DD299266A5 - PAF ANTAGONISTS FOR THE MANUFACTURE OF A MEDICAMENT SUITABLE FOR TREATING HEART DISEASES CAUSED BY REDUCED BETA RECEPTOR STIMULATION - Google Patents

Abstract

The present invention relates to the novel use of the PAF antagonists for the treatment of diseases caused by decreased b-receptor stimulation on the heart and their use for the preparation of a corresponding medicament.

Description

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] diazepinund

6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- (dipropylaminocarbonyl) -4H, 7H-

7. Medicament according to at least one of claims 1 to 3, characterized in that it contains at least one of the following PAF antagonists: (-) - 6- (2-chlorophenyl) -8 _/ 9-dihydro 1-methyl-8 - [(4-morpholinyl) carbonyl] -4H, 7H-

4- (2-chlorophenyl) -9-methyl-2- [3- (4-methylpropyl) -3-propanone-1-yll-6H-thieno [3,2-f] (1,2,4] triazolo [ 4,3-a] [1,4] diazepinund

6- (2-Chlorpheny!) - 8,9-dihydro-1-rethyl-8- (dipropylaminocarbonyl) -4H, 7H-cyclopenta (4,5] thieno [3,2-f] [1,2! , 4] triazolo [4,3-a] [1,4] diazepine, their enantiomers and their physiologically acceptable acid addition salts. 8. Use of a PAF antagonist for the manufacture of a medicament according to claims 7, characterized in that it is for treatment which is due to decreased β-receptor stimulation at the heart or by down-regulation of the β-receptors on the heart caused diseases.

PAF, the sop. platelet activating factor, is an endogenous substance that is released during various pathophysiological processes (see Braquet et al., Pharmacol., Rev. 39, 97-115 [1987]). The most important hemodynamic effects of PAF are seen here in the lowering of blood pressure and in the constriction of the coronary vessels, in addition, a negative inotropic effect on papillary muscles was also observed for PAF (see Robertson et al., J. Pharmacol., Exp. Ther., 243, 834-839 (US Pat. 1987)).

PAF antagonists (see, for example, Prostaglandins 35 [5], 781-851 (1988)), ie for the treatment and prevention of inflammations, allergies, asthma, edemas, bacterial diseases, vascular constrictions, are suitable for the treatment of the PAF caused PAF. especially on the gastrointestinal tract, the brain and the heart, eg

Spastic coronary stenoses, atherosclerosis, arterial and venous thrombosis and the anophylactic and endotoxin shock, but in particular for the treatment of PAF-induced cardiovascular diseases, such. B. for the treatment of Mycocardinfarktes and for the treatment of Schockzus'änden, ie of acute cardiovascular disease.

It is also known that in chronic heart failure, the responsiveness of the cardiac β-receptors for catecholamines is greatly diminished (see Danielsen et al., J. Cardiovasc Pharmacol., 14,171-173 [1989]). It has now been found that PAF not only has a direct negative inotropic effect, but additionally selectively reduces β-adrenergic receptor-mediated contractility, which is an additional negative component in the clinical picture of heart failure and cardiac insufficiency.

PAF antagonists are therefore also useful in the treatment of diminished cardiac stimulation of β-repressor stimulation or by down-regulation (see Terrence P. Kenakin in Pharmacologic Analysis of Drug-Receptor Interaction, pages 198-200, Raven Press, New York , 1987) of the β-receptors in the heart caused diseases, for example for the treatment of insufficient cardiac output in acute heart failure, for example after myocardial infarction and cardiogenic shock, or in chronic cardiovascular diseases such as congestive heart failure, heart failure after myocardial infarction or ischemic cardiomyopathies.

The present invention thus relates to the novel use of the PAF antagonists for the treatment of the abovementioned diseases caused by reduced β-receptor stimulation on the heart and their use for producing a corresponding medicament.

