CN1159183A - Bis-(2-haloethyl)aminophenyl-substituted distamycin derivatives as anticancer and antiviral agents - Google Patents

Abstract

Novel antitumor and antiviral agents of formula (I) wherein n is 2, 3 or 4; one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 alkoxy; and X is halogen; and the salts thereof are disclosed.

Description

Bis-(2-haloethyl)aminophenyl-substituted distamycin derivatives as anticancer and antiviral agents

The present invention relates to novel antitumor alkylating and antiviral agents which combine with the known antibiotic distamycin A

(distamycin A) related, belonging to the class of pyrromidine antibiotics; their reversible and selective interactions with DNA-AT sequences that interfere with replication and transcription have been reported [Nature 203, 1064 (1964); FEBS Communication 7 (1970) 90; Advances in Molecular Biology for Nucleic Acid Research, 15, 285 (1975)].

DE-A-1795539 describes the preparation of distamycin derivatives in which the formyl group of distamycin is substituted by hydrogen or the acid residue of an organic C ₁ -C ₄ fatty acid or cyclopentylpropionic acid.

EP-B-246868 describes distamycin A analogs in which the formyl group of distamycin is substituted by an aromatic, aliphatic or heterocyclic structure bearing an alkylating group.

A selected class of compounds has now been found to fall within the general formula of EB-B-246868, but they have more valuable biological properties than related prior art compounds.

Accordingly, the present invention provides novel site-specific nitrogen mediators, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

其中n是2，3或4R和R₁之一是氢、C₁-C₄烷基、CF₃或C₁-C₄烷氧基，另一个独立地是CF₃、C₁-C₄烷基或C₁-C₄烷氧基；且X是卤素。The present invention provides a new class of compounds of formula (I)

wherein n is 2, 3 or 4R and _one of R and R is hydrogen, C ₁ -C ₄ alkyl, CF ₃ or C ₁ -C ₄ alkoxy and the other is independently CF ₃ , C ₁ -C ₄ alkane or C ₁ -C ₄ alkoxy; and X is halogen.

The present invention also includes pharmaceutically acceptable salts of compounds of formula (I) and all possible isomers converted from formula (I), including monomeric and mixture forms.

The present invention also includes metabolites and pharmaceutically acceptable bioprecursors (also known as prodrugs) of the compounds of formula (I).

Alkyl and alkoxy groups may be branched straight carbon chains.

C ₁ -C ₄ Alkyl is preferably methyl or ethyl.

C ₁ -C ₄ alkoxy is preferably methoxy or ethoxy.

The carbamoyl group and the bishalogenated ethylamino group of the benzene ring are preferably in the meta or para position to each other.

R and R ₁ can be on any free carbon atom of the benzene ring, but not on the same carbon atom. Preferably one of R and R ₁ is hydrogen or C ₁ -C ₄ alkyl, the other is C ₁ -C ₄ alkyl, CF ₃ or C ₁ -C ₄ alkoxy; or R and R ₁ are identical and are C ₁ -C ₄ alkoxy.

Pharmaceutically acceptable salts of the compounds of formula (I) are their salts with pharmaceutically acceptable inorganic or organic acids.

Examples of inorganic acids are hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid; examples of organic acids are acetic acid, propionic acid, succinic acid, malonic acid, citric acid, tartaric acid, methanesulfonic acid and p-toluenesulfonic acid.

A preferred value of n is 3.

X is preferably chlorine or bromine, especially chlorine.

A class of preferred compounds of the present invention are compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein: n is 3; X is chlorine; _one of R and R is hydrogen or C ₁ -C ₄ alkyl, and the other is C ₁ -C ₄ alkyl, CF ₃ or C ₁ -C ₄ alkoxy.

Specific examples of compounds of the invention, especially in the form of salts with hydrochloric acid, are the following compounds: β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methano Base-4-N, N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propane Amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl ) aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1- Methyl-4-[1-methyl-4-[3-ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido] Pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5- Diethyl-4-N, N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino ]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl ) aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1- Methyl-4-[1-methyl-4-[3-ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido ]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl Oxygen-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino] Propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)amino Benzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl -4-[1-methyl-4-[3-trifluoromethyl-4-N, N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino] pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; and β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-tri Fluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole- 2-Formylamino]propionamidine.

