New analogues of vitamin d

FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

 

This invention relates to novel vitamin D analogues which exhibit strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells, including skin cells and cancer cells, as well as immunomodulatory effects, to pharmaceutical preparations containing these compounds, to dosage forms such preparations and to their use for the treatment and prevention of diseases characterized by abnormal cellular differentiation and/or proliferation of cells.

PREREQUISITES TO the CREATION of INVENTIONS

It was shown that 1α,25-dihydroxy-vitamin D3(1,25-(Oh)2D3affects effects and/or production of interleukins (Muller,K. et al., Immunol. Lett., 17, 361-366 (1988)), which indicates a potential use of this compound in the treatment of diseases characterized by a dysfunction of the immune system, e.g. autoimmune diseases, AIDS, homologous disease and reactions of transplants, or other conditions characterized by abnormal production of interleukin-1, such as inflammatory diseases, such as rheumatoid arthritis and asthma.

It was also shown that 1,25-(Oh)2D3able to stimulate the differentiation of cells and to inhibit excessive cell proliferation (Abe, E. et al., Proc. Natl. Acad. Sci., USA, 78, 4990-4994 (1981)), and was made of a CR is polozenie, that this connection can be useful in treating diseases characterized by abnormal cell proliferation and/or differentiation of cells, such as leukemia, myelofibrosis and psoriasis.

It was also suggested that the use of 1,25-(OH)2D3or its prodrugs 1α-OH-D3for the treatment of hypertension (Lind, L. et al., Acta Med.Scand., 222, 423-427 (1987)) and diabetes (Inomata, S. et al., Bone Mineral., 1, 187-192 (1986)). Another indication for 1,25-(Oh)2D3prompted by the recent observation of the connection between hereditary resistance to vitamin D and alopecia: treatment of 1,25-(Oh)2D3can promote hair growth (Editorial, Lancet, March 4, str (1989)). In addition, the fact that topical application of 1,25-(Oh)2D3reduces the size of sebaceous glands in the ears of the male Syrian hamster, suggests that this compound might be useful for the treatment of acne (Malloy V.L. et al., The Tricontinental Meeting for Ivestigative Dermatology, Washington, (1989)).

However, therapeutic possibilities with such indications are strongly limited by the well-known potential effects of 1,25-(Oh)2D3on the metabolism of calcium, elevated concentrations in the blood will promote the rapid development of hypercalcemia. Therefore, the specified connection and some of his strong synthetic analogues are unsatisfactory for use as a drug on the I treatment, for example, psoriasis, leukemia or immune disease, which may require continuous administration of medication in relatively high doses.

Recently described some vitamin D analogues which exhibit some degree of selectivity in relation to the activity of inducing differentiation of cells/inhibition of cell proliferation in vitro compared with effects on calcium metabolism in vivo (which is determined by high concentration of calcium in serum and/or increased excretion of calcium in the urine), which is undesirable limits the dose that can be safely introduced. One of the first pop-analogues calcipotriol (INN) or calcipotriene (USAN), was developed based on the specified selectivity and is now widely known in the world as an effective and safe drug for the topical treatment of psoriasis.

A study with another analog of vitamin D, seocalcitol [1(S),3(R)-dihydroxy-20(R)-(5'-ethyl-5'-hydroxy-hepta-1'(E),3'(E)-Dien-1'-yl)-9,10-scoprega-5(Z),7(E),10(19)-triens]selected on this basis, confirms the concept that systematically introduce the analogues of vitamin D can inhibit the proliferation of cancer cells of the mammary glands in vivo when subconsiously doses (Colston, K.W. et al., Biochem. Pharmacol. 44, 2273-2280 (1992) and Mathiasen, I.S. et al., J. Steroid Biochem. Molec.Biol., 46, 365-371 (1993)).

Related Conn who care, having the following formula, disclosed in WO 98/47866:

where a represents a single or double bond, T mean CH2or CH2CH2; Means in CH2CH2CH=CH orR1and R3mean H or HE, C(R,R) denotes CH2or C=CH2, R2means of CH3and R4means N or R2mean N and R4means of CH3, L is phenyl and R5means HE or C(C1-4alkyl)2OH L or R5mean 2-furyl, which is 5-substituted C(C1-4alkyl)2IT provided that when L is phenyl, And means a single bond, meansT mean CH2, R1and R3each mean HE, C(R,R) means C=CH2, R2means of CH3, R4mean N and R5means With(CH3)2OH, then R5must be in the ortho - or para-position. These compounds are described in WO 98/47866 as applicable for the treatment or prevention are dependent on vitamin D disorders, particularly psoriasis, basal cell carcinoma, disorders of keratinization and keratosis, leukemia, osteoporosis, renal insufficiency, accompanied by hyperparathyroidism, transplant rejection and homologous disease.

The stereochemistry of the compounds described in WO 98/47866, not given if you double tie the (position 22), when the mean SN=SN. However, from the above examples and synthesis obvious that considers only 22-TRANS-compounds. Despite the extensive efforts of the prior art to provide a therapeutically effective products, there remains a need in the new vitamin D analogues with an acceptable combination of desirable therapeutic activity and minimal toxic effects. The compounds of this invention are not disclosed until now, vitamin D analogues with activity inhibition of cell proliferation and promotion of cell differentiation without any unwanted side effects elevated levels of calcium in serum and skin irritation.

BRIEF description of the INVENTION

This invention relates to compounds of General formula I

where X is hydrogen or hydroxy; R1and R2that may be the same or different, signify hydrogen, (C1-C4) alkyl, optionally substituted with one hydroxyl group or one or more fluorine atoms, or together with the carbon atom to which they are attached, R1and R2form (C3-C5)carbocyclic ring, R3means hydrogen, (C1-C4) alkyl, (C1-C4) alkoxy or halogen atom, such as fluorine, chlorine, bromine or IO is.

The configuration of the carbon atoms marked with an asterisk, may be either S or R.

As should be obvious, the compounds of formula I have the CIS-configuration at the double bond in position 22. According to the invention, found that 22-CIS-compounds are significantly more active in the stimulation of cell differentiation and inhibiting undesirable proliferation of cells.

