NO179002B - Ortho-substituted benzoylguanidines and drugs containing them - Google Patents

Abstract

Ortho-substituted benzoylguanidines of the formula I <IMAGE> where: R(1) is equal to halogen, alkyl, -X-R(6), where X is equal to O, S, NR(7) or Y-ZO and R(6) is equal to H, (cyclo)(halo)alkyl(methyl), -CnH2n-phenyl, R(3) is equal to H, -X-R(6), R(2) and R(4) are equal to R(11)-SO1-2-, (di)-alkyl-N-SO2-, or one of the two radicals R(2) or R(4) is equal to hydrogen or is defined as R(1), R(5) is equal to H, methyl, F, Cl, methoxy, and their pharmaceutically acceptable salts. They are obtained by a process in which compounds of the formula II <IMAGE> in which R(1) to R(5) have the meaning mentioned and L represents a leaving group which can be easily substituted nucleophilically, are reacted with guanidine. The compounds I are used for producing a medicament for the treatment and the prophylaxis of heart-rhythm disorders and ischaemically induced damage, as well as for producing a medicament for the inhibition of cell proliferation.

Description

The present invention relates to ortho-substituted benzoylguanidines of formula I

where:

R(1) equals F, Cl, Br, J, (^-(^-alkyl, -X-R(6),

X equals S, NR(7),

R(6) is equal to H, C1-C6 alkyl, -Cn<H>2n-R(8),

n equals zero to 4,

R(8) is equal to phenyl, which is unsubstituted or substituted with 1-3 substituents from the group F, Cl,

R(7) is equal to H or C-L-Cs-alkyl,

whereby R(6) and R(7) together can be 4 or 5 methylene groups,

R(3) is equal to H or halogen

R(2) and R(4) are independently equal to R(11)-SO2-, R(12)R(13)N-SO2-, where

R(II) is equal to C 1 -C 4 alkyl, which is unsubstituted or substituted with phenyl, where phenyl is unsubstituted or substituted with 1-3 substituents from the group F, Cl,

R(12) and R(13) are defined as R(6) and R(7);

or one of both residues R(2) or R(4) is equal to hydrogen or is defined as R(1),

R(5 ) is H.,

as well as their pharmaceutically acceptable salts.

If one of the substituents R(1) to R(13) contains an asymmetry center, then both S- and R-configured compounds belong to the invention. The compounds can also exist as isomers, as diastereomers, as racemates or as mixtures of these.

The indicated alkyl residues can be both straight-chain and branched.

The compounds of formula I can be prepared by reacting compounds of formula II

with guanidine, where R(1) to R(5) have the indicated meanings, and L stands for a weak nucleophilic substitutable leaving group.

The activated acid derivatives of formula II, where L stands for an alkoxy group, preferably a methoxy group, a phenoxy group, phenylthio, methylthio, 2-pyridylthio groups, a nitrogen heteroring, preferably 1-imidazolyl, are preferably obtained in a known manner from corresponding carboxylic acid chloride (formula II, L = Cl), which in due course can be prepared in a known manner from the corresponding carboxylic acid (formula II, L = OH), for example with thionyl chloride.

In addition to the carboxylic acid chloride of formula II (L = Cl), it is also possible to further prepare activated acid derivatives of formula II in a known manner directly from the corresponding benzoic acid derivative (formula II, L = OH), such as, for example, the methyl esters of formula II with L = OCH3 on treatment with gaseous HCl in methanol, the imidazolide of formula II on treatment with carbonyldiimdazole (L = 1-imidazolyl, Staab, Angew. Chem. Int. Ed. Engl. 1, 351-367 (1962)), the mixed anhydride II with CI-COOC2H5 or tosyl chloride in the presence of triethylamine in an inert solvent, as also the activation of the benzoic acid with dicyclohexylcarbodiimide (DCC) or with 0-6[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3- tetramethyluronium tetrafluoborate ("TOTU") (see Weiss and Krommer, Chemiker Zeitung 98, 817 (1974)). A number of suitable methods for the preparation of activated carboxylic acid derivatives of formula II are indicated under the bibliography in J. March, Advanced Organic Chemistry, Third Edition (John Wiley & Sons, 1985), p. 350.

