DE3624779C2 - Process for the preparation of thieno-triazolo-1,4-diazepino-2-carboxylic acid amides - Google Patents

Description

The invention relates to a process for the preparation of Thieno-triazolo-1,4-diazepine-2-carboxylic acid amides of general formula

wherein
R _{1 is} hydrogen, a straight-chain or branched alkyl group having 1-4 carbon atoms, optionally substituted by halogen, preferably Cl or Br, or hydroxy, cyclopropyl, alkoxy having 1-3 C atoms, preferably methoxy, halogen, preferably chlorine or bromine;
R ₂ and R ₃ , which may be identical or different, are hydrogen, a straight-chain or branched alkyl or hydroxyalkyl radical having 1-4 carbon atoms or both radicals R ₂ and R ₃ together with the nitrogen atom is a 5-, 6- or 7-membered ring optionally containing as another heteroatom a nitrogen, oxygen or sulfur atom and wherein the second nitrogen atom may optionally be substituted by an alkyl group having 1-4 carbon atoms, preferably the methyl group;
R _{4 is} phenyl, where the phenyl ring, preferably in the 2-position, can be substituted by methyl, halogen, particularly preferably chlorine or bromine, or trifluoromethyl or α-pyridyl; and
n one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8,
wherein a compound of the general formula

wherein the radicals R ₁ and R _{4 have} the meaning indicated, with an amine of the general formula

wherein R ₂ and R _{3 are} as defined above, is reacted in the presence of sulfonyldiimidazole.

The reaction of the free acid with the amine in the presence Sulfonyldiimidazole is carried out in an inert solvent such as B. dimethylformamide, tetrahydrofuran, dioxane, Methylene chloride, etc. at temperatures between 0 ° C and the Boiling point of the reaction mixture, preferably at room temperature.

According to a preferred method is in a one-pot reaction starting from imidazole and thionyl chloride first formed the sulfonyldiimidazole and then the thieno triazolo-1,4-diazepin-2-yl-carboxylic acid added.  

The reaction procedure is in the following synthesis scheme reproduced

The intermediary formed imidazolidide is suitably not isolated, but directly with the amine implemented.

Under mild conditions, where a saponification is excluded, the intermediate A can be isolated become.  

By the methods described above, for example, the following end products can be obtained:
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid morpholide;
2- [4- (2-chlorophenyl) -9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid morpholide;
[4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - carboxylic acid morpholide;
[4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] - amide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid diethylamide;
8- [4- (2-chlorophenyl) -9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -n-octane-1-carboxylic acid morpholide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid N, N-di (2-hydroxyethyl) amide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid methylamide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid isopropylamide; -
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid dimethylamide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid N-methyl-piperazide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid pyrrolidide;
2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid piperidide;
2- [4- (2-chlorophenyl) -9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid diethylamide;
2- [4- (2-chlorophenyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane 1-carboxylic acid morpholide;
2- [4- (2-chlorophenyl) -9-bromo-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid morpholide;
2- [4- (2-chlorophenyl) -9-methoxy-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid morpholide;
2- [4-phenyl-9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane 1-carboxylic acid morpholide;
2- [4- (2-nitrophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-2 yl] ethane-1-carboxylic acid morpholide;
2- [4- (2-methylphenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-2 yl] -ethane-1-carboxylic acid morpholide;
2- [4- (2-trifluoromethyl-phenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-2 yl] -ethan-1-carboxylic acid morpholide;
2- [4- (2-chlorophenyl) -9-methoxy-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethane-1-carboxylic acid diethylamide;
2- [4- (2-chlorophenyl) -9-methoxy-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid piperidide;
2- [4- (2-chlorophenyl) -9-methoxy-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl ] -ethan-1-carboxylic acid N'-methylpiperazide.

When the starting materials of general formula II is it is mostly about new connections. You get they, starting from the corresponding aldehydes, according to following reaction scheme.

R = alkylcarboxylic acid methyl or ethyl ester or Alkyl dicarboxylic acid methyl or ethyl ester with 1-8 carbon atoms in the alkyl chain

If a dicarboxylic acid ester was used, a of the carboxyl groups at the stage of the aminoketone split off the saponification.

For R ₁ = hydrogen, the reaction starts either from a compound which is reacted with formic acid hydrazide, or a o-formic acid ester is allowed to act on a compound of the formula

For R ₁ = chlorine or bromine, a compound with R ₁ = hydrogen can first be prepared and reacted with chlorine or bromine in pyridine.

