17α-alkyl-17β-hydroxyestratrienes, their using and pharmaceutical preparation

FIELD: organic chemistry, steroids.

SUBSTANCE: invention describes 17α-alkyl-17β-hydroxyestra-1,3,5(10)-trienes possessing anti-estrogenic properties of the general formula (I): wherein Hal means fluorine (F), chlorine (Cl) atoms; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkanoyl, simple cyclic (C3-C7)-ether comprising O-atom; R17' means H, (C1-C4)-alkyl, (C1-C4)-alkanoyl; R17'' means (C1-C4)-alkyl, (C1-C4)-alkynyl; SK means: U-V-W-X-Y-Z-E wherein U means (C1-C13)-alkylene; V means -CH2; W means -N(R6) wherein R means H, (C1-C4)-alkyl; X means (C1-C12)-alkylene; Y means a direct bond between X and Z; Z means possibly fluorinated (C1-C9)-alkylene; E means -CF3. Also, invention describes 17-oxoestra-1,3,5(10)-trienes and 17β-hydroxyestra-1,3,5(10)-trienes as intermediate substances used in synthesis of estratrienes proposed by the invention. Also, invention describes using 17α-alkyl-17β-hydroxyestratrienes for preparing corresponding medicinal agents and pharmaceutical preparations comprising at least one 17α-alkyl-17β-hydroxyestratriene and at least one pharmaceutically acceptable carrier.

EFFECT: valuable medicinal properties of steroids.

5 tbl, 7 dwg

 

The present invention relates to a 17α-alkyl-17β-exectation and intermediate products for their production, to the use of 17α-alkyl-17β-axisratio to obtain drugs, and also to pharmaceutical preparations containing these compounds.

Proposed in the invention compounds have antiestrogenic efficacy, in other words, they exert an inhibitory effect on estrogen. Such substances are described in many publications. So, for example, having antiestrogenic activity of compounds known from application EP 0138504 B1. In this publication we are talking mainly about derivatives östra-1,3,5(10)-trienol, substituted in position 3, in particular, hydroxy - or alkoxygroup in position 17β - hydroxy groups in position 17α in particular hydrogen or alkyl. In addition, these compounds have in position 7α alkyl side chain, which may be partially fluorinated and which, in particular, can be interrupted by amido-, amino-, N-oxide amino-, hydroxy-, sulfanilimide, sulfanilimide and/or sulfanilimide groups.

In the application WO 99/33855 A1 describes 11β-halogen-7α-substituted östra-1,3,5(10)-triene that in position 3 and 17 may contain a hydroxy-group. 7α-side chain is a partially fluorinated, optionally unsaturated hydrocarbon is th circuit, interrupted amine nitrogen atom or sulfanilic, sulfanilic or sulfonyloxy group.

Compounds of this type are also described in the application WO 98/07740 A1. The matter in this publication is substituted on 7α-(ξ-aminoalkyl)-östra-1,3,5(10)-teenah. These connections in position 3 preferably contain hydroxy-, methoxy - or acetyloxy and in position 17α and/or 17β - preferably methyl, respectively triptorelin group. In position 11β provided, preferably a fluorine atom, a in position 7α - alkyl side chain, which in the limit position at least partially fluorinated and interrupted amine nitrogen atom and sulfanilic, sulfanilic or sulfonyloxy group.

In the application WO 97/45441 A1 describes 7α-(5-methylaminomethyl)-östra-1,3,5(10)-triene containing in position 3 and in position 17β a hydroxy-group. In position 17α may be provided by a methyl or ethyl group. In addition, estratriene skeleton can also be in position 2 is substituted by a fluorine atom.

Known compounds was found to form when introduced into the body a number of different, very active metabolites. The formation of these metabolites leads to the appearance of adverse effects and thereby to uncontrolled spectrum of action. First of all can receive obecnie effects or as a result of the spontaneous formation of these metabolites required primary action (antiestrogenic action) will become uncontrollable. The disadvantages of the known compounds should be attributed to their poor compatibility with the oral application. In addition, it was found that the known compounds contribute to the accumulation of alveolar macrophages.

Based on the foregoing, the present invention was based on the task to get with antiestrogenic activity of compounds metabolism which could be controlled and which do not form at all or would have constituted only a minimum of biologically active metabolites. Along with this, in the claimed invention was provided to ensure the necessary compatibility of the proposed connections with their oral application and when they are introduced into the body to eliminate completely or at least to minimize the maximum accumulation of alveolar macrophages.

This problem is solved with the new 17α-alkyl-17β-exectation described in claim 1 of the claims, then with the new 17β-exectation according to clause 16, and 17-exoectations according p, each of which can be used respectively as intermediates for obtaining the proposed invention 17α-alkyl-17β-axisratio. This next task is solved through the use of 17α-alkyl-17β-oxistat is yanow to obtain drugs according to claim 20, and due to containing the proposed invention in connection pharmaceutical composition according to item 21.

Proposed in the invention of 17α-alkyl-17β-axisratio have the following General formula I:

in which

Hal denotes F or Cl and in position 11β associated with estratriene skeleton,

R3denotes hydrogen, C1-C4alkyl, C1-C4alkanoyl or simple cyclic With3-C7ester with O-atom

R17'denotes hydrogen, C1-C4alkyl or C1-C4alkanoyl,

R17"stands With1-C4alkyl, C1-C4quinil, and at least partially fluorinated alkyl residues, R17'-Oh in position 17β and R17"in position 17α associated with estratriene skeleton,

SK denotes the group U-V-W-X-Y-Z-E, which is connected through U in position 7α estratriene skeleton.

In the side chain, the symbols U, V, W, X, Y, Z and E have the following meanings:

U represents either remotemachine or branched C1-C13alkilinity, -alkenylamine or alkynylaryl residue, or a group a-b, where

And is associated with estratriene skeleton and means connected through CH2with estratriene skeleton benzimidazolyl, phenylenebis or connected through an alkyl group with estratriene skeleton C1-C3alcylaryl balance, and

In PR denotes mozopacity or branched C 1-C13alkilinity, -alkenylamine or alkynylaryl the rest,

thus a and b can be linked by an oxygen atom

V represents a group CH2or C(O),

W represents a group N(R6or N+(O-)(R6or solidariedade or N-oxide solidariedade ring, with solidariedade or N-oxide solidariedade ring includes at least one C - atom of the group X and

R6is either N or CH2-R7or C(O)-R7where R7can refer to:

a) hydrogen or

b) remotemachine or branched, non-fluorinated or at least partially fluorinated C1-C14alkyl,

-alkanniny or alkynylaryl residue, which may be single - or multiple times gidroksilirovanii and which may be interrupted by one to three heteroatoms-O - and-S - and/or one to three groups-NR9-where R9represents hydrogen or C1-C3the alkyl residue, or

C) unsubstituted or substituted aryl or heteroaryl residue, or

d) unsubstituted or substituted C3-C10cycloalkenyl residue, or

d) unsubstituted or substituted C4-C15cycloalkylcarbonyl residue, or

(e) unsubstituted or substituted C7-C20Araki the capacity balance or

g) unsubstituted or substituted heteroaryl-C1-C6the alkyl residue, or

C) unsubstituted or substituted aminoalkyl balance or biphenylyl the rest,

X represents preferably remotemachine or branched C1-C12alkilinity, -alkenylamine or alkynylaryl the rest,

