Compounds with hydroxycarbonyl-halogenalkyl by-side chains

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

 

The technical field

The present invention relates to hydroxycarbonyl-halogenosilanes derivative, designed to significantly improve the oral activity of compounds with low activity when administered orally, the compounds with antitumor activity, compounds with estrogenic activity or compounds with antiestrogenic activity.

Background of invention

In the treatment of diseases caused by an abnormal growth of tissue, which depends on some sex steroid hormones such as estrogen, it is very important to inhibit significantly, more preferably to exclude completely induced by hormone action. To this end it is desirable to lower the level of the hormone can affect the receptor site of steroid hormone. For example, an antiestrogen agents usually do when alternative or combination therapy to limit the production of estrogen to the quantity that is less than that required for activation site of the receptor. However, such conventional methods of blocking the production of estrogen cannot sufficiently inhibit the action induced by the estrogen receptor. Practically, even when estrogen is missing completely, some of the receptors is there to be activated. Consequently, I believe that antagonists of estrogen may provide a better therapeutic effect in comparison with the methods only block the production of sex steroid hormone. Thus, were developed numerous antagonists of estrogen. For example, in many patent publications, including U.S. patent No. 4760061, 4732912, 4904661, 5395842 and WO 96/22092 described various antiestrogenic compounds. However, sometimes the antagonists of the prior art can themselves act as agonists and, therefore, more likely to activate the receptor than to block it. For example, as an antiestrogen agent most widely used Tamoxifen. However, this agent has the disadvantage that it exhibits estrogenic activity in some organs (see Minireg and A.Walpole, J.Reprod. Fertile., 1967, 13, 101).

As another non-steroidal anti-estrogenic compounds in WO 93/10741 described derived benzopyrane with aminoacetanilide Deputy(and) (Anthracene, Endorecherche), a typical connection in a series which is EM-343, having the following structure:

The specified connection also has an agonistic effect. Therefore, it is necessary to develop an antiestrogen compound which is sufficiently or completely has no agonist is ical action and which can effectively block the estrogen receptor.

In addition, it is known that 7α-substituted derivatives of estradiol, for example, 7α-(CH2)10CONMeBu derivatives, are steroid an antiestrogen agents without agonistic actions (see EP-A 0138504, U.S. patent 4659516). In addition, a derivative of estradiol with 7α-(CH2)9SOC5H6F5Deputy, also described as a 7α-substituted derivative of estradiol (see Wakeling et al. Cancer.Res., 1991, 51, 3867).

Nonsteroidal antiestrogen agents, do not possess agonistic action, were first described Wakeling et al. in 1987 (see A. Wakeling and Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, in U.S. patent 4904661 described derivatives of phenol with antiestrogenic activity. Such derivatives of phenol usually have a naphthalene skeleton and include, generally, the following connections:

Reported on some derivatives chromane and thiochroman as antiestrogenic compounds that do not possess agonistic action (WO 98/25916). Although existing antiestrogenic compounds that do not possess agonistic action, show a significant therapeutic effect by introduction by intravenous or subcutaneous injection, they exhibit significantly reduced therapeutic effect when administered orally due to their low bioavailability with oral administration the route of administration. Therefore, for convenience in the introduction, it is desirable to develop anti-estrogenic compounds that exhibit a sufficient effect when administered orally and at the same time do not have agonistic activity. Also usually required to develop agents that exhibit a sufficient effect by oral administration.

Description of the invention

The present invention is to develop hydroxycarbonyl-halogenating derivatives created to significantly improve the oral activity of compounds with low activity when administered orally, the compounds with antitumor activity, compounds with estrogenic activity or compounds with antiestrogenic activity, by enhancing their absorption from the intestinal tract and/or improve their stability against metabolism.

Research work of the authors of this invention was aimed at achieving the above objectives, and they found that the side chain of the General formula (1), if it is attached to the original frame connections, enables estrogenic compounds show significantly increased activity by oral route of administration. The present invention was made on the basis of these information.

Namely, the present izaberete the s refers to the connection, consisting of a fragment and groups chemically bound with the specified slice, where the specified fragment contains a compound which has a low activity when administered orally, or its original frame, and the group has the following General formula (1):

in which R1represents a hydrogen atom or a salt-forming metal,

R2is a straight or branched C1-C7halogenating group,

m represents an integer purely from 2 to 14 and

n represents an integer from 2 to 7,

or enantiomers originally specified connection, or hydrates or pharmaceutically acceptable salts of the compounds or its enantiomers.

The present invention also relates to a compound consisting of a fragment and groups chemically bound with the specified slice, where the specified fragment contains the compounds having antitumor activity, or its original frame, and the group has the following General formula (1):

in which R1represents a hydrogen atom or a salt-forming metal,

R2is a straight or branched C1-C7halogenating group,

m represents an integer purely from 2 to 14 and

n represents an integer from 2 to 7,

or enantiomers first is touch the specified connection, or hydrates, or pharmaceutically acceptable salts of the compounds or its enantiomers.

In addition, the present invention relates to a compound consisting of a fragment and groups, chemically fragment, where the specified fragment contains the compounds having estrogenic activity, or its original frame, or compounds with antiestrogenic activity, or its original frame, and the group has the following General formula (1):

in which R1represents a hydrogen atom or a salt-forming metal,

R2is a straight or branched C1-C7halogenating group,

m represents an integer purely from 2 to 14 and

n represents an integer from 2 to 7,

or enantiomers originally specified connection, or hydrates or pharmaceutically acceptable salts of the compounds or its enantiomers.

Still, in addition, the present invention relates to a compound having the following General formula (2):

in which R1represents a hydrogen atom or a salt-forming metal,

R2is a straight or branched C1-C7halogenating group,

m represents an integer purely from 2 to 14,

n represents an integer from 2 to 1, and

But GRU is PU, selected from the following formulas (3)to(8) and(10)-(26):

where in formulas(6), (7), (14) and (24) each of R3and R6is a straight or branched C1-C5the alkyl group in the formula (10), (11) and (12) Z10represents a hydrogen atom or acyl group, in the formula (13), (21) and (22) each of Z1, Z2, Z3, Z4, Z5and Z6independently represents a hydrogen atom, a hydroxyl group or a straight or branched C1-C5the alkyl group in the formula (15) R7represents a hydrogen atom or a straight or branched C1-C5the alkyl group in the formula (16) each of Z7, Z8and Z9independently represents a hydrogen atom or hydroxyl group, in formulas (18) and (20) R8is a straight or branched C1-C5alkyl group, straight or branched C2-C5alkenylphenol group or a straight or branched C2-C5alkylamino group, in the formula (23) each of R21, R22, R23and R24independently represents a hydrogen atom, a straight or branched C1-C5alkyl group, straight or branched C1-Csub> 7halogenating group, halogen atom or acyl group, and in formulas (25) and (26) X represents a halogen atom, or enantiomers of the compounds or hydrates, or pharmaceutically acceptable salts of the compounds or its enantiomers.

In addition, the present invention relates to pharmaceutical compositions comprising a compound of General formula (2) as an active ingredient. The present invention also relates to anti-estrogenic pharmaceutical composition comprising the above compound as an active ingredient. Further, the present invention relates to a therapeutic agent against breast cancer, comprising the compound of General formula (2) as an active ingredient.

As used herein, the term “original frame(s)” refers to a partial structure, which is common to a class of compounds with the same or similar pharmacological effect or physico-chemical properties. The original frames include, but are not limited to, the following structures: a steroid, indole, naphthalene, benzofuran, benzothiophene, benzopyran, benzoxazine, 3,4-diphenyl[4.3.0]nonan, 4-(1,2-diphenyl-1-butenyl)phenol, flavone, erythromycin, alkaloid, cephalosporins, β-lactam and their derivatives.

Compounds with low activity when administered orally, the relative is raised to such compounds, are not able to show adequate activity for the desired pharmacological activity when administered orally because they are poorly absorbed from the intestinal tract or rapidly metabolized in the body. Examples include some types of antitumor compounds, some types of estrogenic compounds (e.g., estradiol) and antiestrogenic compounds.

Compounds with antitumor activity include all types of compounds able to inhibit tumor growth. The present invention has special advantages for compounds exhibiting low activity by oral route of administration.

Compounds with estrogenic activity are those compounds which have affinity to the estrogen receptor and amplify the signal mediated by the estrogen receptor. Examples include estradiol.

Compounds with antiestrogenic activity, refer to those compounds, which have antagonistic activity against pharmacological actions of estrogen. Examples include compounds described in the above-mentioned prior art the development of this field.

The present invention relates to compounds, where the fragment is chemically associated with the group with the specified fragment contains a compound which has a low activity is followed by oral administration, the compounds having antitumor activity, the compounds having estrogenic activity or compounds with antiestrogenic activity, or the original frames of data connections, and this group has the General formula (1). As used herein, the term “chemically bonded” means that the group is linked via a covalent bond and the like, including C-C bond, C-O bond, C-N bond, etc. Fragment containing the above compounds or their original frames may have any structure until the possible data communication. To improve stability against metabolism and, consequently, activity by oral route of administration is preferably used With the connection.

Soleobrazutaya metals as R1include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, rare earth metals such as cerium and samarium, as well as zinc and tin. Among them, alkali metals and alkaline earth metals are preferred.

R1preferably may represent a hydrogen atom, alkali metal and alkaline earth metal.

Halogen straight or branched C1-C7halogenating groups as R2include fluorine, chlorine, bromine and iodine, where fluorine is preferred is compulsory. R2may contain one or more halogen atoms. When R2contains two or more atoms of halogen, they may be the same or different, preferably identical halogen atoms. In particular, R2preferably represents perhalogenated group. Alkali in the considered straight or branched C1-C7halogenating groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl and n-heptyl. Preferred are straight or branched C1-C4alkali, i.e. methyl, ethyl, n-propyl, isopropyl and n-butyl.

Examples of straight or branched C1-C7perhalogenated group as R2include the above straight or branched C1-C7alkyl groups, provided that they are perhalogenated, preferably perfluorinated. Also preferred are perhalogenated straight or branched C1-C5alkyl group, and a group of the following General formula (9):

in which each of R4and R5that may be the same or different,represent a straight or branched C 1-C3perhalogenated group. Of them are preferred perfluorinated group. More specifically, particularly preferred are performatively group, perforation group, PERFLUORO-n-through the group and PERFLUORO-n-bucilina group.

In the case when R2in the General formula (2) represents a group of General formula (9), examples of straight or branched C1-C3perhalogenated group as R4and R5include the above straight or branched C1-C3alkyl groups, provided that they are perhalogenated, preferably perfluorinated. In addition, perhalogenated C1alkyl groups are preferred and perfluorinated group is particularly preferred. More specifically, performatrin group is preferred.

In the case when R2in the General formula (2) represents a group of General formula (9), R2preferably represents 1,1,1,3,3,3-hexafluoroisopropanol group.

Given the above definition, R2preferably represents perforation group, perfor-n-through the group, PERFLUORO-n-boutelou group and 1,1,1,3,3,3-hexafluoroisopropanol group.

Examples of straight or branched C1-C5alkyl groups, as the use is of this description, include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and 1-ethylpropyl.

Examples of straight or branched C2-C5alkenylphenol group, as used herein, include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl and 3-butenyl.

Examples of straight or branched C2-C5alkenylphenol group, as used herein, include, but are not limited to, ethinyl, PROPYNYL, 1-butynyl, 2-butynyl and 3-butynyl.

Examples of acyl groups, as used herein, include, but are not limited to, alkylcarboxylic groups, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl and phenylacetyl; alkenylamine groups, such as acryloyl, propiolic, methacryloyl, crotonoyl and isocrotonic, and arylcarboxylic gorpy, such as benzoyl.

Examples of straight or branched C1-C7halogenoalkanes group as R21, R22, R23and R24may be the same groups as listed above for R2.

Group And preferably may represent any of the groups having the formulas (3)to(8) and (10)to(23), especially groups with four the uly (3)-(6), (17)-(20) and (23), and more specific groups have the formula (3), (4) and(17)-(20).

m may preferably represent an integer from 4 to 10.

n may preferably represent an integer from 2 to 7.

A group of the General formula (1), which represents one of the connection components according to the present invention has an asymmetric center, while another component may have an asymmetric center. In addition, the compound of General formula (2) according to the present invention may have asymmetric center in the group And in addition to the asymmetric center in the group of the General formula (1). For this reason, the compounds of the present invention are the enantiomers. It is assumed that all individual enantiomers and mixtures thereof are included in the scope of the present invention. When the group having the asymmetric center in the steroid skeleton represented by one of formulas (3), (4) and (17)-(20), a group of the General formula (1) preferably attached to the steroid original frame 7αor 11β-position.

Also in the General formulas (1) and (2) are preferred both compounds with R - and S-configuration of the asymmetric carbon, to which is attached carboxylic acid or its metal salt.

Among the compounds of General formula (2) are preferred are those compounds in which R1represents the atom of water is kind, alkali metal or alkaline earth metal; R2is perforation group, perfor-n-through the group, PERFLUORO-n-boutelou group or 1,1,1,3,3,3-hexafluoroisopropyl group, m represents an integer from 4 to 10 and n represents an integer from 2 to 6.

Compounds of the present invention can be obtained in the form of hydrates.

Pharmaceutically acceptable salts include, but are not limited to, the above metal salts, for example salts of sodium, potassium and calcium.

Compounds according to the present invention can be introduced in the form of a pharmaceutical composition in any dosage form suitable for the intended route of administration, in combination with one or more pharmaceutically acceptable diluents, wetting agents, emulsifiers, dispersing agents, auxiliary agents, preservatives, buffers, binders, stabilizers and the like. Compounds and compositions can be entered parenteral or oral.

The dose of a compound can be determined appropriately in accordance with the physical data, the age and physical condition of the patient, the severity subjected to treatment, the time elapsed after the onset of the disease, etc. Because it is assumed that the connection of the present invention will have substantially the military higher activity in the oral route of administration, it is usually used in an amount of from 0.1 to 500 mg/day when administered orally in an amount of from 0.1 to 1000 mg/day to 0.1-1000 mg/month, parenteral (intravenous, intramuscular or subcutaneous routes of administration) for an adult patient.

The best way of carrying out the invention

The compound of General formula (1), in particular a compound of General formula (2)may be obtained in accordance with any of the following reaction schemes a-K and 1-19. In these schemes reactions And To and 1-19 (i.e. how And To and from 1 to 19) R2, R3, R6, R7, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, m, and n are as defined above for General formula (1) and (2); each of R11, R12, R13and R16represents a protective group; R33is a straight or branched alkyl group; each of Y1, Y2, Y3, Y4, Y5and Y6independently represents a hydrogen atom, alkyl group (e.g. a straight or branched C1-C5alkyl group) or SIG or11; each of L1and L2represents a leaving group; X represents a halogen atom; m1equal to m-2; R8is a straight or branched C1-C5alkyl group, straight or branched C2-C5alkenylphenol group, or p is you or branched C 2-C5alkylamino group.

The compound of the present invention may include various stereoisomers, because it contains one or more asymmetric carbon atoms. To retrieve a single stereoisomer there are two ways, one using chiral column for the separation of mixtures of stereoisomers, and the other includes asymmetric synthesis. Method using chiral columns can be carried out using a column, commercially available from DAICEL, for example, under the trademark CHIRALPAK OT(+), PR(+) or AD, or CHIRALCEL-OA, OB, OJ, OK, OS, OD, OF, or OG. As for asymmetric synthesis, methods 14-16 illustrate the asymmetric synthesis of the compounds of the invention relating to the asymmetric carbon atom to which is attached a side chain carboxyl group.

Reaction scheme A (Method A)

Note. The compound (I) can be synthesized by the method described in J. Org. Chem., 60 (1995) 5316-5318.

The reaction scheme In (a Way)

Note. The compound (XXI) can be synthesized is a procedure, described in German patent DE4218743A1.

Reaction scheme F (Method F)

in which R8is a straight or branched C1-C5alkyl group, straight or branched C2-C5alkenylphenol group or a straight or branched C2-C5alkylamino group and

M represents the metal.

in which R8is a straight or branched C1-C5alkyl group, straight or branched C2-C5alkenylphenol group or a straight or branched C2-C5alkylamino group and

M represents the metal.

in which each of Y1, Y2and Y3independently represents a hydrogen atom, alkyl group (e.g. a straight or branched C1-C5alkyl group) or SIG or11and each of Z1, Z2and Z3independently represents a hydrogen atom, a hydroxyl group or a straight or branched C1-C5alkyl group.

Reaction scheme 13(Method 13)

in which each of Y1, Y2, Y3, Y4, Y5and Y6independently represents a hydrogen atom, alkyl group (e.g. a straight or branched C1-C5alkyl group) or SIG or11and each of Z1, Z2, Z3, Z4, Z5and Z6independently represents a hydrogen atom, a hydroxyl group or a straight or branched C1-C5alkyl group.

Examples of R* include

Examples of R* include

In the above reaction schemes 14 and 15 (the ways 14 and 15) R2, R11, R12, X, m, n, X, L1and L2are as defined above, R* is a chiral auxiliary moiety and m and m3are integers that satisfy the RH is increased by m=m 3+3.

Examples of R* include

[Method]

Method And illustrates the synthesis of compound (VI) from the compound (I). The compound (I) can be synthesized by the method described in J. ORg. Chem., 60 (1995), 5316-5318.

Stage 1: obtain the compound (III)

In the presence of a catalyst, such as benzylidene(tricyclohexylphosphine)dichloroethene, the compound (I) is subjected to interaction with the compound (II) in a solvent (e.g. methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, giving the compound (III).

Stage 2: Obtain the compound (IV)

Using a catalyst (e.g. palladium on activated carbon, palladium hydroxide, platinum oxide or catalyst of Wilkinson (Wilkinson), the compound (III) hydronaut in an inert solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or b is sole) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (IV).

Stage 3: Obtain the compound (V)

When R11is, for example, methyl group, the compound (IV) is treated with acid (e.g. hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or tribromide boron) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, obtaining the compound (V).

Stage 4: obtain the compound (VI)

The compound (V) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g. water, ethanol, methanol or a mixture of water/ethanol, or a mixture of water/methanol) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (VI).

[Method]

As shown below, the compound (VI)obtained by the method And can also be derived from the compound (I) as follows.

Stage 1: obtain the compound (VIII)

In the presence of a catalyst, such as benzylidene(tricyclohexylphosphine)dichloroethene, the compound (I) is subjected to interaction with compound (VII) in a solvent (e.g. methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylether amide) at a temperature in the range from -78° C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (VIII).

Stage 2: obtain the compound (IX)

Using a catalyst (e.g. palladium on activated carbon, palladium hydroxide, platinum oxide or catalyst of Wilkinson (Wilkinson)), the compound (VIII) hydronaut in an inert solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (IX).

Stage 3: obtain the compounds (X)

The compound (IX) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g. water, ethanol, methanol or a mixture of water/ethanol, or a mixture of water/methanol) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (X).

Stage 4: obtain the compound (XI)

In a solvent (e.g. dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of acid (e.g. hydrogen chloride, sulfuric key is lots or p-toluensulfonate acid) compound (X) is heated to a temperature in the range from 50° C to the boiling temperature of the reaction mixture, obtaining the compound (XI).

Stage 5: obtain the compound (VI)

When R11is, for example, methyl group, the compound (XI) is treated with acid (e.g. hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or tribromide boron) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, obtaining the compound (VI).

