3-amino-6,7-dioxygen-containing steroids, pharmaceutical composition, methods for treatment

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.

EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.

53 cl, 10 tbl, 24 ex

 

The technical field

The present invention relates to 3-amino-6,7-decolorization steroids, compositions comprising these steroids, as well as their therapeutic application.

The level of technology

Inflammatory response (inflammation)

Inflammation is a major localized reaction of the host body to the invading microorganism or tissue damage, this reaction is associated with cells of the immune system. Classic signs of inflammation include redness (erythema), swelling (edema), pain and increased production of heat (hyperthermia) in the area of inflammation. Inflammatory response allows the body to specifically recognize and destroy invading microorganism and/or to repair damaged tissue. Many of the acute modifications in the area of inflammation are either direct or indirect consequence of the massive influx of leukocytes (e.g. neutrophils, eosinophils, lymphocytes, monocytes), which is typical of this reaction. Infiltration and accumulation of leukocytes in tissues leads to their activation and sequential release of mediators of the inflammatory process, such as LTB4, prostaglandins, tumor necrosis factor TNF-α, interleukins IL-β, IL-8, IL-5, IL-4, histamine and proteases, for example, reactive forms of oxygen.

Normal inflammation is predstavljaet a highly regulated process, which is continuously monitored at several levels for each type of cells involved in this reaction. For example, the expression of the proinflammatory cytokine TNF-α is controlled at the level of gene expression, translation, post-translational modification and release of the finished form of the cell membrane. Many proteins that are activated during inflammation, is controlled by the transcription factor NF-kB. Related inflammation reaction in some cases regulated by endogenous anti-inflammatory mechanisms, such as the generation of interleukin IL-10. A characteristic feature of the normal inflammatory response is that it is temporary in nature and after it comes the phase of termination of the inflammatory phenomena in which tissue is returned in its original condition. Considered to be the phase of the termination of the inflammatory phenomena associated with positive regulation and action of anti-inflammatory mechanisms, for example, with the participation of interleukin IL-10, and negative modulation processes associated with inflammation.

Inflammatory disease

Inflammatory disease occurs when the inflammatory response is initiated when this is not necessary, and/or is not terminated normally, but continues and becomes chronic FOTS the extreme condition. Inflammatory disease can treat the whole body (e.g., lupus), or be localized to specific tissues or organs, and thus be a terrible burden for the individual and a heavy economic burden for society. Examples of some of the most common and problematic diseases include asthma, allergies, rheumatoid arthritis, inflammatory diseases of the gastrointestinal tract, psoriasis, emphysema, colitis, diseases associated with graft-versus-host, contact dermatitis and associated with ischemia impaired circulation. Other painful conditions, such as immunological disorders, known to be associated with changes in regulation in the system of chemokine/cytokines and their respective receptors, which may alter viral replication and lead to acquired immunodeficiency syndrome - pathogenesis in AIDS.

It was reported on many processes in tissues, cells, and biochemical processes that are violated in inflammatory diseases, and this was taken into consideration during the development of experimental models and approaches in order to minimize such conditions. Such studies in vitro and in vivo have provided the opportunity for selection and screening of compounds that are highly likely to be therapeutically effective is passed to the relevant inflammatory diseases. For example, the ability of compounds to inhibit allergen-induced accumulation of cells in areas of inflammation, such as eosinophils and lymphocytes, in the washing liquid derived from sensitized animals is an indicator of anti-asthmatic activity. In particular, this model system is useful for assessing the effects of compounds in the treatment in the later stages of the inflammatory reaction and hypersensitivity, which is typical for asthma, in those cases, when the detectable inflammation of the lung.

Asthma and allergies

Asthma and allergies are closely related, convincing proof of this are data from clinical studies showing that there is a certain correlation between severity of asthma and the degree of atopy (allergies). Sensitivity to allergens is considered the most important risk factor for asthma in children and adults, approximately 90% of cases of asthma is atopy.

Allergy is characterized by elevated levels of IgE (antibodies) in the serum. In order to initiate and subsequent atopy asthma or allergic reaction, usually need repeated exposure to the allergen, in a process called sensitization. As soon as B-cells are exposed to allergens, they begin to produce antibodies, which is in contact with the surface of the fat cells. The binding of the two antibodies with the participation of antigen triggers a series of reactions leading to degranulation and the release of several mediators which modulate the inflammatory response. Mediators, which are released or generated when an asthmatic or allergic reactions include histamine, leukotrienes, prostaglandins, cytokines and tryptase.

Asthma is characterized by hypersensitivity of the respiratory tract, episodic periods of bronchospasm and chronic inflammation of the lungs. Obstruction of the respiratory tract is reversible in time or in response to drug therapy. Patients with normal airway can be hypersensitive to a variety of natural stimuli such as cold air, exercise, chemicals and allergens. The most common, causing asthmatic reaction is immediate allergic reaction to known allergens, including pollen, ragweed, pollen, grass, various fungi, mold, dust, cockroaches and Pets. The symptoms of this disease include shortness of breath, wheezing, shortness of breath and cough. The incidence of asthma related deaths increased worldwide, odoevskii over the last twenty years, despite modern methods for the s treatment.

The response of the Airways to allergens is complex and consists of an initial asthmatic reaction (EAR), the peak of which is 20-30 min after exposure to the stimulus, it is characterized by the presence of bronchostenosis and usually stops within 1.5-2 hours. Late asthmatic reaction (LAR), usually occurs within 3-8 hours after the initial exposure to the stimulus, and includes the presence of bronchostenosis, and the development of inflammation and edema in the lung tissue. This inflammation often becomes chronic, with the presence of damage to the epithelium and infiltration of the lung cells in areas of inflammation, such as eosinophils and neutrophils.

Modern methods of treatment of asthma

Glucocorticoids (steroids) are the most effective means of long-term therapy for the treatment of asthma. For example, due to the presence of airway inflammation, even in mild asthma inhaled steroid use even in the early stages of drug therapy. Although steroids are effective anti-inflammatory drugs, they are not too suitable for removal of acute asthmatic attack. The introduction of oral steroids is associated with significant side effects, so constant use to resolve acute asthmatic attack is minimal is poor. Combination therapy is often used in the case of oral administration of steroids, in this case, a combined therapy can be subdivided as follows: anti-inflammatory drugs (e.g. steroids for inhalation or oral use), bronchodilatory means (for example, β2agonists, xantina, anticholinergics) and inhibitors of mediators (e.g., antagonists of cremolino and leukotriene). Generally speaking, the present Arsenal of drugs is not well helps patients suffering from asthma, which is in the state from moderate to severe. Medicines which are safe, only marginally effective, as effective medicines inherent unacceptable side effects associated with the need for a comprehensive monitoring of the patient. In the state of development of the products must satisfy the requirements in relation to undesirable side effects (such as a side effect is vomiting in the case of some inhibitors of phosphodiesterase 4), and to exclude poor pharmacokinetic characteristics and unsatisfactory parameters of metabolism. There is a significant need in therapeutic tools that will allow the implementation is to be safe and effective treatment of inflammatory diseases, such as asthma and allergies. The present invention achieves this and other useful results, as shown in the present description.

The invention

According to the first aspect of the present invention relates to compounds of formula (1) and their pharmaceutically acceptable salts, solvate, stereoisomers and prodrugs, individually or in a mixture,

in which, in each case independently of one another:

R1and R2selected from hydrogen, oxygen, thus to form a nitro or an oxime, amino, -SO3-R, and organic groups containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur, and where R2may represent a direct link with the atom number 3, or R1and R2can together with the nitrogen atom to which they are both attached, form a heterocyclic structure which may be part of an organic group containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, and silicon, and where R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of the core And;

3and R4choose from direct links with atoms numbered 6 and 7 respectively so as to form a carbonyl group, hydrogen or a protective group, provided that R3and/or R4represent a part of the protective group of hydroxyl or carbonyl;

numbers from 1 to 17 each represent a carbon atom, where carbon atoms numbered 1, 2, 4, 11, 12, 15, 16 and 17 may be independently replaced with:

(a) one of the groups: =O, =C(R5)(R5), =C=C(R5)(R5), -C(R5)(R5)(C(R5)(R5))n- and -(O(C(R5)(R5))nO)-, where n ranges from 1 to about 6, or

(b) two of the following groups, which are selected independently: -X, -N(R1)(R2), -R5and-OR6;

and where the carbon atoms numbered 5, 8, 9, 10, 13 and 14 may be independently substituted one of the groups-X, -R5, -N(R1)(R2or-OR6;

in addition to the groups-OR3and-OR4as shown, each of the carbon atoms numbered 6 and 7 may be independently substituted one of the groups-X, -N(R1)(R2), -R5or6;

each of the cores A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;

R5in each case independently selected from H, X, and C1-30-organic fragment, which may not contain the AMB, at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R5may together form the nucleus together with the carbon atom to which they are both attached;

R6represents H or a protective group, such that-OR6represents a protected hydroxyl group, where vicinal groups OR6may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR6may together form a cyclic structure which protects a carbonyl group, and

X represents fluoride, chloride, bromide and iodide.

According to another aspect of the present invention relates to a pharmaceutical composition comprising a steroid compound, as described above, pharmaceutically acceptable carrier, excipient or diluent.

According to another aspect of the present invention relates to a method of treating inflammation comprising the administration to a subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

According to another aspect of the present invention relates to a method of preventing inflammation comprising the administration to a subject in need this, prophylactically effective amount is TBA steroid compounds, as specified above.

In accordance with another aspect of the present invention relates to a method of treating asthma, which comprises the administration to a subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method for the treatment of allergic diseases, including, but not limited to, the presence of cutaneous and ocular indications, which includes an introduction to the subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method of treating chronic obstructive pulmonary disease, which includes an introduction to the subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method of treatment of allergic dermatitis, which includes an introduction to the subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method for the treatment of solid tumors, which includes an introduction with whom bectu, in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method of treating AIDS, which comprises the administration to a subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method for the treatment of circulatory disorders during ischemia, which includes an introduction to the subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

In accordance with another aspect of the present invention relates to a method of treating cardiac arrhythmia which comprises the administration to a subject in need of such treatment, a therapeutically effective amount of a steroid compound, as described above.

These and related aspects of the present invention is described in more detail below.

Brief description of drawings

In Fig. 1A and 1B shows the design of synthetic transformations that can be used to convert 3-aminosteroid 3-nitrogen-containing steroid of the present invention.

In Fig. 2A, 2B and 2C shows a set of bar charts showing the effect of compound 89 (a reaction to the dosage, 4 the eskers daily oral) on ovalbumin-induced accumulation of cells in areas of inflammation in the lung wash fluid obtained from sensitized rats Brown Norway. In Fig. 2A shows the accumulation of eosinophils in Fig. 2B shows the accumulation of neutrophils and in Fig. 2C shows the accumulation of lymphocytes.

In Fig. 3A, 3B and 3C shows a set of bar charts showing the effects of compound 28 (response to dose, 4 doses daily, orally) on ovalbumin-induced accumulation of cells in areas of inflammation in the lung wash fluid obtained from sensitized rats Brown Norway. In Fig. 3A shows the accumulation of eosinophils in Fig. 3C shows the accumulation of neutrophils and in Fig. 3C shows the accumulation of lymphocytes.

In Fig. 4 presents a graph showing the effect of test compounds 28 and 89, with the introduction of orally once daily for 4 days prior to the introduction of provocative tests, on allergen-induced resistance changes in lung in sensitized Guinea pigs.

In Fig. 5 presents a graph showing the effect of test compounds 28 and 89, with the introduction of orally once daily for 4 days prior to the introduction of provocative tests, on allergen-induced changes in the elasticity of the lung in sensitized Guinea pigs.

In Fig. 6 presents a graph is K, showing duration antiprogestational activity of the tested compounds 89, when ingested in quantities of 1 mg/kg once daily for 4 days prior to the introduction of provocative tests, on allergen-induced resistance changes in the lungs of sensitized Guinea pigs.

In Fig. 7 presents a graph showing the duration antiprogestational activity of the tested compounds 89, when ingested in quantities of 1 mg/kg once daily for 4 days prior to the introduction of provocative tests, on allergen-induced changes in the elasticity of the lungs of sensitized Guinea pigs.

Detailed description of the invention

The present invention relates to compounds, compositions and methods suitable for the treatment and/or prevention of various illnesses. For example, in accordance with one aspect of the present invention provides a method of treatment and/or prevention of inflammatory diseases. The method comprises the administration to a subject in need, an effective amount of the compounds of formula (1) or its pharmaceutically acceptable salt, MES, stereoisomer or prodrug, or an effective amount of a composition containing the compound of formula (1) or its pharmaceutically acceptable salt, MES, stereoisomer or PR is a medicine.

Before describing the invention in more detail, some terms used in the present description, will be given the following definitions, and also revealed some of the notation used in this description.

A. Definitions of terms.

When used in the present description, the following terms have the specified value, if not specified otherwise.

"Alkyl" represents a monovalent saturated or unsaturated, linear, branched or cyclic, aliphatic (i.e. non-aromatic) hydrocarbon group. In accordance with various embodiments of the invention the alkyl group contains 1-20 carbon atoms, i.e. represents a C1-C20 (or1-C20) group, or represents a C1-C18 group, C1-C12 group, C1-C6 group or a C1-C4 group. Independently, in various embodiments of the invention, the alkyl group contains zero branching (i.e. is a linear chain), one fork, two or more branching than two branching; is saturated; is unsaturated (where unsaturated alkyl group may contain one double bond, two double bonds, more than two double bonds and/or one triple bond, two triple bond, or more than two triple bond); represents or contains a cyclic structure; is the cyclic. Examples of alkyl groups include C1alkyl groups (that is,- CH3(methyl)), C2alkyl groups (that is,- CH2CH3(ethyl), -CH=CH2(ethynyl), and C≡CH (ethinyl)) and C3alkyl groups (that is,- CH2CH2CH3(n-propyl), -CH(CH3)2(ISO-propyl), -CH=CH-CH3(1-propenyl), -CC≡CH3(1-PROPYNYL), -CH2-CH=CH2(2-propenyl), -CH2-C≡CH (2-PROPYNYL), -C(CH3)=CH2(1-methylethenyl) and-CH(CH2)2(cyclopropyl)).

"Aryl" represents a monovalent aromatic hydrocarbon cyclic system. This cyclic system may be monocyclic or condensed polycyclic (e.g. bicyclic, tricyclic, and so on). In various embodiments monocyclic aryl nuclei consist of C5-C10 or C5-C7 or C5-C6, where these numbers with the carbon atoms means the number of carbon atoms forming a cyclic system. The preferred aryl group is a C6 cyclic system, i.e. the phenyl nucleus. In various embodiments of the polycyclic nucleus is a bicyclic aryl group, where the C8-C12 or C9-C10 are the preferred bicyclic aryl groups. Preferred polycyclic aryl group is raftiline the nucleus, which consists of 10 carbon atoms.

"Heteroalkyl" PR is dstanley an alkyl group (as defined earlier), in which at least one of the carbon atoms replaced by a heteroatom. Preferred heteroatoms are nitrogen, oxygen, sulfur and halogen. Heteroatom may, although this is usually not the case, to have the same number of valence bonds, and carbon. Accordingly, in the case where a carbon is replaced by a heteroatom, may need to increase or decrease the number of hydrogen atoms associated with the heteroatom to their number corresponded to the number of valence bonds of the heteroatom. For example, if carbon (valence four) is replaced with nitrogen (three valence), one of the hydrogen atoms, previously attached to the replaced carbon must be removed. Similarly, if the carbon is substituted with a halogen (valence one), then three (that is all) hydrogen atoms, previously attached to the replaced carbon must be removed.

"Heteroaryl" is a monovalent aromatic cyclic system containing carbon and at least one heteroatom in the kernel. In various embodiments the heteroaryl group can contain one heteroatom or 1-2 heteroatoms, or 1-3 heteroatoms, or 1-4 heteroatoms in the kernel. Heteroaryl nucleus can be monocyclic or polycyclic, and polycyclic nucleus may contain condensed, Spiro or bridged connection the poison is. In one of the embodiments of heteroaryl selected from monocyclic and bicyclic cores. Monocyclic heteroaryl nucleus can contain approximately 5-10 atoms members (carbon and heteroatoms), preferably 5-7 and most preferably 5-6 atoms members in the kernel. Bicyclic heteroaryl nucleus can contain approximately 8-12 atoms members or 9-10 atoms members in the kernel. Heteroaryl nucleus can be substituted or unsubstituted. In one of the embodiments of the heteroaryl nucleus is unsubstituted. In another embodiment of the heteroaryl nucleus is substituted. Examples of heteroaryl groups include benzofuran, benzothiophene, furan, imidazole, indole, isothiazol, oxazole, piperazine, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, thiazole and thiophene.

"Heteroatom" is an atom of halogen, nitrogen, oxygen, phosphorus, silicon or sulfur. Groups containing more than one heteroatom can contain different heteroatoms.

"Hydrocarbon group" is a chemical group formed only hydrogen and carbon; "halogenosilanes group" is a chemical group formed only by the halogen and carbon and halogenougljovodonika group" is a chemical group formed only hydrogen, halogen and carbon.

The terms "org the technical group" and "organic fragments" are used interchangeably and refer to a stable structures, which consist of a specified number of atoms of the specified type.

"Pharmaceutically acceptable salt" and its salts" in the case of compounds of the present invention relates to an additive salts of the acid and the additive salts of the base.

The term "additive acid salt" refers to salts derived from compounds according to the present invention and inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and/or organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid and the like acids.

The term "additive salt base" refers to salts derived from compounds according to the present invention and inorganic bases, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. Suitable salts include salts of ammonium, potassium, sodium, calcium and magnesium derived from pharmaceutically acceptable organic the ski non-toxic bases, and include salts of primary, secondary and tertiary amines, including substituted amines of natural origin, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-Diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine and the like.

In those cases, when any variable occurs more than once in any component or compound of formula (1), its definition in each case is independent of its definition in any other case. Valid only such combinations of substituents and/or variables that result in stable compounds. Compounds suitable for use in the methods and compositions according to the present invention, as well as the compounds of the present invention may contain asymmetric centers or be in the form of the racemates, racemic mixtures and individual diastereomers or enantiomers, and their isomeric forms are included in the scope of the present invention. The racemate or racemic mixture does not imply a mixture of stereoisomers in a ratio of 50:50.

According to another aspect of the present invention relates to pharmaceutical compositions, comprising the compound of formula (1)as described above, in combination with a pharmaceutically acceptable carrier, excipient or diluent. Such compositions may be useful for treatment of inflammation or other conditions, as shown in the present description. Song data can also be presented in the form of a dosage form, which may be useful, for example, for the treatment of inflammation.

These compositions are useful, for example, as samples for the study, convenient for construction, suitable pharmaceutical compositions. Necessary for testing the number of compounds according to the present invention is a quantity that can be easily measured using conventional techniques and procedures of quantitative analysis, which are well known and understood by professionals in this area of technology. Necessary for testing the number of compounds according to the present invention will generally vary from about 0,001% by weight to about 100 wt.% from the total mass of the composition. Inert carriers include any material that does not decompose or otherwise not covalently interacts with the compound of the formula (1). Examples of suitable inert carriers are water; aqueous buffers, such as buffers commonly used in the analysis method vysokokapit the main liquid chromatography (HPLC); organic solvents, such as acetonitrile, ethyl acetate, hexane and other solvents, and pharmaceutically acceptable carriers.

"Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical industry and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co (A.R.Gennaro edit. 1985). For example, can be used in sterile saline and phosphate buffered saline solution with physiological pH value. Preservatives, stabilizers, dyes and substances imparting taste and odor, can be included in the pharmaceutical composition. For example, as preservatives may be added sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid (ibid, s). In addition, can be used antioxidants and suspendresume agents (see ibid.).

Steroid compounds of the present invention contain at least four cores, usually denoted as a, b, C and D, as shown below, where the kernel And may be condensed with an additional kernel:

C. Connection.

The present invention relates to compounds of formula (1) and their pharmaceutically acceptable salts, solvate, stereoisomers and prodrugs, individually or in a mixture,

where, in each case, the independent is about:

R1and R2selected from hydrogen, oxygen, thus to form a nitro or an oxime, amino, -SO3-R, and organic groups containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur, and where R2may represent a direct link with the atom number 3, or R1and R2can together with the nitrogen atom to which they are both attached, form a heterocyclic structure which may be part of an organic group containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen and silicon; or where R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of the core And;

R3and R4choose from direct links with atoms numbered 6 and 7 respectively so as to form a carbonyl group, hydrogen or a protective group, provided that R3and/or R4represent a part of the protective group of hydroxyl or carbonyl;

numbers from 1 to 17 each represents a carbon atom, where carbon atoms numbered 1, 2, 4, 11, 12, 15, 16 and 17 may be independently replaced with:

(a) one of the groups: =O, =C(R5)(R5), =CC(R 5)(R5), -C(R5)(R5)(C(R5)(R5))n- and -(O(C(R5)(R5))nO)-, where n ranges from 1 to about 6; or

(b) two of the following groups, which are selected independently: -X, -N(R1)(R2), -R5and-OR6;

and where the carbon atoms numbered 5, 8, 9, 10, 13 and 14 may be independently substituted one of the groups-X, -R5, -N(R1)(R2or-OR6;

in addition to the groups-OR3and-OR4as shown, each of the carbon atoms numbered 6 and 7 may be independently substituted one of the groups-X, -N(R1)(R2), -R5or6;

each of the cores A, B, C and D is independently fully saturated, partially saturated or fully unsaturated;

R5in each case independently selected from H, X, and C1-30-organic fragment, which optionally may contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, and two genialny group, R5may together form the nucleus together with the carbon atom to which they are both attached;

R6represents H or a protective group, such that-OR6represents a protected hydroxyl group, where vicinal groups OR6may together form a cyclic structure which protects the em vicinal hydroxyl groups, and where genialny group OR6may together form a cyclic structure which protects a carbonyl group, and

X represents fluoride, chloride, bromide and iodide.

In accordance with one aspect of the present invention R1and R2selected from hydrogen and organic groups containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulfur. Optional R2represents a direct link with the atom number 3. In accordance with another aspect of the group R1, R2and the N atom to which they are both attached, form a heterocyclic structure which may be part of an organic group containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, and silicon. In accordance with another aspect of R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of a core of A, and 2 or 3 atoms selected from C, N and O so as to form a stable structure. Not necessarily in accordance with these and other aspects of the present invention the organic group contains 1-20 carbon atoms, in another optional embodiment of the image is the shadow of the organic group contains 1-10 carbon atoms.