The 1-alkoxy compound can be obtained from one mentioned above Chloro or bromo compound by reaction with sodium alcoholate receive.

Compounds in which n represents 0 are obtained Compounds with a carboxyl group in the 1-position, such as they are described in DOS 25 03 235; the free acid is, as stated above, further implemented.

The compounds prepared by the process according to the invention have PAF-antagonistic effect.

It is known that PAF (platelet activating Factor) around the phospholipid acetyl-glyceryl ether phosphoryl-choline (AGEPC), which acts as a potent lipid mediator is known, that of animal and human proinflammatory Cells is released. Under such cells Mainly basophilic and neutrophilic Granulocytes, macrophages (from blood and tissues) as well Platelets involved in inflammatory reactions are.  

PAF shows bronchoconstriction in the pharmacological experiment, Lowering blood pressure, triggering a platelet aggregation and a proinflammatory effect.

These experimentally detectable effects of PAF exhibit directly or indirectly to possible functions of this Mediators in anaphylaxis, in the pathophysiology of Bronchial asthma and common in inflammation.

PFA antagonists are needed on the one hand more pathophysiological functions of this mediator on animal and To elucidate human and on the other hand pathological conditions and diseases in which PAF is involved. Examples of the indications of a PAF antagonist are Inflammatory processes of the tracheobronchial tree (acute and chronic bronchitis, bronchial asthma) or kidney (Glomerulonephritis), anaphylactic conditions, allergies and inflammation in the mucous membranes and the skin (eg psoriasis) as well as sepsis, endotoxins or Burns related shock states. Other important Indications for a PAF antagonist are lesions and Inflammations in the area of the stomach and intestinal mucosa, such as z. As gastritis, in general peptic ulcer, but in particular Ulcer of the stomach and ulcer duodeni.

The PAF-antagonistic effect of individual benzodiazepines is known, cf. E. Kornecki et al., Science 226, 1454-1456 (1984). These, as tranquilizers or hypnotics designated and commercially available compounds, however, because of their pronounced CNS effect is used as PAF antagonists in therapy in many cases unsuitable. On the other hand, the compounds according to the invention lack the CNS efficacy, while the PAF antagonist activity in the Compared to the known benzodiazepines up to fifty times larger.

The following are pharmacological test results reported:  

Pharmacological examination results

The PAF antagonist activity of some compounds of formula I was examined by inhibition of platelet aggregation in vitro and antagonization of PAF-induced bronchoconstriction on the anesthetized guinea pig, blood pressure reduction in the anesthetized rat, and skin squirrels in the rat. In addition, these compounds have been tested for potential side effects on the central nervous system. The LD ₅₀ as the measure of acute toxicity was also determined.

1. In vitro Studies: Inhibition of Platelet aggregation

To determine the PAF antagonistic effect of Substances became aggregation induced by PAF of human platelets used in vitro. For the production of platelet-rich plasma (TRP) The blood is taken from a non-jammed Vein using a plastic syringe, in which 3.8% sodium citrate solution. The relationship between sodium citrate solution and blood is 1: 9. After careful mixing, the citrate blood centrifuged at 150 × g (1200 rpm) for 20 minutes. The measurement of platelet aggregation takes place after the method developed by Born and Cross (G.V.R. Born and M.J. Cross, J. Physiol. 168, 178 (1963)), wherein the TRP with constant stirring PAF is added as a trigger of aggregation.

The test substance is added in each case 2-3 minutes before the initiation of the aggregation in a volume of 10 μl. The solvents used are either aqua. Dist., ethanol and / or dimethyl sulfoxide. Control batches receive appropriate volumes of these solvents. After registration of the initial absorbance (2-3 minutes), aggregation is induced with PAF (5 × 10 ^-8 M).

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

Which reached under the influence of the test substance Aggregation value is given as 100%.

Each test substance is tested at concentrations of 10 ^-3 to 10 ^-8 M with a sample size of n = 4 in each case for an inhibitory effect on PAF-induced platelet aggregation. Thereafter, a concentration-effect curve is generated on the basis of 3 concentrations and the IC ₅₀ (concentration with a 50% inhibition of aggregation) is determined. The IK values of compounds of general formula I range between 0.17 and 1.5 μM. This gave 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine-2 -yl] -ethan-1-carboxylic acid diethylamide and 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1.4] diazepino-2-yl-ethane-1-carboxylic acid morpholide with IK ₅₀ values of 0.7 and 0.17, respectively, as particularly potent compounds.

