Application of vitamin d derivatives in treating osteoporosis and related osseous diseases, and, also, new vitamin d3 derivatives

FIELD: medicine.

SUBSTANCE: on should apply the suggested compound of formula 1 for treating and/or preventing osteoporosis and related osseous diseases.

EFFECT: higher efficiency of therapy and prophylaxis.

7 cl, 2 dwg, 21 ex, 6 tbl

 

The scope of the invention

The present invention relates to the use of pharmacologically active analogues of vitamin D in a new way of medical prevention and treatment of osteoporosis and related bone diseases, and pharmaceutical preparations containing these compounds and dosage forms of these drugs. The present invention relates to new pharmacologically active vitamin D analogues, as well as to pharmaceutical preparations containing these compounds, and to pharmaceutical forms of such drugs.

Background of invention

Recently it was shown that 1α,25-dihydroxyvitamin D3(1,25(OH)2D3) effective against assimilation bones, indicating the potential use of this compound in the treatment of osteoporosis and conditions characterized by abnormal bone mineralization. Erben and others (Endocrinology, 139, 4319-4328 (1998)) provide evidence of a direct anabolic action of 1,25(OH)2D3on the bone.

However, therapeutic possibilities of 1,25(OH)2D3when such symptoms are strongly limited by the well-known impact of the hormone on calcium metabolism; elevated concentrations in the blood quickly lead to the strengthening of hypercalcemia. Thus, the specified connection is not quite suitable for the applications as a drug for the treatment of osteoporosis, which may require long-term administration of drugs in relatively high doses.

A known number of oxa - and thia-analogues of vitamin D3.

1α,25-dihydroxy-20-oxa-21-nonvitamin D31α-hydroxy-20-oxa-21-nonvitamin D3described in the publication N. Kubodera et al., Chem. Pharm. Bull., 34, 2286 (1986), 1α,25-dihydroxy-22-oxacillin D3and 25-hydroxy-22-oxacillin D3described in E. Mihaela et al., Chem. Pharm. Bull., 34, 4410 (1986), J. Abe et al., FEBS LETTERS, 226, 58 (1987) and European patent application, publication number 184 112, and 1α,25-dihydroxy-23-oxacillin D31α,25-dihydroxy-23-thevitamin D3described in European patent application, publication number 78704. 24 - and 25-sulfonyl equivalents 1α,25-dihydroxyvitamin D3described in Posner GH, et al., J. Med. Chem., 42, 3425 (1999).

Some of these compounds may have advantages compared to 1,25(OH)2D3providing reduced impact on calcium metabolism compared to 1,25(OH)2D3. However, reports of a possible influence of these compounds on the assimilation of the bones are missing.

Brief description of the invention

Due to serious medical complications in the patient and the relatively limited number of drugs suitable for the treatment of osteoporois, and also because of the gravity of the known side effects of 1,25(OH)2D3the purpose of this image is the shadow is a representation of the active analogues of vitamin D, including new counterparts, with the aim of obtaining drugs for the treatment of osteoporosis, including the application of these compounds to obtain drugs for activation of osteogenesis and treatment or prevention of osteoporosis, such as steroid-induced senile and postmenopausal osteoporosis, osteomalacia and related bone diseases. In addition, the aim of the invention is the creation of active analogues of vitamin D, including new counterparts, with the aim of obtaining medicinal drugs to increase muscle strength, including the treatment of weakness of the skeletal muscles.

The inventors unexpectedly found that the previously described analogs of vitamin D, known as having anti-inflammatory and immunomodulatory actions, as well as inhibiting the proliferation of certain cells, where these analogs are described presents General formula I, and the new compounds of General formula I, have anabolic effects on bone in vivo in models of osteoporosis and related bone disease. In addition, the bone anabolic activity of analogues according to the present invention, including new connections, accompanied by action to strengthen the skeletal muscles. Thus, the compounds being considered even more useful in the treatment of various diseases, osobennosti the treatment of osteoporosis.

Thus, the objective of the present invention consists in obtaining the selected analogues of vitamin D, having the General formulas I and Ia, below. General formula I consider active compounds previously described in international patent application no WO 91/15475, which is included in the description in its entirety by reference.

Therefore, the present invention concerns the use of compounds represented by the General formula I

where

X is hydrogen or hydroxy;

Y represents oxygen or sulfur or oxidized sulfur selected from the group S(O), and S(O2);

R1and R2that may be the same or different, signify hydrogen or the residue after removal of 1 hydrogen atom from a linear, branched or cyclic, saturated or unsaturated C1-C6-hydrocarbon; or R1and R2together with the carbon atom to which they are attached (indicated by an asterisk in formula I)bearing the group X, form3-C8-the carbon cycle;

Q means biradially the residue after removal of 2 hydrogen atoms from a linear, branched or cyclic, saturated or unsaturated C1-C8-hydrocarbon;

R3means hydrogen or the residue after removal of 1 hydrogen atom from a linear, branched or cyclizes the th, saturated or unsaturated C1-C6-hydrocarbon;

R1, R2and/or Q is optionally substituted by one or more deuterium atoms or fluorine and

n is 0 or 1;

and derivatives of the compounds of formula I in which one or more hydroxyl groups converted into a group-O-acyl or O-glycosyl, or phosphate ester, such masked groups hydrolyzed in vivo; to obtain drugs for the treatment and/or prophylaxis of osteoporosis and related bone disease.

Detailed description of the invention

When used in the present invention preferred compounds of formula I are compounds in which Y represents sulfur or oxidized sulfur, such as S(O) or S(O2); and/or the compounds of formula I, where R1and R2together with the carbon atom to which they are attached, bearing the group X, form3-C5-olefinic group, such as3-C5-alkenylphenol group or3-C5-the carbon cycle, this cycle is preferably saturated, such as3-C5-alkylen; and/or the compounds of formula I, where X is hydroxy; and/or the compounds of formula I, where Q means fenelonov group, optionally substituted by one or more fluorine atoms; and/or the compounds of formula I, where R3means hydrogen; and/or the compounds of formula I where n is 1.

Examples of specific compounds used according to the invention, are:

1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy-2-methyl-1-propoxymethyl)-9,10-scoprega-5(Z), 7 (E), 10 (19)-triene (compound 101),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-1-butoxymethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 104), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentyloxide)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 105), 1(S), 3(R)-dihydroxy-20(R)-[3-(1-hydroxycyclohexyl-1-yl)-prop-2-in-1-intoximeter]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 110), 1(S), 3(R)-dihydroxy-20(R)-22(S)-methyl-(4-hydroxyben-2E-EN-1-intoximeter)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 112), 1(S), 3(R)-dihydroxy-20(R)-22(R)-methyl-(4-hydroxyben-2E-EN-1-intoximeter)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 113), 1(S), 3(R)-dihydroxy-20(R)-(2-cyclopropyl-2(S)-hydroxyethyl) thiomethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 114), 1(S), 3(R)-dihydroxy-20(R)-(2-cyclopropyl-2(R)-hydroxyethyl) thiomethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 115), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 118 and 119), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 120), 1(S), 3(R)-dihydroxy-20(R)-22(S)-methyl-(3-hydroxy-3-methyl-1-butylthioethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 122), 1(S), 3(R)-dihydroxy-20(R)-22(R)-methyl-(3-hydroxy--methyl-1-butylthioethyl)-9,10-scoprega-5(Z), 1(E), 10(19)-triene (compound 123), 1(S), 3(R)-dihydroxy-20(R)-22(S)-methyl-(3-hydroxy-3-ethyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 124), 1(S), 3(R)-dihydroxy-20(R)-22(R)-methyl-(3-hydroxy-3-ethyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 125), 1(S), 3(R)-dihydroxy-20(R)-(2-((1-hydroxy-1-ethyl)propyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 143), 1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-ethyl)propyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 146), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 148), 1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy-2-ethyl-1-Outerdiameter)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 150), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-ethyl-1-hexylthiophene)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 151), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxyphenoxy)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 152) and 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-Penta-2(Z)-relaxometer-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 154).

The preferred compounds are:

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butoxymethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 102), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-pentyloxide-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 103), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentyloxide)-9,10-scoprega-(Z), 7(E), 10(19)-triene (soy is inania 106), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-Penta-2(E)-relaxometer-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 107), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-Penta-2-Unlocker)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 108), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-trifluoromethyl-5,5,5-Cryptor-1-Penta-2-Unlocker)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 109), 1(S), 3(R)-dihydroxy-20(R)-[3-(2-hydroxy-2-propyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 111), 1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy-2-methyl-1-propylthiouracil)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 116), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butylthioethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 117), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 121), 1(S), 3(R)-dihydroxy-20(R)-(5-hydroxy-5-methyl-1-hexyloxymethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 126), 1(S), 3(R)-dihydroxy-20(R)-[2-(2-hydroxy-2-propyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 127), 1(S), 3(R)-dihydroxy-20(R)-[2-(3-hydroxy-3-pentyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 128), 1(S), 3(R)-dihydroxy-20(R)-[3-(3-hydroxy-3-pentyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 129), 1(S), 3(R)-dihydroxy-20(R)-[4-(2-hydroxy-2-propyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 130), 1(S), 3(R)-dihydroxy-20(R)-[4-(3-hydroxy-3-pentyl) hair dryer is kemetyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 131), 1(S), 3(R)-dihydroxy-20(R)-[3-(hydroxymethyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 132), 1(S),3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-interculturality-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 133), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 134), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), -10(19)-triene (compound 135), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 136), 1(S), 3(R)-dihydroxy-20(R)-(3-(hydroxymethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 137), 1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), -10(19)-triene (compound 138), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-ethyl-1-Gex-2-Unlocker)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 139), 1(S), 3(R)-dihydroxy-20(R)-(2-hydroxyphenoxy)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 140), 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxyphenoxy)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 141), 1(S), 3(R)-dihydroxy-20(R)-(2-((1-hydroxy-1-methyl)ethyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 142), 1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-ethyl)propyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 144), 1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)e is Il) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 145), 1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 147), 1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 149), 1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-pentyloxide)-9,10-scoprega-5(Z)-7(E), 10(19)-triene (compound 153), 1(S), 3(R)-dihydroxy-20(R)-(4-(hydroxymethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 163), 1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-ethyl)propyl)) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 164), 1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl)) phenylthiomethyl)-22(R)-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 165), 1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl)) phenylthiomethyl)-22(S)-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 166) derivatives of these compounds, where one or more hydroxyl groups are transformed into-O-acyl or O-glucosamine group, or phosphate esters, such protected groups hydrolyzed in vivo; to obtain drugs for the treatment and/or prophylaxis of osteoporosis and related bone disease.