The reaction of an activated carboxylic acid derivative of formula I with guanidine takes place in a known manner in a protic very aprotic polar but inert organic solvent. Here, the reaction of the benzoic acid methyl ester (II, L = OMe) with guanidine, methanol or THF, the temperature is kept between 20" C and the boiling point of this solvent. "In most of the reactions of the compounds II with salt-free guanidine III, the work is preferably done in aprotic inert solvents, such as THF, dimethoxyethane, dioxane. Water can also be used as solvent when reacting II with guanidine.

When L = Cl, one preferably works with the addition of an acid scavenger, e.g. in the form of an excess of guanidine to remove the hydrohalic acid.

Some of the used benzoic acid derivatives with formula II are known and described in the literature. The unknown compounds of formula II can be prepared according to methods known in the literature, by, for example, transferring 2-chloro- or 2-fluoro-5-chlorosulfonyl-benzoic acid with ammonia or an amine to a 5-aminosulfonyl-2-chloro - or -fluorobenzoic acid or with a weak reducing agent such as sodium bisulphite and following alkylation to a 5-alkylsulfonyl-2-chloro- or -2-fluorobenzoic acid and the benzoic acid derivative thus formed is reacted according to one of the process variants described above to the compound I of the invention.

Such carboxylic acids or their esters of formula II with L = OH or for example -O-methyl and R(l) and/or R(3) in the sense of halogen, can also serve as starting compounds for other carboxylic acids, where the halogen R(l )- and/or R(4)-position can very easily be exchanged in a known manner for numerous nucleophilic reagents, such as mercaptan R(6)-SH or primary amine R(6)R(7)NH while forming further benzoic acid derivatives II with L = -OH or -O-methyl.

In a similar way, starting from 5-nitro-2-chlorobenzoic acid, further benzoic acid derivatives (II, L = OH) can be prepared by nucleophilic introduction of a residue R(l) in position 2 (exchanged for Cl) and further conversion of the nitro group, such as reduction to NH2 and subsequent alkylation or displacement, for example by diazotization and the Sandmeier reaction.

Benzoylguanidine I are generally weak bases, and can bind acids to form salts. Suitable acid addition salts are salts of all pharmacologically acceptable acids, for example halides, especially hydrochlorides, lactate, sulphate, citrate, tartrate, acetate, phosphate, methyl sulphonate, p-toluene sulphonate.

Compound I are substituted acylguanidines.

Preferred representatives of esters of acylguanidine are the pyrazine derivative amiloride, which finds use as a potassium-sparing diuretic in therapy. Numerous further compounds of the amiloride type are described in the literature, such as, for example, dimethylamiloride or ethylisopropylamiloride.

Amiloride: R' ,R" = H

Dimethylamiloride: R', R'* = CH3

Ethylisopropyl amiloride: R' = C2H5, R" = CE(CE3)2

Moreover, investigations have become known which refer to the antiarrhythmic properties of amiloride (Circulation 79, 1257-63 (1989)). A wide application as an antiarrhythmic is admittedly opposed by the fact that this effect is only weakly expressed, and by a blood pressure-lowering and saluretic effect, which occurs in connection with this, and these side effects in the treatment of heart rhythm disorders are undesirable.

Reference to antiarrhythmic properties of the amilorides was also found in experiments on isolated animal hearts (Eur. Heart J. 9 (suppl.l): 167 (1988) book abstracts). Thus, for example, it was found for rat hearts that an artificially triggered ventricular fibrillation could be completely suppressed by amiloride. Even more potent than amiloride in this model was the above-mentioned amiloride derivative ethylisopropylamiloride.

In the European explanatory document 416,499 (HOE 89/F 288), benzoylguanidine was described which carries hydrogen in the positions corresponding to the residues R(1) and R(2). US-PS 3,780,027 disclosed acylguanidine, which is structurally similar to the compound of formula I and which can be derived from commercially available loop diuretics such as bumetanide. Correspondingly, a strong salidiuretic activity was found for these compounds. N-amidino-3-furfurylamino-4-chloro-5-methylsulfonyl-benzamide, which is described in this patent, was prepared and in our model showed no antiarrhythmic effect.

