MXPA97002148A - Methods to inhibit endometr mythosis - Google Patents

Abstract

A method for inhibiting endometrial mitosis comprising administering to a human in need thereof an effective amount of a compound having formula (I) wherein R1 and R3 are independently hydrogen, -CH3 (a) or (b) , wherein Ar is optionally substituted phenyl, R 2 is selected from the group consisting of pyrrolidine, hexamethyleneimino and piperidino, and a pharmaceutically acceptable salt or solvate thereof.

Description

METHODS TO INHIBIT ENDOMETRIAL MYTHOSIS DESCRIPTION OF THE INVENTION The uterine lining (endometrium) is made up of tissue, blood vessels and glands that grow via mitosis when stimulated by the hormone estrogen. In women with normal menstrual cycles, hormonal fluctuations activate the growth and detachment of the endometrium every month. If conception occurs, the endometrium nourishes the developing embryo. Most cases of endometrial carcinoma are associated with a precursor lesion called "endometrial hyperplasia". The classification of endometrial hyperplasia is based on the presence or absence of cytological atypia, the presence of dysplasia and the degree of complexity of the architectural pattern. Cytological atypia is the criterion of greatest prediction to determine the probability of progression to carcinoma. In simple or cystic hyperplasia with cytological atypia present, there is an approximately 8% chance of progression to cancer. With complex or adenomatous hyperplasia with cytologic atypia present, the probability is 29%. When atypia is not present REF: 24103 cytological, the rate of progression is 1% for simple hyperplasia and 3% for complex hyperplasia. With continuously elevated estrogen levels, the endometrium remains in its growth phase (fungal activity) at all times, and in some cases leads to an overabundance of endometrial tissue or endometrial hyperplasia. Overgrowth of the endometrium is often a benign condition, but it can also be a precursor of endometrial cancer. Because of this risk, doctors ask women to avoid long-term estrogen therapy without changes, which can lead to overgrowth of the endometrium if the lining does not come off continuously, and to seek rapid treatment for conditions that can lead to production excessive estrogen (the use of progesterone in hormone replacement therapy causes the rupture of vessels and detachment of the accumulation of the endometrium). Doctors base their treatment decisions on several factors. First, they examine the cells that are obtained in the biopsy or D &C. If the cells are normal but simply overabundant, the future development of cancer is less likely in comparison to the case in which the cells are atypical, and which show enlarged nuclei and other unusual characteristics. In some cases, a D &C shows that the cancer has already developed. Mitotic activity is also considered. Endometrial cancer is the most common gynecological pathology and is the fourth most common malignant cancer in women, after breast, colorectal and lung cancers. Approximately 30,000-40,000 new cases of endometrial cancer are diagnosed each year. Although this is the most common pathology, most patients present it in its early stage. Endometrial cancer mainly affects postmenopausal women, in which the average age at diagnosis is 58 years, and less than 5% of cases occur before an age of 40. The frequency of cancer of the endometrium is higher among women with a history of malignant cancers of the breast, endometrium or ovaries, and also in women who belong to a high socioeconomic status. The most significant risk factors for endometrial cancer are obesity and the presence of estrogen without counteracting progesterone. The lack of precision in determining the clinical stage of endometrial carcinoma prevents optimal therapy and analysis with treatment results. Unless a metastatic or systemic disease is identified, the initial approach for all currently medically prepared patients is a total abdominal hysterectomy / bilateral salpingo-oophorectomy. In case it is needed, in the help therapy can be planned based on the surgical-pathological findings that only indicate intrauterine or extrauterine disease. The patient may receive beams of external radiation in the pelvis if the pelvic nodules are positive and from beams of radiation external to the para-aortic fields if the nodes are positive. Patients with other sites of extrauterine disease may require full abdominal radiation. Some patients may need systemic therapy in addition to radiation therapy, based