DE4219659A1 - Bronchial asthma treatment with PAF-antagonist - esp. thieno:triazolo:diazepine deriv., in presence of anticholinergic agent for synergistic effect - Google Patents

Abstract

The use of PAF (platelet activating factor) antagonists (I) and anticholinergics (II) for treatment of bronchial asthma is new. Also claimed are the use of (I) of hetrazepinoid structure in combination with (II) for therapeutic treatment of bronchial asthma; and pharmaceutical compsns. contg. (I) and (II). (I) are thieno (3,2-b)(1,2,4)triazolo (4,3-a)(1,4)diazepine derivs. (or tetracylic and/or thieno- imidazo- diazepine analogues). USE/ADVANTAGE - Simultaneous use of (I) and (II) for treatment of bronchial asthma gives a dose-dependent, synergistic increase in the anti anaphylactic/antiallergic activity of (I). (I) and (II) may be administered simultaneously by inhalation in the same formulation, e.g. an aerosol. Alternatively, (II) is administered by inhalation and (I) is administered orally or parenterally. The dose of (I) depends on the relative PAF receptor binding affinity; typically the oral dose of WEB 2086 as (I) is 40-2000 (esp. 90-120) mg. The combination of (I) and (II) may also be used for treating other chronic obstructive respiratory tract disorders, e.g. bronchitis.

Description

The present invention relates to the use of PAF antagonists in combination with anticholinergics as a medicament - in particular for the treatment of Bronchial asthma as well as drugs containing such Combinations.

The use of PAF antagonists for the therapy of Bronchial asthma and chronic bronchitis is in various patent applications described so to Example in the European patent applications 194 416, 254 245 and others. It is also known that anticholinergics for the treatment of chronic obstructive respiratory diseases (especially the chronic bronchitis) are suitable and clinical be used.

Surprisingly, it was found that a simultaneous use of PAF antagonists and Anticholinergics dose-dependent the antianaphylactic / antiallergic properties the PAF antagonists in animal models superadditive (synergistically) reinforced. This finding was so far not to be expected, since the antianaphylactic Properties of anticholinergic drugs until not long in Animal experiments could be occupied.

On the basis of the available findings, it seems natural to Treatment of bronchial asthma a drug to propose that as the active ingredient is a combination of a PAF antagonist and at least one Contains anticholinergic.

Compounds known as PAF antagonists (PAF = platelet activating factor) are used in the Patent literature and the subject-specific literature known, such. In prostaglandins 35, 781 (1988) or  also in Handbook of PAF and PAF antagonists, Pierre Braquest, 1991 by CRC Press, Inc.

Known PAF antagonists are for example L-668750, LG-30435, MK-287, UK 74,505, Y 20411, Y24180, RO 244 736, E 6123, CV 6209, alprazolam, BN - 50,730, BN-50,727, BN-50,766, BN-54,068, BN-50,739, BN-50.726, BN 52.022, BN-52.021, BN-52.020, BN-52.025, BN-52.115, BN-52.111, BN-52.023, BN-52,024, BN-50,580, BN-50,585, Brotizolam, CV 6209, CN - 3988, Dilthiazem, E - 6123, E - 5880, F-1850, FR-49.175, FR-90.0452, FR-10.6969, Kadsurenon, L-653,150, L-668,750, L-652,731, L-659,989, LG-50,643, MK-287, ONO-6240, PCA-4248, R-74.654, RN-70.727, RO-244.736, RO-19 3704, RP-55.778, RP-59.227, RP-55 270, RP - 48 740, RP - 52 770, RU - 45 703, Sch - 37.370, SDZ-64.412, SM-10.661, SRI-63.675, SRI-441, SRI-63,119, SRI-63,072, TCV-309, triazolam, UK - 74,505, UR - 10,324, UR - 11,353, Y - 24,180, Y-20,411, YM-461, YM 264.

