DE3724164A1 - Novel 1,4-benzodiazepines, their preparation and use - Google Patents

Abstract

The novel 1,4-benzodiazepines of the formula Ia or Ib, which are shown in the description, can be prepared by customary methods and are suitable as active compounds for medicaments.

Description

The invention relates to new 1,4-benzodiazepines, their Manufacture according to usual methods and their use as Drugs and as intermediates.

The new 1,4-benzodiazepines correspond to the formulas

wherein
For one of the groups
(a) -OX-CO-OR₄
(b) -OX-CO-R₅
(c) -OY-R₆
(d) -Z-CO-OR₄
(e) -Z-CO-R₅

R₁ for hydrogen; for C₁-C₄-alkyl or for C₃-C₆-cycloalkyl; or, if R is the group (d), (e) or (f), also for C₁-C₄ alkoxy or halogen; R₂ for phenyl, for one or more methyl, halogen, nitro, trifluoromethyl or, if R is the group (d), (e) or (f), also phenyl substituted by methoxy; or for α- pyridyl; R₃ is hydrogen or C₁-C₄ alkyl; R₄ represents a C₁-C₆ alkyl group substituted by a mono- or di- (C₁-C₃-alkyl) amino group; for C₃-C₇-cycloalkyl, which in the case of the 5- or 6-ring can also contain a <N (C₁-C₄-alkyl) group as a ring member and which in the case of the C₇-cycloalkyl can also have a <NCH₃ bridge ; or, if R represents the group (a) or (d), also for hydrogen or C₁-C₆-alkyl; R₅ for one of the groups

R₆ for one of the groups or the group listed under R (f), wherein Z represents a single bond; R₇ and R₈ (independently of one another) for hydrogen; for C₁-C₆ alkyl, allyl or propargyl; and, if R₇ is hydrogen or methyl, R₈ also for C₃-C₆-cycloalkyl, aryl, aralkyl or one of the groups or, if R represents group (b), also for one of the groups -CHR₃-COO- (C₁-C₄-alkyl) or

R₉ and R₁₀ (independently of one another) for hydrogen; for C₁-C₆ alkyl; in addition (together with the nitrogen atom of the group -NR₉R₁₀) for an optionally mono- to tetra-methyl-substituted saturated five- or six-membered ring, which may also contain a further heteroatom (O, S, NR₃); R₁₁ for C₁-C₄ alkyl, aryl or aralkyl; R₁₂ for hydrogen or methyl, one of the radicals R₁₂ optionally also for -CO-O (C₁-C₆-alkyl), R₁₃ for hydrogen; for an optionally hydroxy or amino substituted C₁-C₆ alkyl; for a CO-O (C₁-C₄-alkyl) - or a CO-N- (C₁-C₄-alkyl) ₂ group; R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ (independently of one another) for hydrogen; for an optionally hydroxy or amino substituted C₁-C₆ alkyl; or for phenyl; A and B (independently of one another) for N, CH or C-CH₃, but not both for CH or C-CH₃, D for (CR₁₇R₁₈) _n ; Q for O, S, NH or N (C₁-C₆ alkyl); E for O, S, NR₁₁, CH₂ or a single bond; X for C₁-C₆ alkylene; Y for C₂-C₆ alkylene; Z for C₁-C₆ alkylene, a single bond or the group OCH₂, where the oxygen is bonded to the benzene ring; k for 1, 2, 3 or 4; m for 2 or 3; n for 0, 1 or 2; can stand

optionally in the form of the racemates, the enantiomers, Diastereomers and their mixtures; each as free bases or as acid addition salts, optionally also as quaternized compounds.

In the definitions above and below means "Aryl" one, if necessary, one or more times substituted phenyl, pyridyl, thienyl or furyl radical, where one or more atoms from the Halogen, methyl, methoxy, trifluoromethyl group are present can. "Aralkyl" is a group of aryl- (C₁-C₃-alkyl), where aryl has the above meaning. The carbon chains in the alkyl, alkoxy and alkenyl radicals, also so far these components of other residues can be straight-chain or be branched. With multiple substitution can same or different substituents side by side are available.

"Halogen" includes fluorine, chlorine, bromine and iodine Roger that; fluorine, chlorine and bromine are preferred, especially chlorine and bromine.

Of the alkyl residues (also as far as they are components of others Residues are) methyl and ethyl are particularly important before all methyl.

Within the definitions for the individual symbols are highlight the following meanings:

A and B nitrogen or A CH group and B nitrogen;

R₁: methyl, methoxy and cyclopropyl; R₂2 chlorophenyl; R: preferably linked to the ring system in the 8-position; for groups (a) to (g) the following applies in particular:
in (a): X is C₁-C₃ alkylene,
R₄ in the above meaning, except hydrogen and C₁-C₆ alkyl;
at (b): X is C₁-C₃ alkylene
R₅ is -NR₇R₈ with R₇, R₈ is hydrogen or C₁-C₄-alkyl;
or R₇ is H and R₈ is C₂-C₃-alkyl substituted by N-morpholino or 2,6-dimethylmorpholino;
or
R₅ equal wherein
E is O, N-methyl, CH₂; where E is O, R₁₂ is preferably methyl and k is 2, the methyl groups being in the 2- and 6-position, while for E is CH₂ R₁₂ is especially COOC₂H₅;
at (c): Y is C₁-C₃ alkylene,
R₆ phthalimido or NR₉R₁₀ and R₉ / R₁₀ are H or C₁-C₄-alkyl or NR₉R₁₀ is morpholino, optionally methyl-substituted;
in (d): Z is preferably a single bond,
R₄ in the above meaning, except hydrogen and C₁-C₆ alkyl;
in (e): Z is preferably a single bond,
R₅ NR₇R₈ with R₇ equal to H, at (f): Z is preferably a single bond, likewise D (n = 0), R₁₃ / R₁₄ methyl, R₁₅ / R₁₆ hydrogen,
in (g): X is preferably -CH₂- or -CH₂-CH₂-

The new compounds can be made according to known methods Processes are made.

1. For the preparation of compounds of formula Ia, wherein R is the group
(a): -OX-CO-OR₄ means the compounds of the formula

wherein A, B, R₁ and R₂ have the above meaning, with compounds of the formula

Halogen-X-COOR₄ (III)

(Halogen is bromine or chlorine, X and R₄ as above defined) implemented.

The implementation takes place e.g. B. in a manner known per se, in the presence of a base, e.g. B. potassium carbonate, optionally with the addition of catalytic amounts Sodium or potassium iodide, in an organic Solvents such as acetone, ethyl methyl ketone, Dimethylformamide etc. The applied Reaction temperatures are dependent on Solvent between room temperature and the Boiling temperature of the solvent used.  The compounds of formula II are known or can can be obtained by conventional methods.

The compounds of general formula II are, for. B. from Compounds of the general formula

wherein A, B, R₁ and R₂ have the above meaning, by ether cleavage, e.g. B. with pyridine hydrochloride or Hydrobromic acid. The implementation takes place in a manner known per se Pyridine hydrochloride in the melt at 100-200 ° C, preferably at 150-180 ° C or with hydrobromic acid, preferably with 60% aqueous hydrobromic acid, in the boiling point.

The compounds of general formula IV are partially known or can be analogous to known Processes are made.

Starting from the carboxylic acid esters V of the general Formula Ia with R = -Z-COOR ′ or R = -O-X-COOR ′ (R ′ = lower alkyl) can the corresponding carboxylic acids by saponification, e.g. B. with NaOH or KOH in ethanol, be preserved.

This carboxylic acid ester V and the corresponding acids are also valuable starting points for introduction other functional groups.  

2. To prepare the compounds of formula Ia, wherein R is for the group
(b): -OX-CO-R₅ or (e): -Z-CO-R₅, the corresponding carboxylic acids with the groups -OX-COOH or -Z-COOH or reactive derivatives thereof with the corresponding amines of the formula

or implemented with ammonia.

The conversion into a carboxylic acid chloride is preferred or acid anhydride or the conversion of the acid into Presence of carbonyldiimidazole, sulfonyldiimidazole, Cyclohexylcarbodiimide.

The free acid is reacted with the amine in Presence of a carbodiimide, for example of Cyclohexylcarbodiimide, carbonyldiimidazole or Sulfonyldiimidazole in an inert solvent such as Dimethylformamide, tetrahydrofuran, dioxane or halogenated hydrocarbons at temperatures between 0 ° C and the boiling point of the reaction mixture.