on the sites of dissemination. Patients with stage II disease are at a higher risk of developing extrauterine disease and recurrence. If the cervix is of normal size and thickness, one approach is intrafacial TAH / BSO with determination of the complete surgical stage followed by postoperative irradiation. When the thick cervical part is involved, two options are available. The first is total pelvic irradiation followed by an intracavitary implant, which is then followed by TAH / BSO and sampling of para-aortic lymph nodes. The second option is radical hysterectomy. BSO and pelvic and para-aortic lymphadenectomy with irradiation adapted to the surgical findings, if necessary. In Stage III surgical disease, surgery may be attempted primarily with the use of TAH / BSO with tumor volume removal. Extrapelvic disease, based on site and extension, may require an extended field of irradiation, systemic chemotherapy, or hormone therapy. Patients with stage III disease, by virtue of their vaginal or parametrial extension, need a deep metastatic examination and subsequently irradiation. Most patients with stage IV disease are treated better with systemic therapy which includes hormones or chemotherapy. Pelvic irradiation or hysterectomy is reserved for palliative control purposes. Patients with recurrent endometrial cancer in the pelvis can be treated with radiation therapy. Unfortunately, most of these patients also have distant metastasis. Isolated central recurrences in the pelvis after irradiation are rare. However, if this situation occurs, the selected patients may be candidates for pelvic exenterantive surgery. Most patients with recurrent disease are treated with hormones or chemotherapy. Progestins have been used for decades to treat recurrent endometrial cancer. The total response to progestins is approximately 25%, although recent trials show lower response rates, in the range of 15 to 20%. Patients with endometrial carcinoma with progesterone-positive and estrogen-positive receptors have a better response to endocrine therapy. Most patients with positive receptors respond to progestins, while only 15% with negative receptors respond to therapy. Medroxyprogesterone acetate (Provera) and megestrol acetate (Megace) are the most commonly used agents. Tamoxifen (Nolvadex) has also been used to treat patients with recurrent endometrial cancer, and responses are usually seen in patients who have previously responded to progestins. Several cytotoxic agents have activity on endometrial cancer, but the responses are short-lived and treatment for advanced and recurrent disease is considered palliative. The two most active single agents are doxorubicin and cisplatin. Many combinations of cytotoxic agents have been used, but the results of multi-agent chemotherapy do not appear to be significantly better compared to single-agent chemotherapy. This invention provides methods for inhibiting mitosis of the endometrium, comprising administering to a human in need thereof an effective amount of a compound of formula I wherein R1 and R3 are independently hydrogen, CH O O the alkyl of C _-CQ), -C II-Ar wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidino, hexamethyleneimino and piperidino; and pharmaceutically acceptable salts and solvates thereof. The present invention relates to the discovery that a select group of 2-phenyl-3-aroyl-benzothiophenes (benzothiophenes), those of formula I, are useful for inhibiting mitosis of the endometrium. The therapeutic and prophylactic treatments provided by this invention are practiced by administering to a human in need thereof a dose of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, which is effective in inhibiting mitosis of the endometrium. . The term "inhibit" includes its generally accepted meaning, which includes prohibiting, avoiding, restraining and diminishing, stopping or reversing progression. As such, the present method includes both medical therapeutic and / or prophylactic administration, as appropriate. Raloxifene is a preferred compound of this invention and is the hydrochloride salt of a compound of formula I, wherein R 1 and R 3 are hydrogen and R 2 is 1-piperidinyl. Generally, at least one compound of formula I is formulated with common excipients, diluents or carriers and compressed into tablets, or formulated as elixirs or solutions for convenient oral administration, or administered intramuscularly or intravenously. The compounds can be administered transdermally and can be formulated as sustained release dosage forms and the like.