Examples R1and R2taken separately, include (besides hydrogen) methyl, trifluoromethyl, ethyl, vinyl, normal, ISO - and cyclopropyl and 1-methylvinyl. When R1and R2different, preferably R1means hydrogen, the R 2means cyclopropyl. Preferred compounds where R1=R2means methyl, ethyl, hydrogen or CF3.

It is preferable to use compounds of General formula I, where each of R1and R2independent means1-C2is an alkyl group such as methyl and ethyl, and where Q denotes 1,4-substituted phenylene.

The examples are taken together R1and R2include di-, tri-, Tetra - and pentamethylene. Preferred pentamethylene.

Examples of Q include methylene, di-, tri-, tetramethylene, -CH2-CH=CH-, -CH2-C=C-, (CH2)2CF2, phenylene (C6H4; ortho, meta, pair), -CH2-(C6H4)- (ortho, meta, pair) and -(C6H4)-CH2(ortho, meta, pair). The preferred meta - and para-C6H4. The most preferred pair With6H4.

Examples R3include (besides hydrogen) methyl normal butyl and phenyl. The preferred hydrogen and methyl.

Derivative of the formula I where one or more hydroxyl groups protected groups can again turn into a hydroxyl group in vivo, are also included in the scope of the invention ("biodiversiry derivatives or prodrugs of I"). The term "biodiversiry derivatives or prodrugs of I" includes, but is not in order of limits, derivatives of compounds of the aforesaid formula I where one or more hydro is strong groups transformed into-O-acyl or O-glucosamine group, or phosphate ester, such protected groups hydrolyzed in vivo. Compounds I in which X is hydrogen, represent another type of prodrug. These compounds are relatively inactive in vitro, but can be converted into active compounds of formula I by enzymatic hydroxylation after the introduction of the patient.

In addition, the present invention relates to compounds of the formula Ia

where R1, R2and Q agree to the above values, m=0, 1, or 2; and n=1. Preferred compounds of formula 1A where R1and R2taken separately, include (besides hydrogen) methyl, trifluoromethyl, ethyl, vinyl, normal, ISO - and cyclopropyl and 1-methylvinyl. More preferred are also the compounds of formula Ia, where R1=R2or where each R1and R2independent means1-C2is an alkyl group such as methyl and ethyl, and methyl is preferred.

Preferred compounds of formula Ia, where Q includes methylene, di-, tri - and tetramethylene, -CH2-CH=CH-, -CH2-C=C-, phenylene (C6H4; ortho, meta, pair), -CH2-(C6H4)-(ortho, meta, pair) and -(C6H4)-CH2(ortho, meta, pair). More preferred compounds of formula Ia, where Q denotes the linear propylene, preferably substituted by one or more fluorine atoms, or where Q OSN which denotes unsubstituted fenelonov group. Preferably Q means CH2CH2CF2, meta-C6H4or pair With6H4.

The compounds of formula Ia are also preferably chosen from the group including:

1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 155), 1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 156), 1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl) phenyl sulfanilyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (isomer of compound 159) (compound 157),

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl) phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 158),

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl) phenyl sulfanilyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (isomer of compound 157) (compound 159),

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl) phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 160),

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl) phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (isomer of compound 162) (compound 161), and

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl) phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (isomer of compound 161) (compound 162).

Definition

"C3-C8-carbon cycle" includes saturated cycloalkanes the unsaturated cyclic olefins, such as cycloalkane with one endocycles double bond and 3-8 carbon atoms.

When the terms "include", "includes", "included" or "including" are used in this description, they should be interpreted as specifying the presence of these features, integers, stages or components, but this does not preclude the presence or addition of one or more characteristic features, number, phase, component, or group.

As can be seen from formulas I and Ia, depending on the values of R1, R2, R3and X compounds according to the invention can include multiple diastereoisomeric forms (for example, R - or S-configuration about the carbon atom marked with an asterisk). The invention covers all these diastereoisomer in pure form and mixtures of diastereoisomers. Compounds of the present invention differ structurally from the above oxa - and teasedale the fact that they have the R-configuration at position 20.

Compounds of formula I or Ia where Y=O or S, can be obtained from derivatives of vitamin D 1 (Tetrahedron, 43, 4609 (1987)), for example, means, schematically depicted in schemes 1 and 2. O-Alkylation Ib or S-alkylation III, leading to IV, carry out the processing under alkaline conditions creating a side chain unit of the General formula Z-R, where Z denotes a leaving group such as CL, Br or I) or p-tawassul is phenyloxy or tripterocalyx, and R means -(Q)-[C(R1)(R2)]nX or, optionally, a radical that can be converted into the specified radical on any appropriate subsequent stage (or stages). Thus, R in the compounds IV, V, VI and VII do not necessarily have the same value for a particular sequence of synthesis. The transformation of R -(Q)-[C(R1)(R2)]nX may include several stages, or may include temporary protection of sensitive Teenboy system of the molecule. An alternative method includes processing the intermediate compound II (Z means the aforementioned leaving group) in alkaline conditions creating a side chain unit HY-R, where Y denotes oxygen or sulfur, and R takes values above, to obtain the intermediate compound IV. In addition to any necessary modifications in the side chain (R), the conversion of IV to stage I includes photoisomerization and stage desirelove, by analogy with steps used in the last stages of the synthesis of other analogues of vitamin D (see, European patent No. 0227826).

It may be convenient to change the sequence of the alkylation reaction (d or e) and reaction photoisomerization (g), in this case, (5Z)-isomer I, Ia, II or III is a key intermediate connection.

Creating a side chain blocks, RZ, are either known compounds (some described in the international who Noah patent application PCT/DK89/00079), or can be obtained by methods similar to those described in PCT/DK89/00079. R usually means -(Q)-[C(R1)(R2)]pH1where X1means a protected Oh group, for example, tetrahydropyranyloxy or trialkylsilyl. (Any such TNR-esters RZ, is not described in PCT/DK89/00079, easily obtained from the corresponding alcohol).

Creating a side chain blocks HY-R are also known compounds or can be obtained by methods similar to those used to obtain similar known compounds.

As shown schematically above, at least for the 23-teasedale method does not exclude the transfer alkylation 23-thiol even at the last stage (e.g., IX→Ia (scheme 3).

The compounds of formula I, where Y=S(O) or S(O2)conveniently be obtained by oxidation of the corresponding compounds IV, V, VI, VII or I, where Y=S, for example, using hydrogen peroxide and sodium tungstate in aqueous methanol. (Diastereoisomer the sulfoxidov (Y=S(U)) can be separated by chromatographic).

In this description uses the following standard notation:

Me = methyl

Et = ethyl

WGn= n-propyl

Pri= isopropyl

But= tert-butyl

TNR = tetrahydro-4H-Piran-2-yl

THF = tetrahydrofuran (THF)

Ts = p-toluensulfonyl

TBA = Tetra(n-butyl)ammonium

DMF = dimethylformamide

Notes to charts 1, 2 and 3

a) Interaction with the formal source of R3(for example, restoration of NaBH4for R3=H or interaction with R3Li for R3=alkyl); optional separation of diastereoisomers for R3=alkyl (e.g., by chromatography).

b) Conversion of IT to the leaving group (for example, by totalrevenue for Z=OTs).

c) (i) Nucleophilic substitution thioacetate, (ii) basic hydrolysis.

d) Alkylation of creating a side chain unit R-Z in the presence of a base (e.g., KOHN, KOButor KN), in the presence or absence of a catalyst (for example, 18-Crown-6) in a solvent (such as THF).

e) Interaction with creating a side chain unit R-YH in the presence of a base (such as NaH) in a solvent, for example DMF.

f) Optional modification of the functional group in the side chain.

g) Isomerization with hυtriplet sensitizer, such as anthracene.

h) removing the protection with TBA+F-or HF.

It should be noted that although these intermediate compounds can be protected hydroxyl groups as tert-butyldimethylsilyl esters, the scope of the present invention does not exclude the use of alternative protective groups for hydroxyl, well Izv the STN from the prior art (such as described in T.W.Greene and P.G.M.Wuts, "Protective groups in organic synthesis", 3rded., Wiley, New York, 1999), together with alternative reactions for removing protection.

Description of the drawings

Figure 1 is a graphical illustration of the effect on the mass of the lumbar spine, L4, rats in accordance with the described model in OVX rats, where groups of animals are processed in the diagram below. Under a graphic illustration of the statistical analysis. Differences between groups were investigated using the test Well-Wallis'and including the method of multiple comparisons: ns-NC means insignificant, nt - no means have not been investigated, and * indicates p<0,05. Differences are considered significant at p<0,05. The results are presented in the bar graph as mean values + SD.