In the reaction of the amine with an acid halide or acid anhydride, the amine becomes inert Solvents, for example dimethylformamide, Tetrahydrofuran, dioxane or a suitable Hydrocarbon such as toluene at temperatures between  Room temperature and the boiling point of the Reaction mixture with the acid halide or Acid anhydride implemented, where appropriate acid-binding agent such as sodium carbonate, Sodium bicarbonate or a tertiary organic base, for example pyridine or triethylamine added becomes.

If the amine is a liquid, the reaction can also be carried out in an excess of the amine done without additional solvents.

The acid halide or acid anhydride is obtained from the free acid in the usual way, e.g. B. by reaction the acid with a thionyl halide or through Reaction of an alkali salt of the acid with Acetyl chloride or chloroformic acid chloride.

Using the same methods, the carboxylic acids also the carboxylic acid esters of the formula according to the invention V are manufactured. The alcohols can also in Form of alcoholates are used.

3. For the preparation of the compounds of formula Ia, wherein R is the group
(c): -OX-R₆ means compounds of the formula II with compounds of the formula

Halogen-Y-R₆ (VIII)

wherein Y and R₆ have the above meaning and halogen chlorine is preferably implemented.

The reaction is preferably carried out in the presence of a acid-binding agents, e.g. B. potassium carbonate, in one  suitable organic solvents, e.g. B. acetone, Ethyl methyl ketone or DMF.

The compounds of formula VIII can also be in the form their acid addition salts are used. Also can the compounds of formula VIII instead of halogen also contain another usual leaving group.

The compounds of formula VIII are known or according to usual methods available.

4. For the preparation of compounds of formula Ia, R the group
(c): -OY-R₆ and R₆ NH₂ means, corresponding phthalimido compounds of hydrazinolysis, for. B. in ethanol.

5. For the preparation of compounds of formula Ia, wherein R the group (f):

means, or such compounds of group R (c), in where R₆ stands for (IX), one uses carboxylic acids of the formula

wherein A, B, R₁ and R₂ have the above meaning and W stands for -Z-COOH or -O-X-COOH (Z and X as above defined), with a bisfunctionalized amine, e.g. B. an amino alcohol, an aminomercaptan or one Diamine in the presence of triphenylphosphine, Carbon tetrachloride and a tertiary organic Base in acetonitrile.

The reaction takes place in the temperature range between 0 ° C and the boiling point of the reaction mixture is preferred between 0 ° C and room temperature.

6. Compounds of formula Ia, wherein R is group IX or (c) has the corresponding meaning and Q You get oxygen or sulfur, too the corresponding hydroxy-functionalized Carboxamides by ring closure reaction with Thionyl chloride in an organic solvent, e.g. B. Methylene chloride and optionally subsequent Sulfurization to thiazoline.

This can be done with phosphorus pentasulfide or Lawesson-Reagenz®.

7. For the preparation of compounds of formula Ia, wherein R the group (f) or the group (c), wherein R₆ is is a radical of the formula IX, where Q is NH or N (C₁-C₆ alkyl) is, compounds of the formula Ia with R in the meaning Z-CN or -O-Y-CN about the imidoethyl ester hydrochloride by reaction with an appropriate diamine implemented (Pinner reaction).

Imidoethyl ester hydrochloride is formed  by treating the nitrile with an excess ethanolic hydrochloric acid. The resulting crystalline The crude product is dissolved in ethanol with the diamine (e.g. Ethylenediamine) first under ice cooling, then under Reflux conditions implemented. Its amino function can be alkylated in the case of N-H by known methods will.

Compounds of formula Ia with R equal to -Z-CN or -O-Y-CN is obtained e.g. B. from the corresponding Carboxamides by reaction with phosphorus oxychloride in an inert organic solvent, e.g. B. Dichloroethane under reflux.

8. For the preparation of such compounds of formula Ia, in which R₁ is halogen, can also be appropriate Compounds with R₁ equal to hydrogen in the usual way Way halogenated.

9. For the preparation of compounds of formula Ib with R is equal to one of groups (a) to (e) and R₃ Hydrogen or C₁-C₄ alkyl are the corresponding compounds of formula Ia according to the usual Methods reduced and, to manufacture the Compounds with R₃ is alkyl, then alkylated.

10. Preparation of compounds of formula Ia by ring closure reaction in the case of a compound of the formula

wherein R = -Z-COOR 'or -O- (C₁-C₄) alkyl
Compounds of the general formula Ia which contain a [1,5-a] linked imidazole ring (A nitrogen and B = CH) can be described, for example, in analogy to those in DE-OS 25 40 522 or the Dutch patent application 78 03 585, getting produced.

11. For the preparation of compounds of formula Ib, wherein R represents the rest of the formula IX, is used Functionalized compounds of formula Ib in which R represents group (d) with suitable Reaction partners around.

12. Compounds of the general formula Ia

is obtained from compounds of the general formula Ia with R-OH by reaction with a compound of formula

in the presence of a base. The deprotonation of the hydroxy compounds with the  Base, e.g. As sodium hydride, potassium carbonate or a Alcoholate is carried out in an inert solvent, such as. B. Tetrahydrofuron, methylethyletone, acetone, dimethylformamide or suitable hydrocarbons at one temperature between -10 ° C and the boiling point of the reaction mixture, preferably at room temperature, optionally below Shielding gas. Then the Halogen compounds with subsequent workup known methods.

As far as the compounds of the invention are asymmetrical have substituted carbon atom, they can according to known methods in their optically active antipodes be separated into several asymmetry centers in the Diastereomers and their pairs of antipodes.

If desired, from the compounds obtained, insofar as they are bases, the acid addition salts, insofar as they are Acid addition salts are the bases according to the usual ones Process manufactured.

The raw materials used in the various processes are known or in usual methods To produce analogy processes.

The compounds of the invention have PAF antagonistic effect. It is known that PAF (platelets Activating factor) around the phospholipid Acetyl-glyceryl-ether-phosphoryl-choline (AGEPC), which as potent lipid mediator known from animal and human pro-inflammatory cells is released. Basophils are mainly found among such cells and neutrophils, macrophages (from blood and Tissue) as well as platelets involved in inflammatory reactions involved.  

PAF shows in pharmacological experiment Bronchoconstriction, lowering blood pressure, triggering one Platelet aggregation as well as pro-inflammatory Effect.

These experimentally demonstrable effects of PAF demonstrate directly or indirectly on possible functions of this Mediators in anaphylaxis, in the phatophysiology of the Bronchial asthma and general inflammation.

PAF antagonists are needed for more on the one hand pathophysiological functions of this mediator in animals and educate people and on the other hand pathological Conditions and diseases in which PAF is involved to treat. Examples of the indications of a PAF antagonists are inflammatory processes of the Tracheobronchial tree (acute and chronic bronchitis, Bronchial asthma) or the kidney (glomerulonephritis), of the joints (rheumatic diseases), anaphylactic Conditions, allergies and inflammation in the area of Mucous membranes and the skin (e.g. psoriasis) as well as through Sepsis, endotoxins or burns related Shock conditions. Other important indications for one PAF antagonists are lesions and inflammation in the area the gastric and intestinal mucosa, such as B. gastritis, in general peptic ulcer, but especially ulcer ventriculi and duodenal ulcer.

Furthermore, the compounds according to the invention are suitable for treatment in the following indications: Obstructive pulmonary diseases, such as, for. B. bronchial hyperreactivity, inflammatory lung diseases, such as. B. chronic bronchitis;
Cardiovascular diseases, such as B. polytrauma, anaphylaxis, arteriosclerosis, inflammatory bowel diseases, EPH gestosis (ederma-proteinuria hypertension), diseases of the extracorporeal circulation, ischemic diseases, inflammatory and immunological diseases, immunomodulation during transplantation of foreign tissues, immunomodulation against leukemia.
Metastatic spread z. B. in bronchial neoplasia, diseases of the CNS, such as. As migraines, agarophobia (panic disorder), furthermore, the compounds according to the invention prove to be cytoprotective and organoprotective, e.g. B. for neuroprotection, e.g. B. for cirrhosis of the liver, DIC (disintegrated intravascular coagulation):
Side effects of drug therapy, e.g. B. anaphylactoid circulatory reactions, contrast medium incidents, side effects in tumor therapy; Intolerance to blood transfusions; fulminant liver failure (CCl₄ intoxication) amanitaphalloides intoxication (tuberous leaf poisoning); Symptoms of parasitic diseases (e.g. worm diseases)

New additional indication: immune function in AIDS, Diabetes, juvenile diabetes, diabetic retinopathy, polytraumatic shock, hemorrhagic shock, CNS: Isemia, multiple sclerosis.