[Method]

As shown below, the compound (VI)obtained by methods a and b, can also be produced from compound (XII) as follows.

Stage 1: obtain a compound (XIV)

In the presence of a catalyst, such as benzylidene(tricyclohexylphosphine)dichloroethene, the compound (XII) is subjected to interaction with the compound (XIII) in a solvent (e.g. methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (XIV).

Stage 2: Obtain the compound (IV)

The compound (XIV) dehydration acid (e.g. hydrochloric acid, Hydrobromic acid, a mixture of Hydrobromic acid/acetic acid) is inert solvent (for example, methanol, ethanol) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at 50°and further subjected to hydrogenation analogously to method A, obtaining the compound (IV).

Stage 3: obtain the compound (VI)

The compound (IV) is subjected to hydrolysis and removal of the protective groups is similar to methods a or b, obtaining the compound (VI).

[Method D]

As shown below, the compound (VI)obtained by methods a, b and C can also be obtained from compound (XII) as follows.

Stage 1: obtain the compound (XVI)

In the presence of a catalyst, such as benzylidene(tricyclohexylphosphine)dichloroethene, the compound (XII) is subjected to interaction with compound (XV) in a solvent (e.g. methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (XVI).

Stage 2: obtain the compound (XVII)

The compound (XVI) dehydration acid (e.g. hydrochloric acid, Hydrobromic acid, a mixture of Hydrobromic acid/acetic acid) in an inert solvent (for example, methanol is, ethanol) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at 50°and further subjected to hydrogenation analogously to method A, obtaining the compound (XVII).

Stage 3: obtain the compound (VI)

The compound (XVII) is subjected to hydrolysis, decarboxylation, and removing the protective group is similar to methods a or b, obtaining the compound (VI).

The compound (XII)used as starting substances in methods C and D, can be obtained in accordance with the method described in Tetrahedron., 30 (1977), pp.609-616.

[Method E]

Method E illustrates the synthesis of compound (XXIX), based on the compound (XXI).

Stage 1: obtain the compound (XXII)

In the presence of an organic base (e.g. triethylamine or pyridine), the compound (XXI) is treated with acid chloride of acid (for example, methanesulfonamido or p-toluensulfonate) in an inert solvent (e.g. tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in dichloromethane) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at room temperature, turning (CH2)mOH in the compound (XXI), for example (CH2)m-L1where L1is-OH-SO2CH3or-O-SO2 -C6H4-p-CH3. Thus obtained compound is then treated with a metal halide (e.g. sodium iodide or potassium iodide) in an inert solvent (e.g. acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably acetone) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (XXII).

Stage 2: obtain the compound (XXIV)

In the presence of a base (e.g. sodium hydride, sodium hydroxide or tert-butoxide potassium) compound (XXII) is subjected to interaction with malonic ester (XXIII) (for example, diethylmalonate or diethylmalonate) in an inert solvent (e.g. tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, obtaining the compound (XXIV).

Stage 3: obtain the compound (XXVI)

In the presence of a base (e.g. sodium hydride, sodium hydroxide or tert-butoxide potassium) compound (XXIV) is subjected to interaction with the alkyl halide (XXV), in which L2represents a halogen atom, in an inert solvent (e.g. tetrahydrofuran, dioxane, dichloro ethane, the dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, obtaining the compound (XXVI).

Stage 4: obtain the compound (XXVII)

The compound (XXVI) is treated with sodium hydroxide or potassium hydroxide in a solvent (e.g. water, ethanol, methanol, a mixture of water/ethanol or a mixture of water/methanol) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (XXVII).

Stage 5: obtain the compound (XXVIII)

In a solvent (e.g. dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran) and, if necessary, in the presence of acid (e.g. hydrogen chloride, sulfuric acid or p-toluensulfonate acid) compound (XXVII) is heated to a temperature in the range from 50°C to the boiling temperature of the reaction mixture, obtaining the compound (XXVIII).

Step 6: obtain the compound (XXIX)

When R11is, for example, metal group, the compound (XXVIII) is treated with acid (e.g. hydrogen chloride, sulfuric acid, hydrogen bromide, pyridine hydrochloride or tribromide boron) at a temperature in the range from -78°to the temperature CI the value of the reaction mixture, receiving the compound (XXIX).

The compound (XXI), used as the starting material in method E, can be obtained in accordance with the method described in DE421874A1.

[Method F]

The compound (XXIX)obtained by method E, can also be produced from compound (XXII), in accordance with the following stages.

Stage 1: obtain the compound (XXXI)

In the presence of a base (e.g. sodium hydride, sodium hydroxide or tert-butoxide potassium) compound (XXII) is subjected to interaction with the compound (XXX) in an inert solvent (e.g. tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably tetrahydrofuran) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, obtaining the compound (XXXI).

Stage 2: obtain the compound (XXIX)

The compound (XXXI) is converted into a compound (XXIX) in a manner analogous to method E.

[Method G]

Method G illustrates the synthesis of compounds (ILVIII) on the basis of connection (ILI).

Stage 1: Getting connection (ILIII)

In the presence of a base (e.g. sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium hydride, preferably potassium carbonate) compound (ILI) is subjected to interaction with compound (ILII) in an inert solvent (e.g. acetone, methylethylketone, tetrahydrofuran, preferably in acetone) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at room temperature, obtaining the compound (ILIII).

Stage 2: Obtaining connection (ILIV) rearrangement of Clausena

Connection (ILIII) is dissolved in an inert solvent (for example, N,N-dimethylaniline, N,N-diethylaniline, nitrobenzene, dichlorobenzene, dibromobenzene, preferably N,N-dimethylaniline) and then heated to a temperature in the range from 180°C to the boiling temperature of the reaction mixture, preferably from 180 to 200°receiving connection (ILIV).

Stage 3: obtain the compounds (ILV)

In the presence of a base (e.g. triethylamine, diethylethanolamine, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, preferably pyridine) connection (ILIV) is subjected to interaction with Tf2O (anhydride triftormetilfullerenov acid) in an inert solvent (e.g. dichloromethane, chloroform, benzene, toluene, preferably dichloromethane) at a temperature in the range of 0°C to room temperature, obtaining the compound (ILV).

Stage 4: Getting connection (ILVII)

In the presence of palladium or Nickel catalyst connection (ILV) is subjected to interaction with compound (ILVI) in inert is rastvoritele (for example, simple ether, tetrahydrofuran, dioxane, dimethylformamide, water, preferably dioxane) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, obtaining the compound (ILVII).

Stage 5: Receive join (ILVIII)

Connection (ILVII) make a connection (ILVIII) is similar to methods a, b, C or D.

[Method N]

Method H illustrates the synthesis of compound (LIV), based on the compound (LI), synthesized by the method described in U.S. patent 4904661.

Stage 1: obtain the compound (LII)

The compound (LI) is subjected to interaction with the regenerating agent (for example, sociallyengaged, diisobutylaluminium, sodium borohydride) in an inert solvent (e.g. tetrahydrofuran, dioxane, diethyl ether) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0 to 50°receiving the compound (LII).

Stage 2: obtain the compound (LIII)

In the presence of a suitable acid (for example, iodine, zinc, boron TRIFLUORIDE), the compound (LII) is subjected to interaction with allyltrimethylsilane in an inert solvent (e.g. dichloroethane, dichloromethane, chloroform) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, suppose the equipment from 0 to 50° With receiving the compound (LIII).

Stage 3: obtain the compound (LIV)

The compound (LIII) is subjected to the same procedures, methods a, b, C or D, that is, metathesis, restoration, hydrolysis, decarboxylation, removing the protective groups and so on, obtaining the compound (LIV).

[Method I]

The compound (LIV) can also be synthesized as follows, based on the compound (LI).

Stage 1: obtain the compound (LVI)

In the presence of a base (e.g. sodium hydride, n-utility, tert-utility, diisopropylamide lithium,tert-butoxide potassium) compound (LI) is subjected to interaction with compound (LV) in an inert solvent (e.g. tetrahydrofuran, dioxane, diethyl ether) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from -78 to 0°receiving connection (lvis).

Stage 2: obtain the compound (LVII)

In the presence of a suitable acid (for example, iodine, zinc, boron TRIFLUORIDE), the compound (LVI) is subjected to interaction with cyanoborohydride sodium in an inert solvent (e.g. dichloroethane, dichloromethane, chloroform) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0 to 50°receiving the compound (LVII).

Stage 3: obtain the compound (LVIII)

In the presence of a catalyst (for example, pulled the I on the activated carbon, of palladium hydroxide, platinum oxide) compound (LVII) hydronaut in an inert solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at room temperature, obtaining the compound (LVIII). The compound (LVIII) can be directly obtained from the compound (LVI) by hydrogenation using a catalyst (e.g. palladium on activated carbon, palladium hydroxide, platinum oxide) in an inert solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, preferably tetrahydrofuran, ethyl acetate) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at room temperature.

Stage 4: obtain the compound (LIV)

The compound (LVIII) is subjected to interaction in accordance with the methodology methods E or F, obtaining the compound (LIV).

[Method J]

Method J illustrates the synthesis of compound (LXII), based on the compound (LIX).

Stage 1: obtain the compound (LXI)

In the presence of a base (e.g. sodium hydride, n-utility, tert-butoxide potassium) compound (LIX) is subjected to interaction with the compound (LX) in an inert solvent(for example, dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethylsulfoxide) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0 to 50°receiving the compound (LXI).

Stage 2: obtain the compound (LXII)

The compound (LXIV) is subjected to metathesis, restoration, hydrolysis and removal of the protective groups is similar to the technique of the methods a, b, C or D, obtaining the compound (LXII).

[How To]

The compound (LXII) can also be produced from compound (LIX), as follows.

In the presence of a base (e.g. sodium hydride, n-utility, tert-butoxide potassium) compound (LIX) is subjected to interaction with the compound (LXIII) in an inert solvent (e.g. dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethylsulfoxide) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0 to 50°receiving the compound (LXIV).

Stage 2: obtain the compound (LXII)

The compound (LXIV) is subjected to interaction is similar to the technique of the ways E or F, obtaining the compound (LXII).

The compound of General formula (2), in which a group represented by the formula (8)can be obtained, for example, as shown in examples 6-10, the same or equivalent manner.

[Method 1]

Connection 2 receive, on the basis of the connection is s 1, similarly to the technique of the way that Compound 1 used as starting substances can be obtained in accordance with the method described in WO 99/64393.

[Method 2]

Connection 4 get on the basis of connections 3, similarly to the technique of the method means that the Compound 5 can be obtained by oxidation of compound 4 in accordance with the method described in WO 99/64393. Compound 3 used as starting substances can be obtained in accordance with the method described in WO 99/64393.

[Method 3]

Method 3 illustrates the synthesis of compound (9), on the basis of the connection 6. The connection 6, is used as the starting material can be synthesized, for example, by methods described in J. Org. Chem., 50(1985), 2121-2123, and J. Org. Chem., 61 (1996), 3890-3893.

Stage 1: Getting connection 8

In the presence of a base (e.g. sodium hydride, n-utility, tert-butoxide potassium) compound 6 is subjected to interaction with compound 7 in an inert solvent (e.g. dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethylsulfoxide) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0 to 50°receiving the connection 8.

Stage 2: Obtaining the compound (9)

Compound 8 is subjected to interaction is similar to the technique of the way E receives the connection 9.

[Method 4]

With whom persons 4 illustrates the synthesis of compounds 20, on the basis of the connection 10.

Stage 1: obtain the compound (11)

In the presence of an acid catalyst such as sulfuric acid, compound 10 is heated in alcohol (e.g. methanol, ethanol) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, receiving the connection 11.

Stage 2: Getting connection 12

Amino and hydroxyl groups of compound (11) obtained in stage 1, protect, receiving the connection 12.

Stage 3: Getting connection 13

Compound 12 is treated regenerating agent (e.g. lithium borohydride, etc.) in a solvent (e.g. methanol, ethanol or a mixture of ethanol/ tetrahydrofuran) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at room temperature, receiving the connection 13.

Stage 4: Getting connection 15

The connection 13 is subjected to the reaction of Mitsunobu connection 14, when receiving the connection 15.

Stage 5: Getting connection 16

The connection 15 is subjected to removal of the protection of an amino group, receiving the connection 16.

Step 6: Obtain compound 17

In the presence of a base (e.g. potassium carbonate, tert-butoxide potassium tert-butoxide sodium) connection 16 is subjected to interaction by adding metal catalysate is RA, such as palladium, together with a ligand, such as diphenylphosphinite or 2,2-bis(diphenylphosphino)-1,1'-binaphthyl, preferably by adding the catalyst Tris(dibenzylideneacetone)dipalladium together with 2,2-bis(diphenylphosphino)-1,1'-binaphtyl, in an inert solvent (e.g. benzene, toluene, xylene, dioxane or tetrahydrofuran) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at 100°receiving a connection 17.

Stage 7: the connection 19

In the presence of a base (e.g. sodium hydride, n-utility, tert-butoxide potassium, potassium carbonate) and, optionally, with the addition of the reagent, such as sodium iodide, compound 17 is subjected to interaction with the connection 18 in an inert solvent (e.g. dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, dimethyl sulfoxide, acetone) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, receiving the connection 19.

Step 8: Getting connection 20

Compound 19 is subjected to interaction similar to methods a or b, when receiving the connection 20.

[Method 5]

Method 5 illustrates the synthesis of compounds 27, based on the connection 21.

Stage 1: Obtaining compounds 23

Connection 21 is subjected to protection is using TBS,then subjected to the interaction with the aldehyde 22 and then protect its amino group, receiving a connection 23.

Stage 2: Obtaining compounds 25

Compound 23 obtained in stage 1, alkylate compound 24, receiving the connection 25.

Stage 3: Getting connection 26

The connection 25 is subjected to removal of the protection of the amino group and then treated regenerating agent (for example, sociallyengaged etc) in a solvent (e.g. tetrahydrofuran, simple ether) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at room temperature, receiving a connection 26.

Stage 4: Getting connection 27

The connection 26 is subjected to interaction is similar to mode 4, when receiving the connection 27.

[Method 6]

Method 6 illustrates the synthesis of compound 35, based on the connection 28.

The connection 35 can be synthesized on the basis of the connection 28, as follows.

Stage 1: Getting connection 29

The connection 29 is produced from compound 28 by the method described in Synthesis, 12 (1995), 1493-1495, or an equivalent method.

Stage 2: Getting connection 32

In the presence of a base (for example, hexamethyldisilazide lithium hexamethyldisilazide sodium, hexamethyldisilazide potassium, sodium hydride, n-utility, tert-utility, diisopropylamide lithium, tert-butoxide potassium, aqueous potassium hydroxide, aqueous sodium hydroxide) compound 29 is subjected cooperation is to work with connection 30 or 31 in an inert solvent (for example, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, tert-butyllithium ether, diethyl ether, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, toluene) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from -78 to 0°receiving a connection 32.

Stage 3: Getting connection 33

The connection 32 will isomerized in basic conditions (for example, in a mixture of tetrabutylammonium fluoride/tetrahydrofuran, sodium methoxide/methanol, ethoxide sodium/ethanol, potassium methoxide/methanol, sodium methoxide/propanol, aqueous potassium hydroxide, aqueous sodium hydroxide), followed by removing the protecting group R12and purification by recrystallization, receiving individual isomer of formula 33. In the case when R12represents tert-butyldimethylsilyloxy group, the connection 32 will someresult simultaneously with the removal of TBS in the processing of tetrabutylammonium fluoride and further purified by recrystallization, receiving individual isomer of formula 33.

Stage 4: Getting connection 34

In the presence of a suitable acid (for example, triperoxonane acid, epirate boron TRIFLUORIDE, titanium tetrachloride, aluminium chloride, triftormetilfullerenov acid, hydrochloric acid, sulfuric acid), compound 33 is subjected to interaction with triethylsilane in an inert solvent (for example, Dahl is retana, dichloromethane, chloroform, tert-butyllithium ether, toluene) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably from 0°C to room temperature, receiving a connection 34.

Stage 5: Getting connection 35

The connection 34 is subjected to interaction similar to methods a or b, when receiving the connection 35.

[Method 7]

Method 7 illustrates the synthesis of compound 38, based on the connection 36.

Compound 38 can be synthesized on the basis of the connection 37, similarly to the procedure of method 3. Compounds 36 and 37, which are used as starting substances can be synthesized by methods described in J. Med. Chem., 40 (1997), 2117-2122, and J. Med. Chem., 33 (1990), 3222-3229, or equivalent methods.

[Method 8]

Method 8 illustrates the synthesis of compounds 40, based on the connection 39.

The connection 40 may be synthesized on the basis of the connection 39, similarly to the procedure of method 3. The connection 39 to be used as the starting material can be synthesized, for example, by the methods described in ERA and J. Org. Chem., 60 (1995), 739-741.

[Method 9]

Connection 42 or 43 can be synthesized as follows.

The connection 42 can be synthesized from compound 41 oxidation by Jones (Jones), PCC oxidation, oxidation will Roll (Swern) or ruthenium oxidation (for example, TRAR) 17-hydroxyl gr is PPI. The connection 42 is further subjected to interaction with R8-M, where R8represents a lower alkyl group or lower alkenylphenol group, or a lower alkylamino group, and M represents a metal, such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g. dimethyl sulfoxide, tetrahydrofuran, simple ether, dimethylformamide) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from 0°C to room temperature, receiving a connection 43.

The connection 41, used as the starting material can be synthesized by methods E, F, or 6.

[Method 10]

Connection 45 or 46 can be synthesized as follows.

Compound 45 can be synthesized from compound 44 oxidation by Jones (Jones), PCC oxidation, oxidation will Roll (Swern) or ruthenium oxidation (for example, TRAR) 17-hydroxyl group. The connection 45 is further subjected to interaction with R8-M, where R8represents a lower alkyl group or lower alkenylphenol group, or a lower alkylamino group, and M represents a metal, such as lithium, sodium, potassium, magnesium, calcium or aluminum, in an inert solvent (e.g. dimethyl sulfoxide, tetrahydrofuran, simple ether, dimethylformamide) at a temperature in the range from -78°to pace the atmospheric temperature of the boiling point of the reaction mixture, preferably from 0°C to room temperature, receiving the connection 46.

The connection 44 to be used as the starting material can be synthesized by methods a, b, C or D.

[Method 11]

Connection 53 may be synthesized as follows.

Compound 47 is subjected to protection of hydroxyl groups, and then oxidize between 9 and 11-positions with DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) and the like, receiving a connection 48.

The connection 48 is converted into a connection 49 with a method described in J. Org. Chem., 1995, 60, 5316-5318.

The connection 49 is subjected to oxidation in Turn, the oxidation Jones, PCC oxidation or ruthenium oxidation (for example, TRAR), receiving the connection 50.

The connection 50 is subjected to interaction with the ORGANOMETALLIC reagent (e.g., allylaminogeldanamycin) in an inert solvent (e.g. tetrahydrofuran, simple ether) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from -48°C to room temperature, receiving the connection 51.

The connection 51 dehydration removal of its hydroxyl groups with a mixture of chloride thionyl/pyridine and the like, receiving a connection 52.

The connection 52 can be converted to compound 53 by methods a, b, C or D.

[Method 12]

The connection 55 may b is to be synthesized, exposing the connection 54 reactions, similarly to the procedure of method 3. The connection 54 can be synthesized according to described methods (Drugs of the Future, 1978, 3, 211 to 215; J. Med. Chem., 1967, 10,78-84; J. Med. Chem.,1998, 41, 2928-2931).