Animals are divided into 6 groups:

Group 1: intact control, introduced propylene glycol, 0.1 ml/kg (solvent)

Group 2: control-OVX rats, introduced propylene glycol, 0.1 ml/kg (solvent)

Group 3: OVX rats, introduced on 1α, 25 (OH)2D3, 0.25 microgram/kg

Group 4: OVX rats entered the connection 145, 10 ug/kg

Group 5: OVX rats entered the connection 145, 50 mg/kg

Group 6: OVX rats entered the connection 145, 100 µg/kg

Figure 2 is a graphical illustration of a biomechanical study of lumbar spine, L3.

The cylinder body of the vertebra is explored from p is Arsenalnoe-distal axis in the apparatus for testing material (Alwetron TCT 5, Lorentzen and Wettre, Stockholm, Sweden) at a constant strain rate of 2 mm/min During compression curves load-deformation are recorded and accumulated on the PC (ProLinea 4/33, Compaq, USA). Fmax is the maximum point on the curve strain loads.

Rats treated according to the following model OVX rats, where groups of animals are processed according to the same scheme as for Figure 1. The statistical analysis presented in the graphical illustration, compare the description for Fig 1.

Pharmacological methods - model of osteoporosis in OVX rats

To study bone anabolic characteristics and activities of analogues of vitamin D according to the present invention for the prevention or treatment of demineralization of the skeleton in vivo, using the model on a 4-week OVX rats.

The model in rats subjected oophorectomy (OVX model), which orally for 28 days injected drug use to check analogues of vitamin D. In these models oophorectomy causes changes in the network structure, identical to that observed in the human skeleton age-related changes in menopause. In addition, the model and subsequent analyses performed in standard conditions. 1α,25(OH)2D3use as a standard connection.

Animals and food mode:

Female Sprague Dawley rats, weighing approx the flax 130 g (age 40-45 days) buy MB, Ejby, Denmark. Animal feed industrial manufactured feed and provide free access to food and drinking water. Animals are divided into groups subjected to different processing.

The way oophorectomy:

Animals anastasiou and perform oophorectomy through a dorsal incision.

The treatment of OVX animals begin 2 weeks after oophorectomy.

Animals administered the drug orally for 28 days. Oral dose forcibly injected drugs is 0.1 ml/100 g body weight. Body weight of each animal recorded daily before oral administration of a medicinal product. 1, 14, 21 and 28 day animals are placed separately in 24 hours in cells to determine the metabolism to collect urine. Urine frozen at -20°for subsequent measurement of the calcium content.

On the 28th day of the animals anastasiou and select 2 ml of blood or cardiac puncture or from the ophthalmic veins, then kill animals with CO2. Then select the fraction of serum and frozen at -20°for subsequent measurement of calcium, phosphorus and creatinine.

The uterus is removed and weighed to confirm oophorectomy. Spleen and thymus were removed and weighed to assess the overall immune status.

The left and right femur, left and right is Yu tibia, lumbar vertebrae 3 and 4 (L3 and L4) were removed and cleaned of all soft and connective tissue. Left femur, left and right tibia and L4 is dried in an oven at 50-60°C for at least 24 hours and immediately thereafter weighed. Bones burnt in a furnace at 800°C for 4 hours, dissolve in 1 N. Hcl and analyzed for calcium content in Hitachi 911 auto-analyzer. Right thigh and L3 are left in 0.9% NaCl and frozen at -20°for subsequent biomechanical analysis conducted by Jesper Skovhus Thomson and Lis Mosekilde at Aarhus University, defines various biomechanical parameters.

The effect of compound 145 in comparison with a standard dose of 1,25(OH)2D3(1,25D3) (0.25 microgram/kg) and compared with the OVX control group (given in %) is shown in tables 1-4.

Table 1.
Influence on the content of calcium in the urine
Conn. 1451 ug/kg10 ug/kg25 mg/kg50 ág/kg75 mg/kg100 ág/kg
In crownsMTR/16MTR/16MTR/23MTR/27MTR/23MTR/27MTR/27MTR/23
1,25D3 No<<<<<<<<<==>=<=
Ovx counter.-2310445155373750777463
Table 2.
Influence on the content of calcium in serum
Conn. 1451 ug/kg10 ug/kg25 mg/kg50 ág/kg78 ág/kg100 ág/kg
In crownsMTR/16MTR/16MTR/23MTR/27MTR/23MTR/27MTR/27MTR/23
1.25D3NoNo<<No=sNo
Ovx counter.0361121820-5

Table 3.
Anabolic effect on bone mass
 Connection 1451 ug/kg 10 ug/kg25 mg/kg50 ág/kg75 mg/kg100 ág/kg
 In comparison withMTR/16MTR/16MTR/23MTR/27MTR/23MTR/27MTR/27MTR/23
Thigh1,25D3<=>>=>>>>>>
 Ovx counter.6105414689
Tibia1,25D3<s=>>=>>>>
 Ovxcounter.685313477
Tibial Meta1,25D3<><>=>=
 Ovxcounter. 6148-222-1924
L41.25D3<<=>>=>>>>
 Ovxcounter.9134915111312

Table 4.
Impact on bone strength
 Connection 1451 ug/kg10 ug/kg25 mg/kg50 ág/kg75 mg/kg100 ág/kg
 B comparison to theMTR/16MTR/16MTR/23MTR/27MTR/23MTR/27MTR/27MTR/23
Femoral Dia.1,25D3<==<=>=>>=
 Ovxcounter.  -5 9-154-3
Femoral Meta.1,25D3<=<>>>>>=
 Ovxcounter.  63943315021
L31,25D3<>S<=><=>
 Ovxcounter.  232745223837
< a smaller effect than the standard dose of l,25D3(0.25 microgram/kg)
<= less than or the same effect as a standard doses of 1,25D3(0.25 microgram/kg)
= same effect as a standard doses of 1,25D3(0.25 microgram/kg)
=> same or greater effect as a standard dose of l,25D3(0.25 microgram/kg)
> more action than standard doses of 1,25D3(0.25 microgram/kg)

Table 1 and figure 1 and figure 2 should what is the anabolic actions on bone connection 145 is comparable or even more than 1,25D3it clearly shows increased bone mass (Figure 1) and increased biomechanical strength of bone (Figure 2), whereas a negative action, the effect of liming reduced, which demonstrates the actual anabolic effect of the compound. Therefore this connection is particularly useful in obtaining pharmaceutical compositions for the treatment of these specific diseases in humans and animals.

Pharmaceutical compositions

Although it is possible to introduce only the active ingredient (i.e. in the form of pure chemical compounds), preferably its presence in the form of a pharmaceutical composition. Usually the active ingredient is from 0.1 ppm to 1 wt. % by weight of the composition.

The formulations, both for veterinary use and for treatment of humans, according to the present invention include, therefore, the active ingredient in combination with pharmaceutically acceptable carrier and optionally other therapeutic ingredient (or ingredients). The carrier (s) must be "acceptable"in the sense of being compatible with other ingredients or compositions, and are not harmful for the patient.

The compositions include, for example, the compositions in a form suitable for oral, ophthalmic, re the tal, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular and local, nasal or buccal administration.

The term "standard dosage unit" means a unit, i.e. a single dose which may be administered to the patient and which is easy to handle and easy to pack, preserving the physical and chemical stability standard dose includes either the active material as such or in a mixture with a solid or liquid pharmaceutical diluents or carriers.

The compositions can generally be presented in a standard dosage form and may be obtained by any of the methods well known in the field of pharmacy, see Remington: The Science and Practice of Pharmacy, 19thEd. 1995. All methods include the stage of combining the active ingredient with the carrier that constitutes one or more additional ingredients. Typically, the compositions are obtained by uniform and homogeneous Association the active ingredient with liquid carriers or finely powdered solid carrier, or both, and then, if necessary, conversion of the product into the desired formulation.

The compositions of the present invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or pellets, each of which contains the specified amount of the active ingredient; in the form of a solution or suspension in an aqueous liquid or non-aqueous liquid; or in the form of an emulsion of oil-in-water or emulsion water-in-oil. Preferably dissolving or suspending the active compound in a non-aqueous liquid, such as vegetable oil to be encapsulated in a gelatin capsule. The active ingredient may also be introduced in the form of a bolus, electuary or paste.

Compositions for rectal injection can be in the form of suppositories comprising the active ingredient and a carrier, or in the form of an enema.

Formulations suitable for parenteral administration typically comprise sterile oil or aqueous preparation of active ingredient, which is preferably isotonic to the blood recipient. Transdermal formulations may be in the form of a patch.

Formulations suitable for intra-articular or ocular administration, can be in the form of a sterile aqueous preparation of the active ingredient, which may be in microcrystalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems can also be used to view the active ingredient in a form suitable for intra-articular, and eye use.

Formulations suitable for local or ocular injection, include the Jew is s or semi-liquid preparations, such as liniments, lotions, gels, applicators, emulsions of the type oil-in-water or water-in-oil, such as creams, ointments or pastes; or solutions or suspensions such as drops.

Compositions in the form of tablets or capsules is generally preferable to systemic injections of the active ingredient. The composition in tablet form can be obtained by molding or forming of the active ingredient, optionally, with one or more additional ingredients. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in granular form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface-active agent or dispersing agent. Molded tablets obtained by molding in a suitable machine, a mixture of powdered active ingredient and a suitable carrier moistened with an inert liquid diluent.

For nasal imposition or application by inhalation powder, self-propelled or sprayable formulations, prepared and released in the form of a spray, you can use a sprayer or spray bottle. The prepared compositions typically have a particle size in the range from 10 MK to 100 MK. These compositions the most desirable in the form of finely ground powder for pulmonary introduction from the pores of scovolo inhaler or supplied in the form of a self-propelled powder formulations. If camotecues solution and sprayable compositions of the effect can be achieved either by selection valve having the desired spray characteristics (i.e. able to give a spray with the desired particle size), or by incorporating the active ingredient, such as a suspended powder with controlled particle size. These self-propelled compounds may be feeding the powder compositions or formulations, feeding active ingredient in the form of droplets of a solution or suspension.

