (3 mmol) 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 is stirred overnight with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylforaiamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester, 1.19 g (86%) of 7-chloro-3-(5-diisobutylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl is obtained. -5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 181-182°, which is converted into the hydrochloride with m.p. 161-163°.

Example 135

1.64 g (5 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one was mixed overnight with 1.07 g (12.5 mmol) of piperidine and 40 ml of N,N-dimethylformamide at room temperature. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1, 1.3 g (68%) of 5-methyl-3-[5-(piperidin-1-yl)methyl-1,3,4- oxadiazol-2-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 160-162°, which is converted into the hydrochloride with m.p. 255-257°.

Example 136

1.64 g (5 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one is stirred overnight with 3 g (21 mmol) of diisopropylamine and 30 ml of N,N-dimethylformamide at 70°. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1, after recrystallization from acetic ester, 1.32 g (67%) of 3-(5-diisopropylaminomethyl-1,3,4-oxadiazol-2-yl) is obtained )-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 199-200°, which is converted into the hydrochloride with m.p. 232-234°.

Example 137

1.64 g (5 mmol) 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]-benzodiazepine-6-one is stirred overnight with 2.26 g (17.5 mmol) of di-sec-butylamine and 25 ml of N,N-dimethylformamide at 75°. After evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1, after recrystallization from ethyl acetate, 1.35 g (64%) of 3-(5-di-sec-butylaminomethyl-1,3,4-oxadiazole) is obtained -2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one with m.p. 80-83°, which translates into the hydrochloride (amorphous).

Example 138

Solutions of 340 mg (1 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one 0.87 ml (5 mmol) of N-ethyldiisopropylamine and 0.17 ml (2.1 mmol) are added to 15 ml of methylene chloride of allyl bromide and the mixture is stirred for 12 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 250:10:1). 280 mg (66%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepin-8-one, Rf=0.41 (silica gel, ethyl ester-acetic acid).

Example 139

Solutions of 756 mg (2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one 2.4 ml (13.8 mmol) of N-ethyldiisopropylamine and 0.67 ml (8 mmol) of allyl bromide are added to 20 ml of methylene chloride and the mixture is stirred for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). 645 mg (79%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H,10H-azeto-[1,2-a ]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one as a colorless foam, Rf=0.52 (silica gel, methylene chloride/methanol/aqueous-ammonia 140:10:1 ).

Example 140

Solutions of 453 mg (1.2 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one, 1.5 ml (8.6 mmol) of N-ethyldiisopropylamine and 0.28 ml (2.4 mmol) of dimethylallyl bromide are added to 20 ml of methylene chloride and the mixture is stirred for 20 hours at room temperature. The reaction solution is then diluted with methylene chloride and washed three times with water. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). 240 mg (43%) of (S)-1-[3-bis-[(3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-5-yl]-11 are obtained, 11a-dihydro-8H,10H-azeto-[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one as a colorless foam, Rf= 0.55 (silica gel, methylene chloride/methanol/aqueous-ammonia 140:10:1).

Example 141

Solutions of 600 mg (1.9 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] 4 ml (8.6 mmol) of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one are added to 20 ml of dimethylformamide. -bromo-propane and the mixture is stirred for 12 hours at 70°. The reaction solution is then evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). 410 mg (54%) of (S)-1-(dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-,11,11a-tetrahydro-8H,10H-azeto-[1,2-a] are obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.55 (silica gel, methylene chloride/methanol/aqueous-ammonia 140:10:1)

Example 142

Solutions of 340 mg (1 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepin-8-one in 10 ml of dimethylformamide is added 1.74 ml (10 mmol) of N-ethyldiisopropylamine and 0.55 ml (6 mmol ) of 1-bromo-propane and the mixture is stirred for 12 hours at 70°. The reaction solution is then evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 240:10:1). 162 mg (38%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepin-8-one, Rf=0.55 (silica gel, ethyl ester-acetic acid/methanol 40:1).

Example 143

Solutions of 1.5 g (4.74 mmol) 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-one in 40 ml of dimethylformamide, 7 ml (23 mmol) of N-ethyldiisopropylamine and 0.9 ml (9.9 mmol) of 1-bromo-propane are added and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 250:10:1). 930 mg (49%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 2,3-f][1,4]-diazepin-6-one with m.p. 128.5-130.0°.

Example 144

Solutions of 0.6 g (1.9 mmol) 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-one in 20 ml of dimethylformamide, 4 ml (23.4 mmol) of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of 1-bromo-propane are added and the mixture is stirred 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, ethyl ester-acetic acid/methanol 25:1). 440 mg (57%) of 3-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro dihydro-4H-imidazo[1,5-a]thieno are obtained [2,3-f][1,4]-diazepin-6-one, as colorless foam, Rf=0.34 (silica gel, ethyl ester-acetic acid/methanol 25:1).

Example 145

Solutions of 2.0 g (6.3 mmol) 7-(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-4-one is added to 50 ml of dimethylformamide, 7.5 ml (43.6 mmol) of N-ethyldiisopropylamine and 2.3 ml (25.3 mmol) of 1-bromo-propane and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 250 mg (10%) of 7-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 2,3-f][1,4]-diazepin-4-one, as colorless foam, Rf=0.46 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 146

Solutions of 2.0 g (6.3 mmol) 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-one is added to 50 ml of dimethylformamide, 3.75 ml (21.8 mmol) of N-ethyldiisopropylamine and 1.15 ml (12.7 mmol) of 1-bromo-propane and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 460 mg (20%) of 7-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 3,2-f][1,4]-diazepin-4-one, as a colorless foam, Rf=0.31 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 147

Solutions of 1.0 g (3.16 mmol) 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-one is added to 30 ml of dimethylformamide, 3.7 ml (21.8 mmol) of N-ethyldiisopropylamine and 1.4 ml (12.6 mmol) of 1-bromo-propane and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 290 mg (22%) of 7-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 3,2-f][1,4]-diazepin-4-one, as a colorless foam, Rf=0.37 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 148

Solutions of 1.0 g (3.16 mmol) 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-one in 30 ml of dimethylformamide, 1.85 ml (10.9 mmol) of N-ethyldiisopropylamine and 0.7 ml (6.3 mmol) of 1-bromo-propane are added and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 290 mg (25%) of 7-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 3,2-f][1,4]-diazepin-4-one, as a colorless foam, Rf=0.37 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 149

Solutions of 1.0 g (3.16 mmol) 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-one in 30 ml of dimethylformamide, 3.75 ml (21.8 mmol) of N-ethyldiisopropylamine and 0.94 ml (12.6 mmol) of 1-bromo-ethane are added and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 250 mg (21%) of 7-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 3,2-f][1,4]-diazepin-4-one, as a colorless foam, Rf=0.56 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 150

Solutions of 0.54 g (1.7 mmol) 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-one is added to 20 ml of dimethylformamide, 2.35 ml (13.6 mmol) of N-ethyldiisopropylamine and 1.1 ml (10.2 mmol) of butyl bromide and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 265 mg (36%) of 3-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 2,3-f][1,4]diazepin-4-one, as a colorless foam, Rf=0.73 (silica gel, methylene chloride/methanol/aqueous-ammonium ak 110:10:1).

Example 151

Solutions of 0.54 g (1.7 mmol) 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-one in 20 ml of dimethylformamide, 2.35 ml (13.6 mmol) of N-ethyldiisopropylamine and 0.76 ml (10.2 mmol) of ethyl bromide are added and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 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-4-one, as a colorless foam, Rf=0.66 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 152

Solutions of 0.500 g (1.52 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] 0.87 ml of N-ethyldiisopropylamine and 0.28 ml (3 mmol) of 1-bromo-propane are added to 15 ml of imidazo[5,1-c]thieno[3,2-e][1,4]-diazepin-8-one , after which the mixture is stirred for 12 hours at 70°. Diethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is extracted twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.324 g (57%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11, 11a-dihydro-8H,10H-azeto-[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.24 (silica gel, acetic acid ethyl ester/methanol 20:1).

Example 153

Solutions of 0.54 g (1.7 mmol) 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-one is added to 20 ml of dimethylformamide, 1.17 ml (6.8 mmol) of N-ethyldiisopropylamine and 0.55 ml (5.1 mmol) of butyl bromide and the mixture is stirred for 1 hour at 70°. The reaction solution is then evaporated, after which the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed three times with methylene chloride. The organic phases are dried over magnesium sulfate, filtered and evaporated. The obtained residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 110:10:1). 310 mg (47%) of 3-(5-butylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 2,3-f][1,4]-diazepin-6-one, as a colorless foam, Rf=0.73 (silica gel, methylene chloride/methanol/aqueous-ammonia 110:10:1).

Example 154

a) A suspension of 141.4 g (2.32 mol) of hydroxylamine hydrochloride in 1.2 l of methanol is added dropwise within 10 min to a freshly prepared solution of sodium methanolate in methanol (from 53.46 g (2.32 mol) of sodium in 1 l of methanol), after which stir for 30 min at room temperature. The secreted NaCl is filtered. The resulting filtrate is mixed in portions with 433 g (2.32 mol) of phthalimidoacetonitrile (Ber. 55,2961 (1921)) so that the temperature does not rise above 40°. The suspension is stirred overnight, filtered and the crystals obtained are dried at 60°/10 torr. 475 g of (E and/or Z)-N'-hydroxy-1,3-dioxo-2-isoindolineacetamidine are obtained as colorless crystals with m.p. 192-195°.

b) To a suspension of 50 g (228 mmol) of (E and/or Z)-N'-hydroxy-1,3-dioxo-2-isoindolinacetamidine in 11 dimethylformamide, 40 g (228 mmol) of chloroacetic anhydride is added in portions acid, after which it is stirred for two hours at 100°. The brown solution was evaporated and partitioned between methylene chloride and water. The aqueous phase is subsequently washed one more time with methylene chloride. The organic phases are dried with magnesium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/ethyl ester-acetic acid 20:1), and then crystallized from methylene chloride/diethyl ether. 36 g (57%) of 2-(5-chloromethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione with m.p. 96.5 - 98°.

c) Solutions 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 are added dropwise 35.6 (260 mmol) of dipropylamine is added at room temperature, after which it is stirred for 24 hours at room temperature. The yellow solution is washed with sat. sodium hydrogencarbonate solution, dry with sodium sulfate, filter and evaporate. The resulting residue is chromatographed (silica gel, methylene chloride/water-ammonia 19:1). 38 g (85%) of 2-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione are obtained as a yellowish gray oil, Rf= 0.12 (silica gel, methylene chloride/water-ammonia 19:1).

d) Solutions of 38 g (l 11 mmol) of 2-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in 300 ml of ethanol 400 ml of methylamine (33% in ethanol) is added dropwise. It is mixed for 1.5 hours at 70° and then evaporated. The residue is stirred in methylene chloride. The filtrate is concentrated and chromatographed (silica gel, methylene chloride/methanol 19:1). 15.6 g (66%) of (3-aminomethyl-1,2,4-oxadiazol-5-ylmethyl)-dipropylamine are obtained as a yellow oil, Rf=0.25 (silica gel, methylene chloride/methanol 19:1).

e) A solution of 15.6 g (73.5 mmol) of (3-aminomethyl-1,2,4-oxadiazol-5-ylmethyl)-dipropyl-amine in 100 ml of methyl-ester-formic acid is heated for seven hours at reflux. Then the solution is evaporated, and the residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 14 g (79%) of N-(5-dipropyl-aminomethyl-1,2,4-oxadiazol-3-ylmethyl)-formamide are obtained, Rf=0.28 (silica gel, methylene chloride/methanol 19:1).

f) A solution of 2.4 g (10 mmol) of N-(5-dipropyl-aminomethyl-1,2,4-oxadiazol-3-ylmethyl)-formamide in 25 ml of methylene chloride in 4.3 ml (30 mmol) of diisopropylamine is added dropwise at 0° 0.92 ml (10 mmol) phosphorus oxide chloride in 5 ml methylene chloride and stir for 45 minutes at 0°. The solution is poured onto ice water and extracted twice with methylene chloride. The organic phases are dried with magnesium sulfate, filtered and evaporated. The obtained 5-(dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)isocyanide is used without further purification in the following reaction described under h).

g) A solution of 7.23 g (42.75 mmol) 6H-thieno-[2,3-d][1,3]oxazin-4,6(7H)-dione (J. chem. Res. (M), 1986, 1459 ) and 1.99 g (24.75 mmol) of L-azetidine-2-carboxylic acid in 30 ml of dimethylformamide and 16 ml of acetic acid were mixed at 120° for 16 hours. The brown solution is evaporated, and the resulting brown residue is crystallized from ethanol. 3.74 g (42%) of (S)-7,7a-dihydroazeto[1,2-a]thieno[2,3-e][1,4]diazepine-4,8(6H,9H)-dione are obtained as colorless needles with m.p. 272-274°.

h) A solution of 1.94 g (9.3 mmol) of (S)-7,7a-dihydroazeto[1,2 -a]thieno-[2,3-e][1,4]diazepine-4,8(6H,9H)-dione in 20 ml of dimethylformamide, after which it was stirred for 40 min at -30°. After cooling to -60, a solution of 2 ml (9.3 mmol) of diphenyl-ester-chloride-phosphoric acid in 5 ml of dimethylformamide is added dropwise so that the temperature does not rise above -45°. Then it is mixed for another 30 minutes.

Meanwhile, 1.2 g (10.3 mmol) of potassium tert-butylate is dissolved in 20 ml of dimethylformamide at -60° and mixed with 2.2 g (10 mmol) of 5-(dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl) of isocyanide in 20 ml of dimethylformamide. The reaction mixture obtained above is added dropwise to the solution thus obtained at -70° via a dropwise addition funnel cooled to -40°. The resulting dark brown grainy solution is stirred for another 1 hour at -60° and after neutralization with 10 ml of acetic acid at -40° it is poured onto ice water, after which it is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20 : 1) gave 0.370 g (10%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11, 11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]-thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, RM). 21 (silica gel, ethyl ester-acetic acid/methanol 20:1).

Example 155

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 (EP A 27 214) in 20 ml of N,N-dimethylformamide, after which it is stirred for 40 minutes at -30°. After cooling to -60°, a solution of 2 ml (9.3 mmol) of diphenylester-chloride-phosphoric acid in 5 ml of N,N-dimethylformamide is added dropwise so that the temperature does not exceed -45°. It is then mixed for another 30 minutes.

Meanwhile, 1.2 g (10.3 mmol) of potassium tert-butylate is dissolved in 20 ml of N,N-dimethylformamide at -60°, mixed with 2.2 g (10 mmol) of 5-(dipropylaminomethyl-1,2,4-oxadiazole-3 -ylmethyl)-isocyanide in 20 ml of N,N-dimethylformamide. The mixture obtained above is added to the solution obtained in this way at -70° via the addition funnel cooled to -40°. The resulting dark-brown grainy solution is stirred for another hour at -60° and after neutralization with 10 ml of acetic acid at -40° it is poured onto ice water, after which it is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20 : 1) gave 0.480 (12%) of 7-fluoro-5-methyl-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)- 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as a colorless foam, Rf==0.26 (silica gel, methylene chloride/methanol/aqueous-ammonia 140:10:1) .