2. In vivo investigations 2.1. Antagonization of PAF-induced bronchoconstriction on anesthetized guinea pigs

Spontaneously breathing male, weighing 300-450 g Guinea pigs will be 1 hour before i. v. infusion of PAF (30 ng / (kg x min)) with the test substance or a control vehicle orally. 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 induces a strong, persistent bronchoconstriction, which is based on the Tidal volume, compliance and resistance is measured and also a reduction in blood pressure. After about 7-10 minutes, death occurs. With the described PAF antagonists these can Effects on respiration and blood pressure as well as admission of death. The required Cans range between 0.5 and 5 mg / kg p. o. and 0.5 to 1.0 mg / kg i. v. ,

2.2. Antagonization of PAF-induced blood pressure reduction on the anesthetized rat

Normotone, male, 200-250 g Wistar Rats are interperitoneal with 2 mg / kg urethane anesthetized. The carotid artery and vena jugularis are cannulated. An intravenous PAF infusion (30 ng / (kg x min)) induced in the Control animals a strong, sustained blood pressure reduction. This can be dose-dependent by intravenous Injections (cumulative administration) of the  described compounds in a dose range of 0.01 to 0.5 mg / kg. Also an oral or intravenous administration of the compound Beginning of PAF infusion may be the hypotensive Effect of the above-mentioned PAF infusion dose-dependently prevent.

2.3. Antagonization of PAF induced skin squares on the rat (Modified after P.P. Koelzer and K. H. Wehr, Arzneim.-Forsch. 8, 181 (1958)

Intracutaneous injection of PAF induces a Hautquaddel, the expression of a PAF-related Increasing the vascular permeability is.

Male Wistar rats with a body weight of 250 ± 20 g is shaved the abdominal wall (short). Thereafter, 1 ml / kg of a 1% trypan blue solution injected through a tail vein to the animals. symmetrical to the midline (linea alba) will be at three Make intracutaneous at intervals of about 1.5 cm Injections of physiological saline or PAF solution (12.5 to 25.0 ng / place in 0.1 ml) administered. While at the injection site of saline no reaction, PAF caused one Skin reaction (wheal) caused by a blue coloration different intensity - depending on the PAF dose - became visible. By simultaneous intracutaneous Administration of the compounds described at doses of 0.5 to 5 μg / site (in 0.1 ml) or by an intravenous pretreatment in doses of 0.2 to 3 mg / kg could cause this PAF-induced skin reaction be prevented.  

3. Effects on the central nervous system

It is well known that substances of this structural type cause central nervous system effects, but which are responsible for a compound with PAF-antagonistic effect not are desired. Therefore, the compounds described were in terms of their hypnogenic and anticonvulsive Effect and its influence on the locomotion checked. A possible hypnotic effect was on 400-450 g guinea pig examined. cans up to 200 mg / kg p. o. of these substances were not Able to have a hypnotic or sedative effect to produce these animals.

To test an anticonvulsant effect of 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 to 100 mg / kg p. o. of these compounds (1 hour before pentetrazole) showed in this test no influence on the by pentetrazole (125 mg / kg i.p., LD 100) Mortality.

The effect on night motility (locomotion) of Mice (20-25 g body weight) may be in a photocell cage to be examined. Thereby the number becomes the light beam interruptions measured. Cans up to 300 mg / kg p. o. Of the above compounds showed no activity.

4. Acute toxicity to mice

The mean lethal dose (LD ₅₀ ) after oral administration was between 3 and 4 g / kg for the investigated compounds. The LD ₅₀ values after intravenous administration ranged between 400 and 700 mg / kg.

The novel compounds of general formula I can warm-blooded animals topically, orally, parenterally or by Be administered inhalation. The connections are in this case as active ingredients in conventional dosage forms before, z. In compositions that are substantially from an inert pharmaceutical carrier and an effective Dose of the active ingredient exist, such as. Eg tablets, Dragees, capsules, wafers, powders, solutions, suspensions, Inhalation aerosols, ointments, emulsions, syrups, suppositories etc. An effective dose of the invention Compounds is between 1 and 50 when administered 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 inhalation should solutions that are 0.01 to 1.0, preferably 0.1 to 0.5% active ingredient used.

