MXPA99007885A - Compositions for treating or preventing prostatic cancer - Google Patents

Abstract

Compounds represented by general formula (I) which are useful as the active ingredient of novel compositions having therapeutic or preventive effects on prostatic cancer. In said formula (I) R1 and R2 represent each hydrogen, hydroxy or lower alkoxy.

Description

COMPOSITION FOR THE TREATMENT OR PREVENTION OF PROSTATE CANCER TECHNICAL FIELD The present invention relates to a novel composition for the treatment or prevention of prostate cancer, the use of a compound to produce a pharmaceutical preparation for the treatment or prevention of prostate cancer, and a method of treating or preventing the same by administering a effective amount of the compound to warm-blooded animals.

TECHNICAL BACKGROUND The testosterone 5a reductase inhibitor is known as a therapeutic agent for benign prostatic hypertrophy, which reduces the size of the prostate by a mechanism of action that inhibits the growth of prostate cells caused by excess male hormones (and mainly dihydrotestosterone). In addition, testosterone 5a reductase inhibitors such as Finasteride are marketed as a therapeutic agent to treat benign prostatic hypertrophy in the United States of America and Europe. There are some testosterone 5a reductase inhibitors in which clinical studies are being carried out to develop them as therapeutic agents for prostate cancer. The reductive effects on the prostate correspond to the potency of the inhibitory activity of testosterone 5a reductase. However, different from benign prostatic hypertrophy, the therapeutic effects on prostate cancer do not correspond to the potency of the inhibitory activity of testosterone 5a reductase alone, since a greater number of factors intervene with respect to the proliferation of cancer of the prostate. prostate.

BRIEF DESCRIPTION OF THE INVENTION Not all of the compounds included in the present application are unknown compounds; for example, N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5a-androst-1-ene-17β-carboxamide is a compound described in the Japanese patent application (Kokai) No. Hei 8-73492 and the Japanese Patent Publication (Kokoku) No. Hei 8-19151, and is an inhibitor of testosterone 5a reductase. The inventors of the present invention carried out for many years a formal investigation on the synthesis of derivatives having testosterone 5a reductase inhibitory activity and their pharmacological activity. The inventors found that compounds such as those mentioned above that have a specific structure, exhibit an excellent therapeutic or preventive effect of prostate cancer, and carried out the present invention. The objective of the present invention is to provide a composition for the treatment or prevention of prostate cancer. Furthermore, another object of the present invention is to provide a use of the aforementioned compound for the manufacture of a pharmaceutical compound for the treatment or prevention of prostate cancer, and a therapeutic or preventive method therefor, by administering an effective amount of the aforementioned compound previously to warm-blooded animals. Namely, the novel composition of the present invention for the treatment or prevention of prostate cancer contains as an active ingredient a compound represented by the formula (I), pharmacologically acceptable salts thereof or another derivative thereof, and preferably contains as an active ingredient. N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5 -androst-1-ene-17β-carboxamide, and more preferably it is taken orally. In addition, the novel use of a compound represented by the formula (I), pharmacologically acceptable salts thereof or other derivatives thereof, to produce a pharmaceutical composition for the treatment or prevention of prostate cancer, preferably the use of N- is described. [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5a-androst-1-ene-17β-carboxamide, to produce a pharmaceutical composition for the treatment or prevention of prostate cancer, and more preferably it is taken orally. In addition, the novel therapeutic or preventive method of the present invention is a therapeutic or preventive method for prostate cancer., which comprises the administration of an effective amount of a compound represented by the formula (I), pharmacologically acceptable salts thereof or another derivative thereof, to warm-blooded animals, preferably a therapeutic or preventive method for prostate cancer, which comprises the administration of an effective amount of N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5a-androst-1-ene-17β-carboxamide, to warm-blooded animals , and more preferably taking it orally; wherein R and R may be the same or different, and represent a hydrogen atom, a hydroxyl group or a lower alkoxy group. In the formula (I), the term "lower alkoxy group" means a straight or branched chain alkoxy group having from 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, S-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy and 2,3-dimethylbutoxy, preferably a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, more preferably a methoxy group. The term "pharmacologically acceptable salts thereof" means the salts of the compound (I) of the present invention, which can be converted to salts thereof; examples of said salts preferably include alkali metal salts such as a sodium salt, a potassium salt and a lithium salt, alkaline earth metal salts such as a calcium salt and a magnesium salt, and metal salts such as an aluminum salt, an iron salt and a zinc salt. In addition, the compound (I) of the present invention, when allowed to stand in the atmosphere, can absorb some moisture and can, as a result, associate with water of absorption, or can be converted to a corresponding hydrate. Said compounds are also included in the present invention. The compound (I) of the present invention can be prepared according to the procedure shown below.

