Inhibitors of steroid-sulfatase

 

(57) Abstract:

The invention relates to medicine. A method of inhibiting steroid-sulfatase of activity of a subject, comprising introducing the compound comprising a ring system and a sulphamate group of the formula

< / BR>
where each of R1and R2independently selected from hydrogen, alkyl, alkenyl, cycloalkyl and aryl, or R1and R2together they are alkylene, optionally containing one or more heteroatoms or groups in alkalinous chain. The connection in terms of substitution sulphamate group on sulfate and incubation with steroid-sulfatase enzyme (E. C. 3.1.6.2) at pH 7.4 and 37oProvides inhibition of the specified enzyme with a value of less than 50 m. 2 C. and 14 C.p. f-crystals, 5 tab., 5 Il.

The invention concerns new compounds used as inhibitors of steroid-sulfatase containing pharmaceutical compositions.

It is known that the precursor steroids or prohormones, having a sulfate group at the 3-position of the steroid nucleus, are of great importance as intermediates in the metabolism of steroids in the human body. Astrosolar and dehydroepiandrosterone-sulfa is x as estrone and estradiol, in the human body. In particular, it is known that astrosolar, for example, represents one of the main circulating precursors of estrogen, especially in premenopausal women, and the activity of estrone-sulfatase with tumors of the breast in 100-1000 more than other enzymes involved in the formation of estrogen [James et al., Steroids, 50, 269-279 (1987)].

Other estrogens, such as estrone and estradiol, especially in their higher education in the body, strongly influence and are located in the body in various diseases, for example, the breast cancer see Breast Cancer Treatment and Prognosis: R. A. Stoll, pp.156-172. Blackwell Scientific Publications (1986) and control over the production of estrogen is a specific goal of many directions of anticancer therapy, including chemotherapy and surgical approach, for example, oophorectomy (removal of ovaries) and adrenalectomy (resection of the adrenal gland). With regard to endocrine therapy, all efforts are focused so far only on the concentration of aromatase inhibitors, i.e. compounds able to inhibit the activity of aromatase activity, which shows the scheme of the metabolism of estrogen (Fig.1), consists in the conversion of androgens, such as Androstenedione and testosterone ester is ü to affect another part of the metabolic pathway of estrogen or rather into two different parts, in other words the transformation of sulfate DES and estrone sulfate in DES and estrone, respectively, under the influence of the activity of steroid-sulfatase when using 3-monoalkylation-steroid-esters as inhibitors of steroid-sulfatase, in particular, estrone-3-monomethylfumarate.

1. The aim of the present invention is to provide new compounds able to inhibit the activity of steroid-sulfatase in vitro and in vivo.

2. The aim of the present invention is the creation of new compounds with high activity as inhibitors of steroid-sulfatase in vitro and in vivo.

3. In addition, the aim of the present invention is to provide a pharmaceutical composition effective in the treatment estrogenzawisimy tumors.

4. The aim of the invention is a pharmaceutical composition effective in the treatment of breast cancer.

5. Further aim of the invention is also developing a treatment for estrogenzawisimy tumors in mammals, particularly in humans.

6. Finally, the aim of the invention is to develop a method of treatment of breast cancer in mammals, particularly in women.

The present invention is based is sustained fashion high level of activity. These compounds are esters of sulfamic acid and polycyclic alcohols, sulfate which is a substrate for enzymes having the activity of steroid-sulfatase (EC 3.1.6.2), N-alkyl and N-aryl derivatives of these esters of sulfamic acid and their pharmaceutically acceptable salts.

The compounds of formula I

< / BR>
in which R1and R2each independently of one another represent hydrogen, alkyl, cycloalkyl, alkenyl and aryl, or together they represent alkylene, optionally containing one or more heteroatoms or groups in the chain of alkylene, and the group-O-polycyclic structure represents the balance of polycyclic alcohol sulfate which is a substrate for enzymes having the activity of steroid-sulfatase (EC 3.1.6.2).

As for alcohols, sulfates which are a substrate for enzymes having the activity of steroid-sulfatase, then we are talking about polycyclic alcohols, sulfates of which, i.e. derivatives of the formula

< / BR>
when maintaining steroid-sulphatase EC 3.1.6.2 PR pH 7.4 and temperature 37oC give value TOmless than 50 mcmole.