Supplied in the form of a self-propelled powder compositions preferably include dispersed particles of solid active ingredients and liquid propellant having a boiling point below 18°C at atmospheric pressure. Liquid propellant may be any propellant known as suitable for medical use, and may include one or more acceptable for use in medicine inert gases or mixtures thereof. Typically, the propellant has 45-99,9% wt./wt. from the composition, while in the ingredient has 1 ppm - 1% wt./wt. from the composition.

In addition to the aforementioned ingredients, the formulations according to the invention can include one or more additional ingredients such as diluents, buffer solutions, corrigentov, binders, surfactants, thickeners, smazyvaesh, preservatives, for example, methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like.

As indicated above, the compounds of formula I or Ia can be used for the treatment or prophylaxis of osteoporosis and related bone disease. Therefore, the invention also relates to a method of treatment of osteoporosis and related conditions, including introduction to the needy in this patient an effective amount of the compounds of formula I or Ia.

In addition, the invention relates to the use of compounds of the formula Ia in pharmaceutical compositions for local or systemic treatment or prevention of disease in man or animal, can be treated with vitamin D or vitamin D analogues, such as, for example, psoriasis and other disorders of keratinization, HIV-induced dermatitis, wound healing, various forms of cancer, such as leukemia, breast cancer, glial brain tumors, osteogenic sarcoma, myelofibrosis, melanoma, other skin carcinomas, and diseases or disorders of the immune system, such as the reaction of the "host versus graft and graft versus host and graft rejection, and autoimmune diseases such as discoid lupus erythematosus and systemic lupus erythematosus, diabetes mellitus and chronic autoimmune dermatosis type, e.g. the R, scleroderma and common bladderwort, and inflammatory diseases such as asthma and rheumatoid arthritis, as well as other painful conditions, including hyperparathyroidism, particularly secondary hyperparathyroidism associated with renal failure, decreased mental activity, or senile dementia (Alzheimer's disease and other neurodegenerative diseases, hypertension, acne, alopecia, skin atrophy, for example, steroidinduced skin atrophy, skin ageing, including photoaging, and their use for the activation of osteogenesis and treatment/prevention of osteoporosis and related bone disease and osteomalacia. In addition, the bone anabolic activity of new compounds according to the invention is also accompanied by action to strengthen the skeletal muscles.

The required amount of the compounds of formula I or Ia therapeutic actions varies, of course, depending on the particular compound, the route of administration and in need of treatment of a mammal. Compounds according to the invention may be introduced parenterally, intra-articular, gastrointestinal, or local ways. They are well absorbed when introduced through the intestine, and this is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders such as psoriasis, or ocular disease and, preferred local or intestinal form.

These compounds may be used in combination with other pharmaceuticals or therapeutic effects. In the treatment of osteoporosis, these compounds can be conveniently combined with other therapeutic means for the treatment or prevention of osteoporosis, including estrogens, SERMs (selective estrogenreceptor modulators) or bisphosphonates. In the treatment of psoriasis, these compounds may be used in combination with other antipsoriaticescoe drugs, such as steroids or other methods of treatment such as phototherapy or UV phototherapy, or a combination of PUVA-therapy. In the treatment of cancer the present compounds may be used in combination with other anti-cancer drugs or anti-cancer therapeutic methods, such as radiation therapy. To prevent grafting reaction and graft versus host, or in the treatment of autoimmune diseases, these compounds useful in combination with other immunosuppressive/immunoregulatory drugs or treatments, for example, with cyclosporine A.

The present invention also relates to a method of treating patients suffering from one or more pathological disorders and, this method consists in entering the required treatment to the patient an effective amount of one or more compounds of the formula I or Ia, alone or in combination with one or more other therapeutically active compounds usually applied for the treatment of these pathological conditions. Treatment of these compounds and/or additional therapeutically active compounds can be carried out simultaneously or intermittently. Preferred pathological conditions treatable by the present compounds are induced by steroids, age, and postmenopausal osteoporosis.

For systemic treatment is administered daily dose of 0.001-100 μg per kg body weight, preferably 0.01 to 50 μg/kg of body weight of the mammal, for example, 0.05-30 mg/kg of the compounds of formula I or Ia, usually corresponding to a daily dose for an adult is from about 0.5 mg to 6 mg of the topical treatment of dermatological disorders prescribe ointments, creams or lotions containing 0.1-500 µg/g and preferably 0.1 to 100 µg/g of compound of formula I or Ia. For local application in ophthalmology designate eye ointments, drops or gels containing 0.1-500 µg/g and preferably 0.1 to 100 µg/g of compound of formula I or Ia. Oral compositions are usually in the form of tablets, capsules, or drops, containing 0.05-50 μg, before occhialino 0.1 to 25 mg of the compounds of formula I or Ia to the standard dose.

The invention is also disclosed in the following methods of preparation and examples, which are not considered as limiting the scope of the invention and the attached items.

METHODS of preparation AND EXAMPLES

A common part

Typical examples of the compounds Ia are listed in table 5. Intermediate compounds for schemes 1, 2 and 3 referred to in the methods of production, marked with the numbers in accordance with the formulas in table 6. They are used to illustrate typical syntheses of representative examples of compounds Ia.

For the spectrum of1H-NMR (300 MHz) the values of chemical shifts (δ) are given in ppm for solutions in deuterated chloroform (except where otherwise stated) relative to the internal standard - tetramethylsilane (δ=0) or chloroform (δ=7,25). The value for multiplet, or just installed (doublet (d), triplet (t), Quartet (q)) or not (m)are approximately at the midpoint, except when specified interval (s = singlet, ush = extended). Constant interaction (J) are given in Hertz and sometimes rounded to the nearest unit. For the spectrum of13C-NMR (75.5 MHz) the values of chemical shifts (δ) are given in ppm for solutions in deuterated chloroform (except where otherwise stated) relative to the inner one hundred who dantata - tetramethylsilane (δ=0) or chloroform (δ=76,81).

The ether means diethyl ether and dried over sodium. THF dried over nitrobenzophenone. Petroleum ether refers to the fraction of pentane. If not specified, % means about/about%. Interaction is carried out at room temperature unless otherwise stated. The procedure involves thinning the specified solvent (other than organic reaction solvent), extraction with water and then with saturated salt solution, dried over anhydrous gSO4and concentration in vacuo to obtain a residue. Chromatography is performed on silica gel.

Table 5: Examples of compounds of formula Ia, where n=0 (compound 147, 148, 149) or n=1. (Connection 101-154 formula I listed in the corresponding table 1, described in No. 091/15475 included in the description by reference). Details are given for compounds showing an example No.; other compounds can be obtained from known starting materials using similar reaction sequences.

Table 6: Intermediate compounds used in the synthesis of compounds of formula I or Ia (Connection 2-66 listed in the corresponding table 2, described in WO91/15475 and received by the ways of obtaining 1-64 and General methods 1-7 described in WO 91/15475 listed as a reference).

Ways to get

A method of obtaining a 1: connection 67

Method: General methods 3.

Compound IV: compound 68.

Eluent for chromatography: 0-4% ethyl acetate in petroleum ether.

13C-NMR: δ 148,1, 140,4, 135,0, 123,9, 122,9, 117,9, 111,0, 75,6, 71,9, 67,3, 55,9, 55,6, 45,8, 45,5, 44,6, 40,4, 39,2, 35,6, 31,8, 28,6, 26,9, 25,8, 25,7, 25,7, 25,6, 24,1.

A method of obtaining a 2: connection 68

Method: General methods 2, when replacing the DMF in THF/hexamethylphosphoric triamide 20:1 (V/V).

Compound II: compound 5.

R-YH: connection 69.

13C-NMR: δ 153,4, 142,7, 135,4, 123,9, 121,5, 116,4, 106,5, 75,6, 70,0, 67,0, 56,1, 55,6, 45,6, 43,8, 40,3, 39,2, 36,4, 35,6, 31,8, 28,7, 26,9, 25,6, 24,8, 24,1, 23,3, 21,9, 18,6, 18,1, 17,9, 12,3, 2,1, -4,9, -5,1, -5,1.

The method of obtaining 3: compound 69 3,3-debtor-4-methyl-4-(trimethylsilyloxy)potential

Method: Methylanisole (3 M, 2 equiv.) in ether is added to 4-bromo-2,2-diperbadankan (D. Morel and F. Dawans, Tetrahedron, 33, 1445-7, (1977)) in the air. Processing gives 5-bromo-3,3-debtor-2-methylpropan-2-ol.13C-NMR: δ 123,9, 72,8, 35,2, 23,4, 23,1. The processing of the specified compound (2.0 g), triethylamine (1.70 ml) and 4-(dimethylamino)pyridine (59 mg) in dichloromethane (25 ml) trimethylsilylpropyne (1,52 ml) at room temperature over night, gives, after treatment with dichloromethane and chromatography (1-3% ethyl acetate in petroleum ether as eluent), 1-bromo-3,3-debtor-4-methyl-4-(trimethylsilyloxy)pentane.13C-NMR: δ 123,6, 75,5, 35,2, 24,2, 23,9, 2,1. The compound obtained (1,62 g) is subjected to interaction with O-ethylxanthate potassium (1.80 g) in acetone (15 ml) at room temperature overnight and treated with chloroform/saturated aqueous ammonium chloride, getting S-(3,3-debtor-4-methyl-4-(trimethylsilyloxy)pentyl)-O-ethylxanthate.