Example 156

a) A solution of 10 g (55.2 mmol) of 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and 5.66 g (55.2 mmol) of L-azetidine-2-carboxylic acid in 75 ml of dimethylformamide and 15 ml of acetic acid is mixed at 120° for 16 hours. The brown solution is evaporated, and the resulting brown residue is crystallized from ethanol. 6 g (42%) of (S)-5-fluoro-1,2,4,9,10,10a-hexahydroazeto[2,1-c][1,4]benzodiazepine4,10-dione are obtained as yellowish-gray needles with m.p. 232-233.5°.

b) A solution of 2.05 g (9.3 mmol) of (S)-S-fluoro-1,2,4 ,9,10,10a-hexahydroazeto[2,1-c][1,4]benzodiazepine-4,10-dione in 20 ml of 20 ml of dimethylformamide was stirred for 40 minutes at -30°. After cooling to -60°, a solution of 2 ml (9.3 mmol) of diphenyl-ester-chloride-phosphoric acid in 5 ml of dimethylformamide is added dropwise so that the temperature does not exceed -45°. It is then mixed for another 30 minutes.

Meanwhile, 1.2 g (10.3 mmol) of potassium tert-butylate is dissolved in 20 ml of dimethylformamide and mixed with 2.2 g (10 mmol) of 5-(dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)- of isocyanide in 20 ml of dimethylformamide. The mixture obtained above is added to the solution obtained in this way at -70° via the addition funnel cooled to -40°. The resulting dark-brown grainy solution is stirred for another hour at -60°, and after neutralization with 10 ml of acetic acid at -40°, it is poured onto ice water, after which it is extracted three times with methylene chloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester acetic acid/methanol 20 : 1) gave 0.360 (9%) of (S)-8-fluoro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12 ,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, R=0.28 (silica gel, methylene chloride/methanol/aqueous -ammonia 140:10:1).

Example 157

A solution of 2.2 g (9.3 mmol) (S)-5,6-difluoro-1,2,4 ,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione in 20 ml of N,N-dimethylformamide and stirred for 40 minutes at -30°. After cooling to -60°, a solution of 2 ml (9.3 mmol) of diphenyl-ester-chloride-phosphoric acid in 5 ml of N,N-dimethylformamide is added dropwise so that the temperature does not exceed -45°. It is then mixed for another 30 minutes.

In the meantime, 1.2 g (10.3 mmol) of potassium tert-butylate is dissolved in 20 ml of N,N-dimethylformamide and mixed at -60° with 2.2 g (10 mmol) of 5-(dipropylaminomethyl-1,2,4-oxadiazole-3 -ylmethyl)-isocyanide in 20 ml of N,N-dimethylformamide. At -70°, the mixture obtained above is added to the solution obtained in this way via the addition funnel cooled to -40°. The resulting dark brown grainy solution is stirred for another 1 hour at -60° and after neutralization with 10 ml of acetic acid at -40° it is poured onto ice water, after which it is extracted three times with methylene chloride. The combined organic phases are dried over sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester acetic acid/methanol 20 : 1) gave 0.380 (9%) of (S)-7,8-difluoro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl) -12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as a colorless foam, Rf=0.25 (silica gel, methylene chloride/methanol /aqueous-ammonia 140:10:1).

Example 158

Solutions of 2.8 g (9.68 mmol) (E)- and/or (Z)- (S)-1-(amino-hydroxyimino-methyl)-11,11a-dihydro-8H,10H-azeto[2,1 -c]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one 1.9 g (11.1 mmol) of chloroacetic anhydride is added to 25 ml of N,N-dimethylformamide acid and stir for 1.5 hours at room temperature. Then it is heated for 2 hours at 105°. The solution is evaporated and the residue is partitioned between 2N sodium hydroxide solution and methylene chloride. The aqueous phase is washed again with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The obtained residue is crystallized from methylene chloride/ethanol. 2.4 g (71%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] are obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a yellowish gray powder with m.p. 210-213°.

b) A suspension of 400 mg (1.15 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2- a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide, add 0.36 ml (3.45 mmol) of diethylamine and stir for 12 hours at room temperature. The solution is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution is extracted with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The residue is chromatographed (silica gel, ethyl ester-acetic acid/methanol 10:1). 410 g (92%) of (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] are obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.31 (silica gel, ethyl ester-acetic acid/methanol 10 : 1).

Example 159

A suspension of 400 mg (1.15 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] 0.6 ml (3.45 mmol) of dibutylamine is added to imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide and stirred for 12 hours at room temperature . The solution is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution is extracted with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The residue is chromatographed (silica gel, ethyl ester-acetic acid/methanol 10:1). 425 g (84%) of (S)-1-(5-dibutylaminoniethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] are obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.31 (silica gel, ethyl ester-acetic acid/methanol 10 : 1).

Example 160

A suspension of 400 mg (1.15 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] midazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide, 0.34 ml (3.45 mmol) of piperidine is added and stirred for 12 hours at room temperature . The solution is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution is extracted with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The residue is chromatographed (silica gel, ethyl ester-acetic acid/methanol 15:1). 375 g (82%) of (S)-1-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1, 2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as colorless foam, Rf=0.22 (silica gel, ethyl-ester-acetic acid/methanol 15 : 1).

Example 161

a) Solutions of 18.92 g (68.48 mmol) (E)- and/or (Z)-3-(amino-hydroxyimino-methyl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a ]thieno[2,3-f][1,4]diazepin-6-one is added to 250 ml of N,N-dimethylformamide with 13.44 g (78.5 mmol) of chloroacetic anhydride and stirred for 1.5 hours at room temperature. Then it is heated for 2 hours at 105°. The solution is evaporated and the residue is partitioned between 2N sodium hydroxide solution and methylene chloride. The aqueous phase is washed again with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The obtained residue is crystallized from methylene chloride/ethanol. 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-one as a yellowish-gray powder with m.p. 221-223°.

b) Suspension of 1 g (3 mmol) 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-one 0.73 g (9 mmol) of propylamine is added to 30 ml of N,N-dimethylformamide and stirred for 12 hours at room temperature. The solution is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution is extracted with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The residue is chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 140:10:1). 0.86 g (80%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto-[1,2-a ]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.38 (silica gel, methylene chloride/methanol/aqueous-ammonia 140 : 10 :1) .

Example 162

0.93g (3 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed overnight with 0.51 g (3 mmol) of benzyl bromide and 0.52 g (4 mmol) of N-ethyldiisopropylamine in 10 ml of methylene chloride at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 6/1 gives 3-(3-benzylaminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro -4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride (0.25 g; 17%) with m.p. 195-198°.

Example 163

0.93g (3 mmol) 3-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed with 0.99 g (6.6 mmol) of 5-bromo-1-pentene and 1.04 g (8 mmol) of N-ethyldiisopropylamine in 20 ml of N,N-dimethylformamide overnight at 100°. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester gives 3-{3-[bis-(pent-4-enyl)aminomethyl]-1,2,4-oxadiazol-5-yl}-5-methyl- 5,6-Dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride (0.55 g; 38%) with m.p. 167-169°.

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-one is mixed over the weekend at 70° with 2.7 g (20 mmol) of 4-bromo-1-butene and 2.7 g (23 mmol) of N-ethyldiisopropylamine in 30 ml of N,N- dimethylfomamide. Evaporation of the solvent and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded after recrystallization from acetic ester 0.61 g (13.5%) of 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 a melting point of 143- 5°, which is converted into the hydrochloride with m.p. 145-150°.

Example 165

a) Suspension of 17 g (64.6 mmol) 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7 -carboxylic acid (EP 285 837 A1) in 100 ml of N,N-dimethylformamide, 11.5 g (71 mmol) of 1,1-carbonyldiimidazole is added in portions. The resulting light brown solution is heated for 45 minutes at 50°. The solution is then cooled to room temperature and 20 ml of aqueous ammonia is added dropwise. After stirring again for 30 minutes, the reaction mixture is poured into 100 ml of ice water, and the resulting precipitate is filtered off and washed with water, ethanol and finally with ether. After drying at 70°/10 tor, 15 g (89%) of the amide 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f] are obtained [1,4]diazepine-7-carboxylic acids as colorless crystals with m.p. >250°.

b) Suspension of 15 g (57.2 mmol) of amide 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-ph1,4]diazepine-7 -carboxylic acid in 80 ml of dioxane and 20 ml of pyridine at 5-8°, 8.7 ml (62.9 mmol) of trifluoroacetic acid hydride is added dropwise. The obtained yellowish-gray solution is stirred for 2.5 hours at 50° and then poured into 220 ml of ice water. The resulting precipitate is filtered off. After drying at 70°/10 torr, 12.70 g (91%) of nitrile 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f] are obtained [1,4]diazepine-7-carboxylic acid as a white powder with m.p. 197-200°.

c) 8.7 g (35.6 mmol) of nitrile 5-methyl-4-oxo-5,6-dihydro-4H-imidazo is added to a freshly prepared solution of sodium methylate in methanol (from 1.1 g (49.9 mmol) of sodium in 200 ml of methanol) [1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxylic acid and 3.7 g (53.4 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred for 16 hours at room temperature. The suspension is then evaporated, and the residue is mixed with 100 ml of water. The resulting precipitate is filtered off and dried under high vacuum. 7.70 g (78%) of (E)- and/or (Z)-7-(amino-hydroxyimino-methyl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno are obtained [3,2-f][1,4]diazepin-4-one as a colorless powder with m.p. 216-217°.

d) 5.40 g (33.3 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 5.40 g (30.5 mmol) of BOC-glycine in 150 ml of N,N-dimethylformamide and the mixture is stirred for 30 minutes at 50°. Then 7.70 g (7.58 mmol) of (E)- and/or (Z)-7-(amino-hydroxyimino-methyl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] are added thieno[3,2-f][1,4]diazepin-4-one and stirred for 15 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 19:1). 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] are obtained thieno[3,2-f][1,4]diazepin-4-one as a colorless foam, Rf=0.35 (silica gel, methylene chloride/methanol 19:1).

e) A solution of 8.40 (20.2 mmol) 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-one in 50 ml of trifluoroacetic acid is stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 10 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried with sodium sulfate, filtered and evaporated. The obtained residue is crystallized from methylene chloride/ethanol. 5 g (78%) of 7-(5-aminoniethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[ 3,2-f][1,4] diazepin-4-one as a yellowish-gray powder with m.p. 181-183°.

Example 166

2.98 g (9.25 mmol) (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-9-one is mixed for 60 hours with 3.2 g (25 mmol) of N-diethyldiisopropylamine and 2.5 g (18.5 mmol) of 4-bromo-1-butene in 20 ml of N,N -dimethyl-formamide at 75°. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 0.62 g (15%) of (S)-1-{3-[bis-(but-3-enyl)aminomethyl]-1,2,4-oxadiazole -5-yl}-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 80-87°.

Example 167

1.5 g (4.5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-one is stirred for 24 hours in 10 ml of benzylamine at room temperature. Evaporation of the reaction mixture, chromatography of the residue eluting with methylene chloride/methanol 19/1 and crystallization from ethyl acetate and hexane yielded 1.3 g (71%) of 3-(5-benzylaminomethyl-1,2,4-oxadiazol-3-yl) -5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with a melting point of 88-92°, which is converted into the hydrochloride with m.p. 178-182°.

Example 168

1.8 g (4 mmol) (S)-1-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a] pyrrolo[2,1-c][1,4]benzodiazepine-9-one is dissolved in 50 ml of methanol and hydrogenated in the presence of 60 mg of 5% palladium-carbon at normal pressure and room temperature. The catalyst is separated and the solution is evaporated. Chromatography of the residue on silica gel eluting with methylene chloride/methanol 19.5/0.5 yields 1 g (60%) of (S)-1-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-11,12, 13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 198-201°. RO 48-6686.

Example 169

1.5 g (4.5 mmol) (S)-1-(3-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one is stirred for 2 hours with 1.1 ml (14 mmol) of pyrrolidine and 30 ml of N,N-dimethylformamide at 80°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 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-one, which is converted to the hydrochloride with m.p. 251-254°.

Example 170

1.5 g (4.2 mmol) (S)-1-(3-chloromethyl-1,2,4-oxadiazol-5-yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1- c]-imidazo[1,5-a][1,4]benzodiazepine-9-one is mixed for 2.5 hours with 0.8 ml (9.7 mmol) of ethyl iodide and 2.5 ml (14.7 mmol) of N-ethyldiisopropylamine in 30 ml of N,N- of dimethylformamide at 80°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19.5/0.5 yielded 0.8 g (46%) of (S)-8-chloro-1-(3-diethylaminomethyl-1,2,4-oxadiazole-5 -yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 169-171°.

Example 171

1.5 g (4.5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6 dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-6-one is stirred for 20 hours in 1 ml (14 mmol) of 3-pyrroline and 30 ml of N,N-dimethylformamide at 80°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 0.2 g (12%) of 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-one, which is converted to the hydrochloride m.p., 215-220°.

Example 172

1.7 g (5 mmol) 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-one is stirred for 2 hours 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 is taken up in methylene chloride and washed with aqueous ammonia. After drying the organic phases over magnesium sulfate, evaporating the solvent and recrystallization of the residues from acetic ester and hexane, 1.17 g (65%) of 3-(5-cyclopropylaminomethyl-1,2,4-oxadiazol-3-yl)-8- fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, m.p. 176-178°, which is converted to the hydrochloride.

Example 173

2.2 g (6.3 mmol) 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-one is mixed with 20 ml (183 mmol) of benzylmethylamine overnight at room temperature and 1 hour at 70°. After evaporation of the reaction mixture, the residue is chromatographed under elution with acetic ester. After crystallization from acetic ester, 1.80 g (66%) of 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, mp 161-162°, which is converted to 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-one is dissolved in 15 ml of N,N-dimethylformamide and deprotonated with 0.44 g (10 mmol) of a 55% sodium hydride dispersion in oil. After the addition of 1.7 g (10 mmol) of propyl iodide, it is stirred overnight at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 2.46 g (54%) of 3-(5-N-BOC-N-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5,6 -dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, m.p. 148-150°.

b) 2.53 g (6.6 mmol) 3-(5-N-BOC-N-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1, 5-a][1,4]benzodiazepine-6-one is stirred overnight at room temperature with 30 ml of 3N methanolic hydrochloric acid. The resulting suspension is diluted with ether, cooled to 0° and filtered (glass filter, Nutscha). 1.99 g (77%) of 5-methyl-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one as hydrochloride with m.p. 248-250°.

Example 175

a) 10 g (60 mmol) of BOC-glycine is dissolved in 50 ml of N,N-dimethylformamide, mixed in portions with 9.73 g (60 mmol) of 1,1'-carbonyldiimidazole and stirred for 20 min at 55°. After the addition of 15.5 (57.1 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime, stirring was continued overnight at 90° . The reaction mixture is concentrated, the residue is dissolved in methylene chloride, and the solution is washed three times with water. After drying the solution, evaporation of the solvent and crystallization of the residue from ethanol, 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, m.p. 108-113°.

b) 15.9 g (38.7 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-one is stirred for 3 hours in 40 ml of trifluoroacetic acid at room temperature. The solution is concentrated, the residue is taken up in methylene chloride, and the solution is washed with saturated sodium bicarbonate solution. The aqueous phase is extracted three times with methylene chloride and six times with ethyl acetate. After drying and evaporation of the combined organic phases and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1, 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 m.p. 192-195°.

