DE10015939A1 - Thrombolytic agent useful e.g. for treating or preventing deep vein leg thrombosis, pulmonary embolism or restenosis comprises new or known 3-phenyl-4,5-dihydro-2-phenylbenz(e)indole derivatives - Google Patents

Abstract

The use of 3-phenyl-4,5-dihydro-2-phenylbenz(e)indole derivatives (I) as thrombolytic agents is new. 13 Specific compounds (I) are new. The use of 3-phenyl-4,5-dihydro-2-phenylbenz(e)indole derivatives of formula (I) or their salts as thrombolytic agents is new. R = H, 1-6C alkyl or thienyl; or phenyl (optionally substituted by halo, CF3, 1-6C alkyl, 1-6C alkoxy, 1-6C alkanoyloxy, 1-6C alkanoylamino, NO2, CN, OH, NH2 or Ph); R1 = COOH, (1-6C) alkoxycarbonyl, CONH2, N-(1-6C alkyl)-carbamoyl, CONHOH, 3-7C N,N-dialkylcarbamoyl or 4-10C dialkylphosphonyl-alkoxycarbonyl; R2 = H, halo, OH, SH, CF3, 1-6C alkyl, 1-6C alkoxy, 1-6C alkanoyloxy, 1-6C alkanoylamino, 1-6C alkanoylthio, OC(S)NH2, (1-5C) alkylthiocarbamoyloxy, SC(O)NH2, (1-5C) alkylcarbamoylthio, NHC(O)NH2, (1-5C) alkylcarbamoylamino, 2-6C dialkylamino, 2-7C dialkylthiocarbonyloxy, 3-7C dialkylcarbamoylthio or 3-7C dialkylcarbamoylamino; R3 = H, 1-6C alkanoyl or Ph; D = H, halo, 1-6C alkyl, 1-6C alkoxy, 1-6C alkanoyloxy, 1-6C alkanoylamino, NH2, NO2 or CF3, and n = 1 or 2. Independent claims are included for the following: (1) the following new compounds (I) and their salts: 3-(4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(3-carboxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 2,3-diphenyl-4,5-dihydro-benz(e)indole, 3-(4-carboxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(4-carboxy-3-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole (Ia), 3-(3,4-dimethoxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(3-nitro-4-methylamino-phenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(3-bromophenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(4-hydroxy-3,5-dibromophenyl)-4,5-dihydro-2-phenylbenz(e)indole, 3-(4-aminocarbonyl-phenyl)-4,5-dihydro-2-phenylbenz(e)indole and 3-(3-aminocarbonyl-phenyl)-4,5-dihydro-2-phenylbenz(e)indole, and (2) preparation of the new compounds.

Description

Benz [e] indoles of the general formula fall under the scope of protection of US Pat. No. 3,878,225, which corresponds to German Offenlegungsschrift 2,407,671

in the
R is a hydrogen atom, a C _1-6 alkyl, thienyl or phenyl group or one by halogen atoms, by trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy , C _1-6 alkanoylamino, nitro, cyano, hydroxyl, amino or phenyl groups substituted phenyl group,
R _{1 is} a carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl or hydroxycarbamoyl group, an N, N-dialkyl carbamoyl group with a total of 3 to 7 carbon atoms. atoms or a dialkyl-phosphinyl-alkoxycarbonyl group with a total of 4 to 10 carbon atoms,
R _{2 is} a hydrogen or halogen atom, a hydroxyl, mer capto, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyl oxy, C _1-6 alkylthio -, Amino-, C _1-6 alkylamino, C _1-6 alkanoyl amino, C _1-6 alkanoylthio, thiocarbamoyloxy, C _1-5 alkylthiocarbamoyloxy, carbamoylthio, C _1-5 alkyl carbamoylthio, carb amoylamino or C _1-5 alkyl carbamoylamino group, a dialkyl amino group with a total of 2 to 6 carbon atoms, a di alkylthiocarbamoyloxy group with a total of 3 to 7 carbon atoms, a dialkylcarbamoylthio group with a total of 2 to 7 carbon atoms or a dialkylcarbamyl group 3 to 7 carbon atoms in total,
R _{3 is} a hydrogen atom, a C _1-6 alkanoyl or phenyl group,
D is a hydrogen or halogen atom, a C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, C _1-6 alkanoylamino, amino, nitro or trifluoromethyl group and
n is the number 1 or 2, and their salts, which have an anti-inflammatory and analgesic effect.