[Method 13]

The connection 56 can be converted to compound 57 using the following steps: 1) 1,2-addition X-Mg-(CH2)mOR12, 2) dehydration, 3) restore and 4) unprotect (R12), and then introducing into the reaction, similarly to scheme E, giving the connection 58.

[Method 14]

In the presence of a catalyst, such as benzylidene(tricyclohexylphosphine)dichloroethene, the connection 59 is subjected to interaction with chiral olefin 60 in a solvent (e.g. methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethyl sulfoxide or dimethylformamide) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably at the boiling temperature of the reaction mixture, giving a connection 61. The connection 61 is then subjected to the following reactions, in this order: (a) recovery, unprotect and hydrolysis, or (b) recovery of hydrolysis and removal of protection, receiving the connection 62.

(a) Recovery, unprotect and hydrolysis

1) Restore

In the presence of a catalyst (e.g. palladium on activated carbon, is hydroxide palladium, oxide or platinum catalyst of Wilkinson) connection 61 hydronaut in an inert solvent (e.g. methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably at room temperature, to obtain the product recovery

2) Removing protection

Then carry out the removal of the protection of phenolic hydroxyl groups with obtaining an unsecured product.

3) Hydrolysis

As an example, if R* represents a group of formula 63, the product after removal of the protection is additionally treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (for example, a mixture of tetrahydrofuran/water mixture of diethyl ether/water mixture of dioxane/water mixture dimethoxyethane/water, methanol/water mixtures of ethanol/water) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at room temperature, receiving a connection 62.

(b) Restoring, hydrolysis and removal of protection

1) Restore

In the presence of a catalyst (e.g. palladium on activated carbon, palladium hydroxide, platinum oxide or rolled atora of Wilkinson) connection 61 hydronaut in an inert solvent (for example, methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane or benzene) at a temperature in the range of 0°C to the boiling temperature of the reaction mixture, preferably at room temperature, with product recovery.

2) Hydrolysis

As an example, if R* represents a group of formula 63, the product is further treated with lithium hydroxide, sodium hydroxide, lithium hydroxide plus hydrogen peroxide, sodium hydroxide plus hydrogen peroxide or tetrabutylammonium hydroxide plus hydrogen peroxide in a solvent (for example, a mixture of tetrahydrofuran/water mixture of diethyl ether/water mixture of dioxane/water mixture dimethoxyethane/water, methanol/water mixtures of ethanol/water) at a temperature in the range from room temperature to the boiling temperature of the reaction mixture, preferably at room temperature, receiving carboxylic acid.

3) Removing protection

Then carry out the removal of the protection of phenolic hydroxyl group, receiving the connection 62.

Chiral olefin of formula 60 used in the method above, can be obtained as shown in reaction scheme 15.

[Method 15]

[Synthesis of chiral olefin]

In the presence of a base (for example, diisopropylamide lithium hexamethyldisilazide lithium hexamethyldisilazide sodium, utility), NMRA connection 67 is subjected to the interaction with R 2(CH2)n-L1in an inert solvent (e.g. tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from -30°C to room temperature, receiving a connection 60.

Chiral olefin 60 also can be synthesized as follows.

In the presence of a base (for example, diisopropylamide lithium hexamethyldisilazide lithium hexamethyldisilazide sodium, utility), NMRA connection 67 is subjected to interaction with the connection 69 in an inert solvent (e.g. tetrahydrofuran, toluene, diethyl ether, hexane, preferably tetrahydrofuran) at a temperature in the range from -78°C to the boiling temperature of the reaction mixture, preferably from -30°C to room temperature, receiving a connection 60.

[Method 16]

The connection 70 can be converted to compound 73 is similar to the technique of the way 14.

[Method 17]

Connection 75 with the substituents R21, R22, R23and R24in its benzene ring, can be converted to compound 77 using a technique similar to the method of G. Each of R21, R22, R23and R14independently represents a hydrogen atom, a straight or branched C1-C5 alkyl group, a straight or branched C1-C7halogenating group, halogen atom or acyl group.

[Method 18]

The connection 78 is subjected to interaction with the connection 79 in the presence of a base, receiving the connection 80. Connection 81 may be synthesized from compound 80 in accordance with methods 3 and K.

[Method 19]

The connection 82, synthesized according to the method described in J. Med. Chem., 1057 (1984), is subjected to reaction Friedel-connection 83, and then treated in accordance with method 3.

Examples

The present invention is more specifically explained by the following examples. However, it should be understood that the present invention is not limited in any way by these examples. In order to explain the effectiveness of the compounds according to the present invention, illustrative compounds were tested for their anti-estrogenic activity in the example below tests. Table 1 shows the chemical structures obtained in examples of the compounds.

Table 1
Example No.Chemical structure
3
4
5
6
7

8
9
10
11
12
13
14
15
16
17
18
19

20
21
22
23
24
25
26
27
28
29
30
31
32

33
34
35
36
37
38
39

Example 1

Synthesis of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene

(Stage 1)

6-Methoxy-2-naphthol (22.1 g, 127,0 mmol) was dissolved in acetone (200 ml). To the obtained restoratively potassium carbonate (70,2 g, 508,0 mmol) and allyl bromide (16.5 ml, 191,0 mmol) followed by stirring for 2 days at room temperature. After filtration of the reaction mixture, the organic solvent drove away under reduced pressure. To the residue was added water, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic solvent again drove, getting 6-methoxy-2-(2-propenyloxy)naphthalene (24,9 g, yield 91%) as a crude product.

1H-NMR (270 MHz, Dl3): δ 7,66-of 7.60 (m, 2H, Ar-H), 7.18 in-7,10 (m, 4H, Ar-H), 6,20-6,05 (m, 1H, CH2=CHCH2-), the 5.45 (DD, J=18,8, 1.3 Hz, 1H, CH2=SNSN2-), 5,31 (DD, J=10,5, 1.3 Hz, 1H, CH2=SNSN2-), to 4.62 (d, J=5.3 Hz, 2H, CH2=SNSN2-), 3,90 (s, 3H, -och3).

(Stage 2)

6-Methoxy-2-(2-propenyloxy)naphthalene (24,9 g to 116.2 mmol) was dissolved in N,N-dimethylaniline (100 ml) followed by heating at boiling under reflux for 15 hours. After distillation of the organic solvent under reduced pressure the residue was added 2 N. aqueous hydrochloric acid, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent the mod is to purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/4) followed by recrystallization from a mixture of ethyl acetate/ hexane, getting 6-methoxy-1-(2-propenyl)-2-naphthol (20,3 g, yield 82%).

1H-NMR (270 MHz, Dl3): δ 7,80 (d, J=9,3 Hz, 1H, Ar-H), 7,56 (d, J=8,9 Hz, 1H, Ar-H), 7,16 (DD, J=9,3, 2.7 Hz, 1H, Ar-H), 7,11 (d, J=2.7 Hz, 1H, Ar-H), 7,07 (d, J=8,9 Hz, 1H, Ar-H), 6,13 is 5.98 (m, 1H, CH2=CHCH2-), 5,10 (DD, J=10,0, 1.3 Hz, 1H, CH2=CHCH2-), 5,04 (DD, J=17,5, 1.3 Hz, 1H, CH2=CHCH2-), is 4.93 (s, 1H, -OH), 3,90 (s, 3H, -och3). with 3.79 (d, J=5,9 Hz, 2H, CH2=CHCH2-).

(Stage 3)

6-Methoxy-1-(2-propenyl)-2-naphthol (18,77 g of 87.6 mmol) was dissolved in dichloromethane (300 ml). To this solution was added dropwise at 0°and pyridine (21,3 ml, 262,8 mmol) and the anhydride triftormetilfullerenov acid (22,1 ml, to 131.4 mmol) and the resulting mixture was stirred for 30 minutes. After completion of the reaction, to the reaction mixture was added water at 0°With, then was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After removal of the solvent,the residue was purified column chromatography on silica gel (eluent: ethyl acetate: hexane=1/9)to give 6-methoxy-1-(2-propenyl)-2-afterdepolarisations (30,8 g, yield 100%).

1H-NMR (270 MHz, Dl3): δ to 7.95 (d, J=9,3 Hz, 1H, Ar-H), of 7.69 (d, J=8,9 Hz, 1H, Ar-H), 7,35 (d, J=8,9 Hz, 1H, Ar-H), 7,25 (DD, J=9,3, 2.7 Hz, 1H, Ar-H), 7,17 (d, J=2.7 Hz, 1H, Ar-H), 6,07-5,04 (m, 1H, CH2SNSN 2-), 5,10 (DD, J=10,0, 1.3 Hz, 1H, CH2=SNSN2-), 5,02 (DD, J=17,2, 1.3 Hz, 1H, CH2=CHCH2-), 3,93 (s, 3H, -och3), the 3.89 (d, J=5.6 Hz, 2H, CH2=CHCH2-).

(Stage 4)

4-Methoxyphenylalanine acid (10,15 g, to 66.8 mmol), hydrate tribalista (77,6 g, 278,3 mmol) and tetrakis(triphenylphosphine)palladium(0) (1,93 g, 1,67 mmol, 3 mol.%) was added to a solution of 6-methoxy-1-(2-propenyl)-2-aftertreatment (19.3 g, 55,66 mmol) in dioxane (300 ml) followed by heating at boiling under reflux for 8 hours in an argon atmosphere. To the reaction mixture was added water, then was extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/9) followed by recrystallization from hexane, getting 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (12,65 g, 75%yield).

1H-NMR (270 MHz, Dl3): δ to 7.95 (d, J=9.8 Hz, 1H, Ar-H), the 7.65 (d, J=8.5 Hz, 1H, Ar-H), 7,35 (d, J=8,9 Hz, 1H, Ar-H), 7,34-7,16 (m, 4H, Ar-H), of 6.96 (d, J=8.6 Hz, 2H, Ar-H), 6,16-of 6.02 (m, 1H, CH2=SNSN2-), is 5.06 (DD, J=10,2, and 1.6 Hz, 1H, CH2=SNSN2), a 4.83 (DD, J=17,2, and 1.6 Hz, 1H, CH2=SNSN2-), of 3.94 (s, 3H, -och3), a 3.87 (s, 3H, -och3), to 3.73 (d, J=5.3 Hz, 2H, CH2=SNSN2-).

Example 2

inches diethyl-2-(5-hexenyl)-2-(4,4,5,5,5-pentafluorophenyl)malonate

A solution of diethyl-2-(4,4,5,5,5-pentafluorophenyl)malonate (4.0 g, 12.5 mmol) in dimethyl sulfoxide (30 ml) was cooled to 10°C. To this solution was added 60% sodium hydride (600 mg, 15 mmol) and the resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was slowly added dropwise 6-bromo-1-hexene (2.5 ml, of 18.75 mmol) followed by stirring for 3 hours at room temperature. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/9)to give diethyl-2-(5-hexenyl)-2-(4,4,5,5,5-pentafluorophenyl)malonate (3,86 g, yield 77%).

1H-NMR (270 MHz, Dl3): δ of 5.82-5,72 (m, 1H, -CH=CH2), 5,02 to 4.92 (m, 2H, -CH=CH2), 4,19 (kV, J=7,3 Hz, 4H, -CO2CH2CH2), 2,10-to 1.86 (m, 8H), 1,53 is 1.34 (m, 6N), of 1.26 (t, J=7,3 Hz, 6H, -CO2CH2CH3).

Example 3

Synthesis of 9-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)nonanalog acid

(Stage 1)

Diethyl-2-(5-hexenyl)-2-(4,4,5,5,5-pentafluorophenyl)malonate obtained in example 2 (1,83 g, 4,55 mmol) and benzylidene(tricyclo xilofon)dichloroethene (94 mg, 0.11 mmol) was added to a solution of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (692 mg, 2.28 mmol) in dichloromethane (10 ml), followed by heating at boiling under reflux for 20 hours in an argon atmosphere. After removal of the solvent the residue was purified column flash chromatography on silica gel (eluent: hexane/ethyl acetate=10/1)to give the target olefin (1.8 g) as a mixture of CIS - and TRANS-forms and dimer side chain. This mixture was dissolved in ethyl acetate (20 ml) and the resulting solution was added 10% palladium-on-carbon (236 mg), followed by stirring for 2 hours at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration and the solvent drove away under reduced pressure. The residue was purified column flash chromatography on silica gel (eluent: hexane/ethyl acetate=4/1)to give diethyl-2-[7-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]heptyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (of 1.05 g, yield 68%).

1H-NMR (270 MHz, Dl3): δ of 7.96 (d, J=9,3 Hz, 1H, Ar-H), to 7.59 (d, J=8,2 Hz, 1H, Ar-H), 7,30-7,21 (m, 4H, Ar-H), 7.18 in-to 7.15 (m, 1H, Ar-H), 6,97 (d, J=8.6 Hz, 2H, Ar-H), 4,18 (kV, J=7,0 Hz, 4H, -CO2CH2CH2), of 3.94 (s, 3H, -och3), 3,88 (s, 3H, -och3), 2,97-only 2.91 (m, 2H, naphthyl-CH2-), 2,09-2,03 (m, 2H, -CH2CF3), 1,99-to 1.82 (m, 4H, alkyl-H), 1,55-of 1.45 (m, 6N, alkyl-H)of 1.23 (t, J=7,0 Hz, 6N, -CO2CH2CH3), 1,10-1,04 (m, 6N, alkyl-H).

(Stage 2)

Diethyl-2-[7-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]heptyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (1,02 g, 1.5 mmol) was dissolved in ethanol (10 ml). To this solution was added sodium hydroxide (1.2 g, 30 mmol) and water (1 ml) and the resulting mixture was heated at the boil under reflux for 3 hours. Diluted hydrochloric acid was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent drove, getting 2-[7-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]heptyl]-2-(4,4,5,5,5-pentafluorophenyl)malonic acid (1.0 g).

Then, the obtained 2-[7-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]heptyl]-2-(4,4,5,5,5-pentafluorophenyl)malonic acid (1.0 g) was dissolved in dimethyl sulfoxide (10 ml) and the mixture was heated for 4 hours at 120°C. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1)to give 9-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)nonanoyl acid (820 mg, yield 94%).

1H-NMR (270 MHz, Dl3): δ of 7.97 (d, J=8,9 Hz, 1H, Ar-H), to 7.59 (who, J=8,2 Hz, 1H, Ar-H), 7,30-7,21 (m, 4H, Ar-H), 7.18 in-to 7.15 (m, 1H, Ar-H), 6,97 (d, J=8.6 Hz, 2H, Ar-H), of 3.94 (s, 3H, och3), 3,88 (s, 3H, -och3), 2,97-only 2.91 (m, 2H, naphthyl-CH2-), 2,38 to 2.35 (m, 1H, -CHCO2), 2,09-of 1.94 (m, 2H, -CH2CF2), 1,73-of 1.41 (m, 8H, alkyl-H), 1,29-of 1.18 (m, 8H, alkyl-H).

(Stage 3)

The solution trichromate boron in dichloromethane (1.0 M, 8.5 ml of 8.47 mmol) was added dropwise to a solution of 9-[6-methoxy-2-(4-methoxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl) nonanalog acid (820 mg, of 1.41 mmol) in dichloromethane (20 ml) at -78°C in argon atmosphere. The reaction mixture was heated with stirring to 0°C for 5 hours. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=3/2) and subsequent column chromatography on silica gel with reversed phase RP-18 (eluent: acetonitrile containing 0.1% triperoxonane acid/water=3/2)to give 9-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)nonanoyl acid (633 mg, yield 81%).

1H-NMR (270 MHz, Dl3): δ to 7.93 (d, J=9.9 Hz, 1H, Ar-H), 7,47 (d, J=8,2 Hz, 1H, Ar-H), 7.18 in-7,11 (m, 5H, Ar-H), 6,85 (d, J=9,3 Hz, 2H, Ar-H), 2,97-only 2.91 (m, 2H, naphthyl-CH2-), 2,34-to 2.29 (m, 1H, -CHCO2), 2,20-1,99 (m, 2H, -CH2CF2), 1,62-of 1.41 (m, 6N, alkyl-H), 1,27-of 1.18 (m, 10H, alkyl-H).

Example 4

Synthesis of 11-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoic acid

Repeating the same methods as described in examples 1, 2 and 3, receiving 11-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoyl acid.

1H-NMR (270 MHz, Dl3): δ 7,98 (d, 1H), 7,54 (d, 1H), 7,33-7,03 (m, 5H), to 6.88 (d, 2H), with 2.93 (t, 2H), 2,5 (m, 1H), 2,2-1,0 (m, 22N).

Example 5

Synthesis of 10-[(1RS, 2RS)-6-hydroxy-2-(4-hydroxyphenyl)-2 methyl-1,2,3,4-tetrahydro-1-naphthyl]-2-(4,4,5,5,5-pentafluorophenyl)decanoas acid

(Stage 1)

6-Methoxy-2-(4-methoxyphenyl)-2-methyl-1,2,3,4-tetrahydronaphthalen-1-it was synthesized by the method described in U.S. patent No. 4904661. A solution of this compound (1.5 g, 5.1 mmol)dissolved in anhydrous tetrahydrofuran (25 ml)was added dropwise to a solution of sociallyengaged in anhydrous tetrahydrofuran (1M in THF, 2.6 ml, 2.6 mmol) at -78°C in argon atmosphere. The reaction was conducted for 1.5 hours. Then the reaction mixture was slowly heated to room temperature and was stirred for 8 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate. The organic layer industry is Ali saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then evaporated, removing the solvent. The obtained residue was dissolved in 1,2-dichloroethane (35 ml). To this solution was added at 0°in argon atmosphere modesty zinc (2,02 g of 6.31 mmol) and allyltrimethylsilane (1,67 ml, 10,52 mmol) and the resulting mixture was stirred for 12 hours at room temperature. To the reaction mixture was added water, then was extracted with dichloromethane. The organic layer was washed saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column flash chromatography on silica gel (eluent: hexane/ethyl acetate=60/1)to give (1RS,2RS)-6-methoxy-2-(4-methoxyphenyl)-2-methyl-1-(2-propenyl)-1,2,3,4-tetrahydronaphthalen (1.27 g, yield 78%).

1H-NMR (270 MHz, Dl3): δ 7,31 (d, 2H, J=7.5 Hz), 6,97 (d, 1H, J=7.9 Hz), to 6.88 (d, 2H, J=8.7 Hz), 6,68-of 6.65 (m, 2H), of 5.53 (m, 1H), 4,76-of 4.57 (m, 2H), 3,81 (s, 3H), of 3.78 (s, 3H), 2,99-2,78 (m, 2H), 2,81 (m, 1H), 2,28 (m, 1H), 1,98-of 1.92 (m, 2H), 1,71 (m, 1H), 1,17 (s, 3H).

(Stage 2)

Thus obtained (1RS, 2RS)-6-methoxy-2-(4-methoxyphenyl)-2-methyl-1-(2-propenyl)-1,2,3,4-tetrahydronaphthalen turned in 10-[(1RS, 2RS)-6-hydroxy-2-(4-hydroxyphenyl)-2-methyl-1,2,3,4-tetrahydro-1-naphthyl]-2-(4,4,5,5,5-Penta is tormentil)dekanovu acid method, similar to example 3.