Y can be a direct link between X and Z, and may also refer to:

and SOn-R10group, but only under the condition that W is a group of N+(O-)(R6or N-oxide solidariedade ring, but not the group N(R6or solidariedade ring, while n denotes 0, 1 or 2, and R10is a direct link between the SOnand Z or remotemachine or branched C1-C6alkilinity, -alkenylamine or alkynylaryl residue, or

b) the group R11or O-R11where R11represents a

1) remotemachine or branched C1-C5alkilinity, -alkenylamine or alkynylaryl residue, or

2) unsubstituted or substituted aryl or heteroaryl residue, or

3) unsubstituted or substituted C3-C10cycloalkenyl residue, or

4) unsubstituted or substituted C4-C15cycloalkylcarbonyl residue, or

5) unsubstituted or substituted C7-C 20Uralkaliy residue, or

6) unsubstituted or substituted heteroaryl-C1-C6the alkyl residue, or

C) grouping CH=CF, or

d) grouping HN-C(O)-NH-R12where R12represents an unsubstituted or substituted Allenby residue and R12associated c Z,

Z represents a direct bond between Y and E or remotemachine or branched C1-C9alkilinity, -alkenylamine or alkynylaryl residue, which may be partially or fully fluorinated;

E represents a group of CF3or at least partially fluorinated aryl group, especially phenyl group.

Otherwise, in the positions 1, 2, 4, 6-9 and 11-16 with estratriene skeleton preferably associated hydrogen atoms. In principle estratriene skeleton can be modified, in particular, due to the presence of hydrocarbon bridge, for example, 15β,16βmethane group.

Hal denotes primarily fluorine.

R3may denote hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl, the corresponding alkanol (acetyl, propionyl, butanoyl) or simple cyclic ether. First of all, R3represents hydrogen, CH3CH3WITH or With5H10O.

R17'and R17"denote primarily methyl, ethyl, n-propyl, isoprop is l, n-butyl, isobutyl and tert-butyl, R17'can additionally represent hydrogen, acetyl, propionyl and butanoyl, and in this case it is also possible the inclusion of the corresponding isomers. R17"along with the specified values may also indicate ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl and 3-butynyl, in addition, trifluoromethyl, pentafluoroethyl, heptafluoropropyl and nonattributed, and in this case it is possible the inclusion of the corresponding isomers. First of all, R17'represents hydrogen, CH3or CH3WITH. The most preferred values of R17"are methyl, ethinyl and trifluoromethyl.

U can be a primarily remotemachine or branched alkalinity balance first and foremost, methylene, ethylene, propylene, butylene, Panteleeva, exelency, gateley, ActiveMovie, nonrenewal, delleney, undecylenoyl, dodecanoyl or tigellinus balance. Preferably U is a (CH2)pwhere p denotes an integer from 2 to 10. Preferably U is a primarily butylene, Panteleeva, exelency or gateley balance. Most preferably, U is a n-butylene balance, i.e. specified in the formula for U (CH2)pp stands 4.

V, not only is em a primarily CH 2. Thus, the grouping U-V in one of the most preferred embodiments of the invention may be an n-pentile.

W represents a first N-oxide amino group of N+(O-)(R6) or Amin N(R6), with R6preferably represents hydrogen or CH2-R7where R7refers primarily hydrogen or methyl or ethyl. Thus, R6represents preferably hydrogen or C1-C3alkyl residue, i.e. primarily metal, ethyl, n-sawn or ISO-propyl residue. In one particularly preferred embodiments of the invention W is a group of N+(O-)(CH3)(N-oxide N-methylaminopropyl).

X preferably represents (CH2)qwhere q denotes 0 or an integer from 1 to 12, i.e. represents a direct bond between W and Y, or remotemachine or branched methylene, ethylene, propylene, butylene, Panteleeva, exelency, gateley, ActiveMovie, nonrenewal, delleney, undecylenoyl or dodecanoyl balance. In one particularly preferred embodiments of the invention, X represents an ethylene, n-propylene, n-butylene, n-Panteleeva, n-exelency, n-gateley or n-octyle the new balance.

Y may represent the first direct link between X and Z. In this case, X represents a longer alkylenes chain, i.e. the first n-hexylen, n-heptylene or n-octile. Y in one of the preferred embodiments of the invention may also be a group of SOnwhere n denotes 0, 1 or 2, i.e. sulfonyloxy, sulfinyl or sulfonyloxy group. If Y represents a group of SOnthen X in this case is a shorter alkylenes chain, primarily n-through chain.

Z preferably represents a direct bond between Y and E or remotemachine or branched C1-C7alkilinity the remainder, which at least partly may be fluorinated. Z can represent primarily methylene, ethylene, propylene or butylene balance, which at least partly may be fluorinated. First of all, Z can represent deformation or remotemachine alkilinity the remainder, which at one end perfluorinated, i.e. is, for example, 1,1-deflorationgay, 1,1,2,2-titrator-n-propylene or 1,1,2,2,3,3-hexaplar-n-butylene balance. Especially preferred are alkylene remains, bearing at one end With atoms only two fluorine atom, and these CF2groups include the s with residue that is In this case, the side chain SK has as end group C2F5.

E preferably represents CF3or pentafluorophenyl. Thus grouping Z-E preferably represents one of the groups selected in turn from the group comprising C2F5With3F7and C4F9and With6F5.

In the scope of the present invention also includes the pharmacologically compatible acid additive salts as well as esters of 17α-alkyl-17β-axisratio. In the case of acid additive salts it comes to their respective salts, formed with inorganic and organic acids. As the acid-additive acceptable salts primarily hydrochloride, hydrobromide, acetates, citrates, oxalates, tartratami and methansulfonate. If R3and R17'denote hydrogen and the result is 3,17β-diol, in this case, it is also possible the formation of esters of the above hydroxycodone. These esters are preferably formed with organic acids, and you can use the same acid that is used for the formation of acid additive salts, namely primarily acetic acid, but equally suitable and higher carboxylic acids, such as propionic, butyric, somalina, Valerian, Isover is anew or pavlikova acid.

New 17α-alkyl-17β-axisratio have several chiral centers, including, for example, a nitrogen atom, a oxidized under certain conditions to N-oxide. Therefore, there are accordingly several stereoisomeric forms of each connection. The compounds of formula I can be represented in the form of the tautomers, stereoisomers and geometric isomers. In the scope of the invention included herein also referred to as all possible isomers, such as E - and Z-isomers, S - and R-enantiomers, diastereomers, racemates and mixtures thereof, including tautomeric compounds. All of these isomeric compounds are, even if not stated otherwise, a part of the present invention. Mixtures of isomers can be separated using conventional methods such as crystallization, chromatography or formation of salts, enantiomers, respectively, E/Z-isomers.