It was thus surprising that the compounds of the invention did not show any unwanted and negative salidiuretic effects, even though they had very good properties against arrhythmias, such as those that occur in oxygen-deficient states. Due to their pharmacological properties, the compounds are eminently suitable as antiarrhythmic drugs with cardioprotective components for infarct prophylaxis and infarct treatment as well as for the treatment of angina pectoris, where they also preventively inhibit, or greatly reduce, the pathophysiological course of the formation of ischemically induced damage, especially in the triggering of ischemically induced cardiac arrhythmias. Due to their protective action against pathologically hypoxic and ischemic situations, the compounds of the formula I of the invention, due to the inhibition of the cellular Na+/H+ exchange mechanism, can be used as drugs for the treatment of all acute or chronic injuries that are ischemically triggered,' or the resulting primary or secondarily induced diseases. This concerns their use as a drug during operative interventions, for example in organ transplantation, where the compounds can be used both for the protection of the organ in the donor before and during removal, and the protection of removed organs, for example during treatment with, or their storage in, physiological bath fluids , as also with the transfer in the recipient organism. These compounds are likewise valuable, protectively effective drugs when carrying out angioplasty operations, for example on the heart, as well as on peripheral requirements. Corresponding to their protective effects against ischemically induced damage, the compounds are also suitable as drugs for the treatment of ischemia in the nervous system, especially the central nervous system, whereby they are, for example, suitable for the treatment of strokes or cerebral oedema. In addition, the compounds of formula I of the invention are also suitable for treating forms of shock, such as allergic, cardiogenic, hypovolemic and bacterial shock.

Moreover, the invention's compounds with formula I, by strongly inhibiting the proliferation of cells, for example, emphasize fibroblast cell proliferation and the proliferation of smooth vascular muscle cells. Therefore, the compounds of formula I are valuable as therapeutics for diseases in which the cell proliferation has a primary or secondary cause, and can therefore be used as antiatherosclerotics, agents against diabetic late complications, cancer diseases, fibrotic diseases such as lung fibrosis, liver fibrosis or kidney fibrosis, organ hypertrophies and hyperplasias, especially in the case of prostatic hyperplasia, respectively, prostatic hypertrophy.

The compounds of the invention are effective easier for the cellular sodium-proton antiport (Na+/H+ exchange), which in several diseases (essential hypertension, atherosclerosis, diabetes, etc.) is elevated also in such cells, where the measurement is easily available, such as for example "in erythrocytes, thrombocytes or leukocytes. The compounds of the invention are therefore suitable as excellent and simple scientific tools, for example in their use as diagnostics for determinations, and rare between certain forms of hypertension, and also atherosclerosis, diabetes, proliferative diseases, etc. Moreover, the compounds of formula Suitable for preventive therapy to prevent the development of high blood pressure, for example essential hypertension.

Medicines, which contain a compound I, can be given orally, parenterally, intravenously, rectally or by inhalation, where the preferred application depends on the disease picture. The compounds I can thus be used alone, or together with galenic excipients and in both veterinary and human medicine.

Which excipients are suitable for the desired drug formulation is known to the person skilled in the art. Alongside solvents, gel formers, suppositories, tablet excipients and other active substances, for example antioxidants, dispersants, emulsifiers, foaming agents, taste correctors, preservatives, solvents or colourings, can be used.

For an oral form of use, the active compound is mixed with suitable additives, such as carriers, stabilizers or inert diluents, and usually placed in the suitable delivery form such as tablets, dragees, suppositories, aqueous, alcoholic or oil solutions. As inert carriers, e.g. gum arabic, magnesia, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch, be used. Here, the supply can take place as well as dry or wet granules. As oil carriers or solvents, for example plant or animal oils come into consideration, such as sunflower oil or cod liver oil.

For subcutaneous or intravenous application, the active compounds, possibly with suitable, common substances such as solubilizers, emulsifiers or additional auxiliaries, are brought into solution, suspension or emulsion. Examples of suitable solvents are the following: Water, physiological saline solution or alcohol, e.g. ethanol, propanol, glycerine, besides also sugar solutions such as glucose or mannitol solutions, or also a mixture of different of the mentioned solvents.

