6,7-oxidized steroids

 

(57) Abstract:

Describes the steroid compounds of formula I having different substitution by oxygen at the steroid ring. Specific functionality that is present on many steroid compounds, is the replacement of oxygen in both positions 6 and 7. So, some steroids have substitution by oxygen at C6 and C7, and some have specific stereochemistry, such as 6 - and 7-oxygen substitution and alpha hydrogen in the 5-position, in addition to - and 7-oxygen substitution. Also describes steroids with 3,4-epoxypolyester. In addition, describes the steroids having 17-pornowww and-lactoovo functionality with substitution by oxygen at C6 and C7 or C15 steroid ring. Connection I provide a safe and efficient lessening symptoms of asthma and allergies. 30 C.p. f-crystals, 21 PL.

Cross-reference to related invention of the application

Under this proposal requires priority from provisional patent application U.S. 60/023450 filed July 11, 1996, and patent applications U.S. 08/679642 filed July 12, 1996, these applications incorporated herein by reference in their entirety.

TECHNICAL AREA

This izabran therapeutic use.

BACKGROUND OF THE INVENTION

Asthma and allergies are closely associated with reliable evidence from clinical studies demonstrating a strong correlation between severity of disease and degree of atopy (allergies). It is believed that sensitization to allergens is the most important risk factor for asthma in children and adults, with approximately 90% of cases of asthma is atopy.

Allergy characterized by elevated levels of IgE (antibodies) in the serum. In a process called sensitization, usually requires repeated exposure to allergens to cause sufficient production of In-cell IgE specific for a particular antigen or of a number of allergens, to start the mechanism of atopy and subsequent asthma or allergic reactions. After cells are exposed to allergens they produce antibodies that bind with the surface of the fat cells. Cross-stitching 2 antibody antigen causes a number of reactions causing degranulation and release of several mediators which modulate the inflammatory response. Mediators, which are released or generated during asthmatic or allergic is characterized by hypervisibility respiratory tract, episodic periods of bronchospasm and chronic inflammation of the lungs. Airway obstruction is reversible with time or in response to therapy drugs. Patients exhibiting a normal airway, can be hyperactive on different existing in the nature of the stimuli, such as cold air, exercise, chemicals and allergens. The most common case, triggering asthmatic reaction is immediate hypersensitivity to common allergens, including ragweed pollen, grass pollen, various fungi, dust mites, cockroaches and Pets. The symptoms of this disease include compression of the chest, stercorosus breathing, shortness of breath and cough. The weak forms of the disease occur up to 10% of the U.S. population, while the UK, Australia and New Zealand reported a higher incidence of this disease. The incidence and mortality of asthma has increased worldwide, doubling over the past 20 years, despite modern treatment methods.

The response of the Airways to an allergen complex and consists of early asthmatic reaction (EAR), which reaches its maximum at 20-30 m is C the time interval from 1.5 to 2 hours. Late asthmatic reaction (LAR) usually occurs within 3-8 hours after the initial impact and includes bronchostenosis, and the development of inflammation and edema in the lung tissue. This inflammation is often chronic with the manifestation of epithelial damage and lung infiltration of inflammatory cells such as eosinophils and neutrophils.

Modern methods of treatment of asthma

Corticosteroids (steroids) are the most effective long-term therapy for the treatment of asthma. Oral steroids are not very useful for keeping the development of acute asthma attacks, and their chronic use in the suppression of asthma is minimal due to the introduction of inhaled steroids. Due to the inflammation of the respiratory tract even in low asthma inhaled steroids used in the treatment of drug at an early stage. No matter how active or inhaled steroids, side effects limit their use, and often use combination therapy. Combination therapy is divided into the following areas: anti-inflammatory medications (such as inhaled and oral steroids), bronchodilators (e.g antagonist leukotrienes).

Cromolyn (for example, dinitrocresolates and nedocromil) inhibit the release of histamine in vitro and prevent bronchial hyperactivity, at the same time, almost without side effects. They are not effective orally and do not have a bronchodilator effect. Usually requires ongoing treatment (a few days) for optimal anti-inflammatory action, although cromolyn have a favorable effect against induced by exercise asthma when they are only 10 minutes before exercise. Gramolini, at best, only more or less effective against forms of asthma from mild to severe.

Corticosteroids (steroids) have a deep effect against pneumonia and are undoubtedly the most effective medicines to treat asthma and allergies. In the fat cells they inhibit the production of metabolites of arachidonic acid (leukotrienes and prostaglandins) and cytokines. Response to inhaled steroids or systemic steroids may occur within 4 hours, but can be within a few days depending on the severity of the disease condition. Without regular continuous treatment with the e, include dysphonia, local irritation and oral candidiasis (fungal infection). Higher doses of inhaled steroids cause suppression of the hPa-axis, which is responsible for regulating the levels of cortisol in serum, metabolism, stress, the function of the Central nervous system and the immune system. Continuous use of high doses of inhaled steroids and oral steroids cause more serious side effects: severe suppression of the hPa-axis, affecting the immune system, hypertension, osteoporosis, peptic ulcers, slow growth in children, behavioral problems, reproductive problems, cataracts, and hematologic disorders.

Beta-antagonists cause return development of bronchospasm, exercise during an asthmatic attack, and possess moderate activity against the beginning of the reaction. Route of administration and duration can vary. Prolonged use of these funds may cause a reduced response to therapy with the development of tolerance. These connections do not have action on the inflammatory response.

Xantina, which are inhibitors of cyclic-AMP phosphodiesterase, also used in bronchodilator therapy. Although xantina EPO relatively narrow, side effects include gastrointestinal disturbances, disorder of the Central nervous system, headache, anxiety, and cardiac arrhythmia. The importance of treatment of inflammation in asthma and allergies has led to reduced use of xantina for therapy.

Anticholinergics, such as ipratropium use to block the contraction of bronchial smooth muscle induced by acetylcholine released as a neurotransmitter. Some positive steps in the treatment of asthma, these drugs are significantly more effective against chronic obstructive pulmonary disease. These medicines are a large number of side effects, including urinary retention, xerostomia, tachycardia, nausea, vomiting, a rush of blood to the face and hypertension.

Inhibitors of 5-lipoxygenase inhibit the generation of leukotrienes, whereas leukotriene antagonists prevent the action of leukotrienes, which are potent bronchospastic mediators released during asthmatic reactions. The use of inhibitors of leukotriene synthesis was associated with an increased content of enzymes in the liver, indicating the need is whether the activity comparable to the activity of cremolino, and activity equivalent to the activity of corticosteroids in low doses.

In General, for patients with asthma from mild to severe forms, insufficient treatment of an existing set of medicines. Medicines which are safe, only more or less effective, while effective drugs have unacceptable side effects with the required extensive monitoring of patients. There is a great need in therapeutic tools that provide a safe and efficient lessening symptoms of asthma and allergies. The present invention provides these and related advantages as described here

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds of formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6;

(b) two of the-X, -R4and-OR1each P>1;

C17 is substituted according to any of (C), (d), (e), (f), (g), (h) and (i);

(c) =C(R2)(R3), except when R14 is substituted with stands;

(d) -R5and-OR6with the proviso that when R10 is substituted with stands, then C5 is not connected directly with oxygen, where R5and R6may together form a direct link, so R17 represents a carbonyl group, or may together with R17 to form a cyclic 3-6-membered simple ester or a 4-6-membered lactone; otherwise, R5is R4or6and R6is an R1or R4;

(e) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4) (R4))nO)-, where n is the number from 1 to about 6, with the proviso that applies one of the following conditions i), ii), iii) or iv):

i) C5 substituted with hydrogen in the alpha configuration and C3 is not connected with oxygen;

ii) if C10 is replaced by stands and ring And aromatic, either R13 or R14 is not replaced by stands;

iii) if NW and C4 are associated with the oxygen atoms and the Deputy OR1the C6 has an alpha configuration, and the Deputy OR1the C7 has the beta configuration, then R17 is not replaced by any of the following groups:
ikorodu with the formation of rings of oxirane provided that C7 has no carbonyl substitution, when C5 is substitution by hydroxyl or-OR1;

(f) two of the following substituents which are independently selected from-X, R4and-OR1provided that applicable one of the above conditions i), ii), iii) or iv);

(g) a cyclic structure formula

< / BR>
where G represents-C(=O)-, -CH(OR1)-, -C(R4)(OR1)- or-C(OR1)(OR1)-, provided that C3 and C4 are not replaced simultaneously by hydroxyl or protected hydroxyl;

(h) two hydrogen atoms if C3 is not replaced by a carbonyl group;

(i) one atom of hydrogen and one group selected from C1-C30-hydrocarbon groups and halogen-substituted C1-C30-hydrocarbon groups, ex-CH(CH3)(CH2)3CH(CH3)2;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal (adjacent) group-OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1can the UP> or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R2, R3and R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

In a preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10 and C13 are independently substituted with one of-X, -R4or1;

C14 substituted by-X, -OR1or-R4excluding methyl;

rings a, b, C and D may be independently a fully saturated, partially saturated or floor is th hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R2, R3and R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

In another preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted

(a) one of: = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following who is one of-X, -R4or1;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

R5and R6may together form a direct bond, therefore, R17 represents a carbonyl group, or may together with R17 to form a cyclic 3-6-membered simple ester or a 4-6-membered lactone; otherwise kstanley fluoride, chloride, bromide and iodide,

with the proviso that when R10 is substituted with stands, then C5 is not linked directly to an oxygen atom.

In another preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

C3 is substituted by one =C(R4)(R4and-C(R4)(R4)(C(R4)(R4))n, where n is the number from 1 to about 6, or two of the-X and-R4with the proviso that R3 is not associated with the oxygen atom;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure, which Sassou structure, which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

In another preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))nand-O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1,

provided that (a) C10 and C13 are not replaced at the same time the stands and (b) where C10 replace iseni, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

In another preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted

(a)onethe=O,=C(R4)(R4)- C(R4
(b) two of the following, which are selected independently: -X, -R4and-OR1,

with the proviso that R17 is not replaced by any of the following groups:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
each of C5, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

C8 substituted by-X or R4and preferably not associated directly with oxygen;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they relate, molar implementation of the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1,

provided that C3 and C4 are not replaced simultaneously by hydroxyl or protected hydroxyl and preferably not replaced both oxygen atoms;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

G represents-C(=O)-, -CH(OR1)-, -C(R4)(OR1)- or-C(OR1) (OR1)-;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the second group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

In another preferred implementation, the compounds have the formula

< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and-O0(C(R4)(R4)nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1 is genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide,

with the proviso that R7 is not carbonyl substitution, when R5 is hydroxy or or1-substitution.

In another preferred implementation of the compounds have a formula selected from

< / BR>
< / BR>
including their pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12 and C16 is independently substituted according to (a) or (b)

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))nand-O(C(R4)(R4))nO)-, where n is the number from 1 to about 6;

(b) two of the-X, -R4and-OR1each chosen independently;
or1and

C17 is substituted according to (C), (d), (e) or (f);

(c) two substituents selected from the group comprising hydrogen, halogen, C1-C30-saturated hydrocarbon radical, ex-CH(CH3)(CH2)3CH(CH3)2, halogen-substituted C1-C30-saturated hydrocarbon radical, C1-C30unsaturated hydrocarbon radicals and halogen-substituted C1-C30unsaturated hydrocarbon radical;

(d) one Deputy, is selected from =C(R4)(R4), with the proviso that R14 is not replaced by stands;

(e) at least one containing an oxygen atom Deputy, is selected from =O, - (O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, HE-OR1;

(f) at least one containing a nitrogen atom Deputy selected from-N(R4)(R4), where two groups R4can together with the nitrogen atom to form one or more rings, which contains a nitrogen atom includes Deputy containing the nitrogen atom of the heterocyclic group, where

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR
R4in each case, independently, selected from H and R5;

R5represents C1-30-organic part, which can optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R5together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide or iodide.

In another aspect the invention provides a pharmaceutical composition comprising a compound according to any of the above descriptions, in combination with a pharmaceutically acceptable carrier or diluent.

In another aspect the invention provides a pharmaceutical composition containing the compound in combination with a pharmaceutically acceptable carrier or diluent, the compound has the formula

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted by-X, -R4and-OR1;

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted to cover the )(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, and

(b) represents two of the-X, -R4and-OR1that is independently chosen in each case;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where the group OR1the C6 and C7 may together form a cyclic structure that protects both hydroxyl group;

R4in each case, independently, selected from H and R5;

R5represents C1-30-organic part, which can optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R5together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide or iodide,

provided that the C15 is not associated with the oxygen atom.

In another aspect the invention relates to the use of the above compounds (any one compound or a mixture thereof) for the manufacture of medicinal sredska with elevated NF-kB.

In another aspect the invention provides a method of treating asthma, comprising introducing to a subject in need, an effective amount of the above-mentioned compounds or salts thereof, or pharmaceutical composition, each as described above.

In another aspect the invention provides a method of treating allergies comprising introducing to a subject in need, an effective amount of the above-mentioned compounds or salts thereof, or pharmaceutical composition, each as described above.

In another aspect the invention provides a method of treating inflammation caused by arthritis, including introduction to the subject in need, an effective amount of the above-mentioned compounds or salts thereof, or pharmaceutical composition, each as described above.

In another aspect the invention provides a method of treating thrombosis, comprising introducing to a subject in need, an effective amount of the above-mentioned compounds or salts thereof, or pharmaceutical composition, each as described above.

In another aspect the invention provides a method of treating a condition associated with the activity is as mentioned compounds or salts thereof, or pharmaceutical composition, each as described above.

In another aspect the invention provides a method of introducing ekzoticheskoy olefinic group at the C17 position of 6,7-digisleeve steroid, including the production of the compounds of formula (10), the interaction of the compounds of formula (10) with a Wittig reagent of the formula (11) in the presence of a base to obtain the olefinic compounds of the formula (12) (scheme I, is given at the end of the description), where each of the compounds of formulas (10) and (12) includes its pharmaceutically acceptable salt and solvate and where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted according to any of (a) and (b):

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6;

(b) two of the-X, -R4and-OR1each selected independently;

each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl carbonyl group, with the condition that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

Ra, Rb and R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide or iodide, which is independently chosen in each case.