The compounds used in the methods of the present invention can be made according to established procedures such as those detailed in U.S. Patent Nos. 4,133, 814, 418, 068, and 4,380,635, all of which are incorporated by reference. at the moment. In general, the process starts with a benzo [b] thiophene having a 6-hydroxyl group and a 2- (4-hydroxyphenyl) group. The starting compound is protected, acylated and deprotected to form compounds of Formula I. Examples of the preparation of such compounds are given in the North American patents mentioned above. The term "optionally substituted phenyl" includes phenyl and phenyl substituted one or two times with Ci-Cg alkyl, C ^ d alkoxy, hydroxy, nitro, chloro, fluoro or tri (chloro or fluoro) methyl. The compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of organic and inorganic acids and bases, and include physiologically acceptable salts that are often used in pharmaceutical chemistry. Such salts are also parts of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like. Salts derived from organic acids such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and alkanedioic hydroxy acids, aromatic acids, aliphatic and aromatic sulfonic acids can also be used. Such pharmaceutically acceptable salts include, therefore, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, oxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β -hydroxybutyrate, butyne-1,4-dioate, hexane-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroxyalate, malonate, mandelate , mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate , becensulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluensulfo nato, xylene sulfonate, tertarate and the like. A preferred salt is the hydrochloride salt.

The pharmaceutically acceptable acid addition salts are usually formed by reacting a compound of formula I with an equimolar or excess amount of acid. The reagents are generally combined in a mutual solvent such as diethyl ether or benzene. The salt is usually separated by precipitation from the solution within about one hour to 10 days and can be isolated by filtration, or the solvent can be removed by distillation by conventional means. The bases usually used for the formation of salts include ammonium hydroxide and alkali metal and alkaline earth metal hydroxides, carbonates, as well as aliphatic and primary, secondary and tertiary amines, aliphatic diamines. Bases especially useful in the preparation of addition salts include ammonium hydroxide, potassium carbonate, methylamine, diethylamine, ethylenediamine and cyclohexylamine. The pharmaceutically acceptable salts generally have characteristics of increased solubility as compared to the compounds from which they are derived and are therefore often more susceptible to formulation as liquids or emulsions. The pharmaceutical formulations can be prepared by methods known in the art. For example, the compounds can be formulated with common excipients, diluents or carriers, and can be constituted into tablets, capsules, suspensions, powders and the like. Examples of excipients, diluents and carriers that are suitable for such formulations include the following: fillers and diluents or diluents such as starch, sugars, mannitol and silicic derivatives, binding agents such as carboxymethylcellulose and other cellulose derivatives, alginates , gelatin and polyvinylpyrrolidone; wetting agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate, - agents for delaying dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds, surfactants such as cetyl alcohol, glycerol monostearate, absorptive transporters such as kaolin and bentonite, and lubricants such as talc, calcium and magnesium stearate and solid polyethylglycols. The compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are suitable for formulation as sustained release dosage forms and the like. The formulations may be constituted so as to release the active ingredient uniquely or preferably in a particular part of the intestinal tract, possibly over a period of time. The coatings, envelopes and protective matrices can be produced, for example, from polymeric substances or waxes The particular dosage of a compound of formula I required to inhibit mitosis of the endometrium according to this invention depends on the severity of the disorder, the route of administration and related factors that will be determined by the attending physician Generally, accepted and effective daily doses are between about 0.1 to about 1,000 mg / day, and more commonly from about 50 to about 200 mg / day. Such dosages will be administered to a subject in need thereof from once to approximately three times each day, or more frequently if necessary, and for a time to effectively inhibit mitosis of the endometrium. a compound of formula I in the form of an acid addition salt, as is This is particularly true in the administration of pharmaceutical substances that have a basic group, such as the piperidino ring. For such purposes the following oral dosage forms are available.

Formulations In the formulations that follow, "Active ingredient" means a compound of formula I.