与式(III)化合物

反应，式(III)中R，R₁和X如上述所定义并且Y是羟基或离去基团；并且如果需要，使式(I)化合物成盐或由其盐获得游离化合物，和/或，如果需要将式(I)化合物异构体混合物分离成单一异构体。The compounds of the present invention and salts thereof can be obtained by a process comprising the compound of formula (II) wherein n is as defined above

with formula (III) compound

Reaction, in the formula (III), R, R and X are as defined above and Y is a hydroxyl group or a leaving group; and if desired, the compound of _the formula (I) is salified or a free compound is obtained from a salt thereof, and/or , if desired to separate the isomeric mixture of the compound of formula (I) into individual isomers.

The reaction of a compound of formula (II) with a compound of formula (III) can be carried out according to known methods, for example as described in EP-B-246868.

Specifically, the leaving group Y may be selected from halogen, especially chlorine, 2,4,5-trichlorophenoxy, 2,4-dinitrophenoxy, succinimidyl-N-oxy and imidazolyl.

The reaction of a compound of formula (II) with a compound of formula (III) wherein Y is -OH is preferably carried out in an organic solvent in a molar ratio of 1:1 to 1:2 in the presence of an organic or inorganic base and a condensing agent, said The solvent is, for example, dimethylsulfoxide, hexamethylphosphoric triamide, dimethylacetamide, dimethylformamide, ethanol, benzene or pyridine; the organic or inorganic base is, for example, triethylamine, diiso Propylethylamine or sodium carbonate or sodium bicarbonate; the condensing agent is, for example, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexyl Carbodiimide. The reaction temperature can vary from about -10°C to about 50°C, and the reaction time is from about 1 to about 24 hours.

Y in the formula (III) is another leaving group, such as halogen, 2,4,5-trichlorophenoxy or succinimide-N-oxygen or imidazolyl, the formula (II) compound and The reaction between compounds of formula (III) can be carried out under similar conditions in the absence of a condensing agent.

Compounds of formula (II) are known compounds or may be prepared using known methods for the preparation of known compounds, see for example Arcamone et al., Italian Chemical Bulletin, 97, 1097 (1967). Compounds of formula (III) are also known compounds or can be prepared by known methods detailed in organic chemistry: see, for example, Journal of Medicinal Chemistry, 9, 882 (1966) and 25, 178 (1982).

The salt formation of the compound of formula (I) and the preparation of the free compound from the salt can be carried out by known common methods.

The isomeric mixture of formula (I) can then be separated into individual isomers using well known methods such as fractional crystallization or chromatography.

The novel compounds of formula (I) prepared according to the above method can be purified by conventional methods, such as silica gel or alumina column chromatography, and/or recrystallized in organic solvents, such as lower aliphatic alcohols, such as methanol , ethanol or isopropanol, or dimethylformamide. Pharmacology

The compounds of the present invention are useful as antineoplastic and antiviral agents. In particular, they exhibit cytostatic properties against tumor cells, so they can be used to inhibit the growth of various mammalian, including human tumors, such as carcinomas, such as breast cancer, lung cancer, bladder cancer, colon cancer, ovary and endometrium cancer. Other tumors for which the compounds according to the invention have been found to be useful are, for example, sarcomas, such as soft tissue and bone tumors, and blood cancers, such as leukemias.

In vitro antitumor activity was assessed in cytotoxicity studies with murine L1210 leukemia cells. Cells are obtained from tumors in vivo and seeded in cell culture medium. Use until the tenth passage cells. Cytotoxicity was measured by counting surviving cells 48 hours after treatment.

The percent cell growth in the treated medium was compared to the control. _IC50 values (concentration that inhibits cell growth by 50% compared to control) were calculated from dose-response curves.

Using the following method, the compound of the present invention was tested in vivo against murine _L1210 leukemia and murine M5076 reticulocyte sarcoma, showing good antitumor activity.

Maintenance of L ₁₂₁₀ murine leukemia in vivo by serial intravenous transplantation. For the experiments, ¹⁰⁵ cells were injected intraperitoneally into CD2F1 female mice obtained from Charles River, Italy. Animals were 8-10 weeks old at the start of the experiments. Compounds were administered iv + 1 day after tumor cell injection.

Maintenance of M5076 reticulocyte sarcoma by serial intramuscular transplantation. For the experiments, 5 × ¹⁰⁵ cells were injected intramuscularly into C57816 female mice obtained from Charles River, Italy. Animals were 8-10 weeks old at the start of the experiments. Compounds were administered intravenously 3, 7 and 11 days after tumor injection.

T.I.＝与对照组相比的抑制肿瘤生长的％Tox：由于毒性而死亡的小鼠数。Survival time and tumor growth of mice were calculated and activity was expressed as T/C%h and TI%.