Example 176

a) 192.4 g (714.6 mmol) (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepine -1-carboxylic acid is suspended in 900 ml of N,N-dimethylformamide, mixed at room temperature with 1.6 g (715 mmol) of 1,1'-carbonyldiimidazole and stirred for 30 minutes at 50°. 173 ml of 25% ammonia is added within 30 minutes at 25-30°. After stirring for 30 minutes, the reaction mixture is solidified, and the residue is dissolved in 500 ml of alcohol. After the addition of 250 ml of ether, it is cooled to 0° and the crystallisate is filtered off (Nutscha) and dried. 133.6 g (69%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzo-diazepine are obtained -1-carboxamide with m.p. 228-230°.

b) 78 g (290 mmol) (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 -carboxamide is suspended in 380 ml of dioxane and 68 ml of pyridine and mixed with 59 ml (424 mmol) of trifluoroacetic acid hydride at 0°. After stirring for two hours at 50°, the reaction mixture is poured into 2 l of ice water, and the crystals are filtered off (Nutscha), washed with water and dried. 60 g (82%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 are obtained -carbonitrile with m.p. 232-234°.

c) 64.7 g (258 mmol) (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 -carbonitrile is heated at reflux for 2.5 hours with 52.8 g (497 mmol) of sodium carbonate and 42.36 g (608 mmol) of hydroxylamine hydrochloride in 1.5 l of alcohol and 300 ml of water. The alcohol is evaporated, and the resulting suspension is cooled to 0°. The crystals are filtered off (Nutscha), washed with water and dried. 68.5 g (93%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 are obtained -carboxamidoxime with a decomposition point of 216°.

d) 34.5 g (122 mmol) (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1 -carboxamidoxime is mixed with 23 g (140 mmol) of chloroacetic anhydride in 200 ml of N,N-dimethylformamide overnight at room temperature and 2 hours at 110°. After evaporation of the reaction mixture, the residue is dissolved in methylene chloride, and the solution is washed with saturated magnesium sulfate solution and concentrated. The residue is chromatographed on silica gel eluting with methylene chloride/methanol 19/1. 24 g (58%) of (S)-1-(5-chloro-methyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one, m.p. 205-207°.

e) 1.4 g (4 mmol) (S)-1-(5-chloro-methyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 1 hour 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 under elution with methylene chloride/methanol 19/1. 1.07g (73%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c] is obtained imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride (amorphous).

Example 177

a) 36.4 g (205 mmol) of BOC-glycine is dissolved in 300 ml of N,N-dimethylformamide and mixed in portions with 35.8 g (220 mmol) of 1,1'-carbonyldiimidazole. The solution is stirred for min at 50°, 54.7 g (194 mmol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][ 1,4]benzo-diazepine-1-carboxamidoxime was further stirred overnight at 90°. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is washed with water, dried over magnesium sulfate and concentrated. Chromatography of the residue on silica gel eluting with acetic ester yields 73 g (89%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H ,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, as a white foam, which is applied in the next step without further purification.

b) 25 g (59.3 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 60 ml of 3 N methanolic hydrochloric acid at room temperature. After evaporation of the solvent, the residue is dissolved in water, and the solution is extracted three times with methylene chloride. The aqueous phase is alkalized with conc. with ammonia and diluted seven times with methylene chloride. Drying the organic phases over magnesium sulfate and evaporating the solvent gives 16.9 g (88%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 211-214°.

Example 178

6.9 g (21.4 mmol) (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-9-one is mixed overnight at 80° and for 2 hours at 100° with 7.65 g (45 mmol) of propyl iodide in 80 ml of 1,3-dimethyl-3,4, 5,6-tetrahydro-2(1H)pyrimidinone and 6.5 g (50 mmol) of N-ethyldiisopropylamine. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 3.32 g (38%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a- dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 208-210°.

Example 179

1.96 g (4.1 mmol) (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one is dissolved in 25 ml of acetic ester and hydrated in the presence of 37 mg of 5% palladium-carbon at normal pressure and room temperature. The catalyst is separated and the solution is evaporated. Chromatography of the residue on silica gel eluting with acetic ester gives 1.49 g (83%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-11,12,13 ,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with mp 222-225°.

Example 180

a) Suspension of 11.9 g (0.0394 mol) (S)-8-chloro-9-oxo-12,12a-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 mixed at 0° with 7.1 ml (0.051 mol) of trifluoroacetic acid hydride. The suspension is stirred for 3 hours at 50°, cooled and poured into ice water. After stirring for 1.5 hours, the suspension is filtered (Nutscha). 11.2 g (100%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carbonitrile as white crystals; d.p. 130° (exp.).

b) 178.7 g (628 mmol) (S)-8-chloro-9-oxo-12,12a-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 are added to a solution prepared from 17.3 g (753 mmol) of sodium.] 1.5 l of methanol. The reaction mixture is stirred overnight at room temperature and then diluted with 1 l of water. The resulting suspension is filtered (Nutscha), and the crystals are dried. 169.7 g (85%) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime with a melting point of 269°.

c) 31.7 g (100 mmol) (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime is suspended in 200 ml of N,N-dimethylformamide and mixed with 18.8 g (110 mmol) of chloroacetic acid hydride. The reaction mixture is heated for 2 hours at 105° and evaporated. Chromatography of the residue on silica gel eluting with chloroform/methanol 9/1 yields 27.9 g (74%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12 ,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 211-212°.

d) 3.76 g (10 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 2 hours with 10 g (82 mmol) of benzylmethylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 4.4 g (95%) of (S)-1-(5-N-benzyl-N-methyl-aminomethyl-1,2,4-oxadiazole-3- yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with d.p. 213-215°.

Example 181

3.76 g (10 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 2 g (20 mmol) of isopropylmethylamine and 20 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester/ethanol 9/1 yielded 3.4 g (90%) of (S)-8-chloro-1-(5-N-isopropyl-N-methyl-aminomethyl-1 ,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H41H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which translates in the hydrochloride with tt. 198-203°.

Example 182

3.76 g (10 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 2.19 g (30 mmol) of diethylamine and 30 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/ethanol 19/1 yielded 4.5 g (96%) of (S)-8-chloro-1-(5-diethylamino-methyl-1,2,4-oxadiazole-3 -yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted into the hydrochloride with m.p.218-220 °.

Example 183

a) 9.8 g (32 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime in 60 ml of N ,N-dimethylformamide and mixed with 7 g (41 mmol) of chloroacetic anhydride and stirred for 1 hour at room temperature and 4 hours at 105°. After evaporation of the solvent, the residue is dissolved in methylene chloride and the solution is washed with saturated sodium carbonate solution and dried over magnesium sulfate. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 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-one.

b) 1.09 g (3 mmol) 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 is mixed for 4.5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.16 g (90%) of 7-chloro-3-(5-dipropyl-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl -5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 212-215°.

Example 184

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-one in 15 ml of N,N-dimethylformamide at 0° to room temperature is deprotonated with 0.44 g of sodium hydride dispersion 55% in oil. 1.7 g (10 mmol) of propyl iodide was added at 10°, and the reaction mixture was further stirred for 5 hours at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester gives 2.50 g (51%) of 7-chloro-5-methyl-3-(5-N-BOC-N-propyl-amino-methyl-1,2, 4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, as a white foam, which is further applied without further purification.

b) 2.5 g (5.1 mmol) 7-chloro-5-methyl-3-(5-N-BOC-N-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H- imidazo[1,5-a][1,4]benzodiazepine-6-one is stirred for 3 hours with 10 ml of 3 N methanolic hydrochloric acid at room temperature. The resulting suspension is cooled to 0° and filtered (Nutscha). After recrystallization from methanol, 0.94 (41%) of 7-chloro-5-methyl-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo[1 ,5-a][1,4]benzodiazepine-6-one hydrochloride with a decomposition point of 235°.

Example 185

1.5 g (4.1 mmol) 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 is stirred for 2 hours at room temperature with 5 g (41.3 mmol) of benzylmethylamine and 10 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 gives 1.29 (72%) 3-(5-N-benzyl-N-methylaminomethyl-1,2,4-oxadiazol-3-yl)-7 -chloro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one which is converted to the hydrochloride with m.p. 214-216°.

Example 186

3.76 g (10 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight at room temperature with 5 g (39 mmol) of dibutylamine and 25 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 4.3 g (92%) of (S)-8-chloro-1-(5-dibutyl-aminomethyl-1,2,4-oxadiazol-3-yl) -12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride with m.p. 120-125°.

Example 187

3.76 g (10 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight at room temperature with 5 g (58 mmol) of piperidine and 25 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 9/1 yielded 4.1 g (96%) of (S)-8-chloro-1-[5-(piperidin-1-yl)methyl-1, 2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 177-179° which is converted into the hydrochloride.

Example 188

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 4 hours at room temperature with 2 g (20 mmol) of hexamethyleneimine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.01 g (92%) of (S)-8-chloro-1-[5-(hexamethyleneimin-1-yl)methyl-1,2,4-oxadiazole -3-yl]-12,12a-5,6-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to hydrochloride (amorph.).

Example 189

1.13 g (3-mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1 -c]imidazo[1,5-a][1,4]benzodiazepine-9-one is mixed overnight at room temperature with 1.5 g (13.3 mmol) of heptamethyleneimine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.2 g (88%) of (S)-8-chloro-1-[5-(heptamethyleneimin-1-yl)methyl-1,2,4-oxadiazole -3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride (amorph. ).

Example 190

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight at room temperature with 3 g (26.5 mmol) of methylcyclohexylamine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 19/1 yielded 0.79 g (69%) of (S)-8-chloro-1-(5-N-cyclohexyl-N-methylaminomethyl-1,2 ,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to hydrochloride (amorph.).

Example 191

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight at room temperature with 2 g (23 mmol) of tert-butylmethylamine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 9/1 yielded 0.81 g (75%) of (S)-1-(5-N-tert-butyl-N-methylaminomethyl-1,2,4 -oxadiazol-3-yl)-8-chloro-12,12-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which translates into hydrochloride (amorph.).

Example 192

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight at room temperature with 2 g (27 mmol) of tert-butylamine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester/methanol 9/1 yielded 0.91 g (88%) of (S)-1-(5-tert-butylamino-methyl-1,2,4-oxadiazole-3 -yl)-8-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride ( amorphous).

Example 193

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is mixed for 5 hours at 80° with 2 g (19.8 mmol) of diisopropylamine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.81 g (73%) of (S)-8-chloro-1-(5-diisopropyl-amino-methyl-1,2,4-oxadiazole-3- yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride (amorph.).

Example 194

1.88 g (5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,1H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is mixed for 2 hours at room temperature with 1.5 g (15 mmol) of diethanolamine and 15 ml of N,N-dimethylformamide. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 9/1 yielded 1.89 g (85%) of (S)-8-chloro-1-(5-dethanol-amino-methyl-1,2, 4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 173-175°, which is converted to the hydrochloride.

Example 195

a) 10.1 g (231 mmol) of sodium hydride dispersion 55% in oil is washed with hexane and suspended in 180 ml of N,N-dimethylformamide. At -40° to -20°, 45.8 g (208 mmol) of (S)-6-fluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1 ,4]benzodiazepine-4,10-dione and deprotonated during 1 hour at -40° to -20°. It is cooled to -60°, a solution of 59 g (219 mmol) of diphenylchlorophosphate in 10 ml of N,N-dimethylformamide and 24.9 g (220 mmol) of isocyano-acetic ester is added one after the other, and then a solution of 24.5 g (218 mmol) is added dropwise. ) of potassium tert-butylate in 50 ml of N,N-dimethylformamide at -60° to -55°. The reaction mixture is warmed to room temperature, neutralized with 7 ml of acetic acid and poured into 600 ml of ice water. It is extracted ten times with methylene chloride, the combined organic phases are diluted four times with water and dried over magnesium sulfate. Evaporation of the solvent and crystallization of the residue from methylene chloride yielded 13.6 g of white crystals. Chromatography of the mother liquor on silica gel eluting with acetic ester gave a further fraction of 10.9 (total yield 62%) ethyl (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto-[2 ,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate with m.p. 226-227°.

b) 40.58 g (128.7 mmol) ethyl (S)-7-fluoro-12,12a-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) of 4N-sodium alkali are heated on a steam bath under reflux for 1.5 hours. The alcohol is evaporated on a rotary evaporator. The aqueous phase is washed twice with methylene chloride and acidified to pH 3-4 with 32.5 ml (130 mmol) of 4N hydrochloric acid. The resulting suspension is cooled and filtered (Kutsche). The filter residue is washed with a little vinegar-water and dried. 36.67 g (99%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acids with m.p. 159-160°.

c) 100 g (348 mmol) (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ] of benzodiazepine-1-carboxylic acid is suspended in 600 ml of N,N-dimethylformamide and mixed with 64.1 (395 mmol) of 1,1'-carbonyldiimidazole. After stirring for 30 minutes at 50°, 80 ml of 25% ammonia is added dropwise at 13° to 20°, and the mixture is further stirred for 30 minutes and poured into 21 liters of water. Filtration (Nutsch) of the resulting suspension and drying of the crystals yielded 52.7 g (76%) of amide (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-1-carboxylic acids with m.p. 223-224°.

d) 75.6 g (264 mmol) of amide (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1, 4]benzodiazepine-1-carboxylic acid is suspended in 340 ml of dioxane and 45 ml of pyridine and at ca. 7° is added dropwise and mixed with 45 ml (323 mmol) of trifluoroacetic anhydride. The reaction mixture is stirred overnight at room temperature and poured into 2 l of water. Filtration (Nutsch) of the resulting suspension and drying of the crystals yielded 45.65 g (64%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1 ,5-a][1,4]benzodiazepine-1-carbonitrile, which is used in the next step without further purification.

e) 4.2 g (180 mmol) of sodium are dissolved in 225 ml of methanol. 13.55 g (195 mmol) of hydroxylamine hydrochloride and 40 g (149 mmol) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-1-carbonitrile and the reaction mixture was stirred overnight at reflux temperature. The suspension is cooled to 5° and filtered (Nutsche). The crystals are additionally washed with water and dried. 38.9 g (87%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime? which is applied in the next stage without further cleaning.

f) 15.9 g (52.8 mmol) (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoximase is mixed with 9.93 g (58 mmol) of chloroacetic anhydride and 50 ml of N,N-dimethylformamide for 0.5 hours at room temperature and 2 hours at 105°. After evaporation of the reaction mixture, the residue is dissolved in methylene chloride, and the solution is washed with saturated sodium bicarbonate solution. By drying the organic phases over magnesium sulfate, evaporating the solvent and chromatography of the residue on silica gel under elution with acetic ester, 11 g (58%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazole-3- yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one.

g) 1.8 g (5 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one was stirred overnight with 2 g (20 mmol) of dipropylamine and 20 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 1.8 g (85%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro -12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride (amorphous).