Formulation 1: Gelatin capsules Hard gelatin capsules are prepared using the following: Ingredient e Quantity (ms / capsule) Active ingredient 0.1 - 1000 Starch, NF 0 - 650 Flueble starch powder 0 - 650 Silicone fluid at 350 centistokes 0 - 15 The ingredients are mixed, passed through a 45 mesh U.S. and it is administered as a filling in hard gelatin capsules. Examples of formulations of raloxifene-specific capsules that have been manufactured include those shown below: Formulation 2: Raloxifene capsule Ingredient Quantity (ma / capsule) Raloxifene 1 Starch, NF 112 Flueble starch powder 225.3 350 centistokes silicone fluid 1.7 Formulation 3: Raloxifene capsule Ingredient Quantity (mg / capsule Raloxifene 5 Starch, NF 108 Flueble starch powder 225.3 350 centistokes silicone fluid 1.7 Formulation 4: Ralox-en capsule Ingredient Quantity (mq / capsule) Raloxifene 10 Starch, NF 103 Flueble starch powder 225.3 350 centistokes silicone fluid 1.7 Formulation 5 -. Raloxifene capsule Ingredient "_ Quantity (mg / capsule) Raloxifene 50 Starch, NF 150 Flowable starch powder 397 350 centistokes silicone fluid 3.0 The above specific formulations can be changed in accordance with the reasonable variations provided. A tablet formulation is prepared using the following ingredients: Formulation 6: Tablets Ingredient Quantity (mg / tafrleta) Active ingredient 0.1 - 1000 Cellulose, microcrystalline 0 - 650 Silicon dioxide, smoked 0 - 650 Stearic acid 0 - 15 The components are mixed and compressed to form tablets. Alternatively, tablets each containing 0.1-1000 active ingredient are manufactured as follows: Formulation 7: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.1 - 1000 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone 4 (as a 10% solution in water) Sodium carboxymethylcellulose 4.5 Magnesium stearate 0.5 Talcum 1 The active ingredient, starch and cellulose are passed through a 45 mesh U.S. and mix carefully. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a mesh screen number 14 U.S. The granules produced in this way are dried at 50 * -60'C and passed through a mesh screen number 18 U.S. Sodium carboxymethyl starch, magnesium stearate and talc briefly passed through a No. 60 U.S. sieve, then added to the granules which, after mixing, are compressed in a tabletting machine to provide tablets. It is manufactured as follows suspensions, each containing 0.1-1000 mg of active ingredient per dose of 5 ml: Formulation 8: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.1 - 1000 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 mg Benzoic acid solution 0.10 ml Taste c.v.

Color c.v.

Purified water up to 5 mi The active ingredient is passed through a 45 mesh U.S. sieve, and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a little water and added, with stirring. Subsequently, enough water is added to produce the required volume.

TEST ASSAY 1 A total of 251 healthy postmenopausal women are included in the study. Each subject had his last menstrual period more than 6 months, but less than 6 years before the start of the treatment phase of the study. The postmenopausal status of each subject is confirmed before starting treatment with serum estradiol < 120 pmol / L and through FSH >30 IU / L. The subjects have not been treated with estrogen for at least the last 3 months before the study and have never been treated with fluoride, calcitonin or bic osphonate. The subjects are in good health and have an age range of 46 to 60 years. The study is a multi-center, randomized, controlled, double-blind study. The subjects who qualified who accepted consent were randomized into one of four treatment groups: placebo, a compound of formula I of 200 mg once a day, a compound of formula I of 600 mg once a day, or 0.625 mg of estrogen once a day. All subjects also received oral calcium carbonate supplements daily (520 mg / day of elemental calcium). All medications and supplements are taken daily in the morning for an 8-week treatment period. Once the treatment is completed (Visit 5), each subject receives ProveraMR, 5 mg / day for 12 days. Using a Pipelle catheter, uterine biopsy is performed at the baseline and after 8 weeks of treatment. Biopsies are performed routinely or routinely and tissue samples are placed in 10% buffered formalin. The samples are recovered by placing them on tissue paper filters and then examined in a general manner and classified according to appearance (color, texture and consistency) and volume. Standard or standard histological processing in paraffin blocks is used and the tissues are cut in series over a minimum of two cuts resulting in serial strips of 6 to 20 cross sections. Since subjects with clinically significant endometrial abnormalities are excluded from the study or are suspended from the study if they develop abnormalities, the biopsies are immediately evaluated for a descriptive diagnosis. This is done by one of two pathologists and is reported immediately to the doctors at the clinic. The main purpose of the biopsies is to determine the degree of morphological estrogenic effect of the treatment under study. Two pathologists are prepared to read the biopsies when reviewing a series of Pipelle biopsies obtained outside the study that represent the entire spectrum of endometrial morphology. Through the use of morphological criteria associated with estrogen-induced proliferation, a classification system is designed to quantify this estrogenic effect and include the most underlying changes that can be found. Ten of these external cases are then classified with this system by each pathologist, and the cases are reviewed together to determine an understanding and use of uniform criteria. After the first twenty cases from the baseline biopsies in the study, they are classified blindly by each pathologist, and the classifications are reviewed to verify the appropriate use of the system. The pathologists evaluate the biopsy samples in search of the following components: 1) the appropriateness of the sample, 2) glandular morphology, 3) stromal morphology and 4) other changes. Additional findings are entered as written comments. The registers in points are generated from the glandular and stromal morphological characteristics and they are totaled and classified in a 4-point streptocyte scale in which the degree of 0 indicates a typical postmenopausal endometrium and a degree of 2 indicates a remarkable effect estrogen The total classifications for both pathologists are averaged and then a final classification of 0 to 3 is assigned. The classification occurs after the initial immediate diagnosis and 10 to 20 cases are usually sequentially classified. It is expected that the classification of scarce tissue is relatively high with respect to the initial biopsy since the typical postmenopausal endometrium is inactive and consists of a very thin tissue lining (5 mm or less) and the Pipelle biopsy is a blind biopsy method, limited. Because the endometrial glands are required to classify the characteristics of the glandular and stromal morphology, the final biopsy should contain glands before any conclusions can be drawn in individual subjects. The adequacy of the sample is defined as follows: If there is no tissue or tissue remnant of endometrial origin that is present, the sample is considered inadequate and is not included in the evaluation.