As pharmaceutical formulations for delivery in the form of aerosols or sprays, e.g. solutions, suspensions, emulsions of the active substance of formula I in a pharmaceutically acceptable solvent, such as in particular ethanol or water, or a mixture of such solvents, suitable. If necessary, the formulation can also contain other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers as well as a carrier gas. Such a preparation usually contains the active ingredient in a concentration of from about 0.1 to 10, in particular from about 0.3 to 3% by weight.

The dosage of the active ingredient of formula I used and the frequency of delivery are related to the potency and side of action of the compound used; moreover, it also depends on the nature and severity of the disease to be treated, as well as the condition, age, weight and individual sensitivity of the treated mammal.

On average, the daily dose of a compound of formula I in a patient of about 74 kg is at least 0.001 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, most preferably 1 mg/kg body weight. In the event of an acute onset of disease, such as immediately after the onset of a heart attack, an even higher, and primarily more frequent, dosage may also be necessary, for example up to 4 single doses per day. day. Especially with intravenous use, such as for a heart attack patient in the intensive care unit, up to 200 mg per day be necessary.

Experimental part.

General instructions for the production of benzoyl-guanidine (I) from benzoic acids (II, L=0H)

One dissolves respectively suspends 0.01 M of the benzoic acid derivative of formula II in 60 ml of anhydrous tetrahydrofuran (THF) and then adds 1.78 g (0.011 M) of carbonyldiimidazole. After stirring for 2 hours at room temperature, 2.95 g (0.05 M) of guanidine is taken up in the reaction solution. After the overnight stirring, the THF is distilled off under reduced pressure (rotavapor), water is added, adjusted to pH 6-7 with 2N HCL, and the corresponding benzoylguanidine (formula I) is filtered off. The benzoylguanidine thus formed can, by treatment with aqueous or methanolic hydrochloric acid or other pharmacologically acceptable acids, be transferred to the corresponding salt.

Example 1:

2-chloro-5-methyl sulfonylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 208-21C<P>C,

from 2-chloro-5-methylsulfonylbenzoic acid (m.p. 182-186'C).

Example 2:

2-chloro-5-piperidylsulfonylbenzoyl-guanidine,

colorless crystals, m.pt. 226-229°C,

from 2-chloro-5-piperidylsulfonylbenzoic acid (m.p. 207-210°C).

Example 3:

2-chloro-5-(1-pyrrolidinyl-sulfonyl)benzoyl-guanidine,

colorless crystals, m.pt. 195-198°C,

from 2-chloro-5-(1-pyrrolidinyl-sulfonyl)benzoic acid (m.p. 205°C).

Example 4:

2-chloro-5-N-methylsulfamoylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 201-203°C,

from 2-chloro-5-N-methylsulfamoylbenzoic acid (m.p. 169-170°C).

Example 5:

2-chloro-5-N,N-dlpropylsulfanoylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 170-173°C,

from 2-chloro-5-N,N-dipropylsulfamoylbenzoic acid (m.p. 102-104°C).

Example 6:

2-Chloro-5-(2-phenylethyl-sulfamoyl)benzoyl-guanidine hydrochloride

colorless crystals, m.pt. 70°C,

from 2-chloro-5-(2-phenylethyl-sulfamoyl)benzoic acid (m.p. 160-163°C).

Example 7: 2-chloro-5-N-methyl-N-(2-phenylethyl)sulfamoyl-benzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 186-188°C,

from 2-chloro-5-N-methyl-N-(2-phenylethyl)sulfamoyl-benzoic acid (m.p. 127-129°C).

Example 8:

2-piperidy1-5-sulfamoylbenzoyl-guanidine,

colorless crystals, m.pt. 247°C,

from 2-piperidyl-5-sulfamoylbenzoic acid (m.p. 248°C, prepared from 2-chloro-5-sulfamoylbenzoic acid in 10 mol of piperidine under inert gas for 24 hours by boiling with reflux cooling, distilling off excess piperidine and treating the residue with water/diluted hydrochloric acid at pH 1-2).