Also of interest are PAF antagonists hetrazepinoider structure, such. B. substituted Hetrazepines of general formula I

Roger that. They are known from the prior art, so z. From the European patent applications:

EP-A-0.176.927, EP-A-0.176.928, EP-A-0.176.929, EP-A-0.194.416, EP-A-0.230.942, EP-A-0.240.899, EP-A-0.254.245, EP-A-0.255.028, EP-A-0.268.242, EP-A-0.279.681, EP-A-0.284.359, EP-A-0.291.594, EP-A-0 298 466, EP-A-0.315.698, EP-A-0.320.992, EP-A-0.342.456, EP-A-0.338.992, EP-A-0.328.924, EP-A-0 342 587, EP-A-0.338 993, EP-A-0 367 110, EP-A-0.368.175, EP-A-0.387.613, EP-A-0.407.955, as well as the European patent application with the File number 91 114 518 and also from the German Laid-open publications DE 40 10 361, 40 10 316, 40 15 137, incorporated herein by reference is, in particular to those in these writings as preferred and particularly preferred mentioned Embodiments.

Of particular interest here are hetrazepines of general formula

wherein
R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, halogen, preferably chlorine and bromine;
R _{2 is} a radical of the formula

wherein A is a branched or unbranched alkyl group having n carbon atoms, wherein
one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8
R ₆ and R ₇ , which may be the same or different, are hydrogen, phenyl, substituted phenyl, an optionally substituted cycloalkyl group of 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group of 1 to 10 - preferably 1-4 - Carbon atoms which may optionally be substituted by halogen, hydroxy, nitro, phenyl, substituted phenyl, amino, substituted amino, C ₁ to C ₈ preferably C ₁ to C ₄ alkoxy may be substituted;
R ₆ or R _{7 is} a saturated or unsaturated, 5- or 6-membered heterocyclic ring which is optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atoms and bonded via a carbon atom or nitrogen;
or
R ₆ and R ₇ together with the nitrogen atom a saturated or unsaturated optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-ring, which may contain nitrogen, oxygen or sulfur as further heteroatoms wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl;
R _{8 is} phenyl, substituted phenyl;
R _{9 is} hydrogen, C ₁ to C ₄ alkyl;
R _{3 is} hydrogen, C ₁ -C ₄ -alkyl;
R _{4 is} phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ -alkyl, preferably methyl, optionally substituted by hydroxy or halogen or
R ₂ and R ₃ together form a fused five- or six-membered ring of the formula

where Ra is a radical of the formula

wherein A, R ₆ , R ₇ , R ₈ and R _{9 have} the abovementioned meaning and
R _{10 is} C ₁ -C ₄ -alkyl or cyclopropyl,
R _{4 is} phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ -alkyl, preferably methyl, optionally substituted by hydroxy or halogen
and X may be nitrogen or CH.

Preferably, such compounds of the general Formula 1, in which

R ₃ = hydrogen, R ₅ = methyl or hydrogen
R ₂ and R ₃ together

With
Ra = CONR ₆ R ₇
R ₆ / R ₇ = C ₃ H ₇ or together with the nitrogen atom is particularly preferably a morpholino radical.
R ₅ = hydrogen, or methyl, X = N
R ₄ = ortho chlorophenyl.

As alkyl groups (even if they are part of another Radicals are) are for example called: methyl, Ethyl, propyl, iso-propyl, butyl, iso-butyl, sec. Butyl, tert-butyl, pentyl, iso-pentyl, hexyl, heptyl, Octyl, nonyl and decanoyl.

As alkenyl groups, for example, the above Alkyl groups, as far as they are at least one Have double bond, such as vinyl (so far no fugitive enamines are formed), propenyl, iso-propenyl, butenyl, pentenyl, hexenyl.

Examples of alkynyl groups mentioned above Alkyl groups, if they have at least one Have triple bonds, such as propargyl, Butynyl, pentynyl, hexynyl.

As cycloalkyl radicals having 3-6 carbon atoms for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is characterized by branched or unbranched alkyl having 1 to 4 carbon atoms, Hydroxy, and / or halogen may be substituted.