TI = % Tox inhibition of tumor growth compared to control: number of mice that died due to toxicity.

Tox assays were performed when mice died in the control group and/or before significant body weight loss and/or spleen and/or liver size reduction were observed.

In these tumor models, the compounds of the present invention have higher antitumor activity than the very similar compounds of EP-B-0246868.

For example, the representative compound β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl base) aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 29325) and β-[1-formyl Base-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formyl Amino]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 29721) and the known compound β-[1- Methyl-4-[1-methyl-4-[1-methyl-4-[4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carba The activity data of amido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine (internal code FCE 24517) against disseminated L ₁₂₁₀ mouse leukemia is shown below. Table 1 Compound (internal code) FCE 29325FCE 29721FCE 24517 mg/kg3.133.133.13 T/C%191183133 Tox0/100/100/10

The activity data in the above table shows that the compound of the present invention with said substituent on the benzene ring of benzoyl mustard has a higher activity than the very similar unsubstituted known compound FCE 24517.

The compound of the present invention can also effectively interfere with the replication activity of pathogenic virus, thereby protecting tissue cells from virus infection.

They are all active against viruses such as DNA viruses such as herpes viruses such as herpes simplex and herpes zoster; RNA viruses such as rhinoviruses and adenoviruses; and retroviruses such as sarcoma viruses such as murine Sarcoma virus and leukemia virus, such as hemophilia virus (Friendleukemia). Herpesviruses, Coxegiviruses, and Respiratory Synocytic Viruses were tested in body fluid media as follows. Serial two-fold dilutions from 200-1.5 mcg/ml were double dispensed into 96-well microtiter plates, 0.1 ml/well, for tissue culture.

Immediately add the cell suspension (2×10 ⁵ cells/ml) infected with about 5×10 ⁻³ TCID ₅₀ virus, 0.1 ml/well.

After 33-5 days of incubation at 37°C in 5% _CO2 , the cell cultures were evaluated microscopically and the minimum inhibitory concentration (MIC) was determined, which is the minimum concentration to determine the elimination of cytopathic effect compared to the infected control group.

The compounds of the invention may be administered to mammals, including humans, by conventional routes, eg parenterally, eg by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.

The dosage depends on the age, weight and physical condition of the patient and the route of administration.

For example, for the compound FCE 20325, a suitable dose administered to an adult patient is about 0.1 to about 150-200 mg per dose, 1-4 times a day.

As mentioned above, the pharmaceutical composition of the present invention contains the compound of formula (I) as an active ingredient and one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention can generally be prepared according to the following conventional methods, and they can be administered in suitable pharmaceutical forms.

For example, solutions for intravenous injection or infusion may contain a carrier such as sterile water or preferably sterile isotonic saline solution.

Suspensions or solutions for intramuscular injection may contain the active compound together with a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol; Docaine hydrochloride.

In formulations for topical application such as creams, lotions or pastes for the treatment of the epidermis, the active ingredient may be admixed with customary oily or emulsifying excipients.

Solid oral dosage forms, such as tablets and capsules, may contain the active ingredient and diluents, such as lactose, dextrose, sucrose, cellulose, corn starch, and potato starch; lubricants, such as silicon dioxide, talc, stearic acid, stearin calcium or magnesium acid and/or polyethylene glycol; binders such as starch, acacia, gelatin, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone; disintegrants such as starch, alginic acid, algae salts, sodium starch glycolate; foaming mixtures; pigments; sweeteners; wetting agents such as lecithin, tewin, lauryl sulfate; and in general, non-toxic pharmacologically inert substances commonly used in pharmaceutical preparations substance. The pharmaceutical preparations can be prepared in a known manner, eg by mixing, granulating, tabletting, sugar-coating or coating processes.

In addition, the present invention also provides a method of treating tumors and viral infections in a patient in need thereof, comprising administering the composition of the present invention to said patient.

Another object of the present invention is to provide a method for combined treatment of cancer or alleviating its symptoms in mammalian cancer patients including humans, the method comprising administering: 1) a compound of the present invention or a pharmaceutically acceptable salt thereof, and 2 ) another antineoplastic agent, their combined use should be sufficient to produce therapeutic effect on time.

The present invention also provides a product comprising the compound of the present invention or a pharmaceutically acceptable salt thereof and another antineoplastic agent as a combined preparation, which can be used simultaneously, separately or sequentially in anticancer therapy.

The term "antineoplastic agent" refers to a mixture comprising a single antineoplastic drug and a "cocktail", ie, a mixture of such drugs in clinical practice.