The activity of the claimed compounds as ingineresti ways, enzymes and steroid intermediates involved in the production of estradiol in vivo.

In Fig.2 presents the histogram of the dose-dependent inhibitory effect of estrone-3-sulpham on the activity of steroid-sulfatase in MCF-7 cells in vitro.

In Fig. 3 shows a dose-dependent inhibitory action of estrone-3-N, N - dimethylcarbamate on the activity of steroid-sulfatase in cells MCF human in vitro.

In Fig. 4 provides a comparison of the response curves for estrone-3-sulpham and estrone-3-N, N-dimethylcarbamate on the activity of steroid-sulfatase in MCF-human cells in vitro.

In Fig. 5 shows a dose-dependent inhibitory action of estrone-3-sulpham with IC50-values (concentration required for 50% inhibition) on the activity of steroid-sulfatase in placental microsomes.

One of the aspects of the invention are new compounds ester of sulfamic acid and polycyclic alcohols. Under polycyclic alcohols such alcohols, sulfates which are a substrate for enzymes having the activity of steroid-sulfatase, and their N-alkyl, N-cycloalkyl, N-alkenyl and N-arylphosphonate. These compounds correspond to Mascitelli, a maximum of about 40, usually no more than 30 deputies. The preferred politiclly can be considered a steroid cyclic structures, the so-called cyclopentanophenanthrene skeleton. Preferably, if sulfamyl or substituted sulfamyl group is the skeleton in the 3-position, we are talking about the compounds of formula II

< / BR>
in which R1and R2have the above values, and the cyclic system ABCD represents a substituted or unsubstituted, saturated or unsaturated steroid nucleus, preferably estrone or deviceparameters.

Other acceptable system of steroid rings are:

substituted estrone, namely 2-Oh-estrone, 2-methoxy-estrone, 4-Oh-estrone, 6-Oh-estrone, 7-Oh-estrone, 16-Oh-estrone, 16-Oh-estrone;

estradiol and substituted estradiol, namely 2-HE-17-estradiol, 2-methoxy-17-estradiol, 4-one-17-estradiol, 6-HE-17-estradiol, 7-HE-17-estradiol, 16-HE-17-estradiol, 16-HE-17-estradiol, 16-HE-17-estradiol, 17-estradiol, 17-estradiol, 17-ethinyl-17-estradiol;

estriol and substituted estriol, namely, estriol, 2-HE-estriol, 2-methoxy-estriol, 4-HE-estriol, 6-HE-estriol, 7-HE-estriol;

substituted dehydroepiandrosterone, namely 6-HE-dehydroamino the practical steroid ABCD system may contain different nemalaysia deputies. In particular, cyclic ABCD system may contain one or more hydroxy, alkyl especially lower alkyl-(C1-6)-substituents, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl and other isomers of pentile, and n-hexyl and other isomers of hexyl, alkoxy especially lower (1-6)alkoxy-substituents, for example, methoxy, ethoxy, propoxy, and so forth, quinil, for example, ethinyl, or halogen, for example fluorine.

Acceptable non-steroid cyclic systems include diethylstilbestrol, stilboestrol and other cyclic systems are provided that sulfates have TOm-value of less than 50 mcmole with steroid-sulphatase EC 3.1.6.2.

If the present invention substituted, N-substituted compounds contain one or two N-alkyl, N-alkenyl, N-cycloalkyl or N-aryl-substituent, preferably if they or each of them contains up to 10 C-atoms. If R1and/or R2alkyl, it is preferable to choose such a value at which R1and R2each independently from each other selected from among lower alkyl groups with 1-5 C-atoms, that is, from among methyl, ethyl, propyl, and so forth. Preferably, if R13, -o- , -m -, and para -). If R1and R2are cycloalkyl, usually cyclopropyl, cyclopentyl, cyclohexyl, and so forth. United together R1and R2are a group of alkylene provided that the ring consists of 4-6 C atoms, optionally torn apart by one or more heteroatoms or groups, for example, -O - or-NH - with 5-, 6 - or 7-membered heterocycle, for example, the research, pyrrolidine or piperidine.