The following examples are given for further explanation the invention:

example 1 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid morpholide

27.2 g (0.4 mol) of imidazole in 200 ml of tetrahydrofuran are dissolved and treated dropwise at 15-25 ° C (0.1 mol) of thionyl chloride (analogous to the method of HA Staab and KW Endel, Angew Chem 73, 26 (1961) Stirring for 10 minutes, then 38.7 g (0.1 mol) of 2- (2-carboxyethyl) -4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3a] [1,4] diazepine (WD Bechtel and KW Weber, J. Pharmac. sci 74, 1265 (1985) and stirred for 15 min at 25-30 ° C. Then the solution of the intermediate becomes 8.4 g (0.1 mol) of morpholine are added and stirring is continued for 1 hour at room temperature, 600 ml of water are added, and the title compound is shaken out three times with 300 ml of methylene chloride each time, after evaporation, evaporation with recrystallization from the methylene chloride phase 35 ml of ethanol 36-38 g (80 × 83%) of colorless crystals of mp. 186-187 ° C.
¹ H-NMR (CDCl ₃₎ δ = 2.64 (2t, -CH ₂ -CO-), 2.71 (3s, _CH3), 3.17 (2t, CH _2), 3.33 to 3 , 81 (8m, morpholine), 4.96 (2s, CH ₂ ), 6.48 (1s, thiophene), 7.28-7.60 (4m, aryl).

The starting material is obtained as follows:

a) 2-Amino-3-o-chlorobenzoyl-5- (2-dicarbethoxyethyl) thiophene

53.9 g (0.3 mol) of o-chlorocyanoacetophenone, 9.6 g of sulfur, 30.4 g (0.3 mol) of triethylamine and 120 ml of dimethylformamide are added with stirring, starting at room temperature with 64.8 g (0, 3 moles) of dicarbethoxybutyraldehyde (DT Warner, J. Am. Chem. Soc., 70, 3470 (1948), b.p. 97 ° C / 0.1 mbar), the temperature rising to 45-50 ° C. The mixture is stirred for 2-3 hours at 60-70 ° C, cooled to room temperature and added 400 ml of water. The resulting thiophene derivative is extracted by shaking three times with 200 ml of methyl tert-butyl ketone each time. After washing with water and drying the organic phase is evaporated and the crystalline residue from isopropanol / water 7: 3 recrystallized.
Yield: 90 g (74% of theory),
Mp 96-98 ° C.

b) 2-Amino-o-chlorobenzoyl-5- (2-carbomethoxyethyl) thiophene

63 g (0.15 mol) of the above compound are refluxed with 120 ml of ethanol and 32.5 g of potassium hydroxide in 50 ml of water for 2 hours. It is evaporated in vacuo, diluted with 50 ml of water and acidified with HCl. The greasy precipitated acid is shaken out several times with ethyl acetate. The extracts are dried and evaporated, the residue is refluxed with 300 ml of toluene and 30 ml of dimethylformamide for 2 hours. After evaporation to about 50 ml to obtain crystals of monocarboxylic acid.
Yield: 20.5 g.

The purified acid melts at 171-173 ° C.

The crude acid is combined with 400 ml of absolute methanol and 0.4 ml of concentrated sulfuric acid for 18 hours Room temperature stirred. It is poured after evaporation of the Methanol on ice, shaken out with methylene chloride and after renewed evaporation from isopropyl ether 15 g of ester, mp. 89-90 ° C.  

c) 2-Bromoacetylamino-3-o-chlorobenzoyl-5- (2-carbomethoxyethyl) - thiophene

27.8 g (0.09 mol) of the above ester are suspended in 700 ml of toluene and mixed with 10 g of sodium bicarbonate in 57 ml of water. While stirring, 7.9 ml bromoacetyl bromide are added gradually at 40-50 ° C and stirred for 30 minutes. It is washed with water, the toluene phase is dried, evaporated in vacuo and crystallized with isopropyl ether.
Yield: 35-37 g,
Mp 104-106 ° C.

d) 2-Aminoacetylamino-3-o-chlorobenzoyl-5- (2-carbomethoxyethyl) - thiophene

35.8 g (0.08 mol) of the above bromoacetyl compound dissolved in 700 ml of ethyl acetate and stirred 2-3 hours at room temperature, dry ammonia introduced. Leave overnight, wash with ice-water, Dries, evaporates and receives 22-25 g of oily amino compound.

e) 7- (2-carbomethoxyethyl) -5-o-chlorophenylthieno 1,4-diazepinone

21.3 g (0.056 mol) of the above compound are dissolved in 500 ml of toluene and boiled with 75 g of silica gel on a water for 2 hours under reflux. The SiO _{2 is} filtered off with suction and the diazepine is extracted with hot methanol. After evaporation of the methanol, 12-15 g of diazepine, mp. 160-162 ° C are obtained.