PAF-associated interaction with tissue hormone (autocoid hormones), lymphokines and other mediators.

The PAF-antagonistic effects of individual benzodiazepines is known, cf. E. Kornecki et al, Science 226, 1454-1456 (1984). For alprazolam was after the below described an IK₅₀ (concentration at a 50% inhibition of aggregation) of 14 µM, for triazolam measured an IK₅₀ of 9 µM. This, as a tranquilizer or hypnotics shown and in stores  located connections are however because of their pronounced sedative effect despite its relatively good PAF antagonistic effect for use as PAF antagonists in therapy in many cases not suitable.

In contrast, the compounds according to the invention are absent sedative effectiveness, while the PAF-antagonistic Effect compared to that of the known benzodiazepines is at least much better.  

The following are the pharmacological Test methods communicated:

Pharmacological test methods

The PAF-antagonistic activity of some compounds Formula I was based on the inhibition of Platelet aggregation in vitro and antagonization the bronchoconstriction caused by PAF on anesthetized guinea pigs, lowering blood pressure at the anesthetized rat and cuticle on the rat examined. In addition, these connections with regard to possible side effects on the central Nervous system checked.

1. In vitro investigations: inhibition of Platelet aggregation

To determine the PAF antagonistic effect of Substances became the aggregation induced by PAF of human platelets used in vitro. For extraction of platelet-rich plasma (TRP) Withdraw blood from an undamaged vein with the help a plastic syringe containing 3.8% Sodium citrate solution. The relation between Sodium citrate solution and blood is 1: 9 the citrate blood is carefully mixed Centrifuge 150 x g (1200 rpm) for 20 minutes. The Platelet aggregation is measured after methods developed by Born and Cross (G.V.R. Born and M. J. Cross, J. Physiol. 168, 178 (1963)), with the TRP with constant stirring PAF as a trigger is added to the aggregation.  

The test substance is added in a volume of 10 µl 2-3 minutes before the aggregation is triggered. Either aqua is used as a solvent. dist., ethanol and / or dimethyl sulfoxide. Control batches contain appropriate volumes of these solvents. After registration of the initial absorption (2-3 minutes) the aggregation is induced with PAF (5 × 10 ^-8 ).

The maximum is used to assess substance effects the first wave of aggregation. The through PAF induced maximum absorption rate (= maximum Aggregation × 100%) is done simultaneously in one Parallel approach (= control approach in one of the channels of the 2-channel aggregometer) for each test batch (second Channel) also checked and used as 100% value.

The reached under the influence of the test substance The aggregation value is given as 100%.

Each test substance is examined at concentrations of 10 ^-3 to 10 ^-8 M with a sample size of n = 4 in each case with regard to an inhibitory effect on the platelet aggregation induced by PAF. Then a concentration-effect curve is created based on 3 concentrations and the IK ermittelt (concentration with a 50% inhibition of aggregation) is determined. The IK values of compounds of the general formula I are generally around values which are less than 9 μM.

2. In vivo studies 2.1. Antagonization of the bronchoconstriction caused by PAF on anesthetized guinea pigs

Spontaneously breathing male, 300-450 g heavy Guinea pigs are 1 hour before an i. v. Infusion of PAF (30 ng / (kg × min)) with the Test substance or a control vehicle orally pretreated. The experimental animals are then with 2 mg / kg urethane anesthetized intraperitoneally, whereupon the jugular vein, the carotid artery and the trachea can be cannulated. The PAF infusion induced in the control animals a strong, persistent bronchoconstriction that based on respiratory volume, compliance and the resistance is measured and also one Lowering blood pressure. After 7-10 minutes death occurs. With the described PAF antagonists can have these effects on breathing and blood pressure as well as the onset of death be prevented.

2.2.Antagonization of those caused by PAF Lowering blood pressure in the anesthetized rat

Normotone, male, 200-250 g Wistar rats are treated with 2 mg / kg urethane Anesthetized intraperitoneally. The artery The carotid and jugular veins are cannulated. An intravenous infusion of PAF (30 ng / (kg × min)) induces a strong, persistent drop in blood pressure. This can dose-dependent through intravenous injections (culmulative administration) of the described  Connections are canceled. Oral too or intravenous administration of the compound Beginning of the PAF infusion can lower the blood pressure Effect of the above-mentioned PAF infusion prevent dose-dependent.

2.3. Antagonizing those induced by PAF Quaternium on the rat (Modified from P. P. Koelzer and K. H. Wehr, drug research. 8th, 181 (1958))

An intracutaneous injection of PAF induced a cuticle that expresses one through PAF conditional increase in vascular permeability.

Male Wistar rats with a body weight the abdominal wall (short) of 250 ± 20 g sheared. Then 1 ml / kg of a 1% Trypan blue solution through a tail vein Animals injected. Symmetrical to the center line (linea alba) are in three places at intervals of about 1.5 cm intracutaneous injections of physiological saline or PAF solution (12.5 to 15.0 ng / site in 0.1 ml). While at the injection site Saline no reaction occurred PAF is a skin reaction (wheal) caused by a Blue color of different intensity - depending on the PAF dose - became visible. By simultaneous intracutaneous administration of the described compounds or one by intravenous pretreatment could be done by PAF induced skin reactions can be prevented.  

3. Effects on the central nervous system

It is well known that substances of this Structure types cause central nervous effects that however, for a compound with PAF-antagonistic Effect are not desired. Therefore, the described connections with regard to their hypnogenic and anticonvulsant effects as well as their Impact on the locomotion checked. A possible Hypnotic effects were seen on 400 to 450 g Guinea pigs examined. Doses up to 200 mg / kg p. O. of these substances were unable to produce one hypnotic or sedative effects on these animals too produce.

To test an anticonvulsant effect, the Pentetrazole antagonism in mice (20 to 25 g Body weight) can be used (M. I. Gluckmann, Current Therapeutic Research, 7: 721, 1965). Cans up at 100 mg / kg p. o. of these connections (1 hour before Pentetrazole) showed no influence in this test by pentetrazole (125 mg / kg i.p., LD 100) induced mortality.

The effect on night motility (locomotion) of Mice (20-25 g body weight) can be in one Photo cell cage to be examined. The Number of light beam interruptions measured. Cans up to 300 mg / kg p. o. of the above connections show no activity.  

In the table below are the PAF values and values for the flunitrazepam binding test of some inventive and some known compounds specified.

Table A

(A) to (m) are as follows Links:  

According to formula Ia

(with R₁ equal to CH₃, R₂ equal to 2-chlorophenyl)

According to formula Ib

The new compounds of the general formulas Ia or Ib can be topical, oral, transdermal, parenteral or through Inhalation can be administered. The connections are here as active ingredients in common Dosage forms before, for. B. in compositions in essentially from conventional pharmaceutical carriers and / or excipients and an effective dose of Active ingredient exist, such as. B. tablets, coated tablets, Capsules, wafers, powders, solutions, suspensions, Inhalation aerosols, ointments, emulsions, syrups, Suppositories. An effective dose of the invention Connections is between 1 and 50 when used orally, preferably between 3 and 20 mg / dose, with intravenous or intramuscular use between 0.01 and 50, preferably between 0.1 and 10 mg / dose. For the Inhalation should be solutions that are 0.01 to 1.0, preferably Contain 0.1 to 0.5% active ingredient can be used.

The following are examples of some pharmaceutical Compositions using compounds of the general formula Ia or Ib as an active ingredient specified. Unless expressly stated otherwise, the parts are parts by weight.  

1. tablets

The tablet contains the following components:

Active ingredient according to formula Ia / Ib 0.020 parts Stearic acid 0.010 parts Dextrose a total of 1,920 parts

Manufacturing:

The substances are mixed together in a known manner and compresses the mixture into tablets, each of which Weighs 1.92 g and contains 20 mg of active ingredient.

2. Ointment

The ointment consists of the following ingredients together:

Active ingredient according to formula Ia / Ib50 mg Neribas ointment (merchandise Scherax) ad 10 g

Manufacturing:

The active ingredient is triturated with 0.5 g of ointment base and the rest of the base in 1.0 g increments and mixed intimately into an ointment. You get a 0.5% ointment. The distribution of the active ingredient in the basis becomes optical under the microscope controlled.  