Examples of antineoplastic agents that may be formulated with the compounds of the present invention or that may be administered in combination therapy include doxorubicin, daunorubicin, epirubicin, idarubicin, etoposide, fluorouracil, melphalan, cyclophosphine, Amide, 4-desmethoxydaunorubicin, bleomycin, vinblastine, and mitomycin and mixtures of two or three of the above.

Accordingly, the compounds of the present invention are useful in the treatment and alleviation of cancer. They can be administered to treatable cancer patients together with an antineoplastic agent such as the above-mentioned anthracycline glycosides, such as doxorubicin, daunorubicin, epirubicin, 4-des Daunorubicin or idarubicin.

Compounds of the present invention and antineoplastic agents such as anthracycline glycosides can improve the symptoms of patients with lymphoma leukemia and sarcoma such as myeloblastic leukemia, neuroblastoma, Wilms tumor or bladder, breast, Lung or thyroid malignancy.

The following examples are intended to be illustrative and not limiting.

The abbreviations DMF, DMSO and P.M.R. stand for dimethylformamide, dimethylsulfoxide and proton nuclear magnetic resonance, respectively. Example 1

Compound β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis-(2-chloroethyl)aminobenzene -1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride first step intermediate 3-methyl-4-N, N-bis(2-chloroethyl)aminobenzoic acid

To a suspension of 2 g of commercially available ethyl 3-methyl-4-aminobenzoate in 100 ml of 25% acetic acid was added 20 ml of ethylene oxide. The mixture was stirred at room temperature for 2 days, neutralized with sodium bicarbonate and extracted with ethyl acetate (2 x 100ml). The combined organic phases were dried ( _Na2SO4 ) and concentrated _in vacuo to give a white precipitate of 3-methyl-4-N,N-bis(2-chloroethyl)aminobenzoic acid which was filtered and suspended in 10 ml of 23% hydrochloric acid solution, cooled in ice, and added 1.8ml of phosphorus oxychloride. The mixture was refluxed for 2 hours, cooled, diluted with water and extracted with ethyl acetate (2 x 50ml).

The combined organic phases were dried ( _Na2O4 ) and the solvent was evaporated in _vacuo , yielding 2 g of the intermediate. mp108-110°C FAB-MS: m/z: 276 (20, [M+H] ⁺ ) PMR (CDCl ₃ ) δ: 7.9 (m, 2H); 7.15 (m, 1H); 3.5 (m, 8H) ;

                                                                           

1.8ml of thionyl chloride was added to a solution of 630mg of the intermediate in 10ml of benzene. The mixture was refluxed for 2 hours, the solvent was evaporated in vacuo, the crude solid residue was dissolved in 15 ml of dioxane, and a small amount of this solution was added to 10 ml of an aqueous solution of 400 mg N-distamycin A and 255 mg sodium bicarbonate. The mixture was stirred for 1 hour, then 2N hydrochloric acid solution was added until pH=1. The solvent was evaporated in vacuo, and the solid residue was purified by flash column chromatography on silica gel using a mixture of dichloromethane and methanol to obtain 500 mg of the title compound. FAB-MS: m/z: 711 (45[M+H] ⁺ ), 258 (75) PMR (DMSO) δ: 10.19 (s, 1H); 9.97 (s, 1H); 9.91 (s, 1H); 8.7(bs, 4H); 8.21(t, J=5.7Hz, 1H); 7.74(m, 2H); 7.29(d, J=1.8Hz, 1H); 7.28(d, J=7.5Hz, 1H); 7.22 (d, J=1.8Hz1H); 7.17(d, J=1.8Hz, 1H); 7.08(d, J=1.8Hz, 1H); 7.05(d, J=1.8Hz, 1H); 6.94(d, J =1.8Hz, 1H); 3.85(s, 3H); 3.83(s3H); 3.80(s, 3H); 3.3-3.7(m, 10H); 2.6(t, J=6.6Hz, 2H); 2.33(s , 3H).