Examples of substituted phenyl are mentioned: 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-fluoromethylphenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 2,3-dichlorophenyl, 2-methylphenyl, 4-methylphenyl, 3-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-butylphenyl, 4-tert-butylphenyl, 4-iso-butylphenyl, 4-pentylphenyl, 2,4-dimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl,  4-methoxyphenyl, 3-ethoxyphenyl, 2-propoxyphenyl, 4-butoxyphenyl, 2,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chlorobenzyl, 2,3-dichlorobenzyl, 2-methylbenzyl, 2-trifluoromethylbenzyl, 4-methoxybenzyl, 3,4,5-trimethoxybenzyl, 2- (2-chlorophenyl) ethyl,

Examples of optionally substituted saturated or unsaturated heterocyclic 5-, 6- or 7-membered rings or heteroaryl radicals are:
Pyrrole, pyrroline, pyrrolidine, 2-methylpyrrolidine, 3-methylpyrrolidine, piperidine - optionally mono- or polysubstituted by C ₁ -C ₄ -alkyl - piperazine, N-methylpiperazine, N-ethylpiperazine, NN-propylpiperazine, N-benzylpiperazine, morpholine , Thiomorpholine, imidazole, imidazoline, imidazolidine, triazole, pyrazole, pyrazoline, pyrazolidine, triazine, 1, 2, 3, 4-tetrazine, 1, 2, 3, 5-tetrazine, 1, 2, 4, 5-tetrazine - wherein said heterocycles may be substituted by alkyl of 1 to 4 carbon atoms, preferably methyl;
Examples of heterocyclic radicals which may be linked via a carbon atom are thiophene, 2-methylthiophene, furan, tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-hydroxymethylfuran, α-pyran, γ-pyran, 1,3-dioxolane, 1, 2-oxathiolane, 1,2-oxathiepan, tetrahydropyran, thiolane, 1,3-dithiane, 1,3-dithiolane, 1,3-dithiolene, wherein the heterocycle is represented by C ₁ -C ₄ -alkyl, C ₁ -C ₄ alkoxy or halogen may be substituted.

As a heterocycle within the scope of the above Definition also generally stands for a 5- to 6-membered ring, which as oxygen heteroatoms, May contain sulfur and / or nitrogen, such as Example thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, Pyrazinyl, quinolyl, isoquinolyl, quinazolyl, Quinoxalyl, thiozolyl, benzothiazolyl, isothiazolyl, Oxazolyl, benzooxazolyl, isoxazolyl, imidazolyl, Benzimidazolyl, pyrazolyl and indolyl.

The PAF antagonists described above are suitable for the application according to the invention. To emphasize is the use of 4- (2-chlorophenyl) -9-methyl-2- [3 (4-morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin (WEB 2086) (I); 6- (2-chlorophenyl) -8,9-dihydro-1- methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H- cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] - [1,4] diazepine (Web 2170) or the 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- [Dipropylaminocarbonyl] -4, 7H-cyclopenta [4,5] - thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepin (Web 2347) as well as in the above European applications highlighted links.

The anticholinergics which can be used according to the invention are known in the art, such as Atrovent, Oxident, Tigloidin, Octamylamine, Fubrogonium iodide, dibulin sulfate, hyoscine hydrobromide, Homatropine hydrobromide, hyoscine amine oxide, amphiols, Hyoscymines, atropine oxides, phenglutarimide, Eucatropine, Homatropine methyl bromide, Octatropine methyl bromides, methdilazines, heteronium bromides, Hyoscine methobromide, thiozinamium methylsulfate, Pentapiperides, caramiphenium chloride, Thihexinol methyl bromide, hexasonium iodide,  Oxysonium iodide, piperphenidol, amprotropine, Troxypyrrolium tosilate, oxyphenhydrazonium bromide, Penthienate methobromides, dimegamides, fencarbamides, Dicarfen, Antiparkin, Naltropin, Aprobit, Cycrimine, Procyclidine, Glycopyrronium bromide, Barbetonii iodidum, camylofine, mepiperphenidol, barespan, DICYCLOVERINES, diphenethyl nicotinamides, metastases, Aminocarbofluorenes, triclazate, pridinol, diphemanil, Tifenamil, Benactyzine, Difemerine, Lachesine, Ambutonium bromide, Emepronium bromide, Promandeline-263, oxyclipin, endobenzyline bromide, Dipiproverins, trihexyphenidyl, metacaraphs, Hexapyrronium bromide tricyclamol, hexocyclium methyl sulfates, dihexyverins, piperidolates, Benaprizine, Despasmin, Poldinmetilsulfat, Mepenzolate bromides, parapenzolate, methanthelinium bromide, Triperides, Methylbenactyl bromide, Prampin methyl nitrate, oxypyrronium bromide, Fluoxyphenonium bromide, oxyphenonium bromide, Trihexoyl chloride, tropirin, tropacine, Etybenzatropine Clidinium bromide, Acemydrite, Prifinium bromide, Diprofene, Anacolin, Pipenzolate bromides, oxybutynin, mespenal, benzomethamine, Decitropines, benzimides, dexetimides, SCH-221, Ethpenal, Propantheline, Buzepide metiodide, Isopropamide iodide, meletimide, deptropion methobromide, Alin "Dr. Lazar", hemicholinium bromide, tropodifen, Atropine octyl bromide, bentipimines, xenytropium bromides, Fentonium bromide, salfluverine, domazoline, Hyoscyamine methyl bromide, elucaine, ritropyrronium bromide, Elantrine, Pitofenone, Zepastin, Droclidinium Bromide, Nolinium bromide, anisodamine, ipragratine, cimetropium Bromides, levodopa, dispan-compositum, butamates, Tropicamin, cyclopentolate, atromepine, proglumide, Atropine methonitrate, meclxamine, Quinidine,  Butynolines, terodilines, alverines, oxyphencyclimines, Sultroponium, benzatropines, pramiverines, biperiden, Benxilonium bromide, Bevonium methyl sulphate, Ciclonium bromides, deptropines, trospium chlorides, Chlorobenzoxamines, timepidium bromides, amixetrin, Rociverine, Trantelinium bromide, Ethylpipethanate Bromides, butropium bromides, tiropramide, oxitropium Bromides, bornaprines.

