Use of linear annelated tricyclics as inhibitors of erythrocyte aggregation.

The present invention relates to the use of compounds of the general formula I<chemistry id="chem0001" num="0001"><img file="EP0318902A2_D0001.tif" /></chemistry>in which<ul id="ul0001" list-style="none"><li>R₁ represents a phenyl ring of the general formula 11,<chemistry id="chem0002" num="0002"><img file="EP0318902A2_D0002.tif" /></chemistry></li><li>where R₂, R_a, R4 may be the same or different and each hydrogen, an alkanesulfonyloxy, trifluoromethanesulfonyloxy, alkanesulfonylamino, trifluoromethanesulfonylamino, N-alkylalkanesulfonylamino, N-alkyltrifluoromethanesulfonylamino, alkylsulfenylmethyl, hydroxyl or alkylsulfyl, alkyl, methylsulfonyl, alkylsulfylyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group, alkylsulfonyl group, or a Alkoxy, amino, alkylamino or dialkylamino group substituted carbonyl group, one by an amino, alkylamino, Dialkylamino or cyclic imino group substituted sulfonyl group, with a methylene group in the 4-position replaced by a sulfur or oxygen atom</li><li>can be, an alkylcarbonylamino, aminocarbonylamino or alkylaminocarbonylamino group, an alkylmercapto, alkylsulfinyl or alkylsulfonyl group, a nitro, halogen, amino, hydroxy, alkyl, alkoxy, alkenyloxy, alkynyloxy, cyanoalkyloxy, carboxyalkoxy , Alkoxycarbonylalkyloxy, dialkylamino, 1-imidazolyl, trifluoromethyl or cyano group,</li><li>or represents a heterocyclic five-membered ring with 1-4 heteroatoms or a heterocyclic six-membered ring with 1-5 heteroatoms, where the heteroatoms can be the same or different and mean oxygen, sulfur or nitrogen and, if desired, can carry an oxygen atom on one or more nitrogen atoms, and the five - or six-membered rings, optionally with one or more alkyl, alkoxy, alkylmercapto, hydroxy, nitro, amino, Halogen or cyano groups can be substituted,</li><li>or in the event that X represents a bond, R₁ in addition to the groups mentioned above, also a hydrogen atom, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, haloalkyl, alkoxyalkyl, carboxylalkyl, alkoxycarbonylalkyl, a hydroxy, mercapto, amino, alkyl mercapto -, formylaminoalkyl or a pyridylcarbonyl-amino group,</li><li>X represents a bond, an alkylene group or the vinylene group,</li><li>A is a nitrogen atom or the group CR₅ can be, where R_s a hydrogen atom, an alkyl,</li><li>Means alkenyl, cycloalkyl, cycloalkenyl, cyano, alkylcarbonyl, alkoxycarbonyl, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or aryl group,</li><li>B is an oxygen atom, a sulfur atom or the group NR₆ means, where R₆ a hydrogen atom</li><li>or represents an alkyl group, or B can be the group CR7R8, where R₇ a hydrogen atom,</li><li>represents an alkyl, alkenyl or cycloalkyl group, and R₈ a hydrogen atom, an alkyl,</li><li>Alkenyl or cyano group, a carbonyl group substituted by a hydroxyl, alkyl, alkoxy, amino, alkylamino, dialkylamino or hydrazino group, or R₇ and Rs together form an alkylidene or cycloalkylidene group, or R₇ and R₈ together with the carbon atom to which they are attached form a spirocycle,</li><li>or their tautomers, optically active forms and racemic mixtures, or their physiological. compatible salts of inorganic and organic acids, for the production of medicinal products with an erythrocyte aggregation-inhibiting effect.</li></ul>

The compounds of general formula I, processes for their preparation and their use as medicaments are described in EP-A-0.161.632, EP-A-0.186.010, EP-A-0.189.103, EP-A-0.207.483, EP-A-0.214.592 and EP- A-0,216,165. The compounds are described in these applications with the following pharmacological effects: increase in cardiac strength, lower blood pressure, influence on platelet aggregation and improvement in microcirculation.