It is particularly preferred according to the invention include the following estratriene General formula I:

1) N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

2) N-oxide 11β-fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptapteridae)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

3) N-oxide (RS)-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

4) N-oxidβ -fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

5) N-oxide 11β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

6) 11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}-17a-methylestra-1,3,5(10)-triene-3,17β-diol,

7) 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

8) 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

9) 17α-ethinyl-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol,

10) 17α-ethinyl-11β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-17β-ol,

11) 11β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-17β-ol,

12) 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-cryptomailer-1,3,5(10)-triene-3,17β-diol,

13) 11β-fluoro-7α-{5-[methyl(6,6,7,7,8,8,8-heptafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

14) 11β-fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptapteridae)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

15) 11β-fluoro-71 -{5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

16) 11β-fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

17) 11β-fluoro-7α-{5-[methyl(9,9,10,10,11,11,11-heptafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

18) 11β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol.

Physical properties of some of the above compounds are listed in table 1.

Proposed in the invention of 17α-alkyl-17β-axisratio differ from the known compounds primarily to the fact that in position 11α in the bound form is one halogen atom and/or at position 17α one alkyl residue. In addition, the preferred connection 17α-the side chain contains N-oxide amino group.

Unlike 3,17β-dihydroxyanthracene that in position 17α not substituted, of the proposed invention 17α-alkyl-17β-axisratio practically not formed any metabolites. Metabolites, as is well known, can also be biologically active. It was found that derivatives of estratriene, resulting from the oxidation associated in position 17β hydroxy-group, when it formed a 17-oxoproline have the extremely high biological activity.

By blocking position 17α alkyl residue, especially With1-C4alkyl group, this oxidation reaction cannot be suppressed, which allows ultimately suppress and various forms of metabolism. Therefore used as active substances estratriene according to the invention are videosofficial efficiency and activity. One of the advantages of these compounds lies in the fact that the effectiveness of the active substance in full it is possible to realize in a single connection.

This creates in turn a favourable environment for the development of appropriate medications, since due to the absence of formation of biologically active metabolites required the effectiveness of these tools, you can ensure a more simple way, based on certain structural principles, which allows a targeted search of active substances.

In addition, the proposed in the invention of 17α-alkyl-17β-axisratio inhibit the action of estradiol almost completely. It means that they are antiestrogens.

To determine the effectiveness of the proposed in the invention compounds was performed in vivo studies on experimental animals, which are used in young rats. To this end IP who was ladowali the growth of the uterus, the oral administration of a medicinal product (test antiestrogenic effect).

The principle of this technique is based on the fact, to identify the impact of having antiestrogenic effect of the compounds when administered in the body simultaneously with estrogen. In rodents, the uterus responds to the introduction of estrogen by increasing its mass (in the proliferation and inclusion into the fabric of water). This growth can be suppressed by simultaneous introduction with antiestrogenic activity of compounds in the appropriate dosage.

The studies used young female rats, the weight of which in the beginning of the experiments was 35-45, Each dose of the test compounds were administered to groups of 5-6 animals. When administered orally, the compounds were dissolved in one part of ethanol (e) and was supplemented with nine parts of peanut butter (AM). To adapt to the new conditions the day before the experiments of young rats were taken directly after weaning and they immediately, including in the cells that gave feed. Then animals daily, once in the three days were administered the test compounds in combination with 0.5 μg of estradiolbenzoateai (EB). EB constantly injected subcutaneously (s.c.), while the test compounds were administered orally (p.o.). 24 hours after the final injection, animals were weighed, slaughtered and they removed the uterus. Then was determined by wet weight of the prepared mares (without content). When this was performed control is basic research. For negative control for each animal daily was administered 0.2 ml of a mixture of e/S. For positive control, each animal daily was administered 0.1 ml of EB.

For each group was determined by the average value of the relative weight of organs (mg/100 g body weight) ± standard deviation (X±), and determined the significance of differences in comparison with the control group (EB) in accordance with the criterion of Dunnet (p<0,05). The degree of suppression (%) compared to DL-control were determined using a computer program. The relative effectiveness of the studied compounds were calculated covariance and regression analysis.

The results of studies of some compounds are presented in table 2. These results were obtained in experiments on the detection of the growth of the uterus while the introduction of 0.5 µg EB/0.1 ml s.c. and having antiestrogenic activity of compounds r.o. at a dose of 0.03 mg/kg body weight and 0.3 mg/kg of body weight.

From the table 2 data shows that by oral administration of the compounds at a dose of about 0.3 mg/kg is possible to achieve almost 100%anti-estrogenic effect.

Proposed in the invention compounds have the same or even higher efficiency compared with the corresponding compounds are not substituted in position 17α. In comparison with these not substituted in position 17α with what disiniame proposed in the invention estratriene differ, in addition, the best compatibility, which makes them much more preferable. The best compatibility is primarily due almost entirely limited by the possibility of formation of metabolites.

Determination of metabolic stability: the experience of the in vitro using 17β-HSD (estradiol-17β-dehydrogenase)

17β-HSD2mediates the enzymatic dehydrogenization in the intestine of the Oh-group in position 17 stranovogo skeleton formation ketogroup.

This experience use the following materials:

Na-phosphate buffer solution: 100 mm Na2HPO4×2H2O and 100 mm NaH2PO4×H2O;

the solution of the studied compounds:

11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol (compound 1 as a representative of compounds of General formula (I) and

11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol (compound 2): 15 μm in the Meon (in the experimental solution of 0.3 μm);

the solution of coenzymes: 2 ml of a mixture of glucose-6-phosphate (160 mm)/MgCl2(80 mm) are added to 400 μl of a solution of glucose-6-phosphate dehydrogenase, then add the 15.6 mg NADP (nicotinamide-adenine-dinucleotide) and 13.4 mg NAD (nicotinamide-adenine-dinucleotide);

the solution microsomes:

intestinal microsome assay (in vitro, the content of the W protein: 24 mg/ml, the content of CYP 450: 0,058 nmole/mg protein)after thawing in a water bath at 37° (˜60 (C) dilute Na-phosphate buffer solution to a protein concentration of 5 mg/ml

Each well is placed in 170 µl of buffer solution and 5 µl of the solutions of the investigated compounds at each time of measurement(0, 10, 20, 30, 45 and 60 minutes) values determined in two replicates. The samples corresponding to the zero point in time measurements, add 250 ál of ice Meon. Directly after this to all wells add 25 ál of a solution of microsomes and 50 μl of a solution of coenzymes. Samples corresponding to zero time measurement, without incubation place for approximately 24 h of storage at a temperature of about -20°C. the Remaining samples are incubated, respectively, for 10, 20, 30, 45 and 60 minutes at 37°and after each of these intervals in the respective samples to stop the reaction dehydrogenization by the addition of 250 ál of ice Meon. Samples prior to analysis using LC/MS/MS store for about 24 hours at a temperature of about -20°and immediately prior to analysis, centrifuged at 3000 rpm for measurement use the supernatant liquid.

Identified using LC/MS/MS concentrations of test compounds and forming the I 17-ketone product is presented in attached to the description of the drawings (figa-2E).