DETAILED description of the INVENTION

The preferred embodiment of the

In the compounds according to the invention, preferably, when X is hydroxy; R1and R2are the same and preferably means (C1-C2)alkyl, optionally substituted with one hydroxyl group or one or more fluorine atoms; and R3means hydrogen, (C1-C2) alkyl, fluorine or chlorine. The preferred positions of the groups C(R1) (R2) (X) are meta, and para. Even more preferred are the compounds of formula I, where R1and R2both represent methyl, trifluoromethyl or ethyl and R3means hydrogen.

The invention also includes diastereoisomeric compounds of formula I in pure form or as a mixture of diastereoisomeric compounds of formula I.

Preferred compounds according to the invention is selected from the group consisting of these compounds, as: 1(S),3(R)-dihydroxy-20(R)-[2(Z)-(3-(2-hydroxy-2-propyl)phenyl)vinyl]-9,10-SECO is regna-5(Z),7(E),10(19)-triene, 1(S),3(R)-dihydroxy-20(S)-[2(Z)-(4-(2-hydroxy-2-propyl)phenyl)vinyl]-9,10-scoprega-5(Z),7(E),10(19)-triene, 1(S),3(R)-dihydroxy-20(R)-[2(Z)-(4-(2-hydroxy-2-propyl)phenyl)vinyl]-9,10-scoprega-5(Z),7(E),10(19)-triene, and hydrolyzable in vivo esters with pharmaceutically acceptable acids.

Used herein, the term "alkyl" refers to any univalent group derived from an alkane by removing a hydrogen atom from any carbon atom, and includes the subclasses of normal alkyl (n-alkyl) and primary, secondary and tertiary alkyl, respectively, and have specified in the description of the number of carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and isobutyl. Alkane refers to an acyclic branched or unbranched hydrocarbon having the General formula CnH2n+2and therefore consisting of hydrogen atoms and saturated carbon atoms.

"Halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.

SYNTHESIS, REACTIONS

Compounds according to the invention can be obtained as shown in scheme Ia. Join alkyne of formula 1A (Calverley, M.J. and Bretting C.Aa.S.; Bioorg. Med. Chem. Lett. 9, 1841-1844, 1993) to the fragment of the aryl side chain of the formula II in the presence of catalytic amounts of a palladium complex such as Pd(PPh3)4or Pd(PPh3)2Cl2, rolled the practical amounts of copper iodide (I) and the Foundation of the organic amine as solvent gives an intermediate compound of formula IIIa. The triple bond in position 22 compounds IIIa restore to 22-CIS-double bond with hydrogen in the presence of catalytic amount of Lindlar catalyst.

For the conversion of intermediate compounds IVa Ia conduct stage photoisomerization and the stage of removing protection, similar to the stages used in the last stages of the synthesis of other analogues of vitamin D, see European patent No. 0227826.

The compounds of formula Ib (20-epimer Ia) are obtained similarly from 20-epimer Ib (Bretting C., Mark C. Hansen, Rastrup Andersen N., 1994, Chemistry and Biologi of 22,23-yne analogs of calcitriol. Norman A.W., Bouillon R, Thomasset m (eds.) Vitamin D - A Pluropotent Steroid Hormone: Structural Stadies, Molecular Endocrinology and Clinical Applications. Walter de Gruyter, Berlin - new York, p.73-74) as a starting material, as shown in figure Ib.

Forming a side chain units of the formula II are either known compounds or can be obtained as shown in scheme II.

Alternatively, the compounds according to the invention can be obtained as shown in scheme III.

The analog of vitamin D formula 2b (M. Calverley, Tetrahedron, 43, 4609, (1987)) with aldehidelor in position 22 reacts with alkyladamantanes formula X with the formation of a mixture of 22 (Z) and 22(E) isomers, from which by chromatography allocate 22(Z) isomer IV.

Notes to the schemes Ia and Ib:

X1 denotes bromine or iodine, Y means in dorog, hydroxy or protected hydroxy-group,

X, R1, R2and R3such as described above.

a) the Combination of the HEC in the presence as catalyst of Pd(PPh3)2Cl2/iodide copper (I).

b) Hydrogenation in the presence of Lindlar catalyst.

(c) Isomerization with hν in the presence of a triplet sensitizer, such as anthracene.

a) Remove the protection using TBAF or HF.

Notes to scheme II:

E. means lower alkyl, such as methyl, ethyl or isopropyl,

X1, R1, R2and R3such as described above.

a) Reaction of a Grignard reagent with R1MgBr or R1MgI.

b) Reaction of Grignard reagent with R2MgBr or R2MgI.

c) Reaction with dihydropyran.

d) Similarobama with Me3SiCl +base.

Notes to scheme III:

R3as specified above.

A represents the group C(R1) (R2) (Y)", where R1, R2and Y are such as defined above, or a group which can easily be turned into "C(R1) (R2) (Y)", for example ester group.

a) Wittig Reaction (alkalinebattery X get on the place of impact based on readily available halide triphenylphosphine XII).

In this description uses the following standard abbreviations: But=tert-butyl, DMF=N,N-dimethy is formamid, DMAP=4-dimethylaminopyridine, Et=ethyl, Ether=simple diethyl ether, pet. erher=petroleum ether, Me=methyl, PPTS=p-toluene-sulfonate pyridinium, Py=pyridine, TBAF=Tetra fluoride-n-butylamine, TBS=tert-butylmethylether, THF=tetrahydrofuran, TNR=tetrahydro-4H-Piran-2-yl, Ts=tosyl.

PHARMACOLOGICAL METHODS

To demonstrate the effectiveness of the compounds of formula I may be used in the analysis for the evaluation of the tested compounds for antiproliferative activity in skin cells, for example, the effect against psoriasis, such as in vitro assays using Nasal, cell lines spontaneously immortalized non-carcinogenic keratinocytes of human skin (Mark C. Hansen et al., J. Invest. Dermatol., 1, 44-48 (1996)), measuring the absorption of3H-thymidine.

Usually the classic effects of 1,25-(Oh)2D3on the calcium balance in the body, including calciumcalcium and colluricincla activity, undesirable for analogues of vitamin D according to this invention, for which the desired selectivity in relation to, for example, inhibition of proliferation of certain cells, the absence of kallemick effects and skin irritation.

So, calciamenta activity of compounds can be determined in rats in vivo, as described previously (Binderup, L., Bramm, E., Biochem. Pharmacol. 37, 889-895 (1988)).