It has now been found that the above compounds as well as the new compounds
(1) 3- (4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(2) 3- (3-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(3) 2,3-diphenyl-4,5-dihydro-benz [e] indole,
(4) 3- (4-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(5) 3- (4-carboxy-3-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(6) 3- (3,4-dimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(7) 3- (3,4,5-trimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] in dol,
(8) 3- (3-nitro-4-methylaminophenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(9) 3- (3-bromophenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(10) 3- (3-nitro-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz- [e] indole,
(11) 3- (4-hydroxy-3,5-dibromo-phenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(12) 3- (4-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole and
(13) 3- (3-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole
and their physiologically tolerable salts also have thombolytic properties, since only the following compounds of the general formula I expressis verbis are described in the above-mentioned US patent:
3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] in dol (see Example 24),
4,5-dihydro-3- (4-hydroxy-3-methoxycarbonylphenyl) -2-phenyl benz [e] indole (see Example 25),
4,5-dihydro-3- (4-N, N-dimethylthiocarbamoyloxy-3-methoxycarbonylphenyl) -2-phenylbenz [e] indole (see Example 26),
4,5-dihydro-3- (4-N, N-dimethylcarbamoylthio-3-methoxycarbonyl phenyl) -2-phenylbenz [e] indole (see Example 27),
4,5-dihydro-3- (3-ethoxycarbonyl-4-hydroxyphenyl) -2-phenylbenz [e] indole (see Example 28),
1-acetyl-3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenyl benz [e] indole (see Example 29),
3- (4-acetoxy-3-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] in dol (see Beispel 30),
2- (tert-butyl) -3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole (see Example 42),
3- (3-carboxy-4-hydroxyphenyl) -4, 5-dihydro-7-methoxy-2-phenyl benz [e] indole (see Example 56),
3- (3-carboxy-4-hydroxyphenyl) -7-chloro-4,5-dihydro-2-phenyl benz [e] indole (see Example 57),
3- (3-carbamoyl-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole (see Example 60),
4,5-dihydro-3- (3-N-ethylcarbamoyl-4-hydroxyphenyl) -2-phenyl benz [e] indole (see Example 61),
3- (3-N, N-diethylcarbamoyl-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole (see Example 62),
4,5-dihydro-3- (3-N-hydroxycarbamoyl-4-hydroxyphenyl) -2-phen ylbenz [e] indole (see Example 63) and
3- (3-carboxy-4-mercaptophenyl) -4,5-dihydro-2-phenylbenz [e] in dol (see example 64).

The present invention thus relates to the new Ver using the above known compounds as throm bolytica, the new compounds above, the new ones above Medicines containing compounds and their use and processes for their manufacture.  

Preferred compounds of the above general formula I are those in which
one of the radicals R ₁ or R ₂ in the 3- or 4-position is a hydroxyl, acetoxy or mercapto group and
the other of the radicals R ₁ or R ₂ in the 3- or 4-position is a car boxy-, C _1-3 -alkoxy-carbonyl-, carbamoyl-, N- (C _1-3 -alkyl) -carb amoyl-, N , N-Di- (C _1-3 alkyl) carbamoyl or hydroxycarbamoyl group and
D mean a hydrogen or chlorine atom or a methoxy group, as well as the new compounds
(1) 3- (4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(2) 3- (3-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(4) 3- (4-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(5) 3- (4-carboxy-3-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
(10) 3- (3-nitro-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole and
(12) 3- (4-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole
as well as their physiologically acceptable salts.