In another aspect the invention provides a method of introducing 6, 7 dioxygenase in the steroid, which includes the receipt of a steroid of formula (13) having a carbonyl group at the C17 and the double bond between C5 and C6, reduction of carbonyl group to a hydroxyl group, then hydroporinae double bond for the formation of a hydroxyl group at C6, where C6-hydroxyl group has a configuration and C7-hydroxyl group has the configuration (scheme II, listed at the end of the description),

where each of the compounds of formulas (13) and (14) includes its pharmaceutically acceptable salt and solvate and where

each of C1, C2, C3, C4, C11, 4
)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))n0)-, where n is the number from 1 to about 6;

(b) two of the-X, -R4and-OR1each selected independently;

each of C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide or iodide.

In another aspect invented aluchemie steroid compounds of formula (15), having a carbonyl group at C3, and the reduction of carbonyl group to hydroxyl group of the regenerating agent (reducing agent) to obtain at least one compound of the formulas (16) and (17) (scheme III, listed at the end of the description),

where each of the compounds of formulas (15), (16) and (17) includes its pharmaceutically acceptable salt and solvate and where

each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted according to any of (a) and (b):

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6;

(b) two of the-X, -R4and-OR1each selected independently;

each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 Prout of N and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to various steroid derivatives having a specific functionality, as described in detail here. These compounds demonstrate effectiveness as a useful means to suppress asthmatic and allergic reactions that they are effective against degranulation of mast cells, inhibition of allergen-induced bronchospasm (acute phase) and inhibition of allergen-induced lung inflammation (late phase). This group of compounds is the new number of agents that have potential therapeutic benefit in the treatment of asthma and allergies, with high activity, broad spectrum of activity and low probability of side effects.

For easy identification of new distinctive characteristics soy is AMI number, below as structure 1. This numbering system will be used here all the time.

Structure 1

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Compounds of the present invention contain at least two asymmetric carbon atoms and therefore exist as enantiomers and diastereomers. If not mentioned specifically, the present invention includes all enantiomeric and diastereomeric form compounds of the above formula. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the above formulas are included in the scope of the present invention.

Methods of synthesis described here, especially when they are taken together with General knowledge in the art, provide sufficient guidance for professionals in the art for carrying out the synthesis, isolation and purification of the preferred compounds described herein, and other similar compounds. Individual enantiomers can be obtained, if necessary, from mixtures of different forms by known methods of separation, such as formation of diastereomers followed by recrystallization.

Compounds of the above formula can be in the form of MES or farmaceutical, fumarate, methanesulfonate, acetate, tartrate,

maleate, lactate, mandelate, salicylate, succinate and other salts known in this field.

The compound of the present invention can be obtained in the form of a composition by combining it with a pharmaceutically acceptable carrier or diluent. Suitable carriers or diluents include physiological saline solution. For specialists in this area it is obvious that the composition of the present invention may contain more than one steroid compound or one or more steroid compounds in combination with one or more non-steroidal compounds.

Typical functionality found on many steroid compounds of the invention is the replacement of oxygen in both of the positions 6 and 7. Thus, some of the steroids of the invention have the model of substitution by oxygen, shown in structure 2. Some of these steroids are additionally characterized by the fact that they have a particular stereochemistry. For example, steroids, 6 - and 7-oxygen substitution, as shown in structure 3, and steroids having an alpha hydrogen in position 5 besides the fact that I have the 6 - and 7-oxygen for ructure 2

< / BR>
Structure 3

< / BR>
Structure 4

< / BR>
In structures 2, 3 and 4, each of the oxygen atoms that are bound to carbons 6 and 7, while associated with the group R1. The group R1represents hydrogen or a protective group for hydroxyl group. Suitable protective groups are listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1981). When the connection structures 2-4 contains vicinal groups OR1(i.e., group-OR1on adjacent carbon atoms), these vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups. Ketal is an example of a protected vicinal groups OR1. Genialny group OR1(i.e., two groups OR1on the same carbon atom may together form a cyclic structure which protects a carbonyl group. Ketal is an example of such a cyclic structure. It should be clear that one or both of the-OR1the C6 and C7 represent carbonyl or protected carbonyl group and, thus, R1the C6 and C7 may be a direct relationship between the oxygen atom and the carbon (C6 or C7), linked to the oxygen atom.

Steroids the image is in the invention is usually in the configuration. In addition, the preferred steroids of the invention may have methyl substituents of s-stereochemistry at positions C10 and/or C13. Compounds of the invention preferably have a C14-hydrogen-stereochemistry when C15 is not a ketone. In the preferred steroids of the invention, which have a Deputy at C17, C17-substitute-stereochemistry.

Steroids with 6,7-deoxyguanosine in-ring according to structure 2, can be synthesized from a number of commercially available steroid precursors with ,-unsaturated carbonyl group in the a ring, including a 4-androsten-3,17-dione (the following compound 1) and dehydroisoandrosterone (below the connection 247). These particular steroid precursors available from Steraloids Inc., Wilton, N. H. Other suitable steroid precursors having C3-oxygen functionality and5the carbon-carbon double bond, can be obtained, for example, from Aldrich Chemical Co., Milwaukee, WI.

Exemplary synthetic sequence for obtaining compounds of structure 2 of 4-androsten-3,17-dione summarized in scheme 1, is given at the end of the description.

First carbonyl functionality 4-androsten-3,17-dione protect carbonyl Zaman)2in benzene and p-TsOH, thereby transforming the carbonyl group in Catalunya group. Other suitable carbonyl protective group are listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1981). In acidic conditions, in which are formed a protective ketone groups, there is a concomitant migration of C4-C5-carbon-carbon double bond at C5-C6-education situation in the end connection 2.

Allyl oxidation of C5-C6-carbon-carbon double bond of compound 2 introduces carbonyl oxygen at C7, thereby forming the connection 3. To do this, allyl oxidation can be used a number of oxidizing agents (oxidants) and experimental conditions, including the complex chromium trioxide/3.5-dimethylpyrazol, chlorproma pyridinium (PCC), pyridinium dichromate (PDC) or RuCl3and tert-butylhydroperoxide.

The recovery obtained C7-ketone suitable regenerating agent provides hydroxyl functionality at C7, as shown in the connection 4. For this purpose, as reducing agents, you can use any of several metal hydrides, including borohydride sodium or sociallyengaged. Usually when restoring C7-ketone is formed configuration-IT polictical protect a hydroxyl protecting group, for example tert-butyldimethylsilyl (TBDMS), to obtain the protected allyl alcohol, as in compound 5. Other suitable hydroxyl protective groups are listed in Greene, see above.

Introduction C6-oxygen can be achieved before and after protection of the C7-hydroxyl group in such a way as hydrobia-tion/oxidation or epoxidation followed by ring opening. For example,5the carbon-carbon double bond of compound 5 can be epoxidizing any of a number of percolat, including m-chloroperbenzoic acid, cryptocercus acid or 3,5-dinitropropanol acid, to obtain epoxide, such as in compound 6. Usually introduced epoxide has a configuration resulting from attack at least zatrudnieniu the surface structure of the steroid ring. Subsequent ring opening of the epoxide can be performed in acidic conditions, such as 80% aqueous acetic acid at 60oC. the Crude mixture contains a mixture of compound 7 (with allyl alcohol in the C6-position of the s-configuration), and C7-silloway derived. This crude mixture can be treated with tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) to obtain a single connection (7). Alternativnaya such reagents as a basic (alkaline) hydrogen peroxide will also introduce a hydroxyl group-configuration at C6.

The connection 7 is an example of compounds having oxidation model structures 2 and 3. The methodology, which compound 1 can be converted into compound structures 2 and/or 3, usually suitable for a wide range of compounds with ,-unsaturated carbonyl group in the a-ring of the steroid. Additional compounds of the structures 2 and/or 3 can be obtained by modification of dihydroxytoluene, such as compound 7. In this case, it may be necessary to protect each of the C6 - and C7-hydroxyl groups, the methodology for achieving such protection is described here below.

Connection 7 or equivalent can be converted into a compound of structure 4. Essentially, this can be done by protecting C6-and C7-hydroxyl groups and C17-carbonyl group and then restore4the carbon-carbon double bond. Lithium in a mixture of ammonia/THF is an example of a suitable reducing agent. This restoration gives the enolate, which can be captured with a suitable electrophile, such as trimethylsilylpropyne or diethylphosphate.

An example of such a transformation is shown in figure 2 (see what oxopropanal and a catalytic amount of (1S)-(+)-10-camphorsulfonic acid (CSA) to obtain acetonide 8. C17-Carbonyl group of compound 8 can be protected by converting it into a hydroxyl group and then protecting hydroxyl group. Chemoselective recovery C17-carbonyl group can be performed by using NaBH4in methanol to obtain compound (9), which, in turn, is subjected to the interaction with a suitable hydroxyl protecting group, for example tert-butyldimethylsilyloxy to obtain salelologa simple ester compounds 10. Compound 10 can be subjected to interaction with lithium in a mixture of liquid ammonia/THF, followed by quenching the reaction by diethylphosphate to obtain compound 11. Compound 11 has a 5-hydrogen and C6 - and C7-dihydroxypropane and thus, is representative compound of structure 4.

In the aspect of the present invention offers olefinic steroids with ekzoticeski olefin in the C17 and the oxygen atoms of both C6 and C7. In one implementation olefinic steroid has the structure 5 including individual enantiomeric or geometric isomers and further including MES, or a pharmaceutically acceptable salt. Structure 5 is defined as follows.

The connection formulas

< / BR>the performance is replaced

(a) one of = O, = C(R4)(R4), -C(R4)(R4)(C(R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10 and C13 are independently substituted with one of-X, -R4or1;

C14 is independently substituted with one of-X, -R4excluding methyl or1;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R2, R3and R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom, librarytest with the carbon atom, with which they are linked, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

Introduction ekzoticheskoy double bonds at C17 easily performed by a Wittig reaction on the basis of C17-carbonyl compounds. The steroids of this invention, with the C17-carbonyl functionality, easily accessible, for example, as the compound 7 obtained according to scheme 1 or by a synthetic sequence, summarized in figure 3, is provided at the end of the description, which begins with a connection 10 (obtained according to scheme 2).

So-And-ring connection 10 can be restored for the formation of the C3 carbonyl group as the only functionality in the a-ring. Scheme 3 illustrates the two-stage sequence for the implementation of this recovery, where the connection 10 restore lithium in liquid ammonia and ether solvent such as diethyl simple ether or THF, receiving a mixture of compounds 12 and 13. This mixture can then oxidize a suitable oxidizing agent, such as PDC, to obtain exclusively the connection 13. Compound 13 can then restore the LS-Selectride(Aldrich Chemical Co., Milwaukee, WI) or other selective regenerating agent for the about then protect as acetate using acetic anhydride and pyridine to obtain compound 15. Instead of the acetate groups you can use other suitable hydroxyl protective group. The removal of the silyl protective group at the C17 can be performed under standard conditions known in the field to remove the silyl protective group, for example, using tetrabutylammonium fluoride (TBAF) to get C17-hydroxyl compounds, such as compound 16. C17-Hydroxyl group can oxidize in the carbonyl group in the normal conditions of oxidation, for example, using oxalicacid in DMSO (dimethyl sulfoxide) and Et3N, to obtain a ketone compound 17.

Compound 17 can be used in many reactions referirovanija, including the reaction of the Wittig type, to obtain compounds of structure 5 with the olefin at C17. For example, compound 17 can be subjected to interaction with bromide ethyltriphenylphosphonium to get metilidinovogo connection 18. For other steroids having ekzoticheskuyu double bond at C17, you can use other source ketones.

As described previously, the compounds containing the carbonyl at C17 (or compounds that contain functionality that is easily converted into a carbonyl group), you can turn the as shown in figure 4, listed at the end of the description, the connection 19 can be converted into the corresponding 17-ethylidene connection 23 platitudinal way. Thus , 3-dihydroxyphenylalanine connection 19 can be protected hydroxyl protective groups (for example, using 2,2-dimethoxypropane and camphorsulfonic acid (CSA) in N,N-dimethylformamide (DMF) to obtain a connection, such as connection 20. Release C17-hydroxyl group from the protective group can be carried out using reaction conditions that are suitable for a specific hydroxyl protective group (in this case, you can use TBAF in THF) followed by oxidation of the formed hydroxyl group (for example, using PDC in CH2C12to obtain compounds containing 17-ketone (21). Interaction of compound 21 with a Wittig reagent, for example a bromide ethyltriphenylphosphonium and tert-piperonyl potassium in toluene gives the connection 22. The liberation of the hydroxyl groups from the protective groups in the olefin 22 gives tetrahydrogestrinone 23.

In some cases, prior to derivatization (transformation into derivative) R17 may be required under protection. For example, in connection 24 (obtained according to scheme 14) C3-ketone must first protect what about the first restore (for example, interaction with NaBH4in ethanol), then allievate (for example, using acetic anhydride in pyridine) to obtain C3,C5-acetoxypropionyl 25. For connection 27 can be used removing the protective group, oxidation and chemical transformation by Wittig at C17, similar to the stages described in scheme 4. Subsequent removal of the protective group at the C6 - and C7-hydroxyl groups (removal Catalinas group connection 27 typically use 80% acetic acid) gives compound 28, which contains ekzoticeski 17-olefin.

In the aspect of the present invention offers steroids with C17-oksigenirovannym and oksigenirovannym at C6 and C7. In one implementation, the steroid has the structure 6 including individual enantiomeric or geometric isomers and further including MES, or a pharmaceutically acceptable salt. Structure 6 is defined as follows.

The connection formulas

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including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, G1
;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

R5and R6may together form a direct link, so R17 represents a carbonyl group, or may together with R17 to form cyclizes>and R6is R1or R4and

X represents fluoride, chloride, bromide and iodide.

Above it has already been suggested many examples of compounds of structure 6 and their syntheses. For example, connection 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 19, 20, 21, 24, 25 and 26 are representative of compounds of structure 6. In connection with other compounds of the invention it provides a lot of additional compounds of structure 6, including their synthesis. Therefore, the average person skilled in the art are able to get a lot of compounds of structure 6, whereas this description.