According to a preferred aspect of the present invention, each of R1and R2represents hydrogen. These steroids not only have the necessary biological activity, but are also a convenient connections-a precursor for other steroids in accordance with the present invention, in which R1and/or R2are not hydrogen.

For example, according to one embodiments of the invention relates to the compound of formula (1)in which R1and R2represent hydrogen, R3and R4choose from direct links with atoms numbered 6 and 7, respectively, so as to form a carbonyl group, a hydrogen atom or a protective group such that R3and/or R4was part of the protective group of hydroxyl or carbonyl, and in addition to the groups-OR3and-OR4as shown, each of the carbon atoms numbered 6 and 7 are replaced by hydrogen atoms possible in those cases where OR3or4represents a carbonyl group; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom at number 13 in the case when it is not part of the unsaturated the Oh communication replaced by stands; the carbon atom number 17 substituted by (a) one of the groups: =O, =C(R5)(R5), =C=C(R5)(R5), -C(R5)(R5)(C(R5)(R5))n- and -(O(C(R5)(R5))nO)-, where n ranges from 1 to about 6; or (b) two of the following groups, which are selected independently: -X, -N(R1)(R2), -R5and-OR6each of the cores A, B, C and D is independently fully saturated, partially saturated or fully unsaturated; R5in each case independently selected from H, X, and C1-30-organic fragment, which optionally may contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, and two genialny group, R5may together form a ring together with the carbon atom to which they are both attached; R6represents H or a protective group, such that-OR6represents a protected hydroxyl group, where vicinal groups OR6may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR6may together form a cyclic structure which protects a carbonyl group; and X represents fluoride, chloride, bromide and iodide.

According to another embodiment of the invention is worn to the compound of formula (1), in which R1and R2represent hydrogen, R3and R4selected from hydrogen or a protective group such that R3and/or R4was part of the protective hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom at number 13 in the case when it is not part of the bonds, substituted stands; the carbon atom number 17 substituted by(a) one of the groups: =C(R5)(R5), =C=C(R5)(R5); or (b) two of the following groups, which are selected independently: -X, -N(R1)(R2and R5each of the cores A, B, C and D is independently fully saturated or partially saturated; R5in each case independently selected from H, X, and C1-30-hydrocarbon, halogenosilanes and halogenougljovodonika group; and X represents fluoride, chloride, bromide and iodide.

According to another embodiment of the invention relates to the compound of formula (1)in which R1and R2represent hydrogen, R3and R4selected from a hydrogen atom or a protective group such that R3and/or R4was part of the protective hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted on uma hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom at number 13 in the case when it is not part of the bonds, substituted stands; the carbon atom number 17 substituted by (a) one of the groups: =C(R5)(R5), =C=C(R5)(R5); or (b) two groups-R5each of the cores A, B, C and D is independently fully saturated or partially saturated; R5in each case independently selected from H and C1-30is a hydrocarbon group.

Specific compounds of the present invention in which R1and R2represent hydrogen, include the following:

According to another aspect of the invention relates to steroids, which are 3-asutamiseni, where the 3-nitrogen is substituted by an organic group. For example, the invention relates to steroid compounds in which R1selected from-C(=O)-R7, -C(=O)NH-R7and-SO2-R7where R7selected from alkyl, heteroalkyl, aryl and heteroaryl groups. In a related embodiment R1is hydrogen and R2represents-CH2-R77selected from alkyl, heteroalkyl, aryl and heteroaryl groups. In one of the embodiments, R7selected from C1-10-hydrocarbon groups. In another embodiment of the-C(=O)-R7includes Biotin. In another embodiment R7selected from alkyl substituted phenyl, halogen-substituted phenyl, alkoxy-substituted phenyl, arylacetamides phenyl and nitrosamines phenyl.

According to another aspect (R1)(R2)N - represents a heterocycle, i.e., N, which is (R1)(R2)N-may be part of a heterocyclic nucleus. Examples include:

and

According to another aspect of one or both of R1and R2include heterocyclic nucleus or a carbocyclic nucleus. Preferred heterocyclic nucleus is

and preferred carbocyclic nucleus is phenyl, including substituted phenyl, such as 3-were, 4-hydroxyphenyl and 4-sulfonatophenyl.

According to another aspect of R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of a core of A. Thus, this is completed with the invention allows to obtain a compound of the formula, below, where Z is 2 or 3 atoms selected from C, N, and O. the Core, including Z, may be saturated or unsaturated.

Examples of such compounds with condensed nuclei include:

According to another aspect of R1is hydrogen and R2include1-10hydrocarbon group.

According to another aspect of R1is hydrogen and R2is heteroalkyl. Suitable heteroalkyl includes, without limitation, With1-10alkyl-W-C1-10alkylen, where W is chosen from O and NH; HO-C1-10alkylen and HO-C1-10alkylene-W-C1-10alkylene-, where W is chosen from O and NH.

According to another aspect, each of R1and R2independently selected from halogen and organic groups containing 1-20 carbon atoms and optionally containing 1-5 heteroatoms selected from nitrogen, oxygen, silicon and sulfur.

According to another aspect, each of R1and R2independently selected from hydrogen, R8, R9, R10, R11and R12where R8choose from C1-10of alkyl, C1-10heteroalkyl containing 1, 2 or 3 heteroatoms, With6-10aryl and C3-15heteroaryl, including 1, 2 or 3 heteroatoms; R9choose from (R8)r-C1-10alkylene, R 8)r-C1-10heteroalkyl, including 1, 2 or 3 heteroatoms, (R8)r-C6-10arylene and (R8)r-C3-15heteroaryl, including 1, 2 or 3 heteroatoms; R10choose from (R9)r-C1-10alkylene, (R9)r-C1-10heteroalkyl, including 1, 2 or 3 heteroatoms, (R9)r-C6-10arylene and (R9)r-C3-15heteroaryl, including 1, 2 or 3 heteroatoms; R11choose from (R10)r-C1-10alkylene, (R10)r-C1-10heteroalkyl, including 1, 2 or 3 heteroatoms, (R10)r-C6-10arylene and (R10)r-C3-15heteroaryl, including 1, 2 or 3 heteroatoms; R12choose from (R11)r-C1-10alkylene, (R11)r-C1-10heteroalkyl, including 1, 2 or 3 heteroatoms, (R11)r-C6-10arylene and (R11)r-C3-15heteroaryl, including 1, 2 or 3 heteroatom, and r is chosen from 0, 1, 2, 3, 4 and 5, with the proviso that R1and R2can join the atom thereby to form with the specified total atom ring.

According to another aspect of the invention relates to steroids, the structure of which is described above, in which each of R1and R2independently selected from hydrogen, R8, R9, R10, R11and Rsup> 12where R8selected from alkyl, heteroalkyl, aryl and heteroaryl; R9choose from (R8)r-alkylene, (R8)r-heteroalkyl, (R8)rarylene and (R8)rheteroaryl; R10choose from (R9)r-alkylene, (R9)r-heteroalkyl, (R9)rarylene and (R9)rheteroaryl; R11choose from (R10)r-alkylene, (R10)r-heteroalkyl, (R10)rarylene and (R10)rheteroaryl; R12choose from (R11)r-alkylene, (R11)r-heteroalkyl, (R11)rarylene and (R11)rheteroaryl, and r is chosen from 0, 1, 2, 3, 4 and 5, provided that R1and R2can join the atom thereby to form with the specified common atom in the ring; R3and R4selected from a hydrogen atom and the protective groups so that R3and/or R4was part of the protective hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom at number 13 in the case when it is not part of the bonds, substituted stands; the carbon atom number 17 substituted by (a) one is th group: =C(R 5)(R5) and =C=C(R5)(R5), or (b) two groups-R5each of the cores A, B, C and D is independently fully saturated or partially saturated; R5in each case independently selected from H and C1-10hydrocarbon groups.

For example, R1and R2selected from a hydrogen atom, CH3-, CH3(CH2)2-, CH3(CH2)4-, CH3WITH-WITH6H5CO-, (CH3)2CHSO2-C6H5SO2-C6H5NHCO -, - CH3(CH2)2NHCO -, - CH3(CH2)2NH(CH2)2-, (CH3)2N(CH2)2-, HOCH2CH2-, HOCH2(CH2)4-, HOCH2CH2NHCH2CH2-, 3-(CH3)C6H4-, 4-(HO)C6H4-, 4-(H2NSO2)C6H4-, 4-((CH3)CH)C6H4-CH2-, 2-(F)C6H4-CH2-, 3-(CF3)C6H4-CH2-, 2-(CH3O)C6H4-CH2-, 4-(CF3O)C6H4-CH2-, 3-(C6H5O)C6H4-CH2-, 3-(NO2)C6H4-CH2-,

or R1and R2may be combined together with the nitrogen atom to which they are both attached, form a heterocycle selected from the

Specific compounds of the present invention, which R 1represents hydrogen, but R2is not a hydrogen include

Thus, in one of the families preferred compounds according to the present invention R1represents hydrogen, but R2is not hydrogen.

In the steroid compounds of the present invention, as shown above, in accordance with one aspect R3and R4represent hydrogen, i.e. steroid replacement is each of the carbon atoms are numbered 6 and 7. In the corresponding embodiment, one or both of the hydroxy-group at the carbon atoms are numbered 6 and 7, are in protected form, i.e. associated with a group, which is protective for the hydroxy-group. Such protective groups are well known in the art and are disclosed, for example, in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, N.Y. (1999). A suitable protective group is catalog group, therefore the present invention relates to compounds of the following structure:

As mentioned above, the present invention relates to steroid compounds, which include compounds defined stereochemistry. One of these is connected to the rd has the stereochemistry, shown in the following structure for R3O - and R4O-:

As also indicated above, the present invention relates to salt forms of steroid compounds according to the present invention, it is preferable to pharmaceutically acceptable salts. According to one of embodiments a-N(R1)(R2) is in a salt form. In other words, -N(R1)(R2) is protonated in such a way that N carries a positive charge. In this case, a steroid compound of the present invention is an additive salt of the acid, as defined above in the present description. In accordance with a preferred aspect of the present invention relates to cleaners containing hydrochloride salts of the compounds of steroid structure above. In accordance with a preferred aspect of the present invention relates to the acetate salts of the compounds of steroid structure above.

As also indicated above, the present invention relates to prodrugs of specific compounds represented by formula (1). According to one aspect of the present invention is directed to obtaining prodrugs of any of the specific compounds represented by formula (1). In accordance with another aspect of the present invention is excluded prodrugs specific is soedinenii, represented by formula (1), i.e. one aspect of the present invention is aimed at obtaining the compounds of formula (1) and pharmaceutically acceptable salts, solvate, stereoisomer, but not prodrugs of these compounds, alone or in a mixture.

In the steroid compounds of the present invention, as mentioned above, in the preferred embodiment, the atom number 17 substituted by the group =C(R5)(R5), and R5selected from hydrogen, halogen, C1-6of alkyl, C1-6hydroxyalkyl and-CO2-C1-6the alkyl. In another preferred embodiment of the atom 17 substituted C1-6the alkyl or C1-6halogenation, or the atom number 17 substituted-OR6or =O, where R6represents hydrogen.

In the steroid compounds of the present invention, as mentioned above, in the preferred embodiment, at least one of the atoms under the numbers 10 and 13 replaced by stands.

In the steroid compounds of the present invention, as mentioned above, in the preferred embodiment, the atoms are numbered from 1 to 16 each represent hydrogen, where the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 can be independently replaced with: (a) one of the groups: =O, =C(R5)(R5), =C=C(R5)(R5), -C(R5)(R5)(C(R5)(R5))n- and -(O(C(R5)(R5))nO)-, where n ranges from 1 to AP is sustained fashion 6, or (b) two of the following groups, which are selected independently: -X, -N(R1)(R2), -R5and-OR6and the atom number 17 represents a carbon atom, a substituted: (a) one of the groups: =C(R5a)(R5a), =C=C(R5a)(R5aand-C(R5a)(R5a)(C(R5a)(R5a))n-, where n ranges from 1 to about 6, or (b) two of the following groups, which are selected independently: -X, -N(R1)(R2and R5awhere R5ain each case independently selected from H, X, and C1-30organic fragment, which optionally may contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, silicon and sulfur; where two genialny group, R5may together form a ring with the carbon atom to which they are both attached. Optional R5ain each case, independently selected from C1-30hydrocarbon, C1-30halogenosilanes, C1-30halogenougljovodonika groups, H and X. In an alternative optional embodiment R5ain each case, independently selected from C1-10hydrocarbon, C1-10halogenosilanes, C1-10halogenougljovodonika groups, H and X. Optional each of the aforementioned embodiments according to the present invention involves a further embodiment, in which R1and R2choose from Fodor is Yes, oxygen thus to form the nitro-group or oxime, amino, -SO3-R, and organic groups containing 1-30 carbon atoms and is independently containing 1-6 heteroatoms selected from oxygen, phosphorus, silicon and sulfur, where R2can be a direct link with atom number 3, or R1and R2together with the N atom to which they are both attached, may form a heterocyclic structure which may be part of an organic group containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from oxygen and silicon; or R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of a core of A. not Necessarily in each of the above embodiments of the present invention offers a further embodiment, in which the carbon atoms number 1, 2, 4, 11, 12, 15 and 16, in the case when they are not part of the bonds, each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14, in the case when they are not part of the bonds, each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands and the carbon atom at number 13 in the case when it is not part of the unsaturated with the ides, replaced by stands. Optional in each of the above embodiments of the present invention offers a further embodiment, according to which the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands and the carbon atom at number 13 in the case when it is not part of the bonds, substituted stands.

In the steroid compounds of the present invention, as shown in this description, in accordance with the preferred embodiment, each of R1and R2represents hydrogen and/or each of R3and R4is hydrogen; and/or a carbon atom number 17 substituted by (a) one of the groups: =C(R5a)(R5a), =C=C(R5a)(R5aand-C(R5a)(R5a)(C(R5a)(R5a))n-, where n ranges from 1 to about 6; or (b) two of the following groups, which are selected independently from-X, -N(R1)(R2and R5awhere R5ain each case independently selected from H, X, and C1-30organic fragment, which optionally may contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, silicon and sulfur, and two genialny group, R5may together form a number of the TSO together with the carbon atom, to which they are both attached.

The steroids of the present invention, unless otherwise stated, each of the cores A, B, C and D is independently fully saturated, partially saturated or fully unsaturated. Thus, the hydrogen atoms attached to carbon atoms in positions 1-17, can be omitted so as to make possible the saturation of the cores A, B, C and/or D. for Example, in the case when it is noted that the carbon atoms numbered 5, 8, 9 and 14 substituted by one hydrogen atom, and also indicated that each of the cores A, B, C and D is independently fully saturated, partially saturated or fully unsaturated, in this case any one or more of the hydrogen atoms attached to the carbon atoms numbered 5, 8, 9, and 14, may be excluded in order to make possible the unsaturation at the carbon atom.

Compounds of the present invention is applied as pharmaceuticals. Preferably the molecular weight of the compounds according to the present invention is relatively low, i.e. less than about 5000 g/mol, typically less than about 4000 g/mol, more typically less than about 3,000 g/mol, more typically less than about 2000 g/mol and very typically less than about 1000 g/mol, where the minimum Molek is popular weight compounds according to the present invention is approximately 300 g/mol, and each of these typical intervals represents a separate embodiment of the present invention.

Steroid compounds of the present invention include pharmaceutically acceptable salts, solvate, stereoisomers and prodrugs, 3-nitrogen-6,7-decelerometers steroids described above, individually or in mixtures with each other.

Steroid compounds of the present invention can, and typically exist in the form of solids including crystalline solid, which can crystallize from common solvents such as ethanol, N,N-dimethylformamide, water and similar solvents. The crystallization process may, depending on the conditions of crystallization, to produce different crystal structures. Usually thermodynamically more stable polymorphic form is more advantageous for the production of steroid compounds according to the present invention on an industrial scale and is the preferred form of connection.

Often the process of crystallization results in MES steroid compounds according to the present invention having the structure shown above. When used in the present description, the term "MES" refers to units that include one or more 3-nitrogen-6,7-decelerometers steroid compound of this izaberete the Oia and one or more solvent molecules. The solvent may be a water, in this case, the MES may be a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as a hydrate, including the monohydrate, dihydrate, hemihydrate, Politologija, trihydrate, tetrahydrate and the like compounds, as well as the corresponding solvated forms. Steroid compounds may be true solvate, while in other cases you can simply hold a random amount of water, or a mixture of water plus some random solvents.

When used in the present description, the term "pharmaceutically acceptable MES" refers to the MES, which retains the biological effectiveness and properties of biologically active 3-nitrogen-6,7-decelerometers steroid compounds according to the present invention. Examples of pharmaceutically acceptable solvate include, but are not limited to, a solvate containing water, isopropanol, ethanol, methanol, DMSO (dimethylsulfoxide), ethyl acetate, acetic acid and ethanolamine. Specialists in the art it is clear that the solvated forms are equivalent nonsolvated forms and, as expected, included in the scope of the present invented who I am. Sykes P.A., Guidebook to Mechanism in Organic Chemistry, 6thEd (1986, John Wiley & Sons, N.Y.) is an example of a link that describes the solvate.

Compounds of the present invention may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof, as expected, included in the scope of the present invention. In accordance with a preferred aspect of the compounds of the present invention are used in optically pure form.

"Pharmaceutically acceptable prodrug", as implied, means a compound that may be converted under physiological conditions or by solvolysis to a biologically active 3-nitrogen-6,7-decelerometers steroid compound described above. Thus, the term "prodrug" refers to a metabolic precursor of steroid compounds according to the present invention that is pharmaceutically acceptable. A prodrug may be inactive at the moment when it is administered to the subject, but in vivo to become active 3-nitrogen-6,7-decelerometers steroid compound of the present invention. Prodrugs, as a rule, rapidly transformed in vivo to obtaining the parent compound of the above formula, for example, hydrolysis in the blood.

Discussion prolec is rst shown T.Higuchi, V.Stella, "Prodrugs as Novel Delivery Systems, Vol.14, ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of these sources of information included in this description by reference. Typical prodrug is a derivative of the steroid compound according to the present invention, which contains a chemically or metabolically degradable group and becomes, as a result of solvolysis or hydrolysis under physiological conditions, the compounds according to the present invention which are pharmaceutically active in vivo. The prodrug in derivative form often has advantages in solubility, compatibility with tissues or characterized by a slow release in the body of a mammal (see, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Preferred prodrug is a compound substituted at the 3-nitrogen of the steroid of the present invention, and Deputy cleaved in vivo, with the receipt of pharmaceutically active compounds.

Steroids according to the present invention, substituted nitrogen in C3 and replaced with oxygen atoms in positions 6 and 7, have unexpected properties that increase the effectiveness of such compounds. For example, the steroid of the present invention has excellent metabolic stability in S9 fraction of liver brow of the ESA. For example, 100% of compounds 28, 89, 139, and 143 remain unchanged after 15 or even 40 min incubation with S9 fractions person. Unexpectedly, it was found that nitrogen substituents located at the atom C3, significantly reduce glucoronidase molecules in the plasma. In addition, the steroids of the present invention containing nitrogen substituents located at the atom C3, such as connections 28, 89 and 83, are soluble in aqueous solutions, showing the solubility >100 mg/ml in Addition, efficacy and pharmacokinetic profile of steroids according to the present invention containing nitrogen substituents located at the atom C3, very suitable for pharmaceutical use. For doses <1.0 mg/kg, once a day, reproducibly shown significant anti-inflammatory activity in vivo models of inflammation. In the case of rats connection 28 and 89 are characterized by an average value of the period of half-transformation 7.5 hours and oral bioavailability ˜100%, whereas in monkeys is the period of half-transformation is 15 hours, and oral bioavailability of 25-30%. The maximum concentration in plasma for both predictable and varies linearly.

C. Obtaining connections.

Compounds according to the present invention can be obtained by the methods of conducting phases, known specialized there in the art or similar stages. The General methodology for conducting reactions of steroids can be found in the "Steroid Reactions", C.Djerassi, Ed. Holden Day, San Francisco, Calif., 1963, and there in the links. General methods of synthesis can be found in "Comprehensive Organic Transformations", R.C. Larock, VCH Publishers, New York. N.Y. 1989, and there in the links. Additional references useful for synthesis of compounds of the present invention are as follows: T.Reichstein; C.H.Meystre, Helv. Chim. Acta, 1932, 22, 728; H. Westmijze; H.Kleyn; P.Vermeer; L.A. van Dijck, Tet. Lett. 1980, 21, 2665; K.Prezewowsky; R.Wiechert, US Pat. No.3682983; P.Kaspar; H.Witzel, J.Steroid Biochem. 1985, 23, 259; W.G.Dauben; T.Brookhart, J. Am. Chem. Soc. 1981, 103, 237; A.J.Manson et al., J. Med. Chem. 1963, 6, 1; R.O. Clinton et al., J. Am. Chem. Soc. 1961, 83, 1478, and J.A.Zderic et al., Chem. And Ind. 1960, 1625.

In the preferred method, as the starting compounds or intermediates using C3, C6, C7 and C17 polyoxygenated steroids. Methods of introduction of the C6 and C7 atoms of oxygen in commercially available source materials described in U.S. patent 6046185. In this U.S. patent also disclosed a variety of ways, according to which the replacement with the preferred stereochemistry can be carried out in clauses C1, C2, C4, C5, C8, C9, C10, C11, C12, C13, C14, C16 and C17. In accordance with the present invention, the oxygen atoms at C6 and C7 may be present in the form of hydroxyl or protected hydroxyl. 6 - and 7-Hydroxyl can be protected individually or they can be part of the kernel. Suitable C the protective groups are listed in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, N.Y. (1999).

As shown in the diagram And ketones, which are compounds 2, or similar compounds may be proaccelerin various alkylating groups with obtaining steroids of the present invention, containing, but not limited to, alkyl, cycloalkyl, aryl and heteroaryl substituents. For example, alkylation of the 17-ketone, representing a compound 2, the anion of acetylene results in 17α-ethinyl-17β-hydroxyl intermediate compound 3. Inversion of the stereochemistry of the Deputy of the atom C17 can be done by the education first methansulfonate with subsequent treatment with silver nitrate (I) in tetrahydrofuran (THF) and water. Dehydration of compound 3 using POCl3in 2,4-lutidine gives compound 4. The tetrabutylammonium fluoride in THF removes the tert-butyldimethylsilyl (TBS) protective group at the 3-hydroxyl to obtain compound 5. Processing 3α-hydroxyl compound 5 using ZnN6·2py, triphenylphosphine and diisopropylcarbodiimide (DIAD) in toluene leads to a 3β-etidocaine 6. ZnN6·2py get the interaction of Zn(NO3)2and NaN3c, followed by treatment with pyridine in accordance with the published methodology M.C.Viaud, P. Rollin, Synthesis, 1990, 130. Restored the e azide with lithium aluminum hydride in diethyl ether (Et 2O) gives the amine 7. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 8.