Under alkyl, cycloalkyl, alkenylamine and aryl groups should be borne in mind groups containing as substituents in one or more groups that do not affect the inhibitory activity of sulfatase in this connection.

Nemchausky substituents can be considered hydroxy, amino, halo, alkoxy, aryl and alkyl.

More preferred compounds of formulas III and IV

< / BR>
< / BR>
in which R1and R2represent1-5alkyl, that is, estrone-3-sulpham and dehydroepiandrosterone-3-sulpham and N-(C1-5)alkyl-derivatives, especially DIMETHYLPROPANE R1= R2= CH3.

Present invention the esters of sulfamic acid get the>R2NSO2Cl, that is, in accordance with the scheme below

< / BR>
In accordance with a specified scheme of the reaction is carried out as follows.

Sodium hydride and sulphonylchloride add with stirring a solution of estrone in anhydrous dimethylformamide at 0oC. subsequently the reaction is carried out while heating to room temperature for 24 hours. The reaction mixture was poured into cold saturated sodium bicarbonate solution and the resulting aqueous phase is extracted with dichloromethane. The combined organic extract is dried over anhydrous magnesium sulfate. After filtration and subsequent evaporation of the solvent in vacuo and semiprivacy with toluene receive the raw residue, which is further purified using flash chromatography.

If necessary, the functional group in the polycyclic alcohol (styrene) can be protected in a known manner with the subsequent removal of protecting groups or groups at the end of the reaction.

For pharmaceutical application of inhibitors of steroid-sulfatase provided by the present invention, can be prepared according to known tested traditional pharmaceutics is more, usually recommended for parenteral use. The average effective dose, depending on the individual activity of the compounds of the present invention, and based on the average weight of a body of a patient (70 kg) varies from 100 to 800 mg/day. The usual dose for preferred and more active compounds ranges from 200 to 800 mg/day, more preferably 200-500 mg/day, more preferably from 200 to 250 mg/day. The medicine can be taken as a single dose, fractional dose or multiple small doses over several days. For oral administration of drugs can be prepared in the form of tablets, capsules, solutions or suspensions containing from 100 to 500 mg of the compound on the standard dose. Preferably, if for parenteral administration the compounds can be prepared using suitable for injecting carriers, and if a single daily dose will contain from 200 to 800 mg, preferably from 200 to 500, more preferably from 200 to 250 mg of these compounds. However, such an effective daily dosage will be very much dependent on the activity inherent to the active ingredient, and to a large extent have determined knogo" application considered, what present invention, inhibitors of steroid-sulfatase can be used for combined therapy or in combination with another inhibitor sulfatase, or, for example, in combination with the aromatase inhibitor, in particular, 4-hydroxyandrostenedione (4-SHE).

A more detailed object of the invention is illustrated by the following examples and test results.

Example 1

Getting estrone-3-sulpham

Sodium hydride (60% dispersion, 2 EQ.) and sulfhemoglobin (2 EQ.) add with stirring a solution of estrone (1 EQ.) in anhydrous dimethylformamide at 0oC. Then the reaction is carried out while heating to room temperature while continuing the stirring, for 24 hours.

The reaction mixture was poured into cold saturated sodium bicarbonate solution and the resulting aqueous phase is extracted with dichloromethane. The combined organic extract is dried over anhydrous magnesium sulfate. After filtration and subsequent evaporation of the solvent in vacuo and semiperipheries with toluene receive the raw product, which is then purified using flash chromatography. The analysis shows the following results:lH (270 MHz, (And 67.8 MHz, CD3OD): 14,53 (sq.18-IU), 22,80 (t), 27,24 (t), 27,73 (t), 30,68 (t) 33,05 (t), 37,01 (t), 39,76 (d), 45,73 (S.18), 51,86 (d), 120,76 (d), 123,54 (d), 127,89 (d), 139,83 (C), 150,27 (C), 273,87 (s=0).

m/Z (%): 349(9) (m+), 270(100), 233(26), 185(43), 172(31), 159(21), 146(36), 91(33), 69(37), 57(73), 43(56), 29(24).

Data analysis:

Designed, 61,87%; N, 6,63%; N, 4,01%;

Found, 61,90%; H, 6.58 Percent; N, 3,95%.