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C1. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C1 for compounds of structure 6 is provided below and depicted on figures 6, 7 and 8. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and/or hydrocarbon substitution at C1 for any connection structures 5-12, where necessary, C1-oxygen and/or hydrocarbon substitution at C1.

The introduction of oxygen functionality at the C1 carbon of the steroid skeleton can deal with any requests guests who eat at Michael with any of the number of alkoxide anions, as depicted in scheme 6, is provided at the end of the description. For example, the exact location 29 can be obtained from compound 13 using standard methodology. Benzyloxyaniline 30 can then be obtained by interaction of Aenon (29) with benzyl alcohol and the law. For the recovery of the C3 ketone compounds 30 and protection of the resulting secondary alcohol in the form of similarverizon (to obtain compound 31) can be followed by catalytic hydrogenation for the formation of Cl-hydroxyl functionality in the connection 32. Oxidation of the secondary alcohol using, for example, PDC in CH2C12you can get a connection 33 with Cl-ketone.

Compounds containing both an alkyl group and a hydroxyl group at C1, can be obtained by the interaction of the compounds with 33 alkyllithium reagent. For example, the interaction of compounds with 33 CH3Li in a simple ether gives a tertiary alcohol compound 34 (scheme 7, provided at the end of the description).

The reaction joining Michael analogous reactions described in scheme 6, can be used to attach the alkyl group in the C1-position. This can be done using a variety of reagents, including R2CuLi, where R can be an alkyl, vinyl is Oia C1-methylsiloxane derivative 35 (scheme 8, listed at the end of the description).

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C2. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C2 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C2 for any connection structures 5-12, where necessary C2-oxygen and/or hydrocarbon substitution.

Compounds containing oxygen at C2, can be obtained in various ways, including hydroporinae salelologa enol ester as shown in scheme 9, is provided at the end of the description. Silloway enol ether can be obtained from may 29 restoring Li/NH3with subsequent removal of the resulting enolate using TMSC1 to obtain compound 36 (or other reagents R3Si1 to get similar salelologa ester enol). Hydroporinae carbon-carbon connection 36 may provide a model 2, 3-dihydroxy-functionalization (compound 19). Oxidation of this dihydroxytoluene using PDC in CH2CL2you can get diketone 38.

3with subsequent removal of the resulting anion alkylating agent provides C2-alkylation. Processing the received enolate methyliodide can give C2-methylated compound 39 (scheme 10, provided at the end of the description). This methodology can be applied for a number of different compounds using a number of different alkylhalogenide.

Compounds of structure 6 may have a hydrocarbon substitution at C3. Exemplary synthetic methodology to provide hydrocarbon substitution at C3 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of hydrocarbon substitution at C3 for any connection structures 5-12, where necessary C3-hydrocarbon substitution.

The Wittig reaction of compound 13 with subsequent reduction of the double bond or alternative modifications will give alkyl - or dialkylphosphate in C3. For example, the interaction of compound 13 with bromide methyltriphenylphosphonium and tert-GFCF in toluene can be used to obtain compound 40 (scheme 11). The reaction of the Simmons-Smith connection 40 with CH2I2and Zn-Cu with posledna be used to obtain dialkylphosphate 42 (scheme 11, listed at the end of the description).

Compounds of structure 6 may have a hydrocarbon substitution at C4. Exemplary synthetic methodology to provide hydrocarbon substitution at C4 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of hydrocarbon substitution at C4 for any connection structures 5-12, where necessary With 4-hydrocarbon substitution.

Alkylation at C4 can be performed first obtaining the enolate anion from Aenon in connection 10 (using, for example, reduction with lithium in liquid ammonia) followed by treatment with a suitable alkylhalogenide, as shown in figure 12, is provided at the end of the description.

Alternative compounds of structure 6 may have a carbonyl functionality at C4. Exemplary synthetic methodology for the formation of carbonyl functionality at C4 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of carbonyl functionality at C4 for any connection structures 5-12, where necessary C4-carbonyl group. As described Niger and hydrocarbon group at C4.

Compounds with ketone (carbonyl) functionality at C4 can be obtained from compound 44 (which, in turn, is produced by deacetylation of acetate 147 of scheme 44) selective totalrevenues, epoxydecane and then ring opening of epoxide with subsequent oxidation of the resulting 4-hydroxyl functionality. For example, as illustrated in figure 13 is given at the end of the description, the processing diol 44 p-toluensulfonate in pyridine and DMF and subsequent interaction get tosilata 45 with tert-GFCF can enter 3, 4-epoxide (compound 46). Treatment of epoxide Me2CuLi gives 3-methylpropane 47 and subsequent oxidation using, for example, PDC in CH2C12gives the target ketone (carbonyl) C4 (compound 48). The epimerization of 3-methylpropane can be performed using tert-GFCF in tert-VION and subsequent treatment of the ketone with methyllithium in THF can be obtained tertiary alcohol at C4 (compound 49).

Alternative compounds of structure 6 may have an oxygen or hydrocarbon substitution at C5. Exemplary synthetic methodology for the formation of oxygen or hydrocarbon substitution at C5 for compounds of structure 6 is provided below. Should the recognition of hydrocarbon substitution at C5 for any connection structures 5-12, where necessary C5-oxygen or hydrocarbon substitution.

Epoxidation of compound 10 with subsequent ring opening can be used for the formation of hydroxy - and then alkoxysilane the C5 carbon skeleton. For example, epoxidation of the double bond in compound 10 can give the corresponding epoxy derivative 50, which can be easily converted to tertiary hydroxyl compound 24 (scheme 14 provided in the end of the description). Subsequent recovery of compound 24 using NaBH4in THF and methylation using Me in the presence of tert-GFCF in THF can give diacetoxyscirpenol 51 (scheme 15 provided at the end of the description). Alkyl substitution at C5 can be done using a suitable alkyldichloro reagent. For example, treatment of compound 10 (CH3)2CuLi simple ether can give C5-methylpropane 52 (scheme 16 provided in the end of the description).

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C9. Exemplary synthetic methodology for the formation of oxygen or hydrocarbon substitution at C9 for compounds of structure 6 is provided below. It should be recognized that the same or similar is for any connection structures 5-12, where necessary C9-oxygen and/or hydrocarbon substitution.

Hydroxylation at the C9-position can be accomplished by interaction 9,11-olefinic compound with m-chloroperbenzoic acid, followed by reduction LiAlH4as depicted in scheme 17, provided at the end of the description. For example, using this methodology, the connection 53 (obtained by dehydration of compound 60, for example, NaH, CS2, MeI, heating) can be used as a starting product for connection 54, which when restoring epoxide can form C9-hydroxyl-containing derivative 55. The subsequent interaction of the tertiary alcohol compound 55 with dimethylsulfate in aqueous sodium hydroxide can be used to obtain the corresponding alkoxyimino, connection 56.

Alternative compounds of structure 6 may have a hydrocarbon substitution at C9. Exemplary synthetic methodology for the formation of hydrocarbon substitution at C9 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of hydrocarbon substitution at C9 for any connection strumarium CH2I2and Zn-Cu with subsequent catalytic hydrogenation can give appropriate C9-alkyl substituted compound 57 (scheme 18 provided at the end of the description).

Alternative compounds of structure 6 may be halide substitution at C9. Exemplary synthetic methodology for the formation of halide substitution at C9 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to education halide substitution at C9 for any connection structures 5-12, where necessary C9-halide substitution.

The introduction of the halogen atom at C9 can be done a number of ways, including interaction C9-tertiary alcohol (see, for example, the connection 55 in scheme 17) with thionyl chloride. Thus, the interaction of compound 55 with SOCl2in CH2Cl2you can use to obtain the chlorinated 59, as shown in figure 19, is provided at the end of the description.

Compounds of structure 6 preferably are methyl Vice C10. However C10-position can be derivateservlet so that it had a lot of functional groups other than methyl. Exemplary synthetic methodology for the formation of oxygen is th same or analogous synthetic methodology can be applied to provide oxygen and/or hydrocarbon substitution at C10 for any connection structures 5-12, where necessary C10-oxygen and/or hydrocarbon substitution.

The derivatization C10-position can be achieved, as shown in figure 20, is provided at the end of the description. 10-Hydroxysteroid 60 (obtained, for example, as shown in the diagram below, 22) can be transformed into derived using nitrosylchloride (NOC1) in pyridine to obtain nitrite derivative, such as 61. Irradiation nitrile 61 can then lead to a mixture Asimov 62 and 63. Connection 63 restore to the appropriate Imin 64 processing water TiCl3in dioxane and acetic acid. Acetate polyacetale 65 can be obtained by processing 64 NaNO2in aqueous acetic acid. It may also lead to the removal of protective groups in 6.7-hydroxyl groups. Acetonide can re-enter the interaction of the crude product with 2,2-dimethoxypropane and camphorsulfonic acid. For alkaline hydrolysis (NaOH, MeOH) to obtain hydroxyaldehyde 66 followed by protection of the secondary alcohol at C11 in the form of benzyl ester using Itug, NaH in DMF to obtain compound 67.

Reaction of Grignard compounds with 67 CH3Mdwg with subsequent oxidation PDC in CH2CL2then oxidation by Bayer-Villiger m-chloroperbenzoic base, for example, sodium methoxide in methanol, to obtain C10-alcohol 69. This C10-hydroxyl group can then be turned into alkoxides similar 70 using, for example, sodium hydride in THF followed by treatment with alkylating agent, such as methyliodide. Alternative conversion of C10-hydroxyl group in connection 69 to the corresponding chloride derivative 71 carried out using glorieuses agent, for example thionyl chloride, as shown in figure 21, is provided at the end of the description.

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C11. Exemplary synthetic methodology for the formation of oxygen and/or hydrocarbon substitution at C11 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and/or hydrocarbon substitution at C11 for any connection structures 5-12, where necessary C11-oxygen and/or hydrocarbon substitution.

Obtaining compounds of structure 6, containing an oxygen function in the C11-position can be carried out according to the route shown in scheme 22, provided at the end of the description of the commercial is its hydroxyl group in the a-ring, in connection 75 (obtained from commercially available compounds 72, scheme 22), the removal of the C3-hydroxyl can be done using a two-stage technique, which includes obtaining methylxanthine using NaH, CS2and CH3I in THF, followed by reduction using n-V3Sn and the removal of the protective group (80% Asón) for connection 77. After the restoration and protection of the 17-ketone with the use of NaBH4in methanol, then TBDMSC1 and imidazole in DMF, oxidation C7-position can be accomplished with the use of a number of oxidizing conditions, such as CDF3and 3,5-dimethylpyrazol in CH2Cl2or Ru13and tert-VION in N2O and cyclohexane. Subsequent recovery (NaBH4, SES3, THF-Meon) C7-ketone and acetylation can give C7-acetoxypropionyl 80. Hydroporinae connection 80 yields a product with model 6, 7, 11-hydroxylation, as in Tirol 81. Protection 6, 7-hydroxyl in compound 81 using 2,2-dimethoxypropane in the presence camphorsulfonic acid (CSA) and subsequent oxidation using PDC in CH2Cl2network connection 82, which contains C11-ketone.

Compounds of structure 6 may alternatively or additionally be ug is the C11 for compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the implementation of hydrocarbon substitution at C11 for any connection structures 5-12, where necessary C11-hydrocarbon substitution.

The transformation of compound 82, C11-ketosteroid, in connection with alkyl Quaternary center may be made as shown in scheme 23, provided at the end of the description.

So, C11-ketosteroid 82 in toluene can be added to a solution of bromide methyltriphenylphosphonium and tert-GFCF to obtain compounds with11the carbon-carbon double bond, such as 83. Subsequent treatment of compound 83 CHI2, Zn-Cu can be obtained cyclopropylbenzene 84. The hydrogenation of cyclopropane ring (H2Pd/C in ethanol) can give dialkylphosphate 85. To get similar alkyl substituted steroids you can use other Wittig reagents.

Monoalkylamines C11-position can be accomplished by applying a chemical conversion by Wittig connections C11-ketone, as described above, with subsequent direct catalytic hydrogenation as shown in scheme 24, provided at the end of the description). For example, catalytic hydrogenation (H2Pd/C is enigne substitution at C11. Exemplary synthetic methodology for the formation of halide substitution at C11 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to education halide substitution at C11 for any connection structures 5-12, where necessary C11-halide substitution.

So, halogenoalkane C11-position can be carried out according to the route shown in scheme 25, provided at the end of the description. For example, treatment of compound 60 halogenation agent such as thionyl chloride in CH2Cl2gives the corresponding 11-chlorinated 87. In General, the hydroxyl functionality can serve as a precursor halide functionality.

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C12. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at C12 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and/or hydrocarbon substitution at C12 for any connection structures 5-12, where necessary C12-kislorod the ANO in scheme 26, listed at the end of the description.

So, C11-ketosteroid, such as the connection 82, can be subjected to interaction with LDA in THF, followed by trapping of the enolate anion compound (Me3N)2P(O)C1 and then recovery of phosphate enol using Li and EtNH2for connection, such as 88, with11,12the carbon-carbon double bond. Epoxidation can be carried out using epoxidised agent such as m-SRVA in CH2Cl2to obtain the corresponding 11, 12-epoxy derivative 89. Subsequent restoration LiA1H4epoxide you can get 12-hydroxy (90), which can oxidize with use of a suitable oxidizing agent such as pyridinium dichromate (PDC) in methylene chloride, to obtain the target C12-ketosteroid 91.

Compounds of structure 6 may have a hydrocarbon substitution at C12. Exemplary synthetic methodology to provide hydrocarbon substitution at C12 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of hydrocarbon substitution at C12 for any connection structures 5-12, where necessary C12-angle is in scheme 27, listed at the end of the description. C11-Ketosteroid 82 (obtained, for example, according to scheme 22) and a strong base, such as diisopropylamide lithium in THF, mixed and treated with an alkylating agent, such as methyliodide to obtain C12-methylated product 92. At this stage C11-ketone can be removed using several methods, including the methods described in connection with the circuit 26 to obtain monomethylamine product 93. Further processing of strong base and an alkylating agent, such as diisopropylamide lithium and methyliodide gives C12-demetilirovanny product 94. And again, this connection can be subjected to restoring the conditions for removal of the C11-ketone group, thereby obtaining C12-DIMETHYLPROPANE 95.