According to the invention, for example, the PAF antagonists known from the literature, for. 3. those from the tetrahydrofuran, thiazole, imido [2,1-alisoquinoline, dihydropyridine, thienodiazepine, benzodiazepine or ginkgolide series such as BN-50726, BN-50739, BN-52020 (ginkgolide A), BN-52021 (Ginkgolide B), BN-52022 (Ginkgolide C), BN-52024 (Ginkgolide J), BN-52063, BN-52111, CV 6209, L 659896, L 659989, Ro 193704, Ro 244736, RP 48740, RP 59227, Sch 37370, SDZ-63-135, SDZ-63-441, SDZ-63-675, SDZ-64-412, WEB 2086, WEB 2093, WEB 2170 and Y 24180 (see, for example, Pharmacol., Rev. 39,120- 145 11987], EP-A-0.176.928, EP-A-0.176.927, 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-AO.291.594, EP-A-0. A-0.298.466, EP-A-0.315.698, EP-A-0.316.456, EP-A-0.320.992, Br. J. Pharmac., 90, 139-146 [1987], Blood and Vessel 16, 558-572 1985] and Drugs of the Future 11, 869-875 [1986]) using the hetrazepine series PAF antagonists (see Agents and Actions 27, 473-476 [19891, EP-A-0194.416 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-0.315.698, EP -A-0.316.456 and EP-A-0.320.992) are preferred, in particular from the thieno [3,2-fl [1,2,4] triazolo [4,3] [1,4] diazepine and 1,2,4-triazolo [4,3-a) [1,4] benzodiazepinreihe.

For example, the following PAF antagonists expressis verbis be mentioned:

cis- (±) -1- [2- [hydroxy [[tetrahydro-5 - [(octadecylaminocarbonyl) oxy] methyl] furan-2-ylmethoxyphosphinyloxy] ethyl] quinolinium hydroxide (SDZ-63441),

cis- (±) -1- [2- [hydroxy [[tetrahydro-2,5-dimethyl-5- (octadecylaminocarbonyl) oxy] methyl] furan-2-yl] methoxyphosphinyloxy] ethyl] quinolinium hydroxide (SDZ) 63675)

trans (±) -tetrahydro-2- [3-methoxy-5-methylsulfonyl-4-propoxyphenyl] -5- (3,4,5-trimethoxyphenyl) -furan (L 659989), (+) - N- (3 - (benzoyl) phenyl] -3- (3-pyridinyl) -1 H, 3 H -pyrrolo [1,2-c] thiazole-7-rarboxyamide (RP 59227), (+ (- N-IS-t-benzyl-phenyll-SO -pyridinium-IH.SH-pyrrololi ^ -c-thiazole ^ -carboxyamide, 3- (3-pyridinyl) -1H, 3H-pyrrolo [1,2-c] thiazole-7-carboxyamide (HP 4870),

2,3-Dihydro-5- [4- [2- (3,4,5-trimethoxyphenyl) ethyl] phenyl] imidazo [2,1-a] isoquinoline (SDZ-64412), 5- (4-trimethylsilylphenyl) -2, 3-dihydro-imidazo [2,1-a] isoquinoline (SDZ-63,135), 1-0- (N-stearylcarbamoyl) -2-0- (methoxycarbonyl) -3-0- [4- (thiazolium-3-yl ) butyl] glycerol (RO 193704), 2- (2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl) -1-ethyl-pyridinium chloride (CV 6209), 3-tert-butyl-hexahydro-4,7b, 11-trihydroxy-8-methyl-9H-1,7a-(epoxymethano) -1H, 6aH-cyclopenta [c] furo (2,3-b] furo [3 ', 2': 3,4] cyclopenta [1,2-d] furan-5,9,12 (4H) -trione (BN 52021),