In addition, the binding with the receptor of vitamin D compounds relative to the binding is of calcitriol in comparison with the compounds of the prior art can be determined in vitro, as described previously (Binderup, L., Bramm, E., Biochem. Pharmacol. 37, 889-895 (1988)).

These compounds are intended for use in pharmaceutical preparations which may be administered at the local or systemic treatment of disorders in humans or animals, such as cancer, leukemia, myelofibrosis and psoriasis, some painful conditions, including hyperparathyroidism, especially secondary hyperparathyroidism associated with renal insufficiency, diabetes mellitus, hypertension, acne, alopecia, aging, AIDS, neurodegenerative disorders such as Alzheimer's disease, homologous reactions, transplant rejection, for the prevention and/or treatment caused by steroid atrophy of the skin and for promotion of osteogenesis and treatment of osteoporosis.

These compounds can be used in combination with other pharmaceutical substances or potential therapeutic agents. In the treatment of psoriasis, these compounds may be used in combination with other medicines for psoriasis, such as steroids, or with other methods such as with light therapy or with ultraviolet irradiation or a combination of PUVA treatment. In the treatment of cancer, these compounds may be used in combination with other anti-cancer drugs or anti-cancer treatments such as radiation therapy. To prevent Ott is rginia transplant and homologous disease or for the treatment of autoimmune diseases, these compounds are useful in combination with other immunosuppressive/immunoregulatory drugs or treatments, for example, with cyclosporine A.

Required for a therapeutic effect to the amount of the compounds of formula I (referred to hereafter as the active ingredient) of course will vary depending on how the specific connections and routes of administration, and the mammal being treated. Compounds according to the invention may be introduced parenterally, intra-articular, enteral or local paths. They are well absorbed when enteral introduction, and it is the preferred route of administration in the treatment of systemic disorders. In the treatment of dermatological disorders, type of psoriasis, or ocular diseases preferred local or enteral form.

Although it is possible to enter only active ingredient in the form of the raw chemical, it is preferable to present it as a pharmaceutical preparation. Usually the active ingredient is from 0.1 ppm to 0.1% by weight of the drug.

Preparations according to this invention, both for veterinary and medical use for humans, thus, contain the active ingredient in combination with pharmaceutically acceptable carrier for him and optionally other therapeutic ingredient (or ingredients). The carrier (s) must be "acceptable" in the sense of compatibility with other ingredients of the preparations and not harmful to his rezip the enta.

Drugs include, for example, drugs in a form suitable for oral, ophthalmic, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, intra-articular and local administration.

The term "uniform dose" refers to a solid, i.e. a single dose which may be administered to the patient and which is convenient in handling and packaging, staying physically and chemically stable standard dose containing either an active connection as such, or its mixture with a solid or liquid pharmaceutical diluents or carriers.

Drugs can be conveniently represented in a uniform dosage form and may be obtained by any methods well known in pharmacy. All methods include the stage of combining the active ingredient with the carrier which contains one or more accessory ingredients. Basically, the drugs are prepared uniform and thorough mixing of the active ingredient with liquid carriers or finely ground solid carriers or both and then, if necessary, shaping the product into the desired product.

Preparations according to this invention suitable for oral administration may be in the form of discrete units such as capsules, sachets, tablets or lozenges, each containing serene is a certain amount of the active ingredient, in the form of powder or granules, in the form of an emulsion of the type oil-in-water or emulsion type water in oil. The active ingredient may also be introduced in the form of a bolus, electuary or paste.

Preparations for rectal injection can be in the form of a suppository containing an active ingredient and a carrier, or in the form of an enema.

Preparations suitable for parenteral administration, usually contain sterile oil or aqueous preparation of active ingredient, which is preferably isotonic with the blood of the recipient. Percutaneous preparations can be in the form of a patch or pad.

Drugs suitable for intra-articular or ophthalmic injection may 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 drugs or biodegradable polymer systems can also be used to deliver the active ingredient as in intra-articular and ophthalmic administration.

Drugs that are suitable for local or ophthalmic injection, contain liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, emulsions of the type oil-in-water or water in oil, such as creams, ointments or pastes or solutions or suspensions such as drops.

In opalanie to the above-mentioned ingredients, the preparations according to this invention may contain one or more additional ingredients, such as diluents, binders, preservatives, etc.

The preparations can also contain other therapeutically active compounds usually applied in the treatment of the above pathological conditions, such as other immunosuppressants in the treatment of immunological diseases or steroids in the treatment of dermatological diseases.

This invention relates also to a method of treating patients suffering from one of the above pathological conditions, this method provides an introduction to a patient in need of treatment an effective amount of one or more compounds of the formula I alone or in combination with one or more diluents or other therapeutically active compounds usually applied in the treatment of these pathological conditions. Treatment of these compounds and/or additional therapeutically active compounds may be simultaneously or at intervals.

When systemic treatment is administered daily dose of 0.001-2 mg per kilogram of body weight, preferably from 0.002 to 0.3 µg/kg body weight of the mammal, for example, 0.003 to 0.3 ug/kg of the compounds of formula I, usually corresponding to a daily dose for adults is from 0.2 to 25 mg. The topical treatment of dermatological disorders prescribe ointments, creams or lotions containing from 0.1-1000 µg/g and preferably is t 1-500 µg/g and more preferably from 10-250 µg/g of compound of formula I. For local application in ophthalmology prescribe ointments, drops or gels containing 0.1-1000 µg/g and preferably from 1-500 µg/g, more preferably from 10-250 µg/g of compound of formula I. Oral medications are prepared preferably in the form of tablets, capsules, or drops, containing from 0.05-100 μg, preferably from 0.1 to 50 μg of the compounds of formula I at a uniform dose.

Hereinafter the invention will be described in the following General procedures, preparations and examples.

EXAMPLES

Total

Examples of compounds of formula I are listed in table 1, whereas the intermediate compounds of formulas VII, VIII and IX are listed in table 2 and the intermediate compounds of formulas III and IV are listed in table 3.

For the spectra of nuclear magnetic resonance (300 MHz) the values of chemical shifts (δ) are given for solutions deuterochloroform relative to internal tetramethylsilane was (δ=0) or chloroform (δ=7,25). The value of a multiplet, either defined (doublet (d), triplet (t), Quartet (q))or not (m), is given when approximated by the midpoint, if not named range (s=singlet, b=broad).