Compounds of structure 6 may have oxygen and hydrocarbon substitution at C12. Exemplary synthetic methodology to provide oxygen and hydrocarbon substitution at C12 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and hydrocarbon substitution at C12 for any connection structures 5-12, where necessary C12-oxygen plus uglevodorodno C12 position of the corresponding C12-ketone. In scheme 28 C12-ketone 91 process alkyllithium reagent, such as methyllithium in diethyl simple broadcast, receiving targeted tertiary alcohol 96.

Compounds of structure 6 may have a carbon, oxygen or halogen, which are called multiple atoms associated with C13. Exemplary synthetic methodology to obtain such a substitution in R13 for a compound of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to provide the same or similar replacement from C13 to any connection structures 5-12, where necessary such C13-substitution.

Deputies at the C13 position can be entered according to the route shown in scheme 29, provided at the end of the description. In a manner similar to the method previously described in scheme 20, C13-position can be replaced by hydrocarbonaceous, for example a methoxy group. So, oxime derived 62 (obtained, for example, as described in scheme 20) restore to the appropriate Imin 97 processing water TS3in dioxane and acetic acid. Acetate polyacetale 98 can be obtained by treating compound 97 NaNO2in aqueous acetic acid. Alkaline hydrolysis (NaOH, MeOH) to obtain hydroxyaldehyde 99 & SMS 100.

The reaction of the Grignard compound 100 can be used to introduce additional functionality at C13. For example, the process of joining 100 methylmagnesium with subsequent oxidation of the resulting C13-secondary alcohol gives methylketones Deputy at C13. It can oxidize, for example, using oxidation for Bayer-Villiger m-chloroperbenzoic acid in methylene chloride to obtain C13-acetoxypropionyl 101. This broadcast can hydrolyze treatment with sodium methoxide in methanol to obtain a tertiary alcohol 102. The subsequent interaction of the alcohol with sodium hydride in THF and then quenching methyliodide can be used to obtain C13-methoxystyrene 103. For other hydrocarbonoclastic you can use other alkylating agents. C13-Hydroxyl can then be converted into the halide, for example chloride, the interaction of alcohol 102 with thionyl chloride, thereby obtaining C13-chloresterol 104, as shown in figure 30, is provided at the end of the description.

Compounds of structure 6 may have a hydrocarbon substitution at C14. Exemplary synthetic methodology to provide hydrocarbon substitution at C14 for connection structure 6 is provided below. Sliderdemo substitution from C14 to any connection structures 5-12, where necessary R14 is a hydrocarbon substitution.

For example, the introduction of alkyl groups at C14-hydrocarbon skeleton of the steroid can be accomplished by alkylation at the C14 position. One approach to achieve this alkylation is indicated on the circuit 31 provided in the end of the description. First receiving Aenon 107 can be done by release from protective groups (TBAF, THF) of compound 105 with subsequent oxidation of the secondary alcohol using PDC in CH2Cl2to obtain C17-ketone derivative 106. The conversion of the ketone 106 in the exact location 107 can be implemented using isopropenylacetate and p-TsOH for intermediate enol acetate and the subsequent receipt of Aenon using the reagents shown in scheme 31. This is followed by turning northward 107 in silloway enol ether 108 by the interaction of Aenon 107 with lithium diethylamide in THF and subsequent interaction of the resulting anion with triisopropylsilane (TIPSOTf). Derived cyclopropane 109 then receives from salelologa simple ether 108 using CH2I2and Zn-Cu. Exemption from protective group salelologa ester enol and cleavage of the cyclopropane ring is achieved using TBAF in THF and ZAT the hydrocarbon substitution at C15. Exemplary synthetic methodology to provide oxygen and/or hydrocarbon substitution at 15 for connection structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and/or hydrocarbon substitution at C15 for any connection structures 5-12, where necessary C15 oxygen and/or hydrocarbon substitution.

For example, the introduction of oxygen functionality at C15 carbon skeleton of the steroid can be accomplished by reaction of the type accession of Michael using any one of a number of alkoxide anions. As shown in scheme 32, provided at the end of the description, 4-methoxybenzylidene 111 (representative derived From 15-hydrocarbonoclastic of the invention, where 4-methoxybenzyloxy (MRMO) serves as a hydroxyl protective group) can be obtained by the interaction of Aenon 107 4-methoxybenzyloxy alcohol and a base (for example, powdered KOH). 4-Methoxybenzyl protective group can be removed under oxidizing conditions, for example by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), for the formation of C15-hydroxyl group (compound 112). When this is followed by oxidation of the secondary SPE 113).

Compounds containing alkyl group at C15, can also be obtained by joining the paired relations by type of Michael's reaction. For example, the interaction connection 107 with organolithium (for example, Me2CuLi) Et2O you can use to obtain methylpropanol 114, as shown in scheme 33, provided at the end of the description.

Compounds containing hydrocarbons (e.g., alkyl) group, and hydrocarbonaceous (for example, alkoxygroup) C15, can be obtained using the Grignard reaction of compound 117, as shown in scheme 34, provided at the end of the description. Connection 117 you can get a three-stage method, including the restoration (for example, recovery using n-V3Sn methylxanthine obtained from C17-hydroxyanisole connection 111) for receiving steroid 115, subsequent oxidative destruction (for example, using DDQ) MRM-protective group to obtain a derived a secondary alcohol 116. Subsequent oxidation of the connection 116 to the corresponding ketone network connection 117. The reaction of the Grignard compound 117 using reagent alkalinized (for example, CH3MDG) in a simple ether gives the tertiary alcohol 118. Methylation of tert what to use instead of the alkylating agent in the circuit 34 and in each diagram here with an alkylating agent), in the presence of a base (for example, K2CO3gives tertiary methoxycoumarin 119.

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C16. Exemplary synthetic methodology for the formation of oxygen and/or hydrocarbon substitution at C16 to compounds of structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied for the formation of oxygen and/or hydrocarbon substitution at C16 for any connection structures 5-12, where necessary C16-oxygen and/or hydrocarbon substitution.

Introduction the tertiary hydroxyl group at C16 carbon skeleton of the steroid can be performed using the Grignard reaction of compound 121, as shown in scheme 35, provided at the end of the description. Ketone 121 can be obtained by gidroborudovaniya of olefin (using, for example, Sia2BH in THF, then aqueous NaOH, H2On connection 308 (obtained from compound 106, as shown in scheme 35) with the formation of alcohol 120. Target C16-ketone functionality can then be generated by oxidation of the secondary alcohol at C16 using, for example, PDC in CH2CL2getting the building to obtain the corresponding derivative of the tertiary alcohol, in this example, the connection 122. Appropriate alkoxybenzenes 123 can then be obtained directly from the connection 122 using a suitable base and alkylhalogenide.

Alkoxygroup at C16 can be obtained directly from the corresponding C16-hydroxycodone. For example, the connection 124 can be obtained by the interaction of the connection 120 with the reagent, for example CH3I, and a base, such as2CO3(scheme 36 provided in the end of the description).

C16-Alkyl groups can be entered by direct alkylation of compounds that contain C17-carbonyl. For example, the interaction connection 106 with CH3I and LDA (you can use other strong base and alkylating agents) in THF gives C16-methylcoumarine 125 (scheme 37 provided in the end of the description).

Compounds of structure 6 may have an oxygen and/or hydrocarbon substitution at C17, including tertiary alcohol and hydroxyl functionality. Exemplary synthetic methodology to provide the tertiary alcohol and hydroxyl substitution at C17 for the connection structure 6 is provided below. It should be recognized that the same or analogous synthetic methodology can be applied to obrazovash-tertiary alcohol substitution.

So, turning on the Grignard reaction, similar to the transformation described in scheme 34, can be used to attach the tertiary alcohol functionality to the C17 position. For example, as shown in scheme 38, provided at the end of the description, the connection 106 can be subjected to interaction with CH3MDG simple ether to obtain the derivative of the tertiary alcohol 126. Methylation of the resulting tertiary alcohol gives the corresponding C17-methoxycoumarin 127. Of course, other alkylating agents can be used to obtain a wide range of hydrocarboncontaining.

In another aspect of the present invention offers a C5-stereoplane steroids, with hydroxylation at C6 and C7, 5-hydrogen and no oxygen atom associated with C3. In one implementation stereoregularity steroid has the structure 7 including individual enantiomeric or geometric isomers and further including MES, or a pharmaceutically acceptable salt. The structure of 7 is defined as follows.

The connection formulas

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C4, C11, C12, C15, C16 and C17 is independently substituted

(a) one sgde n is a number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

C3 is substituted by one =C(R4)(R4and-C(R4)(R4)(C(R4)(R4))n, where n is the number from 1 to about 6, or two of the-X and-R4with the proviso that R3 is not associated with the oxygen atom;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen , who may form a ring, and

X represents fluoride, chloride, bromide and iodide.

Connection patterns 7 are hydroxylation at C6 and C7 and hydrogen. The synthetic sequence for preparing compounds having these structural features, cited in scheme 2, which shows the connection 11. Although the connection 11 is an oxygen atom associated with C3, and thus, is not representative compound of structure 7, the connection 11 can be converted into a compound of structure 7. As shown in scheme 39, provided at the end of the description, the connection 11 can be restored in connection 128, where lithium in a mixture of liquid ammonia/tert-butanol can be used to carry out the necessary repair. Hydrogenation of compound 128 can give the connection 105 with the group-CH2- in C3, as also shown in scheme 39.

As shown in scheme 40, provided at the end of the description, the connection 128 can alternatively be turned into additional compounds of structure 7. So, C17-protected hydroxyl group 128 can be freed from the protective groups to obtain the compound 129 and then C17-hydroxyl group of compound 129 can oxidize in the C17-carbonyl group, as in compound 106.

For example, in the above scheme 39 describes the conversion of compound 11 to compound 105 using the previously described chemical transformations. Thus, chemical transformation, described here in connection with the scheme can be extended to include compounds containing methylene, and not hydroxyl or carbonyl group at C3. In some cases, however, first necessary number of stages of protection and/or removal of protective groups.

In scheme 41, provided at the end of the description, there is shown an example where C3-silicotitanate must first be freed from the protective groups before reaction desoxyribose. The TBDMS group in compound 31 can be removed using TBAF in THF. Getting methylxanthines derived compounds 130 using KN CS2and Me and subsequent recovery using n-V3Sn gives compound (131) containing methylene group at C3 and the protected hydroxyl group at C1. Oxidation of C1-ketone then carried out by removing C1-protective group, followed by use of a suitable oxidizing Agay the structure 7, having C3-alkyl functionality can be obtained using the Wittig reagent (obtained from C3-ketone, as described in connection with figure 11). A number of Wittig reagents that can be used for this purpose, provide deputies with different length and branching of the chain.

In the aspect of the present invention offers demetilirovanie steroids, which have oxygen and/or hydrocarbon substitution at C6 and C7, but are not methyl groups at C10 and C13. In one implementation demetilirovanny steroid has the structure of 8, including its individual enantiomeric or geometric isomers and further including MES, or a pharmaceutically acceptable salt. Structure 8 is defined as follows.

The connection formulas

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted

(a) one of =O, =C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))n)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4eilam, the C14 is not replaced by stands;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

Some examples of compounds containing substituents other than methyl, R10 or R13 are described here in connection with circuits 20, 29 and 30. The substituents include carbon schemes 20, 29 and 30 are connections with no substitution (that is, with the substitution of only hydrogen) at C10 and/or C13. Below are examples discussing synthetic approaches to obtain 19-nor-6,7-diocesana steroids.

The synthesis of many of the various compounds of the present invention is described in detail in connection with compounds 1 and 247, both commercially available starting products. However, obtaining similar compounds, for example compounds 141, which differ only in the absence of C10-methyl substituent can be carried out according to the scheme 42 provided at the end of opinia.

In scheme 42 the original product is commercially available 19-nortestosterone (133) (Steraloids Inc., Wilton, NH, or Aldrich Chemical Company, Milwaukee, WI). Reconnection 133 using NaBH4in ethanol can give the connection 134, which contains the 3-hydroxyl group. After defending the 3-hydroxyl group using TBDMSC1 and imidazole in DMF allyl oxidation obtained, freed from the protective groups of the compound (135), can be used to obtain derived Aenon 136. Recovery and acetylation, as described in the previous sections (scheme 1), followed by gidroborudovaniya using NR3-Throaway. For the protection of 6,7-hydroxyl using 2,2-dimethoxypropane and camphorsulfonic acid can be followed by oxidation of the 17-hydroxyl group using PDC in CH2Cl2for connection 140 containing C17-ketone function. Interaction connection 140 with the Wittig reagent derived from bromide ethyltriphenylphosphonium and tert-GFCF in toluene gives ethylidenenorbornene, which can be freed from the protective groups in 80% acetic acid to obtain trihydroxystilbene 141, which is identical with the compound 333, except for the lack of C10-methyl substituent.

In the aspect of the present invention offers polyarylene steroids with oxygen and/or hydrocarbon substitution at each of C3, C4, C6 and C7, where oxygen and/or hydrocarbon substitution at C6 has an alpha stereochemistry and oxygen and/or hydrocarbon substitution at C7 has a beta stereochemistry. In one implementation policykey steroid has a structure 9, including its individual enantiomeric or geometric isomers and further including her MES or a pharmaceutically acceptable salt. Structure 9 is identified as follows.

The connection formulas

< / BR>
including the tsya

(a)onethe=O,=C(R4)(R4)- C(R4)(R4) ((R4)(R4))nand-O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1,

provided that R17 is not replaced by any of the following groups:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
each of C5, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

C8 substituted by-X or R4and preferably not associated directly with oxygen;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom, selected from the group status is of Pereda, with which they are linked, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

Compounds having oxygen and/or hydrocarbon substitution, shown in structure 9, can be obtained from compound 142, which is obtained as described in scheme 52. As shown in scheme 43, provided at the end of the description, the connection 142 can be epoxidizing number of epoxidation conditions, for example, using m-chloroperbenzoic acid (m-SRV) in dichloromethane to obtain the epoxy compound 143. Ring-opening of epoxy groups with the use of weak organic acids (for example, anhydrous acetic acid, which is preferred) gives compound 144, which is a representative compound of structure 9.