BN-50726 (see Agents and Actions 27, 473-476 [1989]),

4- (2-chlorophenyl) -9-methyl-2- [2- [4- (2-methylpropyl) phenyl] ethyl] -6H-thieno [3,2-f) [1,2,4] triazolo [ 4,3-a] [1,4] diazepine (Y-24180), 1-acetyl-4- (5,8-dihydro-8-methyl-11H-benzo [5,6] cyclohepta- (1,2-) b] pyridin-11-ylidene) -piperidine (Sch-37370), 1- [3- [4- (2-chlorophenyl) -9-methyl-6H-thieno (3,2-f] (1,2,4 ] triazolo [4,3-a] [1,4] diazepin-2-yl] -2-propynyl] -2 [1H] benzo [c] quinolination (RO 244736),

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 21/0),

4- (2-chlorophenyl) -9-methyl-2-F3- (4-morpholinyl) -3-propanone-1-yl] -6H-thieno [3,2-f] [1,2,4] triazolo [ 4,3-a] [1,4] diazepin

6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- (dipropylaminocarbonyl) -4H, 7H-cyclopenta [4,5] thieno [3,2-f] [1,2,4 ] triazolo [4,3-a] [1,4] diazepine (WEB 2347),

[4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolu [4,3-a] [1,4] diazepinl-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] - carboxamide, 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,

2- [4- (2-chlorophenyl) -9-methyl-6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4Jdiazepin-2-yl] - ethan-1-carboxylic acid N, N-di- (2-hydroxyethyDamid]

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 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] ii, 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-yli-ethane 1-carboxylic acid N'-methylpiperazide),

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-carbonsäurepyrrolidid,

2- [4- (2-chlorophenyl) -9-methyl-6H-thienoI3,2-fl [1,2,4] triazoloI4,3-al (1,4] diazepin-2-yl] -ethap-l- Carboxylic acid piperidide, 2- (4- (2-chlorophenyl) -6H-thieno [3,2-f] [1,2,4] triazolo [4,3-a] [1 _l 4] d-jjaxpin-2-yl] - ethane-1-carboxylic acid morpholide, 2-I4- (2-chlorophenyl) -9-bromo-6H-thieno [3,2-f] [1,2,4] triazoloI4,3-a] [1,4] diazepine 2-yl-ethane-1-carboxylic acid morpholide, 2- [4- (2-chlorophenyl) -9-methoxy-6H-thifino [3,2-f, I1,2,4] triazolo [4,3-al [1 4Idiazepin-2-yl-ethane-1-carboxylic acid morpholide, 4- (morpholin-4-yl-carbonyl) -6- (2-chloro-1-yl-1H-methyl) -ABS-tetrahydro-eH-lilbenzothieno (O) -fld.i ^ ltriazoloKaa) [1,4] diazepine, 3- (morpholine · 4 · yl · carbonyl) -6- (2-chlorophenyl) -11 · methylthio · 2,3,4,5-tβ-tetrahydro-8H-I1] -benzothieno [ 3,2-f] [1,2,4] triazolo [4,3-a | [1,4] diazepine, 3 · (N, N-diethylaminocarbonyl) · 6 · (2-chloroethyl) -11-mβthyl · 2,3,4, B tβ-tetrahydro · 8H- [1 lbβnzothiβno | 3,2-f] [ _l- 2,4-triazolo (4,3-a] [1,4] diazepine, 4- (N, N-diethylaminocarbonyl) - 6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H [1] benzothienol3,2-f) [1,2,4ltriazol oI4,3-a] [1,4] diazepine, 4- (4-methylpiperazinylcarbonyl) -e- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H- [1) benzothieno [ 3,2-f) [1,2,4] triazoloI4,3-a) [1,4] diazepine, 4- (N-methylstyl · N-2-hydro [...] ethylaminocarbonyl) -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tθ-tetrahydro-8H- | 1) benzothieno [3,2-f] I1,2,4) triazolo [4,3-a] [1,4] diazepine, 4 - (N, N-dimethylaminocarbonyl) -5- {2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopentat4,5] thieno [3,2-f] (1,2,4] triazolo (4,3-a] 1,4] diazepine, 3- (N, N -diethylaminocarbonyl-5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopenta | 4, 5] thieno [3,2-f] [1,2,4] triazolo (4,3-a] [1,4] diazepine, 3- (N, N-diethylaminocarbonyl-5- (2-chlorophenyl) -10 -bromo-3,4-dihydro-2H, 7H-cyclopenta [4,5] thieno [3,2-fli1,2,4-triazolo [4,3-a] [1,4] diazepine, 4- (morpholine-4 -yl-carbonylmethylaminocarbonyl-5- (2-chlorophenyl) -10-bromo-3,4-dihydro-2H, 7H-cyclopenta [4,5lthieno [3,2-f) I1,2,4] triazolol4,3-a ] [1,4] diazepine, 4- (morpholin-4-yl-carbonyl) -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H- [1] benzothieno [3 , 2-flimidazo [ 1,2-a] [1,4] diazepine, 4- (N, N-diethylamino) -C- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H- [1] benzothieno [3,2-f] imidazoI1,2-a] (1,4) diazepine, 3- (N-morpholinomethyl) -5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H cyclopenta [4,5] thieno [3,2-flH, 2,4] triazolo [4,3-a] [1,4] diazepine, 3- (acetoxymethyl) -5- (2-chlorophenyl) -10- methyl-3,4-dihydro-2H, 7H-cyclopenta [4,5] thieno [3,2-f) [1,2,4) triazolo [4,3-a] [1,4] -