According to the invention, for example, the compounds mentioned above are obtained by reacting a ketone of the general formula

in the
R, R ₃ and D are defined as mentioned above, with an aniline of the general formula

in the
R ₁ , R ₂ and n are defined as mentioned at the beginning.

The reaction is advantageously carried out in a solvent such as ethanol, toluene, glacial acetic acid, ethanol / glacial acetic acid, hydrochloric acid or phosphorus oxychloride at elevated temperatures, e.g. B. at Temperatures between 100 and 200 ° C, preferably at Tempe temperatures between 120 and 175 ° C.

In the implementation described above, given if existing reactive groups such as hydroxy, carboxy, ami no, alkylamino or imino groups during the reaction usual protection groups are protected, which after implementation can be split off again.

For example, the trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,
as protective residues for a carboxyl group, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyra nyl group and
as a protective radical for an amino, alkylamino or imino group, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-dimethoxybenzyl group and additionally for the amino group Phthalyl group into consideration.

The subsequent subsequent splitting off of one used Protective residue takes place, for example, hydrolytically in an aqueous solution Rigen solvent, for. B. in water, isopropanol / water, Te trahydrofuran / water or dioxane / water, in the presence of a Acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, Na trium hydroxide or potassium hydroxide or by ether cleavage, e.g. B. in the presence of iodotrimethylsilane, at temperatures between between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

Cleavage of a benzyl, methoxybenzyl or benzyloxy However, carbonyl radicals are carried out, for example, by hydrogenolysis, e.g. B. with hydrogen in the presence of a catalyst such as Pal ladium / coal in a solvent such as methanol, ethanol, Ethyl acetate, dimethylformamide, dimethylformamide / ace clay or glacial acetic acid, optionally with the addition of an acid such as Hydrochloric acid at temperatures between 0 and 50 ° C, preferably however at room temperature and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

A methoxybenzyl group can also be split off in counter were an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or ace tonitrile / water at temperatures between 0 and 50 ° C, preferred however, at room temperature.

However, a 2,4-dimethoxybenzyl radical is split off preferably in trifluoroacetic acid in the presence of anisole.  

The cleavage of a tert-butyl or tert-butyloxycarbonyl the rest is preferably done by treatment with an acid such as trifluoroacetic acid or hydrochloric acid optionally under Use of a solvent such as methylene chloride, dioxane or ether.

A phthalyl radical is preferably cleaved in Presence of hydrazine or a primary amine such as methyl amine, ethylamine or n-butylamine in a solvent such as Methanol, ethanol, isopropanol, toluene / water or dioxane Temperatures between 20 and 50 ° C.

An allyloxycarbonyl radical is split off by Be act with a catalytic amount of tetrakis (triphenyl phosphine) palladium (O) preferably in a solvent such as Tetrahydrofuran and preferably in the presence of an excess shot of a base such as morpholine or 1,3-dimedone Temperatures between 0 and 100 ° C, preferably at room temperature rature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) - chloride in a solvent such as aqueous ethanol and counter also in the presence of a base such as 1,4-diazabicyclo- [2.2.2] octane at temperatures between 20 and 70 ° C.

The compounds used as starting materials of the general NEN formulas II and III, some of which are known from the literature are obtained by methods known from the literature.

The compounds of formula I and the new compounds can in their salts, especially for pharmaceutical Use in their physiologically compatible salts with organic or organic acids. As Acids come for example hydrochloric acid, bromine water Substance acid, sulfuric acid, phosphoric acid, fumaric acid, Bern tartaric acid, lactic acid, citric acid, tartaric acid or maleic acid into consideration.  

In addition, the compounds of the formula obtained in this way I, if they contain a carboxy group, and that corresponds appropriate new compounds if desired in their salts with inorganic or organic bases, esp especially for pharmaceutical use in your physiolo genetically compatible salts. As bases come here for example sodium hydroxide, potassium hydroxide, cyclo hexylamine, ethanolamine, diethanolamine and triethanolamine in Consideration.