From the connection 144 you can get many other compounds of structure 9. For example, as shown in figure 43, the connection 144 you can deacetylate to get tetragidroalanatov connection 148. Ketone group at the C17 can be subjected to transformation by Wittig as described above, to ensure the approach path to a large class tetrahydrocannabinolic compounds of structure 9.

Structure 6, which has 3,4,6,7-tetracycline system, can the t to have the oxygen atom at C11. Synthetic methodology for the introduction of C11-atom of oxygen, which can be used to obtain the compounds of structures 5-12, including structure 9 may be effected by chemical transformations shown in scheme 44, provided at the end of the description, or chemical transformations, similar chemical transformation shown in scheme 44.

For example, it is better than using commercially available product with C11-hydroxyl functionality or9,11the carbon-carbon double bond, the formation of m-bis-chloridesensitive ether with its subsequent photolysis generate target unsaturation in9,11-position (compound 149). So, C6 -, and C7-hydroxyl in compound 146 (obtained according to the scheme 61) can be protected using 2,2-dimethoxypropane and camphorsulfonic acid to obtain compound 147. Subsequent interaction 147 m-bis-haridusklassifikaatorid in pyridine, followed by photolysis in CC14network connection 149. Protection of the hydroxyl groups of the a-ring with subsequent gidroborudovaniya/oxidation gives C11-hydroxy 151. Complete removal of the protective groups with 80% acetic acid gives Hexal 152.

In practical applications on. In one implementation steroid ketone has the structure 10, including its individual enantiomeric or geometric isomers and further including her MES or a pharmaceutically acceptable salt. The structure 10 is identified as follows.

The connection formulas

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C6, C7, C11, C12 and C16 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

provided that C3, C4, 6 and C7 are not replaced simultaneously by hydroxyl or protected hydroxyl and preferably not replaced both oxygen atoms;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

G represents-C(=O)-, -CH(OR1)-, -C(R4)(OR1)- or-C(OR1)(OR1)-;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1is C what ur, which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

A convenient approach to the C17-side chain in compounds of structure 10 begins with L-carvone, as shown in scheme 45, provided at the end of the description.

L-carvon (153) can be transformed into a compound 154 according to literature methods. See, for example, Tetrahedron Letters, 25(41): 4685-4688 (1984). The primary alcohol in connection 154 is then protected, for example, by conversion into the acetate ester. Remove Catalinas protective group in the compound 155 using acidic conditions gives the aldehyde 156.

Connection 156 may provide an approach to the formation of the C17-side chain in compounds of structure 10, as shown in figure 46, provided at the end of Elfstone and grounds, for connection 157 (used as starting product in scheme 46). Then four hydroxyl groups can be converted into a protected hydroxyl group, such as benzyloxy, as shown in connection 158. Connection 158 is then combined with the aldehyde 156 (scheme 45) in the presence of a Lewis acid to obtain a compound 159. Release s-acetoxyl from the protective group can then be performed as the basis for obtaining delovogo connection 160, which can then oxidize in-lactonase connection 161. Allyl oxidation connection 161 may enter the carbonyl part 15 joint oxidation of benzyl groups (EAP) in benzoate (Bz) group for education connection 162.

Recovery conjugate16the carbon-carbon double bond in the D-ring connection 162 network connection 163. Remove benzoate groups in 163 can be done using basic conditions (e.g., NaOMe in Meon) joint epimerization at C14 to obtain product 164, which contains epimeno mixture of compounds having a CIS-connection C/D-rings and TRANS-connection C/D-rings. Finally, you can protect C15-ketone followed by reduction of the lactone in lactol and removing the protective grumpier, 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-it.

Connection structure 10 may have a C15-ketone and C22,C-epoxypolyester. In fact, compounds containing different functionality in the rings A to D, except C15-ketone and polyacetale side chain, can be obtained using a combination of methodologies described here.

For example, as shown in figure 47, is provided in the end of the description, the connection 176, which contains in C3 methylene, carbonyl at C15 and Polyacetal side chain, can be obtained using the methodology described here. C15-Ketone and Polyacetal side chain can then be entered using the methodology described in detail above (in connection with circuits 45 and 46).

As shown in figure 47, the connection 76 can be freed from the protective groups with N2Pd/C in ethanol to obtain compounds containing C11-hydroxyl functionality, heated in ROS3and pyridine can be obtained compound 167, containing9,11-double bond, and 11,12-isomer. Epoxidation (167) using m-SRVA with subsequent restoration LiAlH4can be used for connection 169, which contains C9-hydroxyl punctuation by Wittig can be done to obtain the olefinic product 171. The transformation of compound 171 lactol 176 can be performed using standard methods described here.

The second example involves derivatization 186, compound that contains C15-ketone and Polyacetal side chain, and Cl-hydroxyl functionality. Connection 186 can be obtained by a multi-stage methods from commercially available starting product 177, as shown in figure 48, is provided at the end of the description. The first stage involves the protection of 178 connection using, for example, ethylene glycol, p-s in benzene. Then join Michael using, for example, benzyl alcohol and potassium hydroxide gives Cl-benzyloxypropionic 179. Recovery using LS-Selectrideketone 179 followed by protection of the resulting alcohol as benzyloxypropionic can be used for connection 180. The transformation of compound 180 in lactol 186 can then be accomplished using the methods described in scheme 47 and described in detail in other previous examples.

Thus, the methodology described here can be used to obtain compounds with a functionality of carbon atoms in the structure of the steroid rings, as well as with Sega invention offers steroids, having oksigenirovannym at C6 and C7 with Piran or lactosidase side chain at C17. In one implementation, the steroid has the structure 11, including its individual enantiomeric or geometric isomers and further including her MES or a pharmaceutically acceptable salt. Structure 11 is defined as follows.

The connection formulas

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C3, C4, C11, C12, C15 and C16 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1,

provided that C3 and C4 are not replaced simultaneously by hydroxyl or protected hydroxyl and preferably not replaced both oxygen atoms;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4or1;

G represents-C(=O)-, -CH(OR1)-, -C(R4)(OR1)- or-C(OR1)(OR1)-;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1predie group OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide.

Obtaining compounds of structure 12 can be accomplished using the methodology outlined here in many places. For example, compound 196 (scheme 49 provided at the end of the description) and 207 (scheme 50, provided at the end of the description) can be synthesized from compounds 30 and 55 multistage ways. The methods used for the conversion of the C17-silyloxy in connection 30 in the olefin 190, similar to the methods described in detail in the previous examples is ostranitsa on the transformation of compounds 55 200 and 200 to 207, respectively.

Chemical transformations described in the above circuits 49 and 50, are just two examples of how the methods discussed here can be applied to obtain compounds containing model 6,7-dioxygenase and a side chain with Polyacetal or-lactone. Thus, the methodology described previously, can be used to obtain compounds with a functionality of at C2, C4, C8, etc.

In the aspect of the present invention offers steroid epoxides. In one implementation steroidal epoxide has the structure 12, including its individual enantiomeric or geometric isomers and further including her MES or a pharmaceutically acceptable salt. The structure 12 is defined as follows.

The connection formulas

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C1, C2, C11, C12, C15, C16 and C17 is independently substituted

(a) one of = O, = C(R4)(R4)- C(R4)(R4) ((R4)(R4))n- and -(O(C(R4)(R4))nO)-, where n is the number from 1 to about 6, or

(b) two of the following, which are selected independently: -X, -R4and-OR1;

each of C5, C8, C9, C10, C13 and C14 is independently substituted with one of-X, -R4orwhich is disposed;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where vicinal groups OR1may together form a cyclic structure which protects vicinal hydroxyl groups, and where genialny group OR1may together form a cyclic structure which protects a carbonyl group, with the proviso that one-OR1or both-OR1the C6 and C7 represent carbonyl or protected carbonyl group;

R4in each case, independently, selected from H and C1-30-organic moiety that may optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide and iodide,

with the proviso that R7 is not carbonyl substitution, when R5 is hydroxy or or1-substitution.

As in the previous examples, the introduction of functional groups at different positions within the structure of the steroid ring compounds containing 3,4-epoxy group, the structure 12 can dosa, the oxygen atom can be put in position at C9 and/or C11 by epoxidation9,11-double bond.

Thus, the recovery LS-selectride with subsequent removal by oxidation using reagents described previously for the connection, such as connection 10 can provide olefin compound 208 (scheme 51). The transformation in9,11the olefin can be carried out using standard methodology, and the simultaneous reaction3,4- and9,11-double bond gives the target epoxides at C3-C4 and C9-C11. Oxidation of the C3-hydroxyl part of the PDC in CH2Cl2you can then use for education target And unsaturated-ring (not necessarily the disclosure epoxy rings can give 3,6,7,9-polyhydroxyalkane steroid 215).

The introduction of alkyl groups at the C16 position can be carried out using chemical transformations, such as those described above. In the following example (scheme 52, provided at the end of the description) methyl group is introduced into this position by condensation enolate D-rings methyliodide. This methodology similar to the methodology described in connection with the scheme 37. As shown in scheme 52, alkilirovanny epoxide 218 can be subjected to conditions of disclosure ring e is tion, discussed in detail in the previous sections. Alternative compounds containing a different stereochemistry at C6 and C7 can be obtained, as described in the next section. For example, selective totalrevenues connection 221 (obtained according to the scheme 73) using p-TsCl in pyridine followed by treatment with potassium carbonate can be obtained containing epoxide compound 223. Subsequent disclosure of the cycle using aqueous acid can give compounds 6, 7-stereochemistry as shown in scheme 53, provided at the end of the description.

Connection with 6,7-stereochemistry can be obtained from commercially available starting materials, as shown in scheme 54, provided at the end of the description. So, cholesterylester can oxidize using RuCl3and t-BuOOH in CH2C12to obtain containing the exact location of the connection 229. Exchange protective groups in C3 on t-BDMS-derived and subsequent recovery system lithium-ammonia and trapping of the enolate anion (MeO)2PC1 receive the enol phosphate 231. The second recovery system lithium-ammonia gives6,7-double bond, which can oxidize OsO4for connection 233 containing the model 3,6, 7-trihydroxyflavone.

Used stamov, consisting of at least one and not more than the maximum number of carbon atoms indicated in this range, usually not more than 30 carbon atoms, and any number of non-carbon atoms.

C1-30-Organic part can be saturated or unsaturated hydrocarbon radical. Saturated hydrocarbon radical is determined in accordance with the present invention as any radical consisting solely of carbon and hydrogen, where a single connection is used exclusively for the connection together of carbon atoms. Thus, any stable system of carbon atoms and hydrogen atoms, having at least one carbon atom, is included within the volume of the saturated hydrocarbon radical according to the invention. Some specific terminology that can be used for reference to specific systems of carbon atoms will be discussed below.

Carbon atoms can form alkyl group, i.e. an acyclic chain of carbon atoms which may be branched or unbranched (linear). Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl represent alkyl groups having from 1 to 4 carbon atoms (usually called is to transform cycloalkyl group, that is, a cyclic system of carbon atoms, where cyclopropyl, cyclobutyl, cyclopentyl are cycloalkyl group of the invention having 3-5 carbon atoms. Additional groups within the scope of "cycloalkyl", as defined here, are polycyclohexylene group, as defined below.

Polycyclohexylene group represents a system of carbon atoms, where at least one carbon atom is part of at least two separately identifiable rings. Polycyclohexylene group may contain a bridge between two carbon atoms, where bicyclo[1.1.0]butyl, bicyclo[3.2.0]octyl, bicyclo[5.2.0]nonyl, tricyclo [2.2.1.01]heptyl, norbornyl and PINANYL are representative examples. Polycyclohexylene group may contain one or more condensed cyclic systems where declines (radical decline) and perhydroanthracene are representative examples. Polycyclohexylene group can contain spirochaetaceae, in which one atom is the only common member of two rings. Spiro[3.4]octyl, Spiro[3.3]heptyl, Spiro[4.5]decyl are representative examples.

In addition, saturated hydrocarbon radical may be sostav the ilen groups. Thus, the group R4or R5can be alkyl group (e.g. methyl) cycloalkyl (for example, tsiklogeksilnogo) Deputy, so that R4or R5is cyclohexylmethyl group. As another example, R4or R5can be cycloalkyl group (for example, cyclooctene) having two alkyl substituent (for example, methyl and ethyl Deputy), so that R4or R5is metiletilchlorfos group. As a last example, R4or R5can be cycloalkyl group with alkyl Deputy, where the alkyl substituent of substituted polycyclohexylene Deputy.

As indicated above, R4or R5may be an unsaturated hydrocarbon radical. This group, R4or R5is defined as having a system of carbon atoms as described above for the saturated hydrocarbon radicals, with the additional feature consists in that at least one connection between any two carbon atoms other than a single bond. An alkyl group with one double bond is called alkenylphenol group, while the alkyl group having more than one double bond, called Ernie group. Alkyl group with a triple bond are called alkenylphenol group, while the alkyl group having more than one triple bond, called alkuperaisilla group where alkadienes (2 triple bond) and alkadienes (3 double bonds) are approximate group.

Similarly, cycloalkyl group can have one or more double or triple links and is included in the amount of unsaturated hydrocarbon radical according to the invention. Cycloalkenyl and cycloalkenyl are common names given to groups having one ring carbon-based with one double or triple bond in the ring, respectively. Cycloalkenyl groups are cycloalkyl group with two double bonds contained in the structure of the ring. The double bond can be ekzoticheskoy to the ring, for example a carbon atom of the ring may be in the group = CH2(i.e. methylidene group) or a higher homolog associated with it.

The ring can be ninasimone to the extent when it is aromatic, and it is still included within the scope of unsaturated hydrocarbon radical. Thus, the aryl group, for example phenyl and naphthyl, included within the volume so the unsaturated hydrocarbon radical, kalkilya (R4or R5represents an alkyl group with at least one aryl Deputy, for example, benzyl) and alcylaryl (R4or R5represents aryl ring with at least one alkyl substitute, such as tosyl) group are included in the limit R4or R5. WITH6-Arily are preferred organic component parts of the invention.