Example 196

1.8 g (5 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 2 hours with 2 g (34 mmol) of propylamine and 20 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 9/1 yielded 1.4 g (73%) of (S)-7-fluoro-1-(5-propyl-aminomethyl-1,2,4- oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride ( amorphous).

Example 197

0.99 g (3 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is stirred overnight in 1.2 g (16 mmol) of diethylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 9/1 yielded 0.9 g (81%) of 3-(diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5 ,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 153-154°, which is converted to the hydrochloride.

Example 198

0.99 g (3 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is stirred overnight in 2 g (16 mmol) of di-butylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 0.82 g (65%) of 3-(dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro- 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 105-110°.

Example 199

1.15 g (3.5 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-9-one was stirred overnight with 0.73 g (10 mmol) of diethylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 1.23 g (93%) of (S)-1-(5-diethyl-aminomethyl-1,2,4-oxadiazol-3-yl) 12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 209-211°.

Example 200

1.15 g (3.5 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[ 1,5-a][1,4]benzodiazepine-9-one was stirred overnight in 1.29 g (10 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.04 g (68%) of (S)-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-12, 12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride (amorph.).

Example 201

a) 30 g (106.7 mmol) of (S)-5-bromo-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione is dissolved in 50 ml of N,N-dimethylformamide, mixed at -20° with 5.6 g (128 mmol) of sodium hydride dispersion 55% in oil (extracted with hexane) and deprotonated for 30 min at -30° to -20°. At -60°, a solution of 43 g (160 mmol) of diphenyl-ester-chloride-phosphoric acid in 25 ml of N,N-dimethylformamide is added and stirred for 35 minutes at max. -45°. Meanwhile, 12 g (107 mmol) of potassium tert-butylate were dissolved separately in 20 ml of N,N-dimethylformamide and mixed with 12.1 (107 mmol) of ethyl ester of isocyanoacetic acid at -60°. Deprotonated ethyl ester isocyanoacetic acid is added dropwise to the reaction mixture at max. –65° within 1 1⁄4 hours. It is then stirred for 1 hour in an acetone/dry-ice bath, neutralized with 10 ml of acetic acid and poured into 500 ml of ice water. It is extracted five times with methylene chloride (1.2 l in total), dried over magnesium sulfate and evaporated to dryness. By recrystallization of the residue from ethanol and ether, 23.7 g (49%) of ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5 -a][1,4]benzodiazepine-1-carboxylate with m.p. 184-185°.

b) 21.8 g (57.9 mmol) ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1, 4]benzodiazepine-1-carboxylate is heated with 17 ml of 4N sodium hydroxide solution and 200 ml of ethanol for 15 minutes at reflux. At room temperature, 17 ml of 4N hydrochloric acid and 250 ml of water are added. The alcohol evaporates, and the suspension cools to 0°. By filtering (Nutscha) and drying the crystals, 19.8 g (98%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5 -a][1,4]benzodiazepine-1-carboxylic acids with m.p. 178-180°.

c) 19.8 g (56.9 mmol) (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ] of benzodiazepine-1-carboxylic acid is suspended in N,N-dimethylformamide, mixed with 10.1 g (62.6 mmol) of 1,1'-carbonyldiimidazole at room temperature and stirred for 30 minutes at 70°. Add 50 ml of 25% ammonia at 25-30 . The reaction mixture is diluted with 50 ml of water and cooled to 0°, and the crystallisate is filtered off (Nutscha) and dried. 133.6 g (69%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamide with m.p. 314-317°.

d) Suspension of 19 g (54.7 mmol) (S)-8-bromo-9-oxo-12,12a-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 is mixed at 7 to 10° with 15 ml of trifluoroacetic acid hydride. The suspension is stirred for 1 hour at room temperature and poured into 600 ml of water. After 1 hour, the suspension is filtered (Nutscha). 13.1 g (72%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carbonitrile with m.p. 133-136°.

e) 13 g (39.5 mmol) (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carbonitrile is mixed with 7.5 g (71 mmol) of sodium carbonate and 5.7 g (82 mmol) of hydroxylamine hydrochloride in 200 ml of ethanol and 40 ml of water for 1 hour at 50° and 10 minutes at 75°. After dilution with 50 ml of water, the suspension is filtered (Nutscha), after which the crystals are dried. 7.33 g (51%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime with m.p. 265-266°.

f) 7 g (19.3 mmol) (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamidoxime is mixed with 3.8 g (22.2 mmol) of chloroacetic anhydride and 50 ml of N,N-dimethylformamide at room temperature for 1 hour and 2 hours at 105°. After evaporation of the reaction mixture, the residue is dissolved in methylene chloride, and the solution is washed with saturated sodium carbonate solution. The organic phase is dried over magnesium sulfate and concentrated. After recrystallization of the residue from methanol, 5.3 g (65%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H are obtained -azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 210-211°.

g) 1.26 g (3 mmol) (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 5 hours with 0.44 g (6 mmol) of diethylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 1.14 g (82%) of (S)-8-bromo-1-(5-diethylaminomethyl-1,2,4-oxadiazole-3- yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one? which is converted into the hydrochloride with m.p. 206-209°.

Example 202

a) Suspension of 12.8 g (35.4 mmol) (S)-8-bromo-9-oxo-11,12,13,13a-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 is mixed at 7 to 10° with 6.5 ml of trifluoroacetic anhydride. The suspension is stirred for 2.5 hours at room temperature and poured into 200 ml of water. After 1 hour, the suspension is filtered (Nutscha). 12.1 (100%) (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1, 4]benzodiazepine-1-carbonitrile with m.p. 253-254°.

b) 12 g (35 mmol) (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1 ,4]benzodiazepine-1-carbonitrile is stirred for 2 hours with 9.6 g (94 mmol) of sodium carbonate and 7.3 g (105 mmol) of hydroxylamine hydrochloride in 170 ml of ethanol and 40 ml of water at the boiling point. After evaporating the alcohol, the obtained suspension is cooled, and the crystals are filtered off (Nutsche) and dried. 11.4 g (86%) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1 ,4]benzodiazepine-1-carbxamidoxime with m.p. 235-237°.

c) 11.5 g (30.6 mmol) (S)-8-bromo-9-oxo-115,13?13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4 ]benzodiazepine-1-carbxamidoxime is mixed with 6.02 g (35.2 mmol) of chloroacetic anhydride in 60 ml of N,N-dimethylformamide for 1 hour at room temperature and 3 hours at 105°. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporating the solvent and chromatography of the residue on silica gel eluting with acetic ester, 10.2 g (76%) of (S)-8-bromo-1-(5-chloromethyl-1,2,4- oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one with m.p. 242-244°.

d) 1.3 g (3 mmol) (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one is stirred for 5 hours with 1.02 g (10 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 1.41 g (94%) of (S)-8-bromo-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl) )-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one, which is converted into the hydrochloride (amorph.) .

Example 203

a) 6.24 g (18.2 mmol) (S)-8-chloro-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a] [1,4]benzodiazepine-1-carboxamidoxime is mixed with 3.43 g (20 mmol) of chloroacetic anhydride and 40 ml of N,N-dimethylformamide for 60 hours at room temperature and 2.5 hours at 105°. Evaporation of the solvent and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yielded 1.88 g (26%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl) )-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 214-217°.

b) 1 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-one is mixed overnight with 0.98 g (7.5 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent and chromatography of the residue on silica gel with ethyl acetate yielded 0.44 g (36%) of (S)-8-chloro-1-(5-dibutyl-aminomethyl-1,2,4-oxadiazol-3-yl)- 7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-one, which is converted to the hydrochloride (amorphous).

Example 204

0.88 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-one was mixed 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 is dissolved in methylene chloride, and the solution is washed with water. By drying the organic phases over magnesium sulfate and evaporating the solvent, 0.9 g (95%) of (S)-S-chloro-1-(5-diethyl-aminomethyl-1,2,4-oxadiazol-3-yl)-7- fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-one, which is converted to the hydrochloride (amorphous).

Example 205

1.19 g (3 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoro-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-one is mixed for 5 hours with 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 is dissolved in methylene chloride, and the solution is washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent, 1.33 g (96%) of 3-(5-dipropyl-aminomethyl-1,2,4-oxadiazol-3-yl)-7-trifluoro-methyl-5,6- dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 216-218°.

Example 206

a) 7 g (20.6 mmol) 5-methyl-6-oxo-7-trifluoro-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzo-diazepine-3-carboxamidoxime it is mixed in 50 ml of N,N-dimethylformamide with 4.05 g (23.7 mmol) of chloroacetic anhydride for 2 hours at room temperature and 2 hours at 105°. After evaporation of the reaction mixture, the residue is dissolved in methylene chloride, and the solution is washed with water. Evaporation of the solvent and chromatography of the residue on silica gel eluting with acetic ester yielded 7.12 g (87%) of 3-(5-chloro-methyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoro -methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 180-184°.

b) 1.19 g (3 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoro-methyl-5,6-dihydro-4H-imidazo[1, 5-a][1,4]benzodiazepine-6-one was stirred overnight 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 is dissolved in methylene chloride, and the solution is washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent, 0.84 g (67%) of 5-methyl-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-trifluoromethyl-5, 6-dihydro-4H-imidazo[1,5-a][1,4]benzo-diazepin-3-benzodiazepine-6-one, which is converted into hydrohexane with m.p. 234-237°.

Example 207

a) 24.9 g (74.1 mmol) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]beizodiazepine-3-carboxylic acid is suspended in 100 ml of N,N-dimethylformamide is mixed with 14.3 g (89 mmol) of 1,1'-carbonyldiimidazole at room temperature and stirred for 30 minutes at 70°. At 25-30°, add 50 ml of 25% ammonia. The reaction mixture is diluted with 200 ml of water and cooled to 0°, and the crystallisate is filtered off (Nutsche) and dried. 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 m.p. 278-279°.

b) A suspension of 21.5 g (64.1 mmol) 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 is mixed at 7 to 10° with 15 ml of trifluoroacetic anhydride. The suspension is stirred for 1 hour at room temperature and poured into 600 ml of water. The suspension is filtered (Nutscha) for 1 hour. 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 m.p. 226-228°.

c) 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 is mixed with 10.3 g (97.7 mmol) of sodium carbonate and 8 g (115.1 mmol) of hydroxylaminohydrochloride in 300 ml of ethanol and 60 ml of water for 1 hour at 50° and 20 minutes at 75°. After dilution with 50 ml of water, the suspension is filtered (Nutscha), and the crystals are dried. 16.95 g (86%) of 7-bromo-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxirn with m.p. 265-266°.

d) 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-carboxamidoxime is mixed with 9.5 g (55.5 mmol) of trifluoroacetic anhydride in 100 ml of N,N-dimethylformamide for 1 hour at room temperature and 3 hours at 105°. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is washed with saturated sodium bicarbonate solution. By drying the organic phase over magnesium sulfate, evaporating the solvent and chromatography of the residue on silica gel eluting with methylene chloride/methanol 9/1, 16.3 g (84%) of 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazole) are obtained -3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 242-244°.

e) 2.04 g (5 mmol) 7-bromo-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one is stirred for 4 hours with 1.5 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylforaiamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.61 g (68%) of 7-bromo-3-(5-dipropyl-aminomethyl-1,2,4-oxadiazol-3-yl)-5- methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 135-145°.

Example 208

2.1 g (5 mmol) (S)-8-bromo-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 2 hours with 1.52 g (15 mmol) of dipropylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded after recrystallization from acetic ester 1.2 g (50%) of (S)-8-bromo-1-(5-dipropylaminomethyl-1,2,4-oxadiazole) -3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 122-124°, which is converted into the hydrochloride with m.p. 196-198°.

Example 209

1.88 g (5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 4 hours with 2 g (2.2 mmol) of bis(2-methoxyethyl)-amine and 15 ml of N,N-dimethylformamide at room temperature . By evaporating the solvent, the reaction mixture is taken up in 4 N sodium-alkali, after which it is extracted three times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent, 2.2 g (93%) of (S)-8-chloro-1-[5-di-(2-methoxyethyl)aminomethyl-1,2,4-oxadiazole-3- yl]-12,12a-dihydro-9H?HH-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with U. 188- 190°.

Example 210

0.94 g (2.5 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 1 g (17 mmol) of propylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the solvent of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/methanol 9/1 yielded 0.92 g (92%) of (S)-8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazole) -3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 237-239°, which is converted to the hydrochloride.

Example 211

1.5 g (4.5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed overnight with 0.5 g (4.4 mmol) of heptamethyleneimine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.2 g (12%) of 345-(heptamethyleneimin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5-methyl -5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 246-248°.

Example 212

0.7 g (2.1 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed overnight with 0.5 g (5 mmol) of hexamethyleneimine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.76 g (90%) of 3-[5-(hexamethyleneimin-1-yl)methyl-1,2,4-oxadiazol-3-yl]- 5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, m.p. 158-159°, which is converted to the hydrochloride.

Example 213

1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 5 g (25 mmol) of dicyclohexylamine and 7 ml of N,N-dimethylformamide at 65°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.8 g (51%) of (S)-chloro-1-(5-dicyclohexylaminomethyl-1,2,4-oxadiazol-3-yl)-12 ,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one which is converted to the hydrochloride with m.p. 155-185°.

Example 214

1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred for 4 hours with 2 g (17 mmol) of 2,6-dimethylpiperidine and 15 ml of N,N-dimethylformamide at 70°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester/methanol 9/1 yielded 0.83 g (61 %) of (S)-S-chloro-1-[5-(2,6-dimethylpiperidine-1- yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine- 9-one, which is converted to the hydrochloride with m.p. 233-236°.

Example 215

1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 2 g (12.7 mmol) of dipentylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.01 g (68%) of (S)-S-chloro-1-(5-(dipentylaminomethyl-1,2,4-oxadiazol-3-yl) )-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride (amorph.).

Example 216

a) 1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2, 1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one was stirred overnight with 2 g (17.7 mmol) of 3,3-dimethylpiperidine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.34 g (98%) of (S)-8-chloro-1-[5-(3,3-dimethyl-piperidin-1-yl)methyl -1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one , which translates into hydrochloride (amorph.).

Example 217

a) 9.8 g (32.1 mmol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime is mixed with 7 g (41 mmol) of trifluoroacetic anhydride in 60 ml of N,N-dimethylformamide for 1 hour at room temperature and 4 hours at 105°. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is washed with saturated sodium bicarbonate solution. The organic phases are dried over magnesium sulfate and concentrated, and the residue is chromatographed on silica gel under elution with acetic ester. 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 208-210°.

b) 1.6 g (4.4 mmol) 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 is stirred for 4.5 hours with 1.1 g (15 mmol) of diethylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 yields 1.50 g (85%) of 7-chloro-3-(5-diethyl-aminomethyl-1,2,4-oxadiazol-3-yl) -5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with m.p. 250-252°.