diazepine, ^

3- (1,2,4-triazolyl-1-yl-methyl) -5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopenta (4,5-thieno [3,2-fl [1,2,4] triazolo [4,3-a] [1,4] diazepine, 3- (N-2,6-dimethylmorpholino-methyl) -5- (2-chlorophenyl) -10-methyl-3, 4-dihydro-2H, 7H-cyclopenta | 4,5] thieno (3,2-f] (1,2,4-triazolo [4,3-a] (1,4! Diazepine, 3-acetoxymethyl-5- (2-chlorophenyl) -3,4-dihydro-2H, 7H-cyclopenta [4,5] thieno [3,2-f | [1,2,4) triazolo [4,3-a] (1,4] diazepine, 4-acetoxymethyl-6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8 H- [1] benzothieno [3,2-f] imidazo [1,2-a] (1,4) diazepine, 3-acetoxymethyl-5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopenta [4,5-thieno [3,2-f] imidazo (1,2 -a) [1,4-diazepine, 3-diethylaminomethyl-5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopenta [4,5] thieno [3,2-tl [1, 2,4] triazolo [4,3-a] (1,4) diazepine, 4-hydroxymethyl-6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H-1-benzothieno [3 , 2-fl (1,2,4] triazolo [4,3-a] [1,4-diazepine, 4- (N-morpholinomethyl) -6- (2-chlorophenyl) -11-methyl-2,3,4, 5-tetrahydro-8H- [1] benzothieno (3,2-fl [ 1,2,4] triazolo [4,3-a] [1,4] diazepine, 4- (pyrazolyl-1-ylmethyl) -6- (2-chlorophenyl) -2,3,4,5-tetrahydro -8H- [1-benzothieno [3,2-f] [1,2,4] triazolo [4,3-a] [1,4] diazepine, 4-t4,4-dimethyl-2-oxazolin-2-yl] -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H [1] benzothienol3,2-f) [1,2,4] triazolo [4,3-a] [ 1,4] diazepine,