As already mentioned at the beginning, the connections of all general formula I and the new compounds and their salts valuable properties, especially thrombolytic Wir by inhibiting the endogenous plasminogen activator Inhi bitor-1 (PAI-1)

For example, the connection
A = 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenyl benz [e] indole

• 1. Examined for their plasminogen activator inhibitor-1 (PAI-1) inhibitory effect as follows:
  Material: 96-well microtiter plates (Greiner),
  96-well plate reader (molecular devices)
  Tris buffer (pH: 8.3) (Chromogenix):
  50 mM tris (hydroxymethyl) aminomethane
  100 mM NaCl
  substrate S-2251 (1.25 mmol / solution in Tris buffer) (Chromogenix)
  Plasminogen (human, 0.375 mg / ml solution in Tris buffer) (Chromogenix)
  Recombinant tissue plasminogen activator (rt-PA, Boehringer Ingelheim Pharma KG) 10 IU / ml
  Tissue plasminogen activator stimulator (human, 0.6 mg / ml solution in Tris buffer) (Chromogenix)
  Recombinant plasminogen activator inhibitor-1 (r-PAI-1, University of Leuven, Belgium) 22.2 IU / ml
  Compound A, dissolved in dimethyl sulfoxide

execution

5.5 µl of the substance solution and 50 µl PAI-1 are pre-incubated in 96-well microtiter plates for 30 minutes at 25 ° C. To 25 µl of this mixture, 200 µl rt-PA, 10 µl plasminogen, 40 µl substrate and 25 µl tissue plasminogen activator stimulator are incubated in 96-well microtiter plates at 37 ° C. The change in color due to the cleaved substrate is measured in a 96 well photometer at 405 nm over an hour. The concentration-dependent influence from compound A is used to calculate the IC ₅₀ value.

• 1. examined for their thrombolytic effect as follows:
  Material: 96-well microtiter plates (Greiner),
  96-because plate reader (SLT)
  Tris buffer (pH: 8.0):
  100 mM tris (hydroxymethyl) aminomethane (Merck)
  150 mM NaCl (Merck)
  Fibrinogen (1.22 mg / ml solution in Tris buffer),
  Casein (bovine, 0.5 mg / ml solution in Tris buffer) (Sigma)
  Thrombin (Boehringer Mannheim) 80 NIHU / ml
  Calcium chloride solution (Merck) 45 mmol / l
  Recombinant tissue plasminogen activator (rt-PA, Boehringer Ingelheim Pharma KG) 50 IU / ml
  9.4 µg / ml Recombinant Plasminogen Activator Inhi bitor-1 (r-PAI-1, University of Leuven, Belgium)
  Compound A, dissolved in dimethyl sulfoxide

execution

4 ul of the substance solution, 5 nM PAI-1, 200 ul fibrinogen and casein and 15 ul thrombin / calcium chloride / rt-PA (1: 1: 1 mixture) are incubated in 96-well microtiter plates at 37 ° C. The change in the turbidity due to the clot formed is measured in a 96 well photometer at 340 nm for 2 hours. The concentration-dependent influence from compound A is used to calculate the ED ₅₀ value.

The following table contains the value found:

The compounds produced according to the invention are well ver sluggish as there are no toxic side effects at therapeutic doses effects could be observed.

Due to their pharmacological properties, the new compounds and their physiologically tolerable salts for the prevention and treatment of venous and arterial thrombo diseases, such as the treatment of tie fen leg vein thrombosis, the treatment of pulmonary embolism, the Treatment of thrombi in atrial fibrillation, prevention of reocclusions after bypass surgery, angioplasty (PT (C) A) or thrombolysis and occlusion in peripheral arterial diseases such as pulmonary embolism, the disseminated intravascular coagulation, prophylaxis of coronary thrombus bose, prevention of stroke and prevention the occlusion of shunts. In addition, the fiction provide antithrombotic support thrombolytic treatment such as rt-PA or streptokinase, to prevent reocclusion after a thrombolytic treatment to prevent Lang PT (C) A, time restosion, to prevent metastasis  and tumor growth, prevention and loading act of tumor-induced venous thrombosis and of fi Brin dependent inflammatory processes suitable.