1H-NMR (300 MHz, Dl3): δ of 7.23 (d, 2H, J=7.5 Hz), 6.90 to (d, 1H, J=7.9 Hz), to 6.80 (d, 2H, J=8.7 Hz), to 6.58 (m, 2H), 2,90 (m, 2H), 2,60 (d, 1H, J=8.7 Hz), is 2.37 (m, 1H), 2,22 (m, 1H), 2,02 (m, 2H), 1,87 (m, 1H), 1,37-1,75 (m, 6N), 0,86-of 1.26 (m, 17H).

Mass spectrum (ESI): 585 (M+1).

Example 6

Synthesis of 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)caronel]phenoxy]pentyl]-6,6,7,7,7-pentafluorophenol acid

(Stage 1)

4-Methoxybenzoic acid (450 mg, 2,96 mmol), chloride thionyl (3 ml, 44.4 mmol) and anhydrous dimethylformamide (1 drop) was added to the anhydrous chloroform (10 ml), the mixture was heated at the boil under reflux for 3 hours in an argon atmosphere and then cooled to room temperature. Then the reaction mixture was concentrated under reduced pressure, the residue was dissolved in anhydrous dichloromethane and was added to the resulting solution of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (760 mg, 2.8 mmol), synthesized by the method described in J. Med. Chem. 1057 (1984), and aluminum chloride (2.37 g, 17,76 mmol) followed by stirring for 4 hours at room temperature. In order to stop the reaction, was added tetrahydrofuran and ice and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over betwedn the m magnesium sulfate. After removal of the solvent, the filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: dichloromethane/hexane=1/1)to give [6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-yl](4-methoxyphenyl)methanon (405 mg, yield 39%) as a yellow oil.

1H-NMR (270 MHz, Dl3): δ 7,80 to 7.75 (m, 2H), 7,52 (d, 1H, J=8.6 Hz), 7,37-7,28 (m, 3H), 6,95 (DD, 1H, J1=a 8.9 Hz, J2=2.2 Hz), 6,78-6,74 (m, 4H), 3,91 (s, 3H), 3,85 (s, 3H), of 3.77 (s, 3H).

(Stage 2)

[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-yl]-(4-methoxyphenyl)methanon (410 mg, of 1.02 mmol) was dissolved in anhydrous dimethylformamide (15 ml) and was added to the obtained solution attentionat sodium (170 mg, 2.04 mmol), followed by stirring for 1.5 hours at a temperature of from 90 to 100°C in argon atmosphere. The reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After removal of the solvent the residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1)to give (4-hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-yl]metano (323 mg, yield of 81.6%) as a yellow oil.

1H-NMR (300 MHz, Dl3 ): δ of 7.70 (d, 2H, J=9,0), 7,51 (d, 1H, J=8,7), 7,33-7,26 (m, 3H), 6,95 (DD, 1H, J1=a 8.9 Hz, J2=2,6 Hz), 6.75 in-6,65 (m, 4H), a 3.87 (s, 3H), and 3.72 (s, 3H).

(Stage 3)

Diethyl-2-(4,4,5,5,5-pentafluorophenyl)malonate (3 g, 9,37 mmol) was dissolved in dimethyl sulfoxide (20 ml) and the resulting solution was added sodium hydride (60%, 525 mg, 13,11 mmol) followed by stirring for 1 hour at room temperature. To the reaction mixture were added 5-bromo-1-chloropentane (7,4 ml, 56.2 mmol), followed by stirring for 1.5 hours at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: dichloromethane/hexane=1/4)to give diethyl-2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluorophenyl)malonate (3.3 g, yield 83%) as a colourless oil.

1H-NMR (300 MHz, Dl3): δ to 4.14 (q, 4H, J=7,1 Hz), 3.46 in (t, 2H, J=6,7 Hz), 2.06 to of 1.64 (m, 8H), 1,50-of 1.36 (m, 4H), 1,24-1,10 (m, 2H), 1,21 (t, 6N, J=7,1 Hz).

(4-Hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-yl]metano (1 g, 2.56 mmol) was dissolved in dimethylformamide (15 ml) and was added to the obtained solution of sodium hydride (60%, 143 is g, 3,59 mmol) followed by stirring for 1 hour at room temperature.

To the reaction mixture were added diethyl-2-(5-chloropentyl)-2-(4,4,5,5,5-pentafluorophenyl)malonate (1.85 g, 4.35 mmol), sodium iodide (769 mg, 5,13 mmol) and tetrabutylammonium iodide (189 mg, 0.51 mmol) followed by stirring for 24 hours at 60°C. Then the reaction mixture was cooled to room temperature, to the reaction mixture were added saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane = 1/9)to give diethyl-2-[5-[4-[(6-methoxy-2-(4-methoxyphenyl) benzo[b]thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (1.4 g, yield 70%) as a yellow oil.

1H-NMR (300 MHz, CDCl3): δ 7,73 (d, 2H, J=9.1 Hz), of 7.48 (d, 1H, J=8.5 Hz), 7,32 (d, 2H, J=8.6 Hz), 7,27 (d, 1H, J=2.3 Hz), 6,91 (DD, 1H, J1=8,8 Hz, J2=2.3 Hz), 6,74 is 6.67 (m, 4H), to 4.15 (q, 4H, J=7,1 Hz), 3,88 (t, 2H, J=6.3 Hz), 3,83 (s, 3H), 3,70 (s, 3H), 2,08-to 1.82 (m, 6N), a 1.75-1,71 (m, 2H), 1,53 to 1.37 (m, 6N), to 1.21 (t, 6N, J=7,1 Hz).

(Stage 5)

Diethyl-2-[5-[4-[(6-methoxy-2-(4-methoxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (1,58 g, 2.03 mmol) was dissolved in dichlor the Tanya (40 ml) and was added to the obtained solution of aluminium chloride (1,62 g, 12.2 mmol) and ethanthiol (0.25 ml, 10,15 mmol) followed by stirring for 1.5 hours at room temperature. Then the reaction mixture was cooled to 0°C, was slowly added tetrahydrofuran (30 ml), then was diluted with water and extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/2)to give diethyl-2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (1.2 g, yield 79%) as a brown foam.

1H-NMR (300 MHz, Dl3): δ 7,73 (d, 2H, J=9.1 Hz), 7,38 (d, 1H, J=8.6 Hz), 7,18 (d, 1H, J=2.3 Hz), 7,14 (d, 2H, J=8.6 Hz), 6,79 (DD, 1H, J1=8.6 Hz, J2=2.3 Hz), 6,72 (d, 2H, J=9.1 Hz), to 6.57 (d, 2H, J=8.6 Hz), 4,17 (q, 4H, J=7,2 Hz), 3,91 (t, 2H, J=6,1 Hz), 2,10-of 1.78 (m, 6N), 1,74 by 1.68 (m, 2H), 1,54-of 1.36 (m, 4H), 1,26-of 1.13 (m, 2H), 1,21 (t, 6N, J=7,2 Hz).

(Stage 6)

Diethyl-2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonate (1.197 g, to 1.59 mmol) was dissolved in ethanol (20 ml) and then was added potassium hydroxide (3.58 g, to 63.8 mmol)dissolved in water (10 ml). After stirring for 24 hours at 80°p is a promotional mixture was cooled to room temperature, concentrated under reduced pressure to remove ethanol, brought to pH 3 with 3 N. aqueous hydrochloric acid and then was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, obtaining 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonic acid (1.1 g) as a brown product, which is then used in subsequent reactions without further purification.

1H-NMR (300 MHz, Dl3): δ to 7.68 (d, 2H, J=9.0 Hz), 7,38 (d, 1H, J=9.0 Hz), 7,24 (d, 1H, J=2.0 Hz), 7,18 (d, 2H, J=8.6 Hz), 6,85 (DD, 1H, J1=9,0 Hz, J2=2.0 Hz), to 6.80 (d, 2H, J=8.6 Hz), 6,63 (d, 2H, J=8.6 Hz), of 3.95 (t, 2H, J=6.0 Hz), 2.21 are of 1.80 (m, 6N), 1,74 is 1.70 (m, 2H), 1,58-to 1.21 (m, 6N).

(Stage 7)

2-[5-[4-[(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]pentyl]-2-(4,4,5,5,5-pentafluorophenyl)malonic acid (1.1 g, was 1.58 mmol) was dissolved in dimethyl sulfoxide (10 ml) and was stirred for 3 hours at 120°C. the Reaction mixture was cooled to room temperature, diluted with water and then was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatograph is she on silica gel (eluent: ethyl acetate/hexane=1/1), getting 2-[5-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo [b]thiophene-3-yl)carbonyl]phenoxy]pentyl]-6,6,7,7,7-pentafluorophenol acid (732 mg, 71%yield) as a yellow solid.

1H-NMR (300 MHz, DOD): δ to 7.68 (d, 2H, J=8,8 Hz), 7,38 (d, 1H, J=8,8 Hz), 7,25 (d, 1H, J=2.3 Hz), 7,18 (d, 2H, J=8.6 Hz), 6,85 (DD, 1H, J1=8,8 Hz, J2=2.3 Hz), 6,79 (d, 2H, J=8,9 Hz), 6,63 (d, 2H, J=8.6 Hz), of 3.95 (t, 2H, J=6.5 Hz), 2,85 (m, 1H), 2,15-of 1.94 (m, 2H), 1,78-of 1.29 (m, N).

Mass spectrum (ESI): 651 (M+1).

Example 7

Synthesis of 8-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]-2-(4,4,5,5,5-pentafluorophenyl) octanoic acid

Repeated the same technique as described in example 1, obtaining 8-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]-2-(4,4,5,5,5-pentafluorophenyl)octanoic acid.

1H-NMR (300 MHz, Dl3): δ to 7.68 (d, 2H, J=8.6 Hz), 7,38 (d, 1H, J=8.7 Hz), 7.24 to 7,16 (m, 3H), 6,86-of 6.78 (m, 3H), 6,62 (d, 2H, J=8,3 Hz), of 3.95 (t, 2H, J=6.4 Hz), 2,35 (m, 1H), 2,15-of 1.95 (m, 2H), 1.77 in-1,25 (1m, 4H).

Mass spectrum (ESI): 665 (M+1).

Example 8

Synthesis of 2-[2-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]ethyl]-6,6,7,7,7-pentafluorophenol acid

Repeated the same technique as described in example 1, obtaining 2-[2-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]ethyl]-6,6,7,7,7-pentafluorophenol acid.

1H-NMR (30 MHz, Dl3+CD3OD): δ of 7.70 (d, 2H, J=8,9 Hz), 7,50 (d, 1H, J=8,8 Hz), 7,26 (d, 1H, J=2.2 Hz), 7,20 (d, 2H, J=8.6 Hz), 6.90 to (DD, 1H, J1=8,8 Hz, J2=2.2 Hz), 6,70 (d, 2H, J=8,9 Hz), of 6.65 (d, 2H, J=8.6 Hz), 4,10-3,90 (m, 2H), 2,58 (m, 1H), 2,18-of 1.84 (m, 4H), 1,82-of 1.52 (m, 4H).

Example 9

Synthesis of 2-[3-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]propyl]-6,6,7,7,7-pentafluorophenol acid

Repeated the same technique as described in example 1, obtaining 2-[3-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]propyl]-6,6,7,7,7-pentafluorophenol acid.

1H-NMR (300 MHz, Dl3): δ 7,73 (d, 2H, J=8,8 Hz), 7,47 (d, 1H, J=8,8 Hz), 7,27 (d, 1H, J=2.2 Hz), 7,21 (d, 2H, J=8.6 Hz), 6,86 (DD, 1H, J1=8,7 Hz, J2=2.3 Hz), 6.73 x (d, 2H, J=8,9 Hz), to 6.67 (d, 2H, J=8.6 Hz), of 3.94 (t, 2H, J=6,1 Hz), 2,39 (m, 1H), 2,10-of 1.97 (m, 2H), 1,82-of 1.55 (m, 8H).

Mass spectrum (ESI): 623 (M+1).

Example 10

Synthesis of 2-[4-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3-yl)carbonyl]phenoxy]butyl]-6,6,7,7,7-pentafluorophenol acid

Repeated the same technique as described in example 1, obtaining 2-[4-[4-[(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-yl)carbonyl]phenoxy]butyl]-6,6,7,7,7-pentafluorophenol acid.

1H-NMR (300 MHz, Dl3): δ 7,71 (d, 2H, J=8,8 Hz), 7,54 (d, 1H, J=8.7 Hz), 7,26 (d, 1H, J=2.3 Hz), 7,19 (d, 2H, J=8.6 Hz), to 6.88 (DD, 1H, J1=8,8 Hz, J2=2.3 Hz), 6,69 (d, 2H, J=8,8 Hz), only 6.64 (d, 2H, J=8,6), 3,93 (t, 2H, J=6,1 Hz), of 2.38 (m, 1H), 2,15 to 1.47 (m, N).

Mass spectrum (ESI): 637 (M+1).

Example 11 Synthesis of 10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-4-yl]-2-(6,6,7,7,7-pentaverate)decanoas acid

(Stage 1)

Chloride thionyl (0,65 ml) was added to (R)-4-hydroxyphenylglycine (1,00 g, 5,98 mmol) in methanol (10 ml), followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (20 ml). To the resulting solution was added saturated aqueous sodium bicarbonate solution (20 ml) and di-tert-BUTYLCARBAMATE (1,57 g, 7.19 mmol) followed by stirring for 4 hours at room temperature. Then the reaction mixture was separated into organic and aqueous layers, the organic layer was washed successively with water and saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate. Then the organic layer was concentrated under reduced pressure, the obtained solid substance was washed with a mixture of ethyl acetate/hexane, obtaining the methyl ester of (R)-N-(tert-butoxycarbonyl)-4-hydroxyphenylglycine (1.47 g, yield 87%).

1H-NMR (300 MHz, Dl3): δ to 7.18 (2H, d, J=8.6 Hz), 6,74 (2H, d, J=8.6 Hz), 5,71 (1H, user. C), 5,50-the ceiling of 5.60 (1H, m), 5,18-of 5.26 (1H, m), 3,71 (3H, s), 1,43 (N, C).

(Stage 2)

Methyl benzyl (0,66 ml of 5.55 mmol) was added to methyl ether (R)-(N-tert-butoxycarbonyl)-4-hydroxyphenylglycine (1.42 g, of 5.05 mmol) and potassium carbonate (768 mg, to 5.56 mmol) in acetone (5 ml). The resulting mixture was stirred over night at room temperature and then was heated at the boil under reflux for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, then washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Then the organic layer was concentrated under reduced pressure, the obtained solid substance was washed with a mixture of ethyl acetate/hexane, obtaining the methyl ester of (R)-N-(tert-butoxycarbonyl)-4-benzyloxyaniline (1,67 g, yield 89%).

1H-NMR (270 MHz, Dl3): δ 7,30 was 7.45 (5H, m), 7,27 (2H, d, J=8.6 Hz), to 6.95 (2H, d, J=8.6 Hz), 6,40-6,55 (1H, m), 6,20-6,30 (1H, m), of 5.05 (2H, s), 3,71 (3H, s), 1,43 (N, C).

(Stage 3)

To the methyl ether of (R)-N-(tert-butoxycarbonyl)-4-benzyloxyaniline (200 mg, 0,538 mmol) and tetrahydroborate lithium (23 mg, 1.06 mmol) in tetrahydrofuran (2 ml) was added ethanol (4 ml), followed by stirring overnight at room temperature. The reaction mixture was acidified (pH 4) 10%citric acid and conc is piss off under reduced pressure. To the obtained residue was added ethyl acetate, then washed successively with water and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, obtaining (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (187 mg, yield 100%).

1H-NMR (270 MHz, Dl3): δ 7,27 was 7.45 (5H, m), 7,21 (2H, d, J=8.6 Hz), of 6.96 (2H, d, J=8.6 Hz), of 5.05-5,20 (1H, m), of 5.05 (2H, s), 5,65-5,80 (1H, m), 3.75 to of 3.85 (2H, m), 2,35 (1H, user. C)1,43 (N, C).

(Stage 4)

Diisopropylethylamine (0.10 ml, 0,603 mmol) was added to (R)-2-(tert-butoxycarbonyl)amino-2-(4-benzyloxyphenyl)ethanol (161 mg, 0,469 mmol), 5-benzyloxy-2-bromophenol (131 mg, 0,469 mmol) and triphenylphosphine (160 mg, 0,610 mmol) in tetrahydrofuran (3 ml) in a stream of nitrogen, followed by stirring for 5 hours at room temperature, the reaction mixture was added diisopropylethylamine (0.05 ml, 0,302 mmol) followed by stirring for 3 hours at room temperature. To the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography n is silica gel (eluent: ethyl acetate/hexane=1/4, V/V)to give (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (214 mg, 75%yield).

1H-NMR (270 MHz, Dl3): δ 7,25 was 7.45 (13H, m), to 6.95 (2H, d, J=8.6 Hz), 6,40-6,55 (2H, m), 5,35-of 5.50 (1H, m), of 5.05 (2H, s)to 5.00 (2H, s), 4.95 points-of 5.05 (1H, m), 4,05-of 4.25 (2H, m), 1,42 (N, m).

(Stage 5)

Triperoxonane acid (1 ml) was added to (R)-N-(tert-butoxycarbonyl)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (200 mg, 0,331 mmol) in methylene chloride (1 ml) followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, podslushivaet saturated aqueous sodium bicarbonate and then extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=2/1 V/V)to give (R)-2-(5-benzyloxy-2-bromophenoxy)-1-(4-benzyloxyphenyl)ethylamine (127 mg, yield 76%).

1H-NMR (270 MHz, Dl3): δ 7,25 was 7.45 (13H, m), 6,97 (2H, d, J=8.6 Hz), 6.42 per-6,53 (2H, m), 5,07 (2H, s)to 5.00 (2H, s), 4,42 (1H, DD, J=8,9 and 3.6 Hz), a 3.87 (1H, DD, J=8,9, and 8.9 Hz), 1.77 in (2N, users).

(Stage 6)

A solution of (R)-2-(5-benzyloxy-2-bromophenoxy)-1-4-benzyloxyphenyl)ethylamine (120 mg, 0,238 mmol), Tris(dibenzylideneacetone)diplegia (11 mg, 0.012 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (15 mg, 0,024 mmol) and tert-butoxide potassium 937 mg, 0,330 mmol) in toluene (2.5 ml) was stirred for 3 hours at 100°in a stream of nitrogen. After cooling, to the reaction mixture was added water, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5 V/V)to give (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin (55,4 mg, yield 55%).

1H-NMR (270 MHz, Dl3): δ 7,25-7,50 (N, m), 6,98 (2H, d, J=8.6 Hz), to 6.58 (1H, d, J=8.6 Hz), 6,55 (1H, d, J=2.6 Hz), 6.48 in (1H, DD, J=8,6, and 2.6 Hz), 5,07 (2H, s), 4,99 (2H, s), 4,39 (1H, DD, J=8,9, and 2.6 Hz), 4,22 (1H, DD, J=10,6, and 2.6 Hz), of 3.96 (1H, DD, 10,6, a 8.9 Hz), to 3.73 (1H, users).

(Stage 7).

A solution of (R)-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (47,6 mg, 0,112 mmol), sodium iodide (67 mg, 0,450 mmol), potassium carbonate (31 mg, 0,224 mmol) and allyl bromide (0.04 ml, 0,473 mmol) in acetone (1 ml) was stirred for 3 hours at 50°in a stream of nitrogen and then heated at the boil under reflux for 7 hours. After cooling, to the reaction mixture were added in the u, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5, V/V)to give (R)-4-allyl-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin (44 mg, yield 85%).