3. Cream

composition
Active ingredient according to formula Ia / Ib50 mg Neribas ointment (commercial product Scherax) ad 10 g

Manufacturing

The active ingredient is triturated with 0.5 g of cream base and the rest of the base in 1.0 g increments and after incorporated with pestle. You get one 0.5% cream. The distribution of the active substance in the The basis becomes optical under the microscope controlled.

4. Ampoule solution

Composition:
Active ingredient according to formula Ia / Ib 1.0 mg sodium chloride 45.0 mg aqua per inj.ad 5.0 ml

Manufacturing:

The active ingredient is at its own pH or optionally at pH 5.5 to 6.5 dissolved in water and sodium chloride as Isotonance added. The solution obtained is filtered pyrogen-free and the filtrate under aseptic Conditions filled into ampoules, which are then sterilized and melted. The ampoules contain 1 mg, 5 mg and 10 mg of active ingredient.  

5. Suppositories

Each suppository contains:
Active ingredient according to formula Ia / Ib 1.0 part cocoa butter (mp 36-37 ° C) 1200.0 parts carnauba wax 5.0 parts

Manufacturing

Cocoa butter and carnauba wax melted together. The active ingredient is added at 45 ° C add and stir until a complete dispersion arose.

The mixture comes in appropriate sized shapes poured and the suppositories packed appropriately.

6. Inhalation solutions

Composition:
a) Active ingredient according to formula Ia / Ib 500 mg Na-EDTA 50 mg benzalkonium chloride 25 mg sodium chloride 880 mg distilled water 100 ml

Manufacturing:

96% of the amount of water are presented in it successively Na-EDTA, benzalkonium chloride, Sodium chloride and active ingredient clearly dissolved and with the rest of the water. The solution is in Bottled 20 ml dropper bottles. One dose (20 drops, 1 ml) contains 5 mg of active ingredient.  

b) Active ingredient according to formula Ia / Ib500 mg Sodium chloride 820 mg distilled water ad 100 ml

Manufacturing

96% of the amount of water are presented in it successively dissolved the active ingredient and sodium chloride, filled up with the remaining water and the solution in Can container (4 ml) filled. The solution contains 20 mg of active ingredient.

example 1 6- (2-chlorophenyl) -8- (2-imidazolin-2-yl) -1-methyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

3.5 g (11 mmol) 8-cyano-6- (2-chlorophenyl) -1-methyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine are mixed with 7 g a 30% ethanolic hydrochloric acid added and under Exclusion of moisture stored in the refrigerator for 6 days, occasionally shaking the suspension. Man is concentrated in a vacuum and processes the raw Imidoester hydrochloride directly on. To do this, you give up the residue 6 g (0.1 mol) ethylenediamine and heated 3 hours at 80 ° C. After cooling, dilute with Dichloromethane, washes several times with water, dries the organic phase and constricts.

The residue is recrystallized from ether

Yield 1 g of mp. 186-189 ° C.

The starting compound is obtained in the following way.

Starting from 2-acetamido-5-methyl-2'-chlorobenzophenone is obtained analogously to the instructions for 1,3-dihydro-5- phenyl-7-methoxycarbonyl-2H- [1,4] benzodiazepin-2-one (Sternbach et. Al. Helv. Chim. Acta 186, 1720 (1969)), 1,3-dihydro-5- (2-chlorophenyl) -7-methoxycarbonyl-2H- [1,4] benzodiazepin-2-one, mp. 245-248 ° C.

37.5 g (0.114 mol) of this benzodiazepinone are in 350 ml of pyridine with 32 g of phosphorus pentasulfide for 5 hours Heated to 65 ° C. The reaction mixture is then poured into 700 ml a 20% saline solution, then with water diluted and the precipitated benzodiazepine-2-thione filtered off and washed with ethanol. The raw product, 39 g, can be implemented without further purification.  Recrystallization from isopropyl ether leads to the thione of Mp 246-248 ° C.

39 g (0.113 mol) of the thione in 500 ml 10 g of hydrazine hydrate are added to tetrahydrofuran and 30 Minutes at room temperature. The suspension will Filtered through diatomaceous earth and concentrated to dryness. The The tube product is dissolved in 540 ml of anhydrous ethanol; after adding 106 ml of triethyl orthoacetic acid heated to reflux for 1 hour. To Evaporation of the solvent and recrystallization Ethyl acetate gives 33 g of 6- (2-chlorophenyl) - 1-methyl-8- (methoxycarbonyl) -4H- [1,2,4] triazolo [3,4-a] - [1,4] benzodiazepines, mp 169-173 ° C.

A pure analytical substance is obtained from Recrystallization from methanol / ether: mp 178-180 ° C.

The compound can also be derived from the benzodiazepine-2-thione Acetic acid hydrazide can be produced.

15 g (40 mol) 6- (2-chlorophenyl) -8-methoxycarbonyl-1- methyl- [1,2,4] triazolo [3,4-a] benzodiazepine are described in 750 ml of saturated methanolic ammonia solution 2 days touched. The precipitated carboxamide is filtered from: 9.7 g (69%) of mp. 308-310 ° C.

9.7 g (28 mmol) of 8-aminocarbonyl- (2-chlorophenyl) - 1-methyl- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine heated for 5 hours under reflux in a mixture of 150 ml Dichloroethane and 10 ml phosphorus oxychloride. You pour then on ice, separates the organic phase and washes them again with water. After usual The organic phase is worked up by Recrystallization from ethyl acetate 7 g (75%) of the cyanide m.p. 240-242 ° C.  

Example 2 6- (2-chlorophenyl) -8- (4,4-dimethyloxazolin-2-yl) -1-methyl-4H- [1,2,4] triazolo [3,4-a] [1,4] benzodiazepine

33 g (0.09 mol) of that described in Example 1 6- (2-chlorophenyl) -8-methoxycarbonyl-1-methyl-4H- [1,2,4] - triazolo [4,3-a] [1,4] benzodiazepines with 4.5 g (0.113 mol) sodium hydroxide in a mixture of 120 ml Water, 400 ml of tetrahydrofuran and 400 ml of methanol Boiling temperature saponified in 1 hour. You narrow it Mix in, take up with water and acidify with glacial acetic acid at. The precipitated crystals are isolated and dried.

Yield 28.6 g (90%) of 8-carboxy-6- (2-chlorophenyl) -1- methyl- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine, mp. 350-352 ° C.

1.75 g (5 mmol) of the benzodiazepine carboxylic acid thus obtained together with 0.45 g (mmol) 2-amino-2-methyl-1-propanol and 1.5 g (mmol) of triethylamine in a 10 ml mixture of anhydrous Pyridine / acetonitrile (1: 1) submitted. At room temperature 4 g of triphenylphosphine dissolved in 10 ml of same solvent mixture within 3 h. To The suspension is concentrated for 24 h and the residue is added Ether, then extracted with ethyl acetate, the extracts are combined and after distilling off the solvent Chromatographed silica gel (eluents: Dichloromethane / methanol 95/5). The clean fractions are crystallized from ether after evaporation. Yield: 1.5 g (75%) of mp 235-236 ° C.

The title link can also be accessed in the following ways:  1 g (2.3 mmol) 6- (2-chlorophenyl) -8 - [(1,1-dimethyl-2- hydroxyethyl)] aminocarbonyl] -1-methyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine are in 50 ml dichloromethane treated with 0.6 ml of thionyl chloride and 5 h Room temperature stirred. After concentration is with ice offset and made alkaline. You extract the Mix several times with dichloromethane and work the organic phase as usual. You crystallize it Residue from ether and receives 0.7 g (75%) of Dimethyloxazoline.

The above starting amide is obtained by implementing the im Example 1 described with carboxylic acid 2-Amino-2-methyl-propanol according to the known Carbonyldiimidazole process. Mp 172-175 ° C (hydrate)

Example 3 6- (2-chlorophenyl) -8- (4,4-dimethylthiazolin-2-yl) -1-methyl- 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

1 g (2.5 mmol) of those obtained in Example 2 Dimethyloxazoline compound is heated in 5 ml of xylene together with 2 g (9 mmol) of phosphorus pentasulfide. After this Cool down, dilute with dichloromethane and shake with Water out. The organic phase becomes as usual worked up. The residue is purified by chromatography on silica gel with eluent dichloromethane / methanol (95: 5). The clean fractions are made from ethyl acetate / ether recrystallized.

Yield 0.6 g (57%) of the thiazoline, mp. 235 ° C.  