Usually, the combination according to the invention at the same time in a common formulation by inhalation, for example as a metered dose inhaler, administered.

With concurrent administration but is also the application in temporal context in separate formulations to understand. While the anticholinergic almost exclusively in an inhalable formulation is applied, the PAF antagonist can be taken orally parenterally as a suppository. The PAF antagonists are active ingredients in conventional dosage forms, z. In Compositions consisting essentially of a inert pharmaceutical carrier and an effective Dose of the active ingredient exist, such as. Eg tablets, Drag'es, capsules, wafers, powders, solutions, Suspensions, emulsions, syrups, suppositories etc.

An effective single oral dose of the PAF antagonist Web 2086 is between 40 and 2000 mg, preferably 80-150 mg, more preferably 90-120 mg. The Single doses of other PAF antagonists are classified as general compared to this compound according to their relative  PAF receptor binding affinities. Connections with a higher receptor affinity than (I) require one lower therapeutic dose.

Examples of galenic preparations of the PAF antagonists are listed below:

example 1 Tablets containing 80 mg of substance

composition Active ingredient | 80.0 mg corn starch 57.0 mg lactose 48.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 1.0 mg 190.0 mg

production method

The active ingredient, cornstarch, lactose and Polyvinylpyrrolidone are mixed and mixed with water moistened. The moist mixture is passed through a sieve pressed with 1.5 mm mesh size and at about 45 ° C. dried. The dry granules are passed through a sieve beaten with 1.0 mm mesh size and with Magnesium stearate mixed. The finished mixture presses on a tablet press with punches of 7 mm Diameter, which are provided with a part notch, too Tablets.

Tablet weight: 190 mg.  

Example 2 Drag'es containing 50 mg of substance

composition Active ingredient | 50.0 mg corn starch 41.5 mg lactose 30.0 mg polyvinylpyrrolidone 3.0 mg magnesium stearate 0.5 mg 125.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve of 1 mm mesh size, dried at about 45 ° C and then strikes the granules through the same sieve. After admixing magnesium stearate, corrugated drag cores having a diameter of 6 mm are pressed on a tableting machine. The Drag'ekerne thus prepared are coated in a known manner with a layer consisting essentially of sugar and talc. The finished Drag'es are polished with wax.
Drag'e weight: 175 mg.

Example 3 Tablets containing 50 mg of substance

composition Active ingredient | 50.0 mg calcium phosphate 70.0 mg lactose 40.0 mg corn starch 35.0 mg polyvinylpyrrolidone 3.5 mg magnesium stearate 1.5 mg 200.0 mg

manufacturing

The substance, calcium phosphate, lactose and Cornstarch are mixed with a watery polyvinyl uniformly moistened with pyrrolidone solution. The crowd will through a sieve with 2 mm mesh size, in Drying cabinet dried at 50 ° C and again sieved. After admixing the lubricant is the Granules pressed on a tableting machine.  