Example 2

Getting estrone-3-N-methylsulfonate

Repeat the procedure described in example 1, but instead of sulfhemoglobin take the same amount of N-methylsulfonylamino. In the analysis given the following results:

lH (270 MHz, CDCl3): of 0.91 (s, 3H, C18-IU), 1,28 by 1.68 (m, 6N), 1,93-2,60 (series of m, 7H), 2,90-2,95 (m, 2H), equal to 2.94 (d, 3H, J=5,13 Hz, N-), 4,68-4,71 (Shir.m, changeable, 1H), 7,02-7,07 (m, 2H), 7,26-7,32 (m, 1H).

m/Z (%): 364 (M+N)+.

Example 3

Getting estrone-3-N,N-dimethylcarbamate

Repeat the procedure described in example 1, but instead of sulfhemoglobin take the same amount of N,N-dimethylsulfoxide.

When analysing receive the following output:lH (270 MHz, D13): to 0.92 (s, 3H, C18-IU), 1,39 is 1.75 (m, 5H), 1,95-2,60 (series of m, 6N), 2,82 (s, 3H, ), 2,96-3,00 (m, 4H), 2,98 (s, 3H,),? 7.04 baby mortality (Shir.d, 2H, J=7,69 Hz), 7,29 (Shir.d, 1H, J=7,88 Hz).

m/Z(%): 377 ( 3,60%.

Example 4

Inhibition of steroid-sulfatase activity in MCF7cells under the action of estrone-3-sulpham

Under steroid-sulfatase should be understood sterile sulphatase EC 3.1.6.2.

Steroid-sulfatase activity measured in vitro, using for this purpose the intact MCF-7 cancer cells in the breast of man. Hormone-dependent cell line is widely used to regulate the growth of cancer cells in the breast of man. It differs hard steroid-sulfatase activity [MacIndoe et al. , Endocrinology, 123, 1281-1287 (1988), Purohit and Reed, Int.J.Cancer, 50, 901-905 (1992)] and can be obtained in the USA from American cell culture collection, and in the UK, for example, from the king's Fund cancer research. Cells treated in minimum essential medium (Flow Laboratories, Irwine, Scotland) containing 20 mmol HEPES, 5% serum of newborn cattle, 2 mmol glutamine, amino acids and of 0.075% sodium bicarbonate. Up to 30 containers with samples of cell cultures (25 cm2sow about 2x105cells on each tank, using the above environment. Cells grown to 80% of mergers, the medium is changed every third day.

Intact monolayers of MCF-7 cells in three versions to 25 cm2what Britain) and incubated for 3-4 hours at 37oWith 5 Ptolemy (h5the number of disintegrations per minute) (6,7-3H-estrone-3-sulfate) (specific activity 60 curies/mmol of Nuclear society of New England, Boston, mA, USA) in nestorgames serum minimum medium (2.5 ml) together with estrone-3-sulpham (11 concentrations: 0; 1 M; 0,01 m; 0,1 m; 0.01 nm; 0.1 nm; 1 nm; 0.01 µm; 0,1 μm; 1 μm). After keeping each tank is cooled and the environment pipette is introduced into a separate tube containing (14With/estrone) h3disintegrations per minute. Specific activity 97 Curie/mmol was obtained from Amerikanskogo International radiochemical centre (Amersham, UK). The mixture is shaken for 30 seconds with toluene (5 ml). Experiments show that >90% (14C) estrone and <0,1% (3H/estrone -) sulfate are removed from the aqueous phase as a result of such processing. Part (2 ml) the organic phase is removed, evaporated and define the content of the3H and14N in the residue, using for this purpose the method of scintillation spectrometry. Gidralizovanny weight of estrone-3-sulfate is calculated from the received3N-values (adjusted for volume environment and used the organic phase is added to highlight14C-estrone) and specific activity substra of man (positive control) and containers without cells (for determining obviousness nonenzymatic hydrolysis of the substrate). The number of cell nuclei in each tank is determined using counter Cultura after treatment of the monolayers of cells saponins. One tank in each series are used to assess the condition of the membrane of a cell and its viability, using for this purpose the exclusive method tripan blue [H. J. Phillips (1973)]. Tissue culture and its applications (D. F. Kruse and M. K. Patterson, pages 406-408, Academic Press, new York).