However, the compounds described in the abovementioned applications are primarily suitable for the treatment of those diseases in which an increase in the strength of the heart and a reduction in the blood pressure are in the foreground, an additional pharmacological effect being the improvement of the flow in the microcirculation by inhibiting platelet aggregation on the one hand and is achieved by increasing the contractility of the heart on the other hand.

Surprisingly, it has now been found that compounds of the general formula have a pronounced action with regard to the inhibition of erythrocyte aggregation. These compounds are therefore also suitable for the treatment of diseases in which erythrocyte aggregation plays an important role in pathogenesis, such as, for example peripheral, coronary or cerebral circulatory disorders, shock conditions, degenerative vascular diseases, rheumatic diseases, various types of ulcers, necrotic processes in tumors, degenerative disorders of the retina, nerves and muscles, or various skin diseases. In particular, the treatment of arterial occlusive diseases, ischemic conditions, venous insufficiency or diabetes mellitus is also possible. With the help of these compounds, it is now also possible to treat diseases which are not associated with a weakening of the heart or an increase in blood pressure, but which are caused by an increased tendency to erythrocyte aggregation to play an important role. This implements a new promising therapeutic principle, since these compounds are the first compounds that reduce erythrocyte aggregation in pharmacologically relevant concentrations and are rheologically active.

If R is a phenyl ring of the general formula 11, the alkyl part of R₂, R₃ and R4 mentioned substituents contain 1-5 carbon atoms, preferably 1-4 carbon atoms. In this sense, preference is given, for example, to methanesulfonyloxy-, ethanesulfonyloxy-, n-propanesulfonyloxy-, isopropanesulfonyloxy-, trifluoromethanesulfonyloxy-, methylsulfenylmethyl-, ethylsulfenylmethyl-, n-propylsulfenylmethyl-, methylsulfinylmethyl- methylsethyl- methylsulfylmethyl- ethylsulfylmethyl- ethylsulfylmethyl- -, n-Propylsulfonylmethyl-, methanesulfonylamino-, ethanesulfonylamino-, n-propanesulfonylamino-, trifluoromethanesulfonylamino-, n-methylmethanesulfonylamino-, N-ethyl-methanesulfonylamino-, N-methyl-ethanesulfonylamino-, N-ethyl-ethanesulfonylamino-, N-isopropylethanesulfonylamino-, N-methyl-n-propanesulfonylamino-, Nn-propyl-n-propanesulfonylamino-, N-methyltrylamino-sulfones -Ethyl-trifluoromethane sulfonylamino-, N-isopropyl-trifluoromethanesulfonylamino-, methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, methylaminocarbonyl-, ethylaminocarbonyl-, dimethylaminocarbonyl, di-n-propylaminocarbonyl-, N-methylethylaminocarbonyl, trifluoromethyl, methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, n-butylaminosulfonyl, n-pentylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, di-n-propylaminosulfonyl, di-n-propylaminosulfonyl, -, propionylamino, methylcarbonylamino, ethylaminocarbonylamino or propylaminocarbonylamino group, a methyl, ethyl, propyl, methoxy, ethoxy, propyloxy, allyloxy, 2-butenyloxy, 3-butenyloxy, 2-pentenyloxy, Propargyloxy, 2-butynyloxy, 3-butynyloxy, cyanomethyloxy, cyanoethyloxy, methoxycarbonylmethyloxy, methoxycarbonylethyloxy, methylmercapto, ethylmercapto, methylsulfinyl, ethylsulfinyl, methylsulfonyl or ethylsulfonyl group.

In the case of sulfonyl groups, which can be substituted by cyclic imino groups, the morpholino, thiomorpholino, pyrrolidino, piperidino and hexamethyleneiminosulfonyl groups are preferred.