1H-NMR (270 MHz, Dl3): δ 7,25 was 7.45 (10H, m), 7,20 (2H, d, J=8.6 Hz), to 6.95 (2H, d, J=8.6 Hz), 6,74 (1H, d, J=9.6 Hz), 6,50-6,56 (2H, m), 5,68-to 5.85 (1H, m), 5,06-5,17 (2H, m), of 5.05 (2H, s), to 4.98 (2H, s)to 4.33 (1H, d, J=6,9, 3.0 Hz), 4,19 (1H, DD, J=10,9, 3.0 Hz), 4,11 (1H, DD, J=10,9, 6.9 Hz), 4,85-to 4.98 (1H, m), 3,47 (1H, DD, J=16,8, 6,3 Hz).

(Stage 8)

1)Solution of (R)-4-allyl-7-benzyloxy-3-(4-benzyloxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazine (177 mg, 0,382 mmol), ethyl ester of 2-(6,6,7,7,7-pentaverate)non-8-ene acid (285 mg, 0,765 mmol) and benzylidene(tricyclohexylphosphine)dichloroethene (16 mg, 0.019 mmol) in dichloromethane (2 ml) was heated at the boil under reflux for 5 hours in a stream of nitrogen. The reaction mixture was additionally mixed with the ethyl ester of 2-(6,6,7,7,7-pentaverate)non-8-ene acid (71 mg, 0,190 mmol) and benzylidene(tricyclohexylphosphine)dichlororuthenium (16 mg, 0.019 mmol) and then heated at the boil under reflux for 2 hours. After cooling the Oia, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: chloroform/hexane=3/1, V/V)to give oil (197 mg).

2) the Mixture of oil obtained above in 1)and 10% Pd-C (13 mg, 0.012 mmol) in a mixture of ethanol/methanol (1:1, 3 ml) was stirred for 13 hours at room temperature in a stream of hydrogen. After filtering the reaction mixture through celite mother liquor was concentrated under reduced pressure. The obtained residue was subjected to two additional reactions of recovery, as stated above. The resulting residue was further purified column chromatography on silica gel (eluent: ethyl acetate/hexane-1/2 1/1, V/V)to give ethyl-10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo [1,4]oxazin-4-yl]-2-(6,6,7,7,7-pentaverate)decanoate (a 60.2 mg, yield 26%).

1H-NMR (270 MHz, CD3OD): δ 7,13 (2H, d, J=8.6 Hz), 6,78 (2H, d, J=8.6 Hz), of 6.65 (1H, d, J=8.6 Hz), 6,36 (1H, DD, J=8,6, and 2.6 Hz), of 6.29 (1H, d, J=2.6 Hz), 4,27 (1H, DD, J=6,3, 3.0 Hz), 4,00-4,20 (4H, m), 3,20-to 3.35 (1H, m), 2,80-2,95 (1H, m), 2,30 at 2.45 (1H, m), 2.00 in of 2.23 (2H, m), 1,15-1,70 (25N, m).

(Stage 9)

An aqueous solution of sodium hydroxide (1 ad, 1 ml) was added to ethyl-10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-4-yl]-2-(6,6,7,7,7-pentaverate)decanoate (56,8 mg, 0,0902 mmol) in ethanol (1 ml) in a stream of nitrogen, followed by stirring for 7 hours at 50°C. After cooling the reaction, see the camping was acidified using 1 N. aqueous hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1, V/V)to give 10-[(R)-7-hydroxy-3-(4-hydroxyphenyl)-3,4-dihydro-2H-benzo[1,4]oxazin-4-yl]-2-(6,6,7,7,7-pentaverate)dekanovu acid (41,4 mg, yield 76%).

1H-NMR (270 MHz, CD3OD): δ 7,13 (2H, d, J=8.6 Hz), 6,78 (2H, d, J=8.6 Hz), only 6.64 (1H, d, J=8.6 Hz), 6,37 (1H, DD, J=8,6, and 2.6 Hz), of 6.29 (1H, d, J=2.6 Hz), 4,21 is 4.35 (1H, m), of 4.12 (1H, DD, J=10,6, 3.0 Hz), of 4.05 (1H, DD, J=10,6, and 6.6 Hz), 3,20-to 3.35 (1H, m), 2,82-2,95 (1H, m), 2,25-of 2.38 (1H, m), 2.00 in of 2.21 (2H, m), 1,10-1,70 (22N, m).

Example 12

Synthesis of 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]2-(6,6,7,7,7-pentaverate)decanoas acid

(Stage 1)

A solution of 3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11-she (mg 148, 8 persons, 0,318 mmol) in anhydrous tetrahydrofuran (2.5 ml) was cooled to -10°C in argon atmosphere. To this solution was added dropwise a 1.0 M solution of allylanisole in simple anhydrous ether (1.5 ml, 1.5 mmol) and the resulting mixture was stirred for 15 hours at room temperature. The reaction mixture was cooled to 0°With added water and then saturated wagnerstr ammonium chloride. Then the reaction mixture was extracted with ethyl acetate, the organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After removal of the solvent the residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=6/1)to give 3,17βbis(benzyloxy)-11α-(2-propenyl)östra-1,3,5(10)-triene-11β-ol (150,4 mg, yield 93%).

1H-NMR (270 MHz, Dl3): δ 7,79 (d, J=10 Hz, 1H, Cl-H), 7,44-7,29 (m, 10H), 6,82-6,76 (m, 2H, C2 and C4-H), 6,00-to 5.85 (m, 1H, olefinic H), 5,20-5,12 (m, 2H, olefinic H), 5,04 (s, 2H, Ph-CH2), 4,55 (s, 2H, Ph-CH2), 3,44 (t, J=8 Hz, 1H, C17-H), is 2.88 (DD, J=14,8 Hz, 1H, allylic CH2), 2,78-of 2.58 (m, 2H), 2,50 (DD, J=14,7 Hz, 1H, allylic CH2), of 2.23 (d, J=11 Hz, 1H), 2,11 (d, J=14 Hz, 1H), 2,08-of 1.95 (m, 1H), 1,90-1,15 (m, N), of 1.07 (s, 3H, C18-H).

(Stage 2)

Benzylidene(tricyclohexylphosphine)dichloroethene (5.9 mg, 0,00717 mmol) was added to a solution of 3,17βbis(benzyloxy)-11α-(2-propenyl)östra-1,3,5(10)-triene-11β-Ola (65,5 mg, 0,129 mmol) and ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (101,3 mg, 0,272 mmol) in dichloromethane (0.5 ml) followed by heating at boiling under reflux for 2.5 hours in an atmosphere argon. After cooling, to the reaction mixture were added ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (100 mg, 0,269 mmol) and benzylidene(tricyclohexylphosphine)dichlo the ruthenium (6 mg, 0,00729 mmol), then heated at the boil under reflux for 3 hours in argon atmosphere. After cooling, to the reaction mixture was further added ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (100 mg, 0,269 mmol) and benzylidene (tricyclohexylphosphine)dichloroethene (6 mg, 0,00729 mmol), then heated at the boil under reflux for 6.5 hours in an argon atmosphere and left to cool. In addition, benzylidene(tricyclohexylphosphine)dichloroethene (6,8 mg, 0,00826 mmol) was added to a solution of 3,17βbis(benzyloxy)-11α-(2-propenyl)östra-1,3,5(10)-triene-11β-Ola (84,5 mg, 0,166 mmol) and ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (124 mg, of 0.333 mmol) in dichloromethane (0.5 ml) followed by heating at boiling under reflux for 2.5 hours in an argon atmosphere. After cooling, to the reaction mixture were added ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (124 mg, of 0.333 mmol) and benzylidene(tricyclohexylphosphine)dichloroethene (6,8 mg, 0,00826 mmol), then heated at the boil under reflux for 3 hours in argon atmosphere. After cooling, to the reaction mixture was further added ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate (124 mg, of 0.333 mmol) and benzylidene(tricyclohexylphosphine)dichloroethene (6,8 mg, 0,00826 mmol), then heated at the boil under reflux for 6.5 hours in the atmosphere is fere argon and left to cool. Thus obtained two reaction mixtures were combined and concentrated under reduced pressure. The residue was purified flash chromatography on silica gel (eluent; hexane/ethyl acetate=5/1)to give ethyl-10-[3,17βbis(benzyloxy)-11β-hydroxyestra-1,3,5(10)-triene-11α-yl]-2-(6,6,7,7,7-pentaverate)-8-decenoic (186,4 mg, yield 74%).

1H-NMR (270 MHz, Dl3): δ 7,79 (d, J=10 Hz, 1H), 7,45-7,25 (m, 10H), 6,82-6,72 (m, 2H), 5,62-of 5.40 (m, 2H, olefinic H), 5,04 (s, 2H, Ph-CH2), 4,55 (s, 2H, Ph-CH2), of 4.13 (q, J=7 Hz, 2H, COO-CH2), 3,42 (t, J=8 Hz, 1H), 2.95 and-1,14 (m, N), of 1.07 (s, 3H).

(Stage 3)

30%solution Nug in acetic acid (2 ml) was added to a solution of ethyl-10-[3,17βbis(benzyloxy)-11β-hydroxyestra-1,3,5(10)-triene-11α-yl]-2-(6,6,7,7,7-pentaverate)-8-decenoate (155,4 mg of 0.182 mmol) in ethanol (8 ml) followed by stirring for 24 hours at 50°C. After cooling, the reaction mixture was poured into saturated an aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After concentration under reduced pressure, the obtained residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=20/1)to give oil. The oil was dissolved in a mixed solvent, is present from ethanol (5 ml) and methanol (5 ml), 10%palladium-on-carbon (78.8 mg) was added to the resulting solution followed by stirring for 14 hours at room temperature in a hydrogen atmosphere. After blowing nitrogen to the reaction mixture was added 10%palladium-on-carbon (74,0 mg), followed by stirring for 15 hours at room temperature in a hydrogen atmosphere. The reaction mixture was filtered and concentrated, the residue was dissolved in methanol (10 ml). Again to the reaction mixture was added 10%palladium-on-carbon (80 mg), followed by stirring for 2 days at room temperature in a hydrogen atmosphere. After filtration of the reaction mixture and concentrating the residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=10/1)to give oil. The oil was further purified using plates with silica gel (manifesting solvent: hexane/ethyl acetate=2/1)to give ethyl-10-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(6,6,7,7,7-pentaverate)decanoate (14.6 mg, yield 12%).

1H-NMR (270 MHz, Dl3): δ 7,00 (d, J=8.6 Hz, 1H), 6,62 (DD, J=8,6, and 2.6 Hz, 1H), 6,55 (d, J=2.6 Hz, 1H), 5,28 (users, 1H, Ar-OH), 4,15 (kV, J=7,3 Hz, 2H, COO-CH2), 3,70 (t, J=8.6 Hz, 1H), 2,90-1,10 (m, N), of 0.91(s, 3H).

The Rf-value: 0,45 (the plate with silica gel, developing solvent: hexane/ethyl acetate=2/1).

(Stage 4)

the Teal-10-[3,17β -dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(6,6,7,7,7-pentaverate)decanoate (11,1 mg, 0,0168 mmol) was dissolved in a mixed solvent consisting of ethanol (0.5 ml) and tetrahydrofuran (0.5 ml). To this solution was added 1 N. aqueous NaOH solution (0.5 ml) and the resulting mixture was heated at the boil under reflux for 5 hours. After cooling, to the reaction mixture were added saturated aqueous solution of ammonium chloride, then extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After concentration under reduced pressure the resulting residue was purified using plates with silica gel (manifesting solvent: hexane/ethyl acetate=1/1)to give 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(6,6,7,7,7-pentaverate)dekanovu acid (5.3 mg, yield 50%).

1H-NMR (270 MHz, Dl3): δ 7,00 (d, J=8,3 Hz, 1H), 6,62 (d, J=8,3 Hz, 1H), is 6.54 (s, 1H), of 3.73 (t, J=8,1 Hz, 1H) 2,90-of 1.07 (m, N), to 0.92 (s, 3H).

Mass spectrum (ESI): 653 (M+Na).

The Rf-value: 0,22 (silikagelevye plate exhibiting solvent: hexane/ethyl acetate=1/1).

Example 13

Synthesis of 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(4,4,5,5,5-pentafluorophenyl)undecanoic acid

(Stage 1)

n-Utility (2.5 M in hexane, 40 ml, 100 is mol) was added to tert-piperonyl potassium (1 M in tetrahydrofuran, 100 ml, 100 mmol) at -70°C in nitrogen atmosphere followed by the addition of Diisopropylamine (19,1 g, 100 mmol) at the same temperature. After stirring the mixture for 10 minutes was added dropwise at -70°C for 10-15 minutes 17β-(tert-butyldimethylsiloxy)-3-petoksista-1,3,5(10)-triene (10 g, 25 mmol), synthesized by the method described in Tetrahedron Lett., 3223 (1988), and dissolved in tetrahydrofuran (40 ml)and the resulting mixture was stirred for 4 hours. To the reaction mixture was added trimethylboron (15.6 g, 150 mmol), then heated to a temperature of ice, stirred for 1 hour and additionally mixed with 30% hydrogen peroxide (35 ml) for 1 hour at room temperature. The reaction mixture was again cooled on ice and in order to stop the reaction, was added 10%aqueous sodium thiosulfate solution (150 ml). Then the reaction mixture was extracted with simple ether, the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After removal of the solvent the residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=5/1 3/1)to give 17β-(tert-butyldimethylsiloxy)-3-petoksista-1,3,5(10)-triene-6-ol (scored 8.38 g, yield 82%).

1H-NMR (300 MHz, Dl3): δ to 7.18 (d, J=8.5 Hz, 1H, Cl-CH), 7,11 (d, J=2.7 Hz, 1H, C4-CH), 6,77 (DD, J=8,5, 2.7 Hz, 1H,-CH), of 4.8 (m, 1H), of 3.78 (s, 3H, C3-och3), 3,62 (m, 1H), 2,3-2,2 (m, 3H), 2,0-1,8 (m, 2H), 1,7-1,1 (m, 8H), 0,87 (s, N), of 0.71 (s, 3H, C18-CH3), and 0.04 (s, 3H), of 0.03 (s, 3H).

(Stage 2)

17β-(tert-Butyldimethylsiloxy)-3-petoksista-1,3,5(10)-triene-6-ol (14.4 g, 34.5 mmol) was dissolved in dichloromethane (250 ml). To the resulting solution was added manganese dioxide (29 g) and powdered molecular sieves 4(7.2 g), followed by stirring for 1 hour at room temperature. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane, receiving 17β-(tert-butyldimethylsiloxy)-3-petoksista-1,3,5(10)-triene-6-he (11,36 g, yield 79%).

1H-NMR (300 MHz, Dl3): δ at 7.55 (d, J=3.0 Hz, 1H, C4-CH), 7,34 (d, J=8.5 Hz, 1H, Cl-CH), 7,10 (DD, J=8,5, 3.0 Hz, 1H, C2-SN), of 3.84 (s, 3H, C3-och3), 3,66 (m, 1H), 2,74 (DD, J=16,8, 3.3 Hz, 1H), 2,5-2,3 (m, 2H), 2,19 (DD, J=16,8, 13,2 Hz, 1H), 2,0-1,8 (m, 3H), 1,7-1,2 (m, 5H), 0,89 (s, N in), 0.75 (s, 3H, C18-CH3), and 0.04 (s, 3H), of 0.03 (s, 3H).

TPL 159-160°C.

(Stage 3)

A solution of 17β-(tert-butyldimethylsiloxy)-3-petoksista-1,3,5(10)-triene-6-she (2,12 g, 5 mmol) in anhydrous 1,2-dimethoxyethane (30 ml) was cooled to -70°C in nitrogen atmosphere and the resulting solution was added hexamethyldisilazide potassium as a solid (1.1 g, 5.5 mmol) to follow them by stirring for 1 hour, maintaining the temperature at -70°C. Then was added distilled modesty allyl (1.68 g, 10 mmol) at -70°using a syringe and the reaction mixture was heated to 0°C for 1 hour. An hour later, to the reaction mixture was added water at 0°With, then was extracted with simple ether. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. After removal of the solvent the residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=20/1 15/1)to give 17β-(tert-butyldimethylsiloxy)-3-methoxy-7αβ-(2-propenyl) östra-1,3,5(10)-triene-6-he (2.0 g, yield 88%) (ratio 7α/7β about 1/6).

The above mixture was dissolved in a solution of sodium methoxide (0.1 M) and heated at boiling under reflux for 2 hours, obtaining a mixture having a ratio of 7α/7βequal to about 7/1.

1H-NMR (300 MHz, Dl3spectrum 7α-substituted compounds): δ 7,53 (d, 1H, J=2,8 Hz, C4-CH), 7,32 (d, 1H, J=8,5 Hz, Cl-CH), to 7.09 (DD, J=8,5, 2,8gts, 1H, C2-CH), by 5.87-5,72 (m, 1H), 5,02 of 4.9 (m, 2H), of 3.84 (s, 3H, C3-och3), 3,68 (m, 1H), 2.77-to of 2.64 (m, 1H), 2,6-of 2.54 (m, 1H), 2,4-2,3 (m, 2H), 2,22-to 2.06 (m, 2H), 2,0-of 1.85 (m, 2H), 1,65-1,2 (m, 6N), and 0.9 (s, N in), 0.75 (s, 3H, C18-CH3), of 0.05 (s, 3H), of 0.03 (s, 3H).

(Stage 4)

17β-(tert-Butyldimethylsiloxy)-3-methoxy-7α² -(2-propenyl)östra-1,3,5(10)-triene-6-he (5,78 g, 12.7 mmol) was dissolved in tetrahydrofuran (30 ml). To this solution was added fluoride, Tetra-n-butylamine (1 M in tetrahydrofuran, 60 ml) and the resulting mixture was heated at the boil under reflux for 4 hours in nitrogen atmosphere. After cooling, to the reaction mixture was added water, then was extracted with simple ether. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, getting 17β-hydroxy-3-methoxy-7αβ-(2-propenyl)östra-1,3,5(10)-triene-6-it is in the form of a mixture of diastereomers, which was then recrystallized from diisopropyl ether (70 ml), receiving 17β-hydroxy-3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-6-he (2,61 g, yield 60%) as a single isomer.

1H-NMR (270 MHz, Dl3,): δ 7,53 (d, J=3.0 Hz, 1H, C4-CH), 7,32 (d, J=8.5 Hz, 1H, Cl-CH), to 7.09 (DD, J=8,5, 3.0 Hz, 1H, C2-SN), of 5.84-5,74 (m, 1H), 5,01 to 4.92 (m, 2H, olefinic H), of 3.84 (s, 3H, C3-och3), 3,84 of 3.75 (m, 1H, 17-CH), 2,80 of 2.68 (m, 1H, C9-CH), 2,63-2,52 (m, 1H, C7-SN), of 2.51-of 2.38 (m, 2H, allyl-CH2and C11-CH2), 2,24-2,05 (m, 3H), allyl-CH2and C8-SN and C16-CH2), 2,02 is 1.91 (m, 1H, C11-CH2), 1,71-of 1.33 (m, 7H), of 0.79 (s, 3H, C18-CH3).

TPL 122-123°C.