Connection 1 is resistant to metabolism in the intestine microsomes in the absence of such stability in liver microsomes, which presumably indicates the flow in both tissues of different metabolic reactions in phase 1. However, in none of both fabrics not produced the expected product of the reaction with 17β-HSD, ie 11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-one, compound 3. In contrast, compound 2, not containing the 17-methyl group, broken down in the intestine microsomes and produce the corresponding 17-ketone. Due to this factor, the stability of the connection 1 to the metabolism (metabolic resistance) can be explained by the blocking reaction with 17β-HSD, which is completely suppressed due to the 17β-methyl group. Therefore, we can assume that alkyl, for example methyl, group or Alchemilla or Alchemilla, for example ethyl group, located next to the 17-Oh group, in an unexpected way prevents its oxidation in the gut (in contrast to the liver) with the formation of ketone, resulting in a higher oral bioavailability.

Thus, the proposed in the invention compounds are characterised inter alia exceptionally high bioavailability, which allows the introduction of these compounds into the patient PT is keeping a high level of their content in serum. Due to the above-mentioned high compatibility created the opportunity for a successful and reliable therapy because of using the proposed in the invention compounds can achieve such a level of active compounds in serum, which provides a sufficient time interval required to achieve the level of action of the corresponding connection. Under the act refers to the concentration of the active substance in the serum, the minimum required to achieve the desired effect with a corresponding indication.

Proposed in the invention of 17α-alkyl-17β-axisratio General formula I are especially suitable for obtaining the appropriate medicines. Accordingly the invention relates also to pharmaceutical preparations which, together with at least one 17α-alkyl-17β-existentional General formula I, having the substituents Hal, R3, R17', R17", U, V, W, X, Y, Z and E with their open higher values contain at least one pharmaceutically compatible carrier.

Pharmaceutical preparations, respectively, the compositions according to the invention, receive a known manner using conventional solid or liquid carriers or diluents and the conventional pharmaceutical and technical AIDS in accordance with the pre is perceived by the method of introduction and in the appropriate dosage. Preferred compositions are one or the other dosage form suitable for oral, enteral or parenteral, for example intraperitoneal (I.P. Pavlova.), intravenous (i.v.), intramuscular (i.m.) or percutaneous application. Such dosage forms are, for example, tablets, filmtablette, coated tablets, pills, capsules, powders, creams, ointments, lotions, liquids, such as syrups, gels, injectable liquid such as intended for intraperitoneally, intravenous, intramuscular, or percutaneous injection, etc. are Suitable for these purposes are further depot forms, such as implantable compositions, as well as suppositories. While some of the songs from the number called, depending on their type of free offer in the invention estratriene gradually or all of a number after a short period of time.

As pharmaceutical preparations for oral administration may apply capsules, pills, tablets, pills, and liquids or other known oral dosage forms. In this case, medicines can be formed in such a way that they release the active substances or within a short period of time, or had a depot effect, i.e. ensured long, slow intake of de the corresponding substances in the body, in other words, showed prolonged action. Uniform dose along with at least one estratriene can contain one or more pharmaceutically compatible carriers, for example, substances for adjusting the rheology drugs, surfactants, dissolution promoters, microcapsules, microparticles, granules, diluents, binders, such as starch, sugar, sorbitol and gelatin, further fillers such as silicic acid and talc, substances imparting lubricity, dyes, flavorings and other substances.

Appropriate tablets can be produced, for example, by mixing the active substance with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrating agents such as corn starch or alginic acid, binders, such as starch or gelatin, with substances, which impart lubricity, such as carboxypolymethylene, carboxymethylcellulose, acatitla cellulose or polyvinyl acetate. Tablets can also consist of several layers.

Accordingly can be manufactured pills by applying the obtained analogously to the tablets of the core coating (shell) is usually used for such purposes substances, such as e.g. the measures as polyvinylpyrrolidone or shellac, gum Arabic, talc, titanium dioxide or sugar. When this shell beans can also consist of several layers, it makes possible the use of such auxiliary substances, as specified above for tablets.

Containing active substances of the capsule can be produced, for example, by mixing the active ingredient with a suitable inert carrier such as lactose or sorbitol, and then encapsulating the mixture in gelatin capsules.

Proposed in the invention estratriene can be formed also in the form of a solution, which is intended for oral administration and which, along with active estratriene included as other components pharmaceutically compatible oil and/or pharmaceutically compatible lipophilic surfactant, and/or pharmaceutically compatible hydrophilic surfactant, and/or pharmaceutically compatible miscible with water, the solvent.

To achieve higher bioavailability of the proposed invention the active substances compounds can be formed also in the form of cyclodextrines of clathrates. For this purpose, the compounds are subjected to interaction with α-, βor γ-cyclodextrin or its derivatives.

In the case of cu the MOU, ointments, lotions and applied externally fluids they must be able to supply proposed in the invention compounds in the body in sufficient quantities. In these dosage forms contain auxiliary substances, for example substances for adjusting the rheology of drugs, surfactants, preservatives, dissolution promoters, solvents, substances that enhance the ability of the proposed invention estratriene to penetrate the skin, colors, flavors and protective equipment for the skin, such as air conditioners and regulators humidity. In the composition of the medicinal product, together with the proposed in the invention compounds may include additional or other active substances [Ullmanns Enzyklopädie der technischen Chemie, volume 4, 1953, SS-39; J. Pharm. Sci., 52, 1963, SS and forth; H.v. Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete, Pharm. Ind., 2, 1961, SS and forth; Dr. H.P.Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, Izd-vo Cantor AG, Aulendorf/Württ., 1971].

Proposed in the invention compounds can also be used in the respective solutions such as physiological saline, solutions for infusion or injection. Parenteral application of the active ingredients can be dissolved or suspended in an appropriate physiologically compatible with the second diluent. As such diluents suitable primarily oil solutions, as, for example, solutions in sesame oil, castor oil and cottonseed oil. To improve the solubility may be added dissolution promoters, such as benzyl benzoate or benzyl alcohol.

To obtain an injectable preparation, you can use any carrier liquid, which is proposed in the invention compounds are dissolved or emulsified. Such fluids often contain substances-viscosity regulators, surfactants, preservatives, dissolution promoters and other additives with which the solution was transferred to isotonic. Together with estratriene according to the invention in the body can be entered and other active ingredients.

Proposed in the invention estratriene can be applied in the form of a depot injection or implant preparation, which, for example, for percutaneous introduction. Such drugs can be formed in such a way as to provide a slow, gradual release of the active substance. For this purpose you can use known techniques, for example to apply dissolving or provided with a corresponding membrane depo-forms. As inert materials, the implant may contain, for example, biodegradable p is the materials and synthetic silicones, in particular silicone rubber. Estratriene if percutaneous injection can, for example, to plug in the patch.

Another possibility is the use of compounds according to the invention is that they are buried in the transdermal system and thus used for transdermal administration.

For better penetration through the skin to provide therapeutically effective levels of the proposed compounds in the blood of these compounds, similarly to that described in the application WO 01/76608 for other antiestrogens can be incorporated into the appropriate transdermal system. Such transdermal systems are a special relationship between present them in two penetration enhancers, primarily lauric acid and propylene glycol.