Example 4 Capsules containing 50 mg of substance

composition Active ingredient | 50.0 mg corn starch 268.5 mg magnesium stearate 1.5 mg 320.0 mg

manufacturing

Substance and cornstarch are mixed and mixed with water moistened. The moist mass is sieved and dried. The dry granules are sieved and washed with Magnesium stearate mixed. The final mixture is in Hard gelatine capsules size 1 bottled.

Example 5 Suppositories containing 50 mg of substance

composition Active ingredient | 50.0 mg Adeps solidus 1650.0 mg 1700.0 mg

manufacturing

The hard fat is melted. At 40 ° C, the milled active substance dispersed homogeneously. It will open Cooled to 38 ° C and slightly pre-cooled Suppository forms poured out.

Example 6 Oral suspension containing 50 mg of substance per 5 ml

composition Active ingredient | 50 mg hydroxyethyl 50 mg sorbic acid 5 mg Sorbitol 70% 600 mg glycerin 200 mg Aroma 15 mg Water ad 5 ml

manufacturing

Distilled water is heated to 70 ° C. This is where dissolved with stirring hydroxyethyl cellulose. After adding of sorbitol solution and glycerin is brought to room temperature cooled. At room temperature, sorbic acid, flavor and substance added. For venting the suspension is evacuated with stirring.  

Examples of inhalable formulations are:

1. inhalation aerosol

composition Combination according to claim 1 1.00 parts by weight soy lecithin 0.20 parts by weight liquefied propellant gas mixture (Frigene 11, 12 and 114) ad 100.00 parts by weight

The preparation is in aerosol container with Dispensed filling valve. The valve is like that designed that the single dose 5 mg Contains active ingredient combination.

2. Metered aerosol

Active ingredient combination according to the invention 0.005 parts by weight trioleate 0.1 parts by weight Monofluorotrichloromethane and difluorodichloromethane 2: 3 ad 100.00 parts by weight

The suspension is in a usual Aerosol container filled with dosing valve. Per Operation is preferably 50 ul suspension issued. The drug combination can if desired, also higher doses (eg. 0.02% by weight).  

Methods and results

1. Combination of an anticholinergic (Atrovent) with a PAF antagonist in the model of Antigen-induced lethality of passively sensitized Mice.

Female Balbc mice (21-25 g) were exposed 24 h Antigen / ovalbumin provocation passive with a rabbit heterologous serum at 1 ml / kg i.p. sensitized. Propranolol (to enhance the anaphylactic reaction, and elimination adrenergic Compensation reflexes) was 0.1 mg / kg i.p. 15 minutes. before OA, Atrovent and / or WEB 2170 10 min. before OA i.v. injected. The lethality rate after OA provocation was evaluated at the times 30 min. and 60 min.

In summary, the combination showed Atrovent + WEB 2170 in the selected dosages surprisingly an overly additive (if not synergistic) effect  against the antigen-induced lethality to passive sensitized mice.

2. Displacement of the DWK (dose-response curve) of a PAF antagonists against the PAF-induced Bronchoconstriction in the presence of a Anticholinergic.

Sober guinea pigs (Pirbright white, Ivanovas) were anesthetized with urethane and a tracheostomy tube (Measurement of the peak respiratory flow as a measure of the Airway resistance) and cannulas in the jugular vein (i.v. Application) and A. carotis (recording of the Blood pressure) implanted. The decrease of the max. Respiratory flow and its inhibition were at the time of Max. Change (in the first few minutes) evaluated. The Protocol was as follows: WEB 2086 (dosage range 0.001 mg / kg-0.1 mg / kg i.v.) was taken with or without Atropine (0.1 mg / kg i.v.) 10 min before, acetylcholine, Ach 0.02 mg / kg i.v.) 5 min. Before PAF (100 μg / kg i.v.) administered.

The DWK for WEB 2086 against PAF-induced Bronchoconstriction was in the presence of the Anticholinergic atropine (0.1 mg / kg i.v.) tends to moved to the left (see fig.). This supports the Claim that anticholinergics, although they have been shown not to act directly against PAF, in vivo surprisingly the dose of a Lessen PAF antagonists, which is necessary to inhibit PAF-induced bronchoconstriction. Therefore, the combination appears one Anticholinergic with a PAF antagonist to Therapy of chronic obstructive Respiratory diseases (bronchial asthma, bronchitis) meaningful.