Example 9:

2-benzylamino-5-sulfamoylbenzoyl-guanidine,

colorless crystals, m.pt. 191-193°C,

from 2-benzylamino-5-sulfamoylbenzoic acid (m.p. 246°C, prepared from 2-chloro-5-sulfamoylbenzoic acid in 20 equivalents of benzylamine for 8 hours at 130°C/inert gas and treatment with water/diluted HC1 at pH 1- 2).

Example 10: 2-N-methyl-N-(2-phenylethyl)amino-5-sulfamoylbenzoylguanidine hydrochloride,

colorless crystals, m.pt. 180°C,

from 2-N-methyl-N-(2-phenylethyl)amino-5-sulfamoylbenzoic acid (m.p. 240°C, preparation by heating 2-fluoro-5-sulfamoylbenzoic acid and N-methyl-2-phenylethylamine in 10- 15 hours in dimethylacetamide in the presence of 4 equivalents of ethyl diisopropylamine at 120°C, evaporation of solvent and treatment of the residue with water and dilute HCl at pH 1-2).

Example 11

2-N-methyl-N-(2-phenylethyl)amino-5-methylsulfonylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 123°C,

from 2-N-methyl-N-(2-phenylethyl)amino-5-methylsulfonylbenzoic acid (amorphous oil, preparation from 2-chloro-5-methylsulfonylbenzoic acid and N-methyl-2-phenylethylamine analogously to example 10 for 8 hours at 140° C).

Example 12: 5-N-methyl-N-(2-phenylethyl)sulfamoyl-2-piperidinobenzoyl-guanidine,

colorless crystals, m.pt. 85°C,

from 5-N-methyl-N-(2-phenylethyl)sulfamoyl-2-piperidinobenzoic acid (amorphous intermediate without defined m.p., preparation from 2-chloro-5-N-methyl-N-(2-phenylethyl)sulfamoylbenzoic acid and piperidine analogous to example 8).

Example 13: 2-(2-chlorophenylthio)-5-methylsulfonylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 284-286°C,

from 2-(2-chlorophenylthio)-5-methylsulfonylbenzoic acid (m.p. 210-216°C, prepared by reaction of 2-chloro-5-methylsulfonyl-benzoic acid methyl ester with 1 equiv. of 2-chlorothiophenol and excess of K2C03 in DMF at 90° C for 7 hours and hydrolysis of the thus formed 2-(2-chlorophenylthio)-5-methylsulfonyl-benzoic acid methyl ester m.p. 145°C) in a mixture of dioxane and caustic soda at room temperature).

Example 14: 2-(2,6-dichlorophenylthio)-5-methylsulfonylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 288-290°C,

from 2-(2,6-dichlorophenylthio)-5-methylsulfonylbenzoic acid (m.p. 244°C, prepared analogously to example 13 from 2-chloro-5-methylsulfonylbenzoic acid methyl ester with 1 equiv. of 2,6-dichlorothio-

phenol and hydrolysis of the thus formed 2-(2,6-dichlorophenylthio)-5-methylsulfonyl-benzoic acid methyl ester (m.p. 139°C) analogously to example 13.

Example 15:

5-methylsulfonyl-2-piperidinobenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 124-130°C,

prepared from 5-methylsulphonyl-2-piperidinebenzoic acid (m.p. 198°C, prepared prepared by reaction of 2-chloro-5-methylsulphonylbenzoic acid through several hours of boiling with a reflux condenser, evaporation of excess piperidine and subsequent treatment with water/diluted HC1 at pH 1-2).

Example 16:

2,4-dichloro-5-sulfamoylbenzoyl-guanidine hydrochloride

colorless crystals, m.pt. 240°C,

by reacting 2,4-dichloro-5-sulfamoylbenzoic acid with guanidine according to the general method described above.

Example 17:

2-amino-4-chloro-5-sulfamoylbenzoyl-guanidine hydrochloride

colorless crystals, m.pt. 318-320°C,

by reacting 2-amino-4-chloro-5-sulfamoylbenzoic acid with guanidine according to the general method described above.

Example 18:

5-Methylsulfamoyl-2-piperldinylbenzoyl-guanidine hydrochloride

colorless crystals, m.pt. 212-214°C,

by reacting 5-methylsulfamoyl-2-piperidylbenzoic acid with guanidine according to the general method described above.