Example 218

1.6 g (4.4 mmol) 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 is mixed for 48 hours with 3.6 g (21 mmol) of dibutylamine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.23 g (61%) of 7-chloro-3-(5-dibutyl-aminomethyl-1,2,4-oxadiazol-3-yl)-5- methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 140-142°, which is converted into the hydrochloride with m.p. 184-187°.

Example 219

1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 1.7 g (9 mmol) of dihexylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.89 g (56%) of (S)-8-chloro-1-(5-dihexylaminomethyl-1,2,4-oxadiazol-3-yl)- 12,12a-dihydro-9H,1H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride (amorph.).

Example 220

1.15 g (3.5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is stirred for 1 hour with 1 g (8.8 mmol) of 3,3-dimethylpiperidine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/ethanol 9/1 yielded 1.32 g (92%) of 3-[5-(3-chloromethyl-1,2,4-oxadiazol-3-yl)- 5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one was mixed for 1 hour with 1 g (8.8 mmol) of 3,3-dimethylpiperidine and 10 ml of N ,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/ethanol 9/1 yielded 1.32 g (92%) of 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 U. 167-168°, which translates into hydrochloride.

Example 221

1.15 g (3.5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed for 1 hour with 1 g (1.7 mmol) of piperidine and 10 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with ethyl acetate/ethanol 9/1 yielded 0.98 g (74%) of 5-methyl-3-[5-(piperidin-1-yl)methyl-1,2,4 -oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 167-168°, which is converted to the hydrochloride.

Example 222

1.3 g (3.6 mmol) 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 is mixed overnight with 1.6 g (8.9 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 0.69 g (42%) of 7-chloro-3-(5-diisobutyl-aminomethyl-1,2,4-oxadiazol-3-yl)-5- methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 158-160°, which is converted into the hydrochloride with m.p. 125-128°.

Example 223

1.13 g (3 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1- c]imidazo[1,5-a][1,4]benzodiazepine-9-one is stirred overnight with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.07 g (76%) of (S)-8-chloro-1-(5-diisobutyl-aminomethyl-1,2,4-oxadiazol-3-yl) )-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to the hydrochloride with m.p. 125-140°.

Example 224

72 g (212 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is stirred for 16 hours in 150 ml (1.06 mol) of diisopropylamine and 300 ml of N,N-dimethylformamide at 80°. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is extracted twice with 100 ml of 2N hydrochloric acid. The organic phases are dried over magnesium sulfate and evaporated. Chromatography of the residue on silica gel eluting with acetic ester/methanol/acetic acid 95/3/2 and recrystallization from ethanol yields 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 m.p. 125-140°.

Example 225

1 g (3 mmol) (5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine -6-one is stirred overnight with 3 ml (17 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide at room temperature. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with acetic ester yielded 1.2 g (94%) of 3-(5-diisobutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6- dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 170-1 72°, which is converted into the hydrochloride with m.p. 200-202°.

Example 226

1.65 g (5 mmol) 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one is mixed for 24 hours with 3 ml (17.5 mmol) of di-sec-butylamine and 25 ml of N,N-dimethylformamide at 75°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with methylene chloride/methanol 19/1 and crystallization from acetic ester yielded 1.23 g (58%) of 3-(5-di-sec-butylaminomethyl-1,2,4-oxadiazole-3 -yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-6-one with m.p. 155-157°, which is converted into the hydrochloride with m.p. 133-140°.

Example 227

1.82 g (5 mmol) 7-chloro-3K5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1, 4]benzodiazepine-6-one is stirred overnight with 3 ml (21.3 mmol) of diisopropylamine and 20 ml of N,N-dimethylformamide at 80°. Evaporation of the reaction mixture and chromatography of the residue on silica gel eluting with cyclohexane/ether/isopropanol/ammonia 15/15/5/0.5 yielded 1.41 g (66%) of 7-chloro-3-(5-diisopropyl-aminomethyl-1,2, 4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepn-6-one with m.p. 58-63°, which is converted into the hydrochloride with m.p. 230-231°.

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-one is stirred for 2.5 hours with 3 g (50 mmol) of isopropylamine and 20 ml of N,N-dimethylformamide at room temperature. After evaporation of the solvent, the residue is dissolved in methylene chloride, and the solution is washed twice with water. The organic solution is dried over magnesium sulfate and concentrated. Recrystallization of the residue from acetic ester yields 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 m.p. 142-144°, which is converted into the hydrochloride with m.p. 252-254°.

Example 229

a) Suspension of 7.07 g (21.3 mmol) (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c] [1,4]benzodiazepine-1-carboxamidoxime in 50 ml of N,N-dimethylformamide was mixed with 4.0 g (23.4 mmol) of chloroacetic anhydride. The resulting yellow solution is stirred for 2 hours at 105° and then completely freed from the solvent. The oily product is chromatographed over silica gel with methylene chloride/methanol 9:1 as eluant, and the obtained oily product is recrystallized from acetic ester/ether. The mother liquor is concentrated, the residue is chromatographed once more over silica gel with acetonitrile as eluant, and the additional portion of the product obtained is recrystallized from acetic ester/ether. 6.27 g (75%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as white crystals; d.p. 184-186° and [α]D20= +36.1° (MeOH, c=1%).

b) Suspension of 1.85 g (4.74 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 30 ml of N,N-dimethylformamide was mixed with 1.73 g (23.7 mmol) of diethylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 19:1 as eluant. 1.54 g (76%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as a light yellow oil. One sample was recrystallized from ether to give white crystals; d.p. 151-153° and [α]D20=+35.5° (MeOH, c=1%).

c) 0.84 g (1.96 mmol) (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 10 ml of ethanol was mixed with 0.41 ml (1.96 mmol) of 4.78 N ethanolic hydrochloric acid. After stirring for 10 minutes at room temperature, the resulting solution is completely free of solvent. The residue is recrystallized from ethanol/ether. 0.70 g (77%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one hydrochloride (1:1) as white crystals; d.p. 205-207° [α]D20=+25.20 (MeOH, c=1%).

Example 230

a) Suspension of 1.85 g (4.74 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 30 ml of N,N-dimethylformamide was mixed with 2.40 g (23.7 mmol) of dipropylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 19:1 as eluent. 2.03 g (94%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as light yellow oil.; [α]D20=+29.3° (MeOH, c=1%).

b) 1.93 g (4.24 mmol) (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 20 ml of ethanol was mixed with 0.88 ml (4.2 mmol) of 4.78 N ethanolic hydrochloric acid. After stirring for 10 minutes at room temperature, the resulting solution is completely free of solvent. The residue is recrystallized from ethanol/ether. 1.42 g (68%) of (S)-84dor-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one hydrochloride (1:1) as white crystals; d.p. 183-185° [α]D20=+24.4° (MeOH, c=1%).

Example 231

a) Suspension of 1.85 g (4.74 mmol) (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H- imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 30 ml of N,N-dimethylformamide was mixed with 3.06 g (23.7 mmol) of dibutylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 19:1 as eluent. 2.15 g (94%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one as light yellow oil.; [α]D20=+28.7° (MeOH, c=1%).

b) 2.01 g (4.16 mmol) (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one in 20 ml of ethanol was mixed with 1.12 ml (4.14 mmol) of 3.70 N ethanolic hydrochloric acid. After stirring for 10 minutes at room temperature, the resulting solution is completely free of solvent. The residue is recrystallized from ethanol/ether. 1.99 g (92%) of (S)-8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[ 1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-9-one hydrochloride (1:1) as white crystals; d.p. 163-165° and [α]D20=+23.2° (MeOH, c=1%).

Example 232

a) 0.66 g (1.9 mmol) 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-one is dissolved in 20 ml of N,N-dimethylformamide. At room temperature, a weak stream of ethylamine gas is introduced for 1 hour, whereby the reaction temperature rises to 36°. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 19:1 as eluent. After compacting, a yellowish-gray foam is obtained, which is absorbed in ether. 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-one as yellowish-gray crystals; d.p. 166-168°.

b) 0.37 g (1.04 mmol) 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-one in 6 ml of ethanol was mixed with 0.31 ml (1.14 mmol) of 3.70 N ethanolic hydrochloric acid. After the addition of 20 ml of acetic ester at 0°, crystals are separated. 0.30 g (73%) 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-one hydrochloride (1:1) as white crystals; d.p. 250-252° (exp.).

Example 233

a) 19.8 g (0.0639 mol) 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbon of acid is suspended in 100 ml of N,N-dimethylformamide under argon gassing and at room temperature is mixed in portions with 10.9 g (0.0671 mol) of 1,1-carbonyldiimidazole. After the evolution of CO2 has stopped, the yellowish-gray suspension is stirred for 30 min at 50°, and cooled at a temperature below 25° within approx. Mix with 20 ml of 25% ammonia for 10 minutes. After 15 minutes of mixing, the obtained brownish solution is poured into 600 ml of ice water. The mixture is stirred for 30 min at room temperature and filtered, after which the crystals are washed again with a total of 200 ml of water. After drying, 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 as yellowish-gray crystals; d.p. 292-294°.

b) 14.4 g (0.0466 mol) 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide is suspended in 60 ml of dioxane and 8 ml of pyridine and at a temperature of ca. 8° within 10 min by adding dropwise the mixture with 10.3 g (0.049 mol) trifluoroacetic anhydride. It is mixed for 3 hours at 50° and poured into 400 ml of water. It is extracted with acetic ester, dried over magnesium sulfate, filtered and the filtrate is concentrated. The residue is dissolved in 300 ml of hot ethyl acetate, the solution is filtered through 100 g of silica gel (Nutsche), the silica gel is washed again with 200 ml of ethyl acetate, and the filtrate is evaporated. 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 are obtained as light-yellowish crystals; d.p. 221-223°.

c) 1.0 g (0.0432 mol) of sodium is dissolved in 60 ml of methanol. At room temperature, 8.85 g (0.0304 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-3-carbonitrile and 3.25 g (0.0469 mol) of hydroxylamine hydrochloride. The white suspension is stirred for 67 hours at room temperature and evaporated, after which the residue is mixed with 100 ml of water and the crystals are filtered off. Drying the crystals yields 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 -carboxamidoxime as white crystals; d.p. 228-231°.

The aqueous phase is extracted with acetic ester, dried over magnesium sulfate, filtered and concentrated, thereby obtaining an additional 0.95 g (10%) of material (m.p. 225-228°).

d) Suspension of 7.0 g (0.0216 mol) 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxamidoxime in 70 ml of N,N-dimethylformamide was mixed with 4.38 g (0.0256 mol) of chloroacetic anhydride. The resulting yellow solution is stirred for 2 hours at 100°, and then freed completely from the solvent. The oily product is taken up in 300 ml of acetonitrile, after which the solution is mixed with activated carbon, boiled at reflux and hot filtered through 100 g of silica gel; the silica gel is washed with 200 ml of acetonitrile and the filtrate is evaporated. The crystalline foam is suspended in 100 ml of ether and filtered off (Nutsche). Additional material can be obtained from the mother port. A total of 5.65 g (68%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo is obtained [1,5-a][1,4]benzodiazepine-6-one, as white-yellow crystals; mp 215-218°.

e) Suspension of 1.30 g (3.4 mmol) 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-one in 13 ml of N,N-dimethylformamide was mixed with 1.24 g (0.017 mol) of diethylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether/n-hexane. 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-one as white crystals; d.p. 140-144° (exp.).

f) 1.28 g (3.06 mmol) 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-one is mixed with 0.91 ml (3.36 mmol) of 3.7 N ethanolic hydrochloric acid in 20 ml of ethanol. After stirring for 10 minutes at room temperature, the resulting white suspension was mixed with 100 ml of ether and filtered (Nutsche). 1.31 g (94%) of 74-dor-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-one hydrochloride (1:1) as white crystals; d.p. 206-209° (exp.).

Example 234

a) Suspension of 1.30 g (3.4 mmol) 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-one in 13 ml of N,N-dimethylformamide was mixed with 1.72 g (0.017 mol) of dipropylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether/n-hexane. 1.32 g (87%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one as white crystals; d.p. 143-146° (exp.).

b) 1.25 g (2.8 mmol) 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one is mixed with 0.84 ml (3.07 mmol) of 3.7 N ethanolic hydrochloric acid in 20 ml of ethanol. After stirring for 30 minutes at 0°, the resulting white suspension was mixed with 100 ml of ether and the resulting white suspension was filtered off (Nutsche). 1.13 g (84%) of 7-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) as white crystals; d.p. 209-211° (exp.).

Example 235

a) Suspension of 1.30 g (3.4 mmol) 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-one in 13 ml of N,N-dimethylformamide was mixed with 1.44 g (0.017 mol) of dipropylamine. After stirring for 16 hours at room temperature, the resulting solution is completely free of solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether/n-hexane. 1.39 g (95%) of 7-chloro-8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro- 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one as white crystals; d.p. 210-212° (exp.).

b) 1.37 g (3.18 mmol) 7-chloro-8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro- 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one is dissolved in 50 ml of hot ethanol and 0.95 ml (3.5 mol) of 3.7 N ethanolic hydrochloric acid is mixed at 40°. After stirring for 30 minutes at 0°, the solution is set to a volume of approx. 20 ml and mixed with 100 ml of ether. The resulting white suspension is filtered off (Nutsche). 1.30 g (88%) of 7-chloro-8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro- 4H-imidazo[1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) as white crystals; d.p. 240-243° (exp.).

Example 236

a) Suspension of 1.20 g (3.14 mmol) 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-one in 20 ml of N,N-dimethylformamide was mixed with 1.59 g (0.0166 mol) of diisopropylamine. After stirring for 20 hours at 80°, the resulting solution is completely free from the solvent. The residue is chromatographed over silica gel with methylene chloride/methanol 39:1 as eluent. The product is recrystallized from ether/n-hexane. 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-one as white crystals; d.p. 153-156°.

b) 0.82 g (1.84 mmol) 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-one is dissolved in 20 ml of hot ethanol and 0.55 ml (2.02 mmol) of 3.7 N ethanolic hydrochloric acid is mixed at 0°. After 30 minutes of mixing at 0°, the solution solidifies completely. The product is recrystallized from hot acetonitrile/acetic ester. 0.74 g (83%) 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-one hydrochloride (1:1) as white crystals; d.p. 206-210° (exp.).