The necessary to achieve a corresponding effect Dosage is expediently 0.1 when administered intravenously to 30 mg / kg, preferably 0.3 to 10 mg / kg, and oral Administration 0.1 to 50 mg / kg, preferably 0.3 to 30 mg / kg, each 1 to 4 times a day. For this purpose, according to the invention provided compounds of formula I, optionally in com combination with other active substances, together with one or several inert customary carriers and / or diluents means, e.g. B. with corn starch, milk sugar, cane sugar, micro crystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / gly cerin, water / sorbitol, water / polyethylene glycol, propylene glycol kol, cetylstearyl alcohol, carboxymethyl cellulose or fat containing substances such as hard fat or their suitable Ge mix into common galenic preparations like tablets, Dragees, capsules, powders, suspensions or suppositories work.

The following examples are intended to illustrate the invention purify:  

example 1 3- (3-carboxy-4-hydroxypheny) -4,5-dihydro-2-phenylbenz [e] indole

A mixture of 2.8 g (10.6 mmol) of 1-phenacyl-2-tetralone, 1.62 g (10.6 mmol) of 5-aminosalicylic acid and 50 ml of glacial acetic acid are stirred at 140 ° C. for 90 minutes. After evaporation of the solvent, the residue is chromatographed on silica gel, methylene chloride being used as the eluent. The desired fractions are combined and concentrated.
Yield: 2.32 g (57% of theory) of yellow crystals,
Melting point: 219-220 ° C
C ₂₅ H ₁₉ NO ₃ (381.44)
Mass spectrum: M ⁺ = 381

The following compounds are obtained analogously.

• 1. 3- (4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 225-227 ° C
  C ₂₅ H ₁₉ NO (337.42)
  Mass spectrum: M ⁺ = 337
• 2. 3- (3-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 201-204 ° C
  C ₂₅ H ₁₉ NO ₂ (365.44)
  Mass spectrum: M ⁺ = 365
• 3. 2,3-diphenyl-4,5-dihydro-benz [e] indole
  Melting point: 150-151 ° C
  C ₂₄ H ₁₉ N (321.42)
  Mass spectrum: M ⁺ = 321
• 4. 3- (4-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 257-261 ° C
  C ₂₅ H ₁₉ NO ₂ (365.44)
  Mass spectrum: M ⁺ = 365
• 5. 3- (4-carboxy-3-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 259-262 ° C
  C ₂₅ H ₁₉ NO ₃ (381.44)
  Mass spectrum: M ⁺ = 381
• 6. 3- (3,4-Dimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 140-141 ° C
  C ₂₅ H ₁₉ NO ₃ (381.48)
  Mass spectrum: M ⁺ = 381
• 7. 3- (3,4,5-Trimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  C ₂₇ H ₂₅ NO ₃ (411.51)
  Mass spectrum: M ⁺ = 411
• 8. 3- (3-nitro-4-methylaminophenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 165-168 ° C
  C ₂₅ H ₂₁ N ₃ O ₃ (395.47)
  Mass spectrum: M ⁺ = 395
• 9. 3- (3-bromophenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 72-74 ° C
  C ₂₄ H ₁₈ BrN (400.33)
  Mass spectrum: M ⁺ = 399/401 (Br)
• 10. 3- (3-nitro-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 124-134 ° C
  C ₂₄ H ₁₈ N ₂ O ₃ (382.42)
  Mass spectrum: M ⁺ = 382
• 11. 3- (4-Hydroxy-3,5-dibromophenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 174-175 ° C
  C ₂₄ H ₁₇ Br ₂ NO (495.24)
  Mass spectrum: M ⁺ = 493/495/497 (Br)
• 12. 3- (4-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole
  Melting point: 260-261 ° C
  C ₂₅ H ₂₀ N ₂ O (364.45)
  Mass spectrum: M ⁺ = 364
• 13. 3- (3-aminocarbonylphenyl) -4, 5-dihydro-2-phenylbenz [e] indole
  Melting point: 183-186 ° C
  C ₂₅ H ₂₀ N ₂ O (364.45)
  Mass spectrum: M ⁺ = 364