Claims (11)

1. Use of PAF antagonists and Anticholinergics for the treatment of Bronchial asthma. 2. Use of PAF antagonists hetrazepinoider Structure in combination with anticholinergics for therapeutic treatment of the asthma barrel. 3. Use of compounds according to claim 1 or 2, characterized in that the PAF antagonist is the general formulas wherein
R _{1 is} hydrogen, a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl, which may optionally be substituted by hydroxy or halogen, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, halogen, preferably chlorine and bromine;
R _{2 is} a radical of the formula wherein A is a branched or unbranched alkyl group having n carbon atoms, wherein
n is one of the numbers 0, 1, 2, 3, 4, 5, 6, 7 or 8
R ₆ and R ₇ , which may be the same or different, are hydrogen, phenyl, substituted phenyl, an optionally substituted cycloalkyl group of 3 to 6 carbon atoms, a branched or unbranched alkyl, alkenyl or alkynyl group of 1 to 10 - preferably 1-4 - Carbon atoms which may optionally be substituted by halogen, hydroxy, nitro, phenyl, substituted phenyl, amino, substituted amino, C ₁ to C ₈ - preferably C ₁ to C ₄ alkoxy may be substituted;
R ₆ or R _{7 is} a saturated or unsaturated, 5- or 6-membered heterocyclic ring which is optionally mono- or polysubstituted by branched or unbranched alkyl having 1 to 4 carbon atoms and bonded via a carbon atom or nitrogen;
or
R ₆ and R ₇ together with the nitrogen atom a saturated or unsaturated optionally mono- or polysubstituted by branched or unbranched alkyl groups having 1 to 4 carbon atoms substituted 5-, 6- or 7-ring, which may contain nitrogen, oxygen or sulfur as further heteroatoms wherein each additional nitrogen atom may be substituted by a branched or unbranched alkyl group having 1 to 4 carbon atoms, preferably methyl;
R _{8 is} phenyl, substituted phenyl;
R _{9 is} hydrogen, C ₁ to C ₄ alkyl;
R _{3 is} hydrogen, C ₁ -C ₄ -alkyl;
R _{4 is} phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ -alkyl, preferably methyl, optionally substituted by hydroxy or halogen or
R ₂ and R ₃ together form a fused five- or six-membered ring of the formula where Ra is a radical of the formula wherein A, R ₆ , R ₇ , R ₈ and R _{9 are} the aforementioned
Have meaning and
R _{10 is} C ₁ -C ₄ -alkyl or cyclopropyl,
R _{4 is} phenyl, where the phenyl ring may be monosubstituted or polysubstituted, preferably halogen, nitro and / or trifluoromethyl;
R _{5 is} hydrogen, hydroxy, C ₁ -C ₄ -alkyl, preferably methyl, optionally substituted by hydroxy or halogen
and X may be nitrogen or CH. 4. Use of compounds of the general formula according to claim 3 wherein R ₃ = hydrogen, R ₅ = methyl or hydrogen R ₂ and R ₃ together With
Ra = CONR ₆ R _{7 is} particularly preferably R ₆ / R ₇ = C ₃ H ₇ or together with the nitrogen atom is a morpholino radical.
R ₅ = hydrogen, or methyl, X = N
R ₄ = ortho chlorophenyl. 5. Use according to claim 1 or 2, characterized characterized in that the PAF antagonist is a derivative a thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] - diazepines, a cyclopenta [4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine or a 2,3,4,5-tetrahydro-8H-pyrido- [4 ', 3': 4,5] thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine is.   6. Use according to claims 1-3, characterized characterized in that as PAF antagonist WEB 2086 or WEB 2170 is used. 7. Use according to claim 1 or 2 characterized characterized in that as PAF antagonist Y 20 411, Y 24 180, RO 24 4736, E 6123, BN 50 730, BN 50 739 or BN 50 726 is used. 8. Use according to claim 1, characterized characterized in that