The dosage proposed in the invention compounds of General formula I is determined by the physician depending on the type of medicinal product, methods of administration, nature and severity of the disease. Appointed to conduct the number of connections varies widely, the basic principle is to achieve the desired therapeutic effect. Depending on the condition being treated, and on the method of the introduction of a number of assigned connections may be 0.1-25 mg/is g body weight, preferably 0.5 to 5 mg/kg of body weight per day. For humans, this corresponds to a daily dose of from 5 to 1250 mg. Preferred daily dosage for humans is 50-200 mg. relates primarily to the treatment of tumors. This dose may be administered in the form of a single dose in a single dose per day or distribute it based on two servings per day or more.

Compounds of General formula I are, as mentioned above, compounds with pronounced, strong anti-estrogenic effect. Therefore, these compounds are suitable for treatment estrogenzawisimy diseases, such as breast cancer (second-line therapy of breast carcinoma after failure of tamoxifen; for adjuvant treatment of breast carcinoma instead of tamoxifen), carcinoma of the endometrium, prostate hyperplasia, infertility, associated with impaired ovulation, and melanoma.

Compounds of General formula I can also be used as a component described in, for example, in application EP 346014 B1 products containing estrogen and pure antiestrogen, namely, simultaneously, sequentially or separately for selective oestrogen therapy in women during or after menopause. Compounds of General formula I can be used in conjunction with antigestagens (additional antagonists of progest what Ron) for the treatment gormonzavisimykh tumors (ER 310542 A).

Other indications for which can be used compounds of General formula I, include hair loss in men, diffuse alopecia, alopecia induced by chemotherapy, as well as hirsutism (Hye-Sun Oh, and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93, 1996, SS-12530).

In addition, compounds of General formula I can be used for getting medicines for the treatment of endometriosis. In addition, compounds of General formula I can be used to obtain pharmaceutical compositions intended for the control of fertility (fertility) men and women (issues of control male fertility are considered in the application DE 19510862.0 A).

Proposed in the invention estratriene can be obtained by methods similar to known.

Figure 1 shows a reaction scheme according to which can be obtained proposed in the invention compounds. Proposed in the invention of 17α-alkyl-17β-axisratio indicated in the diagram by the concept of "17α-methylamine and 17α-melaminated". In contrast, compounds designated as "17α-methyl"in position 7α contain a side chain without the amino group. Compounds that are in position 17β bear a hydroxy or alkoxygroup in position 17α - alkyl group and in position 7α - side chain amino group of a, denoted as "17α-met the Lamin". Accordingly, the compounds denoted by the concept of "17α-methylamines are amine-N-oxides of the aforementioned "17α-methylamino" connections.

If R3has a value other than N, then carry out the etherification using reagent R3while X denotes a leaving group.

Further, the compounds indicated as "17βTHEY are estratriene that in position 17β contain hydroxy or alkoxygroup, but in the side chain in position 7α contain no 17α-alkyl, or amino group. Compounds identified as "17-keto are estratriene that in position 17 are oxoprop, but in the side chain in position 7α assume no amino group. Other compounds identified as "17β-HE-Amin", "17-ketamin", "17β-HE-aminexil" and "17β-ketoiminate"have corresponding samples of substitution.

In principle, all the above compounds can be obtained based on 17 exocoetidae. Getting 17 exocoetidae partially described, for example, in the application WO 99/33855 A1. Other derivatives which in this publication in addition to the stated compounds with the same pattern of substitution, although not represented, can be obtained in a similar way. Similarly, you can get also proposed in the present invention estratriene based on 17β-hydroxy - or 17β-al is oxyconti ("17β "HE"). These derivatives are also described, for example, in the aforementioned application WO 99/33855 A1. This publication describes also carried out according to a similar method of obtaining 17β-hydroxy - or 17β-alkoxysilane and 17 exocoetidae with the amino group in the side chain in position 7α. Since the starting compounds is not described, this means that they are known and are commercially available products, or these compounds are synthesized analogously as described. Below as examples retrieves some compounds, the precursors, intermediates and target products.

Upon receipt of the proposed in the invention compounds are used, among others, some known methods (see, for example, EP 0138504 B1, WO 97/45441 A1, WO 98/07740 A1, WO 99/33855 A1).

Proposed in the invention of 17α-alkyl-17β-axisratio can be obtained from the corresponding 17β-axisratio ("17β " HE"). The synthesis of these starting compounds are also described in particular in application WO 97/45441 A1 and WO 98/07740 A1. Side chain in position 7α you can build, for example, by the method described in WO 98/07740 A1.

Then formed 17β-hydroxy - or 17β-alkoxysilane with the amino group in the side chain in position 7α by oxidation to oksidirovanii to the corresponding 17-exocoetidae ("17-ketamin"). In these the order may apply the usual oxidizing agents, such as compounds of chromium(VI) oxidation by Jones), nitric acid, pyrolusite, selenium dioxide and SO3in pyridine. Ketones can also be obtained by catalytic dehydrogenation using metallic copper, silver, chromate copper and zinc oxide at elevated temperature or by dehydrogenation using ketones, for example cyclohexanone, or oxidation Oppenauer. If the side chain contains a reducing group, such as S - or SO-group, after pereokislenie these groups optionally selectively again.

In another embodiment, method 17β-axisratio not containing the amino group in the 7α-side chain, can directly oxidize to 17-oxoacetate ("17-keto), and then these 17-oxoacetate known to minirovat 7α-side chain.

Then you can enter an alkyl group in position 17α. For these purposes may be used conventional nucleophilic alkylating agents, such as Grignard reagents or alkyllithium connection. The result of this reaction are formed as required 17α-alkyl-17β-axisratio (namely "17α-methyl", provided that extend from their 17β-hydroxyestradiol not containing the amino group in the side chain in position 7α ["17β-HE"], "17α-methylamine", provided that extend from the STA is ejstvujuschij 7-hydroxyestradiol, containing the amino group in the side chain at position 17α ["17β-HE-Amin"]. In addition, obtained as an intermediate product 17-oxoacetate you known way to alkilirovanii, and then 7α-side chain to minirovat.

If provides for N-oxide amino compounds (i.e. marked as "17β-HE-aminexil" or "17-ketoiminate" or "17α-melaminated"), the corresponding estratriene with the amino group in the 7α-side chain ("17β-HE-Amin", "17-ketamin", "17α-methylamine") are oxidized, for example using hydrogen peroxide. When this reaction secondary Oh-group in position 17β not oxidized.

Alternatively, get proposed in the invention of 17α-alkyl-17β-axisratio above 17β-hydroxyatrazine with the amino group in the side chain in position 7α ("17β-HE-Amin") also serve as starting materials. While they are first converted into the corresponding N-oxide amino compounds ("17β-HE-aminexil"), using for these purposes, the above conventional oxidizing agents such as hydrogen peroxide. Then, the formed N-oxide amino compounds ("17β-HE-aminexil") are oxidized to the corresponding ketone ("17-ketoiminate"), using the same oxidizing agents, as mentioned above. When it is formed on 17 exocoetidae, containing N-oxide amino group in the 7α-side chain.

To obtain the proposed invention 17α-alkyl-17β-axisratio ketogroup in turn according to the above guidelines is subjected to interaction with the appropriate nucleophilic alkylating agents. The formation of 17α-alkyl-17β-axisratio N-oxide amino group in the 7α-side chain ("17α-melaminated").