R4or R5include organic parts, which contain a heteroatom. Heteroatoms according to the invention are any atom other than carbon or hydrogen. A preferred class of heteroatoms are present in the nature of the atoms (except carbon and hydrogen). Another preferred class are the nonmetals (except carbon and hydrogen). Another preferred class consists of boron, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium and halogen (i.e. fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine). Another preferred class consists of nitrogen, oxygen, sulfur and halogen. Another preferred class consists of nitrogen, oxygen and sulfur. Oxygen is the preferred heteroatom. Nitrogen is the preferred Goethe is e, at least one Deputy, containing at least one heteroatom. In this paragraph, R4will be used for reference as to R4and R5. In other words, R4may be a hydrocarbon radical, as defined above, where at least one hydrogen atom replaced by a heteroatom. For example, if the heteroatom is oxygen, the Deputy may be a carbonyl group, i.e., two hydrogen atoms on the same carbon atom substituted on the oxygen with the formation of groups or ketone or aldehyde. Alternative one hydrogen may be replaced by an oxygen atom in the form of hydroxy, alkoxy, aryloxy, aralkylated, alkylacrylate (where alkoxy, aryloxy, aralkylated, alkylacrylate can be together marked hidrocarburos), heteroaromatic, -OC(O)R4, Catala, acetal, polumetla, Polyacetal, epoxy and S3M Heteroatom may be halogen. The heteroatom can be nitrogen, where the nitrogen forms a part of the amino (-NH2-THE OTHER4, -N(R4)2), alkylamide, arylamide, arylalkylamine, alkylsilane, nitro, -N(R4)SO3M or aminocarbonylmethyl. The heteroatom may be a sulfur where the sulfur forms part Tilney, thiocarbonyl, -SO3M, sulfonylurea, such as formyl, cyano, -C(O)OR4-C(O)OM, -C(O)R4, -C(O)N(R4)2, carbamate, carbohydrate and carbohidrazona acid.

In the above exemplary heteroaromatics the substituents M represents a proton or metal ion. Preferred metal ions in combination with a counterion form a physiologically tolerated salt. The preferred metal of which may be formed of metal ion includes alkali metal [e.g., lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs)], alkaline earth metal [e.g. magnesium (MD), calcium (CA) and strontium (Sr)] or manganese (MT), iron (Fe), zinc (Zn) or silver (Ad). Preferred groups M are alkali metals or alkaline earth metals. Preferred groups M are sodium, potassium, magnesium and calcium. Preferred groups M are sodium and potassium.

Another class of organic parts according to the invention are hydrocarbon radicals, as defined above, where at least one carbon atom is replaced by at least one heteroatom. Examples of such organic parts are heteroseksualci (cycloalkyl group having at least one carbon replaced by less so on. Collectively, this class of organic parts can be called heterogeneously (heteropneustidae radicals). Another example of such organic parts has a heteroatom, a connecting bridge (a) radical, which is bound to be an organic part, and (b) the rest of the organic part. Examples include alkoxy, aryloxy, arylalkyl and alkylaminocarbonyl, which may collectively be referred to here hydrocarbonoclasticus or parts. Thus, -OR4represents the approximate R4group of the invention. Another example is-other4.

Examples of heterocyclization are pyrrolidinyl, piperidinyl, tetrahydrofuranyl, di - and tetrahydropyranyl. Examples of geterotsiklicheskie radicals are formed from pyrrolidine, imidazolidine, oxazolidine, pyrazolidine, piperidine, piperazine and research. Examples geterotsiklicheskikh substituents are radicals formed by removal of hydrogen from 2 - and 3-pyrroline, oxazoline, 2 - and 4-imidazoline and 2 - and 3-pyrazoline.

Although organic part can have up to 30 carbon atoms, the preferred organic part of the invention have less than 30 carbon atoms, for example up to 25 and is in carbon or up to 12 or 10 carbon atoms. A preferred class of organic parts have up to 8 or 6 carbon atoms.

The following examples are exemplary of the organic part R4and R5where R4or R5connects to the steroid ring through a carbon atom include alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkylaryl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, allyloxycarbonyl, alkenylacyl, alkyloxyaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, aryloxyalkyl, heterocalixarenes, carboxylic acid, cyano and formyl.

The following examples are exemplary of the organic part R4and R5where R4or R5connects to the steroid ring through the oxygen atom of: hydroxy, oxo, alkoxy, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, aryloxy, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, heterocyclics.

The organic part R4and R5may contain a nitrogen atom through which the organic part R4or R, where L2and L3independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, formyl, heterocyclyl, alkylaryl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl and heterocalixarenes, so that L2and L3together can be alkylene or Alcanena, through this, they in combination with the nitrogen atom to which they are attached, form a 3-8-membered saturated or unsaturated ring.

The following examples are exemplary of the organic part R4and R5where some R4or R5connects to the steroid ring through a sulfur atom: alkylsulfate, alkynylaryl, alkylsulfate, cycloalkylation, cycloalkenyl, allsolid, generalkonsulat, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, geterotsiklicheskikh and groups of the formula: -S(OH)nH-S(OH)nL4, -S(O)mOH, -S(O)mOL4, -OS(O)mOL4and-O(S)mOH, where L4selected from alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.

In visionarily and aryl group (collectively denoted by hydrocarbon groups, R4or R5can be fully or partially galogenirovannyie and/or substituted groups L5up to five. Heterocyclyl, heterocyclic, heterocalixarenes, heterocalixarenes and geterotsiklicheskikh (collectively denoted heterocyclyl groups R4) can be similarly fully or partially galogenirovannyie and/or substituted groups L5up to five.

Group L5contain atoms of carbon, oxygen, nitrogen or sulfur, through which they combine with a carbon atom of the hydrocarbon groups R4or R5or carbon atom or nitrogen heterocyclyl groups R4or R5.

The following groups represent the approximate group L5where the carbon atom in L5connected with hydrocarbon or heterocyclyl group, R4: alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, alkylaryl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl, allyloxycarbonyl, alkenylacyl, alkyloxyaryl, cycloalkylcarbonyl, cycloalkylcarbonyl and aryloxyalkyl.

The following groups represent the approximate group L5where the CI atom, is kenlake, alkyloxy, cycloalkane, cycloalkenyl, aryloxy, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic.

Group L5may contain a nitrogen atom through which the group L5connected with hydrocarbon or heterocyclyl group, R4or R5. Examples include nitro - and nitrogen-containing groups of the formula-NL6L7where L6and L7independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, formyl, alkylsulphonyl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl and arylcarbamoyl, so that L6and L7together can be alkylene or Alcanena, thereby forming in combination with the nitrogen atom to which they are attached, a 3-8-membered saturated or unsaturated ring.

The following groups represent the approximate group L5where the sulfur atom of L5connected with hydrocarbon or heterocyclyl group, R4or R5: alkylsulfate, alkynylaryl, alkylsulfate, cycloalkylation, cycloalkenyl, allsolid, alkylcarboxylic, alkenylboronic, alkyne is rmula: -S(OH)nL8, -S(O)mHE, -S(O)mOL8, -OS(O)mOL8and-O(S)mOH, where L8selected from alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.

In an exemplary organic parts of R4and R5alkyl, Alchemilla, Alchemilla, cycloalkyl, cycloalkenyl and aryl groups, which form a part of the5(collectively denoted by hydrocarbon groups of L5can be fully or partially galogenirovannyie and/or substituted groups L9up to three. Heterocyclyl, heterocyclic, heterocalixarenes, heterocalixarenes, geterotsiklicheskikh (collectively denoted heterocyclyl groups L5can be fully or partially galogenirovannyie and/or substituted groups L9up to three.

Group L9contain atoms of carbon, oxygen, nitrogen or sulfur, through which they are connected with a hydrocarbon group of L5or heterocyclyl group L5.

The following examples are exemplary of the group L9where the carbon atom in L9connected with hydrocarbon or heterocyclyl group L5: alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, arylcarbamoyl, heterocalixarenes, allyloxycarbonyl, alkenylacyl, alkyloxyaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, aryloxyalkyl and heterocalixarenes.

The following examples are exemplary of the group L9where the oxygen atom of L9connected with hydrocarbon or heterocyclyl group L5: hydroxy, oxo, alkoxy, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, aryloxy, heterocyclic, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, geterotsiklicheskikh.

Group L9may contain a nitrogen atom through which the group L9connected with hydrocarbon or heterocyclyl group L5. Such nitrogen-containing group L9include nitro and groups having the formula-NL10L11where L10and L11are independently hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, formyl, alkylsulphonyl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl and heterocalixarenes, so that L10and L11together they could to 8-membered saturated or unsaturated ring.

The following groups represent the approximate group L9where the sulfur atom of L9connected with hydrocarbon or heterocyclyl group L5: alkylsulfate, alkynylaryl, alkylsulfate, cycloalkylation, cycloalkenyl, allsolid, generalkonsulat, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, geterotsiklicheskikh and groups of the formula: -S(OH)nL12, -S(O)mOH, -S(O)mOL12, -OS(O)mOL12and-O(S)mOH, where L12selected from alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl and heterocyclyl.

In an exemplary organic parts of R4and R5alkyl, Alchemilla, Alchemilla, cycloalkyl, cycloalkenyl and aryl groups, which form a part of the9(collectively denoted by hydrocarbon groups of L9can be fully or partially galogenirovannyie and/or substituted groups L13up to three. Heterocyclyl, heterocyclic, heterocalixarenes, heterocalixarenes, geterotsiklicheskikh (collectively train the HN and/or substituted groups L13up to three.

Group L13contains an atom of carbon, oxygen, nitrogen or sulfur, through which the group L13connects with a hydrocarbon group of L9or heterocyclyl group L9.

The following examples are exemplary of the group L13where the carbon atom in L13connected with hydrocarbon or heterocyclyl group L9: alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, alkylaryl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl, heterocalixarenes, allyloxycarbonyl, alkenylacyl, alkyloxyaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, aryloxyalkyl and heterocalixarenes.

The following examples represent groups L13where the oxygen atom of L13connected with hydrocarbon or heterocyclyl group L9: hydroxy, oxo, alkoxy, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, aryloxy, heterocyclic, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, geterotsiklicheskikh.

Group L9
. Such nitrogen-containing group L13include nitro and groups having the formula-NL14L15where L14and L15independently represent hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, formyl, alkylsulphonyl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarbamoyl and heterocalixarenes, so that L14and L15together can be alkylene or Alcanena, thereby forming in combination with the nitrogen atom to which they are attached, a 3-8-membered saturated or unsaturated ring.

The following examples represent groups L13where the sulfur atom of L13connected with hydrocarbon or heterocyclyl group L9: alkylsulfate, alkynylaryl, alkylsulfate, cycloalkylation, cycloalkenyl, allsolid, generalkonsulat, alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl, arylcarboxylic, geterotsiklicheskikh and groups of the formula-S(O)nL14, -S(O)mHE, -S(O)mOL14, -OS(O)mOL14and-O(S)mOH, where L14selected from alkyl, alkenyl, quinil, cycloalkylation 0, 1 or 2.

Some of the substituents R4and R5may contain asymmetric carbon atoms. Compounds containing such substituents may therefore exist in enantiomeric and diastereomeric forms and in the form of their racemic mixtures. They are all included within the scope of the present invention. The racemate or racemic mixture does not imply a mixture of stereoisomers 50:50.

In accordance with the description of the exemplary organic parts R4or R5the following terms shall have these meanings, unless otherwise stated.

The terms alkyl, alkenyl and quinil are hydrocarbons with unbranched or branched chain, having from 1 to 30 carbon atoms (at least two carbon atoms for alkenylphenol group) and not having unsaturation or having at least one double bond or at least one triple bond, respectively. The number of carbon atoms is preferably from 1 to 20 and from 1 to 10.

The terms cycloalkyl and cycloalkenyl refers to cyclic hydrocarbon groups of carbon atoms from 3 to 8, where cycloalkyl group is saturated and cycloalkenyl group has at least one double bond in Prel, cyclohexyl, cycloheptyl and cyclooctyl.

The term aryl refers to aromatic groups which have at least one ring having a system of conjugated PI-electrons, and includes carbocyclic aryl, heterocyclic aryl and burilnye group.

The term carbocyclic aryl refers to aromatic groups, where the atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include phenyl, naftalina and indenolol group.

Heterocyclic aryl refers to mono - or bicyclic ring system of the carbon atoms of from 5 to 12, where each monocyclic ring may have from 0 to 4 heteroatoms, and each bicyclic ring may have from 0 to 5 heteroatoms selected from N, O and S, provided that these heteroatoms are not vicinal oxygen atoms and/or sulfur. Examples of such mono - or bicyclic systems of rings include (without limitation) benzofuran, benzothiophene, indole, benzopinacol, coumarin, isoquinoline, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, triazole, quinoline, pyrimidine, pyridine, pyridone, pyrazin, pyridazine, isothiazol, isoxazol and tetrazole.

Biaryl refers to phenyl, substituted carbate joining the phenyl ring.

Heterocyclyl refers to a stable 5 to 7-membered mono - or bicyclic or stable 7-10-membered bicyclic heterocyclic ring system any ring of which may be saturated or ninasimone and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and where the heteroatoms nitrogen and sulfur may be optionally oxidized and the nitrogen heteroatom may be optionally quaternity, including any bicyclic group in which any of videopreteen heterocyclic ring condensed with the benzene ring. Heterocyclic ring may be attached to the steroid ring via any heteroatom or carbon atom of the heterocyclic ring, which leads to the creation of a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxazepines, azepine, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, hinokitiol, isothiazolinone, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothiazyl, thiomorpholine, themorphological, themorphological and oxadiazolyl. Morpholino means the same as morpholinyl.

Heterocyclics and heterocalixarenes refer to heterocyclyl groups linked through an oxygen atom or carbonyl group, respectively with one or more of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Heterocalixarenes refers to heterocyclisation connected via a carbonyl group with one or more of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Geterotsiklicheskikh refers to heterocalixarenes group linked through an oxygen atom with one or more of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Alkylsulphonyl, alkenylboronic, alkynylaryl, cycloalkylcarbonyl, cycloalkylcarbonyl and arylcarbamoyl belong to

the parts where the carbonyl group (Sdney group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9and alkyl, Alchemilla, Alchemilla, cycloalkyl, cycloalkenyl or aryl group, respectively, also connected with the carbonyl group.

Allyloxycarbonyl, alkenylacyl, alkyloxyaryl, cycloalkylcarbonyl, cycloalkylcarbonyl and aryloxyalkyl are parts where the carbonyl group (C=O) provides the carbon atom through which this part is connected with one of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9and alkoxy, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl or alloctype also respectively connected with the carbonyl group.