In particular, are preferred for<ul id="ul0002" list-style="none"><li>R₂ Hydrogen, an alkylsulfonyloxy-, trifluoromethylsulfonyloxy-, alkylsulfenylmethyl-, alkylsulfinylmethyl-, alkylsulfonylmethyl-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, trifluoromethylsulfonylamino- or N-alkyltrifluoromethyl- sulfonyl, amine, hydroxylamino, hydroxylamino, amine, hydroxylamino, amine, hydroxylamino, amine, hydroxylamino, amine, hydroxylamino, amine, by hydroxylaminoamino, a, by hydroxylamino, a, by methyl Dialkylamino group substituted carbonyl group or a sulfonyl group substituted by an amino, dialkylamino or morpholino group, wherein each of the above-mentioned alkyl parts may contain 1 or 2 carbon atoms, a nitro, cyano or alkylaminosulfonyl group having 1-4 carbon atoms, an alkylcarbonylamino, aminocarbonylamino or N-alkylaminocarbonylamino group, an alkylmercapto, alkylsulfinyl or alkylsulfonyl group, where each of the aforementioned alkyl parts can contain 1 or 2 carbon atoms, a halogen, amino, hydroxyl, dialkylamino, alkyl, alkoxy, Alkenyloxy or alkynyloxy group preferably having 1-3 carbon atoms, a cyanomethyloxy or methoxycarbonylmethyloxy group, the trifluoromethyl group or the 1-imidazolyl group, for R₃ Hydrogen, an alkyl group with 1-3 carbon atoms, an alkoxy or dialkylamino group with 1 or 2 carbon atoms in each alkyl part or a halogen atom and</li><li>for R₄ Hydrogen or the methoxy group.</li></ul>

The phenyl moiety can carry 1 to 3 substituents.

Preferred monosubstituted phenyl compounds are the hydroxy, C₁-C₃ Alkyl, C_i-C₃ Alkoxy, allyloxy, propargyloxy, cyanomethyloxy, methoxycarbonylmethyloxy, halogen, nitro, cyan, aminocarbonyl, methoxycarbonyl, amino, C₁-C₃ Dialkylamino, C₁-C₃ Alkylmercapto, C₁-C₃ Alkylsulfinyl, C₁-C₃ Alkylsulfonyl, C₁-C_a Alkylsulfonyloxy-, and the 1-imidazolylphenyls, where the substituent can be in the 2-, 3- or 4-position.

Preferred disubstituted phenyls contain, as substituents, an alkanesulfonyloxy-, trifluoromethylsulfonyloxy-, alkylsulfenylmethyl-, alkylsulfinylmethyl-, alkylsulfonylmethyl-, alkylsulfonylamino-, N-alkyl-alkylsulfonylamino-, trifluoromethylsulfonylamino-fluorine, a-hydroxylamino- or N-a Amino, alkylamino or dialkylamino group substituted carbonyl group or one substituted by an amino, Dialkylamino or morpholino group substituted sulfonyl group, an alkylaminosulfonyl, alkylcarbonylamino, aminocarbonylamino or N-alkylamino carbonylamino group, a hydroxy, alkyl, alkoxy, allyloxy, propargyloxy, cyanomethyloxy, methoxycarbonylmethyloxy , Nitro, amino, dialkylamino, alkylmercapto, alkylsulfinyl, alkylsulfonyl or a 1-imidazolyl group, where the two substituents can be the same or different and are in 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-position, but preferably in the 2,4-, 2,5- and 3,4-position, and the aforementioned alkyl radicals, alone or in combination with other radicals. Can have 1-3 carbon atoms.

Preferred trisubstituted phenyl contain hydroxyl and methoxy groups as substituents.