Data for estrone-3-sulpham presented in table 1 and Fig. 2 and 4. The results of the evaluation of steroid-sulfatase activity is expressed as mean values 1 standard deviation of the total product (estrone+estradiol) formed during the incubation period (20 hours) calculated for the 106cells and for values with statistical significance in the percentage reduction (inhibition) in the incubation process without the use of estrone-3-sulpham. t-student test is used to confirm the statistical significance of the results.

Example 5

Inhibition of steroid-sulfatase activity in MCF-7 cells under the action of estrone-3-N,N-dimethylcarbamate.

Experimental conditions analogous to those described in example 4 is used to obtain results for estrone-3-N, N-dimethy the x concentrations, namely 0; 0,001 μm; 0.01 µm; 0.1 ám and 1 ám instead of estrone-3-sulpham.

Results for estrone-3-N,N-dimethylcarbamate presented in table 2 and Fig. 3 in the same expression as in table 1 and Fig.2, respectively. Additionally in Fig.4 presents a comparison of the curves of the logarithm of the dose with estrone-3-sulpham.

Example 6

Inhibition of steroid-sulfatase activity in MCF-7 cells pre-treated estrone-3-N,N-dimethylsulphamoyl and estrone-3-sulpham

The conditions of the experiment, similar to that described in example 4 is used to determine the effect of MCF-7 cells pre-treated estrone-3-N, N-dimethylsulphamoyl and estrone-3-sulpham respectively.

Intact monolayers first incubated for 2 hours at 37oWith from 0.1 μm estrone-3-sulpham, estrone-3-N,N-dimethylcarbamate or one environment (the control group). The medium containing the cells is removed by suction and the cells three times successively washed with 5 ml of medium (5 ml each time). Received the washed cells are then re-suspended and incubated for 3-4 hours at 37oC in a medium containing 5 pmoles (h5disintegrations per minute) (6,7-3N)-estrone-3-sulfate. All togglemute and estrone-3-N,N-dimethylcarbamate, presented in table 3 by analogy with table 1.

Example 7

Inhibition of steroid-sulfatase activity in placental microsomes under the action of estrone-3-sulpham

Sulfatase-positive human placenta from normal pregnancy (Obstetric Ward, St.Mary's Hospital, London) crushed scissors and washed once with chilled phosphate buffer (pH 7.4, 50 mmol), then re-suspended in chilled phosphate buffer (5 ml/g tissue). Homogenization complete processing in the homogenizer Ultra-Turrax. The product is treated three times for 10 seconds with breaks for 2-min cooling on ice. Fragments of nuclei and cellular material is removed by centrifugation (4o(C ) at 2000 g for 30 minutes and part of the supernatant layer (2 ml) store at -20oC. the Concentration of protein in the supernatant layer is determined according to the method of Brentford [Ann.Biochem., 72, 248-254 (1976)].

To conduct incubation (1 ml) using a protein concentration of 100 µg/ml, substrate concentration of 20 mcmole (6,7-3H)-estrone-3-sulphate (specific activity 60 curies/mmol, Nuclear centre of New England, Boston, mA, USA). The duration of incubation for 20 minutes at 37oC. Apply 8 consentia incubation period, each sample was cooled and the medium (1 ml) pipette is introduced into a separate tube, filled (14C)-estrone(h3disintegrations per minute) (specific activity 97 Curie/mmol, production Amerikanskogo international radiochemical centre, Amersham, UK). The mixture is shaken for 30 minutes with toluene (5 ml). Experiments show that >90% 14C-estrone and <0,1%3H-estrone-3-sulfate is removed from the aqueous phase in such processing. Part (2 ml) the organic phase is removed, evaporated and define the content of the3H and14With the remainder using the method of scintillation spectrometry. Weight hydrolyzed estrone-3-sulpham determined by calculations based on the value of 3N (adjusted for volume environment and used the organic phase and to highlight14C-estrone) and the specific activity of the substrate.