Scheme And

i) KCCH; (ii) POCl3, 2,4-lutidine; (iii) Bu4NF, THF; (iv) ZnN6·2py, Ph3P, DIAD, toluene; (v) LiAlH4Et2O, water, MeCN.

As shown in the diagram, the steroids of the present invention having allene functional group can be obtained from intermediate compounds similar to compound 3. An example is the reaction of compound 3 with LiAlH4and AlCl3in THF with obtaining Allen 9. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 10. Processing 3α-hydroxyl compound 10 using ZnN6·2py, triphenylphosphine and diisopropylcarbodiimide (DIAD) in toluene leads to a 3β-etidocaine 11. Recovery azide 11 with lithium aluminum hydride in Et2O gives amine 12. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 13.

Scheme B

i) LiAlH4, AlCl3, THF; (ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) LiAlH4Et2O; v) HCl, water, MeCN.

As shown in the diagram, the steroids of the present invention, provided is alkylamino functional group, can be obtained from arenovich intermediates. An example is the treatment of compound (9) using n-BuLi in THF, leading to the 17β-etinilnoy connection 14. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 15. Processing 3α-hydroxyl compound 15 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to a 3β-etidocaine 16. Recovery azide 16 with lithium aluminum hydride in Et2O gives amine 17. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 18.

Scheme

i) n-BuLi, THF; (ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) LiAlH4Et2O; v) HCl, water, MeCN.

As shown in scheme D, the steroids of the present invention and containing alkenylphenol functional group can be obtained from alkenovich intermediates. An example is the controlled hydrogenation of compound 14 using as a catalyst of Pd-CaCO3obtaining alkene 19. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 20. Processing 3α-hydroxyl compound 20 using ZnN6·2py, triphenylphosphine and DIAD in Tolu is Le leads to a 3β -etidocaine 21. Recovery azide 21 with lithium aluminum hydride in Et2O gives amine 22. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 23.

Scheme D

i) H2Pd-CaCO3; ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) LiAlH4Et2O; v) HCl, water, MeCN.

Compound 2 can be used in many reactions obtain olefinic compounds, including reaction type of reaction, Wittig, to obtain the compounds of the present invention and containing ekzoticheskuyu olefinic group at C17. For example, as shown in scheme E, compound 2 can be processed by ethyltriphenylphosphonium and tert-piperonyl potassium (KOtBu) to give compound 24, in which R1=methyl and R2=hydrogen. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 25. Processing 3α-hydroxyl compound 25 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to a 3β-etidocaine 26. Recovery azide 26 with lithium aluminum hydride in Et2O gives amine 27. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 28, in which R1=methyl and R2= the waters of the genus.

By analogy with the synthesis shown in scheme E, ketones, such as compound 2, can be subjected to interaction with other reagents of the type of Wittig reagents, such as (but not limited to) methyl-, propyl-, butyl-, pentyl or hexyltrichlorosilane with obtaining steroids of the present invention and is similar to the connection 28, in which R2= hydrogen and R1= hydrogen, ethyl, propyl, butyl or pentyl.

Scheme E

i) EtPPh3Br, KOtBu, toluene; (ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) LiAlH4Et2O; v) HCl, water, MeCN.

The steroids of the present invention may contain ekzoticheskie double bond E and/or Z geometry. For example, as shown in scheme E, Z-olefin 24 in cyclohexane may be subjected to UV irradiation in the presence of diphenyldisulfide that leads to isomerization in the E-olefin 29. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 30. Processing 3α-hydroxyl compounds 30 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to the formation of 3β-etidocaine 31. Recovery azide 31 with lithium aluminum hydride in Et2O gives Amin 32. Treatment using HCl in THF and water leads to the removal of the acetonide group and education am ninagloriani salt 33.

Scheme F

i) (PhS)2, hν, cyclohexane; (ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) LiAlH4Et2O; v) HCl, water, MeCN.

Many of the steroids of the present invention with functionalized side chains can be obtained using such methods as promoted by Lewis acids condensation with aldehydes and Michael acceptors. For example, as shown in scheme G, the connection 24 can interact with methylpropionate in the presence of diethylaluminium with the formation of a connection 34. The double bond can be subjected to hydrogenation using a catalyst, such as platinum, receiving of the connection 35. The tetrabutylammonium fluoride in THF remove the protective group at the 3-hydroxyl with the formation of a connection 36. Processing 3α-hydroxyl connection 36 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to the formation of 3β-etidocaine 37. Recovery azide 37 lithium aluminum hydride in Et2O gives amine 38. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 39.

Scheme G

i) HCCCO2Me, Et2AlCl; (ii) H2Pt; (iii) Bu4NF, THF; (iv) ZnN6·2py, Ph3 P, DIAD, toluene; (v) H2Pd, EtOAc; (vi) 80%acetic acid.

Using 3-aminosteroid, such as any of steroids received in accordance with schemes a to G can be synthesized many compounds of the present invention containing secondary and tertiary amino groups. In Fig. 1A and 1B are some areas of synthesis, which can be used to produce 3-amino compounds of the present invention. For example, methods of rehabilitation amination can be used for condensation of the primary (see Fig. 1A) and secondary (see Fig. 1B) amines with aldehydes (RC(=O)H) and ketones (RC(=O)R1). Although it is not shown in Fig. 1A and 1B, compounds containing two aldehyde groups, i.e. dialdehyde General formula NA(=O)R-C(=O)H, can interact with 3-aminosteroid with the formation of a steroid-containing heterocyclic structure in position 3. In addition (or alternatively) methods reductive amination can be used for condensation of 3-ketosteroids with secondary heterocyclic amines. When using these approaches, the present invention allows to obtain compounds in which R1and R2may together with the N atom to which they are both attached, form a heterocyclic structure which may be part of the organic gr is PPI, containing 1-30 carbon atoms, and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, and silicon. Commercial sources and links to chemical literature make accessible to the ordinary person skilled in the field of technology receiving a variety of aldehydes (including dialdehyde) and ketones that can be used to produce steroid compounds of the present invention. Methods reductive amination described, for example, in Synthesis 1975, 135; J. Am. Chem. Soc. 1971, 93, 2897; M. Freifelder in "Catalytic Hydrogenation in Organic Synthesis", J. Wiley & Sons 1978, Ch. 10; Russ. Chem. Rev. 1980, 49, 14, as well as in these references. Cm. also J. Chem. Soc. Perkin Trans 1 1998, 2527, Synlett 1999, 1781, and in the references.

Primary (see Fig. 1A) and secondary (see Fig. 1) amines can be subjected to condensation with aryl compounds (ArX) for getting multiple aryl-substituted amine compounds of the present invention. Commercial sources and links to chemical literature make accessible to the ordinary person skilled in the field of technology many of aryl compounds which can be used to produce steroid compounds of the present invention. Examples of methods of amination of aryl compounds can be found in J. Org. Chem. 2000, 65, 1158, and in a review published in Angew. Chem. Int. ed. 1998, 37, 2046, and see where the link is.

The methodology for the interaction of the primary (see Fig. 1A) and secondary (see Fig. 1) amines with anhydrides (RC(=O)Cl) and sulphonylchloride (RSO2Cl) with the formation of this amide and sulfonamidnuyu derivatives of the present invention, accordingly, is well known to specialists in the field of organic chemistry in the context of other amine compounds, and the same technique can be used for amine derivative according to the present invention. Commercial sources and links to chemical literature make available to a person skilled in the art many acid chlorides and sulphonylchloride that can be used to produce steroid compounds of the present invention.

The methodology for the interaction of the primary (see Fig. 1A) and secondary (see Fig. 1) amines with isocyanates (RN=C=O) and isothioscyanates (RN=C=S) to obtain the derivatives of urea and thiourea, respectively, are well known to experts in the field of organic chemistry in the context of other amine compounds, and the same technique can be used for amine derivative according to the present invention. Commercial sources and links to chemical literature make accessible to the ordinary person skilled in the field of technology many of Isola is the ATA and isothioscyanates, which can be used to produce steroid compounds of the present invention. Review article in Russ. Chem. Rev. 1985, 54, 249, and are links that describe examples of the synthesis of a variety of substituted ureas and thioureas can be used in carrying out the invention.

Thus, when used appropriately selected aldehydes, ketones, aryl compounds, acid chlorides, sulphonylchloride, isocyanates and/or isothioscyanates specialist in the art can obtain steroid compounds, in which R1and R2selected from hydrogen and organic groups containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulphur.

The steroids of the present invention may contain a condensed heterocycles such as pyrazole, isoxazol and pyrimidine (but not limited to). As shown in scheme N, the connection 43 is an example of a condensed pyrazole according to the present invention, for which the synthesis of the parent compound 40 is described in U.S. patent 6046185. Processing connection 40 with ethyl formate in pyridine in the presence of NaOMe results hydroxymethylene intermediate connection 41. Interaction connection 41 with hydrazinehydrate in EtOH leads to about the education pyrazol derivative 42, the treatment of which with tetrabutylammonium fluoride in THF gives compound 43.

Scheme H

i) EtO2CH, NaOMe, pyridine; (ii) N2H4, EtOH; (iii) Bu4NF, THF.

As shown in scheme I, intermediate compounds, such as compound 41 can be turned into isoxazoles, an example of which is the connection 44. Processing hydroxymethylene intermediate connection 41 with ammonium hydroxide in pyridine with the subsequent removal of the protection of the 6 - and 7-hydroxyl using tetrabutylammonium fluoride in THF leads to isoxazol 44.

Scheme I

i) HONH2·HCl, pyridine; (ii) Bu4NF, THF.

As shown in scheme J, the intermediate compounds, such as compound 41 can be turned into a pyrimidine, an example of which is the connection 44a. Processing hydroxymethylene intermediate connection 41 hydrochloride of benzamidine and potassium hydroxide in ethanol with subsequent removal of the protection of the 6 - and 7-hydroxyl using tetrabutylammonium fluoride in THF leads to pyrimidine 44a.

Scheme J

i) hydrochloride of benzamidine, KOH, EtOH; (ii) BU4NF, THF.

In addition, when used as intermediates for such compounds that contain closability at the carbon atom in position the AI 3 and =SNON the substituents at the carbon atom in position 2, the present invention allows to obtain a set of compounds in which R1may represent a chain of two or three atoms attached to the atom number 2 in such a way that-NR1- forms part of a condensed bicyclic structure consisting of a core of A.

The interaction of 3-ketosteroids with hydroxylamine and pyridine can be used to obtain Asimov steroids of the present invention. The oxime steroid contains R2in direct connection with the atom number 3, thus providing a double bond between the carbon atom at the 13-th and N, and R1is HE. Primary amines can be oxidized to a nitro compounds using, for example, dimethyldioxirane. Thus, R1and R2can represent oxygen. Methods of obtaining functional nitro described in J. Org. Chem. 1989, 54, 5783. The interaction of 3-ketones with dimethyl leads to N,N-dimethylhydrazone derived steroids, which are the subject of the present invention, in which R2represents a direct link with the atom number 3, and R1is NMe2. Processing dimethylhydrazone of steroid derivatives with hydrazine results in Gerasimovich of steroid derivatives of the present invention. Description of methods of synthesis of N,N-dimethylhydrazone and hydrazones m which should be found in J. Org. Chem. 1966, 31, 677. Primary amines can also be subjected to interaction according to methods known in the art, with sulfonic/sulphuric acids and esters with getting sulphamate derivatives, i.e. steroids, in which the atom number 3 is associated with the-N-SO3-R and R represents H or an organic group containing 1-30 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon and sulphur.

D. Pharmaceutical compositions.

The present invention allows to obtain a pharmaceutical or veterinary composition (hereinafter simply indicated as a pharmaceutical composition containing the compound of formula (1)as described above, in a mixture with a pharmaceutically acceptable carrier. The invention also provides a composition, preferably a pharmaceutical composition comprising an effective amount of a compound as described above, in combination with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be in any form that allows the introduction of the composition to the patient. For example, the composition may be in the form of solids, liquids or gaseous substances (aerosol). Typical routes of administration include, but are not limited to, peroral is Noah, local, parenteral, sublingual, rectal, vaginal, ocular and intranasal administration. The term parenteral as used in this description means of subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion technique. The pharmaceutical compositions of the present invention can be prepared so that they contained the active ingredient was bioavailable in the introduction of the composition to the patient. Compositions that will be administered to the patient, have the form of one or more unit dosage forms, and, for example, a tablet may be a single dosage form, and the container with the compound of the formula (1) in aerosol form can make a lot of unit dosage forms.

Substances used to obtain pharmaceutical compositions should be pharmaceutically pure and non-toxic in the quantities used. Specialist in the art it will be clear that the optimal dosage of the active ingredient (ingredients) in the pharmaceutical composition will depend on many factors. Determining factors include, but are not limited to, type of entity (e.g., human), the particular form of the active ingredient, route of administration and composition used.

Typically, the pharmacist is ical composition includes one or more active compounds of the formula (1), as described above, in a mixture with one or more carriers. The carrier (s) may be such that the compositions are, for example, in the form of tablets or powder. The carrier (s) can be liquid, so that the composition, for example, will represent a syrup for oral administration or a liquid for injection. In addition, the carrier (s) may be gaseous, in order thus to obtain aerosol composition suitable for inhalation.

In that case, when the composition is intended for oral administration, it is preferably either in solid or in liquid form, and semi-solid, semi-liquid form, suspension and gel forms are forms that are considered in the present description as a solid or liquid forms.

As for solid compositions for oral administration, the composition may be prepared in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers or similar forms. Such a solid composition will typically contain one or more inert diluent or edible carrier. Additionally, you may attend one or more of the following adjuvants: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose is whether gelatin; fillers such as starch, lactose or dextrins; a means of contributing to the disintegration of the dosage form, such as alginic acid, sodium alginate, Primogel, corn starch and similar substances; lubricants such as magnesium stearate or sarotex (Sterotex); a means of improving the slip, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; substances imparting taste and odor, such as peppermint oil, methyl salicylate or orange flavoring, and coloring agent.

In that case, when the composition is in the form of a capsule such as a gelatin capsule, it may contain, in addition to the above substances, a liquid carrier such as polyethylene glycol, cyclodextrin or fatty (non-volatile) oils.

The composition may be in the form of a liquid, for example in the form of an elixir, syrup, solution, emulsion or suspension.

The fluid may be intended for oral administration or for administration by injection, in the form of two samples. In the case where the composition is intended for oral administration, preferred compositions contain, in addition to compounds that are the subject of the present invention, one or more sweeteners, preservatives, tinted substance/product and Wuxi is ITIL taste and smell. In the case where the composition is intended for administration by injection may include one or more surfactant, a preservative, a tool to improve wetting, dispersing agent, suspendisse agent, buffer, stabilizer and an isotonic agent.

Liquid pharmaceutical compositions of the present invention, regardless of whether they are in the form of a solution, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological solution, ringer's solution, isotonic sodium chloride, fatty (non-volatile) oils such as synthetic mono or diglycerides which may serve as a solvent or suspendida environment, glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; complexing agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate or phosphate buffers, and means for adjusting the isotonicity such as sodium chloride and dextrose. The preparation for parenteral vvedeniye to be enclosed in ampoules, disposable syringes or vials containing multiple single doses, made of glass or plastic. Saline is the preferred adjuvant. Composition for injection is preferably sterile.

A liquid composition intended for either parenteral or oral administration should contain such amount of the compounds of formula (1)that was obtained appropriate dosage. Usually this amount is at least 0.01% of the compound of the present invention in the composition. In that case, if it is assumed oral administration, this number can vary from 0.1% to about 80% by weight of the entire composition. Preferred compositions for oral administration contain from about 4% to about 50% of the active compounds of formula (1). Preferred compositions and preparations according to the present invention are prepared so that a unit dosage form for parenteral administration contain from 0.01 to 2 wt.% active connection.

The pharmaceutical composition may be intended for local use, and in this case, the carrier may suitably consist of a solution, emulsion, ointment or gel base. The basis of, for example, may include one or more of the trail is the future: vaseline, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. In the pharmaceutical compositions for topical application may be available thickeners. In that case, if it is assumed transdermal introduction, the composition may include transdermal patch or device for medicinal electrophoresis. Compositions for topical application may contain the compound of formula (1) in a concentration of from about 0.1% to about 10% wt./about. (the unit of mass per unit volume).

The composition may be intended for rectal administration, in the form of, for example, suppositories, which melts in the rectum and release the drug. Composition for rectal injection may contain oil-based as suitable, and it does not irritate the filler. Such bases include, but are not limited to, lanolin, cocoa butter and polyethylene glycol.

The composition may include various substances, which modify the physical form of a solid or liquid single dosage forms. For example, the composition may include substances which form a covering shell around the active ingredients. Substances which form a covering membrane, usually are inert and can be selected from, for example, sa is the Arosa shellac and other means forming intersolubility shell. Alternatively, the active ingredients can be placed in a gelatin capsule.

Compositions in solid or liquid form may include an agent that binds to the active component (components) and thus contributes to the delivery of active ingredients. Suitable agents that may act in this capacity include monoclonal or polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may be in the form of gaseous dosage forms, for example be in the form of an aerosol. The term "aerosol" is used to describe a variety of systems, ranging between natural colloidal systems and systems that are enclosed in the packing under pressure. Delivery can be via a liquefied or compressed gas or a suitable pumping unit, which distributes active ingredients. Aerosols compounds of the present invention can be delivered in single phase, two phase or three-phase system in order to deliver the active(s) ingredient(s). The system of delivery of the aerosol includes the necessary container, activators, valves, subcontainers, fixing devices and the like, which together may form the abortion practices. Preferred aerosol can be determined by a person skilled in the art without undue experimentation.

Regardless of the form (solid, liquid or gaseous) of the pharmaceutical composition of the present invention may contain one or more pharmaceutical agents used in the treatment of inflammation (including asthma, allergies, rheumatoid arthritis, multiple sclerosis etc), proliferative disorders (tumors), diseases to be treated by regulating calcium (including hypertension, cardiac arrhythmia, and the like) and the acquired immune deficiency syndrome (AIDS).

The pharmaceutical composition can be obtained according to methods well known in the pharmaceutical field.

Compositions intended for administration by injection can be obtained by mixing the compounds of formula (1) with water in such a way as to obtain a solution. To facilitate obtain a homogeneous solution or suspension may be added surfactant. Surfactants are compounds that are not covalently interact with the compound of the formula (1) in such a way as to facilitate dissolution or homogenization of the suspension of the active compound in the aqueous delivery system.

E. Biological activity.

Connect the tion, disclosed in the present description and is represented by formula 1, or a composition comprising one or more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in the implementation of the method of treatment or prophylaxis of an inflammatory condition or disease of the patient, and the method includes the administration to a patient in need this, the compounds or compositions according to the present invention, in an amount that is effective for the treatment or prophylaxis of an inflammatory condition or disease of the patient.

The inflammatory condition or disease may include respiratory inflammation (for example, where respiratory disease is an asthma, or where respiratory disease is a chronic obstructive pulmonary disease, or where respiratory disease is a emphysema); the inflammatory condition may be an autoimmune condition or disease; the inflammatory condition or disease may be lupus erythematosus; inflammatory condition or disease may include acute or chronic inflammation of bone and/or cartilage separation of the joints; the inflammatory condition or disease may be an arthritis selected from rheumatoid arthritis, agachskogo arthritis, diseases of Steele; the inflammatory condition or disease may be a disease of the Central nervous system; the condition or disease may be associated with infiltration of leukocytes; the condition or disease may be associated with edema; the condition or disease may be associated with ischemic circulatory disorder; condition or disease may be associated with increased levels of cytokines inflammation zone (for example, where the cytokine inflammation zone is an interleukin (IL)-4, or where the cytokine inflammation zone represents IL-5, or where the cytokine inflammation zone represents IL-10, or where the cytokine inflammation zone is an IL-13, or where the cytokine inflammation zone represents IL-9, or where the cytokine inflammation zone represents IL-1, or where the cytokine inflammation zone represents IL-2, or where the cytokine inflammation zone represents IL-6, or where the cytokine inflammation zone represents IL-18, or where the cytokine inflammation zone is an IL-3, or where the cytokine inflammation zone represents IL-8, or where the cytokine inflammation zone represents IL-12, or where the cytokine inflammation zone represents the tumor necrosis factor TNF-αor where the cytokine inflammation zone is a TGF-βor where the cytokine inflammation zone isone GM-CSF, or where the cytokine inflammation zone represents IFN-γor where the cytokine inflammation zone represents LTB4, or where the cytokine inflammation zone is a member of the family of castellations, or where the cytokine inflammation zone is a cytokine secreted by immune T cells upon activation (RANTES), or where the cytokine inflammation zone is eotaxin 1, 2, or 3, or where the cytokine area of inflammation is an inflammatory protein in macrophages (MIP)-1αor where the cytokine inflammation zone is a chemoattractant of monocytes - protein-1 2 , 3, or 4); the condition or disease may be associated with altered levels of adhesion molecules in inflammation (for example, where the adhesion molecule is a molecule adhesion to the vascular endothelium (VCAM-1 or 2), where the adhesion molecule is an intercellular adhesion molecule (ICAM-1 or 2), where the adhesion molecule is an antigen-4 the later stages (VLA-4); where the adhesion molecule is an antigen-1, associated with the function of white blood cells (LFA-1); where the adhesion molecule is a selectin); the inflammatory condition or disease may be a multiple (multiple) sclerosis; inflammatory condition or disease may be a pulmonary zarkadas; the inflammatory condition of ilizarova can be an eye inflammation or allergies; the inflammatory condition or disease may be an allergic rhinitis; the inflammatory condition or disease may be an inflammatory disease of the gastrointestinal tract (for example, granulomatosus disease - Crohn's disease or ulcerative colitis); the inflammatory condition or disease may be an inflammatory skin disease (e.g. psoriasis or dermatitis); the inflammatory condition or disease may be a graft-versus-host; the inflammatory condition or disease may be vascular (e.g., vasculitis); the inflammatory condition or disease may be an atherosclerotic disease.