f) 7- (2-carbomethoxyethyl) -5-o-chlorophenylthieno 1,4-diazepine-2-thione

10 g (0.03 mol) of the above diazepinone are dissolved in 100 ml Diglyme with 6.8 g of phosphorus pentasulfide and 5 g of sodium bicarbonate Stirred at 70-80 ° C for 3 hours. The suspension is poured onto ice, stirred for 30-45 minutes and sucks off the crystals. After drying receives 10 g of thione of mp. 185-186 ° C.

g) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] ethan-1-carboxylic acid methylester

6.1 g (0.016 mol) of the above sulfur compound are in Dissolved 100 ml of tetrahydrofuran and after addition of 1 g Hydrazine hydrate stirred at 45-50 ° C for 30 minutes. It is then evaporated in vacuo. Stay behind 5-5.2 g of oil which crystallize with isopropyl ether (Mp 175-177 ° C).

The hydrazino compound gives on heating in 35 ml Ortho-acetic acid ester at 80 ° C, evaporation from methylene chloride Ether 3 g of triazolodiazepine from Mp 114-115 ° C.

The same compound is from the thione with acetic hydrazide accessible.

From 6.1 g of the methyl ester is obtained after saponification in alcoholic-aqueous potassium hydroxide solution 5.7-5.8 g of the free Carboxylic acid of mp. 196-198 ° C.  

Example 2 2- [4- (2-Chlorophenyl-9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid morpholide

Starting from 15 g of 2- [4- (2-chlorophenyl) -9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine -2-yl] - ethane-1-carboxylic acid, mp 227-230 ° C, the title compound is obtained in analogy to Example 1.
Yield: 15.0 g (86.5% of theory),
Mp 159-160 ° C.
¹ H-NMR (CDCl _3); δ = 0.96-1.40 (4m, cyclopropyl-CH ₂ -), 1.93-2.28 (1m, cyclopropyl) 2.64 (2t, CH ₂ -CO-), 3.15 (2t, CH ₂ ), 3.31-3.77 (8m, morpholine), 4.91 (2s, CH ₂ -7 ring) 6.44 (1s, thiophene), 7.22-7.60 (4m, aryl ).

The starting compound is obtained as follows:

38 g (0.1 mol) of 7- (2-carbomethoxyethyl) -5-o-chlorophenyl thieno-1,4-diazepine-2-thione (see Example 1) of Mp 185-186 ° C with 11 g of cyclopropylcarboxylic acid hydrazide boiled in 50 ml of dioxane for 1 hour under reflux. After evaporation left behind by trituration with ether 30 g of red crystals of mp. 148-150 ° C, which is in 1 l Toluene in the presence of 140 g of silica gel for 4 hours Heated water separator. Then it is cooled, filtered off with suction and the triazole compound with hot methanol extracted. It remains as a residue of the extraction 24 g of viscous oil, which can be boiled for one hour Saponified 250 ml of 2 l alcoholic potassium hydroxide solution. After usual Work-up, 15-18 g of the carboxylic acid are obtained, which can be converted directly into the amide.  

Example 3 [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -carbonsäuremorpholid

36 g (0.1 mol) of the corresponding carboxylic acid (KH Weber et al DOS 25 03 235, 29. 7. 1976, p 14), mp. 302 ° C, as described in Example 1, with 10 g of morpholine in Implemented dimethylformamide. 38 g (89% of theory) of viscous oil are obtained.
¹ H-NMR (CDCl _3); δ = 2.75 (3s, _CH3), 3.71 (8s, morpholine), 4.97 (2s CH ₂ -7-ring) 6.83 (1s, thiophene), 7.26 to 7.64 (4m , Aryl).

Example 4 [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -carboxamide

3.7 g (0.01 mol) of the corresponding carboxylic acid methyl ester (KH Weber et al, DOS 25 03 235, 29. 7. 1976, p 14), mp. 230-232 ° C, are converted into the corresponding acid. In analogy to Example 1 gives the title compound.
Yield: 3.5 g (98% of theory),
Mp 300 ° C (decomp.).
¹ H-NMR (CDCl _3); δ = 2.66 (3s, _CH3), 4.85 (2s, CH _2), 7.50 (1s, thiophene), 7.52 (4H, aryl), 7.65 and 8.25 (2s, NH ₂ ).