Thus, to obtain the proposed invention 17α-alkyl-17β-axisratio form, in particular, also the intermediate products of the following General formula II, which are also the object of the present invention:

In the formula

Hal denotes F or Cl and in position 11β associated with estratriene skeleton,

R3denotes hydrogen, C1-C4alkyl, C1-C4alkanoyl or simple cyclic ether With3-C7ester with O-atom

R17'denotes hydrogen, C1-C4alkyl or C1-C4alkanoyl and in position 17β associated with estratriene skeleton and

SK denotes the group U-V-W-X-Y-Z-E, which is connected through U in position 7α estratriene skeleton, with U, V, X, Y, Z and E have the values indicated above, and W represents a group of N+(O-)(R6or N-is sidnee solidariedade ring, this N-oxide solidariedade ring includes at least one C-atom of the group X, and R6has the above value.

Otherwise, as mentioned above, in positions 1, 2, 4, 6-9 and 11-16 with estratriene skeleton are connected preferably hydrogen atoms. In principle estratriene skeleton can also be modified, in particular due to the presence of hydrocarbon bridge, for example, 15β,16βmethane group.

Especially preferred 17α-alkyl-17β-existentielle c N-oxide amino group in the 7α-the side chain of General formula II are the following compounds:

X1) N-oxide 11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol,

X2) N-oxide 11β-fluoro-7α-[5-(methyl{3-[(2,3,4,5,6-pentafluorophenyl)sulfanyl]propyl}amino)pentyl]östra-1,3,5(10)-triene-3,17β-diol,

X3) N-oxide 11β-fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluorophenyl)sulfanyl]propyl}amino)pentyl]östra-1,3,5( 10)-triene-3,17β-diol,

X4) N-oxide 11β-fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluorophenyl)sulfinil]propyl}amino)pentyl]östra-1,3,5(10)-triene-3,17β-diol,

X5) N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol,

X6) N-oxide (S)-1(S)-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-dio is and,

X7) N-oxide, (R)-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

X8) N-oxide 11β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol.

Physical properties of these compounds are presented in table 3.

The object of the present invention are also formed upon receipt of the proposed 17α-alkyl-17β-axisratio as intermediates 17-oxoacetate N-oxide amino group in the 7α-side chain. These compounds have the General formula III

In the formula

Hal denotes F or Cl and in position 11β associated with estratriene skeleton,

R3denotes hydrogen, C1-C4alkyl, C1-C4alkanoyl or simple cyclic ether With3-C7ester with O-atom and the

SK denotes the group U-V-W-X-Y-Z-E, which is connected through U in position 7α estratriene skeleton, with U, V, X, Y, Z and E have the values indicated above, and W represents a group of N+(O-)(R6or N-oxide solidariedade ring, and this N-oxide solidariedade ring includes at least one C-atom of the group X, and R6has the above value.

Otherwise, as mentioned above, in positions 1, 2, 4, 6-9 and 11-6 with estratriene skeleton are connected preferably hydrogen atoms. In principle estratriene skeleton can also be modified, in particular, due to the presence of hydrocarbon bridge, for example, 15β,16βmethane group.

Particularly preferred 17-exoectations N-oxide amino group in the 7α-the side chain of General formula III include the following compounds:

Y1) N-oxide 11β-fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluorophenyl)sulfinil]propyl}amino)pentyl]östra-1,3,5(10)-triene-3-ol-17-she

Y2) N-oxide 11β-fluoro-7α-[5-(methyl{3-[(4,4,5,5,5-pentafluorophenyl)sulfanyl]propyl}amino)pentyl]östra-1,3,5(10)-triene-3-ol-17-she

Y3) N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-it.

Physical properties of these compounds are presented in table 4.

Compounds of General formula II, as well as compounds of General formula III are compounds with antiestrogenic action. Therefore, in principle, they can be used with the same indications as above for compounds of General formula I.

In more detail below explains the options of method of obtaining the proposed in the invention compounds.

Version 1.1 of the way

(Getting 17-exoectations N-oxide amino group in the side chain based on 17β-hydroxyestradiol with the amino group in the side chain through the corresponding 17-oxoethylidene)

a) 11β-the top-7α -{5-{methyl{7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-one (the angle of rotation αDthis compound (No. Z14) is given in table 5)

To a solution of 1.23 g of the complex of pyridine-sulfur trioxide in 10 ml of dried dimethyl sulfoxide at 10°With added dropwise 1.5 ml of ethyldiethanolamine. Then add 1,72 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol (compound No. Z9), and 10 ml of dried dimethyl sulfoxide and stirred for 30 min at room temperature. Then diluted with ethyl ether, acetic acid, washed with saturated sodium hydrogen carbonate solution, water and sodium chloride solution, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographic on silica gel using dichloromethane/methanol. In this way receive 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-one. [α]D=+58,2° in chloroform.

b) N-oxide 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-she

A solution of 0.5 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-she's in 11 ml of methanol and 11 ml of chloroform is mixed with 3.5 ml of 30%hydrogen peroxide solution and within 5 days was stirred at room temperature is E. Then mixed with sodium thiosulfate, poured into water, extracted three times with dichloromethane, washed to neutral pH, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographic on silica gel using dichloromethane/methanol. In this way receive 401 mg N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-it is in the form of a solid substance with tPL84-86°C. [α]D=+53,6° in chloroform.

in) N-oxide 11β-fluoro-7α-{5-[methyl[7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

A suspension of 2.3 g of cerium chloride(III) in 23 ml of tetrahydrofuran is mixed at (0°C 3,19 ml of a 3 molar solution methylacrylamide in diethyl ether and stirred for 30 minutes Then to this mixture is added dropwise a solution of 250 g of N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-she's in 5 ml of tetrahydrofuran, then stirred for 24 h at room temperature, mixed at 0°With 10 ml of a solution of ammonium chloride, extracted with ethyl ether, acetic acid, washed with water, dried over sodium sulfate, concentrated in vacuo, dissolved in 5 ml methanol and 5 ml of chloroform, mixed with 2 ml of 30%hydrogen peroxide solution and within 5 days was stirred at anatoy temperature. Then mixed with sodium thiosulfate, poured into water, extracted three times with dichloromethane, washed to neutral pH, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographic on silica gel using dichloromethane/methanol. The result is 165 mg N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol with tPL122°C.