13C-NMR: δ 214,0, 123,7, 75,6, 69,7, 30,5, 28,2, 24,0, 13,5, 2,1. The resulting compound (0.6 g) is subjected to interaction with ethanolamine (0,22 ml) in DMF (5 ml) for 30 min at room temperature and treated with water/ether. Chromatography (ether/petroleum ether 1:100, as eluent) gives compound 69.13C-NMR: δ 123,9, 75,5, 35,8, 24,0, 17,0, 2,1.

The method of obtaining 4: connections 70 and 72

Connections get by applying the method of obtaining 41 WO 91/15475, except that used as a starting material compound 57 instead of the connection 15. The connection 70, the lowest Rf,13C-NMR: δ 150,8, 148,1, 144,1, 139,8, 135,3, 128,8, 127,4, 122,9, 122,7, 120,1, 118,0, 110,9, 72,3, 71,8, 67,3, 65,3, 55,7, 45,8, 45,3, 44,6, 40,3, 31,7, 31,6, 31,3, 28,5, 26,1, 25,6, 25,6, 23,1, 21,5, 19,5, 18,0, 17,9, 12,0, -4,9, -5,0, -5,3.

The connection 72, the highest Rf,13C-NMR: δ 150,6, 148,1, 144,7, 139,8, 135,3, 129,0, 126,9, 122,7, 122,0, 119,8, 118,1, 111,0, 72,3, 71,9, 67,3, 65,6, 56,2, 55,9, 45,9, 45,5, 44,6, 40,6, 31,7, 31,6, 31,0, 28,5, 26,9, 25,7, 25,6, 23,1, 21,6, 18,7, 18,0, 17,9, 12,3, -4,9, -5,0, -5,3.

The method of obtaining 5: connection 71

Connection get by applying the method of obtaining 42 in WO91/15475, for those who except what is used as a starting material compound 57 instead of the connection 43 and/or 44.

13C-NMR: δ 150,8, 148,1, 139,9, 139,6, 135,4, 129,6, 129,0, 126,1, 123,7, 122,7, 118,1, 111,0, 72,2, 71,8, 67,3, 61,6, 55,8, 55,6, 45,8, 45,3, 44,6, 40,4, 31,7, 30,5, 29,5, 28,4, 26,3, 25,6, 25,6, 23,1, 21,3, 19,4, 18,0, 17,9, 12,1, -4,9, -5,0, -5,3.

The method of obtaining 6: connection 73

Connection get by applying the method of obtaining 42 in WO 91/15475, except that used as a starting material compound 74 instead of the connection 43 and/or 44.13C-NMR: δ 155,0, 148,1, 139,6, 138,3, 135,4, 127,7, 125,2, 122,7, 118,1, 111,0, 72,3, 71,8, 67,3, 61,7, 55,9, 55,7, 45,8, 45,3, 44,6, 40,4, 31,6, 30,4, 28,5, 26,3, 25,6, 25,6, 23,1, 21,3, 19,4, 18,0, 17,9, 12,0, -4,9, -5,0, -5,3.

The method of obtaining 7: connection 74

Method: General methods 3.

Starting material: compound 82.

Eluent for chromatography: 0-50% ether in petroleum ether.

13C-NMR: δ 148,1, 146,5, 140,3, 135,7, 135,1, 128,8, 124,8, 122,9, 117,9, 111,0, 72,1, 71,8, 67,3, 55,9, 55,6, 45,8, 45,5, 44,6, 40,8, 40,3, 35,2, 31,5, 28,6, 26,8, 25,7,25,6, 23,3, 21,7, 18,7, 18,0, 17,9, 12,2, -4,9, -5,0, -5,3.

The method of obtaining 8: connection 75 and 76

Connections get by applying the method of obtaining 41 WO91/15475, except that used as a starting material compound 74 instead of the connection 15.

Connection 75, the highest Rf,13C-NMR: δ 152,1, 148,1, 142,7, 139,8, 135,3, 125,3, 123,7, 122,7, 118,1, 111,0, 72,1, 71,9, 67,3, 65,6, 56,2, 55,9, 45,9, 45,5, 44,6, 40,6, 31,6, 31,0, 28,5, 27,0, 25,6, 25,6, 23,1, 21,6, 18,7, 18,0, 17,9, 12,3, -4,9, -5,0, -5,3. The connection 76, the highest Rf,3 C-NMR: δ 152,8, 148,1, 142,2, 139,8, 135,2, 125,2, 124,3, 122,7, 118,0, 110,9, 72,2, 71,8, 67,3, 65,3, 55,7, 55,7, 45,8, 45,3, 44,6, 40,3, 31,6, 31,2, 28,5, 26,0, 25,6, 25,6, 23,1, 21,5, 19,5, 18,0, 17,9, 12,0, -4,9, -5,0, -5,3.

The method of obtaining 9: connection 77

Method: General method 7.

Starting material: compound 78.

13C-NMR: δ 7,42 (m, 2H), 7,17 (m, 2H), from 6.22 (d, 1H), 6,00 (d, 1H), 5,17 (d, 1H), 4,89 (s, 1H), around 4.85 (d, 1H), 4,36 (m, 1H), 4,18 (m, 1H), 3,25 (DD, 1H), 2,88 (DD, 1H), and 2.83 (DD, 1H), 2,43 (DD, 1H), 2,20 (DD, 1H), 1,99 (t, 1H), 1,68 (C, 6N), 1,90-of 1.20 (m, 13H), a 1.08 (d, MN), 0,86 (s, N), of 0.51 (s, 3H), of 0.05 (s, N).

The method of obtaining 10: connection 78

Method: General methods 3.

Starting material: compound 79.

Eluent for chromatography: 0-20% ether in petroleum ether.

1H-NMR: δ a 7.92 (d, 1H), 7,41 (t, 1H), 7,28(d, 1H), 7,10 (t, 1H), from 6.22 (d, 1H), 6,02 (d, 1H), 5,17 (d, 1H), around 4.85 (d, 1H), 4,35 (m, 1H), 4,17 (m, 1H), 3,81 (s, 3H), 3,19 (DD, 1H), 2,82 (DD, 1H), 2,72 (DD, 1H), 2,43 (DD, 1H), measuring 2.20 (DD, 1H), 1,98 (t, 1H), 1,95-of 1.30 (m, 13H), a 1.08 (d, 1H), 0,90 (s, N), of 0.56 (s, 3H), of 0.05 (s, N).

The method of obtaining 11: connection 79

Method: General methods 2.

Compound II: compound 5.

R-YH: Methyl-2-mercaptobenzoic.

1H-NMR: δ to 7.93 (d, 1H), 7,41 (t, 1H), 7,28 (d, 1H), 7,13 (t, 1H), 6,44 (d, 1H), of 5.82 (d, 1H), equal to 4.97 (d,1H), is 4.93 (d, 1H), 4,51 (DD, 1H), 4,21 (m, 1H), 3,91 (s, 1H), 3,19 (DD, 1H), 2,87 (d, 1H), 2,73 (DD, 1H), to 2.55 (DD, 1H), 2,31 (d, 1H), 2,07 (t, 1H), 1,95-of 1.35 (m, 15 NM), of 1.09 (d, 1H), 0,89 (s, N)to 0.85 (s, N), or 0.57 (s, 3H), of 0.05 (s, N).

The method of obtaining 12: connection 80

Method: General methods 3.

Starting material: compound 81.

Eluent for chromatography: 0-20% ether in petroleum ether.

13C-NMR: δ 148,1, 146,3, 140,3, 137,0, 135,0, 128,2, 127,1, 126,5, 123,0, 122,9, 117,9, 111,0, 71,9, 67,3, 55,9, 55,6, 45,8, 45,5, 44,6, 40,9, 40,3, 35,3, 34,8, 28,6, 26,8, 25,7, 25,6, 23,2, 21,7, 18,6, 18,0, 18,0, 12,3, 7,6, -4,9, -5,0, -5,3.

The method of obtaining 13: connection 81

Method: General methods 2.

Compound II: compound 5.

R-YH: 3-(3-mercaptophenyl)pentane-3-ol (cf. G.Grue-Sorensen, E.Binderup and L.Binderup, "Vitamin D, a pluripotent steroid hormone: Structural studies, molecular endocrinology and clinical applications", Eds. A.W.Norman, R.Bouillon and M.Thomaset, Walter de Gruyter, New York, 1994, p.75-76).

13C-NMR: δ 153,4, 146,3, 142,7, 137,0, 135,4, 128,2, 127,1, 126,5, 123,0, 121,5, 116,4, 106,5, 70,0, 67,0, 56,0, 55,6, 45,6, 43,8, 40,9, 40,2, 36,4, 35,3, 34,8, 28,7, 26,7, 25,7, 25,6, 23,3, 22,1, 21,8, 18,6, 18,1, 17,9, 12,3, 7,6, -5,0, -5,1, -5,1.

The method of obtaining 14: connection 82

Method: General methods 2.

Compound II: compound 5.

R-YH: 2-(4-mercaptophenyl)propane-2-ol (cf. G.Grue-Sorensen, E.Binderup and L. Binderup, "Vitamin D, a pluripotent steroid hormone: Structural studies, molecular endocrinology and clinical applications", Eds. A.W.Norman, R.Bouillon and M.Thomaset, Walter de Gruyter, New York, 1994, p.75-76).

13C-NMR: δ 153,4, 146,5, 142,6, 135,7, 135,4, 128,8, 124,8, 121,4, 116,4, 106,5, 72,1, 70,1, 67,0, 56,0, 55,6, 45,6, 43,7, 40,8, 40,2, 36,4, 35,2, 31,5, 28,7, 26,8, 25,7, 25,6, 23,3, 21,8, 18,7, 18,0, 17,9, 12,3, -5,0, -5,1, -5,1.

The method of obtaining 15: compound 83

Method: General methods 3.

Starting material: compound 84.