PROCEDURE A (III) wherein R1 and R2 have the same meanings as defined above. Process A is a method for preparing the desired compound (I) by condensing a carboxylic acid derivative (II) with an amine derivative (III). Step A 1 consists in preparing the compound (I) by reaction of the compound (II) or a reactive derivative thereof with a compound (III). The reaction is carried out according to conventional methods in the synthesis of peptides, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method. In the above methods, the azide method is carried out as follows: the compound (II) or an ester thereof is reacted with hydrazine in an inert solvent (eg, dimethylformamide) at about room temperature to prepare a hydrazide of amino acid The amino acid hydrazide is reacted with a nitrous acid compound to produce an azide derivative, followed by the treatment of the azide derivative with an amine derivative (III). The nitroso acid compound usable herein may include, for example, alkali metal nitrites such as sodium nitrite or alkyl nitrites, such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent, and the solvent usable herein may include, for example, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide and pyrrolidones such as N-methylpyrrolidone. 2-step reactions [preparation of the azide and amide derivative (I)] are generally carried out in a reaction vessel. The reaction temperature is from -50 ° C to 0 ° C for the first reaction, and from -10 ° C to 10 ° C for the last reaction, and the reaction time is from 5 minutes to 1 hour for the first reaction , and from 10 hours to 5 days for the last reaction. The active ester method is carried out by a reaction of the compound (II) with an active esterification agent to give an active ester, followed by reaction of the active ester with an amine derivative (III). Both reactions are preferably carried out in an inert solvent, and the solvent usable herein may include, for example, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as diethyl ether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile.

The active esterification agent usable herein may include, for example, N-hydroxyl compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbomeno-2,3-dicarboximide, or disulfide compounds such as sodium disulfide. dipyridyl, and the active esterification reaction is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature is from -10 ° C to 100 ° C in the active esterification reaction, and at about room temperature in the reaction of the active ester compound with the amine derivative (III), and the reaction time is 30 minutes to 80 hours for both reactions. In the reaction of the active ester with the amine, 4-dimethylaminopyridine can be added to the reaction system. The mixed acid anhydride method is carried out by preparing a mixed acid anhydride of compound (II), followed by reaction of the mixed acid anhydride with an amine derivative. The reaction for preparing the mixed acid anhydride derivative is achieved by reaction of the compound (II) with an agent to form a mixed acid anhydride derivative [eg, lower carbon dioxide haiogenated carboxylic acids such as chlorocarbonate ethyl and isobutyl chlorocarbonate, lower alkanoyl halides such as pivaloyl chloride, diaryl cyanophosphoric acids or lower alkyl, such as diethyl cyanophosphate and diphenyl cyanophosphate, or sulfonyl halides such as 2,4,6-triisopropyl chloride benzenesulfonyl, paratoluenesulfonyl chloride and methanesulfonyl chloride] in an inert solvent (for example, the halogenated hydrocarbons, amides and ethers described above). The reaction is preferably carried out in the presence of organic amines such as triethylamine and N-methylmorpholine, the reaction temperature is -10 ° C to 50 ° C, and the reaction time is 30 minutes to 20 hours. The reaction of the mixed acid anhydride derivative with the amine derivative (III) is preferably carried out in an inert solvent (for example, the hydrocarbons, amides and halogenated ethers described above) in the presence of the organic amines. The reaction temperature is from 0 ° C to 80 ° C, and the time required for the reaction is from 1 hour to 48 hours. The reaction is carried out in the coexistence of the compound (II), the compound (III) and an agent to form a mixed acid anhydride derivative without isolation thereof. The condensation method is carried out by a reaction of the compound (II) with the amine (III) derivative directly in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or 2-chloro-1-methylpyridinium / triethylamine iodide. The present reaction is carried out in a manner similar to that described in the preparation of the active ester.

In the case where a protected hydroxyl group is present in R1 and R2, the protecting group can be removed in accordance with conventional methods. The compound (II) that is used as a raw material, or the active ester thereof, is known or is prepared according to known methods [eg, J. Med. Chem., 27, 1960 (1984); J. Med. Chem., 29, 2298 (1986)]. In addition, the compound (III) is known or prepared according to known methods [for example: Synthesis, 593 (1976); J. Org. Chem., 36, 305 (1971); Angew. Chem., 82, 138 (1970); Synthesis, 24 (1978); Synthetic Commun., 18, 777 (1988); Synthetic commun., 18, 783 (1988); Organic Reaction, 3, 337 (1946); Org. Synthesis, 51, 48 (1971); Tetrahedron, 30, 2151 (1974); and J. Org. Chem., 37, 188 (1972)] and, for example, a compound is prepared that serves as a raw material in the present invention having a portion of H2N-C (Me) (Me) -Ph (R1) R2) of according to the method described in Synthesis, P. 24 (1978). The reaction scheme is shown below: (wherein R1 and R2 have the same meanings as defined above, Me represents a methyl group and Ph represents a phenyl group), and comprises a Grignard reaction, a hydroxyl group azidation reaction and a reduction reaction.

BRIEF DESCRIPTION OF THE FIGURE Figure 1 shows an anti-tumor effect against human prostate cancer in Example 1. Vertical axis: Relative ratio of tumor volume (expressed in logarithm) Horizontal axis: Number of days after initial administration Cross points: Control group Black points: Finasteride administration group Circle points: Compounds administration group 1. Compound 1: N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo -4-aza-5a-androst-1-ene-17β-carboxamide BEST WAY TO CARRY OUT THE INVENTION In the sequential, the present invention will be described in greater detail with respect to the examples and the reference example, the scope of the present invention is not limited thereto.

EXAMPLE 1 Test 1 of antitumor activity A solid tumor, which was reliably excised under the skin, was obtained by subcutaneously subculturing the LNCaP strain of human prostate cancer from a system of cultured cells purchased from the American Type Culture Collection (ATCC) 5 to 6 times in male nude mice. and females. This strain of human prostate cancer was used in the test. A fragment of 3 mm2 of solid cancer of this strain was transplanted under the skin of the axillary region of nude BALB / cAJd -nu mice (Nippon Clea, males, 8 weeks old). Mice in which the tumor was reliably excised approximately 20 days later, were randomly assigned to groups of 8 to 10 animals each. The mice were orally administered N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5-androst-1-ene-17β-carboxamide (compound 1, 100 mg / kg ) or Finasteride (100 mg / kg) at the rate of 0.1 ml / 10 g of body weight once a day in the morning for 28 consecutive days. The diameter of the tumor was measured twice a week, and the tumor volume V (V = ab2 / 2) was calculated from the major axis (a) and the minor axis (b). The relative volume ratio for each mouse was represented as Vn / Vo. The rate of inhibition of tumor growth (%) was determined from the relative volume ratio for each mouse. Tumor growth inhibition regimen (%) = (1 -Vn / Vo) x 100 Vn: Volume of tumor in n day Vo: Volume of tumor in the first day of administration.

Results: Relative volume ratio data are shown in Figure 1. Finasteride is marketed in the United States and Europe as a drug for the treatment of benign prostatic hypertrophy, and clinical studies are currently underway to its use as a drug for the treatment of prostate cancer. Figure 1 shows that Finasteride does not exhibit any inhibitory activity of tumor growth; however, compound 1 exhibits tumor growth inhibitory activity, of which the maximum rate of tumor inhibition for 28 days was 30%. Accordingly, compound 1 is useful as a therapeutic agent for prostate cancer.

EXAMPLE 2 Test 2 of antitumor activity Naked male mice (4-5 weeks old) without thymus were used in the test. The nude mice were reared in an aseptic condition. LNCaP cells from human prostate cancer were purchased from the American Type Culture Collection (ATCC). The LNCaP cells (5 x 10 6) were transplanted subcutaneously into the nude mice to form a solid tumor, and were then used in the test. The lower abdomens of the nude mice were cut approximately 2 cm under anesthesia to expose the prostate. The prostatic membrane was carefully opened, and a tumor fragment of LNCaP cells was inserted into it. The opening in the prostatic membrane was closed with absorbable suture. The prostate was returned to the abdominal cavity, and the incision in the lower abdomen was sutured with absorbable suture. These mice were randomly assigned to groups of 20 animals each. These groups were designated as a group of compound 1 to which said compound (20 mg / kg) was administered, Finasteride group to which Finasteride was administered (20 mg / kg), and control group not dosed. It was confirmed that the transplanted tumor was absorbed in the mouse when the tumor grew until it could be measured from the outside of the mouse body, and then administration of compound (I) and Finasteride was started. Compound 1 and Finasteride were orally administered daily at the dosage levels described above. The volume of the transplanted tumor was calculated in accordance with the formula shown in Example 1. In addition, the mice were immediately necropsied when they died due to cancer, and the tumor was weighed. The presence of metastasis was also confirmed at the same time. Sections of metastatic tissue were prepared by imbibing them in paraffin after fixing them with 10% formalin. The tissue sections were stained with hematoxylin and eosin, followed by examination of the metastasis. The Student t test was carried out on the weights of the transplanted tumors for all groups. In addition, the Fisher test was carried out in cases of metastasis in each of the groups. The Mann-Whitney U-test and the Student's t-test were carried out in the two groups used for comparative purposes with respect to effects that prolong life. The chi square test (x2) according to Pearson was carried out on the survival rate on day 63 after the tumor transplant in particular. The risk index of less than 5% was considered significant for these tests.

RESULTS TABLE 1 As is clear from Table 1, the group of compound 1 exhibited a much better survival rate compared to the Finasteride group.

REFERENCE EXAMPLE 1 N-M -Methyl-1 - (4-methoxyphenyl) etn-3-oxo-4-aza-5a-androst-1-ene-17β-carboxamide 1.0 g of 3-oxo-4-aza-5a-androst-1-ene-17β-carboxylic acid, 1.6 g of triphenylphosphine and 1.4 g of 2,2'-dipyridyl disulfide were added successively to 30 ml of toluene. dried, and the mixture was stirred at room temperature overnight. The reaction mixture as such was subjected to column chromatography on 35 g of silica gel, and eluted with acetone / methylene chloride (1: 9 to 1: 1) to obtain 1.11 g of the 2-pyridyldithio ester derivative . 5.0 g of the synthesized 2-pyridylthio ester derivative in a manner similar to that described above and 5.0 g of 1- (4-methoxyphenyl) -1-methylethylamine were successively added to 30 ml of dry methylene chloride, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with 100 ml of methylene chloride, washed with 1 N hydrochloric acid, water, aqueous sodium hydrogen carbonate and a saturated saline solution. The methylene chloride layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on 15 g of silica gel, and eluted with acetone / methylene chloride (1: 9 to 1: 1) to obtain 5.2 g of the title compound. NMR spectra (CDCI3) d ppm: 0.68 (3H, s), 0.98 (3H, s), 0.90-2.20 (16H, m), 1.70 (3H, s), 1.72 (3H, s), 3.35 (1 H , t, J = 9 Hz), 3.80 (3H, s), 5.48 (1 H, br.), 5.76 (1 H, br.), 5.83 (1 H, d, J = 10 Hz), 6.82 (1 H, d, J = 10 Hz), 6.88 (2H, d, J = 9 Hz), 7.32 (2H; d, J = 9 Hz) IR spectra vmax crt? 1 (KBr): 2969, 2938, 1672, 1599, 1514, 1455, 1248, 1181, 1035, 825.