Constants of spin-spin interaction (J) are given in Hertz (Hz) and sometimes approximated to the nearest unit.

The ether means diethyl ether, dried over sodium. THF dried over nitrobenzophenone. Petroleum ether refers to pentanol faction. is eacli usually carried out in an argon atmosphere at room temperature, if not stated otherwise. Used procedure involves the dilution specified in the description of the solvent (or organic solvent for the reaction, extraction with water and then with saturated salt solution, dried over anhydrous MgSO4and concentration in vacuum to obtain a residue. Chromatography carried out on silica gel.

Table 1.

Examples of compounds of formula I
Connection # Synthesis No.Proc.Position. *)R1R2R3x
101120(R)3MeMeHOH
102220(S)4MeMeHOH
103320(R)4MeMeHOH
10420(S)3MeMeHH
10520(R)4MeMeHH
10620(S)3EtEtHOH
10720(R)3EtEtHOH
10820(R)4MeMe2-ClOH
10920(S)4EtEt2-FOH
11020(R)4MeMe2-och3OH
11120(S)4MeMe2-MeOH
11220(S)3MeMe5-ClOH
11320(S)3MeMe5-FOH
11420(R)3EtEt5-och3OH
11520(S)3MeMe 5-MeOH
11520(S)3MeMe5-isopr.OH
11620(S)3EtEt6-ClOH
11720(S)3MeMe6-FOH
11820(R)3EtEt6-och3OH
11920(S)3MeMe6-OEtOH
12020(S)3MeMe6-MeOH
12120(S)3MeMe6-EtOH
12220(S)3MeMe6-isopr.OH
*)=-C(R1) (R2) (X)

Table 2.

Non-limiting examples of intermediate connection of the Affairs of the formula VII, VIII and IX
Synthesis No.Conn. No.GP **)FormulaX1R1R2R3
131VII4-IMeMeH
241VII3-IMeMeH
352VIII4-IMeMeH
462VIII3-IMeMeH
573IX4-IMeMeH
81aVII3-IEtEtH
92VIII3-IEtEtH
101VII4-IMeMe5-Cl
112VIII4-IMe/td> Me5-Cl
121aVII4-BrEtEt5-F
133IX4-BrEtEt5-F
141VII4-BrMeMe5-OMe
152VIII4-BrMeMe5-OMe
161VII4-IMeMe5-Me
173IX4-IMeMe5-Me
181VII3-BrMeMe5-Cl
192VIII3-BrMeMe5-Cl
201VII3-BrMeMe5-F
212VIII3-Br MeMe5-F
221aVII3-IEtEt5-OMe
232VIII3-IEtEt5-OMe
241VII3-IMeMe5-Me
252VIII3-IMeMe5-Me
261VII3-BrMeMe5-iPr
272VIII3-BrMeMe5-iPr
281aVII3-IEtEt4-Cl
292VIII3-IEtEt4-Cl
301VII3-IMeMe4-F
3123-IMeMe4-F
321aVII3-IEtEt4-och3
332VIII3-IEtEt4-och3

Synthesis No.Conn. No.GP **)FormulaX1R1R2R3
341VII3-IMeMe4-OEt
352VIII3-IMeMe4-OEt
361VII3-IMeMe4-Me
372VIII3-IMeMe4-Me
381VII3-IMeMe4-Et
392VIII 3-IMeMe4-Et
401VII3-IMeMe4-iPr
412VIII3-IMeMe4-iPr
**)=The General procedure

Table 3.

Non-limiting examples of intermediate compounds of formulas III and IV
Connection # Synthesis No.FormulaPosition. ***)R1R2YR3
426IVb4MeMeOHH
437IV(z)b4MeMeOHH
448IIIa4MeMeOTHPH
459IIIa4MeMeOHH
4610IVa4 MeMeOHH
4711IV(z)a4MeMeOHH
4812IVa3COOMeH
4913IV(z)a3COOMeH
5014IV(z)a3MeMeOHH
51IIIb3MeMeHH
52IVb3MeMeHH
53IIIa4MeMeHH
54IVa4MeMeHH
55IIIb3EtEtOHH
56IVb3EtEtOH H
57IIIa3EtEtOHH
58IVa3EtEtOHH
59IIIa4MeMeOH2-Cl

75
Connection # Sint. No.FormulaPosition. ***)R1R2YR3
60IVa4MeMeOH2-Cl
61IIIb4EtEtOH2-F
62IVb4EtEtOH2-F
63IIIa4MeMeOH2-OMe
64IVa4MeMeOH2-OMe
65/td> IIIb4MeMeOH2-Me
66IVb4MeMeOH2-Me
67IIIb3MeMeOH5-Cl
68IVb3MeMeOH5-Cl
69IIIb3MeMeOH5-F
70IVb3MeMeOH5-F
71IIIa3EtEtOH5-OMe
72IVa3EtEtOH5-OMe
73IIIb3MeMeOH5-Me
74IVb3MeMeOH5-Me
IIIb3MeMeOH5-iPr
76IVb3MeMeOH5-iPr
77IIIb3EtEtOH6-Cl
78IVb3EtEtOH6-Cl
79IIIb3MeMeOH6-F
80IVb3MeMeOH6-F
81IIIa3EtEtOH6-OMe
82IVa3EtEtOH6-OMe
83IIIb3MeMeOH6-OEt
84IVb3MeMeOH6-OEt
85IIIb3MeMeOH6-Me
86IVb3MeMeOH6-Me
87IIIb3MeMeOH6-Et
88IVb3MeMeOH6-Et
89IIIb3MeMeOH6-iPr
90IVb3MeMeOH6-iPr
***)=-C(R1) (R2) (Y)

GENERAL METHODS

General method 1

The reaction metalmilitia with a complex ester of the formula V

To stir cooled with ice to a solution of complex methyl ester V (27 mol) in dry ether (20 ml) is added dropwise during 20 minutes to a filtered solution of Grignard reagent prepared from magnesium (1.47 g, 60 mmol) and under the conditions (4,0 ml, 64 mmol) in dry ether (40 ml). After stirring for two hours at room temperature the reaction is th mixture slowly pour in water (40 ml). The phases are separated and the aqueous phase extracted with ether (3×50 ml). The combined ether phases are sequentially extracted with 1 N. aqueous solution of HCl (50 ml), water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried over MgSO4and concentrated in vacuo before the formation of a dark oil. The crude oil is purified by chromatography on silica gel, to obtain a ketone of formula VI as a by-product and the alcohol of formula VII as the main product.