Eluent for chromatography: 0-20% ether in petroleum ether.

1H-NMR: δ 7,44 (d, 1H), 7,22 (m, 1H), of 6.96 (d, 1H), 6.87 in (t, 1H), 6,72 (s, 1H), to 6.19 (d, N), 5,98 (d, 1H), 5,15 (d, 1H), A 4.83 (D, 1H), 4,35 (t, 1H), 4,15 (m, 1H), 2,98 (DD, 1H), and 2.79 (DD, 1H), 2,56 (DD, 1H), 2,41 (DD, 1H), 2,18 (DD, 1H), 2,03 (t, 1H), 1,95-1,3 (m, 13H), of 1.05 (d, 3H), 0.88 to (C, 18), 0,34 (s, MN), 0,03 (m, N).

The method of obtaining 16: compound 84

Method: General method 2. The reaction conditions are changed from 30 min at room temperature to 10 min and 60°C.

Compound II: compound 5.

R-YH: 2-mercaptoethanol (use 10-fold molar excess relative to compound 5).

1H-NMR: δ was 7.45 (d, 1H), 7,22 (m, 1H), of 6.96 (d, 1H), 6,65 (t, 1H), 6.73 x (s, 1H), 6.42 per (d, 1H), 5,79 (d, 1H), equal to 4.97 (t, 1H), 4.92 in (t, 1H), 4,51 (DD, 1H), 4,20 (m, 1H), 2,98 (DD, 1H), 2,84 (DD, 1H), 2,56 (DD, 1H), 2,50 (d, 1H), 2,29 (d, 1H), 2,00 (t, 1H), 1,95-1,3 (m, 13H), of 1.06 (d, 3H), 0,89 (s, N), 0,84 (s, N), 0,35 (s, ZN), of 0.05 (m, N).

Method get 17: connection 85

Method: General methods 2.

Compound II is replaced by a connection 87. The reaction conditions are changed from 30 min at room temperature to 10 min and 60°C.

R-YH: 3-mercaptoethanol (use 10-fold molar excess relative to the compound 87).

Eluent for chromatography: 0-20% ether in petroleum ether.

13C-NMR: δ 155,6, 148,1, 140,3, 139,3, 135,0, 129,6, 122,9, 120,8, 117,9, 115,2, 112,4, 111,0, 71,8, 67,4, 55,9, 55,6, 45,8, 45,5, 44,6, 40,3, 35,2, 28,6, 26,8, 25,7, 25,6, 23,3, 21,8, 18,7, 18,0, 18,0, 12,3, -4,9, -5,0, -5,3.

Method get 18: connection 86

Method: General method 2. The reaction conditions are changed from 30 min at room temperature to 10 min and 60°C.

Compound II: Obedinenie 5.

R-YH: 3-mercaptoethanol (use 10-fold molar excess relative to compound 5).

Method get 19: connection 87

Method: General methods 3.

Starting material: compound 5.

Eluent for chromatography: 10% ether in petroleum ether.

13C-NMR: δ 148,1, 144,4, 139,9, 135,2, 133,1, 129,5, 127,7, 122,8, 118,0, 111,0, 74,1, 71,8, 67,3, 55,7, 52,2, 45,8, 45,1, 44,6, 39,6, 35,2, 28,5, 26,6, 25,6, 25,6, 23,1, 21,7, 21,4, 18,0, 17,9, 16,5, 12,1, -4,9, -5,0, -5,3.

The method of obtaining 20: connection 88

Method: General method 2. The reaction conditions are changed from 30 min at room temperature to 10 min and 60°C.

The compound of formula II is replaced by a connection 87.

R-YH: 4-mercaptoethanol (use 10-fold molar excess relative to compound 5).

13C-NMR: δ 154,4, 148,1, 140,4, 135,0, 132,9, 127,7, 122,9, 117,9, 115,8, 111,0, 71,8, 67,4, 55,9, 55,5, 45,8, 45,5, 44,6, 42,9, 40,3, 35,4, 28,6, 26,8, 25,7, 25,6, 23,3, 21,7, 18,6, 18,0, 18,0, 12,2, -4,9, -5,0, -5,3.

Method get 21: connection 89

Method: General method 4.

Source material V is replaced by a compound of General formula VIII: connection 87. Connection 89 purified by recrystallization from ethyl acetate.

The method of obtaining 22: connection 90

Method: apply the method used in the method of obtaining 3 WO 91/15475, but substituting compound 2 compound 3.

The method of obtaining 23: connection 91

Method: apply the method used in the method of obtaining 3 WO 91/15475, but replacing the joint is 2 connection 4.

The method of obtaining 24: connection 92

Method: General methods 3.

Source material: the compound 90.

Eluent for chromatography: 10% ether in petroleum ether.

The method of obtaining 25: connection 93

Method: General methods 3.

Source material: 91 connection.

Eluent for chromatography: 10% ether in petroleum ether.

The method of obtaining 26: connection 94

Method: General method 4.

Source material V: 92 connection.

The method of obtaining 27: connection 95

Method: General method 4.

Source material V: 93 connection.

EXAMPLES

Example 1

1(S), 3(R)-dihydroxy-20(R)-(2-((1-hydroxy-1-methyl) ethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 142

Method: General method 4.

Source material V: connection 77.

1H-NMR: δ 7,44 (m, 2H), 7,19 (m, 2H), 6,36 (d, 1H), 6,02 (d, 1H), 5,32 (d, 1H), 4,99 (s, 1H), 4,89 (s, 1H), 4,42 (m, 1H), 4,13 (m, 1H), 3,25 (DD, 1H), 2,88 (DD, 1H), 2,82 (DD, 1H), 2,58 (DD, 1H), 2,30 (DD, 1H), 2.05 is a 1.25 (m, N), 1,68 (C, 6N), a 1.08 (d, 3H), of 0.53 (s, 3H).

Example 2

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-ethyl) propyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 144

Method: General method 4.

Source material V: connection 80.

1H-NMR: δ 147,7, 146,5, 142,7, 137,2, 133,1, 128,4, 127,3, 126,7, 124,9, 123,2,117,2, 111,8, 70,8, 66,9, 56,1, 55,8, 45,8, 45,3, 42,9, 41,2, 40,3, 35,5, 35,0, 29,0, 26,8, 23,5, 22,1, 18,8, 12,5, 7,8.

Example 3

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl) e is Il)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, the connection 145

Method: General method 4.

Source material V: connection 74.

13C-NMR: δ 147,7, 146,7, 142,6, 135,8, 133,2, 129,0, 125,0, 124,8, 117,3, 111,8, 72,3, 70,8, 66,8, 56,1, 55,8, 45,8, 45,2, 42,9, 41,0, 40,3, 35,4, 31,7, 29,0, 26,9, 23,5, 22,1, 18,9, 12,5.

Example 4

1(S), 3(R)-Dihydroxy-20(R)-(2-hydroxy)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 147 Method: General method 4. Source material V: compound 83.

1H-NMR: δ was 7.45 (d, 1H), 7.23 percent (t, 1H), 6,97 (d, 1H), 6,85 (t, 1H), 6,74 (s, 1H), 6,34 (d, 1H), 5,98 (d, 1H), 5,31 (d, 1H), equal to 4.97 (d, 1H), 4,42 (m, 1H), 4,21 (m, 1H), 2,98 (DD, 1H), 2,80 (DD, 1H), 2,52 (m, 2H), to 2.29 (DD, 1H), 2,0-1,20 (m, N), of 1.06 (d, 3H), 0,35 (s, 3H).

Example 5

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 148

Method: General method 4.

Source material V: connection 85

13C-NMR: δ 155,8, 147,6, 142,7, 139,4, 133,1, 129,8, 125,0, 121,1, 117,2, 115,5, 112,7, 111,9, 70,9, 66,9, 56,1, 55,7, 45,8, 45,3, 42,9, 40,5, 40,3, 35,3, 29,0, 26,9, 23,6, 22,1, 18,9, 12,5.

Example 6

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 149

Method: General method 4.

Source material V: connection 88.

13C-NMR: δ 154,8, 147,6, 142,8, 133,2, 133,0, 127,7, 125,0, 117,2, 116,0, 111,9, 70,9, 66,9, 56,2, 55,7, 45,8, 45,3, 43,1, 42,8, 40,4, 35,5, 29,0, 26,9, 23,6, 22,1, 18,7, 12,4.

Example 7

1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 155

Method: General method 5.

Source material V: connection 67.

13C-NMR: δ 147,6, 142,7, 133,2, 124,9, 124,4, 117,3, 111,8, 73,1, 70,8, 66,8, 56,1, 55,7, 45,8, 45,3, 42,9, 40,4, 39,4, 35,7, 32,2, 29,0, 26,9, 24,8, 23,5, 23,5, 22,1, 18,8, 12,5.

Example 8

1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, the connection 156

Method: method For producing a 41 in WO 91/15475

The source material I: connection 155.

13C-NMR: δ 147,7, 142,1, 133,5, 126,1, 124,7, 117,5, 111,8, 73,1, 70,8, 66,8, 60,5, 58,5, 56,3, 56,0, 45,8, 45,3, 42,9, 40,4, 31,9, 28,9, 26,2, 23,5, 23,4, 22,0, 19,4, 18,4, 12,8.

Example 9

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, compound 157 (isomer of compound 159)

Method: General method 4.

Source material V: connection 70.

13C-NMR: δ 151,3, 147,7, 143,8, 141,9, 133,7, 129,0, 127,8, 124,5, 123,1, 120,4, 117,5, 111,7, 72,3, 70,7, 66,7, 65,3, 55,9, 55,8, 45,6, 45,2, 42,9, 40,4, 31,8, 31,8, 31,4, 28,9, 26,2, 23,4, 21,8, 19,7, 12,2.