If multiple fragments of the epithelium are obtained from the surface of the endometrium, the sample can not be classified. However, the biopsy is considered adequate and is assigned a grade of 0 on the 4-point scale, indicating that there has been no estrogenic effect.

If broken endometrium is obtained with glands, the biopsy is adequate and classified to determine the glandular and stromal characteristics.

If an intact endometrial tissue is obtained, the biopsy is adequate and classified to determine the glandular and stromal changes. In addition, the volume of the tissues is taken into account as an indication of the estrogenic effect.

The glandular morphology is the main classification factor for adequate biopsy samples.

Stromal morphology is the secondary classification factor for adequate biopsy samples. Tables 1 and 2 show the characteristics that are used to classify each sample that has glands and / or stroma present. Four characteristics are used to classify the glands: shape, areas e? nuclear cross section to cellular cytoplasm, nuclear pseudostratification and mitotic activity.

Table 1. Glandular Characteristics: Streptocity Classification Estrogenic Effect / Value in Points No Streptogenicity Streptogenicity Characteristics Limited High Glandular Estrogenicity (0 Points) t 1 Punt (2 Points) Shape Small, Open, straight Open, cystic straight tortuous tubular rabies l. (Continued): Glandular Characteristics. Classification of? S retinocity Estrogenic Effect / Value in Points Without estregenosidad estregenosidad Characteristics It is limited Glycogenicity (0 Points) - (1 Point) (2 Points) Very High Moderate Low (< 50%) core to cyt (> 75%) ratio (75% to 50%) plasma Pseudostrati- None Limited Diffuse Nuclear Fication MitOSiS None Rare Disperses a lot Note: At least 20 gland profiles are used to classify mitotic activity (four sections in series of limited samples).

In smaller samples, a minimum of gland profiles in serial sections before concluding that mitosis is not evident. Table 2 lists the characteristics of the stroma and "other". Four characteristics are also used to classify the stroma: density, mitosis, metaplastic changes in epithelium and tissue volume.