as PAF antagonist alprazolam, BN 50,730, BN - 50,727, BN - 50,766, BN - 54,068, BN - 50,739, BN - 50,726, BN 52,022, BN - 52.021, BN - 52.020, BN - 52.025, BN - 52.115, BN - 52.111, BN - 52.023, BN - 52.024, BN - 50.580, BN-50,585, Breadizolam, CV 6209, CN-3988, Dilthiazem, E - 6123, E - 5880, F - 1850, FR-49.175, FR-90.0452, FR-10.6969, Kadsurenon, L-653,150, L-668,750, L-652,731, L-659,989, LG-50,643, MK-287, ONO-6240, PCA-4248, R-74.654, RN-70.727, RO-244.736, RO-19 3704, RP-55.778, RP-59.227, RP - 55 270, RP - 48 740, RP - 52 770, RU - 45 703, Sch-37,370, SDZ-64,412, SM-10,661, SRI-63675, SRI-441, SRI-63119, SRI-63,072, TCV-309, triazolam, UK-74,505, UR-10.324, UR-11.353, Y-24.180, Y-20.411, YM-461, YM 264 is used. 9. Use according to claim 1 or 2, characterized characterized in that the anticholinergic from the Group Atrovent, Oxident, Tigloidin, Octamylamine, Fubrogonium iodide, dibulin sulfate, hyoscine hydrobromide, Homatropine hydrobromide,  Hyoscinamine oxide, amphiols, hyoscymines, atropines oxides, phenglutarimide, eucatropines, homatropines methyl bromide, octatropine methyl bromide, Methdilazine, Heteronium bromide, Hyoscine methobromide, thiozinamium methylsulfate, Pentapiperides, caramiphenium chloride, Thihexinol methyl bromide, hexasonium iodide, Oxysonium iodide, piperphenidol, amprotropine, Troxypyrrolium tosilate, oxyphenhydrazonium bromide, Penthienate methobromides, dimevamides, Fencarbamides, dicarfen, antiparkin, naltropine, Aprobit, Cycrimine, Procyclidine, Glycopyrronium bromides, Barbetonii iodidum, Camylofin, Mepiperphenidol, Barespan, DICYCLOVERINE, Diphenethyl nicotinamide, Metals, Aminocarbofluorenes, triclazate, pridinol, Diphemanil, tifenamil, benactyzine, difemerine, Lachesine, Ambutonium bromide, Emepronium bromide, Promandeline-263, oxyclipin, endobenzyline bromide, Dipiproverins, trihexyphenidyl, metacaraphs, Hexapyrronium bromide tricyclamol, hexocyclium methyl sulfates, dihexyverines, piperidolates, Pepethanate, Benaprizine, Despasmin, Polydimethyl sulfate, mepenzolate bromide, Parapenzolate, methanthelinium bromide, triperids, Methylbenactyl bromide, Prampinmethylnitrat, Oxypyrronium bromide, fluoxyphenonium bromide, Oxyphenonium bromide, trihexoyl chloride, tropirin, Tropacine, Etybenzatropine Clidinium bromide, Acemydrite, Prifinium bromide, Diprofene, Anacolin, Pipenzolates bromide, oxybutynin, mespenal, Benzomethamine, Decitropine, Benzetimide, Dexetimide, SCH-221, Ethpenal, Propantheline, Buceptants metiodide, isopropamide iodide, Meletimide, Deptropine Methobromide, Alin "Dr.  Lazar ", hemicholinium bromide, tropodifen, Atropine octyl bromide, bentipimines, Xenytropium bromide, Fentonium bromide, Salfluverine, domazoline, hyoscyamine methyl bromide, Elucaine, Ritropyrronium bromide, Elantrine, Pitofenone, Zepastine, Droclidinium Bromide, Nolinium bromide, anisodamine, ipratine, Cimetropium bromide, levodopa, dispan-compositum, Butamata, tropicamine, cyclopentolates, Atromepine, Proglumide, Atropine methonitrate, Meclxamine, quinidine, butinolines, terodilines, Alverine, Oxyphencyclimine, Sultroponium, Benzatropines, pramiverines, biperiden, benxilonium bromides, Bevonium methylsulfate, Ciclonium bromide, Deptropines, trospium chlorides, chlorobenzoxamines, Timepidium bromide, amixetrine, rociverine, Trantelinium bromide, ethyl piperates bromides, Butropium bromides, tiropramide, oxitropium Bromides, bornaprines. is selected. 10. Pharmaceutical composition containing one PAF antagonists and an anticholinergic. 11. Pharmaceutical composition according to claim 10, characterized in that the anticholinergic as claim 9 is defined.