Example 10

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl) ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, the connection 158

Method: General method 4.

Source material V: connection 71.

13C-NMR: δ 151,1, 147,6, 141,9, 140,1, 133,5, 129,8, 129,2, 126,3, 124,7, 123,9, 117,5, 111,8, 72,4, 70,8, 66,8, 61,8, 56,0, 55,9, 45,6, 45,2, 42,9, 40,5, 31,9, 30,6, 28,9, 26,4, 23,4, 21,7, 19,6, 12,4.

Example 11

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, link is 159 (isomer of compound 157)

Method: General method 4.

Source material V: connection 72.

13C-NMR: δ 150,8, 147,7, 144,9, 142,1, 133,4, 129,2, 127,2, 124,7, 122,2, 120,0, 117,5, 111,8, 72,5, 70,8, 66,8, 65,8, 56,4, 56,1, 45,8, 45,3, 42,9, 40,6, 31,9, 31,8, 31,1, 28,9, 27,0, 23,4, 22,0, 18,9, 12,5.

Example 12

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl) ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, the connection 160

Method: General method 4.

Source material V: connection 73.

13C-NMR: δ 155,4, 147,6, 141,8, 138,3, 133,6, 127,9, 125,5, 124,6, 117,6, 111,8, 72,4, 70,7, 66,8, 61,9, 56,1, 55,9, 45,6,.45,2, 42,8, 40,4, 31,8, 31,7, 30,5, 28,9, 26,4, 23,4, 21,7, 19,6, 12,3.

Example 13

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, compound 161 (isomer of compound 162)

Method: General method 4.

Source material V: 75 connection.

13C-NMR: δ 152,4, 147,7, 142,9, 142,1, 133,5, 125,6, 124,7, 123,9, 117,5, 111,8, 72,4, 70,8, 66,8, 65,8, 56,4, 56,1, 45,8, 45,2, 42,9, 40,6, 31,8, 31,1, 28,9, 27,0, 23,4, 22,0, 18,9, 12,5.

Example 14

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl)phenylsulfonyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, connection 162 (isomer of compound No. 161)

Method: General method 4.

Source material V: connection 76.

13C-NMR: δ 153,3, 147,7, 141,8, 133,7, 125,5, 124,5, 117,5, 111,7, 72,2, 70,6, 66,7, 65,3, 55,9, 45,6, 45,2, 42,9, 40,3, 31,8, 31,4, 28,9, 26,1, 23,4, 21,8, 19,7, 12,2.

Example 15

1(S), 3(R)-dihydroxy-20(R)-(4-(hydroxymethyl) phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-three is h, connection 163

Method: General methods 2.

Compound II is replaced by a connection 89.

R-SH: 4-Mercaptobenzyl alcohol.

The residue after processing purify by chromatography (silica gel; ethyl acetate as eluent)to give compound 163.

Example 16

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-ethyl)propyl))phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene, the connection 164

Method: General methods 2.

Compound II is replaced by a connection 89.

R-SH: 3-(4-Mercaptophenyl)pentane-3-ol.

The residue after processing purify by chromatography (silica gel; ethyl acetate as eluent)to give compound 164.

Example 17

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl))phenylthiomethyl)-22-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene, compound 165 (isomer of compound 166)

Method: General methods 2.

Compound II is replaced by a connection 94.

R-SH: 2-(4-Mercaptophenyl)propane-2-ol.

The residue after processing purify by chromatography (silica gel; ethyl acetate as eluent)to give compound 165.

Example 18

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl))phenylthiomethyl)-22-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene, compound 166 (isomer of compound 165)

Method: General methods 2.

Compound II is replaced by the connection 95.

R-SH: 2-(4-Mercaptophenyl)propane-2-ol.

The residue after processing purify by chromatography (silica gel; ethyl acetate is as eluent), receiving a connection 166.

Example 19

Capsules containing compound 145

Compound 145 was dissolved in peanut oil to a final concentration of 10 μg/ml (oil).

10 mass parts of gelatin, 5 mass parts of glycerin, and 0.08 mass parts of potassium sorbate and 14 mass parts of distilled water are mixed under heating to form soft gelatin capsules. Then make 100 μl of compound 145 oil solution, so that each capsule contains 1 mg of compound 145.

Example 20

1) Drops containing compound 145 in the form of an oil solution

0.1 g of compound 145 and 0.5 g Dα-alpha-tocopherol (antioxidant) is dissolved in the triglycerides of medium chain length (Medium Chain Triglycerides) (Ph.Eur) to obtain 100 liters (=94,5 kg). The product is filtered and the solution is transferred into brown vials having a suitable tube with a pipette or strip-dropper, to be able to drop 1 ml of the solution under 25 drops.

1 ml of solution contains 1 mcg connection 145 and 0.04 micrograms connection 145 to drop. The vial is closed with a suitable screw cap made of polypropylene.

2) Drops containing compound 145 in the form solubilizing aqueous solution

A) 0.2 g of compound 145 and 2 g of D,L-alpha-tocopherol dissolved in a stainless steel container in 10.2 kg (14 liters) of ethanol 99.9% and 2 the g Cremophor RH40(R) (polyoxyl 40 hydrogenated castor oil).

B) 54 kg of purified water, 0.015 kg of citric acid monohydrate, 0,950 kg of sodium citrate, 45 kg of sorbitol and 0.150 kg methylparaben is dissolved when heated in a separate container.

After cooling below 25°the solution is slowly poured into the solution And stirring the mixture. Cremophor RH40 forms in this micellar solution in which water-insoluble compound 145 and D,L-alpha-tocopherol remain in the product in solution. Finally, to the drug add purified water, getting 113 kg (=100 l) drug with a pH in the range of 6.5-7.5). The product is filtered and bottled in brown bottles, equipped with a suitable tube with a pipette or gasket-dropper and screw cap.

1 ml of the preparation contains 2 micrograms of compound 145, subdivided, for example, 20 drops, each of which corresponds to 0.1 to micrograms connection 145.

Example 21

Liquid for injection containing compound 145

Compound 145 (active substance) 10 mcg

The dihydrate dinatriumfosfaatti (buffer) to 15.4 mg

Dehydrate monopotassium phosphate

(buffer) 2 mg

Sodium chloride 0.8 mg

Sodium ascorbate (antioxidant) 5 mg

Solutol® HS 15 from BASF (solubilizer) 5 mg

Water for injection up to 1 ml

Solutol® HS 15 is dissolved in water for injection, heating to a maximum temperature of 80°C. Create a protective nitrogen layer.

Add buffer substances and sodium chloride, and then the solution is cooled up to a maximum of 30° C. Then add sodium ascorbate, and, finally, the resulting solution dissolve the connection 145.

Then the solution is sterile filtered and autoclave at a suitable temperature-time mode.

1. The use of the compounds of formula I

where X is hydrogen or hydroxy;

Y represents oxygen or sulfur, or oxidized sulfur selected from the group S(O), and S(O2);

R1and R2that may be the same or different, signify hydrogen or the residue after removal of 1 hydrogen atom from a linear, branched or cyclic, saturated or unsaturated C1-C6-hydrocarbon; or R1and R2together with the carbon atom to which they are attached (indicated by an asterisk in formula I)bearing the group X, form C3-C8-the carbon cycle;

Q means biradially the residue after removal of 2 hydrogen atoms from a linear, branched or cyclic, saturated or unsaturated C1-C8-hydrocarbon;

R3means hydrogen or the residue after removal of 1 hydrogen atom from a linear, branched or cyclic, saturated or unsaturated C1-C6-hydrocarbon;

R1, R2and/or Q is optionally substituted by one or more deuterium atoms Il is fluorine;

n is 0 or 1;

and derivatives of the compounds of formula I in which one or more hydroxyl groups converted into a group-O-acyl or O-glycosyl, or phosphate esters, such protective groups are hydrolyzed in vivo; to obtain drugs for the treatment and/or prophylaxis of osteoporosis and related bone disease.

2. The use of the compounds of formula I according to claim 1, where Y represents sulfur or oxidized sulfur selected from the group S(O) or S(O2).

3. The use of the compounds of formula I according to claim 1, where R1and R2together with the carbon atom to which they are attached (indicated by an asterisk in formula I)bearing the group X, form C3-C5-alkylenes group or a C3-C5-the carbon cycle, this cycle is preferably saturated.

4. The use of the compounds of formula I according to claim 1, where Q means fenelonov group, optionally substituted by one or more fluorine atoms.

5. The use of the compounds of formula I according to claim 1, where R3means hydrogen.

6. The use of the compounds of formula I according to claim 1, where n is equal to 1.

7. The use of the compounds of formula I according to claim 1, which is represented in the form of diastereoisomers in a pure form or a mixture of diastereoisomers.