In addition, the present invention provides a method of treatment or prevention of a disease or condition of the patient, where the disease or the patient's condition is associated with pathological conditions that include infiltration of leukocytes, and this method includes the administration to a patient in need this, the compounds or compositions according to the present invention in an amount that is effective for the treatment or prevention of a disease or condition associated with pathological conditions that include infiltration of leukocytes.

In addition to the, the present invention provides a method of treatment or prevention of asthma in a patient, comprising the administration to a patient in need this, the compounds or compositions of the present invention in an amount that is effective for the treatment or prevention of asthma.

In addition, the present invention provides a method of treatment or prevention of Allergy in a patient, comprising the administration to a patient in need this, the compounds or compositions of the present invention in an amount that is effective for the treatment or prevention of Allergy.

In accordance with the method according to the present invention the compound of formula (1) or a composition comprising the compound of formula (1) and a pharmaceutically acceptable carrier, diluent or excipient, may, although not required, to lead to the achievement of one or more of the following desired outcomes for a subject, which entered the compound of formula (1), as defined above, or a composition containing one of these compounds and a pharmaceutically acceptable carrier, diluent or filler:

1) inhibition of infiltration of leukocytes (e.g. neutrophils, eosinophils, etc.);

2) inhibition of the activation of leukocytes;

3) a change in the ratio of lymphocytes (e.g., the ratio of cells IN and TN);

4) inhibition Hamata the SIS leukocytes;

5) inhibition of the production and/or release of TNF-α;

6) inhibition of the production and/or release of a chemokine (e.g., eotaxin etc.);

7) inhibition of the production, release and/or function of adhesion molecules (e.g., VCAM, VLA-4, and so on);

8) inhibition of edema;

9) the inhibition of the production and/or release of cytokines - interleukin (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12, IL-13, IL-18);

10) inhibition of release of inflammatory mediator (e.g., leukotrienes, tryptase, adenosine, etc.);

11) inhibition of release of histamine;

12) the inhibition of the manifestations of asthma;

13) inhibition of allergic manifestations.

The compounds presented in the present description by the formula (1) (i.e. compounds of formula (1) or otherwise, the compounds of the present invention, or compositions comprising one or more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in the implementation of the method of treatment or prevention of proliferative disorders in a patient, and the method includes the administration to a patient in need this, the compounds or compositions according to the present invention in an amount that is effective for the treatment or prevention of proliferative disorders the patient. When used in the present invention, the term proliferative violation includes, without limitation, all types of leukemia and solid tumors that are susceptible to undergo the process of differentiation or apoptosis of interrupting their cell cycle.

The compounds presented in the present description by the formula (1) (i.e. compounds of formula (1) or otherwise, the compounds of the present invention, or compositions comprising one or more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in the implementation of the method of treatment or prevention of diseases treatable by adjusting the calcium in the patient, and the method includes the administration to a patient in need this, the compounds or compositions according to the present invention in an amount that is effective for the treatment or prevention of disease in a patient. When used in the present invention, the term "curable disease by regulating calcium in the patient" includes, without limitation, cardiac arrhythmia, atrial fibrillation, acute coronary syndrome, hypertension, ischemic circulatory disturbances, sudden attack, stroke, epilepsy, demyelinating diseases such as multiple (disseminated) sclerosis pain, epileptic condition, atherosclerosis and diabetes.

The compounds presented in the present description by the formula (1) (i.e. compounds of formula (1) or compounds of the present invention, or compositions comprising one or more of the above compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in the implementation of the method of treatment or prevention of acquired immunodeficiency syndrome (AIDS) patients, with the specified method comprises administration to a patient in need this, the compounds or compositions according to the present invention in an amount that is effective for the treatment or prevention of acquired immunodeficiency syndrome patients. When used in the present invention, the term "acquired immunodeficiency syndrome" by infection with human immunodeficiency virus type I includes, without limitation, associated complications, such as complex dementia with acquired immunodeficiency syndrome and neurosensory acquired immunodeficiency syndrome.

Thus, the method according to the present invention may be useful for treatment of inflammation, including both acute and chronic inflammation, and proliferative disorders (cancer, tumors, disease, treatable through the regulation of calcium in a patient, and AIDS. When used in this description, the term "inflammation" includes, without limitation, ankylosing spondylitis, arthritis (where this term includes more than 100 varieties of rheumatoid disease), asthma, chronic obstructive pulmonary disease, Allergy, allergic rhinitis, Crohn's disease, fibromyalgia syndrome, gout, inflammation of the brain (including multiple sclerosis, dementia complex in the acquired immunodeficiency syndrome, Lyme encephalopathy, herpes encephalitis, a disease of Creutzfeldt-Jakob disease and cerebral toxoplasmosis), emphysema, inflammatory disease of the gastrointestinal tract, mucous colitis, ischemic circulatory disturbances, allergic dermatitis, erythematous youth pulmonary sarcoidosis, Kawasaki disease, osteoarthritis, inflammatory disease of the renal pelvis, psoriatic arthritis (psoriasis, rheumatoid arthritis, psoriasis, graft tissue/organ, graft versus host disease, scleroderma, spondyloarthropathy, systemic lupus erythematosus, pulmonary sarcoidosis, vasculitis, atherosclerosis, cardiomyopathy, autoimmune myocarditis and ulcerative colitis.

The method of the present invention involves the introduction of a therapeutically effective amount of the compounds of formula (1), including its salts, compositions, etc. When using the AI in the present description the actual number, denoted by the term "therapeutically effective amount"will depend on the method of administration, type of warm-blooded animal, treated, and the physical characteristics of the concrete considered a warm-blooded animal. These factors and their interaction in the determination of such number of well-known specialist in the field of medicine. This quantity, and method of administration can be set in such a way as to achieve optimal efficacy but will depend on such factors as weight, diet, concomitant treatment, and other factors that are known to the expert in the field of medicine.

An effective amount of a compound or composition according to the present invention will be sufficient to treat inflammation, proliferative diseases, diseases to be treated by adjusting calcium, or AIDS in warm-blooded animals such as man. Methods of introducing an effective amount of anti-inflammatory drugs are well known in the art and include the introduction by inhalation, oral or parenteral form. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, slow-release implants and systems for transdermal delivery, or dispensing system dosage forms DL is inhalation, using sprinklers for dry powder, or the metering device under pressure, allowing you to enter multiple doses.

Dose and frequency is chosen in such a way as to achieve effective maintenance of the tools without the harmful effects. This number usually varies between dosage of approximately from 0.001 to 100 mg/kg/day, and typically from about 0.01 to 10 mg/kg/day, oral or intravenous. Dosage also varies approximately from 0.0001 to 10 mg/kg/day for intranasal or inhalation administration.

The compounds of formula (1), including the compounds used according to the methods and compositions mentioned above can be obtained in accordance with the scheme shown in the following examples. The following examples are intended for illustration and are not limiting the scope of invention.

Unless otherwise specified, flash chromatography and column chromatography is carried out using silica gel 60 Merck (230-400 mesh mesh). Flash chromatography can be carried out in accordance with the methodology described in "Purification of Laboratory Chemicals", 3rdedition, Butterworth-Heinemann Ltd., Oxford (1998), Eds. D.D.Perrin and W.L.F.Armarego, page 23. Column chromatography refers to the manner in which the rate of flow of eluent through the material of the filler is determined by the gravity. In all cases the flash chromatography and radial (circular) chromatography can be used interchangeably. Radial chromatography carried out using silica gel on the device Chromatotron Model#7924T (Harrison Research, Palo Alto, California). Unless otherwise stated, the indicated values of Rfreceive by thin-layer chromatography, using silica gel 60 Merck (Silica Gel 60 F254, Merck KgaA, 64271, Darmstadt, Germany). Brine is a saturated solution of sodium chloride.

Also, if not stated otherwise, chemicals and reagents receive from well - known suppliers of chemical products, such as firm Aldrich (Milwaukee, WI); EM Industries, Inc. (Hawthorne, NY); Fisher Scientific Co. (Hampton, NH) and Lancaster Synthesis, Inc. (Windham, NH). Sulfo-NHS-Biotin receive from Pierce (Rockford, IL). Resin MP-TsOH, resin PS-DIEA, resin PS-Trisamine and resin PS-Benzaldehyde get from Argonaut Technologies, San Carlos, CA). Gases get from Praxair (Vancouver, B.C.). Cell line, unless otherwise indicated, are obtained from government or commercial sources, for example from the American tissue culture collections (ATCC, Rockville, MD).

Examples synthesis

Example 1

3-Amino-6,7-dihydroxy-17-italianthere

The connection 49, a typical representative compounds of the present invention is obtained in accordance with scheme 1. Many compounds related to compound 49 can be obtained by using a similar methodology. The original connection 45 may be obtained according to the method described in U.S. patent 6046185. Rafinirovaniyu ketone 45 exercise with what ispolzovaniem of ethyltriphenylphosphonium and KO tBu in toluene. Processing 3β-hydroxyl compounds 46 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to the formation of 3α-etidocaine 47. The restoration of the azide with lithium aluminum hydride in Et2O gives Amin 48. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 49.

Scheme 1

i) CH3CH2PPh3Br, KOtBu, toluene; (ii) ZnN6·2py, Ph3P, DIAD, toluene; (iii) LiAlH4Et2O; (iv) HCl, THF, water.

Synthesis of compound 46

The solution containing COtBu (0.24 g, 2.0 mmol), EtPPh3Br (0.75 g, 2.0 mmol) and toluene (2.5 ml), stirred at room temperature in argon atmosphere. After 1 hour, the dark red solution is cooled on ice and add ketone 45 (184 g, 0.508 mmol), the resulting solution was allowed to warm to room temperature. After stirring over night the reaction mixture was quenched by adding 10 ml of water, diluted with 60 ml ethyl acetate (EtOAc), separated and washed with 2×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. After purification column chromatography with elution with mixture of EtOAc/hexane in a ratio of 1:1 to obtain 171 mg (90%) of compound 46 as a colorless film.

Synthesis of compound 47

DIAD (of 0.44 ml, 2.14 mmol) dobavlyayte drops for 10 minutes at room temperature the solution, containing 3β-gidroksosoedinenii 46 (400 mg, 1.07 mmol), ZnN6·2py (246 mg, 0.80 mmol), Ph3P (560 mg, 2.14 mmol) and toluene (of 10.7 ml) in an argon atmosphere. After 4 hours the reaction mixture was loaded onto a column Packed with silica gel in a mixture of 10% ethyl acetate/hexane, and elute with a mixture of 20% ethyl acetate/hexane to obtain 422 mg (99%) of compound 47 as a white solid.

Synthesis of compound 48

Alumoweld lithium (42 mg, 1.04 mmol) is added to a cooled with ice to a solution of azide 47 (415 mg, 1.04 mmol) in 5.2 ml Et2O in an argon atmosphere. The reaction mixture is allowed to warm to room temperature. After 2 hours of cooling on ice, the solution was diluted with 25 ml of diethyl ether and slowly quenched by adding 2 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, the solution was diluted with 50 ml ethyl acetate, washed with 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. The crude substance is purified using a column of silica gel pre-filled in a mixture of 1% Et3N/CH2Cl2and washed with a mixture of 5% MeOH/CH2Cl2. The crude substance is loaded into CH2Cl2, elute with a mixture of 5% MeOH/CH2Cl2and then mix in the ratio 95:5:2 CH2Cl2:Meon:Et3N, getting a white foam, which, according to1H NMR spectroscopy, which contains traces Et 3N. Substance placed in 50 ml of hexane, washed with 2×20 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate, getting 322 mg (83%) of compound 48 as a white foam.

Synthesis of compound 49

A solution containing 3α-aminosidine 48 (317 mg, 0,850 mmol), 4 M HCl in dioxane (255 μl, of 1.02 mmol), THF (13,6 ml) and water (3.4 ml), stirred at room temperature overnight. The solution is concentrated to dryness, triturated with acetone portions 3×10 ml, viparita acetone after each grinding. After concentrating receive 301 mg (96%) of compound 49 as a white solid. Liquid chromatography/mass spectroscopy (LC/MS, LC/MS - direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 334,16; C21H36NO2.

Example 2

3-Amino-6,7-dihydroxy-17-methodenstreit

For example alkenes, related to the connection 49, shown in scheme 2. Rafinirovaniyu ketone 45 using methyltriphenylphosphonium and COtBu in tetrahydrofuran leads to a 17-methyladenosine connection 50. Processing using ZnN6·2py, PPh3and DIAD in toluene leads to the formation of 3α-etidocaine 51. Recovery of lithium aluminum hydride in THF leads to the formation of 3α-etidocaine 52. Treatment with 80%acetic acid Pref is the CIO to remove the acetonide protective group and education ammoniates salt 53. Alternatively, the connection 52 is treated with hydrochloric acid in acetonitrile and water, receiving cleaners containing hydrochloride salt 54.

Scheme 2

i) CH3PPh3Br, KOtBu, THF; (ii) ZnN6·2py, Ph3P, DIAD, toluene; (iii) LiAlH4Et2O; (iv)80%acetic acid or HCl, water, MeCN.

Synthesis of compound 50

The solution containing COtBu (2.0 g, 16.9% mmol), MePPh3Br (6.0 g, a 16.8 mmol) and 27 ml of THF, stirred at room temperature in argon atmosphere. After 1 hour, the yellow solution was added the ketone 45 (2.00 g, 5,52 mmol), the resulting solution is refluxed for 1 hour. The reaction mixture was quenched by adding 50 ml of saturated sodium chloride solution, diluted with 100 ml ethyl acetate (EtOAc), separated and washed with 25 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. After purification column chromatography with elution with mixture of EtOAc/hexane in a ratio of 1:1 receive 1,90 g (95%) of compound 50 as a white solid.

Synthesis of compound 51

DIAD (0,85 ml, 4,10 mmol) is added dropwise within 15 minutes at room temperature to a solution containing 3β-hydroxyl compound 50 (739 mg, 2.05 mmol), ZnN6·2py (473 mg, 1.54 mmol), Ph3P (1,075 mg, 4,10 mmol) and toluene (20 ml)in an argon atmosphere. After 4 hours, p is a promotional mix is loaded on the column, filled with silica gel in a mixture of 10% ethyl acetate/hexane, and elute with a mixture of 20% ethyl acetate/hexane to obtain 743 mg (94%) of compound 51 as a white foam.

Synthesis of compound 52

Alumoweld lithium (77 mg, of 1.93 mmol) is added to a cooled with ice to a solution of 3α-azide 51 in 5 ml THF and 5 ml of diethyl ether in an argon atmosphere. The reaction mixture is allowed to warm to room temperature. After 4 hours the solution is cooled on ice, diluted with 25 ml of diethyl ether and slow quenched by adding 5 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, the solution was diluted with 50 ml ethyl acetate, washed with 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. The crude substance is purified on a column of silica gel pre-filled with a mixture of 1% Et3N/CH2Cl2and washed with a mixture of 5% MeOH/CH2Cl2. The crude substance is loaded into CH2Cl2, elute with a mixture of 5% MeOH/CH2Cl2and then mix in the ratio 95:5:2 CH2Cl2:Meon:Et3N getting 636 mg (92%) of compound 52 as a white solid.

Synthesis of compound 53

A solution containing 3αAmin 52 (287 mg, 0,799 mmol) and 10 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was concentrated, obtaining a white foam. Add acetone (10 ml) irector exposed to ultrasound for to dissolve the substance, and then evaporated. Add another 10 ml of acetone, is exposed to ultrasound and evaporated, getting 301 mg (99%) of compound 53 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 320,19; C20H34NO2.

Synthesis of compound 54

A solution of 4 M HCl in dioxane are added to a solution of amine 52 in 1 ml of acetonitrile and 50 μl of water. The obtained rubbery solid is diluted with 2 ml of acetonitrile and vigorously stirred until then, until it forms a solid substance. The solid is filtered off and dried, receiving 50 mg (63%) of compound 54. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 320,19; C20H34NO2.

Example 3

3-Amino-6,7-dihydroxy-17-methodenstreit (alternative synthesis)

The intermediate connection 52 also synthesized using an alternative approach, shown in scheme 3. Sideropenia alcohol 45 using ZnN6·2py, triphenylphosphine and DIAD in toluene leads to the formation of 3α-etidocaine 55. Hydrogenation of the azide using as a catalyst of palladium (Pd) on carbon gives Amin 56. Rafinirovaniyu connection 56 using methyltriphenylphosphonium and COtBu in tetrahydrofuran drive is it to the 17-methyladenosine connection 52.

Scheme 3

i) ZnN6·2py, Ph3P, DIAD, toluene; (ii) H2Pd, EtOAc; (iii) CH3PPh3Br, KOtBu, THF.

The synthesis of compounds 55

DIAD (2.4 ml, 11.6 mmol) is added dropwise within 20 minutes at room temperature to a solution containing 3β-hydroxyl compound 45 (2,108 g of 5.81 mmol), ZnN6·2py (1,34 g, 4,36 mmol), Ph3P (3,05 g, 11.6 mmol) and toluene (58 ml)in an argon atmosphere. After interaction during the night the reaction mixture was loaded onto a column Packed with silica gel and elute with a mixture of 20% ethyl acetate/hexane to obtain 1,14 g (50%) of compound 55 as a white foam.

Synthesis of compound 56

The solution containing azide 55 (1.10 g, 2,84 mmol), 10%Pd on carbon (60 mg, 0,057 mol) and 28 ml of ethyl acetate, stirred at room temperature overnight in a hydrogen atmosphere. The solution is filtered through celite, elwira with ethyl acetate. After purification by radial chromatography with elution with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2 receive 892 mg (81%) of compound 56 as a white solid.

Synthesis of compound 52

The solution containing COtBu (175 mg, 1.48 mmol), MePPh3Br (528 mg, 1.48 mmol) and 3 ml of THF, stirred at room temperature in argon atmosphere. After 1 hour, the yellow solution was added the ketone 56 (100 mg, 0,277 mmol) and the scientists of the solution is kept under stirring at room temperature over night. The reaction mixture was quenched by adding 5 ml of water, diluted with 50 ml ethyl acetate (EtOAc), separated and washed with 10 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. After purification by radial chromatography with elution with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2 obtain 96 mg (97%) of compound 52 as a white solid.

Example 4

3-Amino-6,7-dihydroxy-17-floridalottery

Halogenated analogs, related to the connection 49, can be obtained using for referirovanija halogenated reagents. Scheme 4 shows the synthesis of 20-fluorinated analogue connection 64. Hydroxyl group in compound 45 protect by treatment of tert-butyldimethylsilyloxy and imidazole in dimethylformamide (DMF). Rafinirovaniyu ketone 57 using anion of triethyl-2-fluorescent-1-phosphonoacetate yields a mixture of compound 58 and its geometric isomer. Connections can be separated by chromatography on silica gel. Recovery of lithium aluminum hydride ester groups in the environment Et2O gives allyl alcohol 59. Processing complex of sulfur trioxide and pyridine in THF followed by the addition of lithium aluminum hydride allows you to get dihydroxypropane connection 60. Tetrabutylammonium in THF removes the protective group 3-HYDR is xelnaga connection with obtaining connection 61. Sideropenia using ZnN6·2py, PPh3and DIAD in toluene leads to the formation of 3α-etidocaine 62. The restoration of the azide with lithium aluminum hydride in THF gives 3αAmin 63. Treatment using HCl in THF and water removes protection 6 - and 7-hydroxyl groups and the formation of ammoniacloridegas salt 64.

Scheme 4

i) TBSCl, imidazole, DMF; (ii) (EtO)2P(O)CHFCO2Et, LiN(TMS)2, THF; iii) LiAlH4Et2O; (iv) SO3Py, THF, LiAlH4; v) Bu4NF, THF; (vi) ZnN6·2Py, Ph3P, DIAD, toluene; (vii) LiAlH4Et2O; (viii) HCl, THF, water.

Synthesis of compound 57

The solution containing the ketone 45 (4,73 g of 13.1 mmol), TBSCl (3,01 g and 19.6 mmol), imidazole (2.67 g, is 39.2 mmol) and DMF (52 ml), stirred at room temperature overnight. The white suspension was diluted with 250 ml EtOAc, washed with 2×50 ml of water and 50 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate, receiving 5,97 g (96%) of compound 57 as a white solid.

Synthesis of compound 58

Bis(trimethylsilyl)amide lithium (10.0 ml of 1.0 M solution in THF, 10.0 mmol) is added to a room temperature solution of (EtO)2P(O)CHFCO2Et (2.65 g, 10.5 mmol) in THF (22 ml) in an argon atmosphere. After 1 hour, add a solution of ketone 57 (2.50 g, a 5.25 mmol) in THF (20 ml) and the resulting solution is boiled OBR is Tim fridge for 4.5 hours, then stirred at room temperature overnight. The reaction mixture was quenched by addition of 1.5 ml of a saturated solution of NaHCO3and then partially concentrated to remove most of THF. The residue is diluted with 200 ml EtOAc, washed with 3×20 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. The crude substance is purified column chromatography, elwira a first mixture of 2.5%and then 5% EtOAc/hexane, receiving 1.50 g (50%) of compound 58 as a white solid.

Synthesis of compound 59

Alumoweld lithium (106 mg, of 2.66 mmol) is added to a cooled with ice to a solution of ester 58 (1.50 g, of 2.66 mmol) in Et2O (13 ml) in an argon atmosphere. The solution is allowed to warm to room temperature. After 3 hours the solution is cooled on ice and slowly add 20 ml of a saturated solution of Na2SO4. After 10 minutes the solution was diluted with 150 ml EtOAc, washed with water and saturated sodium chloride solution, dried over MgSO4filter and concentrate, receiving 1.44 g (yield quantitative) of the compounds of formula 59 in the form of a white foam.

Synthesis of compound 60

The complex of sulfur trioxide and pyridine (69,5 mg, 0,428 mmol) is added to a cooled with ice to a solution of allyl alcohol 59 (149 mg, 0,285 mmol) in THF (2.8 ml) in an argon atmosphere. After 6 hours add alumoweld lithium (68 mg, 1,71 mol), p is the following which the solution is allowed to warm to room temperature over night. The solution is cooled on ice and slowly add 5 ml of a saturated solution of Na2SO4. After 10 minutes the solution was diluted with 75 ml of EtOAc, washed with water and saturated sodium chloride solution, dried over MgSO4, filtered and concentrated, gaining 109 mg (76%) of the compounds of formula 60 in the form of a white solid.