By analogy, the following compounds can be obtained using appropriate intermediates: β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4- N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride FAB-MS: m/z: 725(90[M+H] ⁺ ) UV(EtOH95%) λ310.ε=42985P.MR(DMSO)δ: 10.22(s, 1H); 10.01(s, 1H); 9.94 (s, 1H); 8.99 (s, 2H); 8.64 (s, 2H); 8.21 (t, J = 5.7Hz, 1H); 7.61 (s, 2H); 7.29 (d, J = 1.7Hz, 1H) ;7.21(d, J=1.7Hz, 1H); 7.18(d, J=1.7Hz, 1H); 7.08(d, J=1.7Hz, 1H); 7.05(d, J=1.7Hz, 1H); 6.91 (d, J=1.7Hz, 1H); 3.86(s, 3H); 3.84(s, 3H); 3.81(s, 3H); 3.62(m, 2H); 3.60-3.30(m, 8H); 2.62( m, 2H); 2.35(s, 6H).β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N, N- Bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride; β-[ 1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1 -formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4- [1-Methyl-4-[3-methoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2- Formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethoxy-4- β- [1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N, N-bis(2-chloroethyl)aminobenzene-1- Formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4-[ 1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formyl Amino]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N , N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; and β- [1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N,N-bis(2-chloroethyl ) aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine. Example 2

Tablets (tablet weight 0.250 mg, containing 50 mg active substance), can be prepared as follows: Composition per 10,000 tablets β-[1-methyl-4-[1-methyl 4-[1-methyl-4-[3-methyl-4-N, N-bis(2-chloroethyl)aminobenzene-1- Formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride; lactose corn starch talc magnesium stearate 500g1,400g500g80g20g

β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-bis(2-chloroethyl)aminobenzene- 1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-carboxamido]propionamidine hydrochloride, lactose and half the amount of cornstarch are mixed; the mixture is then pressurized Pass through a 0.5mm mesh sieve.

Cornstarch (10 g) was suspended in warm water (90 ml) and the resulting paste was used to granulate the powder mixture. The granules are dried and finely crushed on a 1.4 mm mesh screen, then the remaining amount of starch, talc and magnesium stearate are added, carefully mixed and compressed into tablets.

Example 3

Capsules (each weighing 0.200 g, containing 20 mg of active substance), can be prepared as follows: The composition of each 500 capsules β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1 -Formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride; lactose cornstarch magnesium stearate 10g80g5g5g

The formulation is encapsulated in two-piece hard gelatin capsules, 0.200 g per capsule. Example 4

Intramuscular injection 25mg/ml

25g of β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-bis(2-chloroethyl)aminobenzene- 1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine hydrochloride was dissolved in sterile propylene glycol (1000ml) to prepare an injectable pharmaceutical composition substance and seal it into 1-5ml ampoules.

Claims (10)

1. Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n is 2, 3 or 4R and _one of R and R is hydrogen, C ₁ -C ₄ alkyl, CF ₃ or C ₁ -C ₄ alkoxy and the other is independently CF ₃ , C ₁ -C ₄ alkane or C ₁ -C ₄ alkoxy; and X is halogen. 2. The formula (I) compound and pharmaceutically acceptable salt thereof of claim 1, wherein: n is 3; X is chlorine; R and R ₁ are hydrogen or C ₁ -C ₄ alkyl, and the other is C ₁ -C ₄ alkyl, CF ₃ or C ₁ -C ₄ alkoxy. 3. A compound selected from the group consisting of β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two ( 2-Chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl- 4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-carboxamido] Pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl -4-[3-Ethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole- 2-Formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N,N- Bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; Base-4-[1-methyl-4-[1-methyl-4-[3-methoxy-4-N, N-bis(2-chloroethyl)aminobenzene-1-carboxamido] Pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl -4-[3-Ethoxy-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole -2-Formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxy-4-N,N-di (2-Chloroethyl)aminobenzene-1-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine; β-[1-methyl -4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole- 2-Formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4 -[3-Trifluoromethyl-4-N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole- 2-Formylamino]propionamidine; and β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4 -N,N-bis(2-chloroethyl)aminobenzene-1-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]pyrrole-2-formylamino]propionamidine, or their pharmaceutically acceptable salts. 4. A salt of the compound of claim 3, wherein said salt is the hydrochloride. 5. A method for the preparation of a compound of formula (I) or a salt thereof, comprising the compound of formula (II) wherein n is as defined in claim 1 with formula (III) compound Reaction, R in formula (III), R and X are as defined in claim ₁ and Y is a hydroxyl group or a leaving group; And if desired, make formula (I) compound salify or obtain free compound by its salt, and Or, if desired, isomeric mixtures of compounds of formula (I) can be separated into individual isomers. 6. A pharmaceutical composition comprising a suitable carrier and/or diluent and the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, for use as an antineoplastic and antiviral agent. 8. A combined preparation product containing the compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and another antineoplastic agent, which can be used simultaneously, separately or sequentially in anticancer therapy. 9. Use of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition as an antitumor and antiviral agent. 10. A method of treating a mammal suffering from a tumor, the method comprising administering to said mammal a therapeutically effective amount of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof.