JPH01500111A - 11-desoxy-17α-hydroxycorticosterone derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] 11-desoxy-17α-hydroxycorticosterone derivative field of invention The present invention is useful for bioorganic chemistry, and more particularly for both antitumor and hormonal activity. A novel 11-dehyde which is useful in medicine as a cancer treatment agent and an immunosuppressant. Suoxy-17α-hydroxycorticosterone derivative (hormonal cell suppressant) Regarding.

Background of the invention Corticoids, their biosynthetic intermediates and cytotoxic acid esters of different structures Tel is known to those skilled in the art.

These are pregnenolone and p-G (2-riO.

Esters with ethyl) aminophenylacetic acid (chlorophenacyl): 3α-hydroxy-5-pregnen-20-one-3α-p-di(2-chloroethyl) chill) aminophenylacetate and esters of desoxycorticosterone and chlorophenacil: 21-hydroxy-4-pregnene-3,20-dione-21-[p-di(2- (chloroethyl)aminophenyl acetate].

The antitumor properties of these compounds have been studied, but the research remains inadequate. . Walker carcinosarcoma W-256, chronic leukemia and hormone-dependent tissue origin in rats The anti-inflammatory properties of the compound against certain tumors such as cervical cancer CC-5 and breast cancer R-13762 Tumor activity is confirmed. However, these compounds are associated with lymphocytic leukemia. It did not show any activity regarding L1210 [Dai-. P, Nfina (Z, P , Sof’ina), F.

Dee, Lagova-r (N, D, Lagova), I, M, Gualuev7 (10M, Valueva), Z, V, Kuzmina (Z, V, Kuz 'm1na), E, F, Skodinskaya (E, N, 5hkodinsk aya), A, M, Khaletsky (A, M, Khaletsky) Rossiday Das of Nioru Union Kenko/Ference on Kemi Therapy Og Marignant Tehumours (Proceedtngs of I A11-Union C□nference on Chemiother apy of Malignant Tumors) S Riga , 1968, pp. 44.1-443; M.

Wall (M, Wa　l　l　), Gee, Abernetay CG.

Abernethy), F, Carol, Dee.

Taylor (D), J.M., Kem (J.

Med, Chem, ), 1969, 12, pp. A3-1810-818; F.

Dee, Lakoua. Experimenta A/Il Oncology (Experime Oncology) 1982, vol. 4, Ya. 5. pp. 38-42 reference〕.

Esters of corticoids, more particularly hydrocortisone and β-chloroethyl Cal/J minic acid ester: 9αF, 11β, 16α, 17α, 26-citra Oxypregner 1,4-diene-3,20-dione-21-[bis-(2-k) Loloethyl) Cal Gumate), 16.17-7 Se) Nido and triamcinolone-acetonide and β-chloroethylcarbamate Terni 11β, 17α, 21-trihydroxy-pregnene-4-3,20-dione- 21-[Bis(2-chloroethyl)carbamate] It has been known. These compounds are biologically active and stimulate murine fibroblast L It inhibits the growth of -929 cultures and reacts with cell receptors. However, this Their biological effects are reversible [Masry, A., Gui et al. −. Braun (V, Braun), C, N1elsen , W, Pratt, Zoei, Met, Kem, (J, Med.

Chem, ), 1977, vol. 20, Ya 9. p. 1134-1139] .

Synthetic corticoids - prednisolone and p-di(2-chloroethyl)aminopher Ester with nylbutyric acid (chlorampsyl): the following formula %formula%) Pregna-1,4-diene-3,20-dione-11β, 17.2 1-trihydroxy-21-(p--diC2-chloroethyl)aminophenylbu Thyrates are known to those skilled in the art, and this compound includes [gredonimustine (Pre dnimustins) J product name is given [D, Alftochi] , - (D, Al f tchew), Ai, Rush, Anne, Chia, Shineko Lu, Fenu.

(I, Ru5h, Ann, Chir, Gynaecol, Fenw, )　s 1969 1vol, 56.234; Jay, Kaufman (J.

Kaufmann), G, Hunjura (G, Hunjura) A, Mittelmann, C, Are ngsta), Gee, Mar74-CG.

Murphy), Cancer, Treat, Rep, (Cancer.

Treat, Rep, ) 1976, vol, 60, A3, pp. 277-279 ].

The preparation "Prednisolone" is effective in the treatment of systemic blood diseases and, to a lesser extent, breast cancer. It is useful in oncological clinics for physical therapy. Side effects of “prednimustine” is mainly associated with hematologic toxicity.

Disclosure of invention The present invention discloses a novel 11-desoxy- The present invention aims to provide a 17α-oxycorticosterone derivative.

This 11-7” soxy-17α-oxycorticosterone derivative is new. Until now unknown from the literature.

The purpose of the present invention is to induce 11-desoxy-17α-hydroxycorticosterone. The body has the following general formula: [In the above formula, R is -Co(CH2)nC6H4N(CH2CH2 Ct)2 and n=1.3]. will be accomplished.

In the compound according to the present invention, mineralocorticoids and Hormones in glucocorticoid biosynthesis - mesoieta and estrogen 11-7'suoxy-17α-oxycorticosteroids that can be metabolized according to their type Use Ron.

The compounds according to the present invention are 11-7'suoxy-17α-hydroxycorticosteroids. and p-di(2-chloroethyl)aminophenylalkanoic acid ester. I'm here.

Examples of compounds according to the invention are 11-desoxy-17α-hydroxy-21-C P-di(2-chloroethyl)aminophenyl acetate]corticosterone and and 11-desoxy-17α-hydroxy-21-[p-di(2-chloroethyl [aminophenylbutyrate] corticosterone.

The compounds according to the present invention are substantially insoluble in water and can be used in organic solvents (chloroform, solvent, etc.). non-hygroscopic white or yellowish soluble in Contains white fine crystals and acquires a yellow color after long storage in light. This compound is 5-0 It is stable for long periods of time when stored in the dark at temperatures within the range of °C.

The following formula: The compound according to the present invention represented by 11-desoxy-17α-hydroxy Shows high antitumor activity proven against leukemia. This antitumor effect is important for the lifespan of animals. has been shown to prolong life and recover some animals.

The compound according to the present invention has a highly toxic alkylating agent, namely chlorophene. Advantages due to low toxicity compared to Nacil and Chlorambucil have. Therefore, the equimolar amount of chlorine contained in the dosage of the compound according to the invention Phenacyl and chlorambucil are 5-10 times higher than their own dosage.

To study the antitumor activity of the compounds according to the invention, induced re-implanted and spontaneous tumor 1 hematopoietic hyperplasia lastoses) and transplanted solid tumors were used. The following mold was used: L1 210, P-388, hemocytoblastosis osts) La, MOPC-406% Viral sunno4 leukemia (lym pholeukosis) Mazurenko LMC-1, C a-755, breast cancer skin that metastasizes to the lungs, alveolar breast cancer PMK-1, Small intestine adenocarcinoma AKATON, large intestine adenocarcinoma AKATOL, Lewis lung cancer LL, lung adenocarcinoma RL- 67, liver cancer G-22c #G-60-G-61, sarcoma 5-37 and S -180, DMBA (dimethylbenzanthracene) induced and spontaneous breast cancer, and DMN (dimethylhydrazine)-induced tumors of the large intestine.

The research was carried out on line mice and their first hinterland, as well as hybrid mice and It was conducted on rats.

The compounds were administered to animals subcutaneously in kernel oil. Administration conditions are in the table below. As shown.

For comparison purposes, the known hormonal cytostatic agent estracyte ) (estra-1,3,5-(10) train-3,17β-diol-3 N-[bis-(2-chloroethyl)carbame)-17-nadolium phosphate Chlorophenacyl was administered subcutaneously in a solution of 0.9% NaCl. and chlorambucil were administered intraperitoneally in a 10% solution of ethanol to Syn(β-[p-di(2-10loethyl)aminophenyl]-α-alanine hydride rochloride) was administered intraperitoneally in a 0.9% solution of NaCL and prednisolone. Zolone (pregnagene-1,4-trio-11β, 17α, 21-dione -3,20) was administered orally in Denzon glue.

The criteria for determining the antitumor activity of the compounds according to the invention are as follows: prolongation of the lifespan of animals; (ELAS%) and tumor growth inhibition (TGI, H).

Where T is the average lifespan of treated animals and C is the average lifespan of control animals.

where 0 is the mean tumor volume in the group of treated animals and K is the mean tumor volume in the group of control animals. This is the mean tumor volume.

In cases of tumors induced by carcinogens or spontaneous tumors, the antitumor effect The criteria are: TGI, CH or tumor size compared to its initial value. Decrease in Z, Ch. Started spontaneously and after being provoked.

Data regarding the antijacemia activity of the compounds according to the invention are shown in Table 1.

Table 1 1, 11-desoxy-17α-hydroxy-21-(p-di(2-k) loloethyl) - aminophenyla Ceft) Corticosterone 10-25/24X52, 11-desoxy- 17α-hydroxy-21-[:P-di(2-k loloethyl)-aminophenylbu Thyrate] Corticosterone 15-35/24X53, Chlorophenacyl 1 ．． 5-3/24X54, chlorambucil 2.5-4/24X55, 11-de Suoxy-17α-hydroxycorticosterone 7-15/24X56, 1 1-desoxy-17α-hydroxycorticosterone + chloro 7/24X5 +7 Enacyl 1.5/24X5 7, 11-desoxy-17α-hydroxycorticosterone + chlora 7~ 15/24X5+Mupsil 2.5~4/24X5 Table 1 (continued) Extending the lifespan of animals, chi 1-52-61-52-61-52-61-52-61.31 81 76 1 05 344 (33% recovery) 2, 20 82 70 18 3, 15 87 41 46 9 4, 7 49 35 5, 6-7 0 17 6・46 7, 19 57 35 Table 2 (h) x number of administrations 1, 11-desoxy-17α-hydroxy-21-[:p-di(2-ri 4 5×10 loethyl)-aminophenyl a Cetate] Corticosterone 10-25/24X52, Chlorophenacyl 1 ．． 5-2/24 X 53・11-desoxy-17α-hydroxycortico Sterone 7~10/24X54, prednisolone 4~10/24X55, sa Lucolycin 2~3/24X5 6, Estrasite 100/24X5, -- Lock / □□→□-Drop- From Table 1, it can be seen that both compounds according to the present invention 8. MORC-406, demonstrated to prolong the survival of animals with La and LMC-1 It is understood that it exhibits anti-jacemia activity.

The antitumor effect of the compound according to the present invention is due to the alkylation contained in the compound molecule. The effect is superior to that of other drugs (chlorophenacil and chlorampcil).

The compounds according to the present invention are chlorophenacyl, chlorampcil and 11-desoxoxyl. The effect when combined with C-17α-hydroxycorticosterone is also excellent.

Table 2 shows 11-desoxy-17α-hydroxy-21-( p-di(2-chloroethyl)aminophenyl acetate] Anti-corticosterone Data regarding tumor efficacy are shown.

From Table 2, it can be seen that the compounds according to the present invention have high antitumor activity and a wide range of antitumor effects. It is understood that The compounds according to the present invention can be used to inhibit the growth of virtually all tumors. Prevents growth by 80-99%. This compound has components that make up its molecule, other components. Tumors not sensitive to luticoids and the hormonal cell agent estracyte active in animals with .

11-desoxy-17α-hydroxy-21-[1p-zo(2-chloroethyl (aminophenyl acetate) corticosterone is related to its activity on numerous forms. The known alkylating preparation sarcolycin is superior.

11-desoxy-17α-hydroxy-21,-(p-di(2-10 loethyl ) Aminophenyl acetate] Corticosterone has long-lasting antitumor effects. inhibit the growth of tumors for more than one month after the completion of the treatment process; This increases the lifespan of animals by 27 to 73 cm compared to controls (Table 3). ).

Table 3 11-desoxy-17α-hydroxy-21-(p--/-(2-chloroethyl Duration of antitumor effect of corticosterone (aminophenyl acetate) Treatment of tumor type, dose (m9A9), post-transplant interval (h) x administration number of days 1. Lung adenocarcinoma RL-6745X1 2 2. Breast cancer KML that metastasizes to the lungs Same as above 103, Sarcoma 5-37 Same as above 2 4, Liver cancer G-22C15/24X5 6-105, Lewisian epidermoid lung cancer LL Same as above 2-66, Breast cancer Ca-755 Same as above 2-6 7. Small intestine adenocarcinoma AKATON Same as above Table 3 from 2 to 6 (continued) 11-desoxy-17α-hydroxy-21-Cp fruit duration Inhibition of tumor growth, prolongation of lifespan, 1, 81 82 80 27 2, 80 53 61 57 4, 80 68 57 65 5, 76 56 39 38 6, 92 73 82 73 7, 66 55 46 46 11-desoxy-17α-hydroxy-21-(p-di(2-chloroethyl) Aminophenyl acetate] Corticosterone is found in the chest of rats and mice. comparing the size of induced and spontaneous tumors to their size before treatment. Repetitions to reduce and demonstrate the absence of a therapeutic black core for this compound. The activity during the treatment process is also shown (Table 4).

11-desoxy-17α-hydroxy-21-(p-di(2-chloroethyl) Aminophenylacetate] The hormonal effect of corticosterone is due to its Associated with exhibiting cocorticoid activity.

Under certain conditions of administration, this compound can reduce the amount of 11-desoxy contained in the compound. -17α-Hydroxycorticosterone as well as 25-day adrenalectomized young Extending the lifespan (biological test for glucocorticoid activity) of young rats ( up to 113 chi and 115% respectively). The hormonal effects of the compounds according to the invention Its distinctive feature lies in its ability to induce a short-lived estrus response in animals. This compound Luticoid activity has also been demonstrated in studies of the biochemical mechanisms of its antitumor effects. ing. This compound interacts with the cytoplasmic receptors of glucocorticoids, Blocks the binding of [3H]-dexamethacin to cytoplasmic receptors. glucocorti The high affinity of this compound for coid receptors is due to the dissociation of the receptor complex. This is proven by the value of the number being a small value equal to 9.5X10M.

11-desoxy-17α-hydroxy-21-(p-di(2-chloroethyl) Aminophenyl acetate)) Corticoid activity is observed in transplanted tumors of animals, i.e. RL-67, G-60, G-61, G-22c, Ca-755.

Glucocorticoid levels in S-37, AKATOL and AKATON It reacts with septa and exhibits high antitumor activity against those tumors. animals by it The inhibition of specific binding of [3H]-dexamethacin in tumors of 70-100e Reach sK. 11-desoxy-17α-hydroxy-21-(p-di(2-k) (loloethyl) aminophenylacetate] Corticosterone is involved in human tumors. It also reacts with cytoplasmic receptors for glucocorticoids. That in case of human lung cancer The reaction inhibited specific binding of [3H]-dexamethacin by 83%, and breast cancer 53% for gastric cancer, 69% for gastric cancer and 8% for renal cancer. It is 4%.

11-desoxy-17α-hydroxy-21-[: p-di(2-chloroethyl [Le) Aminophenyl acetate] Corticosterone penetrates into the cell nucleus and Chroma of both cells and normal cells (rat, pedigree ■-star renal cancer PA, normal kidney) interacts with the receptor region of Chin.

Regarding the manifestation of alkylating properties, 11-desoxy-17α-hydroxy-21 -[p-di(2-chloroethyl)aminophenyl acetate]corticosterone chlorophenacil contained in its compound, especially in its effect on tumors. There is a difference between The alkylating power is the The method was used to deoxygenate both tumor (sarcoma S-37) and normal (lung) cells. evaluated through the kinetics of the appearance of crosslinks and breaks in DNA molecules. Ta. Regarding the number of crosslinks and retention time in the DNA molecules of cells of 5-37, 1 1-desoxy-17α-hydroxy-21-[p-di(2-chloroethyl)a Minophenyl acetate] Corticosterone is the chlorophena contained therein. Sill is excellent. In normal tissues, 11-desoxy-17α-hydro xy-21-(p-di(2-chloroethyl)aminophenyl acetate) Regeneration of DNA damaged by Costello begins earlier than in tumor tissue . This indicates that the compound shows selectivity in its damaging effect on the DNA of tumor cells. It shows.

Table 4 Aminophenyl acetate] Effects of corticosterone Ya tumor group dosage (m9A9), Duration per process Interval (h) x number of administrations 1. Mouse control spontaneity breast cancer 2.11-desoxy-17α 15/24X5-hydroxy-21- (3 weeks between [p-di(2-chloroe separated 2 processes) 3, rat control DMBA invitation breast cancer 4, 11-desoxy-17α 15/24X5-hydroxy-21- (5 weeks between [p-di[2-chloroene] 2 steps at intervals] Table 4 (continued) 11-desoxy-17 to spontaneous and induced breast cancer in repeated treatments α-Hydroxy-21-[: p-di(2-chloroethyl)-aminophenyl a Cetate] Effect of corticosterone situation: decrease or increase in tumor size relative to initial size; prolongation of lifespan (10); Bi, chi experimental week 2, 2337 +7 days 20502516114, 33321124 +2623 +31318 Toxicological studies of the compounds according to the invention were carried out on mice.

The gap between toxic and tolerable doses was shown to be sufficiently large. 11 -desoxy-17α-hydroxy-21-(p-di(2-chloroethyl)ami Nophenylacetate] Corticosterone is a chlorophyllite compound contained in the compound. It has a toxicity 93 times lower than that of henacyl. M in a single administration of the compound TD and LD5o values are equal to 44mg7kg and 80mμg, respectively; Their values for chlorophenacil are 9 and 24 to 15m97, respectively. m17kg K is equal. 11-desoxy-17α-hydroxy-zl-[p -di(2-chloroethyl)aminophenylbutyrate] corticosterone is the same It has low toxicity. Its MTD after one dose is equal to 350 mg/kg, but Its value for lorambucil is equal to 9 to 25 m97.

Toxicological studies have shown that 11-desoxy-17α-hydroxy-21-(p-di(2 -Chloroethyl)aminophenyl acetate] The use of corticosterone is limited by dose-dependent gastrointestinal and neurotoxicity (diarrhea, vomiting, spasticity) We showed that it is possible to

Preparations and preparations with alkalizing properties, which usually limit the administration of prednisone Hematotoxicity caused by 11-desoxy-17α-hydroxy-21-[p-di(2 -Ryloloethyl)aminophenyl acetate] Limit the administration of corticosterone. do not have.

Compounds according to the invention exhibit immunosuppressive effects at a single maximum tolerated dose (MTD) The characteristics of humoral immunity after the introduction of this compound are essentially reduced compared to the control. , and remains low for more than 1.5 months. Immunosuppression of this compound The antidrug effect is significant for T-suppressors and at doses lower than a single dose. is shown.

The method for producing the compound according to the present invention is simple and can be carried out by the method shown below. I can do it.

The synthesis of compounds according to the invention can be represented by the following formula: In the above formula, R' is -CH2CH(CH3)2, R is -(CH2)nC6H 4N(CH2CH2Ct)2, n=1.3.

The compound is prepared by the mixed anhydride method, and this method has been experimentally proven. gives better results compared to anhydrous and chloride methods. mixed anhydride The method involves mixing cytotoxic derivatives of impalerian acid and phenylalkanoic acid. It is based on the acylation of hydroxy compounds of steroids with anhydrides.