Example 4 8-methoxycarbonyl-6- (2-chlorophenyl) -1-methyl-4H-imidazo- [1,2-a] [1,4] benzodiazepine

To 3.1 g (9 mmol) of 5- (2-chlorophenyl) -7-methoxy- carbonyl-1H, 3H- [1,4] benzodiazepine-2-thione in 60 ml anhydrous dioxane, 1.6 g of propargylamine and then heated under reflux for 3 hours and stirred another hour at room temperature. The one after pulling it off of the remaining solvent is in Dichloromethane / water added. The aqueous phase is extracted again with dichloromethane, the collected organic phases washed with water, the solvent removed and the residue from ethyl acetate / ether recrystallized. 2.1 g are obtained 5- (2-chlorophenyl) -7- (methoxycarbonyl) -3H-2-propargyl- amino- [1,4] benzodiazepine, mp 202-205 ° C.

1.6 g (4.37 mmol) of the compound thus obtained are dissolved in 7.5 ml of concentrated sulfuric acid at 100 ° C for 10 minutes heated. After cooling, pour on ice, alkalized with ammonia solution and extracted with dichloromethane.

The aqueous phase is adjusted to pH = 5 and that precipitated 8-carboxy-6- (2-chlorophenyl) -1-methyl- 4H-imidazo [1,2-a] [1,4] benzodiazepine filtered off and dried.

Yield: 1 g (65% of theory); Mp 295-297 ° C.

The organic phase is concentrated. 0.2 g is obtained (13% of theory) 8-methoxycarbonyl-6- (2-chlorophenyl) - 1-methyl-4H-imidazo [1,2-a] [1,4] benzodiazepine dated Mp 150-151 ° C.  

Example 5 a) 8- (3-Etoxycarbonyl-propyloxy) -1-methyl-6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

A suspension of 2 g (0.006 mol) of 8-hydroxy-1-methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo- [4,3-a] [1,4] benzodiazepine and 2.48 g of anhydrous potassium carbonate in 55 ml of ethyl methyl ketone is heated to reflux with stirring for one hour. The reaction mixture is allowed to cool, a solution of 1.29 g (0.0066 mol) of ethyl 4-bromobutyrate is added dropwise and the mixture is heated to boiling for a further seven hours. The solvent is distilled off in vacuo and the remaining residue is partitioned between water and methylene chloride. The organic phase is extracted successively with cold 5% sodium hydroxide solution and water, dried over sodium sulfate and concentrated in vacuo. 1.6 g (61% of theory) of the title compound of melting point 157-159 ° C. (ethyl acetate) are obtained.
C₂₃H₂₃ClN₄O₃ (438.93)

Calc .: C 62.94 H 5.28 Cl 8.08 N 12.76 Found: C 62.73 H 5.29 Cl 7.94 N 12.68

The following are obtained analogously:  

b) 8- (Ethoxycarbonyl-methoxy) -1-methyl-6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

Melting point: 167-170 ° C
C₂₁H₁₉ClN₄O₃ (410.87)

Calc .: C 61.39 H 4.66 N 13.64 Found: C 60.97 H 4.61 N 13.48

c) 8- (Ethoxycarbonyl-methoxy) -1-methyl-6-phenyl-4H- [1,2,4] - triazolo [4,3-a] [1,4] benzodiazepine

Melting point: 207-208 ° C (acetonitrile)
C₂₁H₂₀N₄O₃ (376.42)

Calc .: C 67.01 H 5.36 N 14.88 Found: C 66.91 H 5.34 N 14.91

d) 8- (1-ethoxycarbonyl-ethoxy) -1-methyl-6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

1 H-NMR (CDCl₃ TMS int.): W 1.18, 1.25 (t, 3H, 7 Hz, CH₃, 1.59 (d, 3H, 7 Hz, CH₃) 2.59 (s, 3H, CH₃), 3.90 - 4.40 (m, 2H, -CH₂-O-), 4.18 (d, 1H, -CH₂-, A / B System J _AB 12 Hz), 4.66 (m, 1H, -CH <), 5.25 (d, 1H, -CH₂-, A / B System J _AB 12 Hz), 6.68 (m, 1H, aroma), 7.02- 7.71 (m, 6H, aroma)

e) 8- (1-ethoxycarbonyl-ethoxy) -1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3a] [1,4] benzodiazepine

Melting point: 184-186 ° C (ethyl acetate / gasoline)
C₂₂H₂₂N₄O₃ (390.45)

Calc .: C 67.68 H 5.68 N 14.35 Found: C 67.35 H 5.60 N 14.27

f) 8- (Cyano-methoxy) -1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] be-nzodiazepine

Mp .: 185-186 ° C (acetonitrile / diisopropyl ether)
C₁₉H₁₅N₅O (329.37)

Calc .: C 69.29 H 4.59 N 21.26 Found: C 69.27 H 4.62 N 21.40

g) 8- (Ethoxycarbonyl-methoxy) -1-methyl-6-phenyl) -4H-imidazo [1,2-a] [1,4] benzodiazepine

by reacting 8-hydroxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine with ethyl bromoacetate
Mp 182-184 ° C (acetonitrile)

Calc .: C 70.83 H 5.64 N 11.19 Found: C 70.15 H 5.59 N 11.23  

Example 6 a) [1-Methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] benzodiazepin-8-yl] oxylacetic acid

6 g (0.016 mol) of 8- (ethoxycarbonyl-methoxy) -1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine are mixed with 0.8 Saponified g (0.02 mol) of sodium hydroxide in a mixture of 50 ml of alcohol and 120 ml of water at room temperature in one hour. The reaction solution is concentrated, the residue is taken up in water and the solution is made slightly acidic with 2N hydrochloric acid while cooling with ice. The carboxylic acid obtained is isolated and dried.
Yield: 4.6 g (83% of theory); Mp 260-263 ° C
The following are produced analogously:

b) [1-Methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiaze-pin-8-yl] oxyacetic acid

Melting point: 236-238 ° C.

c) 2 - {[1-Methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiaze-pin-8-yl] oxy} propionic acid

1 H-NMR (CD₄O, TMS int.): Δ 1.52 (d, d, 3H, CH₃, J 7 Hz), 2.56 (s, 3H, CH₃), 4.31 (d, 1H, -CH₂-, A / B system J _AB 12 Hz), 4.72 (q, 1H, -CH <), 5.27 (d, 1H, -CH₃-, A / B system J _AB 12 Hz), 6.68 (d, 1H, aromatic J 3 Hz ), 7.18-7.80 (m, 6H, aroma.)

d) [1-methyl-6-phenyl-4H-imidazo [1,2-a] benzodiazepine 8-yl] oxyacetic acid

from 8- (ethoxycarbonyl-methoxy) -1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] b-enzodiazepine
Melting point: 270 ° Z.

Example 7 a) 1-Methyl-8- (2-morpholin-4-yl-ethoxy) -6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

A mixture of 3.25 g (0.01 mol) of 8-hydroxy-1-methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4 ] b-enzodiazepine, 5.5 g of anhydrous potassium carbonate and 100 ml of ethyl methyl ketone are heated to boiling for one hour with stirring. After cooling, the reaction mixture is mixed with 2.1 g (0.011 mol) of N- (2-chloroethyl) morpholine hydrochloride and heated under reflux for 22 hours. The solvent is drawn off, the residue is taken up with methylene chloride / water and the organic phase is washed successively with 5% sodium hydroxide solution and water. The methylene chloride solution is dried and evaporated under reduced pressure. The oily residue is purified by column chromatography on silica gel, first using acetone and then a mixture of acetone and ethanol (80:20) as the eluent. When the main fractions are concentrated, a viscous oil is obtained which crystallizes with diisopropyl ether. After recrystallization from ethyl acetate, 2.6 g (60% of theory) of the desired compound of melting point 145-146 ° C.
C₂₃H₂₄ClN₅O₂ (437.94)

Calc .: C 63.08 H 6.52 Cl 8.10 N 15.99 Found: C 62.84 H 5.49 Cl 7.81 N 15.91

The following are obtained analogously:

b) 1-methyl-8- (3-morpholin-4-yl-propyloxy) -6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