Synthesis of compound 61

The solution containing compound 60 (410 mg, 0,810 mmol), Bu4NF (0,89 ml of 1.0 M solution in THF, 0.89 mmol) and THF (5 ml), refluxed in an argon atmosphere. After 1.5 hours the solution is cooled to room temperature, diluted with 75 ml of EtOAc, washed with water (20 ml) and a saturated solution of sodium chloride (2×20 ml), dried over MgSO4filter and concentrate. The residue is filtered through silica gel, elwira EtOAc, and get 318 mg (100%) of the compounds of formula 61 in the form of a white solid.

Synthesis of compound 62

DIAD (0.33 ml, of 1.59 mmol) is added dropwise within 10 minutes at room temperature to a solution of 3β-alcohol 61 (312 mg, coefficient was 0.796 mmol), ZnN6·2py (183 mg, 0,597 mmol), Ph3P (417 mg, of 1.59 mmol) and toluene (8.0 ml) in an argon atmosphere. After 3 hours the reaction mixture was loaded onto a column Packed with silica gel in a mixture of 10% EtOAc/hexane, and elute with a mixture of 20% EtOAc/hexane, getting 322 mg (97%) of compound 62 in the form of a crystalline substance.

Synthesis of compound 63

Alumalite the lithium (29 mg, 0.75 mmol) is added to a cooled with ice to a solution of azide 62 (314 mg, 0,753 mmol) in Et2O (7.5 ml) in an argon atmosphere. The solution is allowed to warm to room temperature with stirring overnight. The solution is cooled on ice and slowly quenched by adding 10 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, the solution was diluted with 75 ml ethyl acetate (EtOAc), washed with 20 ml of water, 2×20 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. The crude substance is purified using a column of silica gel pre-filled with a mixture of 1% Et3N/CH2Cl2and washed with a mixture of 5% MeOH/CH2Cl2. The crude substance is loaded into CH2Cl2, elute with a mixture of 5% MeOH/CH2Cl2and then with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2, getting a white solid. According to the analysis method1H NMR spectroscopy substance contains traces Et3N, therefore, the substance is placed in 75 ml of CH2Cl2and washed with water (2×25 ml), dried over MgSO4filter and concentrate, getting 137 mg (47%) of compound 63 in the form of a colorless film.

Synthesis of compound 64

A solution containing 3α-aminosidine 63 (137 mg, 0.35 mmol), 4 M HCl in dioxane (105 μl, 0.42 mmol), THF (5.6 ml) and water (1.4 ml), stirred at room Tempe is the atur during the night. The solution is concentrated and the residue is twice placed in 3 ml of methanol and concentrate, receiving 130 mg (96%) of compound 64 as not quite white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 352,14; C21H35FNO2.

Example 5

3-Amino-6,7-dihydroxy-17-carbomethoxyamino

Rafinirovaniyu compounds related to compound 57, can also be carried out in order to synthesize 21-carboalkoxylation counterparts. Figure 5 shows an example of the synthesis of 21-carbomethoxyamino connection 69. Rafinirovaniyu ketone 57 using anion trimethyl-2-phosphonoacetate gives a mixture of compounds 65 and its geometric isomer. These compounds can be separated by chromatography on silica gel. Tetrabutylammonium in THF removes the protective group at the 3-hydroxyl compounds with the formation of compound 66. The introduction of the azide group using ZnN6·2py, PPh3and DIAD in toluene leads to the formation of 3α-etidocaine 67. Hydrogenation of the azide using Pd on carbon gives 3αAmin 68. Treatment with 80%acetic acid removes the protection of the 6 - and 7-hydroxyl groups and the formation of ammoniates salt 69.

Scheme 5

i) (MeO)2P(O)CHFCO2Me, LiN(TMS) 2, THF; (ii) Bu4NF, THF; iii) ZnN6·2py, Ph3P, DIAD, toluene; (iv) (H2Pd, EtOAc; (v) 80%acetic acid.

Synthesis of compound 65

Bis(trimethylsilyl)amide lithium (2,00 ml of 1.0 M solution in THF, 2.00 mmol) is added to a room temperature solution of (MeO)2P(O)CH2CO2IU (390 mg, 2.10 mmol) in THF (22 ml) in an argon atmosphere. After 3 hours, add a solution of ketone 57 (509 mg, 1.07 mmol) in THF (2 ml) and the resulting solution was refluxed for 3 days. The reaction mixture was quenched by adding 5 ml of water, diluted with 75 ml of EtOAc, washed with 2×15 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. The crude substance is purified column chromatography, elwira a mixture of 5% EtOAc/hexane, getting 307 mg (54%) of compound 65 as a colorless film. There are also 119 mg (21%) Z-isomer.

Synthesis of compound 66

The solution containing compound 65 (296 mg, 0,550 mmol), Bu4NF (0,61 ml of 1.0 M solution in THF, 0.61 mmol) and THF (3 ml), refluxed in an argon atmosphere. After 1 hour, the solution is cooled to room temperature, diluted with 20 ml EtOAc, washed with 10 ml of water and 2×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate, getting 230 mg (100%) of compound 66 as a white solid.

Synthesis of compound 67

DIAD (252 μl, ,28 mmol) is added dropwise to a room temperature solution, containing 3β-alcohol 66 (230 mg, 0.55 mmol), ZnN6·2py (147 mg, 0.48 mmol), Ph3P (335 mg, 1.28 mmol) and toluene (6.4 ml)in an argon atmosphere. After 2 hours the reaction mixture was purified by radial chromatography, elwira a mixture of 15% EtOAc/hexane, and getting 203 mg (84%) of compound 67.

Synthesis of compound 68

The solution containing azide 67 (203 mg, 0.45 mmol), 10%Pd on carbon (48 mg, 0.045 mmol) and 4.5 ml of EtOAc, stirred at room temperature in a hydrogen atmosphere for 3 days. The solution is filtered through celite, using as eluent EtOAc and MeOH, and getting 165 mg (88%) of compound 68.

Synthesis of compound 69

The solution containing the amine 68 (165 mg, 0.40 mmol) and 2 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was diluted with 10 ml of toluene and then concentrated to remove residual acetic acid. Rubbing the residue with 10 ml of cyclohexanone, followed by filtering and drying allows to obtain 117 mg (67%) of compound 69 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 378,17; C22H36NO4.

Example 6

Salt of acetic acid 3α-amino-6α,7β-dihydroxyandrost-17-she

A similar technique can be used to produce compounds with different functionalities the atom C17. For example,17-Ketobemidone compound is obtained by treating compound 56 80%acetic acid to obtain the salt of acetic acid 3α -amino-6α,7β-dihydroxyandrost-17-she (70) (see table 2).

Synthesis of compound 70

The solution containing the ketone 56 (67 mg, 0.16 mmol) and 1 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was diluted with 10 ml of toluene and then concentrated to obtain 63 mg (100%) of compound 70. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 322,18; C19H32NO3.

Example 7

3-Amino-6,7-dihydroxy-17-hydroxysteroid

17-Hydroxylamine analogues can be obtained from ketones, related to the connection 56, thus, as shown in scheme 6. Carbonyl group in compound 56 restore using NaBH4in methanol, receiving exclusively 17β-hydroxyl isomer 71. Treatment with 80%acetic acid removes the acetonide protective group and education ammoniates salt 72.

Scheme 6

i) NaBH4, MeOH; (ii) 80% acetic acid.

Synthesis of compound 71

Cooled with ice a solution of ketone 56 (100 mg, 0.28 mmol), NaBH4(16 mg, 0.41 mmol) and 1.4 ml Meon subjected to interaction within 2.5 hours. The reaction mixture was quenched by adding 1 ml of water and concentrated to remove most of the Meon. The residue was diluted with 40 ml of CH2Cl2washed 2×10 ml of NASA the military solution of sodium chloride, dried over MgSO4filter and concentrate, receiving 90 mg (90%) of compound 71.

Synthesis of compound 72

The solution containing the amine 71 (90 mg, 0.25 mmol) and 2 ml of 80%acetic acid, heated at 40°C for 2 hours. The reaction mixture was diluted with 10 ml of toluene and then concentrated to remove residual acetic acid. The residue is dissolved in 1 ml Meon and 5 ml of hexane, concentrated and dried, receiving 86 mg (90%) of compound 72 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 324,19; C19H34NO3.

Example 8

Salt 3α-amino-6,7-dihydroxy-17-methodenstreit

6 - and 7-Hydroxyl group can be protected using a variety of protective groups. Suitable protective groups are listed in Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, N.Y. (1999). Figure 7 shows examples of analogs that can be synthesized using 6 - and 7-hydroxyl groups are protected as simple methyl ether. The original connection 73 is described in U.S. patent 6046185. Generate dianion connection 73 using NaH in dimethylformamide, followed by alkylation with methyliodide allows you to get a connection 74. Treatment with 80%acetic acid removes the protective groups as cyclic ketal is s, and tert-butyldimethylsilyl ether protective groups. Rafinirovaniyu ketone 75 using methyltriphenylphosphonium and COtBu in THF leads to a 17-methyladenosine connection 76. Sideropenia using ZnN6·2py, PPh3and DIAD in toluene gives 3α-etidocaine 77. Recovery of lithium aluminum hydride in THF leads to a 3α-Amin 78. Treatment using HCl in THF and water leads to the formation of ammoniacloridegas salt 79. After processing the connection 78 acetic acid is obtained anonymousyou salt 80.

Scheme 7

i) NaH, MeI, DMF; (ii) 80% acetic acid; (iii) CH3PPh3Br, KOtBu, THF; (iv) ZnN6·2Py, Ph3P, DIAD, toluene; (v) LiAlH4Et2O; vi) HCl, Et2O, MeOH or acetic acid.

Synthesis of compound 74

To a solution of diol 73 (1,49 g, 3.10 mmol) in 15 ml DMF under nitrogen atmosphere add sodium hydride (0.50 g, 12.4 mmol). After 2 hours the solution is cooled on ice and added dropwise within 30 seconds MeI (1,93 ml of 30.9 mmol). The reaction mixture is allowed to warm to room temperature with stirring overnight. The reaction mixture is diluted with 100 ml of Et2O, washed with 10 ml of water and 2×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate, receiving 1.73 g of the crude compound 74 in the form of pale is altago oil.

Synthesis of compound 75

The solution containing the crude compound 74 (1.73 g, 3.10 mmol) and 15 ml of 80%acetic acid, stirred for 4 hours at room temperature. The solution is concentrated and the residue is placed in 50 ml of EtOAc, washed with 2×20 ml of a saturated solution of NaHCO3and 2×10 ml of a saturated solution of sodium chloride, dried over MgSO4, filtered and concentrated, gaining 1.18 g of the crude compound 75 as a white foam.

Synthesis of compound 76

The solution containing COtBu (1,09 g, 9,20 mmol), MePPh3Br (3,30 g, 9,20 mmol) and 15 ml of THF, stirred at room temperature under nitrogen atmosphere. After 2 hours, the yellow solution was added the crude ketone 75 (1,17 mg, is 3.08 mmol) and the resulting solution was left under stirring at room temperature over night. The reaction mixture was quenched by adding 2 ml of water, diluted with 100 ml ethyl acetate (EtOAc), washed 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. After purification column chromatography with elution with a mixture of 80% EtOAc/hexane obtain 890 mg contaminated with impurities compound 76 as a white solid.

Synthesis of compound 77

DIAD (1,05 ml, 5.08 mmol) is added dropwise within 10 minutes at room temperature to a solution of 3β-alcohol 76 (885 mg, 2.54 mmol), ZnN6·2Py (585 m is, 1,90 mmol), Ph3P (1,33 g, 5.08 mmol) and toluene (25 ml) in an argon atmosphere. After 11 hours, the reaction mixture was purified column chromatography, elwira a mixture of 15% EtOAc/hexane and getting 594 mg (63%) of compound 77 in the form of a crystalline solid.

Synthesis of compound 78

Alumoweld lithium (0,79 ml of 1 M solution in Et2O, of 0.79 mmol) is added to a cooled with ice to a solution of azide 77 (588 mg, 1.57 mmol) in 15.7 ml Et2O in an argon atmosphere. After 10 minutes the solution is allowed to warm to room temperature while continuing the stirring for the night. After 1 hour of cooling on ice, the solution slowly quenched by adding 10 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, and the liquid decanted. The residue was washed with 2×25 ml of EtOAc and washing liquid combined with previously dekotirovaniem ether solution. The solution is washed 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. After purification column chromatography with elution with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2 receive 434 mg (79%) of compound 78 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 348,20; C22H38NO2.

Synthesis of compound 79

Hydrogen chloride (0,26 ml of 1.0 M solution in Et2O, 0.26 mmol) are added to a solution of amine 78 (60 mg, 0,17 mmol) in 2 ml of Et2O. the Obtained gel-like substance was dissolved in 5 ml of methanol and concentrated. The residue is dissolved in 1 ml of methanol, diluted with 5 ml of cyclohexane and concentrated, gaining 66 mg (100%) of compound 79 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 348,20; C22H38NO2.

Synthesis of compound 80

The solution containing the amine 78 (61 mg, 0,17 mmol) and 1 ml of acetic acid, allowed to stand at room temperature for 30 minutes. The solution was diluted with 5 ml of toluene and koncentriruiutsia placed in 5 ml of hexane, concentrated, and the residue is dried for 2 hours using the device Abderhalden for drying with irrigation acetone, and obtain 71 mg (100%) of compound 80 in the form of a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 348,20; C22H38NO2.

Example 9

Salt 3β-amino-6,7-dihydroxy-17-methodenstreit

The stereochemistry of the atom C3 can be changed with obtaining derivatives of 3βammonium salts of a variety of compounds related to compound 49. The stereochemistry of the atom C3 may be subject inversion in 3 phase synthesis as shown in scheme 8 for the synthesis of the connection is on the 28 and 83. 3β-hydroxyl compound 46 in turn 3β-mesilate 81 using methanesulfonanilide and pyridine. Heating connections 81 and treatment with cesium acetate in DMF at 100°leads to the formation of 3αacetate connection 82. The sequence of transformations for the inversion is completed by methanolysis of acetate group in connection 82 with the use of sodium methoxide and receiving 3α-hydroxyl compound 25. The process of joining 25 ZnN6·2py, triphenylphosphine and DIAD in toluene results in 3β-etidocaine 26. The restoration of the azide with lithium aluminum hydride in Et2O leads to the formation of 3β-amino compounds 27. Treatment using HCl in THF and water leads to the removal of the acetonide group and education ammoniacloridegas salt 28. Similarly, in the processing of the connection 27 of 80%acetic acid to remove the acetonide group and get anonymousyou Sol 83. When using methods shown in scheme 8, compound 50 is converted into a compound 89, compound 61 is converted into a compound 95 (see table 1). Connection 26, 27, 87, 88, 89, 93, 94 and 95 are examples of compounds of the present invention and having a 3β stereochemistry.

Scheme 8

i) MsCl, pyridine; (ii) CsOAc, DMF, 100°C; (iii) NaOMe, MeOH; (iv) ZnN6·2py, Ph3P, DIAD, toluene; (v) LAlH 4Et2O; vi) 4 M HCl in dioxane, THF, water or 80%acetic acid.

Synthesis of compound 81

Methanesulfonanilide (1.2 ml, 16 mmol) is added to cooled with ice to a solution of 3β-hydroxyl compound 46 (3.0 g, 8.0 mmol) in pyridine (20 ml) in an argon atmosphere. After 4 hours the solution is cooled with ice and add 20 ml of a saturated solution of NaHCO3. After 15 minutes the solution was diluted with 150 ml EtOAc and washed with 3×25 ml saturated sodium chloride solution, dried over MgSO4, filtered and concentrated, gaining 3.6 g (100%) of compound 81 as not quite white foam.

The synthesis of compound 82

The solution containing mesilate 81 (3.6 g, 8.0 mmol), cesium acetate (4.6 g, 24 mmol) and 40 ml of DMF is heated at 100°C for 24 hours. The solution was diluted with 100 ml of water, extracted with 2×100 ml of Et2O, washed with 2×50 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate, receiving approximately 3 g of the crude compound 82.

The synthesis of compounds 25

A solution containing Na (398 mg, 17.3 mmol) in Meon (21,5 ml), add 3α-acetate 82 (1.8 g, 4.3 mmol) in THF (10 ml). After 2 hours, add 20 ml of water and the resulting solution was diluted with 100 ml EtOAc, sequentially washed with a saturated solution of NaHCO3, water and saturated sodium chloride solution, dried over MgSO4filter and concentrate, receiving 1,58 g (98%) untreated the military compound 25 as a yellow foam substance.

Synthesis of compound 26

DIAD (1.70 ml, 8,24 mmol) is added dropwise within 10 minutes at room temperature to a solution of 3α-alcohol 25 (1.54 g, 4,12 mmol), ZnN6·2py (0,94 g, 3,99 mmol), Ph3R (2.16 g, 8,24 mmol) and toluene (44 ml) in an argon atmosphere. After stirring over night the reaction mixture was loaded onto a column Packed with silica gel in a mixture of 10% EtOAc/hexane, and elute with a mixture of 10% EtOAc/hexane to obtain 0,89 g (61%) of compound 26 as a white solid.

Synthesis of compound 27

Alumoweld lithium (146 mg, 3,66 mmol) is added to cooled with ice to a solution of azide 26 (1,46 g, 3,66 mmol) in 18.3 ml Et2O in an argon atmosphere. The reaction mixture is allowed to warm to room temperature. After 1.5 hours the solution is cooled on ice, diluted with 25 ml Et2O and slowly quenched by adding 20 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, the solution was diluted with 50 ml EtOAc, washed with 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate the receiving of 1.31 g (96%) of compound 27 as a white foam.

Synthesis of compound 28

A solution containing 3β-aminosidine 27 (227 mg, 0,609 mmol), 4 M HCl in dioxane (183 μl, 0.73 mmol), THF (9.7 ml) and water (2.4 ml), stirred at room temperature overnight. After evaporation of THF and water, the residue is placed in 5 ml of m is of canola, then concentrated, triturated with 5 ml of acetone, resulting in a gain of 224 mg (100%) of compound 28 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 334,10; C21H36NO2.

Synthesis of compound 83

The solution containing the amine 27 (412 mg, 1.10 mmol) and 5 ml of 80%acetic acid, stirred at room temperature for 4 hours. The reaction mixture was diluted with 5 ml of toluene, after which koncentriruiutsia second time dissolved in 5 ml of toluene and concentrated to remove residual acetic acid. The resulting residue is twice triturated with 10 ml of CH2Cl2after which concentrate getting 430 mg (99%) of compound 83 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 334,19; C21H36NO2.

Synthesis of compound 84

Methanesulfonanilide (0.33 ml, 4.2 mmol) is added to a cooled with ice to a solution of 3β-hydroxyl compound 50 (754 mg, of 2.09 mmol) in pyridine (5.3 ml) in an argon atmosphere. After 4 hours the solution is cooled on ice and add 5 ml of a saturated solution of NaHCO3. After 15 minutes the solution was diluted with 60 ml ethyl acetate and washed 3 times with saturated solution of sodium chloride, dried over MgSO4filter and concentrate the, getting 860 mg (94%) of compound 84 as not quite white solid.

Synthesis of compound 85

The solution containing mesilate 84 (860 mg, a 1.96 mmol), cesium acetate (1.13 g, 5,88 mmol) and 10 ml of DMF is heated at 95°C for 32 hours. The solution was diluted with 50 ml of water, extracted with 2×100 ml of Et2O, washed with 2×30 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. After purification column chromatography with elution with a mixture of 5%and then 8% EtOAc/hexane, receive 558 mg (71%) of compound 85 as a white solid.

Synthesis of compound 86

A solution containing Na (128 mg, to 5.56 mmol) in Meon (7 ml), add 3α-acetate 85 (558 mg, 1.38 mmol). After 2 hours, add 5 ml of a saturated solution of NaHCO3and the resulting solution was diluted with 100 ml EtOAc. The solution was washed with water (2×20 ml) and a saturated solution of sodium chloride (2×20 ml), dried over MgSO4filter and concentrate, getting 491 mg (99%) of compound 86 as a white solid.

Synthesis of compound 87

DIAD (or 0.57 ml, is 2.74 mmol) is added dropwise within 15 minutes at room temperature to a solution of 3α-hydroxycodone 86 (493 mg, 1.37 mmol), ZnN6·2py (315 mg, of 1.03 mmol), Ph3P (718 mg, is 2.74 mmol) and toluene (13,7 ml) in an argon atmosphere. After 3.5 hours the reaction mixture was loaded into a column Packed with silicagel who eat in a mixture of 10% EtOAc/hexane, and elute with a mixture of 10% EtOAc/hexane to obtain 390 mg (74%) of compound 87 in the form of a viscous oil.

Synthesis of compound 88

Alumoweld lithium (40 mg, 1.01 mmol) is added to a cooled with ice to a solution of etidocaine 87 (390 mg, 1.01 mmol) in 5 ml of diethyl ether in an argon atmosphere. The reaction mixture is allowed to warm to room temperature. After 2 hours the solution is cooled on ice, diluted with 25 ml of diethyl ether and slowly quenched by adding 2 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, after which the solution was diluted with 40 ml ethyl acetate, washed with 3×15 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. The crude substance is purified column chromatography using a column of silica gel pre-filled in a mixture of 1% Et3N/CH2Cl2and washed with a mixture of 5% MeOH/CH2Cl2. The crude substance is loaded into CH2Cl2, elute with a mixture of 5% MeOH/CH2Cl2and then with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2, getting 277 mg (76%) of compound 88 as a white solid.

Synthesis of compound 89

The solution containing aminosilane 88 (270 mg, 0,752 mmol) and 10 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was concentrated, obtaining a white foam. Add another 10 ml of AC the tone, exposed to ultrasound and evaporated to obtain 285 g (100%) of compound 89 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 320,26; C20H34NO2.

Synthesis of compound 90

Methanesulfonanilide (0,20 ml, 2.56 mmol) is added to a cooled with ice to a solution of 3β-hydroxyl compound 61 (501 mg, 1.28 mmol) in pyridine (3.2 ml) in an argon atmosphere. After 4 hours the solution is cooled on ice and add 5 ml of a saturated solution of NaHCO3. After 15 minutes the solution was diluted with 50 ml EtOAc and washed 3 times with saturated solution of sodium chloride, dried over MgSO4filter and concentrate, getting 590 mg (98%) of compound 90 as a white foam.