Means R_i a heterocyclic five-membered ring with 1-4 heteroatoms or a heterocyclic six-membered ring with 1-5 heteroatoms, where the heteroatoms of the aforementioned five- or six-membered rings can be the same or different and denote nitrogen, oxygen or sulfur and can optionally carry oxygen on one or more nitrogen atoms , the pyrrole, furan, thiophene, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, triazole, tetrazole, Thiadiazole, oxadiazole, pyrazine, N, N'-dioxypyrazine, pyrimidine, N, N'-dioxy-pyrimidine, pyridazine, oxazine, thiazine, triazine, tetrazine, pyridine, and N -Oxy-pyridine residue.

Alkyl, alkoxy and alkyl mercapto substituents in the heterocyclic five and six rings can contain 1-6, preferably 1-4 carbon atoms. The methyl, ethyl, methoxy, ethoxy, methylmercapto and ethyl mercapto radical is preferred. Halogen is to be understood as fluorine, chlorine and bromine, preferably chlorine.

X is a bond and R is₁ an alkyl, alkenyl or alkynyl radical, this means straight or branched chains with up to eight carbon atoms. In this sense, the methyl, ethyl, propyl, butyl, pentyl, hexyl, vinyl, propenyl and propynyl radical is preferred. X is a bond and R is_i a cycloalkyl or cycloalkenyl radical, this means rings with three to seven members. In this sense, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl radical is preferred. If X is a bond and Ri is an alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl radical, the alkyl or alkoxy groups can contain 1 to 6 carbon atoms.

In this sense, preference is given to ethoxymethyl, methoxyethyl, ethoxyethyl, carboxymethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, propoxycarbonylethyl, hydroxymethylethyl, hydroxylethyl , Hydroxypropyl, hydroxybutyl radical.

For X, a bond, a methylene, ethylene or the vinylene group is preferred.

A means the group pCR_s and R₅ an alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group, the alkyl or alkoxy radicals mentioned can contain 1-7 carbon atoms, preferably 1-5 carbon atoms. The acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group are preferred.

B means the group NR₆ and R₆ an alkyl group, the methyl, ethyl, propyl, isopropyl, butyl, 2-butyl and 1,1-dimethyl-ethyl group are preferred.

B means the group CR₇R₈ and R₇ and / or Rs is an alkyl, cycloalkyl, alkenyl or a carbonyl group substituted by an alkyl, alkoxy, alkylamino or dialkylamino group, each of the abovementioned alkyl or alkenyl parts can be straight-chain or branched and 1-6 or 2 -6 carbon atoms and said cycloalkyl part contain 3-7 carbon atoms. In this sense, preference is given to R₇ a hydrogen atom, the methyl, ethyl, isopropyl, 3-pentyl, cyclopentyl or cyclohexyl group. R₈ may preferably represent the hydrogen atom, a methyl, ethyl, isopropyl, 3-pentyl, cyano, carboxy, acetyl, propinyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and hydrazinocarbonyl group.

Form R₇ and R₈ together with the carbon atom to which they are attached, a cycloalkyl ring, it is preferably the spirocyclopropyl, spirocyclobutyl, spirocyclopentyl and spirocyclohexyl group. Form R₇ and R₈ together an alkylidene or cycloalkylidene group, the isopropylidene or cyclohexylidene group is preferred.