Example 5 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid diethylamide

3.87 g (0.01 mol) of the corresponding carboxylic acid (see Example 1) are reacted in methylene chloride in analogy to Example 1 with diethylamine. After customary work-up and chromatography over a column filled with SiO ₂ (methylene chloride / 4% methanol), 1.8-2.0 g of a viscous oil are obtained.
¹ H-NMR (CDCl _3); δ = 1.09 and 1.12 (2x3t, C ₂ H ₅ ) 2.52 (2t CH ₂ -CO), 2.72 (3s, CH ₃ ), 3.03-3.56 (6m , C ₂ H ₅ and CH ₂ ), 4.90 (2s, CH ₂ -7 ring), 6.44 (1s, thiophene), 7.25-7.55 (4m aryl).

Example 6 [4- (2-chlorophenyl) -9-methyl-6-H-thieno [3,2-f] [1,2,4] triazolo- [4,3-a] [1,4] diazepin-2-yl] -methancarbonsäuremorpholid

20 g (0.054 mol) of [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazole [4,3-a] [1,4] diazepin-2-yl] -methanecarboxylic acid are reacted in analogy to Example 1 in 500 ml of tetrahydrofuran. After stirring overnight at room temperature, evaporation, absorption in methylene chloride, washing with sodium bicarbonate solution and filtration through a SiO ₂ column, it was possible by Umkristalisation from ethyl acetate 9.4 g of the title compound, mp. 143-144 ° C are obtained.
¹ H-NMR (CDCl _3): δ = 2.74 (3s, CH _3), 3.36 to 3.82 (8 m, morpholine), 3.88 (2s, CH ₂ -CO), 4.97 (2s, CH ₂ -7 ring), 6.51 (1s, thiophene), 7.25-760 (4m, aryl).

The carboxylic acid is accessible in the following way:

Diethyl malonate and bromoacetaldehyde acetal give the dicarbethoxypropionaldehyde (Kp _0.01 : 92-95 ° C.) by literature methods, which can be converted into the corresponding 2-aminobenzoylthiophene analogously to Example 1 using chlorocyanoacetophenone and sulfur. Saponification, decarboxylation and esterification with methanol / sulfuric acid give the 2-amino-3- (o-chlorobenzoyl) -5- (carbomethoxy-methyl) -thiophene, bromoacetylation, amination and ring closure afforded the corresponding diazepinone, m.p. 180-182 ° C. The resulting thione melts at 184-185 ° C. Treatment of the thione with hydrazine and subsequent reaction with orthoacetic acid ester leads to Triazolothienocarbonsäuremethylester, mp. 139-141 ° C; subsequent saponification with alcoholic-aqueous potassium hydroxide gives the free carboxylic acid, mp. 257-259 ° C.

Example 7 3- [4- (2-chlorophenyl) -9-methyl-6-H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -propan-1-carboxylic acid morpholide

10 g (0.025 mol) of 3- [4- (2-chlorophenyl) -9-methyl-6-H-thieno [3,2-f] [1,2,4] triazolo [4.3 -a] [1,4] -diazepin-2-yl] -propane-1-carboxylic acid in tetrahydrofuran reacted with morpholine and give after chromatographic workup 10.5 g (89% of theory) of a viscous almost colorless oil.
¹ H-NMR (CDCl ₃ ): δ 2.00 (2m, CH ₂ ), 2.37 (2m, CH ₂ CO), 2.71 (3s, CH ₃ ), 2.87 (2m, CH ₂ ), 3 , 26-3.83 (8m, morpholine), 4.94 (2s, CH ₂ -7 ring), 6.41 (1s, thiophene), 7.24-7.61 (4m, aryl).

We received the starting material in the following way:

Starting from cyclohexanone is known from the literature Method (L. Claisen, Ber., Dsch., Chem., Ges. 40, 3907) Accessible to enol ethers, which are subjected to ozonolysis (V. Schmid, Count, Liebigs Ann. Chem. 656, 97 (1962). Obtained is the 5-formylvalerate, the as already described for 2-amino-3-benzoylthiophene-5 propanecarboxylic acid ester is reacted. The result thiophenezepine obtained melts at 152-153 ° C Further reaction with phosphorus pentasulfide analogously to Example 1 f gives the thione of mp 176-178 ° C. The implementation with hydrazine and reaction with orthoacetic acid ester Example 1 g lead to the corresponding ester, which with alcoholic potassium hydroxide to the carboxylic acid of the melting point 257-259 ° C is saponified.  