Synthesis of compound 91

The solution containing mesilate 90 (590 mg, 1.25 mmol), cesium acetate (722 mg, 3,76 mmol) and 6.2 ml of DMF is heated at 100°C for 24 hours. The solution was diluted with 50 ml of water, extracted with 2×50 ml Et2O, washed with 2×30 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. After purification column chromatography with elution with a mixture of 8% EtOAc/hexane, get 297 mg (55%) of compound 91 as a white solid.

Synthesis of compound 92

A solution containing Na (63 mg, 2.7 mmol) in Meon (3.4 ml), add 3α-acetate 91 (297 mg, 0684 mmol) in THF (1 ml). The solution is stirred over night. Add 5 ml of water and 80 ml of EtOAc, washed twice with water and twice with a saturated aqueous solution of sodium chloride, dried over MgSO4filter and concentrate, getting 251 mg (94%) of compound 92 as a white solid.

Synthesis of compound 93

DIAD (0,26 ml of 1.24 mmol) is added dropwise during 10 minutes to a room temperature solution containing 3α-alcohol 92 (243 mg, 0,620 mmol), ZnN6·2py (143 mg, 0,465 mmol), Ph3P (325 mg, 1,24 mmol) and toluene (6.2 ml)in an argon atmosphere. After 4 hours the reaction mixture was loaded into a column Packed with silica gel in a mixture of 10% EtOAc/hexane, and elute with a mixture of 20% EtOAc/hexane to obtain 209 mg of the crude compound 93 as a yellow oil.

Synthesis of compound 94

Alumoweld lithium (20 mg, 0.50 mmol) is added to a cooled with ice to a solution of the crude azide 93 (209 mg, 0.50 mmol) in 5 ml of Et2O in an argon atmosphere. The reaction mixture is allowed to warm to room temperature. After 4 hours the solution is cooled on ice, diluted with 25 ml diethyl ether (Et2O) and slowly quenched by adding 2 ml of a saturated solution of Na2SO4. After 10 minutes, a white precipitate is formed, after which the solution was diluted with 50 ml ethyl acetate (EtOAc), washed 3×10 ml of a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. ocimene substance chromatographic, using a column with silica gel pre-filled with a mixture of 1% Et3N/CH2Cl2and washed with a mixture of 5% MeOH/CH2Cl2. The crude substance is loaded into CH2Cl2, elute with a mixture of 5% MeOH/CH2Cl2and then with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2, receiving 97 mg of the crude compound 94 as a white solid.

Synthesis of compound 95

A solution containing 3β-aminosidine 94 (97 mg, 0.25 mmol), 4 M HCl in dioxane (74 μl, 0.30 mmol), THF (4 ml) and water (1 ml), stirred at room temperature. After 4 hours the solution is concentrated and the residue is placed in 5 ml of methanol and concentrated. The resulting residue is twice triturated with 5 ml of acetone and concentrated. White solid was dissolved in approximately 0.5 ml of water and slowly add acetone (5 ml), until, until crystals appear. The crystals are filtered, washed with acetone and dried, receiving 66 mg of compound 95 in the form of colorless fine needles. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 352,09; C21H35FNO2.

Example 10

3-Amino-6,7-dihydroxy-17-alkylthio

Any compounds containing 17(20)-alkenylphenol functional group may contain a double bond, which is subjected to hydrogenation using H2in prisutstvie the catalyst, such as 10% Pd on carbon. For example, the connection 96 is produced from compound 28 as shown in scheme 9. Similarly, the connection 97 is produced from compound 49 using the same methodology shown in scheme 9 (see table 2).

Scheme 9

i) H2Pd on carbon, methanol.

Synthesis of compound 96

The solution containing olefin 28 (52 mg, 0.14 mmol), 10% Pd on carbon (15 mg, 0.014 mmol) and methanol (3 ml), stirred at room temperature overnight. The solution is filtered through celite, elwira 50 ml of methanol, and concentrate, receiving 50 mg (96%) of compound 96 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 336,24; C21H38NO2.

Synthesis of compound 97

The solution containing olefin 49 (844 mg, 2.28 mmol), 10% Pd on carbon (243 mg, 0,228 mmol) and methanol (11 ml), stirred at room temperature overnight. The solution is filtered through celite, elwira 50 ml of methanol, then concentrated. The residue is triturated with 10 ml of acetone, filtered and dried, obtaining 801 mg (94%) of compound 97 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 336,21; C21H38NO2.

Example 11

3-second-Amino-6,7-dihydroxy-11-methodenstreit

Any amines, related to the connection 52 may be subjected to condensation with the aldehyde or ketone to obtain a secondary or tertiary amines. Interaction of compound 52 with a solution of 4-isopropylbenzaldehyde and isopropoxide titanium in THF, followed by reduction with sodium borohydride results in connection 99. Treatment with 80%acetic acid removes the acetonide groups and education ammoniates salt of compound 100. Connection examples 101-107 were synthesized using methods shown in scheme 10 (see table 6).

Scheme 10

i) 4-isopropylbenzaldehyde, Ti(OiPr)4, THF; NaBH4, MeOH; (ii) 80%acetic acid.

Synthesis of compound 99

Isopropoxide titanium (IV) (120 μl, 0.42 mmol) is added to a room temperature solution containing the amine 52 (100 mg, 0.28 mmol), 4-isopropylbenzaldehyde (46 μl, 0.31 mmol) and 1.4 ml of THF under nitrogen atmosphere. After 12 hours, add a solution of NaBH4(29 mg, 0.78 mmol) in 1 ml EtOH and interaction is carried out for a further 8 hours. The reaction mixture was quenched by adding 3 ml of saturated sodium chloride solution, diluted with 30 ml EtOAc, separated, washed with a saturated solution of sodium chloride, dried over MgSO4filter and concentrate. After cleaning the radial chromatographie who obtain 50 mg (36%) of compound 99.

Synthesis of compound 100

The solution containing the amine 99 (50 mg, 0.10 mmol) and 1 ml of 80%acetic acid, stirred at 40°C for 3 hours. The reaction mixture was twice treated portions of toluene (5 ml), then concentrated, and then once treated with acetone and hexane, receiving 25 mg (51%) of compound 100. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 452,27; C30H46NO2.

Synthesis of compound 101

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with 2-vorbesuregen (32 μl, 0.32 mmol)to give 43 mg of amine intermediate. Amine intermediate connection process, using 1 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrated, gaining 49 mg (37%) of compound 101 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 428,22; C27H39FNO2.

Synthesis of compound 102

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with 3-(trifluoromethyl)benzaldehyde (41 μl, 0.31 mmol), produces the 61 mg of amine intermediate. Amine intermediate connection process, using 1 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrated, gaining 64 mg (45%) of compound 102 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 478,18; C28H39F3NO2.

Synthesis of compound 103

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with anise aldehyde (42 mg, 0.31 mmol)to give 30 mg of amine intermediate. Amine intermediate connection process, using 1 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrate, receiving 18 mg (14%) of compound 103. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 440,23; C28H42NO3.

Synthesis of compound 104

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with 4-(triptoreline)benzaldehyde (44 μl, 0.31 mmol)to give 86 mg of amine PR is an interstitial compound. Amine intermediate connection process using 1.5 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrated, gaining 84 mg (57%) of compound 104 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 494,15; C28H39F3NO3.

Synthesis of compound 105

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with 3-phenoxybenzaldehyde (60 mg, 0.32 mmol)to give 73 mg of amine intermediate. Amine intermediate compound is treated with 1 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrated, gaining 87 mg (58%) of compound 105 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 502,20; C33H44NO3.

Synthesis of compound 106

Using the procedure described for the synthesis of compound 99, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with 3-nitrobenzaldehyde (46 mg, 0.31 mmol), receiving 18 mgaming intermediate compounds. Amine intermediate connection process, using 1 ml of 80%acetic acid at 40°C for 3 hours. The reaction mixture was diluted with 5 ml of toluene and concentrated. The resulting residue is dissolved in 1 ml of acetone, diluted with 5 ml of hexane and concentrate, receiving 18 mg (14%) of compound 106 in the form of not-quite-white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 455,20; C27H39N2O4.

Synthesis of compound 107

Using the procedure described for the synthesis of compound 99, the amine 52 (200 mg, 0.55 mmol) is subjected to interaction with 3-pyridinecarboxamide (82 μl, 0.61 mmol)to give 100 mg of amine intermediate. The suspension containing amine intermediate compound, 4 M HCl in dioxane (65 μl, 0.26 mol), 110 μl of water and 2.2 ml of acetonitrile, stirred at room temperature for 1 hour. The solution is filtered and dried solid is getting 77 mg (30%) of compound 107 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 411,21; C26H39N2O2.

Example 12

3 Cycloamino-6,7-dihydroxy-17-italianthere

Any ketone, related to the connection 108 may be subjected to condensation with the amine using methods shown in CX is IU 11. Synthesis of starting compound 108 is described in U.S. patent 6046185. Interaction connection 108 with piperidine and cyanoborohydride sodium in methanol gives compound 109 in the form of a mixture of isomers of the atom C3. Treatment with 80%acetic acid removes the acetonide protective group and education ammoniates salt 110. Connection 111 according to the sample synthesized using methods shown in scheme 11, except that instead of acetic acid using hydrochloric acid (see table 5). 3-Cycloamino group is a group attached at position 3, where the carbon atom at position 3 is attached directly to the nitrogen atom, this nitrogen atom is part of a heterocyclic ring.

Scheme 11

i) piperidine, Ti(OiPR)4, THF; NaBH4, MeOH; (ii) 80%acetic acid.

Synthesis of compound 109

The solution containing the ketone 108 (200 mg, 0.54 mmol), piperidine (266 μl, 2.68 mmol), 100 mg of molecular sieves, 3Å, NaBH3CN (24 mg, 0.38 mmol) and 5.4 ml Meon, stirred at room temperature for 24 hours. The reaction mixture was diluted with 20 ml of water and extracted with 2×20 ml of CH2Cl2. The combined extracts are washed with 10 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. Untreated, vases is in purify by radial chromatography, elwira 20% Meon/CH2Cl2and getting 112 mg (47%) of the compounds of formula 109 in the form of a white solid.

Synthesis of compound 110

The solution containing amines 109 (102 mg, 0.23 mmol) and 5 ml of 80%acetic acid, heated at 40°C for 1 hour. The solution is concentrated and the residue is placed in 2 ml of MeOH, diluted with 15 ml of toluene and concentrated. The residue is triturated with 5 ml of acetone, filtered and dried to obtain 44 mg (42%) of compound 110 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 402,31; C26H44NO2.

Synthesis of compound 111

Using the procedure described for the synthesis of compounds 109, the ketone 108 (200 mg, 0.54 mmol) is subjected to interaction with morpholine (234 μl, 2.68 mmol)to give 56 mg of amine intermediate. Amine intermediate connection process using 5 ml of 80%acetic acid at 40°C for 1 hour. The solution is concentrated, diluted with 5 ml MeOH and concentrated. Using1H and13C NMR studies reveal that the acetonide group was deleted, but the salt was formed a little or not at all formed. The substance is treated with 4 M HCl solution in dioxane (32 μl, 0.13 mmol) and 2 ml of acetone to obtain a white precipitate. The suspension was diluted with 2 ml of acetone, filtered and dried to obtain 48 mg (20%) with the organisations 111 in the form of a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 404,20; C25H42NO3.

Example 13

The transformation of 3-oxosteroid 3-second-aminosteroid

Any ketones, related to the connection 108 may be subjected to condensation with the amine using the methodology shown in scheme 12. Methylamine are added to a solution containing compound 108 and isopropoxide titanium in THF, followed by reduction with sodium borohydride. The solution is filtered and elute through MP-TsOH-resin receiving the connection 112 in the form of a mixture of isomers in C3. Treatment using HCl in acetonitrile and water leads to the formation of ammoniacloridegas salt 113. Connection 114-129 according to the example were synthesized using methods shown in scheme 12, except that instead of hydrochloric acid using acetic acid in the case of the examples according to which receive armeniaarmenia salt (see table 5).

Scheme 12

i) of methylamine hydrochloride, Ti(OiPR)4, THF; NaBH4, MeOH; ii) HCl, water, acetonitrile.

Synthesis of compound 112

Isopropoxide titanium (IV) (270 μl, of 0.92 mmol) is added under nitrogen atmosphere to a room temperature solution containing the ketone 108 (250 mg, 0.67 mmol), methylamine hydrochloride (41 m is, 0.61 mmol) and 1.5 ml of THF. After 12 hours, add a solution of NaBH4(65 mg, 1.7 mmol) in 2.3 ml of EtOH and interaction hold for another 10 hours. The reaction mixture was quenched by addition of 0.5 ml of water and filtered to remove a white precipitate. The solution is loaded onto a column containing 600 mg of MP-TsOH resin and elute 3 ml Meon, then 4 ml of 2 M NH3in the Meon. The fraction of NH3/Meon concentrate, receiving 76 mg (32%) of compound 112.

Synthesis of compound 113

The suspension containing compound 112 (76 mg, 0.21 mmol), 4 M HCl in dioxane (75 μl, 0.30 mol), 50 μl of water and 1 ml of acetonitrile, stirred at room temperature for 1 hour. The solution is filtered and dried solid substance, receiving 38 mg (13%) of compound 113 as a gray solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 348,19; C22H38NO2.

Synthesis of compound 114

Using the procedure described for the synthesis of compound 112, the ketone 108 (200 mg, of 0.53 mmol) is subjected to interaction with Propylamine hydrochloride (47 mg, 0.49 mmol)to give 72 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl, receiving 34 mg (17%) of compound 114. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 376,22; C24H42NO2.

<> Synthesis of compound 115

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with amylamine (70 μl, 0.61 mmol)to give 82 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl, receiving 75 mg (28%) of compound 115 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 404,28; C26H46NO2.

Synthesis of compound 116

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with cyclopentylamine (60 μl, 0.61 mmol)to give 99 mg of amine intermediate. Amine intermediate connection process using 200 μl of acetic acid for 1 hour, and diluted twice, and then concentrate from portions of toluene in a volume of 1 ml, the Residue triturated with 1 ml of cyclohexane, filtered and dried to obtain 98 mg (35%) of compound 116. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 402,27; C26H44NO2.

The synthesis of compound 117

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with cyclohexylamine (70 μl, 0.61 mmol)to give 120 mg of amine intermediate connection is possible. Amine intermediate connection process using 0.5 ml of acetic acid for 1 hour, and diluted twice, and then concentrate from portions of toluene in a volume of 1 ml of the resulting residue triturated with 1 ml of cyclohexane, filtered and dried to obtain 101 mg (32%) of compound 117. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 416,25; C27H46NO2.

Synthesis of compound 118

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with pyrrolidine (51 μl, 0.61 mmol)to give 70 mg of amine intermediate. Amine intermediate connection process using 50 ml of acetic acid for 1 hour, and add 1 ml of cyclohexane, receiving solid, which is filtered and dried to obtain 65 mg (22%) of compound 118. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 388,28; C25H42NO2.

Synthesis of compound 119

Using the procedure described for the synthesis of compound 112, the ketone 108 (200 mg, of 0.53 mmol) is subjected to interaction with N-propylethylenediamine (60 μl, 0.49 mmol)to give 99 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl, receiving 47 mg (20%) of compound 119. LC/MS (direct the management, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 419,32; C26H47N2O2.

Synthesis of compound 120

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with N,N-dimethylethylenediamine (65 μl, 0.61 mmol)to give 93 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl, receiving 77 mg (29%) of compound 120 in the form of a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 405,28; C25H45N2O2.

Synthesis of compound 121

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with piperazine (52 mg, 0.61 mmol)to give 33 mg of amine intermediate. Amine intermediate connection process using 200 μl of acetic acid for 1 hour, and diluted twice, and then concentrate from portions of toluene in a volume of 1 ml of the resulting residue triturated with 1 ml of cyclohexane, filtered and dried to obtain 39 mg (14%) of compound 121. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 403,23; C25H43N2O2.

Synthesis of compound 122

Using the procedure described for the synth is for connection 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with ethanolamine (33 μl, 0.61 mmol)to give 136 mg of amine intermediate. Amine intermediate connection process using 75 μl of solution in HCl, receiving 124 mg (50%) of compound 122 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 378,19; C23H40NO3.

Synthesis of compound 123

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with 5-amino-1-pentanol (63 mg, 0.61 mmol)to give 129 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl in getting 65 mg (24%) of compound 123 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 420,25; C26H46NO3.

Synthesis of compound 124

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with 2-(2-aminoethylamino)ethanol (62 μl, 0.61 mmol)to give 90 mg of amine intermediate. Amine intermediate connection process using 75 μl of a solution of HCl, receiving 79 mg (28%) of compound 124 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 the M NH 4OAc in a mixture of water with MeCN in the ratio 4:1): 421,24; C25H45N2O3.

Synthesis of compound 125

Using the procedure described for the synthesis of compound 112, the ketone 108 (200 mg, of 0.53 mmol) is subjected to interaction with m-toluidine (52 μl, 0.49 mmol)to give 95 mg of amine intermediate. Amine intermediate connection process using 75 μl of HCl solution to obtain 43 mg (19%) of compound 125. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 424,23; C28H42NO2.

Synthesis of compound 126

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with 4-aminophenol (67 mg, 0.61 mmol)to give 138 mg of amine intermediate. Amine intermediate connection process using 75 μl of HCl solution to obtain 41 mg (14%) of compound 126. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 426,18; C27H40NO3.

Synthesis of compound 127

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with sulfanilamide (105 mg, 0.61 mmol)to give, after purification by radial chromatography, 24 mg of amine intermediate. Amine intermediate connection process, the IP is using 75 μl of HCl solution to obtain 23 mg (7%) of compound 127. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 489,17; C27H41N2O4S.

Synthesis of compound 128

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with 3-aminomethylpyridine (62 μl, 0.61 mmol)to give 108 mg of amine intermediate. Amine intermediate compound is subjected to interaction with 1 ml of 80%acetic acid at 40°C for 1 hour. The reaction mixture was concentrated and diluted twice, and then concentrate 1 ml of toluene. The resulting residue triturated with 1 ml of cyclohexane, filtered and dried to obtain 117 mg (41%) of compound 128. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 425,24; C27H41N2O2.

Synthesis of compound 129

Using the procedure described for the synthesis of compound 112, the ketone 108 (250 mg, 0.67 mmol) is subjected to interaction with histamine (68 mg, 0.61 mmol)to give 120 mg of amine intermediate. Amine intermediate compound is subjected to interaction with 1 ml of 80%acetic acid at 40°C for 1 hour. The reaction mixture was concentrated and diluted twice, and then concentrate 1 ml of toluene. The resulting residue is twice triturated with ml. of cyclohexane, filtered and dried to obtain 128 mg (38%) of compound 129. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 428,23; C26H42N3O2.

Example 14

The transformation of 3-aminosteroid 3-acylaminoalkyl

Amide and sulfonamidnuyu analogues can be obtained from any amine, related to the connection 52. Figure 13 shows the synthesis of amide 131. Acetylation of amine 52 in CH2Cl2using the acid chloride of acetic acid and diethylamine associated with the resin, results in amide 130. Treatment with 80%acetic acid removes the acetonide groups receiving dihydroxylated 131.

Scheme 13

i) the acid chloride of acetic acid, PS-DIEA, CH2Cl2; PS-Trisamine; (ii) 80%acetic acid.

Synthesis of compound 130

The solution containing the amine 52 (100 mg, 0.28 mmol), the acid chloride of acetic acid (50 μl, 0.70 mmol), 440 mg of resin PS-DIEA and 2.4 ml of CH2Cl2, stirred at room temperature for 16 hours. The resin is filtered off and the filtrate is incubated for 2 hours with 260 mg of resin PS-Trisamine. The resin is filtered off and the filtrate concentrated. After purification by radial chromatography receive 69 mg (62%) of compound 130.

Synthesis of compound 131

The solution containing amide 130 (69 mg, 0,17 mmol) and 1 ml of 80% of the UKS the red acid, heated at 40°C for 1 hour. The reaction mixture was diluted twice and concentrated from 5 ml of toluene, and then once with 5 ml Meon and once with 1 ml of acetone and 5 ml of hexane to obtain 62 mg (62%) of compound 131 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 384,16; C22H35NNaO3, 362,20; C22H36NO3, 344,18; C22H34NO2.

Synthesis of compound 132

Using the procedure described for the synthesis of compound 130, the amine 52 (88 mg, 0.24 mmol) is subjected to interaction with benzoyl chloride (65 μl, of 0.56 mmol)to give 64 mg of the amide intermediate. The solution containing amide intermediate compound and 2 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was diluted twice and concentrated from 5 ml of toluene, and then once with 5 ml Meon and once with 1 ml of acetone and 5 ml of hexane to obtain 55 mg (55%) of compound 132 as a white solid (see table 3). LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 446,18; C27H37NNaO3, 424,29; C27H38NO3, 406,19; C27H36NO2.

Synthesis of compound 133

Using the procedure described for the synthesis of compound 130, the amine 52 (100 mg, 0.28 mmol) is subjected to vzaimode setiu with isopropylacetanilide (63 μl, 0,56 mmol)to give 38 mg sulfonamidnuyu intermediate compounds. The solution containing sulfonamidnuyu intermediate connection and 1.5 ml of 80%acetic acid, heated at 40°C for 1 hour. The reaction mixture was diluted twice and concentrated from 5 ml of toluene, and then once with 5 ml Meon and once with 1 ml of acetone and 5 ml of hexane to obtain 35 mg (29%) of compound 133 as not quite white solids (see table 3). LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 426,14; C23H40NO4S.

Synthesis of compound 134

Using the procedure described for the synthesis of compound 130, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with benzosulphochloride (90 μl, 0.70 mmol)to give 105 mg sulfonamidnuyu intermediate compounds. The solution containing sulfonamidnuyu intermediate connection and 2 ml of 80%acetic acid, heated at 40°C for 5 hours. The reaction mixture was diluted twice and concentrated from 5 ml of toluene, and then once with 5 ml Meon and once with 1 ml of acetone and 5 ml of hexane to obtain 83 mg (65%) of compound 134 as a white solid (see table 3). LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 482,11; C26H37NNaO4S, 477,17; C26H41N2O4S, 460,15; H38NO4S.

Example 15

3-Aceraminophen-6,7-hydroxy-17-italianthere

Figure 14 shows the synthesis of amide 135. The interaction of amine 83 with trimethylamine and a water-soluble complex form bioteknologi ether N-hydroxysuccinimide in methanol and water leads to the production of biotinylated amide analogue 135.

Scheme 14

i) sulfo-NHS-Biotin, Et3N, MeOH, water.