1 H-NMR (CDCl₃, TMS int.): Δ 1.72-2.12 (m, 2H, -CH₂-), 2.43 (m, 6H, -CH₂-N <, 2-CH₂-morpholine), 2.61 (s, 3H, CH₃). 3.70 (m, 4H, -CH₂-morpholine), 4.00 (t, 2H, J 6 Hz, -CH₂-O-), 4.18 (d, 1H, -CH₂- A / B system J _AB 12 Hz), 5, 52 (d, 1H, -CH₂-, A / B system J _AB 12 Hz), 6.70 (d, 1H, aromatic, J 3 Hz), 7.06 - 7.72 (m, 6H, aromatic)

c) 1-Methyl-8- (2-morpholino-ethoxy) -6-phenyl-4H- [1,2,4] triazolo [4,3-a] [- 1,4] benzodiazepine

Melting point: 141-143 ° C (ethyl acetate / ether)
C₂₃H₂₅N₅O₂ (403.49)

Calc .: C 68.47 H 6.25 N 17.63 Found: C 68.59 H 6.35 N 17.29

d) 8- (2-dimethylaminoethoxy) -1-methyl-6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

1 H-NMR (CDCl₃, TMS int.): Δ 2.32 (s, 6H, N-CH₃); 2.63 (s, 3H, CH₃), 2.70 (t, 2H, -CH₂-, J 6 Hz), 4.00 (t, 2H, -CH₂- J 6 Hz), 4.18 (d, 1H, -CH₂-, A / B system J _AB 12 Hz), 5.50 (d, 1H, -CH-, A / B system, J _AB 12 Hz), 6.75 (d, l, H, aromatic J 3 Hz), 7.09 - 7.73 (m, 6H, aroma.)

Example 8 a) 8- (Ethoxycarbonyl-methoxy) -1-methyl-6- (2-chlorophenyl) - 5,6-dihydro-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

A solution of 1 g (0.0024 mol) of 8- (ethoxycarbonyl-methoxy) -1-methyl-6- (2-chlorophenyl) -4H [1,2,4] triazolo [4,3-a] benzodiazepine is added in a mixture of 15 ml dichloromethane and glacial acetic acid while stirring with 0.8 g zinc dust and allowed to react for six hours at room temperature. The suspension is filtered off over silica gel and washed with dichloromethane. The combined filtrates are made alkaline with dilute ammonia solution with cooling. The organic phase is washed with water, dried and evaporated. The dark oil which remains is purified by chromatography on silica gel (acetone).
Yield: 300 mg (30% of theory); Mp 187-189 ° C.
C₂₁H₂₁ClN₄O₃ (412.88)

Calc .: C 61.09 H 5.13 Cl 8.59 N 13.57 Found: C 60.74 H 5.17 Cl 8.77 N 13.29

Example 9 1-methyl-8- (2-morpholin-4-yl-ethoxy) -6- (2-chlorophenyl) -5,6- dihydro-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

1 g (0.016 mol) of 1-methyl-8- (2-morpholin-4-yl-ethoxy) - 6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine are reduced with Zn dust analogously to Example 8.  After appropriate work-up, you get the concentration the organic phase 0.9 g of oil with diisopropyl ether is brought to crystallization. The crystals are vacuumed and dried. 400 mg (40% of theory) are obtained the dihydro compound of mp. 208 ° C (dec.).

Example 10 a) 1-Methyl-8- (3-phthalimido-propyloxy) -6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

A mixture of 1.5 g (0.0046 mol) of 8-hydroxy-1-methyl 6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine, 1.9 g of anhydrous potassium carbonate and 60 ml Ethyl methyl ketone is stirred for one hour Heated to reflux. The reaction mixture is left somewhat cool, add 1.47 g (0.0055 mole) 3-Bromopropylphthalimide too, heated for a further 7 hours boil and then distill the solvent in Vacuum. The arrears with Methylene chloride / H₂O added. The organic Phase is with 5% sodium hydroxide solution and water washed, dried and evaporated. The residue is triturated with acetone; the resulting crystals are suctioned off and column chromatographed on Silica gel (methylene chloride / methanol 98: 2) cleaned. 1.1 g (46.6% of theory) are obtained; Mp 234-236 ° C Phthalimido compound. Analogously you get:

b) 1-methyl-8- (2-phthalimido-ethoxy) -6- (2-chlorophenyl) - 4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine.

Mp 198-199 ° C (acetonitrile).  

Example 11 8-hydroxy-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine

A mixture of 14 g (0.046 mol) of 8-methoxy-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine [mp. 197-198 ° C; Chem. Pharm. Bull. 21, 2382 (1973)] and 150 ml of 60% hydrobromic acid are heated under reflux for one and a half hours. The reaction solution is concentrated in vacuo on a rotary evaporator, the residue is taken up in water and the solution is mixed with 20% sodium hydroxide solution until the reaction is strongly alkaline. It is filtered through diatomaceous earth and the reaction solution is brought to a pH of 5 to 6 with ice-cooling with 6N hydrochloric acid. The phenol obtained is redissolved in 2N sodium hydroxide solution and precipitated again by acidification (pH 5 to 6) with hydrochloric acid. The crystals are washed with water, suspended in acetonitrile, suction filtered and dried at 130 ° C. in a vacuum drying cabinet.
Yield: 10 g (70% of theory);
Mp <320 ° C (dec.).

Example 12 8-hydroxy-1-methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo- [4,3-a] [1,4] benzodiazepine

Starting from 8-methoxy-1-methyl-6- (2-chlorophenyl) -4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine (mp. 199-200 °) analogue to Example 11 gives the title compound Mp 302-304 ° C (dec.).

1 H-NMR (CD₄O, TMS int.): Δ 2.60 (s, 3H, CH₃), 4.29 (d, 1H, -CH₂- A / B System J _AB 12 Hz), 5.20 (d, 1H, -CH₂- A / B system, J _AB 12Hz), 6.28 (d, 1H, aromatic J 3 Hz), 6.90 (d, d, 1H, aromatic J o / m 9 3Hz), 7.28-7.70 (m, 5H, aroma.)

Example 13 N- (ethoxycarbonyl-methyl) - [(1-methyl-6-phenyl-4H- [1,2,4] - triazolo [4,3-a] [1,4] benzodiazepin-8-yl) oxyacetic acid amide]

1.74 g (5 mmol) (1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] - benzodiazepin-8-yl) -oxyacetic acid are in one Solvent mixture of 40 ml of anhydrous Tetrahydrofuran and 10 ml of anhydrous dimethylformamide submitted. Then 0.89 g (5.5 mmol) of N, N′- Carbonyldiimidazole and stirred for 2 hours Room temperature. Then 0.56 g (5.5 mmol) of triethylamine and 0.77 g (5.5 mmol) glycine ethyl ester hydrochloride admitted. After 15 hours the mixture is concentrated the residue is taken up in dichloromethane / water and successively with water 2N sodium hydroxide solution and water extracted. The organic phase is dried concentrated and the residue thus obtained with Diisopropyl ether brought to crystallization. 1.5 g (69% of theory) of the title compound of Melting point 152-153 ° C (alcohol / diisopropyl ether).

Example 14a 1-methyl-6-phenyl-8- (3-pyridylmethoxy-4H- [1,2,4] triazolo- [4,3-a] [1,4] benzodiazepine

A suspension of 1.74 g (0.006 mol) of 8-hydroxy-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] - benzodiazepine and 0, 6 g of sodium hydride (50% suspension in mineral oil) in 100 ml of anhydrous dimethylformamide is stirred under nitrogen for 90 minutes and then 3-chloromethyl-pyridine hydrochloride is added in portions. After twelve hours, the reaction mixture is largely concentrated on a rotary evaporator, water is added with cooling and the mixture is extracted with methylene chloride. The organic phase is washed successively with 5% sodium hydroxide solution and water, dried and evaporated. The residue is purified by column chromatography on silica gel [eluent: dichloromethane / methanol (95: 5)]. After evaporation, the clean fractions are recrystallized from acetonitrile.
Yield: 1.1 g (48% of theory); Mp 199-201 ° C
C₂₃H₁₉N₅O (381.44)

Calc .: C 72.42 H 5.02 N 18.36 Found: C 72.29 H 5.14 N 18.25

Example 14b 1-methyl-6-phenyl-8- (3-pyridylmethoxy) -4H-imidazo [1,2-a] - [1,4] benzodiazepine

Starting from 1.74 g (0.006 mol) of 8-hydroxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine, 1.4 g (61, 4% of theory) of the title compound.
Melting point: 179-180 ° C (acetonitrile)
C₂₄H₂₀N₄O (380.45)

Calc .: C 75.77 H 5.30 N 14.73 Found: C 75.63 H 5.14 N 14.67

Preparation of the starting material for Example 14b
8-methoxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine and
8-hydroxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine

A suspension of 35 g (0.124 mol) of 7-methoxy-6-phenyl 6-phenyl-1H, 3H- [1,4] benzodiazepin-2-thione (mp. 219-221 ° C) in 700 ml of anhydrous dioxane with 13.7 g Propargylamine added and refluxed for three hours heated. The reaction solution is then on The rotary evaporator was concentrated and the residue was added Methanol / water added. The organic phase will washed several times with water, over sodium sulfate dried and evaporated.