Alkoxy, alkenylacyl, alkyloxy, cycloalkane, cycloalkenyl, aryloxy belong to groups, where the oxygen is bound to the alkyl, alkenylphenol, alkenylphenol, cycloalkyl, cycloalkenyl or aryl group, respectively, and where the oxygen atom is associated with one of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Alkalicarbonate belong to groups, where the oxygen is bound with alkylcarboxylic, alkenylamine, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl or arylcarbamoyl group, respectively, and where oxygen is associated with one of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Alkylsulfate, alkynylaryl, alkylsulfate, cycloalkylation, cycloalkenyl and allsolid belong to groups where sulfur is associated with alkyl, alkenylphenol, alkenylphenol, cycloalkyl, cycloalkenyl or aryl group, respectively, and where the sulfur atom is associated with one of the steroid ring, a hydrocarbon group, R4, hydrocarbon groups of L5or a hydrocarbon group of L9.

Alkylcarboxylic, alkenylboronic, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl and arylcarboxylic belong to the group where the sulfur atom is associated with alkylcarboxylic, alkenylamine, alkylcarboxylic, cycloalkylcarbonyl, cycloalkylcarbonyl or arylcarbamoyl group, respectively, and where the sulfur atom is associated with one who PPy L9.

Alkylene refers to the bridge with a non-branched chain, containing from 1 to 5 carbon atoms which may be substituted by 1-3 lower alkyl groups or a fully or partially halogenated lower alkyl groups.

Albaniles refers to the bridge with a non-branched chain containing 2 to 5 carbon atoms and having one or two double bonds, which may be substituted by 1-3 lower alkyl groups or a fully or partially halogenated lower alkyl groups.

Akinyan refers to the bridge with a non-branched chain containing 2 to 5 carbon atoms and having one or two triple bond, which may be substituted by 1-3 lower alkyl groups or a fully or partially halogenated lower alkyl groups.

The lower alkyl group refers to a C1-C5-alkyl groups, such as stands, ethyl, n-propylene, isopropyl, n-butile, tert-butile, sec-butile, isobutyl, n-pentile, isopentyl and so on.

Halogen refers to fluorine, chlorine, bromine and iodine and halogenated group refers to the carbon atom having at least one attached halogen atom.

Formyl otnositssya.

Pharmaceutically acceptable salt include acid additive salts and basic additive salt.

Acid additive salts refer to those salts which are formed from the steroid compounds of the 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.

Basically additive salts include those salts which are formed from steroids of the invention and inorganic bases, such as salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., Suitable salts include salts of ammonium, potassium, sodium, calcium and magnesium, salts formed from pharmaceutically acceptable organic non-toxic bases, vklyuche amines, 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, purines, piperazine, piperidine, N-ethylpiperidine and the like.

In another implementation of the present invention provides compositions that include 6,7-diocesano steroid compound, as described above, in a mixture or otherwise in Association with one or more inert carriers and, if necessary, an optional ingredients. The pharmaceutical composition containing the compound in combination with a pharmaceutically acceptable carrier or diluent, the compound has the formula:

< / BR>
including its pharmaceutically acceptable salt and solvate, where

each of C5, C6, C7, C8, C9, C10, C13 and C14 is independently substituted by-X, -R4and-OR1;

each of C1, C2, C3, C4, C11, C12, C15, C16 and C17 is independently substituted by Deputy selected from (a) or (b), where

(a) represents one of =O, =C(R4) (R4), -C(R4)(R4)(C(R4two of X, -R4and-OR1that is independently chosen in each case;

rings a, b, C and D may be independently a fully saturated, partially saturated or fully ninasimone;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group, where the group OR1the C6 and C7 may together form a cyclic structure that protects both hydroxyl group;

R4in each case independently selected from H and R5;

R5represents C1-30-organic part, which can optionally contain at least one heteroatom selected from the group consisting of boron, halogen, nitrogen, oxygen, silicon and sulfur, where two genialny group, R4together with the carbon atom to which they are bound, may form a ring, and

X represents fluoride, chloride, bromide or iodide,

provided that the C15 is not associated with the oxygen atom.

In preferred compositions the C17 is substituted hydrocarbon group, such as1-C7is an alkyl group, or such as olefinic group of the formula = C(R4)(R4), where preferably R4represents hydrogen or C1-C10-alkyl; predpochtite preferred compositions C17 is substituted by two atoms, independently selected from hydrogen atoms and halogen, or R17 is substituted by at least one oxygen atom, or R17 is substituted by hydroxyl or protected hydroxyl group, or R17 is substituted carbonyl or protected carbonyl group, or R17 is substituted by alkoxygroup. In preferred compositions Vice C17 does not include

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In another preferred composition C15 is substituted with two hydrogen atoms and/or C4 is replaced by hydrogen and one of-X, -R5or1and/or C5 substituted by hydrogen, and/or C4 is associated with at least one hydrogen, so that when C4 is associated with two atoms of hydrogen, then R3 is not associated with either oxygen or two hydrogen atoms. In another preferred composition C4 is associated with two atoms of hydrogen only when C3 is not associated with either oxygen or two hydrogen atoms. In another preferred composition C4 is associated with stands, only when C4 is not associated with the two metelli or formyl. In other preferred compositions of the compounds have a hydrogen at the C5 alpha-configuration. In another preferred compositions of the compounds are group-OR1the C6 with an alpha configuration. In another preferred and the compounds have the Deputy OR1the C6 with the alpha configuration and Deputy-OR1the C7 with beta-configuration. In other preferred compositions of the compounds have at least one of C3 and C4 associated with the oxygen atom, and in a preferred implementation of both C3 and C4 are associated with the oxygen atom. In another preferred composition C10 compounds substituted methyl group and/or C13 compounds substituted methyl group, or as C10 and C13 compounds are substituted with methyl groups. In a preferred composition as C6 and C7 are associated with hydrogen atoms. In another preferred composition of at least one of C1, C2, C3, C4, C5, C8, C9, C10, C11, C12, C13, C14, C15, C16 and C17 is substituted exclusively with hydrogen atoms and more preferably C1 and C2 are substituted exclusively with hydrogen atoms and/or C11 and C12 are substituted exclusively with hydrogen atoms and/or C15 and C16 are substituted exclusively with hydrogen atoms. In preferred compositions, the compounds have a saturated ring a and/or saturated ring, and/or saturated ring With, and/or saturated ring D. the Preferred compositions with compounds having a saturated ring, and more preferred compositions with compounds having a fully saturated case in one preferred compositions C3 and C4 compounds are not substituted, both, only hydrogen atoms. These compositions can be used to treat asthma, allergies, inflammation, including arthritis and thrombosis. These compositions can also be molded in a medicinal product, which can be used in the treatment of, for example, asthma, allergies, inflammation, including arthritis and thrombosis.

These compositions can be used as, for example, standards for quantitative analysis, the conventional means for producing large quantities of goods or pharmaceutical compositions. Quantitatively analyzing the amount of coupling is such a number, which is easily measurable by standard methods and techniques of quantitative analysis, as is well known and acknowledged by experts in the field. Amenable to quantitative analysis of the amount of compounds of the invention will usually be from about 0,001% by weight to about 80 wt.% of the total weight of the composition. Inert carriers include any product that does not destroy or otherwise, does not react covalently with the compound of the invention. Examples of suitable inert carriers are water, aqueous buffers, such as buffers, usually suitable for analysis of high-performance liquid hromatografische acceptable carriers.

Thus, the present invention provides a pharmaceutical or veterinary composition (hereinafter simply referred to as a pharmaceutical composition) containing 6,7-diocesano steroid compound, as described above, in a mixture with a pharmaceutically acceptable carrier. The invention further provides a pharmaceutical composition comprising an effective amount of 6,7-digisleeve steroid compounds, as described above, in Association with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention can be in any form that allows you to enter the composition to the patient. For example, the composition may be in solid, liquid or gas (aerosol) form. Typical routes of administration include, without limitation, oral, local, parenteral, sublingual, rectal, vaginal, and intranasal. The term parenteral used here, includes techniques of subcutaneous injections, intravenous, intramuscular, vnutriserdechno injection or infusion. The pharmaceutical composition of the invention is prepared in such form, in order to allow the active ingredients contained therein to be bioavailable upon introduction of the composition to the patient. The composition is doses), where, for example, a tablet may be a single dosage unit, and a container of steroid in the form of an aerosol can contain multiple dosage units.

The materials used to obtain pharmaceutical compositions should be pharmaceutically pure and non-toxic in the quantities used. Specialists in the art should be obvious that the optimal dose of the active ingredient(s) in the pharmaceutical composition will depend on various factors. Appropriate for this factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, route of administration and the applied composition.

In General, the pharmaceutical composition includes an active 6,7-dookisleniya steroid compounds, as described here, in a mixture with one or more carriers. The carrier(s) may be in the form of particles, so that the compositions are, for example, in the form of tablets or powder. The carrier(s) may be liquid, then the composition are, for example, oral syrup or injectable liquid. In addition, the carrier(s) may be a gas to form an aerosol composition, which can be used, for example, for inhalation for solid, or liquid form, and semi-solid, semi-solid, suspension and gel forms are included within the forms considered here either as a solid or as a liquid.

As solid compositions for oral administration, the composition may be made 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. In addition, you may attend one or more of the following adjuvants: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins; dezintegriruetsja agents such as alginic acid, sodium alginate, primogel, corn starch and the like; lubricants such as magnesium stearate or sarotex; moving agents, such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, corrigent, such as peppermint, methyl salicylate or orange corrigent, and coloring agent.

When the composition is in the form of capsules, for example,trangleball or fatty oil.

The composition may be in the form of a liquid, such as elixir, syrup, solution, emulsion or suspension. Two examples of the composition can be a liquid for oral administration or for delivery by injection. Preferred compositions, when they are intended for oral administration, contain in addition to these compounds, one or more of the sweetening agent, preservatives, dye/coloring matter and amplifier-corrigent. In compositions intended for administration by injection may be included one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and an isotonic agent.

Liquid pharmaceutical compositions of the invention, regardless of whether they are solutions, 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 saline, ringer's solution, isotonic sodium chloride, fatty oils such as synthetic mono or diglycerides which may serve as a solvent or suspendida cf the AK benzyl alcohol or methyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the establishment of toychest, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, suitable syringes and ampoules into multiple doses, made of glass or plastic. Physiological saline is the preferred adjuvant. Injectable pharmaceutical composition is preferably sterile.

A liquid composition intended for either parenteral or oral administration should contain a number of compounds of the invention that has been received appropriate dosage. Usually this amount is at least 0.01% of the compound of the invention in the composition. When the composition is intended for oral administration, this number can vary between 0.1 and 70% by weight of the composition. Preferred oral compositions contain between about 4% and about 50% of the active steroid compounds. Preferred compositions and preparations according to the present invention receive so that a parenteral dosage EDI is designed for local administration, in this case, the carrier may suitably include a solution, emulsion, ointment or gel base. The core can contain, for example, one or more of the following components: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. In the pharmaceutical compositions for local injection may be present thickeners. If the composition is intended for percutaneous introduction, it may include percutaneous patch or device for iontophoresis. Local ready formulation may contain a concentration of the compounds of the invention from about 0.1 to about 10% wt./about. (mass per unit volume).

The composition may be intended for rectal injection in the form of, for example, suppositories, which will melt in the rectum and release the drug. Composition for rectal injection may contain an oily base as a suitable non-irritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol.

The composition may include various materials which modify the physical form of a solid or liquid dosiro the active ingredients. The materials that form the covering shell, usually inert and can be selected, for example, of sugar, shellac, or other agents for intersolubility coatings. Alternative active ingredients can be enclosed in a gelatin capsule.

The composition in solid or liquid form may include an agent that binds to the active steroid compound(s) and thereby assists in the delivery of active components. Suitable agents that may act in this capacity include monoclonal and polyclonal antibodies, a protein or a liposome.

The pharmaceutical composition of the present invention may consist of gaseous dosage units, for example it may be in the form of an aerosol. The term aerosol is used to denote the various systems, stretching from colloidal systems of nature to systems consisting of pressurized packages. Submission can be liquefied or compressed gas or a suitable pump system, which delivers the active ingredients. Aerosols compounds of the invention for delivery of active ingredient(s) may be submitted in single-phase, two-phase or three-phase systems. Delivery of the aerosol includes the necessary cotticelli aerosols can be determined by the person skilled in the art without undue experimentation.

Regardless of whether the pharmaceutical composition of the present invention in solid, liquid or gaseous form, it may contain one or more known pharmacological agents used in the treatment of asthma, allergies, inflammation (including arthritis) or thrombosis.

The pharmaceutical compositions can be obtained by methodology well known in the pharmaceutical field. Various steroid compounds are the active ingredients in pharmaceutical compositions intended for therapeutic use, and they are widely used as active ingredients, and accordingly, the person skilled in the art are familiar with obtaining such compositions. Steroid compounds of the present invention can be manufactured in the form of pharmaceutical compositions in a similar manner.

The composition is intended for administration by injection can be obtained by combining 6,7-digisleeve steroid with water to form a solution. To facilitate the formation of homogeneous solution or suspension can be added surfactant. Surfactants are compounds that Nicollette system for delivery.

The above-described compounds and compositions are used in the treatment of allergies and asthma, arthritis and/or thrombosis. The above-described compounds and compositions can also be used to treat a condition associated with elevated NF-kB, where the subject in need this, enter the number of compounds (or compositions containing compound, effective to reduce the activity of NF-kB. Used herein, the term "treatment of allergies and asthma, arthritis and/or thrombosis" refers to the treatment of allergies and asthma, arthritis and thrombosis and to prevent the development of allergic reactions, bronchostenosis, inflammation and blood clots that cause thrombosis and associated diseases. Used herein, the term " activity of NF-kB refers to any increase or decrease in the transcriptional activity of genes, which can be attributed, directly or indirectly, link any of the members of the NF-kB family of proteins with all the DNA sequences recognized by this family of proteins.