Example 8 4- [4- (2-Chlorophenyl-9-methyl-6-H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -butan-1-carboxylic acid morpholide

15 g (0.036 mol) of 4- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] -triazolo- [4,3-a] [1 , 4] -diazepin-2-yl] -butane-1-carboxylic acid give, analogously to Example 1 with morpholine in dimethylformamide as solvent, the title compound as a pale yellow viscous oil (yield 13 g = 75% of theory).
¹ H-NMR (CDCl _3); δ 1.72 (4m, -CH ₂ -CH ₂ -), 2.87 (2m, CH ₂ CO), 2.71 (3s, CH ₃ ), 2.83 (2m, CH ₂ ), 3.30 -3.77 (8m, morpholine), 4.93 (2s, CH ₂ -7 ring), 6.41 (1s, thiophene), 7.21-7.58 (4m, aryl).

The carboxylic acid is obtained from commercially available cycloheptanone analogous to Example 7 over the corresponding aldehyde from bp ₁₅ : 115-120 ° C, the thienotriazolo-1,4-diazepine-2-butancarbonsäuremethylester, mp. 119-121 ° C after saponification of the same and melts at 133-134 ° C.

Example 9 2- [9-bromo-4- (2-chlorophenyl-6-H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid morpholide

4.4 g (0.001 mol) of 2- [4- (2-chlorophenyl) -6-H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1, 4] -diazepin-2-yl] -ethane-1-carboxylic acid morpholide of mp. 188-189 ° C (see Example 19) is dissolved in 44 ml of chloroform, 2 ml of pyridine and 0.7 ml of bromine and stirred overnight at room temperature , The light brown reaction solution is washed with sodium bicarbonate / water, the organic phase is dried and the solvent is concentrated, on addition of ether 3.1 g (60% of theory) of the title compound are obtained as pale brown-gray crystals which are at 181-182 ° C melt.
¹ H-NMR (CDCl _3): δ = 2.66 (2t, CH ₂ CO), 3.17 (2t, CH _2), 3.31 to 3.75 (8m, morpholine), 4.95 (2s , CH ₂ ), 6,46 (1s, thiophene), 7,30-7,55 (4m, aryl).

Example 10 2- [4- (2-chlorophenyl) -9-methoxy-6-H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -ethane-1-carboxylic acid morpholide

2.6 g (0.5 mmol) of the 9-bromo compound of Example 9 are stirred with a solution of 3.7 g of potassium hydroxide in 400 ml of methanol at 50-60 ° C for 1 hour. After evaporation of the methanol, the residue is mixed with ice-water and extracted with methylene chloride. The organic phase is dried and the solvent is concentrated in vacuo. The residue which remains is recrystallised from ethyl acetate, giving 1.8 g (76% of theory) of the title compound of mp. 163.degree.-164.degree.
¹ H-NMR (CDCl _3): δ = 2.62 (2t, CH _2), 3.11 (2t, CH _2), 3.32 to 3.77 (8m, morpholino), 4.27 (3s, CH ₃ ), 4.88 (2s, CH ₂ ), 6.36 (1s, thiophene), 7.36 (4s, aryl).

Example 11 8- [4- (2-chlorophenyl) -9-cyclopropyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -n-octane-1-carboxylic acid morpholide

4.63 g (0.01 mol) of the corresponding carboxylic acid are converted into the amide analogously to the process described in Example 1. This gives 4.4 g (84.6% of theory) of viscous oil.
¹ H-NMR (CDCl _3); δ = 1.12-1.14 (12m, (CH ₂ ) ₆ ), 2.72 (3s, CH ₃ ), 2.68 (2t, CH ₂ -CO), 3.15 (2t, CH ₂ ) , 3.31-3.78 (8m, morpholine), 4.90 (2s, CH ₂ ), 6.42 (1s, thiophene), 7.25-7.60 (4m, aryl).

Starting compound for the carboxylic acid is the 9-formylnanancarboxylic acid methyl ester of bp ₀₀₅ 101-104 ° C, which is obtained according to RA Volkmann et al, J. Org. Chem. 48, 1767 (1983).

Following the methods described above were further the following compounds are obtained:

The following are examples of some pharmaceutical Compositions using compounds of general formula I as an active ingredient. Unless otherwise stated, it is The parts are parts by weight.

1. tablets

The tablet contains the following ingredients:

Active ingredient according to formula I. 0.020 parts stearic acid 0.010 parts dextrose 1,890 parts total 1,920 parts

manufacturing

The substances are mixed together in a known manner and the mixture is compressed into tablets, of which Each weighs 1.92 g and contains 20 mg of active ingredient.