The production of mixed anhydrides takes place at a temperature of +5°C in the medium of an aprotic solvent such as benzene. The reaction is carried out in the presence of 1 molar amount of triethylamine. mixed anhydride is Hydroxy group in the side chain of 11-desoxy-17α-hydroxycorticosterone into the acylation reaction.

The method according to the invention can be easily implemented on a commercial scale. Because this This method is simple and does not require high power consumption.

All reagents used in this method are known compounds and are easily available. .

For a better understanding of the invention, some specific examples are provided below.

Example 1 11-desoxy-17α-hydroxy-21-[p-di(2-chloroethyl) -Aminophenyl acetate] Production of corticosterone (1) 15.99 (0,057 g mol) of chlorophenacil was dissolved in dry benzene. , at a temperature of +5°C triethylamine y8.0 m/(5,83 &, 0.57 g mol) and isovaleric acid chloride 7, Bml (7,71 g, 0.0649 mol) is added.

The reaction mixture was stirred for 1 hour at a temperature of 5°C, then 200 °C of dry acetonitrile was added. m1 and 11-desoxy-17α-hydroxycorticosterone 20.0g 0,0579 mol) is added. The reactants were heated at a temperature of 80°C for 4 hours. , after adding 100 ml of benzene, the formed organic layer was diluted with water and sodium bicarbonate. Wash successively with a solution of water and again with water.

The organic layer is separated and dried using anhydrous sodium sulfate. 5. Wait until the solvent dries. It is removed by distillation in vacuo at a temperature below 0°C. The resulting residue is in benzene and benzene-ethyl acetate. Elute with a mixture of (6:1)

Silfor (S i 1 u f o 1) System Ben on Uv254 plate 11-dehyde having an Rf of about 0.500 in (3:2) soxy-17α-hydroxy-21-[p-di(2-chloroethyl)aminof phenyl acetate] Collect the fractions containing corticosterone.

The solvent is distilled off in vacuo and the final product (1) is crystallized from ether. Collection The rate is 17.99 fl (51,54 chi).

Calculated value, %: C65.55, H7.16, CAl1.73C3, H43Ct2N 05 Experimental values, CH: C65,44, H7,12, CLll, 56UV spectrum (Eta in alcohol): λmax 256 nm: IR spectrum: ν(,,,01,742 crn, 1,723 crn.

1.653crn-' C Yoct 744α, 6860. 11-desoxy-17α-hydroxy-21-(p-di(2-chloroethyl) Aminophenylbutyrate] Corticosterone (II) (7) M compound The production of (2) is carried out in the same manner as the synthesis of the compound described in Example 1 above.

In the acylation reaction, 11-desoxy-17α-hydroxycorticosterone Lahiniin valeric acid and p-di(2-chloroethyl)aminophenylbutyric acid Add the mixed anhydride. The reaction mixture is stirred for 4 hours at a temperature of 80°C. . Subsequent operations are carried out as described in Example 1 above. The product is a silica gel color. Chromatography was carried out using a mixture of Be/Z/-ethyl acetate (6:1 ). The yield of compound ■ is calculated to be 40% based on the starting hormone. be.

Experimental value, Chi: C66°85, H7,59, ct 11.19C55H47Ct2 NO5 Calculated value, CH: C66,43, H7,,48, CL 11.22° Industrially applicable ability Derivatives of 11-desoxy-17α-hydroxycorticosterone are useful in the treatment of cancer. It is useful in medicine as well as for organ and phase 7 tissue transplants.

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Claims (2)

[Claims] 1. General formula below: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, R is -CO(CH2)nC6H4N(CH2CH2Cl)2, n=1,3 11-desoxy-17α-hydroxycorticosterone represented by derivative. 2. The following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ 11-desoxy-17α-hydroxycorti according to claim 1 having Costerone derivative.