Synthesis of compound 135

The solution containing compound 83 (97 mg, 0.25 mmol), Et3N (104 μl, 0.75 mmol), sulfo-NHS-Biotin (120 mg, 0.27 mmol), 2.5 ml MeOH and 2.5 ml of water, stirred at room temperature overnight. The reaction mixture was concentrated and purified using column chromatography with reversed phase and elwira a mixture of 5% water/Meon, to obtain 89 mg (64%) of compound 135 as not quite white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 560,30; C31H50N3O4S.

Example 16

3-Urea-6,7-hydroxy-17-methodenstreit

Any amines, related to the connection 52 may be subjected to interaction with isocyanates or isothioscyanates obtaining compounds containing urea or timeonline functional groups. Connection 136, 137 and 138 are examples of ureas, which were sintesio the Ana using, shown in figure 15 (see table 3).

Scheme 15

i) phenylisocyanate, PS-Trisamine, CH2Cl2; (ii) 80%acetic acid.

Synthesis of compound 136

The solution containing the amine 52 (100 mg, 0.28 mmol), phenylisocyanate (76 μl, 0.70 mmol) and 2.4 ml of CH2Cl2, stirred at room temperature for 16 hours. The solution is incubated for 2 hours with 260 mg of resin PS-Trisamine. The resin is filtered off and the filtrate concentrated. After purification by radial chromatography receive 95 mg (71%) of compound 136.

Synthesis of compound 137

The solution containing urea 136 (95 mg, 0.20 mmol) and 2 ml of 80% acetic acid, heated at 80 C for 2 hours. The reaction mixture is diluted and concentrated from 5 ml of toluene, then with 5 ml Meon and then 5 ml of hexane. After purification by radial chromatography with elution with a mixture of CH2Cl2:Meon:Et3N in the ratio 95:5:2 receive 40 mg (33%) of compound 137. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 461,18; C27H38N2NaO3, 439,22; C27H39N2O3, 421,25; C27H37N2O2.

Synthesis of compound 138

Using the procedure described for the synthesis of compound 137, the amine 52 (100 mg, 0.28 mmol) is subjected to interaction with propositionem (52 μl, of 0.56 mmol), recip what I 72 mg urea intermediate. The solution containing urea intermediate connection and 2 ml of 80%acetic acid, heated at 80°C for 2 hours. The reaction mixture was diluted twice and concentrated from 5 ml of toluene, and then once with 5 ml Meon and once with 5 ml of hexane to obtain 51 mg (45%) of compound 138 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 427,21; C24H40N2NaO3, 405,25; C24H41N2O3.

Example 17

3-Urea-6,7-hydroxy-17-dimethylpyridine steroid

Any other compounds related compounds 88 or 89, can undergo a rearrangement using methods shown in scheme 16. Processing connection 88 is heated to 50°With hydrochloric acid in methanol and water leads to the removal of the acetonide protective groups in promoting migration of the 18-methyl group to the atom R17 and education ammoniacloridegas salt 139. Treatment of compound 89 in the same conditions leads to the connection 139. Compounds according to examples 140-148 were synthesized as described in scheme 16 (see table 4).

Scheme 16

i) HCl, water, methanol, 50°C.

Synthesis of compound 139

The solution containing compound 88 (300 mg, 0,834 mmol), 4 drops of concentrated HC, 2 ml methanol and 2 ml of water, heated at 50°C for 72 hours. The reaction mixture was concentrated and the residue double-dilute and concentrated from 5 ml of methanol. The residue is treated using 2 ml of methanol, diluted with 15 ml of acetone and concentrated. The resulting residue is triturated with 5 ml of acetone, filtered and dried, obtaining 286 mg (96%) of compound 139 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 320,20; C20H34NO2.

Synthesis of compound 139

Using the procedure described for the synthesis of compound 139 from compound 88, is subjected to the interaction of compound 89, receiving 145 mg (77%) of compound 139 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 320,20; C20H34NO2.

Synthesis of compound 140

Using the procedure described for the synthesis of compound 99, Amin 88 (200 mg, 0.55 mmol) is subjected to interaction with m-Truelove aldehyde (90 μl, 0.61 mmol). After purification by radial chromatography with elution with a mixture of 5% Meon/EtOAc obtain 127 mg of amine intermediate. The solution containing amine intermediate compound, 4 drops of concentrated HCl, 1 ml MeOH and 1 ml of water, heated at 50°C for 20 hours. The reaction mixture three times resbala is t, and then concentrated from 5 ml MeOH and once with 5 ml of acetone, receiving 74 mg (30%) of compound 140 as not quite white foam. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 424,24; C28H42NO2.

Synthesis of compound 141

Using the procedure described for the synthesis of compound 99, Amin 88 (200 mg, 0.55 mmol) is subjected to interaction with 3,4-diferentialglea (67 μl, 0.61 mmol). After purification using radial chromatography elwira a mixture of 30% EtOAc/hexane obtain 88 mg of amine intermediate. The solution containing amine intermediate compound, 4 drops of concentrated HCl, 1 ml MeOH and 1 ml of water, heated at 50°C for 20 hours. The reaction mixture was diluted three times, and then concentrated from 5 ml MeOH and once with 5 ml of acetone, receiving 73 mg (28%) of compound 141 as not quite white foam. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 466,42; C27H38F2NO2.

Synthesis of compound 142

Using the procedure described for the synthesis of compound 59, Amin 49 (200 mg, 0.55 mmol) is subjected to interaction with 3,4-dimethoxybenzaldehyde (70 μl, 0.61 mmol). After purification using radial chromatography elwira a mixture of 40% EtOAc/hexane to obtain 67 mg of amine intermediate. Dissolve the, containing intermediate amine, 4 drops of concentrated HCl, 1 ml MeOH and 1 ml of water, heated at 50°C for 20 hours. The reaction mixture was concentrated and the residue diluted three times, and then concentrated from 5 ml MeOH and once with 5 ml of acetone, receiving 43 mg (16%) of compound 142 in the form of a yellow solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 470,27; C29H44NO4.

Synthesis of compound 143

The solution containing the compound 28 (200 mg, 0,540 mmol), 4 drops of concentrated HCl and 3 ml of water, heated at 50°C for 72 hours. The reaction mixture was concentrated and the residue diluted three times, and then concentrated from 5 ml of methanol. The resulting residue is treated with 3 ml of methanol, diluted with 20 ml of acetone and concentrated. The resulting residue is triturated with 10 ml of acetone, filtered and dried, obtaining 179 mg (90%) of compound 143 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 334,20; C21H36NO2.

Synthesis of compound 144

Isopropoxide titanium (IV) (270 μl, of 0.92 mmol) is added to a room temperature solution containing the ketone 108 (250 mg, 0.67 mmol), aniline (56 μl, 0.61 mmol) and 1.5 ml of THF in an argon atmosphere. After 12 hours, add a solution of NaBH4(65 mg, 1.7 mmol) 2.3 the l EtOH and interaction is carried out for a further 8 hours. The reaction mixture was quenched by addition of 0.5 ml of water and filtered to remove a white precipitate. The solution is loaded onto a column containing 600 mg of MP-TsOH resin and elute 9 ml Meon, then 9 ml of 2 M NH3in the Meon. The fraction of NH3/Meon concentrated, the residue is placed in 4 ml of THF, treated, using 500 mg of resin containing PS-benzaldehyde, and filtered to remove residual aniline. The solution is concentrated and the residue is placed in 2 ml of a mixture in the ratio of 9:1 THF and water, and 100 μl of concentrated HCl. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue is triturated with 1 ml of cyclohexane, filtered and dried, obtaining 62 mg of compound 144 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 410,03; C27H40NO2.

Synthesis of compound 145

Using the procedure described for the synthesis of compound 144, the connection 108 (250 mg, 0.67 mmol) is subjected to interaction with 3-(trifluoromethyl)aniline. The intermediate product was then purified using radial chromatography and then subjected to interaction with 100 µl of concentrated HCl in 2 ml of a mixture of THF and water in the ratio of 9:1. After stirring at room temperature overnight, the reaction mixture was concentrated, the obtained residue R is washed with 1 ml of cyclohexane, filtered and dried, obtaining 23 mg of compound 145 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 477,94; C28H39F3NO2.

Synthesis of compound 146

Isopropoxide titanium (IV) (216 μl, 0.73 mmol) is added to a room temperature solution containing the ketone 108 (200 mg, 0.54 mmol), benzylamine (53 μl, 0.49 mmol) and 1.2 ml of THF in an argon atmosphere. After 12 hours, add a solution of NaBH4(52 mg, 1.4 mmol) in 1.7 ml EtOH and interaction should be performed within 6 hours. The reaction mixture was quenched by adding 1 ml of water and filtered to remove a white precipitate. The solution was diluted with 70 ml of CH2Cl2, washed with 10 ml of water and 20 ml saturated sodium chloride solution, dried over MgSO4filter and concentrate. After purification by radial chromatography, elwira consistently 20% EtOAc/hexane, EtOAc and then with a mixture of CH2Cl2/Meon/Et3N in the ratio 95:5:2, obtain 127 mg 3α-amine intermediate and 26 mg 3β-amine intermediate. The solution containing 127 mg 3α-amine intermediate compound, 1 ml of a mixture of THF and water in the ratio of 9:1 and 0.1 ml of concentrated HCl, stirred at room temperature overnight. The reaction mixture was concentrated, the residue is placed in 5 ml of MeOH is concentrated. The resulting residue triturated with 1 ml of cyclohexane, filtered and dried, obtaining 118 mg (95%) of compound 146 as a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 424,20; C28H42NO2.

Synthesis of compound 147

A solution containing 26 mg 3β-amine derivative, the synthesis of which was described in the synthesis of compound 146, 1 ml of a mixture of THF and water in the ratio of 9:1 and 0.1 ml of concentrated HCl, stirred at room temperature overnight. The reaction mixture was concentrated, the residue is placed in 5 ml of MeOH and concentrated. The resulting residue triturated with 1 ml of cyclohexane, filtered and dried, obtaining 26 mg (100%) of compound 147 in the form of a white solid. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 424,21; C28H42NO2.

Synthesis of compound 148

A solution of compound 78 (63 mg, 0.18 mmol), 4 drops of concentrated HCl, 1 ml methanol and 1 ml of water is heated at 50°C for 48 hours. The reaction mixture was concentrated, the obtained residue twice placed in 5 ml of methanol and concentrated. The residue is placed in 2 ml of hexane, concentrated and dried for 2 hours using the device Abderhalden for drying, irrigation acetone, receiving 69 mg (100%) of compound 148 as a white solid prophetic is TBA. LC/MS (direct introduction, elektrorazpredelenie +ve, 10 mm NH4OAc in a mixture of water with MeCN in the ratio 4:1): 348,20; C22H38NO2.

Table 1
Connection3α- or 3β-NH2R1R2R3HAHex IC50(µm)Calcium (% inhibition at 20 μm)
49αCH3HHHCl11,026,8
53αHHHAcOH17,6-0,8
54αHHHHCl16,119,8
64αCH3FHHCl14.4V6,7
69αHCO2CH3HAcOHof 21.211,2
28βCH3HHHCl 6,829,0
83βCH3HHAcOH7,730,3
89βHHHAcOH11,515,0
95βCH3FHHCl13,511,2
78αHHCH3No20,15,3
79αHHCH3HCl18,49,1
80αHHCH3AcOH10,77,4

td align="center"> AcOH
Table 2
Connection3α- or 3β-NH2R1R2HAHex IC50(µm)Calcium (% inhibition at 20 μm)
70αOOThe concentration is7,0
72αOHHAcOHThe concentration is10,3
96βCH3CH2HHCl7,847,9
97αCH3CH2HHCl9,343,0

Table 3
Connection3α- or 3β-NH2R1R2R3Hex IC50(µm)Calcium (% inhibition at 20 μm)
131αHHCH3CO14,19,9
132αHHC6H5CO10,019,6
133αHH(CH3)2CHSO215,913,8
134αHHC6H5SO2 16,725,1
135βCH3H15,137,3
137αHHC6H5NHCO14,813,0
138αHHCH3(CH2)2NHCO15,09,0

Table 4
Connection3α- or 3β-NH2R1R2R3R4Hex IC50(µm)Calcium (% inhibition at 20 μm)
139βCH3CH3HH10,326,3
140αCH3CH3H3-(CH3)C6H4CH210,2a 21.5
141αCH3CH3H 3,4-(F)2C6H3CH29,436,3
142αCH3CH3H3,4-(CH3O)2C6H3CH215,913,8
143βCH3CH3CH2HH8,622,6
144α and βCH3CH3CH2HC6H56,913,0
145α and βCH3CH3CH2H3-(CF3)C6H422,0-0,2
146αCH3CH3CH2HC6H5CH29,041,7
147βCH3CH3CH2HC6H5CH218,136,3
148αCH3CH3CH3H29,26.6m

Table 5
ConnectionRHAHex IC50(µm)Calcium (% inhibition at 20 μm)
110AcOH10,939,7
111HCl9,353,1
113CH3NHHCl9,845,0
114CH3(CH2)2NHHCl10,2of 37.9
115CH3(CH2)4NHHCl11,140,0
116C5H9NHAcOH9,660,9
117C6H11NHAcOH6,642,2
118AcOH11,041,8
119CH3(CH2)2NH(CH2)2NH2HCl6,154,5
120 (CH3)2N(CH2)2NH2HCl9,144,0
121AcOH14.4V42,4
122HOCH2CH2NHHCl12,3of 31.4
123HOCH2(CH2)4NHHCl16,712,8
124HOCH2CH2NHCH2CH2NH2HClThe concentration is21,0
1253-(CH3)C6H4NH2HCl39,4the 5.7
1264-(HO)C6H4NHHClthe 9.745,0
1274-(H2NSO2)C6H4NHHClthe 10.129,4
128AcOH10,541,0
1292AcOHN.A.13,8

Table 6
Obedinenie RHAHex IC50(µm)Calcium (% inhibition at 20 μm)
1004-((CH3)2CH)C6H4AcOH18,233,2
1012(F)C6H4AcOH10,316,3
1023-(CF3)C6H4AcOH10,09,5
1032-(CH3O)C6H4AcOH11,123,7
1044-(CH3O)C6H4AcOH9,530,3
1053-(C6H5O)C6H4AcOH22,510,2
1063-(NO2)C6H4No8,88,1
1073-C5H4N2HCl17,2the 11.6
The concentration - not determined
N.A. - not active

Examples of the application

Example

The effect of some compounds on allergen-induced inflammation of the lungs

The ability of compounds to inhibit induced allergological cells inflammation zone, such as eosinophils and neutrophils in the circulating fluid, obtained from sensitized animals, an indication that the compound has anti-asthma activity. In particular, this model system is suitable for evaluating the effect of test compounds to treat in the later stages of the inflammatory asthmatic reactions when pneumonia and bronchostenosis are obvious. The test was carried out as follows.

Rats-males line Brown Norway was senzibilizirani to ovalbumin single intraperitoneally injection of 1 mg of ovalbumin, adsorbirovannogo 100 mg Al(OH)3in 1 ml of sterile saline (rat - control group with saline - received only sterile saline solution) on the first day (day 1) and take account of sensitization to day 21. Test compounds were administered orally daily for three days prior to the introduction of provocative tests (days 19, 20, 21) and one day after the introduction of provocative tests (day 22), and the third dose was given 2 hours before the introduction of provocative tests, fourth daily dose was given 24 hours after the introduction of provocative tests (volume = 300 μl/dose). As provocative tests for the rats used 0.5% ovalbumin in saline solution, generated using an atomizer DeVilbiss within 60 minutes per day 21.

After 48 hours the s after the introduction of provocative tests, animals were killed using an excessive dose peritoneal pentobarbital, then the lungs were washed 2×7 ml of cold phosphate buffered saline. The resulting washing liquid was placed on ice. Bronchoalveolar washing fluid was centrifuged, the supernatant was removed. The precipitate was respondible in phosphate buffered saline at 4°C. Cytocentrifugation cooked preparations and stained for differentiation and counting of cell types.

Data showing a protective effect of various test compounds on allergen-induced inflammation of the lungs, are shown in tables 7 and 8. The influence of the dose caused by the reaction of some of the compounds shown in table 9. The tested compounds were introduced into 300 μl of corn oil (tables 7 and 8) or in water (table 9), which was used as the carrier. Control animals received 300 μl of corn oil or water only, i.e. they were not given the drug. The data in tables 7, 8 and 9, represent the percentage of inhibition of the accumulation of leukocytes in relation to the inhibition of the control animals. Negative values in tables 7, 8 or 9 indicate a worsening effect compared to control animals.

Table 7
The influence of testere the s compounds (5 mg/kg/day for 4 days, oral) on ovalbumin-induced accumulation of cells in areas of inflammation in the liquid for washing the lungs, obtained from sensitized rats Brown Norway
Connection% inhibition of eosinophils% inhibition of neutrophil% inhibition of lymphocyte
83673438
97405256
96-94019
64627081
89576064
288587124
53245713
95144530
49523673
1352058107

Table 8
The effect of the test compounds (1 mg/kg/day for 4 days, orally) on ovalbumin-induced accumulation of cells in areas of inflammation in the liquid for washing the light received from the CE is sebilisian rats Brown Norway
Connection% inhibition of eosinophils% inhibition of neutrophil% inhibition of lymphocyte
142-131-1-42
54-82-19-7
107-12223-28
124-55-76-26
129-296-114-71
146824-27
147405836
131165721
138-523533
133-434028

Table 9
The influence of some compounds depending on their dose (different dosage, 4 days daily, orally) on ovalbumin-induced accumulation of cells in areas of inflammation in the liquid for washing the lungs, obtained from sensitized rats Brown Norway
Connection



(mg/kg)
% inhibition of eosinophils% inhibition of neutrophil% inhibition of lymphocyte
10,30,10,0310,30,10,0310,30,10,03
89718035-667225-6702-
2860712954166-10-26708550-5
139424146-636242-563419-
143482928-642557-22-37-43-

The example In

The effect of compound 83 on induced irritant tool ear oedema in mice

A number of mice unequivocally ID manually is provoked by the application of a label on the tail with a marker for applying indelible marks. Mice orally was administered 15 mg/kg of test compound in 100 μl of 45% β-cyclodextrin in saline solution. Mice short subjected to anesthesia with 2% halothane gas and deposited on the inner and outer sides of the left ear of the mouse 2 µg of phorbol-12-myristate-13-acetate in 25 μl of acetone. On the right ear of the mouse in exactly the same way they applied the acetone, which served as the control medium. With the control animals was carried out by the same procedure, but without the test compound. After 3 hours, mice were killed by displacement of the cervical spine was dissected from each ear a standard sample for biopsy and weighed with an accuracy up to 1/10 th of a milligram. The obtained data were analyzed, determining the difference between the data for the left and right ear and calculating % inhibition of edema ((average Rx/average value with the irritating agent) × 100)-100.

Compounds of the present invention showing a protective effect against induced irritant means of ear oedema in mice. For example, the connection 83 inhibits induced irritant tool ear oedema in mice by 38% compared to control animals.

The example

The influence of compounds on the release of hexosaminidase from the fat cells of the rat line (RBL-2H3)

Anti-allergic effects of the compounds of the present invention is assessed and, measuring antigen-induced secretion of hexosaminidase from passively sensitized line of fat cells in rats. The ability of test compounds to inhibit the release of the contents of the fat cells, such as histamine and hexosaminidase is a sign of anti-allergic and/or antihistaminic activity of the compounds. Hexosaminidase released from fat cells with histamine and other mediators in provocative introduction of antigen. The test is as follows.

Cell line RBL-2H3 grown in culture and passively sensibiliser for 1 hour at 37°to dinitrophenol (DNP), using human antibodies to DNP (IgE). Cells incubated with test compound for 30 minutes at 37°and stimulate using 0.5 μg/ml DNP-HSA (antigen) for 30 minutes. Take an aliquot of the supernatant and used for measuring the quantity of hexosaminidase released by provocative introduction of antigen. The number of hexosaminidase present in the supernatant, determine colorimetrically by controlling enzymatic metabolism of p-nitrophenyl-N-acetyl-β-D-glucosaminide (p-NAG) for 60 min at 405 nm. The impact of each of the tested compounds is defined as the percentage of induced antigen reaction (minus background release) to implement the tion in the presence of only DMSO. These values are used to determine the degree of inhibition induced by antigen release hexosaminidase of cells.

Compounds of the present invention exhibit the ability to inhibit induced antigen release of hexosaminidase in response to stimulation by antigen. Compounds were tested at concentrations of 0.3, 3, 10 and 30 μm and determined the size of the IC50. These data are shown in tables 1-6. For example, the connection 119 at a concentration of 6.1 μm inhibits release of hexosaminidase as a response to stimulation by antigen by 50%.

Example D

Metabolic stability of some compounds in the fractions S9 person

therapeutic efficacy of test compounds can often be directly linked to its metabolic stability in vivo. The most well-known available on the market drug undergoes metabolism under the influence of a group of enzymes known as P450 enzymes. Fraction S9 human liver contains all the P450 enzymes, as well as cytoplasmic enzymes that can participate in the metabolism of new chemical substances. The study of metabolism in vitro using fraction S9 person is a common study of the metabolic stability of the new compounds. The test is as follows.

Reagents razmorazhivayutsya ice and mixed to prepare the reference mixture as follows: potassium phosphate (100 mm, pH 7), G6P (0.25 mm), G6PDH (2 U/ml), NADPH (1 mm), UDP (0.25 mm), APSS (0.25 mm) and the fraction S9 (2 mg/ml). A master mix was dispensed into 498 μl in each tube to microcentrifuge. The test compound is distributed in the amount of 2 μl of a 2.5 mm solution (final concentration 10 μm) in the center of the cover corresponding tubes and lid gently close thus to prevent mixing. Simultaneous mixing of the tested compounds and the reference mixture is achieved by tenfold inversion of the tubes, which are then incubated at 37°C and shaken at 150 rpm during the appropriate time of incubation. While incubation is carried out, all the original samples ("time 0") separately mixed, turning three times, with immediate addition of 500 μl of chilled on ice acetonitrile and rolling three times, in order to stop the reaction. Immediately after the expiration of every 15 minutes and 30 minutes incubation complete, each tube add chilled on ice acetonitrile and the contents of the tubes are stirred, turning them three times. All test tubes with samples incubated at -80°C for at least 15 minutes, defrost and re-stirred, turning over. Aliquots 650 μl is transferred to a chromatographic clean test tube filter system with microcentrifuge the eat (nylon membrane, 0.2 μm, S) and centrifuged at 13,000 rpm for 48 seconds. The leachate samples stored at -80°C.