2nd ointment

The ointment consists of the following ingredients together:

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] - [1,4] diazepin-2- yl] -ethan-1-carboxylic acid morpholide | 50 mg Neribas ointment (commodity Scherax), ad 10 g

manufacturing

The active ingredient is triturated with 0.5 g ointment base and the remaining basis in 1.0g aliquots and mixed intimately into an ointment. You get one 0.5% ointment. The distribution of the active ingredient in the Foundation is visually inspected under the microscope.  

3rd cream

composition 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] - [1,4] diazepin-2- yl] -ethan-1-carboxylic acid morpholide | 50 mg Neribas ointment (commodity Scherax), ad 10 g

manufacturing

The active ingredient is triturated with 0.5 g of cream base and the remaining basis in 1.0g aliquots and after with pestle incorporated. You get one 0.5% cream. The distribution of the active ingredient in the Foundation is visually inspected under the microscope.

4. Ampoule solution

composition a) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethan-1-carboxylic acid morpholide | 1.0 mg sodium chloride 45.0 mg Aqua pro inj., Ad 5.0 ml b) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethane-1-carboxylic acid morpholide 5.0 mg sodium chloride 45.0 mg Aqua pro inj., Ad 5.0 ml c) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethane-1-carboxylic acid morpholide 1.0 mg sodium chloride 9.0 mg Aqua pro inj., Ad 1.0 ml

manufacturing

The active ingredient is dissolved in water at intrinsic pH and Sodium chloride added as isotonicity. The obtained Solution is filtered pyrogen-free and the filtrate under aseptic conditions bottled in ampoules, the then sterilized and sealed. The ampoules contain 1 mg, 5 mg and 1 mg of active ingredient.

5. Suppositories

Each suppository contains:

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] - [1,4] diazepin-2- yl] -ethane-1-carboxylic acid morpholide 1.0 parts Cocoa butter (mp 36-37 ° C) 1200.0 parts carnauba 5.0 parts

manufacturing

Cocoa butter and carnauba wax are melted together. At 45 ° C, the active ingredient is added and stirred until a complete dispersion is formed.
The mixture is poured into shapes of appropriate size and the suppositories packed appropriately.

6. Inhalation solutions

composition a) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethan-1-carboxylic acid morpholide | 500 mg Na-EDTA 50 mg benzalkonium chloride 25 sodium chloride 880 mg Distilled water, ad 100 ml

manufacturing

96% of the amount of water are presented, one after the other Na-EDTA, benzalkonium chloride, sodium chloride and active ingredient clearly dissolved and with the remaining water refilled. The solution is filled into 20 ml dropping bottles. One dose (20 drops, 1 ml) contains 5 mg Active ingredient.

b) 2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine 2-yl] -ethan-1-carboxylic acid morpholide | 500 mg sodium chloride 820 mg Distilled water, ad 100 ml

manufacturing

96% of the amount of water are presented, one after the other the active ingredient and sodium chloride dissolved with the The remaining water is filled up and the solution in a single-dose container (4 ml). The solution contains 20 mg Active ingredient.

Claims (2)

1. A process for the preparation of novel thieno-triazolo-1,4-diazepino-2-carboxamides of the general formula wherein
R _{1 is} hydrogen, a straight-chain or branched alkyl group having 1-4 carbon atoms, optionally substituted by halogen or hydroxy; Cyclopropyl, alkoxy of 1-3 carbon atoms, halogen;
R ₂ and R ₃ , which may be identical or different, represent hydrogen, a straight-chain or branched alkyl or hydroxyalkyl radical having 1-4 carbon atoms or both radicals R ₂ and R ₃ together with the nitrogen atom is a 5-, 6- or 7-membered ring optionally containing as another heteroatom a nitrogen, oxygen or sulfur atom and wherein the second nitrogen atom may optionally be substituted by an alkyl group having 1-4 carbon atoms;
R _{4 is} phenyl, where the phenyl ring may be substituted by methyl, halogen, nitro or trifluoromethyl or α-pyridyl and
n is one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8,
characterized in that a corresponding 2-carboxylic acid of the general formula wherein the radicals R ₁ and R _{4 have} the meaning given, in the presence of sulfonyldiimidazole with an amine of the general formula wherein the radicals R ₂ and R _{3 have} the meaning indicated, is reacted. 2. The method according to claim 1, characterized in that in a one-pot reaction starting from imidazole and Thionyl chloride first formed the sulfonyldiimidazole and then with thienotriazolo-1,4-diazepin-2-yl carboxylic acid is reacted.