INDUSTRIAL APPLICATION POTENTIAL The compound (I) of the present invention has excellent antitumor activity and low toxicity. In this way, it is useful as a composition for the treatment or prevention of prostate cancer. The compound (I) or the pharmacologically acceptable salts thereof of the present invention are used as a composition for the treatment or prevention of prostate cancer. The compound (I) itself or mixtures thereof with pharmacologically acceptable excipients, diluents and the like, can be administered orally as tablets, capsules, granules, powders or syrups. These pharmaceutical preparations are prepared by standard techniques that are well known to those skilled in the art using additives. The additives are excipients (for example, organic excipients such as sugar derivatives, for example lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, starch, dextrin and carboxymethyl starch; cellulose such as crystalline cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose and internally bound sodium carboxymethylcellulose; gum arabic; dextran; and swarm; and inorganic excipients such as silicate derivatives, eg light silicic acid anhydride, silicate of synthetic aluminum and aluminate of magnesium metasilicic acid, phosphates, for example calcium phosphate, carbonates, for example calcium carbonate, and sulfates, for example calcium sulfate); lubricants (e.g., stearic acid; metal salts of stearic acid such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as beeswax and whale sperm; boric acid; adipic acid; sulfates such as sulfate sodium, glycol, fumaric acid, sodium benzoate, DL leucine, sodium salts of aliphatic acid, lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate, silicic acids such as silicic acid anhydride and hydrated silicic acid, and the starch derivatives mentioned above); binders (for example, polyvinylpyrrolidone, Macrogol and the same compounds described in the above excipients); disintegration agents (eg, the same compounds described in the above excipients; and chemically modified starches and celluloses such as croscarmellose sodium, carboxymethyl sodium starch and linked polyvinylpyrrolidone); stabilizers (for example, para-oxybenzoates such as methylparaben and propylparaben, alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol, benzalkonium chloride, phenols such as phenol and cresol, thimerosal, dehydroacetic acid, and sorbic acid); correctors (eg, sweetening agents, acidifiers and aromatic chemicals conventionally used); and thinners. The dose varies, depending on the condition and age of the patient. For example, it is convenient to administer 0.001 mg / kg of body weight (preferably 0.01 mg / kg of body weight) as the lower limit, and 20 mg / kg of body weight (preferably 1 mg / kg of body weight) as the upper limit one to several times a day, depending on the symptoms. The preparation examples are shown as follows. However, the scope of the invention is not limited thereto.

EXAMPLE OF PREPARATION 1 Capsules Compound of reference example 1 20 mg Lactose 158.7 Corn starch 70.0 Magnesium stearate 1.3 250 mg The powders described above were mixed and screened through 60 mesh screen, and then the resulting powders were encapsulated in a 250 mg No. 3 gelatin capsule to give a capsule.

EXAMPLE GIVE PREPARATION 2 Tablets Compound of Reference Example 1 20.0 mg Lactose 154.0 Corn starch 25.0 Magnesium stearate 1.0 200 mg The powders described above were mixed and formed into a tablet using a tabletting machine to obtain a 200 mg tablet. The tablet can be coated with sugar, if necessary.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - A composition for the treatment or prevention of prostate cancer, characterized in that it contains as an active ingredient a compound of the formula (I): wherein R1 and R2 are the same or different, and each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group or a lower alkoxy group, or a pharmacologically acceptable salt thereof or another derivative thereof.

2. The composition for the treatment or prevention of prostate cancer according to claim 1, further characterized in that it contains as an active ingredient a compound of formula (I), wherein R1 and R2 are the same or different, and each represents a hydrogen atom, a hydroxyl group or a lower alkoxy group, or a pharmacologically acceptable salt thereof or another derivative thereof.

3. The composition for the treatment or prevention of prostate cancer according to claim 1, further characterized in that the compound of formula (I) is N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3 -oxo-4-aza-5a-androst-1-ene-17β-carboxamide.

4. The composition for the treatment or prevention of prostate cancer according to any of claims 1 to 3, further characterized in that the composition is in a form suitable for oral administration.

5. The use of a compound of formula (I): wherein R1 and R2 are the same or different, and each represents a hydrogen atom, a hydroxyl group, a protected hydroxyl group or a lower alkoxy group, or a pharmacologically acceptable salt thereof or another derivative thereof, for the manufacture of a pharmaceutical preparation for the treatment or prevention of prostate cancer.

6. - The use according to claim 5 of a compound of formula (I), wherein R1 and R2 are the same or different, and each represents a hydrogen atom, a hydroxyl group or a lower alkoxy group, or a salt pharmacologically acceptable thereof or another derivative thereof.

7. The use according to claim 5, wherein the compound of formula (I) is N- [1-methyl-1- (4-methoxyphenyl) ethyl] -3-oxo-4-aza-5a-androst -1-ene-17β-carboxamide.

8. The use according to any of claims 5 to 7, wherein said pharmaceutical preparation is in a form suitable for oral administration.