Table 2. Stromal Characteristics: Classification of strogenicity Table 1. Glandular Characteristics: Classification of Estrocity Estrogenic Effect / Value in Points No Streptogenicity Streptogenicity Limited High Stromal Estrogenicity (0 Points) (l Point) (2 Points) Compact cell density Loose fibrous edematous Mitosis None Rare Any / Many Metaplasia * None Rare Scattered, diffuse Volume of Broken or Moderate, much Abundant, some tissue intact more is intact intact. Metaplasia includes tubular, eosinophilic and squamous type. ~ Used only if the glands show a certain estrogenic effect (1 or 2 points).

The morphological characteristics that indicate a lack of estregenocity generate a classification of 0 points and the characteristics that indicate a limited or significant estrogenic effect generate a classification of 1 or 2 points, respectively. By using this system, a biopsy can receive between 0 and 16 points. In addition to the glandular and stromal morphology, other important morphological features include the progestational effect, inflammatory processes, bleeding, growth of polypoids and other pathological findings that are described but not included in the classification of proliferative effects since the other changes are mainly non-proliferative. The sum of the results obtained from the classifications of the characteristics of glandular morphology and stroma result in a scale of 4-point estrogenicity classification which is assigned to each sample as follows: Grade 0 = 0 to 3 points Typical postmenopausal endometrium with little or no estrogenic effect. Grade I = 4 to 6 points Estrogen effect defined but limited Grade 2 = 7 to 10 points Moderate estrogenic effect Grade 3 = > 10 points Notable estrogenic effect.

As indicated above, if the biopsy samples contain multiple fragments of epithelium from the surface of the endometrium, these samples are assigned a grade of 0. For each biopsy, there are eight classifications: four determinations of glandular morphology, two determinations of Stromal morphology (density and mitosis classifications are combined and metaplasia and tissue volume are combined for statistical analysis), the sum of these six classifications and the degree as defined in the above. The correlation coefficients within the class are calculated to determine the concordance between the two readers with respect to the sum of the classifications obtained in a baseline and at 8 weeks (Fleiss, JL (1981) Statistical Methods for Rates and Proportion np ?, New York: John iley and Sons, p 218.] The baseline, week 8 and the change from the baseline for the classifications of week 8 for each of the eight registers were analyze for treatment of differences using the adjusted Cochran-Mantel-Haenazel statistical techniques for the researcher [Landis, RJ Hey an, ER and Kock, GG (1978). "Average Partial Association in Three- and Contingency Tables: A Review and Discussion of Alternative Tests. "International Statistical Review 46: 237-254.]. The presentation of endometrial glands in the biopsy tissue at the baseline is evaluated and at 8 weeks for the treatment difference using the chi c test. Comparisons of paired treatment between each active treatment and placebo are made if the difference in total treatment is statistically significant. Statistical significance is considered on both sides with a level of significance of 0.05. All statistical analyzes use the SAS system [SAS Institute Inc. (1989), SAS / STAT User's Guide, Version 6, Fourth Edition, Volumes 1 and 2, Cary, NC: SAS Institute Inc.].

A positive result in this trial is the re 'iction of the classification for glandular mitosis indicating a decrease in cell replication in relation to placebo. Table 3 illustrates important results of the study.

Table 3. Mean of 'classifications (± MEE) for glandular characteristics at the end point * Statistically significantly different from placebo, two-tailed test (p <.050) / Significantly different marginally from placebo, two-tailed test (p = .053).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described * the invention as above, property is claimed as contained in the following:

Claims (4)

EIVPPICACIQMES
1. : - Use of a compound having the formula (i) for the preparation of a medicament for inhibiting mitosis comprising administering said compound in which R1 and R; they are independently hydrogen, -CH 3 '-c- (all-C 1-C5 alkyl), -ü-Ar wherein Ar is optionally substituted phenyl; R2 is selected from the group consisting of pyrrolidine, hexamethyleneimino and piperidino; or a pharmaceutically acceptable salt or sclvate thereof.
2. 2. The use according to claim 1, characterized in that the compound is the hydrochloride salt thereof.
3. 3. The use according to claim 1, characterized in that the administration is prophylactic.
4. 4. The use according to claim 1, characterized in that the compound is or its hydrochloride salt.