The residue (35.6 g) is concentrated in 180 ml Sulfuric acid heated to 100 ° C for 15 minutes. After this Cool down, pour on ice, put with ammonia solution alkaline and extracted with methylene chloride. The one after The residue obtained is distilled off on a silica gel column (eluent: methylene chloride / methanol 95: 5) cleaned.

The uniform fractions are combined, evaporated and recrystallized. 6.6 g of 8-methoxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine with a melting point of 184-186 ° C. (ethyl acetate) are obtained.
C₁₉H₁₇N₃O (303.37)

Calc .: C 75.23 H 5.65 N 13.85 Found: C 74.91 H 5.77 N 13.79

and 4.9 g of 8-hydroxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine, melting point 290 ° C. (methanol / coal).
C₁₈H₁₅N₃O (289.34)

Calc .: C 74.72 H 5.23 N 14.52 Found: C 74.59 H 5.27 N 14.38

8-hydroxy-1-methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine can also be implemented by 8-methoxy-1-methyl-6-phenyl-4H-imidazo [1,2] [1,4] benzodiazepine be represented with hydrobromic acid.

Example 15a 1-Methyl-8- (3-morpholin-4-yl-propyloxy) -6-phenyl-4H- [1,2,4] triazolo [-4,3-a] [1,4] benzodiazepine

A suspension of 5 g (0.0172 mol) of 8-hydroxy-1-methyl-6-phenyl-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiaze-pin and 9 , 5 g of anhydrous potassium carbonate in 200 ml of ethyl methyl ketone is heated to the reflux temperature for one hour with stirring. After cooling, the reaction mixture is mixed with 3.78 g of N- (3-chloropropyl) morpholine hydrochloride and heated under reflux for a further 18 hours. The solvent is then distilled off and the residue is taken up in methylene chloride / water. The organic phase is washed successively with dilute sodium hydroxide solution and water, dried and evaporated. The remaining crude product is purified by column chromatography (silica gel; methylene chloride / methanol 95: 5). Yield: 4.4 g (61% of theory); Mp 145-147 ° C
C₂₄H₂₇N₅O₂ (417.51)

Calc .: C 69.04 H 6.52 N 16.77 Found: C 68.84 H 6.60 N 16.55

Example 15b

Analogously to Example 15a, 1-methyl-8- (3-morpholino-propyloxy) -6-phenyl-4H-imidazo- [1,2-a] [1,4] benzodiazepine is obtained by reacting 8-hydroxy-1- methyl-6-phenyl-4H-imidazo [1,2-a] [1,4] benzodiazepine with N- (3-chloropropyl) morpholine hydrochloride
Melting point: 133-134 ° C (ethyl acetate / diisopropyl ether)
C₂₅H₂₈N₄O₃ (416.53)

Calc .: C 72.09 H 6.78 N 13.45 Found: C 72.18 H 6.62 N 13.39

Further compounds of the invention are in the the following tables:

TABLE I

Compounds of the formula

TABLE II

Compounds of formula Ia

NMR spectra of compounds of TABLE I ( δ in ppm) No. 1

1 H-NMR (CDCl₃, TMS int.):

δ

0.90 (d, 6H, 2CH₃, J 7 Hz), 1.79 (m, 1H, CH), 2.61 (s, 3H, CH₃), 3.16 (d, d, 2H, -CH₂- J 6 Hz), 4.17 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.45 (s, 2H, -CH₂-), 5.56 (d, 1H, A / B system -CH₂-, J _AB

12 Hz), 6.50 (d, 1H, NH), 6.75 (d, 1H aroma. J 3 Hz), 7.11-7.72 (m, 6H, arom.).

No. 2

1 H-NMR (CDCl₃, TMS int.):

δ

1.22-2.43 (m, 6H, piperidine), 2.28 (s, 3H, <NCH₃), 2.60 (s, 3H, CH₃), 2.80 (m, 2H, piperidine, 3, 84 (m, 1H, piperidine), 4.15 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.37 (s, 2H, -CH₂-), 5.50 (d, 1H, A / B system J _AB

12 Hz), 6.36 (d, 1H, <NH), 6.71 (d, 1H arom. J 3 Hz), 7.10-7.70 (m, 6H, aroma.).

No. 4

1 H-NMR (CDCl₃, TMS int.):

δ

2.61 (s, 3H, CH₃), 3.31-3.84 (m, 8H, morpholine), 4.13 (d, 2H, -CH₂-), 4.17 (d, 1H, -CH₂- J _AB

12Hz), 4.47 (s, 2H, -CH₂-), 5.52 (d, 1 Hz, -CH₂- A / B system J _AB

12 Hz), 6.75 (d, 1H, arom. J 3Hz), 7.13-7.70 (m, 6H, arom.).

No. 5

1 H-NMR (CDCl₃, TMS int.):

δ

2.56 (s, 3H, CH₃), 3.52 (m, 2H, -CH₂-), 3.75 (t, 2H, -CH₂-), 4.15 (d, 1H, -CH₂- A / B System J _AB

12 Hz), 4.45 (s, 2H, -CH₂-), 5.50 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.72 (d, 1H, aroma J 3 Hz), 7.00-7.70 (m, 6H, aroma, 1 <NH).  

To number 8

1 H-NMR (CDCl₃, TMS int.):

δ

2.59 (s, 3H, CH₃), 4.17 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.45 (s, 2H, -CH₂-), 5.52 (d, 1H, A / B system J _AB

12 Hz), 5.93, 6.52 (1H / 1H, <NH₂), 6.75 (d, 1H, aromatic J 3 Hz), 7.10 (m, 6H, aroma.)

No. 10

1 H-NMR (CDCl₃, TMS int.):

δ

1.29 (t, 3H, CH₃, J 7 H₂), 2.61 (s, 3H, CH₃), 4.11 (d, 2H, -CH₂-, J 5 Hz), 4.18 (d, 1H , -CH₂- A / B system J _AB

12 Hz), 4.25 (q, 2H, -CH₂-O-), 4.50 (s, 2H, -CH₂-), 5.52 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.75 (d, 1H, aromatic J 3 Hz), 7.09 (t, 1H, <NH), 7.13-7.70 (m, 6H, aroma).

To No. 12

1 H-NMR (CDCl₃, TMS int.):

δ

2.45 (m, 4H, morpholine), 2.52 (t, 2H, -CH₂-), 2.61 (s, 3H, CH₃), 3.43 (m, 2H, -CH₂-), 3, 63 (m, 4H, morpholine), 4.18 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.45 (s, 2H, -CH₂-), 5.54 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.73 (d, 1H, arom. J 3 Hz), 7.00-7.72 (m, 6H, aroma 1 <NH).

To No. 13

1 H-NMR (CDCl₃, TMS int.):

δ

2.59 (s, 3H, CH₃), 3.36-3.79 (m, 8H, -CH₂- morpholine), 4.17 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.67 (s, 2H, -CH₂-), 5.51 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.75 (d, 1H, arom. J 3 Hz), 7.11-7.70 (m, 6H, arom.).  

To No. 14

1 H-NMR (CDCl₃, TMS int.):

δ

1.27 (t, 3H, CH₃, J 7 Hz), 1.43-2.11 (m, 4H, piperidine), 2.34-3.45 (m, 3H, piperidine), 2.61 (s , 3H, CH₃), 3.61-4.43 (m, 2H, piperidine), 4.18 (q, 2H, -CH₂-O-), 4.18 (d, 1H, -CH₂- A / B System J _AB

12 Hz), 4.65 (s, 2H, -CH₂-), 5.52 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.75 (d, 1H, arom. J 3 Hz), 7.11-7.86 (m, 6H, aroma).

No. 15

1 H-NMR (CDCl₃, TMS int.):

δ

1.09, 1.13 (t, 6H, CH₃), 2.60 (s, 3H, CH₃), 3.31 (m, 4H, CH₂-N-), 4.18 (d, 1H, -CH₂ - A / B system J _AB

12 Hz), 4.65 (s, 2H, -CH₂-), 5.50 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.72 (d, 1H, aroma J 3 Hz), 7.10-7.65 (m, 6H, aroma).