Compound of formula VII can be crystallized from hexane or a mixture of hexane and simple ether.

Option: General method 1A

Follow the General method 1 except that, instead of under the conditions used ethylbromide.

General method 2

Getting tetrahydro-4H-Piran-2-yl-ether of the formula VIII

The alcohol of formula VII (16 mmol) dissolved in methylene chloride (50 ml), added 3,4-dihydro-2H-Piran (2.4 ml, 26 mmol) and p-toluensulfonate pyridinium (of 0.43 g, 1.7 mmol) and the mixture is stirred at room temperature for 4 hours. The reaction mixture was diluted with ether (150 ml) and extracted with water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried and concentrated in vacuo. The crude product is purified by chromatography on silica gel.

General method 3

Getting simple trimethylsilyl ester of formula IX

To a solution of the compound of formula VII (14 mmol) in anhydrous dichloromethane (50 ml) in an argon atmosphere with stirring and cooling in an ice bath, add triethylamine (42 mmol) and DMAP (25 mg). Under stirring for 20 minutes at 0°With added dropwise trimethylsilane (40 mmol) and stirring is continued for 2-6 hours at room temperature. Add ether (500 ml) and water (100 ml). The organic phase is separated, extracted with water (3×50 ml) and saturated aqueous sodium chloride (50 ml), dried and concentrated in vacuo. The residue is purified by chromatography on silica gel to obtain the desired product as a yellowish oil.

General method 4

The combination of the HEC compounds 1 and fragment side chain of the formula II

Compound 1 (100 mg, 0,17 mmol), the compound of formula II (0.2 mmol), dichloride, bis(triphenylphosphine)palladium (II) (24 mg) and copper iodide (II) dissolved in a mixture of anhydrous triethylamine (5 ml) and anhydrous THF (4 ml) and stirred under argon atmosphere overnight. The reaction mixture was quenched with water (15 ml) and diluted with ether (85 ml). The organic phase is separated, extracted with water (3×15 ml) and saturated aqueous sodium chloride (15 ml), dried and concentrated in vacuo. The residue is purified by chromatography on silica gel (eluent: 1-5% ether in pentane)to get the desired product in the form of an amorphous resin.

General method 5

Hydrogenation in the presence of Lindlar catalyst

The compound of formula III (or 0.57 mmol) dissolved in a mixture of dichloromethane (5 ml) and ethanol (20 ml), add the Lindlar catalyst is (100 mg) and the mixture is stirred in hydrogen atmosphere until until there is no further absorption of hydrogen. The catalyst is filtered off and the filtrate is diluted with ethyl acetate (80 ml). The organic phase is extracted with water (3×15 ml) and saturated aqueous sodium chloride (15 ml), dried and concentrated. The residue is purified by chromatography on silica gel (eluent: 1-5% ether in pentane)to get the desired product in the form of an amorphous resin.

General method 6

Isomerization of the compounds of formula IV to the corresponding 5 (Z) isomer

A solution of the appropriate compound of formula IV (0.3 mmol), anthracene (100 mg) and triethylamine (0.05 ml) in dichloromethane (20 ml) in an argon atmosphere in a flask made of glass Pyrex is irradiated with UV light from a UV lamp high pressure type TQ760 Z2 (Hanau) at a temperature of about 10°C for 20 minutes under stirring. The reaction mixture was concentrated in vacuo and treated with petroleum ether (2×5 ml). After filtration, the filtrate was concentrated in vacuo and purified by chromatography (mixture of ether and petroleum ether as eluent)to obtain specified in the header of the connection specified cooking.

General method 7

The Wittig reaction with a carbonyl compound of formula 2b

The halide triphenylphosphine (XII) (1.2 mmol) dissolved in dichloromethane (10 ml). In an argon atmosphere add the 2n sodium methylate (1.2 ml) and 1(S),3(R)-bis(tert-butyldimethylsilyloxy and)-20(R) - formyl-9,10-scoprega-5(E),7(E),10(19)-triene (2b) (1 mmol). The reaction mixture is stirred in an argon atmosphere during the night, and deep orange color gradually fades to yellow.

The reaction mixture was diluted with ether (25 ml) and extracted with water (2×10 ml), dried and concentrated to obtain a mixture of 22-CIS - and 22-TRANS-isomers as a yellow oil. 22-CIS-isomer allocate chromatography on silica gel (mixture of ether and petroleum ether as eluent).

A General method 8

Getting halide triphenylphosphine formula XII

Triphenylphosphine (2,62 g, 20 mmol) and the bromide of formula XI (20 mmol) dissolved in benzene (12 ml) and stirred over night at room temperature. The precipitate is filtered off, washed with benzene (5×2 ml) and petroleum ether (5 ml) and dried in vacuum to obtain a halide triphenylphosphine formula XII.

A General method 9

Remove protection using HF

To a stirred solution of the appropriate silyl-protected compounds of formula IV(z) (0.25 mmol) in ethyl acetate (1.5 ml) is added acetonitrile (6 ml) followed by addition of 5% solution of hydrofluoric acid in a mixture of acetonitrile-N2About 7:1 (2.0 ml). After stirring for another 45-60 minutes add 1 M potassium bicarbonate (10 ml) and the reaction mixture was treated with (ethyl acetate). The residue is purified by chromatography (eluent: 30% pentane in ethyl acetate), to get what you want from the Association of formula I.

A General method 10

Remove protection using TBAF

To a solution of a suitable silyl-protected compounds of formula IV(z) (0.18 mmol) in THF (4.5 ml) is added TBAF trihydrate (to 0.29 g, 0.9 mmol) and the mixture refluxed for one hour under stirring. After adding 0.2 M sodium hydrogen carbonate (5 ml), the mixture is treated with (ethyl acetate). The residue is purified by chromatography (eluent: 30% pentane in ethyl acetate)to obtain the desired compound of formula I.

A General method 11

Interaction metallice with a complex ester of the formula XIII

To a solution of the appropriate compound of formula XIII (0.33 mmol) in anhydrous ether (10 ml), cooled to -30°C. in the argon atmosphere add motility (0.45 ml, 1.6 M in ether). The reaction mixture is slowly warmed to room temperature for 2 hours and then diluted with ether (15 ml). The ether phase is extracted with water (3×5 ml) and saturated aqueous sodium chloride (5 ml), dried and evaporated in vacuum to get crude product. Its clear by chromatography (mixture of ether and petroleum ether as eluent)to obtain the connection specified in the header of this method.