The leachate samples will be analyzed by the instrument for LC/MS and calculate the percentage of the substance remaining after incubation for 15 and 30 minutes, regarding the content of this substance by incubation at "time 0".

Data characterizing the metabolic stability, are given in table 10 as a percentage of the substances remaining after incubation for 15 and 30 minutes to fractions of human liver S9.

Table 10
Metabolic stability of some compounds after 15 and 30 minutes incubation with fractions of human liver S9 as a percentage of the initial number of connections by incubation at "time 0"
ConnectionRemaining after 15 min, %Remaining after 30 min, %
8392±1991±21
9794±1089±12
9692±1994±21
89100±1798±16
28100±6104±12
4993±685±8
64 104±488±5
139109±26100±10
143100±399±10
14682±663±9
10784±562±6
14280±1155±2
6973±2463±6
10453±1056±18
141100±926±4
13485±5436±15
13793±3171±17
13871±465±65
13260±1740±9
7967±661±14

Example E

The solubility of some compounds in a physiologically compatible compositions

Compounds of the present invention have good solubility in water. For example, the connection 83 soluble in water at a concentration of 225 mg/ml of Compound 83, substituted hydroxyl group at C3, has a solubility in water less than 60 μg/ml of Compounds 28 and 89 are characterized by a solubility at room temperature, equal to ˜30 mg/ml, cat heaven can be significantly increased when heated. These unexpectedly discovered properties suggests that the 3-amino compounds can be easily put into the form of pharmaceutical compositions.

Example F

The influence of some of the tested compounds induced by antigen transfer of calcium

Increasing the calcium concentration in the cytoplasm is a common and crucial phenomenon which accompanies the activation of many types of cell-surface receptors. The increase in intracellular calcium that occurs after agonistic activation of hydrolysis of inositides is caused by the release of calcium from the endoplasmic reticulum and the transfer of calcium across the cell membrane. Increasing the calcium concentration in the cytoplasm is associated with many important reactions of cells in the inflammatory process, including adhesion, motility, gene expression, proliferation and degranulation. Changes in intracellular calcium concentration can affect both quick and long reaction cells. The methodology of the study, designed to evaluate the effects of test compounds on the transfer of calcium is as follows.

Cells Jurcat clone E6.1 grown in RPMI medium supported 10% FBS and 2 mm L-glutamine, transferred into a conical tube with a capacity of 50 ml and centrifuged for 5 minutes at 900 rpm for the formation of a precipitate glue is OK. The resulting supernatant cast, and each residue is washed with 10 ml of HBSS. Collect the cell suspension and centrifuged for 5 minutes at 900 rpm for the formation of a precipitate cells. The obtained supernatant discarded, and the precipitate resuspended in HBSS with 1×107cells/ml cell Suspension is transferred into a 20 mm Petri dishes and incubated at 37,5°C, 5% CO2within 20 minutes.

One volume of Fura 2AM mixed with one volume of the detergent Pluronic F127 (Pluronic F127). In the cell enter the label, using 4 μl of the solution for injection marks on each milliliter of cell suspension. The Petri dish wrapped in aluminum foil to protect from light and placed in the apparatus for shaking tablets for 30 min at room temperature.

The subsequent stage is carried out in a laminar box off the fluorescent lighting. Petri dishes are removed from the apparatus for shaking, labeled cell suspension is transferred into a conical tube with a capacity of 15 ml and twice washed with HBSS as described above. Sediment cells resuspended in 12 ml of HBSS and leave wrapped in foil for 30 minutes at room temperature. Labeled cell suspension in the form of an aliquot (100 μl/well) is transferred into a 96-well white opaque tablet for tissue culture firm Dynex (Dynex). In appropriate wells add 50 ál ka the Dogo test sample and then incubated together for 10 minutes at 37° With the apparatus for reading tablets Wallac 1920 VictorTM(the test samples prepared in HBSS with 20 mm, final concentration 20 μm). The selected connection test on the effect of dose on a corresponding reaction. The tested samples and the activator (anti-CD3 mAb c final concentration of 4 μg/ml, PharMingen) add manually (50 μl) in such a way that the minimum time to obtain the first result after stimulation was approximately 30 seconds. The reaction to the transfer of calcium in response to anti-CD3 mAb measure, conducting research in the endpoint. Fully tablet read for 100 seconds at a speed of 1 hole per second.

The tablet read before adding anti-CD3 in order to control for nonspecific effects samples/drugs. Fluorescence emission was measured at 510 nm upon excitation, varying from 340 to 380 every second using a filter pair excitation/emission. Data for these pairs of wavelengths present in the form of a ratio corresponding to 2 (two) excitation wavelengths. This ratio depends on the dye inside the cells and concentration cells, allowing you to make a real comparison of data from different experiments. Data showing the effect of some compounds on the transfer of calcium to expose what's the impact of allergen cells Jurkat clone E6.1, given in tables 1-6. For example, the connection 116 inhibits calcium 60.9% at a concentration of 20 μm. The value of the IC50to connect 119 is less than or equal to 10 μm, in the case when investigating the effect of dose on response. This suggests that a significant impact on the migration of calcium could be useful in the case of some painful conditions, in which calcium is an important second mediator or effector molecule, including, but not limited to, ischemia, circulatory disorders, such as stroke or myocardial infarction, inflammatory diseases such as asthma or allergies, nerve or muscle disorders, such as Parkinson's disease or epilepsy, cardiac arrhythmia, or hypertension.

Example G

The effect of some compounds on allergen-induced changes in the functioning of the lungs

In asthma the initial response to the introduction of the allergen is characterized by what is happening directly after bronchoconstrictive, which reaches a peak at 20-30 min after exposure to the stimulus and which usually can be removed after approximately 2 hours. Anti-inflammatory drugs, as a rule, are not active bronchodilatory means and not very effective for control of acute asthma bronchoconstriction. This leads to the need of the spine combined modality therapy for treatment as bronchoconstriction, and inflammation.

Guinea pigs line Cam-Hatley was senzibilizirani to ovalbumin (OA) in groups of 5-6 individuals, exposing the impact sprayed in a spray solution of 1% OA in saline solution for 15 min on two consecutive days using a DeVilbiss atomizer in combination with an additional single intradermal injection of 3 μg of OA in saline on the first day (day 1). As was found, the peak sensitization animal to the antigen is observed after 14 days after initial exposure. On the 14th day (day 14) animals were first anestesiologi using ketamine (50 mg/kg intraperitoneally) and xylazine (100 mg/kg intraperitoneally), and then maintained using a 1% halothane entered with a conical tip in the nose. The left carotid artery candleroom, using a system of tubes RE containing 200 IU/ml heparin in saline solution. Perform a tracheostomy and enter into the esophagus by a fluid-filled cannula (PE 160) approximately 7 see the Animal is placed in plethysmography (instrument for recording changes in the volume of a single organ) and the trachea attached to fixed in the casing tracheal tube of stainless steel. The carotid cannula attached to a pressure transducer for monitoring blood pressure and heart rate. In Guinea-pig cause paralysis using pancuronium is Rome (0.8 mg/kg), and ventilate the air with a frequency of 60 Hz and served with a volume of 3 ml using a small Harvard apparatus for artificial ventilation of the lungs of animals.

Data were obtained during a 20-second periods with a sampling rate of 100 Hz on a computer connection physiological recording device using physiological software DIREC and were analyzed using the software ANADAT. Values of the resistance and dynamic lung compliance were obtained from the data signals characterizing the volume, plasticity and the pressure in the lungs in accordance with the method of the Background Niguarda and Wirtz (Von Neeguard & Wirz, 1927), using for analysis isovolumetric multipoint regression models (Ludwig, Robatto et al., 1991) and absolute changes in lung resistance (RLcm H2O/ml/sec) or lung compliance (CDYN, ml/cm H2About). The signals characterizing the volume and the pressure was calibrated before each set of experiments in accordance with standard procedure.

Some measurements related to the functioning of the lungs, carried out in 5-10 minutes, to ensure the stability of the base line, after which the animal was injected provocative test with OA (2% in saline), administered in six (6) volumes of air, obmenivalas is in a single breath in the form of a spray or aerosol at a flow rate of 5 l/min Functioning of the lungs and vascular system were subjected to continuous monitoring throughout the experiment, although the data were collected at defined time points after injection of antigen (10 sec, 1, 2, 3, 4, 5, 10, 20 and 30 min).

The test compounds were injected with light anesthesia with halothane gas when introduced through the probe (0.1-1.0 mg/kg/day, every day) in 300 ml of polyethylene glycol-200 for 4 days to generate the sample, and the last dose was administered 2 hours prior to injection of antigen provoking samples.

Protective effects of selected test compounds on allergen-induced bronchoconstriction shown in Fig. 4 and 5. The duration of activity of compound 89 shown in Fig. 6 and 7. Data are presented as median values ± the standard deviation from the mean. Inhibition of bronchoconstriction with the test compounds could be useful in some diseases, in which is manifested the strong contraction of smooth muscles in response to the introduction of the allergen, such as asthma and allergies.

All publications and patent applications mentioned in the present description, given in reference to the same extent, as if each individual publication or patent application was specifically and individually was included as SS is the CTL. For example, the book in Comprehensive Organic Transformations, A Guide to Functional Group Preparations, Second Edition, Richard C. Larock, John Wiley and Sons, Inc., 1999, and some of the links separately included in the present description as a reference in their entirety.

Based on the above should take into account the fact that although for purposes of illustration in this description of some specific embodiments of the present invention may be implemented with various modifications, without departing from the essence and scope of the present invention. Therefore, the invention is limited only to the above claims.

1. 3-Amino-6,7-decelerometers steroids of General formula

and their pharmaceutically acceptable salt, solvate, stereoisomer, where in each case independently

R1and R2selected from hydrogen, possibly substituted alkyl, aryl, heteroalkyl, where the heteroatom is a nitrogen atom, heteroaryl, where the heteroatom is selected from nitrogen, oxygen and sulfur, or

R1and R2may together with the N atom to which they are both attached, form a heterocyclic structure which may be part of an organic group containing 6-12 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen and oxygen;

R3and R4 selected from hydrogen or a protective group, provided that R3and/or R4represent a part of the protective group of hydroxyl;

numbers from 1 to 17 each represents a carbon atom, where carbon atoms numbered 1, 2, 4, 11, 12, 15, 16 may be independently substituted by two of the following groups, which are selected independently: -R5;

the carbon atom number 17 may be independently replaced with:

(a) one of the groups: =C(R5)(R5), =C=C(R5)(R5); or

(b) two of the following groups, which are selected independently: -R5and-OR6;

and where the carbon atoms numbered 5, 8, 9, 10, 13 and 14 may be independently substituted one of the groups-R5; where

R5in each case independently selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane;

R6represents hydrogen or a protective group, such that-OR6represents a protected hydroxyl group, where vicinal groups OR6may together form a cyclic structure which protects vicinal hydroxyl groups.

2. The compound according to claim 1, in which

numbers from 1 to 16 each represent a carbon atom, where carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 can be independently replaced two of the following groups, which are selected independently: R 5;

the carbon atom number 17 substituted:

(a) one of the groups: =C (R5a)(R5a), =C=C(R5a)(R5a); or

(b) two of the following groups, which are selected independently from: -R5a;

where R5ain each case independently selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane.

3. The compound according to claim 2, in which R5ain each case independently selected from hydrogen, C1-6of alkyl, C1-6halogenoalkane.

4. The compound according to any one of claims 1 to 3, in which R1and R2selected from hydrogen, possibly substituted alkyl, aryl, heteroalkyl, where the heteroatom is a nitrogen atom, heteroaryl, where the heteroatom is selected from nitrogen, oxygen and sulfur, or

R1and R2may together with the N atom to which they are both attached, form a heterocyclic structure which may be part of an organic group containing 6-12 carbon atoms and optionally containing 1-6 heteroatoms selected from nitrogen and oxygen.

5. The compound according to any one of claims 1 to 4, in which the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom number 13 replaced by stands.

6. Obedinenie according to claim 1, in which R1and R2represent hydrogen; R3and R4selected from hydrogen or a protective group, such that R3and/or R4are part of the protection of hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogens;

the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom;

the carbon atom number 10 replaced by stands;

the carbon atom number 13 replaced by stands;

the carbon atom number 17 independently replaced with:

(a) one of the groups: =C(R5)(R5), =C=C(R5)(R5); or

(b) two of the following groups, which are selected independently: -R5and-OR6;

R5in each case independently selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane;

R6represents hydrogen or a protective group, such that-OR6represents a protected hydroxyl group, where vicinal groups OR6may together form a cyclic structure which protects vicinal hydroxyl groups.

7. The connection according to claim 6, in which R1and R2represent hydrogen; R3and R4selected from hydrogen or a protective group, such that R3and/or R4represent a part of the protective groups is hydroxyl; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom number 13 replaced by stands; the carbon atom number 17 independently substituted: (a) one of the groups: =C(R5)(R5), =C=C(R5)(R5); or (b) two of the following groups, which are selected independently: -R5and-OR6; R5in each case independently selected from hydrogen, C1-6of alkyl, C1-6halogenoalkane.

8. The connection according to claim 7, in which R1and R2represent hydrogen; R3and R4selected from hydrogen and protective groups, so that R3and/or R4are part of the protection of hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom; the carbon atom number 10 replaced by stands; the carbon atom number 13 replaced by stands; the carbon atom number 17 substituted: (a) one of the groups: =C(R5)(R5or (b) two of the groups R5; R5in each case, independently, selected from H and C1-6the alkyl.

9. The connection according to one of claims 1 to 8 the following formula:

10. The connection according to one of claims 1 to following formula:

11. The connection according to one of claims 1 to 8 the following formula:

12. The connection according to one of claims 1 to 8 the following formula:

13. The connection according to one of claims 1 to 8 the following formula:

14. The connection according to one of claims 1 to 8 the following formula:

15. The compound according to claim 1, in which the atom number 17 substituted by a group C=(R5)(R5); R5selected from hydrogen, C1-6of alkyl, C1-6hydroxyalkyl.

16. The compound according to claim 1, in which the atom number 17 is substituted by two of the following groups: C1-6alkyl or C1-6halogenated.

17. The compound according to claim 1, in which the atom number 17 substituted by a group-OR6or =O, where R6represents hydrogen.

18. The compound according to claim 1, in which R1selected from-C(=O)-R7, -C(=O)NH-R7, -SO2-R7; where R7selected from alkyl, heteroalkyl, aryl and heteroaryl, these substituents are defined in claim 1.

19. Connection p, in which R7selected from C1-6the alkyl.

20. The connection according to claim 19, in which R7includes Biotin.

21. The compound according to claim 1, in which R1) (R2N - select from:

and

22. The compound according to claim 1, in which R1is hydrogen and R2includes carbocycle.

23. Connection p.22, in which carbocycle represents phenyl.

24. The compound according to claim 1, in which R1is hydrogen and R2includes C1-6alkyl.

25. The compound according to claim 1, in which R1is hydrogen and R2is heteroalkyl, where the heteroatom is a nitrogen atom.

26. Connection A.25, in which R2choose from C1-3alkyl-W-C1-3alkylene-, where W represents NH; -- WITH1-6alkylene-.

27. The compound according to claim 1, in which R1represents hydrogen, and R2represents-CH2-R7where R7selected from alkyl, heteroalkyl, aryl and heteroaryl.

28. Connection item 27, in which R7selected from C1-6, alkyl substituted phenyl, halogen-substituted phenyl, C1-6alkoxy-substituted phenyl.

29. The compound according to claim 1, in which each of R1and R2represents hydrogen.

30. The compound according to claim 1 or 29, in which each of R3and R4represents hydrogen.

31. The connection clause 29 or 30, in which the carbon atom number 17 replaced

(a) one of the following groups: =C(R5a)(R5a), =C=C(R5a)(R5a); or (b) two from EBUSY groups, which is selected independently from R5a; where R5ain each case independently selected from H, C1-6, alkyl, C1-6hydroxyalkyl, C1-6halogenoalkane.

32. The compound according to claim 1, in which R3and R4together form ketal the following structure:

33. The compound according to claim 1, in which-OR3and-OR4have the stereochemistry as shown:

34. The compound according to claim 1, in which-N(R1)(R2) is in a salt form.

35. The compound according to claim 1, in which-N(R1)(R2) is in a salt form, the salt is a halide or acetate salt.

36. The compound according to claim 1, in which at least one of the carbon atoms numbered 10 and 13 replaced by stands.

37. The compound according to claim 1, in which R1and R2independently selected from hydrogen, heteroalkyl, where the heteroatom is a nitrogen atom, heteroaryl, where the heteroatom is selected from nitrogen, oxygen and sulphur.

38. The compound according to claim 1, in which R3and R4selected from hydrogen and protective groups, so that R3and/or R4are part of the protection of hydroxyl groups; the carbon atoms numbered 1, 2, 4, 11, 12, 15 and 16 are each substituted with two hydrogen atoms; the carbon atoms numbered 5, 8, 9 and 14 are each substituted with one hydrogen atom;

atom ug is erode at number 10 replaced by stands; the carbon atom number 13 replaced by stands; the carbon atom number 17 substituted: (a) one of the groups: =C(R5)(R5) or =C=C(R5)(R5); or (b) two of R5; R5in each case, independently, selected from H and C1-6hydrocarbon groups.

39. The compound according to claim 1 or 38, in which R1and R2independently selected from hydrogen, CH3-, CH3(CH2)2-, CH3WITH-C6H5CO-, (CH3)2CHSO2-With6H5SO2-C6H5NHCO -, - CH3(CH2)2NHCO-, CH3(CH2)2NH(CH2)2-, (CH3)2N(CH2)2-NON2CH2-NON2(CH2)4-, HOCH2CH2NHCH2CH2-, 3-(CH3)6H4-, 4-(BUT)6H4-, 4-(N2NSO2)6H4-, 4-((CH3)CH)6H4-CH2-, 2-(F)6H4-CH2-, 3-(CF3)6H4-CH2-, 2-(CH3O)6H4-CH2-, 4-(CF3O)6H4-CH2-, 3-(C6H5O)6H4-CH2-, 3-(NO2)6H4-CH2-,

and

or R1and R2can the be combined together with the nitrogen atom, to which they are both attached, form a heterocycle selected from the

and

40. The compound according to claim 1 the following formula:

41. The compound according to claim 1 the following formula:

42. The compound according to claim 1 the following formula:

43. The compound according to claim 1 the following formula:

44. Pharmaceutical composition for treatment and/or prophylaxis of conditions involving inflammatory reactions of the body, including the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43, and a pharmaceutically acceptable carrier, excipient or diluent.

45. The method of therapeutic treatment of inflammation comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

46. A method of preventing inflammation comprising the administration to a subject in need this, prophylactically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer in which the yubom one of claims 1 to 43.

47. A method of treating asthma, comprising introducing to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

48. A method of treating allergic diseases, including, but not limited to, the symptom skin and eye diseases, comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

49. A method of treating chronic obstructive pulmonary disease, comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

50. The method of treatment of allergic dermatitis, comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

51. A method of treating solid tumors comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

52. The method of treatment is semitecolo circulatory disorders, includes introduction to the subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

53. A method of treating cardiac arrhythmia, comprising the administration to a subject in need, a therapeutically effective amount of the compound or its pharmaceutically acceptable salt, MES or stereoisomer according to any one of claims 1 to 43.

54. Connection p, where cleaners containing hydrochloride salt is a salt or acetate salt.



 

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SUBSTANCE: invention relates to highly labeled analog of physiologically active compound, i. e. to 9α-fluoro-16α-hydroxyprednisolon [3H]-acetonide highly labeled with tritium of the formula (I): . The highly tritium-labeled compound of the formula (I) is necessary for investigation of active non-labeled analog.

EFFECT: valuable properties of compound.

2 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds and preparations.

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

FIELD: cosmetology.

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3 cl, 5 ex

FIELD: organic chemistry, steroids, pharmacy.

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

EFFECT: valuable properties of compounds and composition.

4 cl, 3 sch, 1 tbl, 8 ex

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

The invention relates to an improved method of isolation and purification of saponins

The invention relates to 14,17-C2-bridged steroids of formula I, where R3- O, R6- Hor-(C1-C4)-alkyl, where R6and R7together form an additional bond; R7-or-(C1-C4)-alkyl, where R6and R6both H, or R9and R10each H or together form a bond, R11and R12each H or together form a bond, R13- CH3or2H5; R15- H or C1-C3-alkyl; R16and R16independently H, (C1-C3)-alkyl or C1-C4alkenyl or together form a (C1-C3-alkyliden; R15and R16together form a cyclewhere n = 1, and h - O and R16- N- H, (C1-C3)-alkyl,- H, (C1-C3)-alkyl,- H, (C1-C3)-alkyl or HE; except 14,17-ethano-19-norpregna-4-ene-3,20-dione

FIELD: organic chemistry, steroids, biology.

SUBSTANCE: invention relates to steroid compounds of the general formula (X):

wherein in fragment of the formula XA:

each bond between C6 and C7, between C7 and C8, between C8 and C9, between C8 and C14 and between C14 and C15 is a single or double bond under condition that each atom C6, C7, C8, C9, C14 and C15 is bound with adjacent C-atom by a single bond or one double bond; CR3 means -CHOH; A means methylene or ethylene group; R4 and R4' mean (C1-C4)-alkyl, hydrogen atom (H); R20 means (C1-C4)-alkyl; R23 and R23' mean in common piperidine-1-yl, morpholine-4-yl, pyrrolidine-1-yl, piperazinyl possibly substituted with -OH, benzene, pyridine, pyrimidine, phenyl, alkoxycarbonyl group, or R23 means H and R23' means substituted alkyl. These compounds can be used for stimulation of meiosis in human oocytes. In proposed compounds steroid differs specifically as nitrogen atom of amino-group is bound with C17-atom of steroid skeleton by spacer A.

EFFECT: improved methods of synthesis, valuable biological properties of compounds.

16 cl, 8 dwg, 2 tbl, 30 ex

FIELD: organic chemistry, steroids.

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

EFFECT: valuable medicinal properties of steroids.

5 tbl, 7 dwg

FIELD: organic chemistry, steroids, chemical technology.

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

EFFECT: improved preparing method.

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

FIELD: organic chemistry, steroids, medicine, pharmacy.

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

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

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

38 cl, 1 tbl, 18 ex

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

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

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a method for treatment of allergy by using substituted pyrazoles of the formula (I): . Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced method of treatment.

11 cl, 4 dwg, 2 tbl, 57 ex

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