Version 1.2 of the way

(Getting 17-exoectations N-oxide amino group in the side chain based on 17β-hydroxyestradiol with the amino group in the side chain through the appropriate 17β-hydroxyatrazine N-oxide amino group in the side chain)

a) N-oxide 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17-diol

A solution of 50 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol in 500 ml of methanol and 500 ml of chloroform is mixed with 7.3 g of sodium bicarbonate and 45 ml of 30%hydrogen peroxide solution and stirred for 3 days at room temperature. Then mixed with sodium thiosulfate, poured into water, extracted three times with dichloromethane, washed to neutral pH, dried over sodium sulfate, concentrated to dryness in a vacuum and produce by stirring with diethyl ether is. In this way get to 48.3 g of N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol with tPL131,7°C.

b) N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino}of pentyl}östra-1,3,5(10)-triene-3-ol-17-she

To a solution of 1.23 g of the complex of pyridine-sulfur trioxide in 10 ml of dried dimethyl sulfoxide at 10°With added dropwise 1.5 ml of ethyldiethanolamine. Then add 1,62 g N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol and 10 ml of dried dimethyl sulfoxide and stirred for 30 min at room temperature. Then diluted with ethyl ether, acetic acid, washed with saturated sodium hydrogen carbonate solution, water and sodium chloride solution, dried over sodium sulfate, concentrated to dryness in vacuo and chromatographic on silica gel using dichloromethane/methanol. In this way gain of 1.32 g of N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-it is in the form of a solid substance with tPL84-86°C. [α]D=+53,6° in chloroform.

Version 2.1 of the way

(Getting 17α-methylestradiol N-oxide amino group in the side chain on the basis of 17-oxoacetate with the amino group in the side chain through the corresponding 17-castration N-oxide amino group in the side chain)

a) 11β-Fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol (physical properties of this compound (No. 7) are presented in table 1)

A suspension of 230 g of cerium chloride(III) in 2.3 l of tetrahydrofuran is mixed at 0°With 320 ml of a 3 molar solution methylacrylamide in diethyl ether and stirred for 30 minutes To this mixture are added dropwise 25 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3-ol-17-she (the angle of rotation αDthis compound (No. Z14) is given in table 5) in 250 ml of tetrahydrofuran, and then stirred for 24 h at room temperature, mixed at 0°with a solution of ammonium chloride, extracted with ethyl ether, acetic acid, washed with water, dried with sodium sulfate, concentrated in vacuo and chromatographic on silica gel using dichloromethane/methanol. In this way gain of 19.1 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol with tPL82-85°C. [α]D=+21,8° in chloroform.

b) N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol

A solution of 18 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17βdi is La in 180 ml of chloroform and 180 ml of methanol is mixed with to 2.57 g of sodium bicarbonate and 16.2 ml of 30%hydrogen peroxide solution and within 48 hours was stirred at room temperature. Then diluted with dichloromethane, washed with water and sodium thiosulfate solution, dried over sodium sulfate, concentrated to dryness in a vacuum and produce by stirring with diethyl ether. The result of 18.4 g of N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol with tPL122°C.

Version 2.2 of the way

(Getting 17α-methylestradiol with the amino group in the side chain on the basis of 17-exoectations through the corresponding 17α-methylanthracene)

a) 7α-(5-bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-diol

Suspension of 46.8 g of cerium chloride(III) 0.47 l of tetrahydrofuran is mixed at 0°from 63.8 ml of a 3 molar solution methylacrylamide in diethyl ether and stirred for 1 h and Then added dropwise a solution of 25 g 7α-(5-bromopentyl)-11β-forestry-1,3,5(10)-triene-3-ol-17-she's in 200 ml of tetrahydrofuran, and then stirred for 28 h at room temperature, mixed at 0°With a solution of ammonium chloride, extracted with ethyl ether, acetic acid, washed with water, dried with sodium sulfate, concentrated in vacuo and chromatographic on silica gel using dichloromethane/methanol. In this way gain of 15.1 g 7α-(5-bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-diol with tPL

b) 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol (physical properties of this compound (No. 7) are presented in table 1)

A solution of 18 g 7α-(5-bromopentyl)-11β-fluoro-17α-methylestra-1,3,5(10)-triene-3,17β-diol in 180 ml of dimethylformamide is mixed with 15.9 g (7,7,8,8,9,9,10,10,10-nonattorney)of methylamine and 5 g of sodium carbonate, after which for 8.5 h and stirred at a bath temperature of 80°C. Then poured into water, extracted with ethyl ether, acetic acid, washed with water and saturated sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and chromatographic on silica gel using dichloromethane/methanol. The result is 22.9 g 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol with tPL82-85°C. [α]D=+21,8° in chloroform.

Others proposed in the invention compounds can be obtained in a similar way. Required for these purposes, the intermediate products are further specified in table 5. In addition, some physical properties of these compounds.

td align="left" namest="c4" nameend="c6">  
Table 1
T is mperature melting [° S]The angle of rotation αD1)
1N-oxide 11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol152-154
211β-fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptapteridae)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol, N-oxide137,7+31°
3N-oxide (RS)-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol122+29,6°
4N-oxide 11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol148,5+25,3°
5N-oxide 11β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl-17α-methylestra-1,3,5(10)-triene-3,17β-diol118-120+26°
6 11β-fluoro-7α-{5-[methyl(8,8,9,9,9-pendaftaran)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol68-71+32°
711β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol82-85+21,8
811β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol138+29,8°
917α-ethinyl-11β-fluoro-7a-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-3,17β-diol128-130+13,1°
1017α-ethinyl-11β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}östra-1,3,5(10)-triene-17βol+8,1°
1111β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-17βol+26,9°
1211β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-cryptomailer-1,3,5(10)-triene-3,17β-diol+24,6°
1311β-fluoro-7α-{5-[methyl(6,6,7,7,8,8,8-heptafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol96,3+38,8°
Melting point [°]The angle of rotation αD1)
1411β-fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptapteridae)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol1374-24,6°
1511β-fluoro-7α-{5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol112,6+21,3°
1611β-fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorobutyl)amino]pentyl}-17α-m is telestra-1,3,5(10)-triene-3,17β -diol
1711β-fluoro-7α-{5-|methyl(9,9,10,10,11,11,11-heptafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol
1811β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol88-90+32,5°
1)[α]Din chloroform
Table 2
Antiuterotrophic action
s.c.% inhib.p.o.% inhib.
3N-oxide (RS)-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol0,376
711β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-,17β -diol0,0359
811β-fluoro-7α-(5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol0,394

1. 17α-alkyl-17β-axisratio General formula I

in which

Hal denotes F or Cl and in position 11β associated with estratriene skeleton;

R3denotes hydrogen, C1-C4alkyl, C1-C4alkanoyl or simple cyclic With3-C7ester with O-atom

R17'denotes hydrogen, C1-C4alkyl or C1-C4alkanoyl,

R17"represents C1-C4alkyl, C1-C4quinil, R17'-Oh in position 17β and R17'in position 17α associated with estratriene skeleton,

SK denotes the group U-V-W-X-Y-Z-E, which is connected through U in position 7α estratriene skeleton, where

U is either directly Ipotechniy or branched C 1-C13alkilinity the rest,

V represents a group CH3;

W represents a group N(R6), where R6is either N or C1-C4alkyl,

X represents remotemachine or branched C1-C4alkilinity the rest,

Y represents a direct bond between X and Z,

Z represents remotemachine or branched C1-C9alkalinity residue, which may be partially or fully fluorinated,

E represents a group of CF3,

including their pharmacologically compatible acid additive salts and esters.