Claims (7)

1. Use of benz [e] indoles of the general formula
in the
R is a hydrogen atom, a C _1-6 alkyl, thienyl or phenyl group or one by halogen atoms, by trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy , C _1-6 -alkanoylamino, nitro, cyano, hydroxyl, amino or phenyl groups substituted phenyl group,
R _{1 is} a carboxyl, C _1-6 alkoxy-carbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl or hydroxycarbamoyl group, an N, N-dialkyl carbamoyl group with a total of 3 to 7 carbon atoms. atoms or a dialkyl-phosphinyl-alkoxycarbonyl group with a total of 4 to 10 carbon atoms,
R _{2 is} a hydrogen or halogen atom, a hydroxyl, mer capto, trifluoromethyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyl oxy, C _1-6 alkylthio -, amino-, C _1-6 -alkylamino-, C _1-6 -alkanoyl amino-, C _1-6 -alkanoylthio-, thiocarbamoyloxy-, C _1-5 -alkylthio carbamoyloxy-, carbamoylthio-, C _1-5 - Alkyl carbamoylthio, carb amoylamino or C _1-5 alkyl carbamoylamino group, a dialkyl amino group with a total of 2 to 6 carbon atoms, a di alkylthiocarbamoyloxy group with a total of 3 to 7 carbon atoms, a dialkylcarbamoylthio group with a total of 2 to 7 carbon atoms or a dialkylcarbamyl group 3 to 7 carbon atoms in total,
R _{3 is} a hydrogen atom, a C _1-6 alkanoyl or phenyl group,
D is a hydrogen or halogen atom, a C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkanoyloxy, C _1-6 alkanoylamino, amino, nitro or trifluoromethyl group and
n is the number 1 or 2, and their physiologically tolerable salts as thrombolytics. 2. The following compounds of general formula I according to claim 1:

• 1. 3- (4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 2. 3- (3-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 3. 2,3-diphenyl-4,5-dihydro-benz [e] indole,
• 4. 3- (4-carboxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 5. 3- (4-carboxy-3-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 6. 3- (3,4-dimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 7. 3- (3,4,5-trimethoxyphenyl) -4,5-dihydro-2-phenylbenz [e] in dol,
• 8. 3- (3-nitro-4-methylaminophenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 9. 3- (3-bromophenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 10. 3- (3-nitro-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 11. 3- (4-hydroxy-3,5-dibromophenyl) -4,5-dihydro-2-phenylbenz [e] indole,
• 12. 3- (4-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole and
• 13. 3- (3-aminocarbonylphenyl) -4,5-dihydro-2-phenylbenz [e] indole

as well as their physiologically acceptable salts. 3. Medicament containing a compound according to claim 2. 4. Use of a compound according to one of claims 1 or 2 for the manufacture of a medicinal product with a thrombolyti effect. 5. Process for the manufacture of a medicament according to An Proverb 3, characterized in that in a non-chemical way a connection according to one of claims 1 or 2 in one or several inert carriers and / or diluents is incorporated. 6. A process for the preparation of a compound according to claim 2, characterized in that a ketone of the general formula
in the
R, R ₃ and D are as defined in claim 2, with an aniline of the general formula
in the
R ₁ , R ₂ and n are as defined in claim 2, is implemented and
if necessary, a protective group used during the reaction is subsequently split off or
if desired, a compound thus obtained is subsequently converted into a salt, in particular into a physiologically acceptable salt.