A General method 12

Remove protection of compounds of formula III using PPTS

To a solution of a suitable compound III (0.16 mmol) in 99% ethanol (2 ml) was added PPTS (2 mg) and the mixture is stirred is at 50° C in argon atmosphere for one hour. Add ethyl acetate (15 ml) and the mixture is extracted with saturated aqueous NaHCO3(3×5 ml) and water (5 ml). The organic phase is dried and evaporated in vacuum to get crude product, which was purified by chromatography to obtain the desired connection.

Syntheses

Synthesis of 1 Connection 3

Method: General methods 1

Starting material: methyl-4-iodobenzoate

1H-NMR: δ=7,66 (m, 2H), 7,24 (m, 2H), 1,72 (s, 1H), 1.55V (C, 6N) ppm

Synthesis of 2 Compound 4

Method: General methods 1

Starting material: methyl-3-iodobenzoate

1H-NMR: δ=a 7.85 (t, 1H), EUR 7.57 (DD, 1H), 7,41(DD, 1H), 7,07 (t, 1H), and 1.56 (s, 6N) ppm

Synthesis of 3 Connection 5

Method: General methods 2

Starting material: compound 3

1H-NMR: δ=the 7.65 (m, 2H), 7,20 (m, 2H), 4,42 (m, 1H), 3,95 (m, 1H), 3,39 (m, 1H)and 1.83 (m, 1H), 1.70 to about 1.35 (m, 5H), and 1.63 (s, 3H), 1,49 (s, 3H) ppm

Synthesis of 4 Connection 6

Method: General methods 2

Starting material: compound 4

1H-NMR: δ=7,79 (t, 1H), 7,58 (DD, 1H), 7,42 (DD, 1H), 7,07 (t, 1H), of 4.44 (m, 1H), 3,95 (m, 1H), 3,40 (m, 1H), of 1.84 (m, 1H), 1,72-of 1.35 (m, 5H), and 1.63 (s, 3H), 1,49 (s, 3H) ppm

Synthesis of 5 Connection 7

Method: General method 3

Starting material: compound 3

1H-NMR: δ=a 7.62 (m, 2H), 7,18 (m, 2H), and 1.54 (s, 6N), and 0.09 (s, N) ppm

Synthesis of 6 Connection 42

Method: General method 7

Starting material: bromide 4-(2-hydroxy-2-about the Il)phenilmethylsulfonilftoride.

1H-NMR: δ=7,42 (m, 2H), 7.23 percent (m, 2H), 6,41 (d, 1H), 6,24 (d, J=11.8 Hz, 1H), USD 5.76 (d, 1H), of 5.53 (m, 1H), 4,96 (m, 1H), 4,91 (m, 1H), 4,50 (m, 1H), 4,19 (m, 1H), and 2.83 (m, 1H), to 2.67 (m, 1H), 2.49 USD (DD, 1H), 2,30 (d, 1H), 2,09-a 1.01 (m, 14N), of 1.57 (s, 6N), 1,07 (in, 3H), 0.88 to (C, N), of 0.82 (s, N), 0,19 (s, 3H), of 0.05 (s, 3H), of 0.04 (s, 3H), of 0.03 (s, 3H), of 0.01 (s, 3H) ppm

Synthesis of 7 Connection 43

Method: General method 6

Starting material: compound 42

1H-NMR: δ=7,42 (m, 2H), 7.23 percent (m, 2H), 6,21 (m, 2H), 5,95 (d, 1H), of 5.53 (m, 1H), 5,15 (m, 1H), to 4.81 (m, 1H), 4,35 (m, 1H), 4,16 (m, 1H), 2,78 (m, 1H), 2,66 (m, 1H), 2,41 (DD, 1H), 2,19 (DD, 1H), 2,07 of 1.00 (m, 14N), of 1.57 (s, 6N), of 1.07 (d, 3H), 0,86 (s, N), 0,84 (s, N), 0,19 (s, 3H), 0,04 (m, N) ppm

Synthesis of 8 Connection 44

Method: General method 4

Starting material: compound 5

1H-NMR: δ=7,33 (m, 4H), of 6.45 (d, 1H), of 5.84 (d, 1H), 4,99 (m, 1H), 4,94 (m, 1H), 4.53-in (m, 1H), to 4.38 (DD, 1H), 4,22 (m, 1H), 3,94 (m, 1H), 3,36 (m, 1H), 2,89 (m, 1H), 2,72 (m, 1H), to 2.55 (DD, 1H), 2,32 (m, 1H), 2,15-1,22 (m, N), of 1.64 (s, 3H), of 1.48 (s, 3H), of 1.29 (d, 3H), of 0.90 (s, N), 0,86 (s, N), of 0.64 (s, 3H), 0,06 (m, N) ppm

Synthesis of 9 Connection 45

Method: General method 12

Starting material: compound 44

1H-NMR: δ=7,35 (m, 4H), 6,23 (d, 1H), 6,02 (d, 1H), 5,18 (m, 1H), a 4.86 (m, 1H), 4,36 (m, 1H), 4,18 (m, 1H), 2,84 (m, 1H), 2,70 (m, 1H), 2,44 (DD, 1H), of 2.21 (DD, 1H), 2,12-1,14 (m, 14N), of 1.55 (s, 6N), of 1.28 (d, 3H), 0,87 (s, N), 0,86 (s, N), and 0.61 (s, 3H), of 0.05 (m, N) ppm

Synthesis of 10 Connection 46

Method: General method 5

Starting material: compound 45

1H-NMR: δ=7,44 (m, 2H), 7,26 (m, 2H), 6,44 (d, 1H), and 6.25 (d, J=11.8 Hz, 1H), 5,78 (d, 1H), the 5.45 (m, 1H), to 4.98 (m, 1H), 4.92 in (m, 1H), 4,2 (m, 1H), 4,19 (m, 1H), 2,81 (m, 2H), 2,50 (DD, 1H), 2,30 (m, 1H), 2,10-1,02 (m, 14N), 1,59 (C, 6N), of 1.13 (d, 3H), 0,89 (s, N), 0,84 (s, N), and 0.50 (s, 3H), 0,06 (s, 3H), of 0.05 (s, 3H), of 0.04 (s, 3H), of 0.03 (s, 3H) ppm