Example 237

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 acid (EPA 150 040) in 80 ml of dioxane and 20 ml of pyridine is added dropwise at 5-8° 7.7 ml (55.3 mmol) of trifluoroacetic anhydride. The resulting yellowish-gray solution is stirred for 2.5 hours at 50°, and then poured into 220 ml of ice water. The resulting precipitate is filtered off. After drying at 70°/10 torr, 11 g (85%) of nitrile 7-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4] are obtained. benzodiazepine-3-carboxylic acid as a white powder with m.p. >250°.

b) 2 g (7.8 mmol) nitrile 7-fluoro-5-methyl-6-oxo-5,6- of dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid and 1.1 g (15.6 mmol) of hydroxylamine chloride, after which the mixture was stirred for 16 hours at room temperature. The suspension is then evaporated and mixed with 100 ml of water. The precipitate obtained is filtered off and dried under high vacuum. 2 g (89%) of (E)- and/or (Z)-3-(amino-hydroxyimino-methyl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5 -a][1,4]benzodiazepine-6-one as a colorless foam, 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-hydroxyimino-methyl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1 ,5-a][1,4]benzodiazepine-6-one 1.3 g (7.5 mmol) of chloroacetic anhydride is added to 50 ml of N,N-dimethylformamide and stirred for 1.5 hours at room temperature. Then it is heated for 2 hours at 105°. The solution is evaporated and the residue is partitioned between 2N sodium hydroxide solution and methylene chloride. The aqueous phase is washed again with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The obtained residue is crystallized from methylene chloride/ethanol. 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-one as yellowish-gray powder 205.5-206.5°.

d) A suspension of 1.7 g (4.9 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1, 1 ml (12.2 mmol) of propylamine is added to 5-a][1,4]benzodiazepine-6-one in 40 ml of N,N-dimethylformamide and stirred for 12 hours at room temperature. The solution is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution is extracted with methylene chloride, and the organic phases are dried with magnesium sulfate, filtered and evaporated. The residue is chromatographed (silica gel, ethyl ester-acetic acid/methanol 9:1). 1.21 g (67%) of 3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one, Rf=0.22 (silica gel, ethyl ester-acetic acid/methanol 4:1).

Example 238

490 mg (1.2 mmol) 3-(3-diallylaminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1,4]benzodiazepine-6-one is hydrogenated in 10 ml of acetic ester in the presence of 24 mg of 5% palladium-carbon at room temperature and normal pressure. After separating the catalyst, the solution solidifies. That with a little educt contaminated 3-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][ 1,4]benzodiazepine-6-one is chromatographed on 40 g of silica gel with acetic ester, the eluate is evaporated, the residue is dissolved in 4 ml of isopropanol and the solution is acidified with ethereal hydrochloric acid. The secreted crystals are filtered and dried. 0.37 g (69%) of 3-(3-dipropylaminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one hydrochloride (1:1) as white crystals with m.p. 167-169°.

Example 329

Under argon, a suspension of 0.49 g (1.5 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1 ,5-a][1,4]benzodiazepine-6-one in 8 ml of N,N-dimethylformamide was mixed with 0.41 ml (4.5 mmol) of N-propyl bromide and 1.04 g (7.5 mmol) of potassium carbonate and stirred for 73 hours under argon at room temperature. The solution is filtered, the filtrate is evaporated to give a yellowish oil. The crude product is purified by chromatography on 50 g of silica gel (methylene chloride/acetone 9:1, 4:1, 2:1, finally methylene chloride/methanol 19:1). The eluate is evaporated, the residue is taken up in 5 ml of methanol, and the solution is acidified with ethereal hydrochloric acid, whereby the product crystallizes. The solvent is evaporated again, and the residue is heated in 30 ml of acetic ester. It is cooled in an ice bath and the secreted crystals are sucked off. After drying in a vacuum, 315 mg (51%) of 3-[5-propylaminomethyl)-1,2,4-oxadiazol-3-yl]-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo are obtained [1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1) with m.p. 144-148° (exp.).

Example 240

a) 0.79 g (11.4 mmol) of hydroxylamine hydrochloride and 2.0 g (7.6 mmol) of (S)-9- are added to a freshly prepared solution of sodium methylate in methanol (from 230 mg (10.0 mmol) of sodium in 10 ml of methanol) oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-1-carbonitrile and stirred for 90 hours at room temperature. The suspension is then evaporated, and the residue is taken up in 30 ml of water. The insoluble part is sucked off. The aqueous phase is saturated with table salt, whereby a further product crystallizes. This is sucked off and dried in a vacuum together with the previously obtained material. 2.15 g (95%) of (E)- and/or (Z)-(S)-1-(amino-hydroxyimino-methyl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5 -a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one with m.p. 253-254° (diss., methanol/diethyl ether).

b) Suspension of 1.68 g (5.65 mmol) (E)- and/or (Z)-(S)-1-(amino-hydroxyimino-methyl)-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one in 11 ml of dimethylformamide is added under argon to 1.1 g (6.5 mmol) of chloroacetic anhydride and stirred for 30 min at ca. 25°, and then heated to 110° for 1 hour. The solution is evaporated under high vacuum, and the brown residue is taken up in 20 ml of methylene chloride. The solution is washed three times with 10 ml of saturated sodium hydrogencarbonate solution, and the solvent is evaporated in vacuo. The crude material is chromatographed on 100 g of silica gel (methylene chloride/acetone 9:1, then 4:1). 1.45 g (72%) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5- a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one as colorless crystals with m.p. 205-206° (acetonitrile).

c) A solution of 711 mg (2.0 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1, 5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one in 10 ml of N,N-dimethylformamide was mixed with 0.82 ml (6.0 mmol) of dipropylamine and stirred under argon for 2 hours at room temperature . The solution is evaporated, the residue is mixed with 10 ml of water, and the crystals are filtered off. The crude material is chromatographed on 30 g of silica gel (methylene chloride/acetone 9:1, then 4:1). 840 mg (72%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5- a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one which is converted to the hydrochloride with ethereal hydrochloric acid. Recrystallization from acetonitrile gave 685 mg (73%) of (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one hydrochloride (1:1:3) with m.p. 137-140° (exp.).

Example 241

A solution of 710 mg (2.0 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5- a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one in 10 ml of N,N-dimethylformamide was mixed with 0.5 ml (6.0 mmol) of dipropylamine and stirred under argon for 2 hours at room temperature. The solution is evaporated, the residue is mixed with 10 ml of water, and the crystals are filtered off. Further crude product is obtained by extracting the aqueous phase with methylene chloride. The combined crude materials (0.65 g) are chromatographed on 25 g of silica gel (methylene chloride/methanol 2%, 5%, 10%). 540 mg of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[ 2,1-c][1,4]l-benzodiazepine-9-one, which is dissolved in 5 ml of acetonitrile and then converted to the hydrochloride with ethereal hydrochloric acid. Recrystallization from acetonitrile gave 560 mg (62%) of (S)-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1 ,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one hydrochloride (1:2) with m.p. 169-173° (exp.).

Example 242

A solution of 710 mg (2.0 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5- a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one in 10 ml of N,N-dimethylformamide was mixed with 0.78 ml (6.0 mmol) of N,N,N'-trimethylethylenediamine and stirred under argon 2 hours at room temperature. The solution is evaporated, and the residue is dissolved in 10 ml of water. The solution is saturated with table salt and extracted several times with methylene chloride. The combined extracts are dried with sodium sulfate, filtered and evaporated, whereby 0.85 g of yellowish foam is obtained. The crude material is chromatographed 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). 0.64 g (76%) of (S)-1-[5-[methyl-(2-dimethylamino-ethyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-11,12,13, 13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one. The crude product is dissolved in 10 ml of acetonitrile and filtered through Cilite. It is then acidified with ethereal hydrochloric acid and evaporated. The residue is crystallized from 15 ml of hot acetonitrile. 690 mg (65%) of (S)-1-[5-[methyl-(2-dimethylamino-ethyl)-aminomethyl-1,2,4-oxadiazol-3-yl]-11,12,13,13a are obtained -tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one hydrochloride (1:2) with m.p. 198-200° (exp.).

Example 243

A solution of 711 mg (2.0 mmol) (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5- a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one in 10 ml of N,N-dimethylformamide was mixed with 1.0 ml (6.0 mmol) of dibutylamine and stirred under argon for 3 hours at room temperature. The solution is evaporated, and the residue is mixed in 10 ml of water, and the crystals are suctioned off. The crude product is dissolved in methylene chloride, the solution is dried with sodium sulfate, after which it is chromatographed on 30 g of silica gel (methylene chloride/acetone 9:1, then 4:1). 0.73 g of (S)-1-(5-dibutylamino-methyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a] is obtained pyrrolo[2,1-c][1,4]-benzodiazepine-9-one, which is converted into the hydrochloride in 10 ml of acetonitrile and with ethereal hydrochloric acid. Crystallization from hot acetic ester yields 0.75 g (77%) of (S)-1-(5-dibutylamino-methyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H -imidazo[1,5-a]pyrrolo[2,1-c][1,4]-benzodiazepine-9-one hydrochloride (1:1) with m.p. 115-123° (exp.).

Example 244

a) Suspension of 6.9 g (21.6 mmol) 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid ethyl ester 5.4 ml of 5N sodium alkali is added dropwise to 5 ml of ethanol in 7 ml of water and heated for 30 minutes on a reflux condenser. The solution is filtered hot, solidified at ca. 6 ml and acidify with 5.5 ml 5N hydrochloric acid. The product is extracted. 4.7 g (75%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are obtained as colorless crystals with m.p. 263-267° (exp.).

b) 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 2.7 g (16.8 mmol) of 1,1'-carbonyldiimidazole is added in portions to 25 ml of N,N-dimethylformamide. After the CO2 evolution stops, it is heated for 45 min at 60°. Then the solution is cooled to room temperature and 3.9 ml conc. aqueous solutions of ammonia. After further stirring for 90 minutes, the reaction mixture was poured into 90 ml of ice water and stirred for 1 hour. The white crystals are sucked off and washed again with a little water. After drying in high vacuum, 3.84 g (83%) of the amide 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine- 3-carboxylic acids with m.p. 275-277°.

c) Suspension of 3.72 g (12.8 mmol) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid 1.85 ml (13.4 mmol) of trifluoroacetic anhydride is added dropwise to 17 ml of dioxane and 2 ml of pyridine at <8°. The resulting yellowish-gray solution is stirred for 4 hours at 50 - 60°, cooled and poured into 80 ml of water. The white crystals are filtered off dry under high vacuum. 3.08 g (88%) of 8-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile are obtained as colorless crystals with d.p. 272-275°.

d) 1.1 g (15.8 mmol) of hydroxylamine hydrochloride and 8-chloro-5-methyl-6-oxo-5,6 -dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile and stirred for 18 hours at room temperature. The resulting yellow suspension is cooled in an ice bath and filtered off. Then the raw material is suspended in 10 ml of water, sucked off again and dried in a high vacuum. 2.9 g (89%) of (E)- and/or (Z)-3-(amino-hydroxyimino-methyl)-8-chloro-5-methyl-5,6-dihydro-4H-imidazo[1,5 -a][1,4]benzodiazepine-6-one with m.p. 266-270° (acetonitrile/DMF).

e) Suspension of 0.90 g (2.9 mmol) (E)- and/or (Z)- 3-(amino-hydroxyimino-methyl)-8-chloro-5-methyl-5,6-dihydro-4H-imidazo[1 ,5-a][1,4]benzodiazepine-6-one in 9 ml of dimethylformamide is added under argon to 0.55 g (3.2 mmol) of chloroacetic anhydride and stirred for 1 hour at ca. 25° and then heated for 1 hour at 110°. The solution was evaporated under high vacuum, and the brown residue was taken up in 50 ml of methylene chloride. The solution is washed three times with 10 ml of saturated sodium hydrogencarbonate solution, and the solvent is removed in vacuo. The crude material is chromatographed on 30 g of silica gel (methylene chloride/acetone 9:1). 0.76 g (71%) 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-one as almost colorless crystals with m.p. 229° (acetonitrile).

f) A solution of 370 mg (1.01 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1, 5-a][1,4]benzodiazepm-6-one in 5 ml of N,N-dimethylformamide was mixed with 0.42 ml (3.03 mmol) of dipropylamine and stirred for 2 hours under argon at room temperature. The solution is evaporated, the residue is mixed with 10 ml of water. The white crystals are filtered off. The product is chromatographed on 20 g of silica gel (acetic ester/hexane 1:1, then acetic ester). 259 mg of 8-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one, which is converted to the hydrochloride with ethereal hydrochloric acid. Recrystallization from acetonitrile yields 259 mg of 8-chloro-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a ][1,4]benzodiazepine-6-one, which is converted to the hydrochloride with ethereal hydrochloric acid. Recrystallization from acetonitrile yields 268 mg (54%) of 8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazole[1 ,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1.6) with m.p. 180-192° (exp.).

Example 245

A solution of 278 mg (0.76 mmol) 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-one in 5 ml of N,N-dimethylformamide was mixed with 0.39 ml (2.3 mmol) of dibutylamine and stirred for 1.5 hours under argon at room temperature. The solution is evaporated, the residue is dissolved in 20 ml of methylene chloride, and the solution is washed three times with water. The organic phase is dried with sodium sulfate, filtered and evaporated. The crude material is chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1). 250 mg of 8-chloro-3-(5-dibuylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1 ,4]benzodiazepine-6-one, which is converted to the hydrochloride with ethereal hydrochloric acid. Crystallization from acetonitrile gave 151 mg (39%) of 8-chloro-1-(5-dibutylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1 ,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1.3) with m.p. 165-175°.

Example 246

A solution of 200 mg (0.54 mmol) 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-one in 4 ml of N,N-dimethylformamide was mixed with 0.17 ml (1.65 mmol) of diethylamine and stirred under argon for 1.5 hours at room temperature. The solution is evaporated, the residue is mixed in 10 ml of water. The crystals are suctioned off, the filtrate is extracted once with ethyl acetate, and the extract is evaporated. The combined crude products are chromatographed on 20 g of silica gel (methylene chloride/acetone 4:1,2:1). 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-one, which is converted to the hydrochloride in acetonitrile with ethereal hydrochloric acid. Crystallization from acetonitrile gave 108 mg (42%) of 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 hydrochloride (1:1.9) with m.p. 191-205° (exp.).

Example 247

A solution of 200 g (0.54 mmol) of 8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5- a][1,4]benzodiazepine-6-one in 4 ml of N,N-dimethylformamide was mixed with 0.136 ml (1.65 mmol) of propylamine and stirred under argon for 1.5 hours at room temperature. The solution is evaporated, and the residue is mixed with 10 ml of water. The aqueous phase is extracted with methylene chloride, and the combined extracts are diluted twice with water, dried with sodium sulfate, filtered and evaporated. The combined crude products are chromatographed on silica gel (acetic ester, methylene chloride/methanol 9:1). 126 mg of 8-chloro-3-(5-propyl-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] are obtained [1,4]benzodiazepine-6-one as a foam, which is converted to the hydrochloride in acetonitrile with ethereal hydrochloric acid. Crystallization from hot acetonitrile gives 102 mg (42%) of 8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one hydrochloride (1:1.8) with m.p. 230-240° (exp.).

Example 248

A suspension of 695 mg (2.0 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-one in 7 ml of N,N-dimethylformamide was mixed with 0.78 ml (6.0 mmol) of N,N,N'-trimethylethylenediamine. After stirring for 2 hours at room temperature, the solution solidifies, and the residue is taken up in 70 ml of water. The crystals are filtered off and taken up in 20 ml of a saturated solution of table salt, after which it is extracted four times with acetic ester and three times with methylene chloride. The extracts are dried with sodium sulfate, filtered and evaporated. The residue is recrystallized from acetonitrile. 460 mg (56%) of 3-[5-[methyl-(2-dimethylamino-ethyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-5-methyl-5 is obtained, 6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one, as white crystals. These are dissolved in acetonitrile, and the solution is acidified with ethereal hydrochloric acid. After crystallization from hot acetonitrile, 408 mg (40%) of 3454methyl-(2-dimethylamino-ethyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-8-fluoro-5-methyl-5,6 -dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-6-one hydrochloride (1:2.5) st.t. 217-222° (exp.).