2. Estratriene according to claim 1, wherein R3denotes hydrogen, CH3CH3WITH or With5H10O.

3. Estratriene according to claim 1, wherein R17'denotes hydrogen, CH3or CH3WITH, and R17'denotes methyl or ethinyl.

4. Estratriene according to claim 1, wherein Hal represents fluorine.

5. Estratriene according to claim 1, wherein U represents a group (CH2)pwhere R denotes an integer ranging from 2 to 10.

6. Estratriene according to claim 1, wherein U represents a group (CH2)pwhere R denotes 4.

7. Estratriene according to claim 1, characterized in that the V, not only is no a group of CH 2.

8. Estratriene according to claim 1, wherein W represents a group N(R6), where R6represents hydrogen or C1-C3alkyl.

9. Estratriene according to claim 1, wherein R6represents methyl.

10. Estratriene according to claim 1, characterized in that X represents a group (CH2)qwhere q denotes an integer ranging from 1 to 12.

11. Estratriene of claim 10, wherein X represents a group (CH2)qwhere q denotes 7.

12. Estratriene according to claim 1, characterized in that Y represents a direct bond between X and Z.

13. Estratriene according to claim 1, characterized in that Z represents remotemachine or branched C1-C7alkalinity residue, which is at least partially fluorinated.

14. Estratriene according to item 13, wherein Z represents CF2.

15. Estratriene according to claim 1, wherein E is a group of CF3.

16. Estratriene according to claim 1, wherein group Z-E is a group of C2F5C3F7C4F9.

17. Estratriene according to claim 1, characterized in that the compound represented by the formula

18. Estratriene General formula I, which represent:

11β-fluoro-7α-{5-[methyl(8,8,9,9,9-PENTAFLUORO who yl)amino]pentyl}-17α -methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,9-heptaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

17α-ethinyl-11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-östra-1,3,5(10)-triene-3,17β-diol,

17α-ethinyl-11β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-östra-1,3,5(10)-triene-17β-ol,

11β-fluoro-3-(2-tetrahydropyranyloxy)-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-17β-ol,

11β-fluoro-7α-{5-[methyl(7,7,8,8,9,9,10,10,10-nonattorney)amino]pentyl}-17α-cryptomailer-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(6,6,7,7,8,8,8-heptafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(8,8,9,9,10,10,10-heptapteridae)amino]pentyl}-17A-methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(6,6,7,7,8,8,9,9,10,10,10-undecaprenyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(5,5,6,6,7,7,8,8,8-nonafluorobutyl)amino]pentyl}-17α-methylestra-1,3,5(10)-triene-3,17β-diol,

11β-fluoro-7α-{5-[methyl(9,9,10,10,11,1,11-heptafluorobutyl)amino]pentyl}-17α -methylestra-1,3,5(10)-triene-3,17β-diol or

11β-fluoro-7α-{5-[methyl(9,9,10,10,10-pentatonic)amino]pentyl}17α-methylestra-1,3,5(10)-triene-3,17β-diol.

19. The use of 17α-alkyl-17β-axisratio General formula I according to one of claims 1 to 18 to obtain drugs with antiestrogenic action.

20. Pharmaceutical drug, possess antiestrogenic activity, containing at least one 17α-alkyl-17β-axisratio General formula I according to one of claims 1 to 18, and at least one pharmaceutically compatible carrier.



 

Same patents:

FIELD: organic chemistry, steroids, chemical technology.

SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.

EFFECT: improved preparing method.

56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):

wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.

EFFECT: valuable medicinal properties of compounds, improved method for treatment.

38 cl, 1 tbl, 18 ex

The invention relates to substituted phenylalkylamines, their pharmaceutically acceptable salts and physiologically functional derivatives

The invention relates to a new class 17-acyl-17-prominentnych steroids of formula I, where R1- (CH3)2N-CH3NH-, NH2-, CH3CO - or CH3S-; R2- CH3or CF3-; R3- H, CH3-, CH3O-CH3COO-; R4- H, CH3-, F - or Cl-, and X, which have antiprogesterone activity

The invention relates to an improved method of obtaining carboxamido-4-azasteroid General formula I, in which the dashed lines independently represent either simple or double bond, R, R1, R2and R3each represents hydrogen or an organic radical comprising processing the corresponding intermediate compounds 17-carbonyl-imidazoles anhydrous acid in the presence of amine and, optionally, hydrogenation of the compounds obtained

The invention relates to derivatives of 16-hydroxy-11-(substituted phenyl)-östra-4,9-diene corresponding to the formula I, where R1- C1-6- alkyl, triflate or phenyl, where the phenyl group is optionally substituted by one or more substituents selected from cyano, halogen and C1-4-alkyl, R2is hydrogen or carboxy-1-oxo-C1-6-alkyl; R3is hydrogen, halogen or1-6- alkyl, optionally substituted by one or more1-6-alkoxy, R4is hydrogen or C1-6-alkyl, and X, O or NOH; or their pharmaceutically acceptable salts or MES; describes the methods for their preparation and the pharmaceutical composition is intended for use in medical therapy particularly for the treatment or prevention glucocorticoidavoid diseases or symptoms

FIELD: medicine, pharmacy.

SUBSTANCE: pharmaceutical composition possesses an anti-estrogenic effect. The composition comprises fulvestrant in ricinoleate vehicle, a pharmaceutically acceptable anhydrous ester solvent and pharmaceutically acceptable alcohol. The composition is adopted for intramuscular administration and maintains the therapeutically significant blood plasma fulvestrant concentration for at least 2 weeks. The composition for intramuscular injection provides satisfied releasing fulvestrant for prolonged time.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

32 cl, 4 tbl, 1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

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EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

FIELD: organic chemistry, steroids, pharmacy.

SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

The invention relates to medicine and can be used to treat estrogenzawisimy malignant tumors

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The invention relates to medicine, in particular to hormonal tools, and comes with contraceptive activity gestagen-estrogenic composition

The invention relates to the field of medicine

FIELD: organic chemistry, steroids.

SUBSTANCE: invention describes 17α-alkyl-17β-hydroxyestra-1,3,5(10)-trienes possessing anti-estrogenic properties of the general formula (I): wherein Hal means fluorine (F), chlorine (Cl) atoms; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkanoyl, simple cyclic (C3-C7)-ether comprising O-atom; R17' means H, (C1-C4)-alkyl, (C1-C4)-alkanoyl; R17'' means (C1-C4)-alkyl, (C1-C4)-alkynyl; SK means: U-V-W-X-Y-Z-E wherein U means (C1-C13)-alkylene; V means -CH2; W means -N(R6) wherein R means H, (C1-C4)-alkyl; X means (C1-C12)-alkylene; Y means a direct bond between X and Z; Z means possibly fluorinated (C1-C9)-alkylene; E means -CF3. Also, invention describes 17-oxoestra-1,3,5(10)-trienes and 17β-hydroxyestra-1,3,5(10)-trienes as intermediate substances used in synthesis of estratrienes proposed by the invention. Also, invention describes using 17α-alkyl-17β-hydroxyestratrienes for preparing corresponding medicinal agents and pharmaceutical preparations comprising at least one 17α-alkyl-17β-hydroxyestratriene and at least one pharmaceutically acceptable carrier.

EFFECT: valuable medicinal properties of steroids.

5 tbl, 7 dwg

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