Synthesis of 11 Connection 47

Method: General method 6

Starting material: compound 46

1H-NMR: δ=7,44 (m, 2H), 7,25 (m, 2H), 6,23 (d, J=11.7 Hz, 1H), 6,21 (d, 1H), 5,98 (d, 1H), the 5.45 (m, 1H), 5,16 (m, 1H), a 4.83 (m, 1H), 4,36 (m, 1H), 4,18 (m, 1H) 2,81 (m, 2H), 2,42 (DD, 1H), 2,20 (DD, 1H), 2,07-1,02 (m, 14N), 1,59 (C, 6N), of 1.13 (d, 3H), 0,87 (s, N), 0,86 (s, N), and 0.50 (s, 3H), of 0.05 (m, N) ppm

Synthesis of 12 Connection 48

Method: General method 7

Starting material: bromide 3-ethoxycarbonylmethylene

13C-NMR: δ=166,9, 153,3, 142,8, 140,2, 138,1, 135,2, 132,7, 129,9, 129,6, 128,0, 127,2, 124,9, 121,5, 116,3, 106,6, 70,1, 67,0, 56,8, 56,2, 51,9, 45,6, 43,7, 40,3, 36,4, 34,6, 28,7, 27,0, 25,6, 25,6, 23,3, 22,0, 20,3, 18,0, 17,9, 12,1, -4,9, -5,0, -5,1 ppm

Synthesis of 13 Connection 49

Method: General method 6

Starting material: compound 48

1H-NMR: δ=to 7.93 (t, 1H), 7,88 (m, 1H), 7,44 (m, 1H), 7,38 (m, 1H), 6,28 (d, 1H, J=11.4 in Hz), is 6.19 (d, 1H), 5,97 (d, 1H), 5,52 (t, 1H, J=11,4 Hz), 5,16 (m, 1H), 4,82 (m, 1H), 4,35 (m, 1H), 4,17 (m, 1H), 3,90 (s, 3H), was 2.76 (m, 2H), 2,41 (DD, 1H), 2,2 (DD, 1H), 2,03-of 0.71 (m, 13H), of 1.13 (d, 3H), 0,87 (s, N)to 0.85 (s, N), 0,47 (s, 3H), 0.03 in (m, N) ppm

Synthesis of 14 Connection 50

Method: General method 11

Starting material: compound 49

1H-NMR: δ=7,38 (m, 1H), 7,31 (m, 2H), 7,15 (m, 1H), 6,28 (d, 1H, J=11.5 Hz), of 6.20 (d, 1H), 5,97 (d, 1H), vs. 5.47 (t, 1H, J=11.5 Hz), 5,15 (m, 1H), 4,82 (m, 1H), 4,35 (m, 1H), 4,17 (m, 1H), 2,80 (m, 2H), 2,42 (DD, 1H), measuring 2.20 (DD, 1H), 2,08 to 0.70 (m,14N), was 1.58 (s, 3H), of 1.57 (s, 3H), of 1.12 (d, 3H), 0,86 (s, N)to 0.85 (s, N), 0,47 (s, 3H), 0,04 (m, N) ppm

Synthesis of 15 Bromide 3-ethoxycarbonylmethylene

Method: General method 8

Starting material: ethyl-3-bromeilles

1H-NMR: δ=of 7.90 (m, 17H), 7,60 (t, 1H), 7,25 (m, 1H), 5,55 (d, 2H), 4,24 (K, 2N), of 1.29 (t, 3H) ppm

Synthesis of 16 Bromide 4-(2-hydroxy-2-propyl)phenilmethylsulfonilftoride

Method: General method 8

Starting material: 2-(4-bromomethylphenyl)-2-propanol

1H-NMR: δ=7,88 (m, 3H), 7,72-of 7.60 (m, N), 7,32 (d, 2H), 6,95 (DD, 2H), 4,90 (d, 2H), 1,48 (C, 6N) ppm

Example 1

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

Method: General method 10

Starting material: compound 50

13C-NMR: δ=148,9, 147,6, 142,8, 139,3, 137,9, 133,1, 128,1, 126,8, 126,2, 124,9, 124,8, 122,4, 117,1, 111,7, 72,5, 70,7, 66,8, 56,9, 56,3, 45,9, 45,2, 42,8, 40,4, 34,9, 31,8, 31,7, 29,0, 27,3, 23,6, 22,3, 20,5, 12,4 ppm

Example 2

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

Method: General method 10

Starting material: compound 43

1H-NMR: δ=7,42 (m, 2H), 7.23 percent (m, 2H), 6,33 (d, 1H), 6,24 (d, J=11,4 Hz, 1H), 5,95 (d, 1H), of 5.53 (m, 1H), 5,28 (m, 1H), 4,94 (m, 1H), and 4.40 (m, 1H), 4,19 (m, 1H), 2,88-of 2.50 (m, 3H), 2,28 (DD, 1H), 2,08 of-1.04 (m, N), 1,58 (C, 6N), of 1.07 (d, 3H), of 0.21 (s, 3H) ppm

Example 3

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

Method: General methods 9

And the initial substance: compound 47

1H-NMR: δ=the 7.43 (m, 2H), 7.23 percent (m, 2H), 6,36 (d, 1H), 6,24 (d, J=11,4 Hz, 1H), 5,98 (d, 1H), of 5.53 (m, 1H), 5,28 (m, 1H), 4,96 (m, 1H), and 4.40 (m, 1H), 4,19 (m, 1H), 2,88-of 2.50 (m, 3H), 2,28 (DD, 1H), 2,08 of-1.04 (m, N), 1,59 (C, 6N), of 1.12 (d, 3H), of 0.51 (s, 3H) ppm

Example 4

Capsules containing compound 101

Compound 101 was dissolved in peanut oil to a final concentration of 1 µg connection 101/ml oil. 10 parts by weight of gelatin, 5 parts by weight of glycerin, and 0.08 part by weight of potassium sorbate and 14 parts by weight of distilled water are mixed together by heating and formed into soft gelatin capsules. Then each of them fill 100 μl of compound 101 in oil solution so that the capsule contains 0.1 mg of compound 101.