Example 249

a) 59.3 g (0.3 mol) of 5-chloro-isato-acid anhydride and 30.3 g (0.3 mol) of (S)-azetidine-2-carboxylic acid are suspended in 400 ml of N,N-dimethylformamide/acetic acid 5:1 and heated in an oil bath under argon for 64 hours at 87-90°. The solvent is removed in vacuo, and the residue is taken up in 500 ml of methanol, after which it is stirred for 30 min at room temperature. White, pure crystals are aspirated. The solvent is removed in vacuo, and the semi-crystalline residue is recrystallized from 60 ml of methanol (hot filtration). The products are combined and dried in a vacuum. 61.3 g (86%) of (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione are obtained with m.p. 229-231° (exp.).

b) 23.6 g (0.1 mol) (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione in 300 ml of THF/DMPU 5:1 is added dropwise under argon at ca.-75° to the LDA solution (prepared in the usual way from 16 ml (0.11 mol) of diisopropylamine in 200 ml of THF and 69 ml of 1.6 M n-butyllithium solution in hexane). Mix for another 40 min. At approx. -75° is added dropwise 23 ml (0.11 mol) of diphenylester-chloride-phosphoric acid and stirred for 35 min at -75°. Meanwhile, a further LDA solution was prepared separately as described above (100 ml THF). In addition, ca. -75° solution of 12.0 ml (0.11 mol) ethyl ester isocyanoacetic acid in 20 ml THF/DMPU 1:1. At the beginning, deprotonated ethyl ester-isocyano-acetic acid via a dry-ice-cooled addition funnel is added dropwise to the described reaction mixture at ca. -75° within 30 min. It is then stirred for 2 hours in an acetone/dry-ice bath, 100 ml of a 20% ammonium chloride solution is added at <-60° and poured into 800 ml of ice water. It is extracted three times with 200 ml of methylene chloride, dried with sodium sulfate and evaporated. The brown oil is dissolved in 300 ml of acetic ester, after which 300 ml of n-hexane is slowly added. The crystals are filtered off. The further product is obtained by chromatography of the mother liquor on 300 g of silica gel (methylene chloride/acetone 9:1). After drying in vacuum, 17.8 g (54%) of ethyl ester (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-1-carboxylic acids with m.p. 190-194° (acetic ester).

c) 20.8 g (62.8 mmol) ethyl ester (S)-7-chloro-12,12a-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) of 1N sodium hydroxide solution is heated for 30 min at reflux. The alcohol is evaporated on a rotary evaporator. The residue is dissolved in 250 ml of water and acidified with 1N hydrochloric acid. The crystals are sucked off with water and dried in a vacuum. 18.2 g (96%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxylic acids with m.p. 249-250° (exp.).

d) 3.04 g (10.0 mmol) (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ] of benzodiazepine-1-carboxylic acid is suspended in 15 ml of N,N-dimethylformamide and mixed at room temperature in portions with 1.78 g (l 1.0 mmol) of 1,1'-carbonyldiimidazole. After the CO2 evolution stops, the clear solution is stirred for 30 min. It is mixed at 50°, cooled and at a temperature below 25°, the mixture is added dropwise within approx. 10 min with 2.5 ml conc. ammonia. After 30 minutes of mixing, the obtained suspension is evaporated, and the rest is mixed with water. The white crystals are sucked off and dried in a vacuum. 2.8 g (92%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamide with m.p. 251-253°.

e) 2.38 g (7.85 mmol) (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carboxamide is suspended in 15 ml of dioxane and 1.4 ml of pyridine and at a temperature of ca. At 10°, it is added dropwise and mixed with 1.2 ml (8.25 mmol) of trifluoroacetic anhydride. It is stirred for 45 min at room temperature and 0.26 ml of pyridine and 0.11 ml of trifluoroacetic anhydride are added once more. The reaction mixture was stirred for 30 min. The solvent was then removed in vacuo, and the residue was mixed with 30 ml of water. The crude material is chromatographed on 50 g of silica gel (methylene chloride/acetone 9:1). The product is recrystallized from acetonitrile. 1.75 g (80%) of (S)-7-chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4 ]benzodiazepine-1-carbonitrile with m.p. 258-261°.

f) To the sodium methylate solution (prepared from 1.49 g (64.7 mmol) of sodium and 67 ml of methanol) 4.5 g (65.1 mmol) of hydroxylamine hydrochloride and 12.35 g (43.3 mmol) of (S)-7 are added in portions. -chloro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile and stirred for 108 hours at room temperature . The crystals are sucked off, mixed for 30 min in 40 ml of water, sucked off again and dried in a high vacuum. 13.3 g (96%) of (E)- and/or (Z)-1-(amino-hydroxyimino-methyl)-7-chloro-12,12a-dihydro-9H,11H-azeto[2,1-c ]imidazo[1,5-a][1,4]benzodiazepine-9-one with m.p. 282-283° (exp.).

g) Suspension of 1.59 g (5.0 mmol) (E)- and/or (Z)-1-(amino-hydroxyimino-methyl)-7-chloro-12,12a-dihydro-9H,11H-azeto[2,1 -c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 10 ml of N,N-dimethylformamide is added under argon to 1.0 ml (5.75 mmol) of chloroacetic anhydride and stirred for 1 hour at ca . 25° and then heated for 1 hour at 110°. The solution is evaporated under high vacuum, and the resulting brown residue is dissolved in 120 ml of methylene chloride. The solution is washed three times with 20 ml of saturated sodium bicarbonate solution, and the solvent is removed in vacuo. The crude material is chromatographed on 80 g of silica gel (methylene chloride/acetone 9:1, then 4:1). After drying, 1.47 g (78%) of (S)-7-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one as colorless crystals with m.p. 238-241° (acetonitrile).

h) Suspension of 1.13 g g (3.0 mmol) (S)-7-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[ 2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one in 15 ml of N,N-dimethylformamide was mixed with 0.74 ml (9.0 mmol) of propylamine and stirred for 3 hours under argon at room temperature temperature. The solution is evaporated, the residue is taken up in 20 ml of water, and the aqueous phase is extracted with methylene chloride. The combined extracts are dried twice with water, with sodium sulfate, filtered and evaporated. The crude product is chromatographed on 30 g of silica gel (methylene chloride/acetone 4:1, then 2:1 and finally methylene chloride/methanol 9:1). 840 mg of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c] are obtained imidazo[1,5-a][1,4]benzodiazepine-9-one, which is converted to acetonitrile, in the presence of fumaric acid to fumarate. Recrystallization from acetonitrile gives 588 mg (35%) of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto [2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one fumarate (1:1.4) with U. 13 5-140° (dec.).

Example 250

A suspension of 1.04 g g (3.0 mmol) 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-one in 10 ml of N,N-dimethylformamide was mixed with 1.27 ml (9.0 mmol) of diisopropylamine. After stirring for 18 hours at room temperature, the resulting solution is evaporated, and the residue is taken up in 10 ml of water and mixed for 2 hours in an ultrasonic bath. The crystals are filtered off with suction and dissolved in methylene chloride, and the solution is dried with sodium sulfate, filtered and evaporated. The crude product is chromatographed on silica gel (acetic ester), dissolved in acetonitrile and acidified with ethereal hydrochloric acid. The solution is evaporated again, and the residue is recrystallized from acetonitrile. After drying in a vacuum, 542 mg (38%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[ 1,5-a][1,4]benzodiazepine-6-one as white crystals with m.p. 173-178° (exp.).

Example 251

a) Suspension of 22 g (76 mmol) (S)-10,11,12,12a-tetrahydro-8-oxo-8H4midazo[5,1-c]pyrrolo[1,2-a]thieno[3,2- e][1,4]diazepine-1-carboxylic acid (EP 59 390 A1) in 100 ml of dimethylformamide is added in portions of 12.33 g (76 mmol) of 1,1'-carbonyldiimidazole. The resulting light brown solution is heated for 45 min at 50°. It is then cooled to room temperature and 14 ml of aqueous ammonia solution is added dropwise. After a further 30 minutes, the reaction mixture is poured into 100 ml of ice water, and the resulting precipitate is filtered off and washed again with water, ethanol and finally with ether. After drying at 70°/10 torr, 20 g (91%) of amide (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2 -a]thieno[3,2-e][1,4]diazepine-1-carboxylic acids as colorless crystals with m.p. 222-223°.

b) A suspension of 8.98 g (31.1 mmol) of amide (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3 ,2-e][1,4]diazepine-1-carboxylic acid in 50 ml of dioxane and 5.4 ml of pyridine and at a temperature of 5-8°, 4.44 ml (31.9 mmol) of trifluoroacetic anhydride is added dropwise. The obtained yellowish-gray solution is stirred for 2.5 hours at 50°, and then poured into 220 ml of ice water. The resulting precipitate is filtered off. After drying at 70°/10 torr, the nitrile (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3 ,2-e][1,4]diazepine-1-carboxylic acid as a white powder with m.p. 249-251°.

c) 12.7 g (47 mmol) of nitrile (S)-10,11,12,12a-tetrahydro-8-oxo is added to a freshly prepared solution of sodium methylate in methanol (from 1.55 g (67 mmol) of sodium and 70 ml of methanol) -8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid and 5 g (72.2 mmol) of hydroxylamine hydrochloride, after of which the mixture is stirred for 48 hours at room temperature. The suspension is then evaporated and taken up in 100 ml of water. The resulting precipitate is filtered off and dried in a high vacuum. 9.46 g (66%) of (E)- and/or (Z)- (S)-1-(amino-hydroxyimino-methyl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1 -c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colorless powder with m.p. 106-108°.

d) 1.40 g (8.04 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 1.42 g (8.07 mmol) of BOC-glycine in 13 ml of dimethylformamide and the mixture is stirred for 30 minutes at 50°. Then 2.30 g (7.58 mmol) of (E)- and/or (Z)- (S)-1-(amino-hydroxyimino-methyl)-10,11,12,12a-tetrahydro-8H-imidazo[5, 1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one and stirred for 15 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 10:1). 1.50 g (44%) of (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5, 1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one, as a colorless foam, Rf=0.62 (silica gel, methylene chloride/methanol 10:1).

e) A solution of 1.50 g (3.4 mmol) (S)-1-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[ 5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one in 6 ml of trifluoroacetic acid was stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 10 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried with sodium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 9:1). 850 mg (73%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colorless foam, Rf=0.25 (silica gel, methylene chloride/methanol 9:1).

Example 252

a) Solutions of 5.13 g (18.6 mmol) (S)-11,11a-dihydro-9-oxo-9H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2- e][1,4]diazepine-1-carboxylic acid, 3.15 g (19.4 mmol) of 1,1'-carbonyldiimidazole is added to 30 ml of dimethylformamide all at once at room temperature, and the mixture is stirred for 45 min at 50°. Then 4.16 g (19.9 mmol) of phthaliolglycinamidoxime is added all at once, and the mixture is stirred for 15 hours at 110°. Dimethylformamide is evaporated under high vacuum, and the obtained residue is taken up with 150 ml of water. Extraction with methylene chloride (twice), drying with sodium sulfate, filtration and evaporation gave a pink residue, which was then chromatographed (silica gel, methylene chloride/methanol 20:1). 3.92 g (46%) of (S)-2-[5-(8-oxo-11,11a-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-yl-methyl]-2,3-dihydro-1H-isoindole-1,3-dione as light - brown crystals with m.p. 155-157°.

b) Solutions of 2.4 g (5.23 mmol) (S)-245-(8-oxo-11,11a-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-yl-methyl]-2,3-dihydro-1H-isoindole-1,3-dione in 40 ml of ethanol, 30 ml of methylamine (33% in ethanol) is added dropwise at 70° and stirred for another 2 hours at 70°. The reaction mixture is evaporated, and the residue is chromatographed (silica gel, methylene chloride/methanol 20:1). 1.60 g (93%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] is obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as colorless crystals with m.p. 227° (exp.).

Example 253

a) Suspension of 8.8 g (33.4 mmol) 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3 -carboxylic acid (EP 150 040 A2) in 80 ml of dimethylformamide, 5.66 g (34.9 mmol) of 1,1'-carbonyldiimidazole is added in portions. The resulting light brown solution is heated to 50° for 45 minutes. Then the solution is cooled to room temperature and 8.1 ml of aqueous ammonia solution is added dropwise. After a further 30 minutes, the reaction mixture is poured into 100 ml of ice water, and the resulting precipitate is filtered off and washed again with water, ethanol and finally with ether. After drying at 70°/10 torr, 7.60 g (86%) of the amide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f ][1,4]diazepine-3-carboxylic acids as colorless crystals with m.p. 294-296°.

b) A suspension of 7.43 g (28.3 mmol) of the amide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine- of 3-carboxylic acid in 40 ml of dioxane and 5 ml of pyridine, 4.05 ml (29 mmol) of trifluoroacetic anhydride is added dropwise at a temperature of 5-8°. The obtained yellowish-gray solution is stirred for 2.5 hours at 50°, and then poured into 220 ml of ice water. The resulting precipitate is filtered off. After drying at 70°/10 torr, 5.6 g (81%) of nitrile 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][ 1,4]diazepine-3-carboxylic acid as a white powder with m.p. 206-208°.

c) 5.54 g (22.7 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo nitrile is added to a freshly prepared solution of sodium methylate in methanol (from 0.74 g (32.3 mmol) of sodium and 40 ml of methanol) [1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid and 2.5 g (36.1 mmol) of hydroxylamine hydrochloride, after which the mixture was stirred for 48 hours at room temperature. The suspension is then evaporated and taken up with 100 ml of water. The resulting precipitate is filtered off and dried in a high vacuum. 5.7 g (90%) of (E)- and/or (Z)-3-(amino-hydroxyimino-methyl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno are obtained [2,3-f][1,4]diazepin-6-one as a colorless powder with m.p. 248-250°.

d) 3.82 g (23.5 mmol) of 1,1'-carbonyldiimidazole is added to a solution of 3.85 g (21.9 mmol) of BOC-glycine in 45 ml of dimethylformamide and the mixture is stirred for 30 minutes at 50°. Then 5.7 g (20.56 mmol) of (E)- and/or (Z)-3-(amino-hydroxyimino-methyl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] are added thieno[2,3-f][1,4]diazepin-6-one and stirred for 15 hours at 90°. The resulting brown solution is evaporated under high vacuum, and the resulting brown residue is chromatographed (silica gel, methylene chloride/methanol 10:1). 7.2 g (84%) of 3-(5-BOC-aminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] are obtained thieno[2,3-f][1,4]diazepin-6-one as a colorless foam, Rf=0.28 (silica gel, methylene chloride/methanol 10:1).

e) A solution of 7.2 g (17.2 mmol) 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-one in 15 ml of trifluoroacetic acid1 is stirred for 2 hours at room temperature. The yellow solution is evaporated, the residue is dissolved in water, and the aqueous phase is washed three times with methylene chloride. Then the aqueous phase is made alkaline with 10 ml of aqueous ammonia solution and extracted six times with methylene chloride. The organic phases are dried with sodium sulfate, filtered and evaporated. The resulting residue is chromatographed (silica gel, methylene chloride/methanol 10:1). 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-one as colorless crystals with m.p. 202-204°.