(Stage 5)

Triethylsilane (5 ml) and diethylpyrocarbonate boron (5 ml) was added to a solution of 17β -hydroxy-3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-6-she (1.0 g, 2.9 mmol) in dichloromethane (20 ml) at 0°C. the resulting mixture was heated to room temperature and was stirred for 18 hours. After completion of the reaction, to the reaction mixture were added 10%aqueous potassium carbonate and then extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered. After concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1)to give 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol (935 mg, yield 98%).

1H-NMR (300 MHz, Dl3,): δ then 7.20 (d, J=8.6 Hz, Cl-1H), of 6.71 (DD, J=8,6, 2,4 Hz, C2-1H), 6,60 (d, J=2.4 Hz, C4-1H), 5,86-5,72 (m, 1H), 5,00-of 4.90 (m, 2H, olefin H)of 3.77 (s, 3H, C3-och3), of 3.77-3,71 (m, 1H, 17-CH), 2,80 of 2.68 (m, 1H, C9-CH), 2,63-2,52 (m, 1H, C7-SN), of 2.51-of 2.38 (m, 2H, allyl-CH2and C11-CH2), 2,24-2,05 (m, 3H), allyl-CH2and C8-SN and C16-CH2), 2,02 is 1.91 (m, 1H, C11-CH2), 1,71-of 1.33 (m, 7H), of 0.79 (s, 3H, C18-CH3).

(Stage 6)

Benzylidene(tricyclohexylphosphine)dichloroethene (98 mg, 0.11 mmol) was added to a solution of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-Ola (723 mg, 2.21 mmol) and ethyl-2-(4,4,5,5,5-pentafluorophenyl)-9-decenoate (1,59 g, 4,43 mmol) in dichloromethane (20 m is) followed by heating at boiling under reflux for 20 hours in an argon atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=4/1)to give ethyl-11-[17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)-9-undecenoate (973 mg, yield 67%).

1H-NMR (270 MHz, Dl3,): δ then 7.20 (d, J=8.6 Hz, 1H, Cl-CH), 6,76-6,69 (m, 1H, C2-CH), 6,63 return of 6.58 (m, 1H, C4-CH), 5,42 at 5.27 (m, 2H, olefin-H), 4,15 (kV, J=7,1 Hz, 2H, COO-CH2), 3,78-3,70 (m, 4H, C17-CH and C3-och3), 2,90 2.63 in (m, 2H), 2,41-2,22 (m, 3H), 2,20-of 1.16 (m, 34N), to 0.78 (s, 3H, C18-CH3).

(Stage 7)

Ethyl-11-[17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)-9-undecenoate (970 mg, 1.48 mmol) was dissolved in ethyl acetate (30 ml) and the resulting solution was added 10%palladium-on-carbon (300 mg), followed by stirring for 4 hours at room temperature in a hydrogen atmosphere. The reaction mixture was filtered and concentrated, obtaining ethyl 11-[17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoate (946 mg, yield 97%) as oil.

1H-NMR (270 MHz, Dl3,): δ then 7.20 (d, J=8.6 Hz, 1H, Cl-CH), 6,76-6,69 (m, 1H, C2-CH), 6,63 return of 6.58 (m, 1H, C4-CH), 4,14 (kV, J=7,1 Hz, 2H, COO-CH2), of 3.77 (s, 3H, C3-och3), 3,74 (t, J=8,4 Hz, 1H, 17-CH), 2,94-2,70 (m, 2H), 2.40 a-2,24 (m, 3H), 2,20-of 1.84 (m, 4H), 1,80-to 0.96 (m, 34N), to 0.78 (s, 3H, C18-CH3).

p> (Stage 8)

Ethyl-11-[17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoate (946 mg, 1,43 mmol) was dissolved in dichloromethane (18 ml). To this solution was added dropwise at -78°1 M solution trichromate boron in dichloromethane (4.3 ml, 4.3 mmol). The reaction mixture was slowly heated and stirred for 3 hours at 0°C. to stop the reaction was added water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered. After concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1, receiving ethyl-11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoate (663 mg, yield 72%).

1H-NMR (270 MHz, Dl3,): δ 7,14 (d, J=8,4 Hz, 1H, Cl-CH), 6,66-6,59 (m, 1H, C2-CH), 6,57-6,53 (m, 1H, C4-CH), 5,10 (users, 1H, C3-OH), 4,15 (kV, J=7,1 Hz, 2H, COO-CH3in ), 3.75 (t, J=8,4 Hz, 1H, 17-CH), 2,94 of 2.68 (m, 2H), 2.40 a-2,22 (m, 3H), 2,20-of 1.84 (m, 4H), 1,80-to 0.96 (m, 34N), to 0.78 (s, 3H, C18-CH3).

(Stage 9)

Ethyl-11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoate (660 mg, of 1.03 mmol) was dissolved in a mixed solvent, ostashek from ethanol (10 ml) and water (2.0 ml). To this solution was added NaOH (820 mg, of 20.5 mmol) and the resulting mixture was heated for 4 hours at 60°C. After cooling, to the reaction mixture were added 2 N. aqueous hydrochloric acid, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered. After concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1)to give 11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)undecanoyl acid (613 mg, yield 97%).

1H-NMR (270 MHz, CD3OD): δ 7,07 (d, J=8,4 Hz, 1H, Cl-CH), is 6.54 (DD, J=8,4, 2.3 Hz, 1H, C2-CH), 6,45 (d, J=2.3 Hz, 1H, C4-CH), to 3.67 (t, J=8,3 Hz, 1H, C17-CH), 2,85-2,62 (m, 2H), 2,39-of 1.84 (m, 7H), 1,80-to 0.96 (m, N), to 0.78 (s, 3H, C18-CH3).

Example 14

Synthesis of 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(4,4,5,5,5-pentafluorophenyl)-8-nonenoate obtained separately, repeating the same technique as described in example 13 to give 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,5-pentafluorophenyl)dekanovu acid.

1H-NMR (300 MHz, Dl3,): #x003B4; 7,16 (d, J=8,4 Hz, 1H, Cl-CH), 6,63 (DD, J=8,4 Hz, J=2.7 Hz, 1H, C2-CH), 6,55 (s, 1H, C4-CH in), 3.75 (t, J=8,5 Hz, 1H, C17-CH), 3,60-3,35 (users, 1H, C3-OH), 2,82-by 2.73 (m, 2H), 2,45-of 2.23 (m, 4H), 2,20-0,96 (m, 31N), to 0.78 (s, 3H, C18-CH3).

Example 15

Synthesis of 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonoperated)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(4,4,5,5,6,6,7,7,7-nonoperated)-8-nonenoate obtained separately, repeating the same technique as described in example 13 to give 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonoperated)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ for 7.12 (d, J=8,4 Hz, 1H), of 6.68 (DD, J=8,5, 2.4 Hz, 1H), 6,53 (d, J=2.6 Hz, 1H), 3,68 (t, J=8.5 Hz, 1H), 2.95 and-2,60 (m, 2H), 2,47-2,19 (m, 4H), 2,18-of 1.03 (m, 31N), is 0.69 (s, 3H).

Example 16

Synthesis of 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(3,3,4,4,5,5,6,6,6-nonforensic)-8-nonenoate obtained separately, repeating the same technique as described in example 13 to give 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)dekanovu acid.

1H-NMR (300 MHz, Dl3): δ 7,14 (d, J=8.5 Hz, 1H), 6,62(DD, J=8,2, 2.1 Hz, 1H), is 6.54 (d, J=2.6 Hz, 1H), of 3.77 (t, J=8,1 Hz, 1H), 2,84-of 2.56 (m, 2H), 2,44 (m, 1H), 2,31 (m, 2H), 2,18-1,02 (m, N), to 0.74 (s, 3H).

Example 17

Synthesis of 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(6,6,7,7,7-pentaverate)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate obtained separately, repeating the same technique as described in example 13 to give 10-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(6,6,7,7,7-pentaverate)dekanovu acid.

1H-NMR (300 MHz, Dl3): δ 7,05 (d, J=8,4 Hz, 1H), 6,65 (DD, J=8,6, 2,Hz, 1H), of 6.52 (d, J=2.5 Hz, 1H, in), 3.75 (t, J=8,4 Hz, 1H), 2,92-2,62 (m, 2H), 2,33-2,12 (m, 4H), 2,09-of 1.03 (m, N in), 0.75 (s, 3H).

Example 18

Synthesis of 11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonoperated)undecanoic acid

On the basis of 3-methoxy-7-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(4,4,5,5,6,6,7,7,7-nonoperated)-9-decenoate obtained separately, repeating the same technique as shown in example 13, receiving 11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(4,4,5,5,6,6,7,7,7-nonoperated)undecanoyl the acid.

1H-NMR (300 MHz, Dl3,): δ 7,13 (d, J=8,4 Hz, 1H, Cl-CH), 6,62 (DD, J=8,4, 2.3 Hz, 1H, C2-CH), 6,53 (d, J=2.3 Hz, 1H, C4-CH in), 3.75 (t, J=8,1 and 8.4 Hz, 1H, 17-CH), 2,85 (DD, J=4 and 16,GC, 1H), 2,70(m, 1H), 2,39-of 1.88 (m, 7H), 1,80-to 0.96 (m, N), to 0.78 (s,3H, C18-CH3).

Example 19

Synthesis of 11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol obtained in example 13, and ethyl-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-decenoate obtained separately, repeating the same technique as shown in example 13, receiving 11-[3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid.

1H-NMR (270 MHz, CD3OD): δ 7,07 (d, J=8,4 Hz, 1H, Cl-CH), 6,53 (DD, J=8,4, 2.2 Hz, 1H, C2-CH), 6,45 (d, J=2.2 Hz, 1H, C4-CH), to 3.67 (t, J=8,1 Hz, 1H, C17-CH), 2,87-2,62 (m, 2H), 2,43-of 0.95 (m, N), to 0.78 (s,3H, C18-SN3).

Example 20

Synthesis of 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid

(Stage 1)

Dimethylformamide (11 ml) was added to β-estradiol (1.08 g, 4.0 mmol) under nitrogen atmosphere and then cooled on ice. To the reaction mixture were added sodium hydride (480 mg, 60%suspension), followed by stirring for 10 minutes on ice and then stirring for 1 hour at room temperature. After re-cooling on ice to the reaction mixture was added benzyl bromide (2,05 g, 12 mmol) followed by stirring is for about 10 minutes on ice and then stirring for 20 hours at room temperature. The reaction mixture was extinguished chilled with ice water and was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue triturated with methanol to precipitate solids. The solids were collected by filtration and dried in vacuum, obtaining 3,17βbis(benzyloxy)östra-1,3,5(10)-triene (1,72 g, yield 95%).

1H-NMR (300 MHz, Dl3,): δ 7,45-7,20 (m, 11N), 6,79 (DD, J=9.0 and 3.0 Hz, 1H, C3 CH), 6,72 (d, J=2.7 Hz, 1H, C4-CH), 5,04 (s, 2H), 4,56 (S, 2H), 3,51 (t, J=8,1, 1H), 2,88-and 2.83 (m, 2H), 2,36-of 1.15 (m, 13H), 0.88 to (s, 3H, C18-CH3).

(Stage 2)

To 3,17βbis(benzyloxy)östra-1,3,5(10)-triens (45,2 mg, 0.1 mmol) under nitrogen atmosphere was added dichloromethane (0.2 ml) and methanol (0.1 ml) and then cooled to -78°C. To the reaction mixture was added 2,3-dichloro-5,6-dicyanobenzoquinone (22.7 mg, 0.1 mmol) followed by stirring for 10 minutes at -78°and then stirring for 3 hours at room temperature. The reaction mixture was extinguished saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over be the aqueous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue was purified column chromatography on silica gel (Merck Kieselgel 60, eluent: hexane/ethyl acetate=10/1 → 8/1)to give the target compound - 3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraen (35,7 mg, yield 80%).

1H-NMR (300 MHz, Dl3,): δ rate of 7.54 (d, J=9.0 Hz, 1H, Cl-CH), 7,27 was 7.45 (m, 10H), to 6.80 (DD, J=8.7 and 2.7 Hz, 1H, C3 CH), 6,69 (d, J=2.4 Hz, 1H, C4-CH), 6,12 (m, 1H), of 5.05 (s, 2H), 4,56 (s, 2H), 4,22 (m, 1H), 3,60 (t, J=to 8.7 Hz, 1H), 2,97-2,70 (m, 2H), 2,43-of 1.09 (m, N), of 0.87 (s, 3H, C18-CH3).

(Stage 3)

Catecholborane (1.0 M in tetrahydrofuran, 66,33 ml) was added to 3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraene (27,17 g, 60,30 mmol) at room temperature under nitrogen atmosphere. Next, to the reaction mixture at room temperature was added lithium borohydride (1.31 g, 60,30 mmol) followed by stirring for 10 hours. Under ice cooling, this mixture was added to a mixture of sodium hydroxide (24,12 g, 603,0 mmol), water (70 ml), ethanol (150 ml) and 30% hydrogen peroxide (150 ml), followed by stirring for 1 hour and 45 minutes on ice, and then stirred for 3 hours at room temperature. To the reaction mixture was added a simple ether and water, then was extracted with simple ether. The organic layer was washed successively 10%aqueous solution of the m sodium hydroxide, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator. The residue was purified column chromatography on silica gel (Merck Kieselgel 60, eluent: hexane/ethyl acetate=6/1 to 5.5/1), obtaining the target compound -3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11α-ol (21,56 g, yield 76%).

1H-NMR (300 MHz, Dl3,): δ 7,87 (d, J=8,4 Hz, 1H, Cl-CH), 7,27 was 7.45 (m, 10H), for 6.81 (DD, J=8.7 and 2.7 Hz, 1H, C3 CH), 6,74 (d, J=2,Hz, 1H, C4-CH), of 5.05 (s, 2H), 4,58 (s, 2H), 4,22 (m, 1H), 3,53 (t, J=8,1, 1H), 2,82 (m, 2H), 2,43 (DD, J=12.2 and a 5.4 Hz, 1H), 2,18-2,02 (m, 2H), 1,91-of 1.84 (m, 1H), 1,74-to 1.59 (m, 2H), 1,49-of 1.27 (m, 5H), 0,86 (s, 3H, C18-CH3).

(Stage 4)

Dichloromethane (92,25 ml) was added to oxalidaceae (3,54 ml, 40,59 mmol) under nitrogen atmosphere and the resulting mixture was cooled to -78°C. To the mixture was added dropwise a solution of dimethylsulfoxide (USD 5.76 ml, 81,18 mmol), diluted with dichloromethane (of 18.45 ml). Then the mixture was stirred for 2 minutes at -78°C, was added dropwise a solution of 3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11α-Ola (17,29 g, 36,90 mmol) in dichloromethane (36,90 ml) followed by stirring for 15 minutes at -78°C. To the reaction mixture dropwise added triethylamine (25.7 mm, 184,5 mmol), then stirred for 5 minutes at -78° and heated on the room temperature. The reaction mixture was again cooled on ice, was suppressed by the addition of ice and water and then was extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator, receiving untreated 3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11-he (untreated 18,76 g, quantitative crude product1H-NMR].

1H-NMR (300 MHz, Dl3,): δ 7,41-7,20 (m, 11N), PC 6.82 (DD, J=8.4 and 2.7 Hz, 1H, C3 CH), 6,70 (d, J=2.7 Hz, 1H, C4-CH), to 5.03 (s, 2H), of 4.54 (s, 2H), and 3.72 (t, J=8,1 Hz, 1H), 3.46 in (d, J=10,2 Hz, 1H), 2,84-of 2.66 (m, 3H), 2,47 (d, J=11,4 Hz, 1H), 2,23 and 2.13 (m, 1H), 1,96 is 1.48 (m, 8H), 0,86 (s, 3H, C18-CH3).

(Stage 5)

Tetrahydrofuran (280 ml) was added to the crude 3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11-ONU (35,7 g, a 76.5 mmol) under nitrogen atmosphere and the resulting mixture was cooled to -40°C. To the mixture was added dropwise allylanisole (2.0 M in tetrahydrofuran, 50,0 ml, 100 mmol), then stirred for 10 minutes at -40°and for 1 hour at room temperature. The reaction mixture was again cooled on ice and was suppressed by the addition of ice water and saturated aqueous solution of ammonium chloride. Then the reaction mixture was extracted with ethyl acetate, the organic layer was washed water is the first and saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and to the residue was added hexane to precipitate solids. The solids were collected by filtration and dried in vacuum, obtaining 3,17βbis(benzyloxy)-11α-(2-propenyl)östra-1,3,5(10)-triene-11β-ol (35,81 g, yield 90% 3,17βbis(benzyloxy)östra-1,3,5(10)-triene-11α-Ola).

1H-NMR (300 MHz, Dl3,): δ of 7.82 (d, J=9.6 Hz, 1H, CL-H), 7,44-7,33 (m, 10H), 6,83-6,79 (m, 2H, C2 and C4-H), 6,01-by 5.87 (m, 1H, olefinic H), to 5.21-5,13 (m, 2H, olefinic H), is 5.06 (s, 2H), 4,57 (s, 2H), 3.46 in (t, J=8.7 Hz, 1H, C17-H), 2,90 (DD, J=14.0 and an 8.4 Hz, 1H, allylic CH2), is 2.74 2.63 in (m, 2H), 2,52 (DD, J=14.1 and 7.0 Hz, 1H, allylic CH2in ), 2.25 (d, J=10,8 Hz, 1H), 2,13 (d, J=14.1 Hz, 1H), 2.06 to to 1.98 (m, 1H), 1,88-1,14 (m, N), of 1.09 (s, 3H, C18-H).

(Stage 6)

After cooling the solution 3,17βbis(benzyloxy)-11α-(2-propenyl)östra-1,3,5(10)-triene-11β-Ola (17,20 g, 33,80 mmol) in pyridine (135 ml) to -40°C in an atmosphere of nitrogen was added dropwise chloride thionyl (3,7 ml of 50.7 mmol), then stirred for 10 minutes at -40°and for 1 hour on ice. The reaction mixture was suppressed by the addition of ice and water and then was extracted with a mixed solvent consisting of hexane and tert-butylmethylether simple ether (hexane/tert-butylmethylamine simple is th ether=4/1). The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue triturated with methanol to precipitate solids. The solids were collected by filtration and dried in vacuum, obtaining 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraen (14,92 g, yield 90%).

1H-NMR (300 MHz, Dl3,): δ 7,46-7,25 (m, 11N), 6,78 to 6.75 (m, 2H, C2 and C4-H), 6,01-of 5.89 (m, 1H, olefinic H), 5,18-5,09 (m, 2H, olefinic H), is 5.06 (s, 2H), 4,58 (s, 2H), to 3.58 (t, J=8,4 Hz, 1H, C17-H), 3,30 (DD, J=15,8 and 5.1 Hz, 1H, CH of allyl2), 2,81-of 2.72 (m, 3H), 2,48 (d, J=17,4 Hz, 1H, allylic CH2), 2,16-of 1.36 (m, N), of 0.90 (s, 3H, C18-H).

(Stage 7)

Benzylidene(tricyclohexylphosphine)dichloroethene (90 mg, 0.1 mmol) was added to a solution of 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene (1.0 g, 2.0 mmol) and ethyl-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-decenoate (1,81 g, 4.1 mmol) in dichloromethane (20 ml) followed by heating at boiling under reflux for 5 hours in nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified flash chromatography on silica gel (eluent: hexane/ethyl acetate=4/1)to give this the l-11-[3,17β bis(benzyloxy)östra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecenoate (863 mg, yield 48%).