Example 19:

2,3-dichloro-5-methylsulfonylbenzoyl-guanidine hydrochloride,

colorless crystals, m.pt. 280°C,

by reacting 2,3-dichloro-5-methylsulfonylbenzoic acid with guanidine according to the general method described above.

Example 20:

2-methyl-5-methylsulfonylbenzoyl guanidine hydrochloride

colorless crystals, m.pt. 212°C,

by reacting 2-methyl-5-methylsulfonylbenzoic acid with guanidine according to the general method described above.

Example 21:

2-(2-chlorobenzylamino)-5-sulfamoylbenzoyl-guanidine hydrochloride

colorless crystals, m.pt. 137°C,

by reacting 2-(2-chlorobenzylamino)-5-sulfamoylbenzoic acid with guanidine according to the general method described above.

Claims (7)

1. Ortho-substituted benzoylguanidines of formula I characterized in that the substituents are defined as follows: R(l) is equal to F, Cl, Br, J, C1-C6-alkyl, -X-R(6), X is equal to S, NR(7), R(6) is equal to H, C1-C6 alkyl, -Cn<H>2n<->R(8), n equals zero to 4, R(8) equals phenyl, which is unsubstituted or substituted with 1-3 substituents from the group F, Cl, R(7) equals H or C-L-Cs-alkyl, whereby R(6) and R(7) together can be 4 or 5 methylene groups, R(3) is equal to H or halogen R(2) and R(4) are independently equal to R(11)-SO2-, R(12)R(13)N-SO2-, where R(II) is equal to C 1 -C 4 alkyl, which is unsubstituted or substituted with phenyl, where phenyl is non-sub substituted or substituted with 1-3 substituents from the group F, Cl, R(12) and R(13) are defined as R(6) and R(7); or one of both residues R(2) or R(4) is equal to hydrogen or is defined as R(1), R(5) is H. 2. Compound according to claim 1, characterized in that the substituents are defined as follows: R(l) is equal to F, Cl, C-L-Cs-alkyl, -X-R(6) where X is equal to S or NR(7), R(6) is equal to H, C1-C6-alkyl, -CnB2n-R(8), n equals zero to 4, R(8) equals phenyl, which is unsubstituted or substituted with 1-3 substituents from the group F, Cl, R(7) equals H or methyl, where R(6) and R(7) together can also be 4 or 5 methylene groups, R(3) is equal to H, R(2) and R(4) are - independently of each other - equal to CE3-SO2- or R(12 )R(13)N-SO2-, R(12) and R(13) are equal to R(6) and R(7), or one of both residues R(2) or R(4) is equal to H or defined as R(1), R(5) is equal to H. 3. Compound according to claim 1, characterized in that the substituents are defined as follows: R(l) is equal to F, Cl, C-L-Cs-alkyl, -X-R(6), X is equal to S or NR(7), R(6) is equal to H, C1-C4-alkyl, -Cn<H>2n-R(8), n equals zero to 3, R(8) equals phenyl, which is unsubstituted or substituted with 1-3 substituents from the group F, Cl, R(7) equals H or methyl, where R(6) and R(7) together can also be 4 or 5 methylene groups, R(2), R(3) and R(5) are equal to hydrogen, R(4) is equal to CH3-SO2- or R( 12)R(13)N-SO2- where R(12) is equal to -Cn<B>2n-R(8), n is equal to 1 to 3, R(8) is equal to phenyl, which is unsubstituted or substituted with 1-3 substituents from the group F, Cl, R(13) is equal to H, or R(12) and R(13) also together can be 4 or 5 methylene groups. 4. Use of a compound according to claim 1, for the preparation of a medicament for the treatment and for the prophylaxis of heart rhythm disturbances and of ischemic damage. 5. Use of a compound I according to claim 1, for the production of a drug for inhibiting cell proliferation. 6. Medicine for the treatment and for the prophylaxis of heart rhythm disorders and of ischemic induced damage, characterized in that it contains an effective amount of a compound I according to claim 1, and common pharmaceutical additives. 7. Medicine for inhibiting cell proliferation, characterized in that it contains an effective amount of a compound I according to claim 1, and common pharmaceutical additives.