Example 254

a) Solutions of 5.27 g (20 mmol) 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3 -carboxylic acid in 50 ml of dimethylformamide, 3.39 g (20 mmol) of 1,1'-carbonyldiimidazole is added all at once at room temperature and the mixture is stirred for 30 min at 50°. Then 4.47 g (20 mmol) of phthaloylglycinamimidoxime is added all at once, and the mixture is stirred for 15 hours at 110°. Dimethylformamide is evaporated under high vacuum, and the obtained residue is taken up with 150 ml of water. Extraction with methylene chloride (twice), drying with sodium sulfate, filtration and evaporation gave a pink residue, which was then chromatographed (silica gel, methylene chloride/methanol 20:1). After recrystallization from acetonitrile, 4.21 g (47%) of 5-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1, 4]diazepin-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione as light brown crystals with m.p. 245-246°.

b) Solutions of 4.2 g (9.41 mmol) 5-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4] diazepin-3-ylmethyl)-2,3-dihydro-1H-isoindole-1,3-dione in 50 ml of ethanol, 50 ml of methylamine (33% in ethanol) is added dropwise at 70° and stirred for another 2 hours at 7CP. The reaction mixture is evaporated, and the resulting crystals are filtered off. 1.2 g (40%) 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-one as colorless crystals m.p. 203°(diss.).

Example 255

a) A suspension of 4 g (12.6 mmol) of ethyl ester (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3 ,2-e][1,4]diazepine-1-carboxylic acid in 40 ml of ethanol, 8 ml of hydrazine hydrate is added, and the mixture is heated for 3 hours at reflux. After cooling to 0°, the obtained crystals are filtered, 3.6 g (94%) of hydrazide (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1 ,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acids as colorless needles with mp >260°.

b) A solution of 1.0 g (4.9 mmol) of N-phthaloylglycine in 8 ml of dimethylformamide was mixed at room temperature with 0.83 g (5.11 mmol) of 1,1'-carbonyldiimidazole and then heated to 50°. After 30 min, cool to room temperature, add 1.5 g (5 mmol) hydrazide (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2 -a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid and stirred for 12 hours at room temperature. The obtained suspension is filtered, and the obtained colorless powder is washed with ethanol and diethyl ether. 2.2 g (100%) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-10,11,12,12a- tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid with m.p. >260°.

c) A solution of 10 g (20.4 mmol) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-10,11,12, 12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid in 90 g of polyphosphoric acid is stirred for 1.5 hours at 100°. After cooling to room temperature, the mixture is poured into 300 ml of ice water with good stirring, after which solid sodium carbonate is added until pH=8. Extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20:1) gave 7.5 g (78%) of (S)-2-[5-(8-oxo-10,11,12,12a-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 colorless powder with m.p. >250°.

d) Suspension of 2.5 g (5.3 mmol) (S)-2-[5-(8-oxo-10,11,12,12a-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 30 ml of methylamine (33% in ethanol) is added dropwise to 30 ml of ethanol at 70° and stirred for one hour at 70°. The resulting precipitate is filtered off while hot, and the resulting yellowish powder is washed with ethanol until it becomes colorless. 1.23 g (68%) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-10,11,12,12a-tetrahydro-8H-imidazo[5,1- c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepin-8-one as a colorless powder with m.p. 214-216°.

Example 256

a) A suspension of 6 g (19.8 mmol) of ethyl ester (S)-S-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2 -e][1,4]diazepine-1-carboxylic acid in 50 ml of ethanol, 10 ml of hydrazine hydrate is added and the mixture is heated at reflux for 3 hours. After cooling to 0°, the obtained crystals are filtered, 5.6 g (98%) of hydrazide (S)-S-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1 -c]thieno[3,2-e][1,4]diazepine-1-carboxylic acids as colorless needles with m.p. 260-263°.

b) A solution of 5.8 g (19 mmol) of N-phthaloylglycine in 30 ml of dimethylformamide was mixed at room temperature with 3.2 g (19.75 mmol) of 1,1'-carbonyldiimidazole and then heated to 50°. After 30 min, it is cooled to room temperature, and 5.6 g (19.63 mmol) of hydrazide (S)-S-oxo-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1 -c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid and stirred for 12 hours at room temperature. The obtained suspension is filtered, and the obtained colorless powder is washed with ethanol and diethyl ether. 8.7 g (96%) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-11,11a-dihydro-8H are obtained, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid with m.p. >260°.

c) A solution of 8.5 g (16.8 mmol) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-11,11a-dihydro- 8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepine-1-carboxylic acid in 70 g of poly-phosphoric acid is stirred for 1.5 hours at 100°. After cooling to room temperature, the mixture is poured into 300 ml of ice water with good stirring, after which solid sodium carbonate is added until pH=8. Extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20:1) gave 6.8 g (88%) of (S)-2-[5-(8-oxo-11,11a-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 colorless powder with m.p. >250°.

d) Suspension of 2.5 g (5.4 mmol) (S)-2-[5-(8-oxo-11,11a-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 is added dropwise at 70° to 30 ml of methylamine (33% in ethanol) and stirred for one hour at 70°. The resulting precipitate is filtered off while hot, and the resulting yellowish powder is washed with ethanol until it becomes colorless. 1.18 g (66%) of (S)-1-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a] is obtained imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colorless powder with m.p. 233-235°.

Example 257

a) Suspension of 7.0 g (24 mmol) ethyl ester of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine- 13 ml of hydrazine hydrate is added to 3-carboxylic acid in 70 ml of ethanol and the mixture is heated for 3 hours at reflux. After cooling to 0°, the obtained crystals are filtered, 6.5 g (97%) of hydrazide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f ][1,4]diazepine-3-carboxylic acids as colorless needles with m.p. >260°.

b) A solution of 4.74 g (23.12 mmol) of N-phthaloylglycine in 35 ml of dimethylformamide was mixed at room temperature with 3.9 g (24.07 mmol) of 1,1'-carbonyldiimidazole and then heated to 50°. After 30 min, it is cooled to room temperature, and 6.53 g of hydrazide 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1, 4]diazepine-3-carboxylic acid and stirred for 12 hours at room temperature. The obtained suspension is filtered, and the obtained colorless powder is washed with ethanol and diethyl ether. 10.4 g (97%) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-5-methyl-6-oxo-5,6- of dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid with m.p. >260°.

c) A solution of 5 g (10.8 mmol) of hydrazide (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-5-methyl-6-oxo-5, Mix 6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylic acid in 35 g of polyphosphoric acid for 1.5 hours at 100°. After cooling to room temperature, the mixture is poured into 300 ml of ice water with good stirring, after which solid sodium carbonate is added until pH=8. Extraction with methylene chloride and chromatography (silica gel, methylene chloride/methanol 20:1) gave 4.3 g (89%) of (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-isoindol- 1,3-dione as a colorless powder with m.p. 262-264°.

d) Suspension of 4.3 g (5.4 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 70° add 60 ml of methylamine (33% in ethanol) dropwise and stir for one hour at 70°. The resulting precipitate is filtered off while hot, and the resulting yellowish powder is washed with ethanol until it becomes colorless. 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-one as a colorless powder with m.p. 217-219°.

Example 258

Solutions of 0.632 g (2 mmol) 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-one in 20 ml of dimethylformamide is added with 1.1 ml (12 mmol) of propyl bromide, after which it is stirred for 12 hours at 70°. Dimethylformamide is evaporated, and the residue is partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 20:1) gave 0.395 g (49%) of 3-(5-dipropyl-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-one as a colorless foam, Rf=0.33 (silica gel, ethyl ester-acetic acid /methanol 20:1).

Example 259

Solutions of 0.500 g (1.58 mmol) 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-one is added to 40 ml of methylene chloride, 2 ml (1.5 mmol) of N-ethyldiisopropylamine and 0.97 ml (8 mmol) of allyl bromide, after which it is stirred for 12 hours at 70° . The reaction solution is diluted with methylene chloride and washed with 2N sodium carbonate solution. The aqueous phase is washed twice with methylene chloride, and the organic phases are dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl ester-acetic acid/methanol 10:1) gave 0.510 g (81%) of 3-(5-diallylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5, 6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colorless foam, Rf=0.54 (silica gel, ethyl ester-acetic acid/methanol 10:1).

Example A

(S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-9-one, 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H -imidazo[1,5-a][1,4]benzodiazepine-6-one or another compound, initially as a particularly prominent compound, which can be used as an active substance for the production of injection solutions with the following content:

active substance 1 mg

1n HCl 20 μl

acetic acid 0.5 mg

NaCl 8 mg

benzene-alcohol 10 mg

1n NaOH q.s.ad pH 5

H2O q.s. ad 1 ml

Claims (28)

1. Imidazodiazepines of the general formula, indicated by that [image] Means A together with both carbon atoms marked with α and β one of the residues [image] Q one of the rest [image] R1 and R2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, 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, or together with the nitrogen atom a 5- to 8-membered hetercycle, which in this case contains one further heteroatom or a post-condensed benzene ring, R3 hydrogen and R4 lower alkyl or R3 and R4 together are one di- or trimethyl group and R5 and R6 are each independently hydrogen, halogen, trifluoromethyl, lower alkoxy or nitro, wherein the carbon atom is marked with γ, which shows the S-configuration, if R3 is something other than hydrogen, and from that, addition-salts of acids applicable in pharmacy. 2. Compounds according to claim 1, characterized in that Q stands for the residue Q2. 3. Compounds according to claim 1, characterized in that Q means the residue Q3. 4. Compounds according to one of claims 1 to 3, characterized in that R1 and R2 are each lower alkyl, lower hydroxyalkyl or (C3-C6)-cycloalkyl-lower alkyl or together with the nitrogen atom piperidino or isoindolin-2-yl. 5. Compounds according to one of claims 1-4, characterized in that A is a residue A1 or A2, R5 is hydrogen, chlorine, fluorine, trifluoromethyl or lower alkoxy and R6 is hydrogen or fluorine. 6. Compounds according to one of claims 1-5, characterized in that R3 is hydrogen and R4 is methyl or R3 and R4 together are dimethylene. 7. A compound indicated by the fact that 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-a ][1,4]benzodiazepine-6-one. 8. A compound indicated by the fact that (S)-8-chloro-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto [2,1 -c]imidazo[1,5-a][1,4]benzodiazepine-9-one. 9. A compound characterized by the fact that (S)-1-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-one. 10. A compound characterized by the fact that 8-fluoro-5-methyl-3-[5-(piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo [1,5-a][1,4]benzodiazepine-6-one. 11. A compound characterized by the fact that (S)-1-(5-diallylaminomethyl-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-one. 12. A compound indicated by the fact that 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a] [1, 4]benzodiazepine-6-one. 13. A compound characterized by the fact that 3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo [1,5-c ][1,4]benzodiazepine-6-one. 14. A compound indicated by the fact that 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-one. 15. A compound indicated by the fact that (S)-8-chloro-1-[5-(piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H, 11H-Azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-9-one. 16. A compound characterized by the fact that 7-fluoro-5-methyl-3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-4H-imidazo [1,5-a ][1,4]benzodiazepine-6-one. 17. A compound characterized by the fact that 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-one. 18. A compound characterized by the fact that 7-chloro-3-(5-dipropylaminomethyl-1,3,4-oxadiazo-2-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a ][1,4]benzodiazepine-6-one. 19. A compound characterized by the fact that (S)-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo [5,1-c]thieno[3,2-e][1,4]diazepin-8-one. 20. (S)-H5-dibutylaminomethyl-1,3,4-oxadiazol-2-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno [3,2-e][1,4]diazepin-8-one: 21. A compound characterized by the fact that 3-(5-diisopropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1, 4]benzodiazepine-6-one. 22. A compound characterized by the fact that 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-one. 23. A compound characterized in that (S)-1-(5-diallylaminomethyl-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-one; (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-trifluoromethyl-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-9-one; 3-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine -6-one; 8-fluoro-3-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4 ]benzodiazepine-6-one; and (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c] thieno[3,2-e][1,4]diazepin-8-one. 24. Compounds A compound characterized in that 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo [1,5-a]thieno[ 2,3-f][1,4]diazepin-6-one; 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine -6-one; and (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1, 5-a][1,4]benzodiazepine-9-one. 25. Medicines, especially anxiolytic and/or anticonvulsant and/or muscle-relaxant and/or sedative-hypnotic agents, Compound characterized in that they contain a compound according to one of claims 1-24 and a therapeutically inert carrier. 26. Processes for the production of compounds according to one of claims 1-24, characterized in that a) one reactive functional derivative of one carboxylic acid of the general formula [image] with one amidoxime of the general formula [image] or with one hydrazide of the general formula [image] in which A, R 3 and R 4 have the above meaning, and R 11 and R 21 are each independently lower alkyl, lower alkenyl, lower alkynyl, lower-alkoxy-lower alkyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl -lower alkyl, di-lower alkylamino-lower alkyl or aryl-lower alkyl or together with a nitrogen atom denotes a 5- to 8-membered heterocycle, which in this case contains one further heteroatom or one post-condensed benzene ring, reacts or b) one compound of the general formula [image] in which A, R3 and R4 have the meaning given in claim 1, and X means a leaving group in the presence of a base reacts with one isonitrile of the general formula [image] wherein Q has the meaning set forth in claim 1 and R 11 and R 21 have the above meaning, reacts, or c) one compound of the general formula [image] in which A, Q, R 3 and R 4 have the meanings given in claim 1 and Y means a leaving group reacting with an amine of the general formula [image] in which R1 and R2 have the meaning specified in claim 1 reacts, or d) from some compound of the general formula [image] in which A, Q, R3 and R4 have the meaning stated in claim 1, and R7 denotes one protecting group, protected lower hydroxyalkyl, protected amino-lower alkyl or protected lower alkylamino-lower alkyl and R8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, protected lower hydroxyalkyl, 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 or aryl-lower alkyl or R7 and R8 together mean one protecting group, protecting group (n) which is removed, or e) a compound of the general formula [image] wherein A, Q, R 3 and R 4 have the meaning set forth in claim 1 and R 12 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower hydroxyalkoxy, n/i alkoxy-lower alkyl, (C3-C6)-cycloalkyl, ( C3-C6)-cycloalkyl-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkyl-amino-lower alkyl or aryl-lower alkyl, correspondingly N-alkylated, or f) a compound of the general formula [image] in which A, Q, R3 and R4 have the meaning stated in claim 1, and R12 has the above meaning, and R22 means lower alkenyl or lower alkynyl, it is also reduced if desired g) the compound of the general formula I is converted into a pharmaceutically applicable acid addition salt. 27. Compounds according to one of claims 1-24 characterized in that they are used as therapeutically active substances, in particular as anxiolytic and/or anticonvulsant and/or muscle-relaxing and/or sedative-hypnotic active substances. 28. Use of compounds according to one of claims 1-24, characterized by the production of anxiolytic and/or anticonvulsant and/or muscle-relaxing and/or sedative-hypnotic agents.