4- [4,4-dimethyl-2-imidazolin-2-yl] -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H [1) benzothieno | 3.2 -fl [1,2 ', 4] triazolo (4,3-a] [1,4] diazepine, 4- [1,4,4-trimethyl-imidazolin-2-yl-6 (2-chlorophenyl) - 11-methyl-2,3,4,5-tetrahydro-8H- [1] b-Gnothieno [3,2-f] t1,2,4] triazolo [4,3 · al-1,4] diazepine, 4-aminocarbonyl -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H [1] benzothieno [3,2-f] (1,2,4] triazolo [4,3-a ) [1,4] diazepine, 4- [morpholin-4-yl-carbonyl-6- (2-chlorophenyl) -2,3,4,5-tetrahydro-8H- [1] benzothieno [3,2-f] imidazo [1,5-al- [1,4-diazepine, 4-I4,4-dimethyl-2-thiazolin-2-yl] -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro -8H- [1] benzothieno [3,2-f] [1,2,4] triazolo [4,3-a] (1,4) diazepine, 4-amino-6- (2-chlorophenyl) -11- Methyl-2,3,4,5-tetrahydro-8H- [1-benzothieno [3,2-f! [1,2,4] triazolo [4,3-al] 1,4-diazepine, 3- (N-morpholinyl-methyl ) -5- (2-chlorophenyl) -10-methyl-3,4-dihydro-2H, 7H-cyclopenta | 4,5] thienol3 _/ 2-nimidazo [1,2-a] (1,4) diazepine, 4 - (1,2,4-triazol-1-yl-methyl) -6- (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8HI1 ] benzothieno [3,2-f] [1,2,4] triazolo [4, -al [1,4] diazine and 4- (1,2,4-triazol-1-yl-methyl) -6- ( 2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H- [1] benzothieno [3.2-f] imidazo [1.2-a] [1.4] diazepine, its enantiomers and their physiologically acceptable acid addition salts.

However, particularly valuable PAF antagonists are trans- (±) -tetrahydro-2- [3-methoxy-5-methylsulfonyl-4-propoxyphenyl] -5- (3,4,5-trimethoxyphenyl) -furan, (+ lN-IS -BenzoyDphenyll-S-IS-pyridinyl-D-H-SH-pyrrololipheniazol-carboxyamide, (+ IN-IS-IBenzyDphenyl-S-pyridinyl-D-H-S-pyrrolidinyl) -clothiazole-carboxyamide, SO-pyridyl-D-iH .SH-pyrroloH ^ -clothiazole ^ -carboxyamide, 2- (2-acetyl-C-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl) -1-ethyl-pyridinium chloride .

BN-50726 (see Agents and Actions 27, 473-476 (1989)),

4- (2-chlorophenyl) -9-methyl-2- | 2- [4- (2-methylpropyl) phenyllethyl] -6H-thieno | 3,2-f] [1,2,4) triazolo [4,3 -a) [1,4] diazepine,

1-Acetyl-4- (5,6-dihydro-8-methyl-11H-benzeneB.ojcycloheptali-1-pyrpyridine-1-ylidene) -piperidine, 1- [3- [4- (2-chlorophenyl) -9 methyl-6H-thieno [3,2-f] [1,2,4ltriazolo | 4,3-a] [1,4] diazepin-2-yl] -2-propynyl] -2 | 1H] benzo [c ] quinolinone, 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) -carbonyl] -4H, 7H-cyclopenta-4,5-thieno (3,2-flM, 2,4-triazolo [ 4,3-a] [1,4] diazepine,

4- (2-chlorophenyl) -9-methyl-2- [3- (4-morpholinyl) -3-propanone-1-yll-6H-thieno [3,2-fl [1,2,4] triazolo [4 , 3-a] [1,4] diazepine and 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- (dipropylaminocarbonyl) -4H, 7H-cyclopenta [4,5] thieno [3,2 -f | (1,2,4ltriazolot4,3-al [1,4) diazepine,

their enantiomers and their physiologically acceptable acid addition salts, but especially (-) - 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- (4-morpholinyl) carbonyl) -4H, 7H-cyclopenta [ 4,5] thieno [3,2-fl [1,2,4] triazolo [4,3-a] [1,4] diazepine (substance A),