1H-NMR (270 MHz, Dl3,): δ 7,46-7,21 (m, 11N), is 6.78-6.73 x (m, 2H), 5,50-5,42 (m, 2H), of 5.05 (s, 2H), 4,57 (d, J=2,5 Hz, 2H), 4,15 (kV, J=7,1 Hz, 2H, COO-CH2), 3,60-to 3.52 (m, 1H, 17-CH), 3,20-3,11 (m, 1H), 2,82 of 2.68 (m, 3H), of 2.51-2,22 (m, 2H), 2,20-of 1.16 (m, 28N), of 0.87 (s, 3H, C18-CH3).

(Stage 8)

Ethyl-11-[3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecenoate (500 mg, 0.55 mmol) was dissolved in a mixed solvent consisting of methanol (10 ml) and tetrahydrofuran (1 ml) followed by addition of palladium hydroxide-on-carbon (150 mg) at room temperature. After blowing hydrogen, the reaction mixture was stirred for 23 hours at room temperature and then filtered. The solvent was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate=4/1 3/1 2/1)to give ethyl-11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoate (287 mg, 71%yield).

1H-NMR (270 MHz, Dl3,): δ 7,00 (d, J=8.6 Hz, 1H, Cl-CH), 6,62 (d, J=8.5 Hz, 1H, C2-CH), is 6.54 (d, J=2.3 Hz, 1H, C4-CH), 5,03 (users, 1H, C3-OH), 4,17 (kV, J=7,1 Hz, 2H, COO-CH2), 3,70 (t, J=7.9 Hz, 1H, 17-CH), 2,83-2,60 (m, 2H), 2,58-of 2.30 (m, 3H), 2,24-of 1.74 (m, 7H), 1,74-1,11 (m, 29N), to 0.92 (s, 3H, C18-CH3).

p> (Stage 9)

Ethyl-11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoate (747 mg, of 1.02 mmol) was dissolved in a mixed solvent consisting of ethanol (5 ml) and water (5 ml). To this solution was added NaOH (82 mg, 2.04 mmol) and the resulting mixture was heated for 15 hours at 60°C. After cooling, to the reaction mixture were added 2 N. aqueous hydrochloric acid, then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and then filtered. After concentration under reduced pressure, the obtained residue was purified column chromatography on silica gel (hexane/ethyl acetate=4/1 3/1 2/1)to give 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid (600 mg, yield 84%).

1H-NMR (270 MHz, CD3OD): δ to 6.95 (d, J=8,3 Hz, 1H, Cl-CH), 6,55 (DD, J=8,3, 2,3 Hz, 1H, C2-CH), 6,47 (d, J=2.3 Hz, 1H, C4-CH), 3,63 (t, J=8.6 Hz, 1H, 17-CH), 2,85-of 2.58 (m, 2H), 2,55-of 2.34 (m, 3H), 2,30-of 1.93 (m, 2H), 1,91 is 1.75 (m, 3H), 1,75-1,10 (m, N), to 0.92 (s, 3H, C18-CH3).

Example 21

Synthesis of 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,5-pentafluorophenyl)decanoas acid

On the basis of 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene obtained in the use of the e 20, and ethyl-2-(4,4,5,5,5-pentafluorophenyl)-8-nonenoate obtained separately, repeating the same technique as described in example 20 to give 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,5-pentafluorophenyl)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ 6,99 (d, J=8.7 Hz, 1H, Cl-CH), 6,62 (d, J=8,2 Hz, 1H, C2-CH), 6,55 (d, J=2.3 Hz, 1H, C4-CH), 4,87-3,82 (users, 1H, C3-OH), to 3.73 (t, J=7,4 Hz, 1H, 17-CH), 2,84-to 2.65 (m, 2H), of 2.51 (m, 1H), 2,39 (m, 2H), 2,24-1,12 (m, N), of 0.91 (s, 3H, C18-CH3).

Example 22

Synthesis of 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)decanoas acid

On the basis of 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene obtained in example 20, ethyl-2-(4,4,5,5,6,6,7,7,7-nonoperated)-8-nonenoate obtained separately, repeating the same technique as described in example 20 to give 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ 7,11 (d, J=8,3 Hz, 1H, Cl-CH), 6,62 (d, J=8.6 Hz, 1H, C2-SN), is 6.54 (d, J=2.7 Hz, 1H, C4-CH), 3,94-3,07 (users, 1H, C3-OH), and 3.72 (t, J=7,4 Hz, 1H, 17-CH), 2,82-2,62 (m, 2H), 2,52 (m, 1H), is 2.40 (m, 2H), 2.23 to-1,11 (m, N), of 0.91 (s, 3H, C18-CH3).

Example 23

Synthesis of 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)decanoas acid

On the basis of 3,17βbis(benzyloxy)-11-(2-prop is silt)östra-1,3,5(10),9(11)-tetraene, obtained in example 20, ethyl-2-(3,3,4,4,5,5,6,6,6-nonforensic)-8-nonenoate obtained separately, repeating the same technique as described in example 20 to give 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ 7,07 (d, J=8.5 Hz, 1H), 6,65 (DD, J=8,2, 2.1 Hz, 1H), 6,47 (d, J=2.6 Hz, 1H), 3,82 (t, J=8,2 Hz, 1H), 2.91 in-of 2.58 (m, 2H), 2,53-of 2.23 (m, 3H), 2,19-1,89 (m, 4H), 1.85 to 1,02 (m, N), to 0.92 (s, 3H).

Example 24

Synthesis of 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,5-pentafluorophenyl)undecanoic acid

On the basis of 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene obtained in example 20, ethyl-2-(4,4,5,5,5-pentafluorophenyl)-9-decenoate obtained separately, repeating the same technique as described in example 20, receiving 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,5-pentafluorophenyl)undecanoyl acid.

1H-NMR (270 MHz, Dl3,): δ 7,00 (d, J=8,4 Hz, 1H), 6,59 (DD, J=8,7, 2,Hz, 1H), is 6.54 (d, J=2.7 Hz, 1H), of 3.73-3,71 (m, 1H), 2,88-2,82 (m, 2H), 2,58 is 2.33 (m, 3H), 2,24-of 1.18 (m, 34N), to 0.92 (s, 3H).

Example 25

Synthesis of 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)undecanoic acid

On the basis of 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene obtained in example 20, ethyl-2-(4,4,5,5,6,6,7,7,7-nonaf orgati)-9-decenoate, received separately, repeating the same technique as described in example 20, receiving 11-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)undecanoyl acid.

1H-NMR (270 MHz, CD3OD): δ 7,07 (d, J=8,4 Hz, 1H, Cl-CH), is 6.54 (DD, J=8,4, 2.3 Hz, 1H, C2-CH), 6,45 (d, J=2.3 Hz, 1H, C4-CH), to 3.67 (t, J=8,3 Hz, 1H, 17-CH), 2,85-2,62 (m, 2H), 2.05 is and 1.80 (m, 7H), 1,80-to 0.96 (m, N), of 0.91(s, 3H, C18-CH3).

Example 26

Synthesis of 10-(3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(6,6,7,7,7-pentaverate)decanoas acid

10-(3,17β-Dihydroxyethane-1,3,5(10)-triene-11β-yl)-2-(6,6,7,7,7-pentaverate)cekanova acid obtained in example 12, can also be synthesized by a method similar to that described in example 20 from 3,17βbis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraene, and separately obtained ethyl-2-(6,6,7,7,7-pentaverate)-8-nonenoate.

Example 27

Synthesis of 12-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene obtained separately diethyl-2-(8-nonenal)-2-(4,4,5,5,5-pentafluorophenyl)malonate, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (270 MHz, Dl3 ,): δ 7,98 (d, J=9 Hz, 1H, Ar-H), 7,53 (d, J=8 Hz, 1H, Ar-H), 7,28 for 7.12 (m, 5H, Ar-H), 6.89 in (d, J=9 Hz, 2H, Ar-H), 2,96-2,90 (m, 2H, naphthyl-CH2-), 2,44-to 2.42 (m, 1H, -CHCO2), 2,18-of 1.18 (m, 24N, alkyl-H).

Example 28

Synthesis of 11-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid

On the basis of 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene and separately obtained diethyl-2-(7-octenyl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)malonate, repeating the same methods as described in examples 1, 2 and 3, receiving 11-[6-hydroxy-2-(4-hydroxyphenyl)naphthas-1-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid.

1H-NMR (300 MHz, Dl3,): δ 7,98 (d, J=8,9 Hz, 1H, Ar-H), 7,53 (d, J=8,4 Hz, 1H, Ar-H), 7,13-7,28 (m, 5H, Ar-H), 6.89 in (d, J=8.5 Hz, 2H, Ar-H), of 2.92 (t, J=8,1 Hz, 2H, naphthyl-CH2), 2,46-2,48 (m, 1H, SNCO2N)1,95-of 2.20 (m, 2H, CH2CF2), 1,18-2,11 (m, N, alkyl-H).

Mass spectrum (ESI): 667 (M+1).

Example 29

Synthesis of 12-[6-hydroxy-2-(4-hydroxy-2-were)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 4-methoxy-2-methylphenylacetic acid, obtained separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[6-hydroxy-2-(4-hydroxy-2-were)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

Ȋ 1H-NMR (300 MHz, Dl3,): δ of 7.97 (d, J=8,9 Hz, 1H), 7,53 (d, J=8,4 Hz, 1H), 7,19-7,10 (m, 3H), 7,02 (d, J=8,3 Hz, 1H), 6,77 (d, J=2.1 Hz, 1H), 6,70 (DD, J=8,3, 2.1 Hz, 1H), 4,8 (user., 3H), from 3.0 to 2.8 (m, 1H), 2,7-2,5 (m, 1H), 2,5-2,3 (m, 1H), 2,1 to 1.9 (m, 2H), 1,99 (s, 3H, CH3), 1,8-1,0 (m, 22N).

Example 30

Synthesis of 12-[2-(2-ethyl-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 2-ethyl-4-methoxyphenylacetic acid, obtained separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[2-(2-ethyl-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (300 MHz, Dl3): δ of 7.97 (d, J=9.1 Hz, 1H, Ar-H), 7,52 (d, J=8,4 Hz, 1H, Ar-H), 7,06-of 7.23 (m, 3H, Ar-H), 6,85 (d, J=8,2 Hz, 1H, Ar-H), 6,79 (d, J=2.6 Hz, 1H, Ar-H), is 6.61 (DD, J=8,2, 2.6 Hz, 1H, Ar-H), 2,81-of 2.93 (m, 1H, naphthyl-CH2), 2,49 is 2.75 (m, 1H, naphthyl-CH2), 2,39-of 2.50 (m, 1H, CHCO2H), 2,18-to 2.29 (m, 2H, Agsn2CH3), 1,91-2,12 (m, 2H, CH2CF2), 0,95-1,72 (m, 25N, alkyl-H).

Mass spectrum (ESI): 623 (M+1).

Example 31

Synthesis of 12-[2-(2-fluoro-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 2-fluoro-4-methoxyphenylacetic acid, extracting the Noah separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[2-(2-fluoro-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (300 MHz, Dl3,): δ of 7.97 (d, J=9.1 Hz, 1H, Ar-H), 7,52 (d, J=8.5 Hz, 1H, Ar-H), 7,06-7,25 (m, 4H, Ar-H), 6,64-6,69 (m, 2H, Ar-H), 2,81-2,90 (m, 2H, naphthyl-CH2), 2,40-of 2.50 (m, 1H, CHCO2H), 1,90-2,10 (m, 2H, CH2CF2), of 1.05 to 1.75 (m, 22N, alkyl-H).

Mass spectrum (ESI): 613 (M+1).

Example 32

Synthesis of 12-[6-hydroxy-2-(4-hydroxy-2-triptoreline)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 4-methoxy-2-triftormetilfullerenov acid, obtained separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[6-hydroxy-2-(4-hydroxy-2-triptoreline)naphthas-1-yl]-2-(4,4,5,5,5-pentafluorophenyl) dodecanoyl acid.

1H-NMR (270 MHz, Dl3,): δ of 7.96 (d, J=9 Hz, 1H, Ar-H), to 7.50 (d, J=8 Hz, 1H, Ar-H), 7.24 to 7,01 (m, 6N, Ar-H), 2,89-2,84 (m, 1H), of 2.51-to 2.42 (m, 2H), 2,11-1,15 (m, 24N, alkyl-H).

Example 33

Synthesis of 12-[2-(3-fluoro-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 3-fluoro-4-methoxyphenylacetic acid, extracting the Noah separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[2-(3-fluoro-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (270 MHz, Dl3,): δ of 7.96 (d, J=9 Hz, 1H, Ar-H), 7,51 (d, J=8 Hz, 1H, Ar-H), 7.24 to to 6.95 (m, 6N, Ar-H), 2,94-is 2.88 (m, 2H, naphthyl-CH2-), 2,39 (m, 1H, -SNCO2), 2,16-of 1.18 (m, 24N, alkyl-H).

Example 34

Synthesis of 12-[2-(3,5-debtor-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 3,5-debtor-4-methoxyphenylacetic acid, obtained separately, repeating the same methods as described in examples 1, 2 and 3, receiving 12-[2-(3,5-debtor-4-hydroxyphenyl)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (300 MHz, Dl3,): δ 7,98 (d, J=9.9 Hz, 1H, Ar-H), 7,53 (d, J=8.5 Hz, 1H, Ar-H), 7,14-7,26 (m, 3H, Ar-H), 6,85-of 6.90 (m, 2H, Ar-H), 2,88-to 2.94 (m, 2H, naphthyl-CH2), 2,39-2,48 (m, 1H, SNCO2N), 2,01-2,12 (m, 2H, CH2CF2), 1,24-of 1.88 (m, N, alkyl-H).

Mass spectrum (ESI): 631(M+1).

Example 35

Synthesis of 12-[2-(4-forfinal)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanol acid

On the basis of 6-methoxy-1-(2-propenyl)-2-aftertreatment obtained in example 1 and 4-ftorhinolonovy acid obtained is separately repeating the same methods as described in examples 1, 2 and 3, receiving 12-[2-(4-forfinal)-6-hydroximate-1-yl]-2-(4,4,5,5,5-pentafluorophenyl)dodecanoyl acid.

1H-NMR (270 MHz, Dl3,): δ 7,98 (d, J=9 Hz, 1H, Ar-H), 7,54 (d, J=8 Hz, 1H, Ar-H), 7,31-7,07 (m, 7H, Ar-H), 2,93-2,87 (m, 2H, naphthyl-CH2-), 2,46 to 2.35 (m, 1H, -SNCO2), 2,15-1,14 (m, 24N, alkyl-H).

Example 36

Synthesis of (2R)-11-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid

(Stage 1)

Anhydrous tetrahydrofuran (10 ml) was added to (4S, 5R)-3,4-dimethyl-1-(5,5,6,6,7,7,8,8,8-nonoperational)-5-phenylimidazole-2-ONU (1.20 g, 2.5 mmol) under nitrogen atmosphere and the resulting mixture was cooled to -78°C. To the mixture was added bis(trimethylsilyl)amide lithium (2,75 ml, 1.0 M in tetrahydrofuran, to 2.75 mmol), then stirred for 1 hour. After addition of 8-bromo-1-octene (714 mg, 3.0 mmol) and NMR (1.25 ml) at -78°the reaction mixture was heated with stirring to -50°C for 2 hours and 0°C for 30 minutes and then stirred for 12 hours at 0°C. the Reaction mixture was extinguished saturated aqueous ammonium chloride at 0°and then was extracted with a mixed solvent consisting of ethyl acetate and n-hexane (3:7). The organic layer was washed sequentially with a saturated aqueous solution of potassium bisulfate, saturated aq is m solution of sodium chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue was purified column chromatography on silica gel (Kanto Called, silica gel 60 (spherical, neutral), 40-100 μm, eluent: ethyl acetate/n-hexane=1/5 3/7)to give (4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-decanoyl]-5-phenylimidazole-2-he (to 1.37 g, yield 93%).

Optical purity: 95.5% of de (diastereomeric excess), as measured by HPLC (column: Daicel Chiralpack AD, φ 0,46×25 cm; solvent: n-hexane/isopropanol=97/3, flow rate: 0.5 ml/min, detected wavelength: 206 nm).

1H-NMR (270 MHz, Dl3,): δ 7,32-7,13 (m, 5H), by 5.87-5,72 (m, 1H), of 5.34 (d, J=8,9 Hz, 1H), 5,02-4,91 (m, 2H), 4,10-3,86 (m, 2H), 2,84 (s, 3H), 2,19-1,08 (m, N), of 0.82 (d, J=6.5 Hz, 3H).

(Stage 2)

3-Methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol (377 mg, of 1.16 mmol) and (4S, 5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-decanoyl]-5-phenylimidazole-2-he (1,36 g, 2,31 mmol) was dissolved in anhydrous dichloromethane (12 ml) at room temperature under nitrogen atmosphere. To this solution was added benzylidene(tricyclohexylphosphine)dichloroethene (47,5 mg, 5,78×10-2mmol) and see what camping was heated at the boil under reflux for 5 hours in nitrogen atmosphere. After cooling, the reaction mixture was filtered through a layer of aluminum oxide. The filtrate was concentrated under reduced pressure and the obtained residue was purified flash chromatography on silica gel (Kanto Called, silica gel 60 (spherical, neutral), 40-100 μm, eluent: ethyl acetate/n-hexane=1/1)to give a mixture of (4S, 5R)-3,4-dimethyl-1-[(2R, 9F)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecanoyl]-5-phenylimidazole-2-he (4S, 5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecanoyl]-5-phenylimidazole-2-he (579 mg, yield 57%).

1H-NMR (300 MHz, Dl3,): δ 7,33 for 7.12 (m, 6N), 6.73 x-6,69 (m, 1H), 6,61-6,56 (m, 1H), 5,42-a 5.25 (m, 3H), 4,05-a 3.87 (m, 2H), of 3.77-3,70 (m, 4H), 2,90-a 2.71 (m, 5H), 2,38 was 1.06 (m, 31N), or 0.83 -0,78 (m, 6N).

(Stage 3)

A mixture of (4S, 5R)-3,4-dimethyl-1-[(2R,9F)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecanoyl]-5-phenylimidazole-2-he (4S, 5R)-3,4-dimethyl-1-[(2R,9Z)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecanoyl]-5-phenylimidazole-2-he (579 mg, 653 mmol) was dissolved in ethyl acetate (14 ml) followed by addition of 10%palladium-on-carbon (58 mg) at room temperature. After blowing hydrogen, the reaction mixture was stirred for 19 hours at room is the temperature. After filtering the reaction mixture through celite, the solvent was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (Kanto Called, silica gel 60 (spherical, neutral), 40-100 μm, eluent: ethyl acetate/n-hexane=1/1)to give (4S,5R)-3,4-dimethyl-1-[(2R)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl]-5-phenylimidazole-2-he (579 mg, yield 100%).

1H-NMR (300 MHz, Dl3,): δ 7,33-7,11 (m, 6N), 6.73 x-6,70 (m, 1H), 6,69-6,62 (m, 1H), 5,33 (d, J=7.8 Hz, 1H), 4,05-3,86 (m, 2H), 3,79-3,71 (m, 1H), of 3.77 (s, 3H), 2,94-of 2.72 (m, 2H), 2,84 (s, 3H), 2,38 is 0.99 (m, N), of 0.82 (d, J=5,9 Hz, 3H), 0,78 (s, 3H).