8. The use of the compounds of formula I according to claims 1-7, selected from the group comprising 1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butoxymethyl)-9,10-sec is pregna-5(Z), 7(E), 10(19)-triene (compound 102),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-pentyloxide-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 103),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentyloxide)-9,10-scoprega-(Z), 7(E), 10(19)-triene (compound 106),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-Penta-2(E)-relaxometer-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 107),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-Penta-2-Unlocker)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 108),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-trifluoromethyl-5,5,5-Cryptor-1-Penta-2-Unlocker)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 109),

1(S), 3(R)-dihydroxy-20(R)-[3-(2-hydroxy-2-propyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 111),

1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy-2-methyl-1-propylthiouracil)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 116),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-methyl-1-butylthioethyl)-9,10-scoprega-5(Z), 7(E), 10(19) -triene (compound 117),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 121),

1(S), 3(R)-dihydroxy-20(R)-(5-hydroxy-5-methyl-1-hexyloxymethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 126),

1(S), 3(R)-dihydroxy-20(R)-[2-(2-hydroxy-2-propyl) phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 127),

1S), 3(R)-dihydroxy-20(R)-[2-(3-hydroxy-3-pentyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 128),

1(S), 3(R)-dihydroxy-20(R)-[3-(3-hydroxy-3-pentyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 129),

1(S), 3(R)-dihydroxy-20(R)-[4-(2-hydroxy-2-propyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 130),

1(S), 3(R)-dihydroxy-20(R)-[4-(3-hydroxy-3-pentyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 131),

1(S), 3(R)-dihydroxy-20(R)-[3-(hydroxymethyl)phenoxymethyl]-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 132),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-interculturality-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 133),

1(S), 3(R)-dihydroxy-20(R)-(3-haproxy-3-ethyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 134),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxy-3-ethyl-1-interculturality)-9,10-scoprega-5(Z), 7(E), -10(19)-triene (compound 135),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-methyl-1-pentultimate)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 136),

1(S), 3(R)-dihydroxy-20(R)-(3-(hydroxymethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 137),

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-methyl)ethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), -10(19)-triene (compound 138),

1(S), 3(R)-dihydroxy-20(R)-(4-hydroxy-4-ethyl-1-Gex-2-Unlocker)-9,10-with koprivna-5(Z), 7(E), 10(19)-triene (compound 139),

1(S), 3(R)-dihydroxy-20(R)-(2-hydroxyphenoxy)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 140),

1(S), 3(R)-dihydroxy-20(R)-(3-hydroxyphenoxy)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 141),

1(S), 3(R)-dihydroxy-20(R)-(2-((1-hydroxy-1-methyl)ethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 142),

1(S), 3(R)-dihydroxy-20(R)-(3-((1-hydroxy-1-ethyl)propyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 144),

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 145),

1(S), 3(R)-dihydroxy-20(R)-(2-hydroxy)phenylthiomethyl)-9,10-scoprega-5(Z),

7(E), 10(19)-triene (compound 147),

1(S), 3(R)-dihydroxy-20(R)-(3,3-debtor-4-hydroxy-4-methyl-1-pentyloxide)-9,10-scoprega-5(Z)-7(E), 10(19)-triene (compound 153),

1(S), 3(R)-dihydroxy-20(R)-(4-(hydroxymethyl)phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 163),

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-ethyl)propyl))phenylthiomethyl)-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 164),

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl))phenylthiomethyl)-22(R)-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 165), and

1(S), 3(R)-dihydroxy-20(R)-(4-((1-hydroxy-1-methyl)ethyl))phenylthiomethyl)-22(S)-methyl-9,10-scoprega-5(Z), 7(E), 10(19)-triene (compound 166),

 

Same patents:

The invention relates to a derivative of vitamin D formula (1):

Formula 1

where X = -O - or-S- ; m = 1, 2, 3; R1and R2-H or alkyl; R4-H; R5Is H, OH or R4and R5together form a double 16, 17 connection, R3- YR8where Y is-O - or-S-,

R8-H, alkyl, possibly substituted by F or cycloalkyl, or-NR9R10where R9and R10-H, alkyl, possibly substituted by F or cycloalkyl, R6-OH, possibly substituted, R7-H or a protective group

The invention relates to new derivatives of vitamin D General formula I

< / BR>
where Y1- OH, C1-12alkanoyloxy or optionally substituted benzoyloxy, Y2- H, C1-12alkanoyl or optionally substituted benzoline group, R1and R2together ekzoticheskaya methylene group, R3and R4independently - H, C1-4alkyl, Q - C1-3alkylen, possibly substituted inoris HE in the group, which, in turn, can be etherification, R5and R6at the same time C1-4alkyl, or R5and R6together with carbon atom C-25 form cyclopropyl group, Z is a 5-6-membered aromatic Carbo - or heterocycle, such as phenyl, oxazole, thiazole, furan, thiophene, pyrrole, isoxazol, pyrazole, triazole, pyridine, pyrimidine, possibly substituted C1-12alkylen

The invention relates to novel vitamin D analogues of the formula (I), where X is hydrogen, hydroxy or protected hydroxy; R1and R2is hydrogen, methyl or ethyl; Q3-C6hydrocarbide where hydrocarbide means biradical obtained after removal of two hydrogen atoms from a straight or branched, saturated or unsaturated hydrocarbon, in which any one of CH2group can be optionally replaced by an oxygen atom or carbonyl group such that the carbon atom (C-22), directly associated with the C-20 was a hybridized carbon atom is sp2or sp3i.e

The invention relates to novel vitamin D analogues of formula I, where X Is H or HE, R1and R2- CH3or2H5or together with the carbon atom bearing the group X, can form WITH3-C5carbocycle, Q is a single bond or C1-C8-hydrocarbide, in which one of the groups-CH2- not associated with a group, optionally substituted by an IT group or replaced by an oxygen atom, Y is a single bond or C1-C8-hydrocarbide, or other derivative

The invention relates to vitamin D analogues of General formula I, where X is hydroxy; R1and R2- the same or different, H, CH3WITH2H5or cyclopropyl; Q is methylene, ethylene, tri -, or tetramethylene, optionally substituted hydroxy-group or group-or SIG3where R3Is h, methyl or ethyl; Y is a single bond or C1-C2- hydroxycarbonyl

The invention relates to new derivatives of vitamin D3formula (I), where Q is methylene, ethylene, tri -, or tetramethylene, -CH=CH-, -CH=CH-CH=CH-; Y is a single bond, - CH(OH), -O-(C6H4)-(meta) or-S-(C6H4)-(meta); R1and R2the same or different, is methyl, ethyl, or R1and R2together with the carbon atom marked with an asterisk in formula I bearing a group Z may form WITH3-C6carbocyclization ring; Z is hydrogen or hydroxy, provided that when Y is CH(OH)-, R1and R2- mately, Z is hydroxy, the configuration at C-20 cannot be R

The invention relates to vitamin D analogues of the formula I in which Q represents a C1-C8hydrocarbononly biradical; R represents a C1-C6hydrocarbide; expression hydrocarbide (hydrocarbide) denotes the radical (biradical) obtained after removal of the 1 (2) atom(s) of hydrogen from an unbranched, branched or cyclic, saturated or unsaturated hydrocarbon, or in which two groups of R, taken together with the carbon atom carrying the hydroxyl group can form WITH3-C8carbocyclic ring

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

in which R1 represents H, halogen, OCH3, or OH; R2 represents (a) -X-(CH2)n-CH2-N(R4)R5, where (i) X represents NH or S; n is integer from 1 to 4; R4 and R5, the same or different, represent C1-C4-alkyl, H, -CH2C≡CH, or -CH2CH2OH; or R4 and R5, together, form nitrogen-containing five- or six-membered cycle or heteroaromatic cycle; or where (ii) X represents O; n is integer from 1 to 4; one of R4 and R5 is CH2C≡CH, or -CH2CH2OH and the other H or C1-C4-alkyl; or R4 and R5, together, form imidazole cycle or nitrogen-containing six-membered cycle or heteroaromatic cycle; or R2 represents (b) -Y-(CH2)nCH2-O-R5, where (i) Y represents O; n is integer from 1 to 4; and R6 represents -CH2CH2OH or -CH2CH2Cl; or where (ii) Y represents NH or S; n is integer from 1 to 4; and R6 represents H, -CH2CH2OH, or -CH2CH2Cl; or R2 represents (c) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, or 2,2-diethyl-2-hydroxy-ethoxy; R3 represents H. halogen, OH, or -OCH3. Claimed compounds are novel selective estrogen receptor modulators. Invention also discloses pharmaceutical composition and a method for production of tissue-specific estrogenic and/or antiestrogenic effect in patient, for whom indicated effect is required.

EFFECT: increased choice of estrogen receptor modulators.

19 cl, 7 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: method involves administering selective modulator of steroid sex hormones being in particular compounds of general formula(I) and some quantity of steroid sex hormones precursor selected from a group composed from dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-en-3β,17β-diol and compounds in vivo transformable into one of cited precursors. Bisphosphonates combined with selective estrogen receptor modulators and/or steroid sex hormones precursor are additionally introduced for medically treating and/or inhibiting osteoporosis progress.

EFFECT: enhanced effectiveness of treatment; excluded adverse side effects.

41 cl, 13 dwg, 4 tbl

FIELD: medicine, therapy.

SUBSTANCE: simultaneously for 20 d one should prescribe calcium D3 two times daily in the morning and in the evening per 1 tablet or Beresh Plus drops. The quantity of drops for daily intake is equal to patients body weight in kg and they should be introduced in three stages during meals by drinking them up with sufficient amount of water. Application of the suggested method optimizes calcium exchange in patients with osteoporosis, enables to achieve earlier and more stable results in normalization of calcium content in bones by preventing, thus, osteoporotic fractures.

EFFECT: higher efficiency of pharmacological correction.

1 ex

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin

The invention relates to the stimulation of osteogenesis and may find application in experimental medicine and veterinary

The invention relates to the field of biotechnology, specifically to obtain protein/factor inhibiting osteoclastogenesis (OCIF), and can be used for treatment and immunological diagnosis of diseases involving bone resorption
The invention relates to medicine, in particular to urology and endocrinology

FIELD: medicine, therapy.

SUBSTANCE: simultaneously for 20 d one should prescribe calcium D3 two times daily in the morning and in the evening per 1 tablet or Beresh Plus drops. The quantity of drops for daily intake is equal to patients body weight in kg and they should be introduced in three stages during meals by drinking them up with sufficient amount of water. Application of the suggested method optimizes calcium exchange in patients with osteoporosis, enables to achieve earlier and more stable results in normalization of calcium content in bones by preventing, thus, osteoporotic fractures.

EFFECT: higher efficiency of pharmacological correction.

1 ex

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