4- (2-chlorophenyl) -9-methyl-2-I3- (4-morpholinyl) -3-propanone-1-yl] -6H-thieno | 3,2-fl (1,2,4ltriazolo [4,3- -al (1,4) diazepine (substance

Federation

6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8- (dipropylaminocarbonyl) -4H, 7H-cyclopenta | 4.5) thieno [3,2-f) [1,2,4llriazolo [4 , 3-a] [1,4] diazepine (substance C),

their enantiomers and their physiologically acceptable acid addition salts.

The newly discovered effect of the PAF antagonists has been found, for example, on B = 4- (2-chlorophenyl) -9-methyl-2- | 3- (4-morpholinyl) -3-propanone-1-yl) -eH-thieno [3 , 2-fl [1,2,4-triazolo [4,3-a | [1,4] diazepine tested as follows:

Male rats (Chbb: THOM, approx. 300g) are anaesthetized with hexobarbital sodium (150 mg / kg i.p.). The trachea is cannibalized, and then the animals are despinalized. The animals are artificially ventilated and kept at 37 ° C by means of a heating pad. To measure left ventricular pressure, a Millar tip manometer is inserted over the carotid artery into the left ventricle. This signal is electronically differential and, as LV-dP / dtmax, is a measure of the contraction force of the heart. A catheter in the other carotid artery measures arterial blood pressure. The substances to be tested are injected intravenously via a cannula in the jugular vein.

Isoprenaline (3-100 ng / kg) increases dose-dependently LV-dP / dtmax from 300 ± 90 to 4 450 ± 290 mm Hg / s (n = 6). Following a 45 minute infusion of PAF (50-100ng / kg / min), isoprenaline (3 to 100ng / kg) was re-injected. The effects of 3 and 10ng / kg of isoprenaline were not affected thereby, but the effects on LV-dP / dtmax of 30 and 100 ng / kg of isoprenaline were greatly reduced (about 46% reduction). Then, substance B (10 mg / kg i.v.) was administered, and after 10 minutes, isoprenaline was again injected. Now the responsiveness of the cardialon β receptors was fully recovered and the increase of LV dP / dtmax by isoprenaline was not significantly different from the control values.

It was also shown that PAF does not affect the positive inotropic effect of the histamine-2 agonist dimaprit (1-10 mg / kg) and the adenyl cyclase activator forskolin (3-20 μg / kg).

Due to the newly discovered effect of the PAF antagonists, they are also suitable for the treatment of diseases caused by diminished β-receptor stimulation in the heart or by down-regulation of the β-receptors in the heart, e.g. As for the treatment of insufficient pumping power of the heart in acute heart failure, for example after myocardial infarction and cardiogenic shock, or in chronic cardiovascular diseases such as congestive heart failure, heart failure after myocardial infarction or in ischemic cardiomyopathy, as already mentioned.

The acute toxicities are reported in the literature by numerous PAF antagonists. For example, these data indicate that the PAF-antagonist r verträglk well, and are practically non-toxic, so, the substance A is a 1960 mg / kg / po, substance B has a LD. ₀ of 4600mg / kg po and substance C one of 1700mg / kg / po each on the mouse.

The dosage of a PAF antagonist required to achieve the novel effect of the invention is in the range of the dosages already indicated for PAF antagonists.

In the case of oral dosing, this is expediently between 5 and 100, preferably between 10 and 50 mg per dose in adults, and between 1 and 75 intravenous or intramuscular application, preferably between 1 and 25 mg per dose, in each case 1 to 4 times daily. and correspondingly lower in children depending on their age, e.g. At ¹ A to 1/2 of the above-mentioned dose.

For this purpose, the PAF antagonists and their physiologically acceptable addition salts can be incorporated together with one or more inert excipients in the usual pharmaceutical preparations such as tablets, Dragoes, capsules, wafers, powders, suppositories, suspensions or solutions.