(Stage 4)

(4S, 5R)-3,4-Dimethyl-1-[(2R)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl]-5-phenylimidazole-2-he (445 mg, 0.50 mmol) was dissolved in anhydrous dimethyl ether of ethylene glycol (5 ml) under nitrogen atmosphere and then cooled to 0°C. To this solution was added a solution of hydroxide Tetra-n-butylamine (40% weight/weight, 649 mg, 1.0 mmol) and aqueous hydrogen peroxide (30% weight/weight, 113 mg, 1.0 mmol) and the resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was extinguished saturated aqueous sodium thiosulfate, acidified with a saturated aqueous solution of potassium bisulfate and then extracted with ethyl acetate. Org the organic layer was washed with a saturated aqueous solution of sodium chloride, was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue was purified column chromatography on silica gel (Wako gel C-200, eluent: ethyl acetate/n-hexane=4/6 8/2)to give (2R)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid (360 mg, yield 100%) and (4R, 5S)-1,5-dimethyl-4-phenylimidazoline-2-he (93 mg, yield 98%).

1H-NMR (300 MHz, Dl3,): δ 7,21-to 7.18 (m, 1H), 6.73 x-6,69 (m, 1H), 6,62-of 6.61 (m, 1H), 6.30-in (users, 1H), 3,79-3,71 (m, 1H), of 3.77 (s, 3H), 2,93-of 2.72 (m, 2H), 2,47-a 1.01 (m, 36N), to 0.78 (s, 3H).

(Stage 5)

Anhydrous dichloromethane (10 ml) was added to (2R)-11-(17β-hydroxy-3-petoksista-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid (358 mg, 0.50 mmol) under nitrogen atmosphere and the resulting mixture was cooled to -78°C. To the mixture was added dropwise tribromide boron (1.0 M in tetrahydrofuran, 3 ml, 3.0 mmol), then stirred on ice for 2.5 hours. The reaction mixture was again cooled to -78°and extinguished saturated aqueous sodium bicarbonate for 1 hour. After extraction of the reaction mixture with ethyl acetate the organic layer was washed sequentially with a saturated aqueous solution of potassium bisulfate, saturated aqueous sodium chloride, saturated the aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure using a rotary evaporator and the resulting residue was purified column chromatography on silica gel (Wako gel C-200, eluent: ethyl acetate/n-hexane=4/6)to give (2R)-11-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid (231 mg, yield 60%) as a yellow amorphous mass.

Chemical purity: 99,05% 98,63% detection at a wavelength of 280 and 219 nm, respectively, as measured by HPLC (column: YMC-Pack ODS-A, A-312 ⊘0,6×15 cm; solvent: H2O/MeCN/TFOC=30/70/0,1, flow rate: 1.0 ml/min).

Optical purity: 96,3%de (diastereomeric excess), as measured by HPLC (column: Daicel Chiralpack AD, ⊘0,46×25 cm; solvent: n-hexane/isopropanol/TFOC=90/10/0,1, flow rate: 0.5 ml/min, wavelength of detection: 280 nm).

1H-NMR (270 MHz, Dl3,): δ 7,16-7,13 (m, 1H), 6,64-6,60 (m, 1H), 6,55-is 6.54 (m, 1H), 3,74 (t, J=8.6 Hz, 1H), 2.91 in-to 2.67 (m, 2H), 2,50-a 1.01 (m, 36N), to 0.78 (s, 3H).

Example 37

Synthesis of (2R)-10-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol and (4S,5R)-3,4-dimethyl-1-[(2R)-2-(4,4,5,5,6,6,7,7,7-nonoperated)-8-nonanoyl]-5-phenylimidazole-2-it, polycentral by the method of example 36, repeating the method similar to example 36, receiving (2R)-10-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ for 7.12 (d, J=8,4 Hz, 1H), of 6.68 (DD, J=8,5, 2.4 Hz, 1H), 6,53 (d, J=2.6 Hz, 1H), 3,68 (t, J=8.5 Hz, 1H), 2.95 and-2,60 (m, 2H), 2,47-2,19 (m, 4H), 2,18-of 1.03 (m, 31N), is 0.69 (s, 3H).

Example 38

Synthesis of (2S)-10-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)decanoas acid

On the basis of 3-methoxy-7α-(2-propenyl)östra-1,3,5(10)-triene-17β-ol and (4R,5S)-3,4-dimethyl-1-[(2S)-2-(4,4,5,5,6,6,7,7,7-nonoperated)-8-nonanoyl]-5-phenylimidazole-2-she received separately by way of example 36 was repeated method, analogously to example 36, receiving (2S)-10-(3,17β-dihydroxyethane-1,3,5(10)-triene-7α-yl)-2-(4,4,5,5,6,6,7,7,7-nonoperated)dekanovu acid.

1H-NMR (300 MHz, Dl3,): δ for 7.12 (d, J=8,4 Hz, 1H), of 6.68 (DD, J=8,5, 2.4 Hz, 1H), 6,53 (d, J=2.6 Hz, 1H), 3,68 (t, J=8.5 Hz, 1H), 2.95 and-2,60 (m, 2H), 2,47-2,19 (m, 4H), 2,18-of 1.03 (m, 31N), is 0.69(s, 3H).

Example 39

Synthesis of (2R)-11-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoic acid

(Stage 1)

3,17βBis(benzyloxy)-11-(2-propenyl)östra-1,3,5(10),9(11)-tetraen (491 mg, 1.00 mmol) and (4S,5R)-3,4-dimethyl-1-[(2R)-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-decanoyl]-5-phenylimidazole-2-he (1.18 g, 2.00 mmol), receiving the hydrated in example 36, was dissolved in anhydrous dichloromethane (10 ml) at room temperature in a nitrogen atmosphere, mixed with benzylidene(tricyclohexylphosphine)dichlororuthenium (41 mg, 0.05 mmol) and then heated at the boil under reflux, followed by stirring for 6 hours in nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the obtained residue was purified flash chromatography on silica gel (eluent: ethyl acetate/n-hexane = 3/7)to give a mixture of (4S, 5R)-1-{(2R, 9F)-11-[3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecenoic}-3,4-dimethyl-5-phenylimidazole-2-she and (4S,5R)-1-{(2R,9Z)-11-[3,17βbis(benzyloxy)östra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecanoyl)-3,4-dimethyl-5-phenylimidazole-2-it (664 mg, yield 63%).

1H-NMR (270 MHz, Dl3,): δ 7,45-7,10 (m, N), 6,78-6,70 (m, 2H), 5,58-of 5.40 (m, 2H), 5,32 (d, J=8.7 Hz, 1H), 5,04 (s, 2H), 4,65-4,50 (m, 2H), 4,10-of 3.80 (m, 2H), 3,62-to 3.50 (m, 1H), 3,22 was 3.05 (m, 1H), and 2.83 (s, 3H), 2,80-2,60 (m, 3H), 2,52-of 2.30 (m, 1H), 2,20-1,0 (m, 25N), of 0.87 (s, 3H, C18-CH3), 0,81 (d, J=6.6 Hz, 3H).

(Stage 2)

A mixture of (4S,5R)-1-{(2R,9F)-11-[3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecenoic}-3,4-dimethyl-5-phenylimidazole-2-she (4S,5R)-1-{(2R,9Z)-11-[3,17βbis(benzyloxy)östra-1,3,5(10),9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)-9-undecene the l}-3,4-dimethyl-5-phenylimidazole-2-she (283 mg, 0.27 mmol) was dissolved in a mixed solvent consisting of methanol (12 ml) and tetrahydrofuran (1.2 ml), followed by the addition of palladium hydroxide on carbon (85 mg) at room temperature. After blowing hydrogen, the reaction mixture was stirred for 1 day at room temperature. After filtration of the reaction mixture the solvent was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: ethyl acetate/n-hexane = 3/7)to give (4S,5R)-1-{(2R)-11-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl}-3,4-dimethyl-5-phenylimidazole-2-he (164 mg, yield 70%).

1H-NMR (300 MHz, Dl3,): δ of 7.36 for 7.12 (m, 5H), 6,94-to 6.88 (m, 1H), 6,56-of 6.52 (m, 1H), 6,44-6,36 (m, 1H), 5,64 (s, 1H), 5,35 (d, J=8.7 Hz, 1H), 5,70-of 5.15 (m, 3H), of 4.38 (s, 3H), 4,40-2,60 (m, 36N), 2,43 (s, 3H), 2,34 (d, J=the 6.6 Hz, 3H).

(Stage 3)

(4S,5R)-1-{(2R)-11-[3,17β-Dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl}-3,4-dimethyl-5-phenylimidazole-2-he (140 mg, 0.16 mmol) was dissolved in DME (3 ml). To this solution was added a solution of hydroxide, Tetra-n-butylamine (40% weight/weight, 312 mg, 0.48 mmol) and aqueous hydrogen peroxide (30% weight/weight, 56 mg, 0.48 mmol) and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was extinguished 10%aqueous solution of sulfi the sodium, acidified 2 N. hydrochloric acid and then was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified column chromatography on silica gel (Wako gel C-200, eluent: ethyl acetate/n-hexane = 3/7), then preparative HPLC (YMC-ODS-5-B (3×25 cm), eluent: acetonitrile/water/triperoxonane acid = 90/10/0,1, flow rate: 18 ml/min)to give the target compound (2R)-11-[3,17β-dihydroxyethane-1,3,5(10)-triene-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonforensic)undecanoyl acid (58 mg, yield 52%).

1H-NMR (300 MHz, Dl3,): δ 7,00 (d, J=8,4 Hz, 1H, Cl-CH), 6,55 (DD, J=8,4, 2.4 Hz, 1H, C2-CH), is 6.54 (d, J=2.4 Hz, 1H, C4-CH in), 3.75 (t, J=7.5 Hz, 1H), 2,85-1,10 (m, N), to 0.92 (s, 3H, C18-CH3).

Chemical purity: 98.4 per cent, as measured by HPLC (column: YMC-Pack ODS-A, A-312 ⊘0,6×15 cm; solvent: H2O/MeCN/TFOC=30/70/0,1, flow rate: 1.0 ml/min, wavelength of detection: 220 nm).

Optical purity: 95.7%and de (diastereomeric excess), as measured by HPLC (column: Daicel Chiralpack AD, ⊘0,46×25 cm; solvent: n-hexane/isopropanol/TFOC = 92/8/0,08, flow rate: 0.5 ml/min, wavelength of detection: 280 nm).

Example test 1: Antiestrogenic activity (oral administration)

Test compounds and is followed on their oral anti-estrogenic activity in the following way. In this experiment, test compounds used compounds obtained in examples 5, 12, 14-33, 37 and 38. As control compounds used are those that have the same structure of the original frame, and the test compound, i.e. ZM189154 for examples 5 and 27-33 and ICI182780 for examples 12, 14-26, 37 and 38.

To determine the antiestrogenic activity of mice (ICR, weight 30±2 g), which was ovariectomized 2 weeks before, was administered subcutaneously 17β-estradiolelisaut (Sigma) in an amount of 0.1 μg/mouse for 3 days and measured the degree to which the test compound inhibited the increase in weight of the uterus. In this experiment, each of the test and control compounds suspended in 5%solution of Arabian gum and is administered orally for 3 days at the rate of once a day. 24 hours after the last injection of test animals were killed, the uterus was removed and weighed. The results obtained are presented in table 2.

Table 2

Antiestrogenic activity for ovariectomised mice with the introduction of 17β-estradiol (oral administration, 3 days)
The analyzed compound/dose (oral (r.o.), 3 days)Inhibition (%)
Connection mg/kg
Example 51067
Example 271064
Example 281068
Example 291080
Example 301058
Example 311075
Example 321073
Example 331064
ZM1891541042
Example 121097
Example 141087
Example 151096
Example 161098
Example 171094
Example 181085
Example 191092
Example 201094
Example 211099
Example 221098
Example 231098
Example 241098
Example 251093
Example 261096
Example 3710101
Example 3810100
ICI1827801051

The results in table 2 show that the compounds having a side chain of the General formula (1) according to the present invention, exhibit excellent inhibitory activity against induced by estradiol increased weight of the uterus in comparison with antiestrogenic control connections ZM189154 and ICI182780, which had the same original frame, but had no similar side chain.

Industrial applicability

Compounds of the present invention have a side chain of the General formula (1). Such a side chain allows the compounds according to the invention show improved bioavailability and significantly high activity when administered orally in comparison with conventional compounds, not having such a side chain, such as compounds with low activity when administered orally, the compounds with antitumor activity, compounds with estrogenic activity or compounds with antiestrogenic activity. Consequently, the compounds of the present invention are predominant when f is pharmaceutical use.

1. The compound having the following General formula (2):

in which

R1represents a hydrogen atom or a salt-forming metal,

R2is a straight or branched C1-C7halogenating group,

m represents an integer from 2 to 14, and

n represents an integer from 2 to 7, and

A represents a group selected from the following formulas(3)-(6), (17)-(20), (23), (25) and (26):

where

in the formula (6) R3is a straight or branched C1-C5alkyl group,

in formulas (18) and (20) R8is a straight or branched C1-C5alkyl group, straight or branched C2-C5alkenylphenol group or a straight or branched C2-C5alkylamino group,

in the formula (23) each and the R 21, R22, R23and R24independently represents a hydrogen atom, a straight or branched C1-C5alkyl group, straight or branched C1-C7halogenating group, halogen atom or acyl group, and

in formulas (25) and (26) X represents a halogen atom, or enantiomers of the compound, or a hydrate or pharmaceutically acceptable salt of the compound or its enantiomers.

2. The compound or its enantiomers or hydrates, or pharmaceutically acceptable salt of the compound or its enantiomers according to claim 1, where R2is a straight or branched C1-C5perhalogenated group or a group of the following General formula (9):

in which each of R4and R5that may be the same or different, represents a straight or branched C1-C3perhalogenated group.

3. The compound or its enantiomers or hydrates, or pharmaceutically acceptable salt of the compound or its enantiomers according to claim 1 or 2, where the halogen atom in halogenoalkanes group represents a fluorine atom.

4. The compound or its enantiomers or hydrates, or pharmaceutically acceptable salt of the compound or its enantiomers according to any one of claims 1 to 3, where a represents a group of formula(3), (4), (5), (6), (17), (18), (19), (20) or (23) and m depict is to place an integer from 4 to 10.

5. The compound or its enantiomers or hydrates, or pharmaceutically acceptable salt of the compound or its enantiomers according to any one of claims 1 to 4, where the carbon atom in the General formula (2)is attached to-COOR1the group has the R - or S-configuration.

6. Pharmaceutical composition having anti-estrogenic effect, containing a compound according to any one of claims 1 to 5 as an active ingredient.

7. Therapeutic agent against breast cancer containing the compound according to any one of claims 1 to 5 as an active ingredient.

8. Method of preparing compounds according to claim 1, which includes stages:

i) olefin metathesis of compounds of formula

where R11and R12represent a protective group, with a compound of the formula

where R13represents a protective group, m1represents an integer m-2, and R2, m and n have the meanings indicated in claim 1;

ii) hydrogenation of a double bond;

iii) removing the protective group OR11;

iv) hydrolysis group-CO2R13; and

v) decarboxylation one carboxyl group, provided that at stage i) is a compound of formula (II), step (v) of the method is excluded.

9. The intermediate compound of the formula

where R13is carboxyamide group, m1represents an integer m-2, and R2represents an alkyl fluoride group, m and n have the meanings indicated in claim 1.

10. The intermediate connection according to claim 9, where R2is performanceline group.

Priority points and features:

13.12.1999 according to claim 1 claims for compounds, where A represents a group selected from formulas (3)to(6); according to claim 2, 3, 5, 6; according to claim 4, where A represents a group selected from formulas (3)to(6); PP-10.

24.11.2000 according to claim 1 claims for compounds, where A represents a group selected from formulas (17)-(20); according to claim 4, where A represents a group selected from formulas (17)-(20); item 8.

13.12.2000 according to claim 1 claims for compounds, where A represents a group selected from formulas (23), (25) and (26); according to claim 4, where A represents a group selected from formulas (23), (25) and (26); 7.



 

Same patents:

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 new steroid of General formula I, which manifest themselves as effective antagonists progestins and as mixed or partial agonists progestin

where

R1- (R2R3N(O)r)-, where r=0, 1, each of R2and R3independently - H, C1-6alkyl; or R1-

where q=0, - 1, Y-(CH2)m-, where m=1, 2, 3, 4, 5; or

R1- C1-6alkyl-CO-; R12Is n; X Is O or

,

where -(CH2)m-, where m=2; R6=H; R7=H, C1-6alkyl, C2-6alkenyl,2-6quinil, perhaps HE or substituted BASED; S=0, 1; each of the8and R9independently - H, HE, C1-6alkyl, R10CO., where R10’- H, C1-6alkyl

-Östra-1,3,5(10)-triene-3,17-diol" target="_blank">

The invention relates to labeled steroids, specifically to vysokomernoa tritium-hydroxyestra-1,3,5(10)-triene-17-huili-östra-1,3,5(10)-triene-3,17-diolo General formula I, where R = 0 or R = -HE

The invention relates to an improved method of obtaining on-arilpirolii acids of the formula ArOCH2COOH

The invention relates to an improved method of obtaining a known anti-inflammatory agents - furoate mometasone (I)

The invention relates to new triaromatic the vitamin D analogues of General formula (I):

where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)

where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)

R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,

R3-

where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to derivatives of 2-phenyl-benzo(b) furan and thiophene, which may be suitable for the treatment of dependent estrogenos diseases, such as prostatic hyperplasia, breast cancer, endometrial cancer, populating infertility and melanoma

The invention relates to new optically active proizvodnim of benzopyran formula

< / BR>
where R and R are independently selected from the group consisting of hydroxyl and a moiety that can be converted in vivo in hydroxyl, such as acyloxy, -OR4, -OC(O)R7or-OC(O)OR4(where R4represents alkyl, alkenyl, quinil or aryl; and R7represents amino, alkylamino, aminoalkyl and alkylsulfonyl); and R3represents-CH2- or-CH2CH2-; or its pharmaceutically acceptable salt, where the specified compound or salt is optically active because they contain more than 50% (by weight relative to all stereoisomers) 2S stereoisomers

The invention relates to new derivatives of 4-promenaden, namely derivatives of the formula

where I R1= -OH

R2= --CH3R3= - OH

II R1= -H; R2= -C1; R3= -OH

III R1= -O--CH3; R2= -H;

R3= -Nhaving antiallergic activity, which can be used in medicine

The invention relates to new benzoxazine and piridokshinom compounds of formula I, where part of the Q - condensed phenyl, or condensed pyridyl; Z1is hydrogen, halogen, C1-C6alkyl, phenyl, nitro, sulfonylamino or trifluoromethyl; Z2is hydrogen or halogen; X is hydrogen or oxygen; And - C1-C6-alkyl, C1-C6-alkylaryl or C1-C6-Alkylglucoside, where aryl and heterocyclyl described in the claims, n = 0 to 3; Y is the portion described in the claims, and their pharmaceutically acceptable salts, esters and proletarienne forms

The invention relates to the derivatives of colchicine formula (I), where R denotes methoxy or methylthiourea; R1means a linear or branched C1- C6alkyl, provided that when R is methoxy, R1cannot be methyl; and compounds of formula II, where R is methylthio; R1means a linear or branched C1- C6-alkyl
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