NMR spectra for compounds of Table II ( δ in ppm) number 1

1 H-NMR (CDCl₃, TMS int.):

δ

2.36 (d, 3H, J = <2 Hz), 2.54 (m, 4H, N-CH₂-morpholine), 2.77 (t, 2H, J = 6 Hz, N-CH₂-CH₂O); 3.72 (m, 4H, OCH₂-morpholine), 4.02 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 4.08 (t, 2H, J = 6 Hz, O-CH₂-CH₂N), 5.26 (d, 1H, -CH₂- A / B system J _AB

12 Hz), 6.87 (qu., 1H, J = <2 Hz, CH =), 6.91 - 7.78 (m, 8H, aroma.).

No. 6

1 H-NMR (CDCl₃, TMS int.):

δ

1.24 [s, 6H (CH₃) ₂-C)], 2.63 (s, 3H, CH₃), 3.38 (s, 3H, N-CH₂, NH), 4.08 (d, 1H, -CH₂- A / B System J _AB

13 Hz), 4.67 (s, 2H, OCH₂), 5.44 (d, 1H-CH₂- A / B system J _AB

13 Hz) 6.85 - 7.71 (m, 8H, aroma).

Claims (8)

1. Connections of the formulas whereR for one of the groups
(a) -OX-CO-OR₄
(b) -OX-CO-R₅
(c) -OY-R₆
(d) -Z-CO-OR₄
(e) -Z-CO-R₅ R₁ for hydrogen; for C₁-C₄-alkyl or for C₃-C₆-cycloalkyl; or, if R is the group (d), (e) or (f), also for C₁-C₄ alkoxy or halogen; R₂ for phenyl, for one or more methyl, halogen, nitro, trifluoromethyl or, if R is the group (d), (e) or (f), also phenyl substituted by methoxy; or for α- pyridyl; R₃ is hydrogen or C₁-C₄ alkyl; R₄ represents a C₁-C₆ alkyl group substituted by a mono- or di- (C₁-C₃-alkyl) amino group; for C₃-C₇-cycloalkyl, which in the case of the 5- or 6-ring can also contain a <N (C₁-C₄-alkyl) group as a ring member and which in the case of the C₇-cycloalkyl can also have a <NCH₃ bridge ; or, if R represents the group (a) or (d), also for hydrogen or C₁-C₆-alkyl; R₅ for one of the groups R₆ for one of the groups or the group listed under R (f), wherein Z represents a single bond; R₇ and R₈ (independently of one another) for hydrogen; for C₁-C₆ alkyl, allyl or propargyl; and, if R₇ is hydrogen or methyl, R₈ also for C₃-C₆-cycloalkyl, aryl, aralkyl or one of the groups or,
if R represents group (b), also for one of the groups R₉ and R₁₀ (independently of one another) for hydrogen; for C₁-C₆ alkyl; in addition (together with the nitrogen atom of the group -NR₉R₁₀) for an optionally mono- to tetra-methyl-substituted saturated five- or six-membered ring, which may also contain a further heteroatom (O, S, NR₃); R₁₁ for C₁-C₄ alkyl, aryl or aralkyl; R₁₂ for hydrogen or methyl, one of the radicals R₁₂ optionally also for -CO-O (C₁-C₆-alkyl), R₁₃ for hydrogen; for an optionally hydroxy or amino substituted C₁-C₆ alkyl; for a CO-O (C₁-C₄-alkyl) - or a CO-N (C₁-C₄-alkyl) ₂ group; R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ (independently of one another) for hydrogen; for an optionally hydroxy or amino substituted C₁-C₆ alkyl; or for phenyl; A and B (independently of one another) for N, CH or C-CH₃ but not both for CH or C-CH₃; D for (CR₁₇R₁₈) _n ; Q for O, S, NH or N (C₁-C₆ alkyl); E for O, S, NR₁₁, CH₂ or a single bond; X for C₁-C₆ alkylene; Y for C₂-C₆ alkylene; Z for C₁-C₆ alkylene or a single bond; k for 1, 2, 3 or 4; m for 2 or 3; n can stand for 0, 1 or 2, optionally in the form of the racemates, the enantiomers, diastereomers and their mixtures; in each case as free bases or as acid addition salts, optionally also as quaternized compounds. 2. Compounds of general formulas Ia or Ib according to claim 1, wherein A and B are nitrogen or A CH group and B nitrogen; R₁: methyl, methoxy and cyclopropyl; R₂: 2-chlorophenyl; R: linked in the 8-position with the ring system, the following applies to groups (a) to (g)
in (a): X is C₁-C₃ alkylene
R₄ in the above meaning, except hydrogen and C₁-C₆ alkyl;
in (b): X is C₁-C₃ alkylene,
R₅ is -NR₇R₈ with R₇, R₈ is hydrogen or C₁-C₄-alkyl;
or R₇ equals H and R₈ equals
C₂-C₃ alkyl substituted with N-morpholino or 2,6-dimethylmorpholino; or R₅ the same wherein
E is O, N-methyl, CH₂; where E is O, R₁₂ is preferably methyl and k is 2, the methyl groups being in the 2- and 6-position, while for E is CH₂ R₁₂ is especially COOC₂H₅;
in (c): Y is C₁-C₃-alkylene, R₆ phthalimido or NR₉R₁₀ and R₉ / R₁₀ is H or C₁-C₄-alkyl or NR₉R₁₀ is morpholino, optionally methyl-substituted;
in (d): Z is a single bond, R₄ in the above meaning, except hydrogen and C₁-C₆-alkyl;
at (e): Z is a single bond, R₅ NR₇R₈ with R₇ equal to H, at (f): Z is a single bond, likewise D (n = O), R₁₃ / R₁₄ methyl, R₁₅ / R₁₆ hydrogen,
in (g): Z can mean -CH₂- or -CH₂-CH₂-, optionally in the form of their racemates, their entantiomers, their diastereomers and their mixtures; in each case as free bases or as acid addition salts, optionally also as quaternized compounds 3. Pharmaceutical preparations characterized by a content of a compound according to claim 1 or 2 in addition to conventional carriers and / or auxiliaries. 4. Use of compounds according to claim 1 or 2 in the treatment of diseases in which PAF is involved is. 5. Compounds according to claim 1 or 2 for use for the production of pharmaceutical preparations with PAF antagonistic effect. 6. Method for the treatment of diseases in which the PAF is involved, characterized in that one Compound according to claim 1 or 2 used. 7. A process for the preparation of compounds according to claim 1 or 2 by conventional methods, characterized in that

• a) reacting a compound of formula II with a compound of formula III or that
• b) a compound of the formula Ia, in which R is -OX-COOH or -Z-COOH or a reactive derivative thereof, is reacted with amines of the formula VI or VII or with ammonia or that
• c) reacting a compound of formula II with a compound of formula VIII or that
• d) a compound of the formula Ia, in which R is -OYR′₆, in which R₆ is the phthalimido group, is subjected to hydrazinolysis. or that one
• e) reacting a compound of formula X with a bisfunctionalized amine or that
• f) a compound of the formula Ia, in which R denotes a hydroxy-functionalized carboxamide group, is subjected to ring closure with thionyl chloride and, if desired, the ring oxygen is then exchanged for sulfur or that
• g) a compound of the formula Ia, in which R is -Z-CN or -OY-CN, is converted into the imidoester hydrochloride and this is reacted with a corresponding diamine or that
• h) a compound of formula Ia, in which R₁ is H, halogenated to a compound with R₁ is halogen or that
• i) a compound of formula Ia, in which R₁ reacts bromine or chlorine with an alcoholate or that one
• a compound of general formula II in the presence of a base or as an anion with a compound of general formula implements
  or that one
• l) a compound of formula Ia is reduced by conventional means to corresponding compounds Ib with R₃ equal to H and, if desired, these compounds are alkylated to compounds with R₃ equal to alkyl or that one
• m) reacting functionalized compounds of compounds of the formula Ib with R equal to a radical of group (c) with corresponding reactants or that
• n) the fused-on imidazolo or triazolo ring is generated by a ring closure reaction.

and that, if desired, products obtained approximately present enantiomers or in diastereomers Separate pairs of antipodes and / or that one first Acid addition salts obtained in free bases, initially bases obtained converted into acid addition salts.