Compounds of the general formula 1 in which R 1 is the phenyl radical of the general formula II in which<ul id="ul0003" list-style="none"><li>R₂ Hydrogen, the methanesulfonyloxy, trifluoromethanesulfonyloxy, methanesulfonylamino, trifluoromethanesulfonylamino, methanesulfonylmethylamino, trifluoromethanesulfonylmethylamino, methylsuflinylmethyl, methylsulfonylmethyl, aminocarbonyl, methylaminylethylamino, methylsulfonylamino, methylsulfonylmethyl, methylsulfonyl -, methylsulfonyl, hydroxy, allyloxy, methyl, methoxy, propargyloxy, cyanomethyl, oxy, methoxycarbonylmethyloxy, cyan, chlorine, nitro, Amino, dimethylamino, trifluoromethyl or the 1-imidazolyl group,</li><li>R₃ Hydrogen, which m eans methyl, methoxy, hydroxyl, dimethylamino or chlorine group,</li><li>R₄ Is hydrogen or the methoxy group or</li><li>Ri den pyrrole, furan, thiphene, pyrazole, imidazole, isothiazole, thiazole, oxazole, triazole, tetrazole, thiadiazole, isoxazole, oxadiazole, pyridine, N-oxy-pyridine Represents, pyrazine, pyrimidine, N, N'-dioxypyrimidine, pyridazine, oxazine, thiazine, triazine or tetrazine residue, and their methyl, ethyl, methoxy, ethoxy, methylmercapto, ethylmercapto and chlorine-substituted derivatives, or</li><li>In the event that X represents a bond, in addition to the groups mentioned, there is also a hydrogen atom, the methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, cyclopentenyl, cyclohexyl, trifluoromethyl, hydroxyl, mercapto, methylmercapto, amino group means</li><li>X is a bond which means ethylene or vinylene group,</li><li>A represents a nitrogen atom or the --CH group,</li><li>B represents an oxygen atom, sulfur atom, or the group NR6, where R₆ represents the methyl, ethyl or propyl group, or B represents the group CR₇Rs means where R₇ represents a hydrogen atom or the methyl group and R₈ represents the methyl, ethyl or isopropyl group, or R₇ and Rs together with the carbon atom to which they are attached represent a spirocyclopentyl ring.</li></ul>

For the production of pharmaceuticals, the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as olive oil, for example. suspended or dissolved.

The substances of the general formula I and their salts can be administered enterally or parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers or buffers.

Such additives are, for example, tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation. Solid carriers are, for example Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high-molecular fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high-molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavoring and sweetening agents.

The compounds are usually applied in amounts of 10-2000 mg per day based on 75 kg of body weight. It is preferred to administer 1-2 tablets 2-4 times a day with an active substance content of 5-500 mg. The tablets can also be retarded, which means that 1-2 tablets with 20-1000 mg of active ingredient only have to be given once a day. The active substance can also be injected 1-8 may per day or given by continuous infusion, with amounts of 10-1000 mg per day usually being sufficient.

The erythrocyte aggregation was determined using the mini erythrocyte aggregometer from Myrenne, Rötgen (Kiesewetter et al., Biomed. Technik 27, 209-213 (1982)). As a measure, this device specifies a dimensionless index that increases with the tendency to aggregate.

The tests were carried out with human blood from healthy donors. The blood was adjusted to a hematocrit of 45%, the control solution or a substance solution was added and incubated. Then the erythrocyte aggregation was measured. Each substance was in a concentration of 10^-5 molar examined. Two tests were carried out for each substance with the blood of two donors. The difference in the aggregation indices between the initial value of the control solution and the values ​​with the substance solution was calculated (AE).

The following table lists the available findings on erythrocyte aggregation (AE). The lower the listed value, the more effective the substance. Venoruton, a mixture of different 0- (beta-hydroxyethyl) rutosides, however, works at a comparable concentration of 1.7. 10th^-5 M only a change in the red blood cell aggregation index by -0.4. Even at a concentration of 1.7. 10-3 M the change is only -3.9 ± 0.9.

Venoruton is said to inhibit the tendency of erythrocyte aggregation. (Schmid-Schönbein et al., VASA 4,263-270 (1975)).

Compared to the prior art, the substances mentioned in the present invention inhibit erythrocyte aggregation to a significantly greater extent.<tables id="tabl0001" num="0001"><img file="EP0318902A2_D0003.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0318902A2_D0004.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0318902A2_D0005.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0318902A2_D0006.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0318902A2_D0007.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0318902A2_D0008.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0318902A2_D0009.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0318902A2_D0010.tif" /></tables><tables id="tabl0009" num="0009"><img file="EP0318902A2_D0011.tif" /></tables>