The following examples are intended to illustrate the invention without limiting it:

example 10.0 mg Tablets containing 10mg of substance B 57.0 mg Composition: 48,0mg Substance B 4.0 mg corn starch 1.0 mg lactose polyvinylpyrrolidone magnesium stearate

120.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water. The moist mixture is forced through a sieve of 1.5 mm mesh size and dried at about 45 ⁰ C. The dry granules are beaten through a sieve of 1.0 mm mesh size and mixed with magnesium stearate. The finished mixture is compressed on a tablet press with punches of 7 mm diameter, which are provided with a partial notch, into tablets. Tablet weight: 120mg

Example 2 5.0 mg Dragoes containing 5mg substance B 41,5mg Composition: 30.0 mg Substance B 3.0 mg corn starch 0.5 mg lactose polyvinylpyrrolidone magnesium stearate

80.0 mg

production method

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is pressed through a sieve with 1 mm mesh size, dried at about 45 ⁰ C and then beat the granules through the same sieve. After admixing magnesium stearate on a tableting machine curved Dragoekerno be pressed with a diameter of 6mm. The Dragoekerne thus prepared are coated in a known manner with a layer consisting essentially of sugar and talc. The finished Dragoes are polished with wax. Dragoe weight: 130mg

Example 3

Tablets containing 50 mg of substance B

Composition: 50.0 mg Substance B 70,0mg calcium phosphate 40.0 mg lactose 35,0mg corn starch 3.5 mg polyvinylpyrrolidone 1.5mg magnesium stearate

200.0 mg

manufacturing

The substance B, calcium phosphate, lactose and corn starch are uniformly moistened with an aqueous solution of polyvinylpyrrolidone. The mass is passed through a 2 mm sieve, dried in a circulating oven at 5O ⁰ C and sieved again. After admixing the lubricant, the granules are pressed on a tableting machine.

Example 4

Capsules containing 50mg substance B

Composition: 50.0 mg Substance B 268.5 mg corn starch 1.5mg magnesium stearate 320.0 mg

manufacturing

Substance B and corn starch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is filled into hard gelatin capsules size.

Belspiel5

buppositorlon containing 50mg of substance B

Composition:

Substance B 50 mg

Adepssolidus 1650 mg

1700 mg

manufacturing

The hard fat is melted. 8EI 4O ⁰ C the ground active substance is dispersed homogeneously. It is cooled to 38 ⁰ C and poured into slightly pre-cooled suppository molds.

Example 6

Oralo suspension containing 50mg of substance B per 5ml

Composition: 50 mg Substance B 50mg hydroxyethyl 5mg sorbic acid 600 mg Sorbitol 70% 200 mg glycerin 15mg Aroma

Water ad 5ml

manufacturing

Distilled water is heated to 7O ⁰ C. Herein, hydroxyethyl cellulose is dissolved with stirring. By adding sorbitol solution and glycerol is cooled to room temperature. At room temperature, sorbic acid, flavor and substance B are added. To vent the suspension is evacuated with stirring.

Example 7

Ampoules containing 1 mg of substance B per 5 ml

Composition:

Substance B 1mg

Sodium chloride 45mg

Water for injections ad 5ml

manufacturing

Substance B is dissolved in water at intrinsic pH and sodium chloride is added as isotonicity. The resulting solution is filtered pyrogen-free and the filtrate filled under aseptic conditions in ampoules, which are then sterilized and sealed.

Examples

Ampoules containing 5mg substance B per 5ml

Composition:

Substance B 5mg

Sodium chloride 45mg

Water for injections ad 5ml

Preparation analogous to Example 6.