The results obtained for estrone-3-sulpham presented in table 4 and in Fig. 5. The results of determination of steroid-sulfatase activity are given in table 4 in the form of a General product (estrone+estradiol) formed during the incubation period (as a function of time) and percentage reduction (inhibition) compared with the control group without the use of estrone-3-sulpham. The results obtained for steroid-sulfatase group when using the IC50-values (i.e. the concentration of estrone-3-sulpham, which gives 50% inhibition compared with the control group) at 0.07 mcmole.

Example 8

Inhibition of steroid-sulfatase activity in preparations prepared from liver microsomes isolated from rats treated subcutaneously estrone-3-sulpham

Four groups of female rats of Wistar breed (weighing about 80-110 g) injected subcutaneously with 100 µm injection (once a day for 7 days in liquid medium: propylene glycol) the following substances:

propylene glycol (control group)

estrone-3-sulpham (10 mg/kg/day)

estrone-3-sulfate (10 mg/kg/day) (control substrate)

estrone-3-sulfate (10 mg/kg/day) + estrone-3-sulpham (10 mg/kg/day).

On the eighth day rats hammer and preparation highlight the liver. Microsome compositions liver receive in accordance with the methods described in example 6, except that as the source of the fabrics used liver of rats and spend double the measurement of steroid-sulfatase activity, using (6,7-3N)estrone-3-sulfate and (7-3H) dehydroepiandrosterone-3-sulfate as a separate substrates.

The results of the determination of steroid-self the frame period in the form of mean values + standard value. The results of incubations tissues obtained in the groups of rats treated with estrone-3-sulpham, also presented as a percentage reduction (inhibition) activity of steroid-sulfatase activity in comparison with the corresponding data for the control group.

1. Method of inhibiting steroidsbritney of activity of a subject in need thereof, comprising the introduction of this subject inhibitory amount in respect of asteroidsurfaces compounds containing a ring system and a sulphamate group of the formula

< / BR>
where each of R1and R2independently selected from hydrogen, alkyl, alkenyl, cycloalkyl and aryl, or R1and R2together they are alkylene, optionally containing one or more heteroatoms or groups in alkalinous chain, despite the fact that this connection in terms of substitution sulphamate group on sulfate and incubation with steroidallactones enzyme (E. C. 3.1.6.2) at pH 7.4 and 37oTo ensure its inhibition with a value of less than 50 m.

2. The method according to p. 1, in which the compound is a compound of the formula

< / BR>
where R1and R2have the values listed in paragraph 1.

3. How about on p. 2 or 3, where the polycyclic group is a residue of a Sterol.

5. The method according to p. 4, in which the Sterol is a 3-Sterol.

6. The method according to p. 4 or 5, where the Sterol selected from the group consisting of estrone, dehydroepiandrosterone, substituted astronav or substituted dehydroepiandrosterone.

7. The method according to any of paragraphs. 1-6, where the sulphamate group attached to a cyclic system.

8. The method according to any of paragraphs. 1-7, where R1and R2independently from each other selected from hydrogen, alkyl and cycloalkyl.

9. The method according to any of paragraphs. 1-7, where R1and R2independently from each other selected from hydrogen and alkyl.

10. The method according to any of paragraphs. 1-7, where R1and R2independently from each other selected from hydrogen and C1-10the alkyl.

11. The method according to any of paragraphs. 1-7, where R1and R2independently from each other selected from hydrogen and C1-5the alkyl.

12. The method according to any of paragraphs. 1-7, where R1and R2independently from each other selected from hydrogen and methyl.

13. The method according to any of paragraphs. 1-12, where the compound is chosen from the group comprising 3-sulpham estrone, 3-N, N-dimethylsulphamoyl estrone, 3-N-monomethylaniline a hydrogen.

15. The method according to any of paragraphs. 1-14, where R1and R2represent hydrogen.

16. Method of inhibiting steroidsbritney of activity of a subject in need thereof, comprising the introduction of this subject inhibitory amount in respect of asteroidsurfaces of ester sulfamic acid and polycyclic alcohol, or N-alkyl, N-alkenyl, N-cycloalkyl, or N-arylphosphate such a complex ester, or pharmaceutically acceptable salt of any such ester, or N-substituted complex ether, and alcohol part of this complex is polycyclic ether alcohol sulfate which gidrolizuet enzymes with steroidsbritney (E. C. 3.1.6.2) activity.

 

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