Example 5

Dermatological cream containing compound 101

1 g of almond oil dissolve 0.05 mg of compound 101. To this solution was added 40 g of mineral oil and 20 g of offering self-emulsifying beeswax. The mixture is heated to liquefaction. After adding 40 ml of hot water mixture mix well. The resulting cream contains approximately 0.5 μg of compound 101 in 1 gram of cream.

Example 6

Solution for injection containing compound 101

The solution is applicable for injection contains 10 mg of compound No. 101 here, 15,4 mg dihydrate phosphate disodium, 2 mg of the dihydrate of sodium dihydrophosphate, 0.8 mg of sodium chloride, 5 mg of sodium ascorbate, 5 mg Solutol® HS 15, up to 1 m of the water for injection.

1. The compound of the formula I

where X is hydrogen or hydroxy;

R1and R2that may be the same or different, signify hydrogen, (C1-C4)alkyl;

R3means hydrogen, methyl, fluorine or chlorine,

and it can either hydrolyzed in vivo esters with pharmaceutically acceptable acids.

2. The compound according to claim 1, where X is hydroxy.

3. The compound according to claim 1 or 2, where the starred carbon atom is achiral.

4. The compound according to claim 3, where R1and R2are the same and represented by stands or ethyl.

5. Connection to one of the preceding paragraphs in the form of diastereoisomeric the compounds of formula I in pure form or as a mixture of diastereoisomers.

6. The connection according to one of claims 1, 2 or 5, where the configuration at the chiral carbon atom (starred in formula I) can be R or S.

7. The connection according to one of claims 1 to 4, where the configuration at the carbon atom No. 20 - R or S.

8. Connection to one of the preceding paragraphs, which is selected from the group consisting of such members as:

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

and hydrolyzable in vivo esters with pharmaceutically acceptable acids.

9. The compound according to any one of the preceding paragraphs for use as a drug having activity of inhibiting the proliferation and promotion of cell differentiation.

10. Pharmaceutical composition having activity of inhibiting the proliferation and promotion of cell differentiation, containing an effective amount of a compound according to any one of claims 1 to 9, together with pharmaceutically acceptable carriers and/or diluents.

11. The pharmaceutical composition of claim 10 in a uniform dosage form.

12. The pharmaceutical composition according to claim 11, where the specified uniform dose contains from 0.05-100 μg, preferably from 0.1 to 50 mg of the compound according to any one of claims 1 to 9.

13. The compound according to any one of claims 1 to 9 for the preparation of medicaments for the treatment or prevention of a disease characterized by abnormal cellular differentiation and/or proliferation of cells.



 

Same patents:

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 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

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation eliciting an antihypertensive, anti-anginal, vasodilating, antioxidant and antiproliferative effect. The solid medicinal formulation comprises the following components: carvedilol, disaccharide, magnesium stearate, starch, calcium phosphate, hydroxypropylmethylcellulose, aerosil and carboxymethylcellulose sodium salt. Also, invention discloses a method for preparing this formulation. Invention provides preparing the formulation eliciting high rate and fullness in releasing an active substance in the human body, stability of quality indices for all fitness period and allowing the effective usage in manufacturing the medicinal agent. Invention can be used in treatment hypertension, stenocardia, myocardium ischemia and chronic cardiac insufficiency.

EFFECT: improved preparing method, valuable medicinal properties of formulation.

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new substituted derivatives of norbornylamine with exo-configuration of nitrogen atom and endo-anellated 5-6-membered cycles of the formula (I) and with exo-configuration of nitrogen atom and exo-anellated 5-6-membered cycles of the formula (Ia) , and their pharmaceutically acceptable salts or trifluoroacetates also. In compounds of the formula (I) or (Ia) A means (C1-C4)-alkylene; S1 means optionally (C1-C4)-alkyl; S2 means (C1-C4)-alkyl or hydrogen atom (H) being if S1 and S2 mean alkyl then X in the group [-N+(S1S2)-X-] corresponds to pharmacologically acceptable anion or trifluoroacetate; B means saturated or unsaturated carbon 5- or 6-membered cycle; R1, R2, R3, R4 and R5 have values given in the description. Also, invention relates to a method for preparing these compounds and to a medicinal agent. These compounds can be used for preparing medicinal agents useful for treatment or prophylaxis in breathing impulse disturbance, in particular, in breathing disturbance caused by sleep, transient breathing stop during sleep, snore, for treatment or prophylaxis of acute and chronic renal diseases, in particular, acute and chronic renal insufficiency and, disturbance in intestine, gallbladder, ischemic states of peripheral and central nervous system disturbances, severe attacks and others symptoms. Compounds are inhibitors of sodium-proton exchange, show effect on serum lipoprotein and therefore they can be used in prophylaxis and regression of atherosclerotic alterations.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

21 cl, 70 ex

FIELD: medicine.

SUBSTANCE: vaccine is high molecular weight protein conjugate with angiotensine II taken in high molecular weight protein : angiotensine II proportion of 1:12-55 in % by weight. The conjugate is modified with equilibrium quantity of immunocompetent polyelectrolyte like polyoxydonium.

EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: medicine, endocrinology, pharmacology, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.

EFFECT: improved and valuable medicinal properties of composition.

10 cl, 3 tbl

The invention relates to pharmaceutical industry and relates to pharmaceutical compositions containing 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate, to prevent, treatment or inhibition of the development of a simple retinopathy or preproliferative retinopathy; the method of preventing, treating or inhibiting the development of a simple retinopathy or preproliferative retinopathy; and applying the 2-ethoxy-1-[[2'-(1 N-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid or 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]the benzimidazole-7-carboxylate

The invention relates to medicine, in particular to pharmaceutical compositions containing the blocker of calcium and pharmacologically acceptable alkaline material, which is added in an amount such that the aqueous solution or dispersion solution of a specified pharmaceutical compositions containing a blocker of calcium, would have a pH of at least 8

FIELD: medicine, transplantology.

SUBSTANCE: method involves applying (R)-ibuprofen methanesulfonamide and its nontoxic salts for preparing medicinal agents used for prophylaxis or treatment of ischemic, reprefusion and functional damages of transplanted organs. Invention provides prophylaxis such complications as delayed function of transplant arising in transplantation of organs.

EFFECT: valuable medicinal properties of medicinal agent.

5 cl, 5 tbl, 1 dwg, 2 ex

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