Examples containing 10mg of substance B per 5ml 10mg ampoules Composition: 35 mg 1000 mg 250 mg 5ml Substance B methylglucamine Glucofurol Polyethylene glycol polypropylene glycol Blockpolymor Water for injections ad

manufacturing

In one part of the water, methylglucamine is dissolved and the substance B is dissolved with stirring. After addition of the solvent is made up to the nominal volume with water.

Example 10

Ampoules containing 20mg substance B per 10ml

Composition:

Substance B 20,000mg

Sodium chloride 85,000mg

Sodium dihydrogen phosphate x2H ₂ O 0.925 mg disodium hydrogen phosphate x 2H ₂ O 1.320 mg 0.1 NaOH ad pH

Water for injections ad 10ml

manufacturing

The above ingredients are dissolved in water, and after filtration, the solution is filled into sterilized brown ampoules.

Example 11 Inhalation solution containing 5 mg of substance B per 1 ml

Composition: 500 mg Substance B 50 mg Na-EDTA 25mg benzalkonium chloride 880mg sodium chloride ad 100ml Distilled water

manufacturing

96% of the amount of water are presented, it successively dissolved Na-EDTA, benzalkonium chloride, sodium chloride and substance B and filled with the remaining water. The solution is filled into 20ml dropper bottles.

Of course, the other PAF antagonists according to the invention can be incorporated into the usual galenic preparations in the dosages suitable for them.

Claims (5)

Claims 1. A medicament for the treatment of diseases caused by decreased β-receptor stimulation in the heart or by up-regulation of the β-receptors on the heart, comprising a PAF antagonist in addition to one or more inert carriers. 2. Medicament according to claim 1, characterized in that this is suitable for the treatment of the low pumping power of the heart in acute heart failure. Medicament according to claim 1, characterized in that it is suitable for the treatment of chronic c ^ diovascular diseases such as congestive heart failure, heart failure after myocardial infarction or ischemic cardiomyopathies. 4. Medicament according to at least one of claims 1 to 3, characterized in that it comprises at least one of the PAF antagonists from the series of tetrahydrofuran, thiazole, imido [2.1-a] isoquinoline, dihydropyridine, thienodiazepine, benzodiazepine or Gingkolidderivate contains. 5. Medicament according to at least one of claims 1 to 3, characterized in that it contains at least one of the PAF antagonists from the series of hetrazepines. 6. Medicament according to at least one of claims 1 to 3, characterized in that it contains at least one of the following PAF antagonists: trans- (±) -tetrahydro-2- [3-methoxy-5-methylsulfonyl-4-propoxy-phenyl ] -5- (3,4,5-trimethoxyphenyl) furan, (+ 1N-IBenzoy-D-phenyl-S-pyridyl-D-H 1 H -pyrrolod-1-clothiazole-y-carboxyamide, (+ JNO-IBenzoy-D-phenyl-S-pyridyl-D-IH, S-pyrroloH, -clothiazole-y-carboxyamide, 3- (3 Pyridinyl) -1H, 3H-pyrrolo (1,2-c] thiazole-7-carboxyamide, 2- (2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10- diazaoctacos-1-yl) -1-ethylpyridinium chloride, BN-50726 (see Agents and Actions 27, 473-476 [1989]), 4- (2-chlorophenyl) -9-methyl-2- [2-L4- (2-methylpropyl) phenyl] ethyl] -6H-thieno (3,2-f] [1,2,4] triazolo [4 , 3-a] [1,4] diazepine, 1-Acetyl-4- (5,6-dihydro-8-methyl-11H-benzofoSlcyclohepta-ti ^ -blpyridin-ii-ylidene-1-piperidine, 1- [3- [4- (2-chlorophenyl) -9-methyl -6H-thieno [3,2-f] (1,2,4] triazolo [4,3-a] [1,4] diazepin-2-yl] -2-propynyl) -2 (1H] benzo [c ] -quinolinone 6- (2-chlorophenyl) -8,9-dihydro-1-methyl-8 - [(4-morpholinyl) carbonyl-4H, 7H-