For the treatment of allergies, asthma, arthritis or thrombosis in a warm-blooded animal, such as man, using the effective amount of the compounds or compositions of the present invention. How the effect is known in this area and include the introduction of inhalation, oral and parenteral forms. Such dosage forms include, but are not limited to, parenteral solutions, tablets, capsules, implants with prolonged action and system for percutaneous delivery; or system for metered dose inhalation using a dry powder inhalers or under pressure mnogorazovye inhalation device. Typically, for the treatment of arthritis and thrombosis preferably orally or intravenously, whereas oral or inhaled/intranasal introduction preferable for asthma and allergies. Metered quantity and frequency of injection is chosen to ensure the effective level of the agent without harmful effects. They will usually vary from a dose of about 0.1 to 100 mg/kg / day, typically from about 0.1 to 10 mg/kg / day, when administered orally or intravenously for antiallergic, anti-asthma, antiarthritic or antithrombotic actions. In addition, the dose range is usually from about 0.01 to 1 mg/kg / day when administered intranasally or by inhalation for anti-asthma and anti-allergic effects.

Introduction compounds or compositions of the present invention can be implemented in combination with Lenogo agent to influence asthma, glucocorticoid for effects on arthritis or antihistamine for impact on allergies. Non-steroidal compounds can be entered in conjunction with the steroids of the present invention and/or non-steroidal compounds can be used in combination with steroid compounds of the invention to provide therapy for one or more diseases from allergies, asthma, arthritis and thrombosis.

The following examples are provided for illustration and not for limitation.

Unless otherwise noted, flash chromatography and column chromatography can be performed using Merck silica gel 60 (230-400 mesh mesh). Flash chromatography can be performed according to methodology described in "Purification of Laboratory Chemicals", 3rdedition, Butterworth-Heinemann Ltd. , Oxford (1988), Eds. D. D. Perrin and W. L. F. Armarego, page 23. Column chromatography refers to the way in which the flow rate of eluent through the filling material is determined by the weight. In all cases, flash chromatography and radial chromatography can be used vzaymopony way. Radial chromatography carried out using silica gel on a Chromatotron Model # 7924T (Harrison Research, Palo Alto, California).

Conventional methods of processing the reaction mixture includes dilution of the reaction smeshannym with sodium bicarbonate and then saturated sodium chloride. The organic layer is then dried over MgS4the mixture is filtered and the filtrate is evaporated to dryness in vacuum to give crude product, which may or may not require further purification.

The usual method of treatment for the reaction of Wittig includes a first damping by adding dropwise water. The mixture was then diluted with ethyl acetate and washed with saturated sodium bicarbonate and then saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness.

The usual method of treatment for the reaction of hydroporinae includes pouring the reaction mixture into a saturated solution of sodium chloride (200 ml) and subsequent extraction of the aqueous suspension with methylene chloride and then washing the combined organic layers aqueous 25% solution of sodium thiosulfate. The organic layer is then dried over magnesium sulfate, filtered and evaporated to dryness.

The reaction is usually controlled by thin-layer chromatography (TLC) using silica gel plates 60 F254(EM Science, Gibbstown, New Jersey) and a suitable solvent system. Thin-layer chromatography can be performed according to the method specified in "Purification of Laboratory Chemicals", 3rdedition, Butterworth-Heinemann Ltd., Oxford is ω H2SO4in ethanol and then heated until then, until the spots corresponding to the compounds. Unless otherwise noted, the filtering is performed using filter paper (type 1) Whatman.

EXAMPLES

SECTION 1

Synthesis of 3,4,6,7-polyhydroxylated steroids

Steroids with the same or closely related model hydroxylation patterns of rings, as in connection 237 (structure shown below), can be synthesized on the basis of a number of steroid precursors, including 4-androsten-3,17-dione (1) and other predecessors with C3-oxygen functionalities and5the carbon-carbon double bonds, such as dehydroisoandrosterone (247).

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237 (3,4,6,7,17), where R1=R3=R4=H and R2=R5=OH.

For example, after protection of the ketone functionalities androsten-3,17-dione (1) (example 1, scheme 55) any one of a number of suitable carbonyl protective group and concomitant migration of the carbon-carbon double bond, allyl oxidation is introduced C7-oxygen. For this stage of the oxidation, you can use a number of oxidizing agents and experimental conditions, including, but not limited to, a complex of chromium trioxide/3.5-dimethylpyrazol, chlorine is going regenerating agent provides hydroxyl functionality at C7. For this purpose you can use a number of reducing agents of the type of metal hydrides, including borohydride sodium and sociallyengaged. Usually recovery C7-carbonyl forms a HE-configuration by hydride attack at least hindered side of the steroid.

Introduction C6-oxygen can be performed after the protection of the C7-hydroxyl of a suitable protecting group such as hydroporinae/oxidation or epoxidation followed by ring opening.11The carbon-carbon double bond can be epoxidizing any of a number of percolat, including m-chloroperbenzoic acid, cryptocercus acid or 3,5-dinitropropanol acid. Usually introduced epoxide has a configuration resulting from attack at least zatrudnieniu side steroid cyclic structure. Subsequent ring opening of the epoxide can be performed in acidic conditions, such as 80% aqueous acetic acid at 60oC. This ring opening gives allyl alcohol in the C6-position of the s-configuration. Alternative hydroporinae 5-double bond with a suitable complex of borane and subsequent oxidation with the use of such reagents as the main Perno be entered in C3 - and C4-position, according to the model functionalization of the 4-EN-3-one A-ring. Recovery-unsaturated ketone can be performed with the use of lithium dissolved in liquid ammonia. The resulting enolate is possible to catch the electrophile, such as trimethylsilyloxy or diethylphosphate. Hydroporinae-oxidation salelologa enol ester leads to the introduction of oxygen at C4. This method produces a model 3, 4-hydroxylation. Alternative second recovery using lithium in liquid ammonia phosphate enol forms 3the carbon-carbon double bond. Epoxydecane3-double bond by percolate, such as m-chloroperbenzoic acid, receive-epoxide. The ring opening of the epoxide can be accomplished with the use of a number of acidic or basic conditions. For example, 3,4-epoxy functionality of glacial acetic acid in connection 238 (example 3, scheme 61) gives 3-hydroxy, 4-acetoxymethyl. Removal of acetate groups using any of a number of reagents, including potassium carbonate or sodium methoxide in methanol, gives the model 3,4-hydroxylation.

EXAMPLE 1

Steroid 3,4,6,7,17-pentahydroxy-5-androstane (237) can be synthesized according to the reaction series is,17-dione (1) (20,0 g, of 62.8 mmol) is stirred with ethylene glycol (10 ml) and a catalytic amount of p-toluensulfonate acid (1.0 g, 5.2 mmol) in benzene (500 ml) by boiling under reflux in nitrogen atmosphere for 26 hours (scheme 56 provided at the end of the description). During this time generated by the reaction water is removed using the device, Dean-stark. The mixture was then cooled to room temperature and add Et2O. the Mixture is washed with sodium bicarbonate, then with water and dried over magnesium sulfate. Filtration and concentration to give a pale yellow solid product, which is washed with methanol, getting digital 2 in the form of a white powder (14.6 g, 39,0 mmol, 62%). Monometallic by-product (5,13 g, 15.0 mmol) was isolated from the filtrate and recycle. Total yield, calculated with by-product, is 86% of diketal 2.

Allyl oxidation at the C7 position of diketal 2 with the use of a complex of chromium trioxide/3.5-dimethylpyrazol in dichloromethane gives compound 3 (scheme 56). The chromium trioxide (46,7 g, 467 mmol) and dry dichloromethane (450 ml) is added to the flask under nitrogen atmosphere and then cooled to -20oWith using a mixture of dry ice/solution CaCl2. Add 3,5-dimethylpyrazol (44,9 g, 467 mmol) and smei) and stirring is continued for 7 hours at -20oC. the Reaction mixture was quenched with water and filtered. The filtrate is washed with water, its volume is reduced to 200 ml and then dried over gSO4. Filtration and concentration gives a dark brown oil, which was purified using column chromatography with silica gel (CH2Cl2/EtOAc) to give the exact location 3 with the release of 68% (of 4.95 g, 12.8 mmol).

Recovery may 3 in allyl alcohol 4 (scheme 56) is carried out using sodium borohydride and chloride heptahydrate cerium (III) in THF and methanol. Into the flask containing the exact location 3 (15.3 g, to 39.4 mmol) and SES37H20 (16.0 g, 42,9 mmol) under nitrogen atmosphere, add fresh THF (200 ml) and methanol (50 ml). The parts added NaBH4(3,20 g, and 84.6 mmol) and stirring is continued for 1 hour at room temperature. Add dichloromethane, the mixture was washed with NaOH (0,6 BC), then water and the organic layer dried over MgS4. Filtration and concentration gives compound 4 as a white solid (14.1 g, 36,1 mmol, 92%).

C7-Hydroxyl portion of the alcohol 4 then protect as salelologa ether (scheme 57 provided at the end of the description). Compound 4 (14.1 g, 36,1 mmol) dissolved in dry DMF (50 ml), then add imidazole (5.9 g, to 86.7 mmol) and TBDMSC1 (6.7 g, 44,5 mmol) is practical layer is dried over MgS4. Filtration and concentration gives a light yellow solid product, which is recrystallized from methanol, receiving compound 5 as a white solid with a yield of 61% (11.2 g, of 22.2 mmol).

Subsequent epoxidation of compound 5 (scheme 57) is performed using m-chloroperbenzoic acid (m-CPBA). Compound 5 (0,72 g, 1.4 mmol) dissolved in dry dichloromethane (5 ml) add m-SRV (0.50 g, 2.9 mmol) and the mixture vigorously stirred for 20 minutes. Add saturated sodium bicarbonate and the aqueous suspension extracted with dichloromethane. The combined organic extracts are washed successively with sodium carbonate solution, water, 10% sodium thiosulfate, then with water again. Drying (MgS4), filtration and concentration to give a white solid product, which was purified using flash chromatography, receiving the connection 6 with the release of 77% (or 0.57 g, 1.1 mmol).

Compound 6 is treated with acid to release the C3 and C17-ketones from the protective groups and the disclosure of the epoxy ring part and obtain 6-hydroxy-7-similarcanadian 310 (scheme 57). Aqueous acetic acid (80%, 1 ml) is added to a flask containing compound 6. The mixture is heated at 65oC for 5 hours, cooling the concentrate obtained crude product 310 is used in the next stage without further purification.

Connection 310 (2.30 mg, 5,32 mmol) in THF (10 ml) is treated with tetrabutylammonium fluoride (TBAF) (8 ml, 1 M solution in THF) at room temperature under nitrogen atmosphere for ten minutes to remove silloway protective group (scheme 57). The reaction mixture was concentrated and then purified flash chromatography (CH2Cl2/EtOAC, 3:1) to give compound 7 (1,37 mg, or 4.31 mmol) with a yield of 81%.

Protection 6,7-diol compound 7 performs the processing of 2,2-dimethoxypropane and a catalytic amount of (1S)-(+)-10-camphorsulfonic acid (CSA), receiving acetonide 8 (scheme 58). Compound 7 (1 g, 3.14 mmol) and a catalytic amount of CSA dissolved in dry DMF (2 ml) and 2,2-dimethoxypropane (10 ml). The mixture is heated at 100oC for 0.5 hour. Add dichloromethane and the mixture is washed with water. The organic layer is dried over gSO4, filtered and concentrated, obtaining compound 8 (1.10 g, of 3.07 mol, 98%), which are used directly in the next reaction without further purification.

Chemoselective recovery C17-carbonyl parts (scheme 58) and subsequent protection of the resulting alcohol as salelologa ester are required. Compound 8 (83 mg, 0.23 mmol) dissolved in methanol (250 ml) under nitrogen atmosphere and portions of leaks acid and then neutralized Panso3. The methanol is evaporated and the residue is dissolved in dichloromethane. The mixture is washed with water and dried over MgSO4. Flash chromatography (CH2Cl2/EtOAC, 3: 1) gives compound 9 (72 mg, 0.20 mmol, 87%) as the main product.

After defending C17-hydroxyl group in the form of salelologa ether to obtain compound 10 carry out the restoration of ,-unsaturated ketone in the a-ring using lithium in liquid ammonia recovery enolate trimethylsilylpropyne (scheme 58). A solution of compound 10 (and 75.2 mg, 0,158 mmol) in tert-VION (0,020 ml) and THF (1.5 ml) is transferred into a flask containing metallic lithium in a dry, distilled ammonia (11.4 mg in 10 ml) at -78oC. After curing for 20 minutes at -78oWith to destroy excess lithium add isoprene (0.5 ml). The mixture was then warmed to room temperature and the solvent is evaporated in vacuum. The residue is dissolved in THF (5 ml), cooled to -78oWith and add Et3N (1.1 ml, 0.30 mmol) and TMSC1 (0,80 ml, 0.30 mmol). The cooling bath removed and the mixture is stirred for 15 minutes. Add saturated Panso3and this aqueous layer was extracted with Et2O and dichloromethane. The combined organic layers are washed twice with saturated salt solution, dried over M7% (58.5 mg, 0.10 mmol).

C4-Hydroxyl enter gidroborudovaniya-oxidation salelologa ester enol 235 (scheme 58 provided at the end of Epifania). Compound 235 (58.5 mg, 0,106 mmol) dissolved in dry THF (15 ml) and cooled in an ice bath. Add borane (1.0 M THF complex: of 0.32 ml, 0.32 mmol) and the mixture is heated to room temperature and stirred for 45 minutes. Add more complex NR3-THF (0.16 ml) and stirring is continued for 2 hours. The mixture was then cooled in an ice bath and add 15% NaOH (0.5 ml) and 30% H2O2(0.5 ml). Vigorous stirring is continued for 2 hours. The aqueous layer was then extracted with dichloromethane, then Et2O and the combined organic extracts are washed with 10% aqueous Na2S2O3then with saturated salt solution and dried over gSO4. The crude product is purified using radial chromium adopted, receiving the connection 236 (34,0 mg, 0,0688 mmol, 65%) and the corresponding 3-silloway simple ether (11.8 mg, 0,0208 mmol, 20%).

Two-stage release connection 236 from the protective group using TBAF in THF, then aqueous acid THF gives 3,4,6,7, 17 pentahydroxy-5-androstane (237).

EXAMPLE 2

Steroid 3, 4-epoxy-6, 7, 17 trihydroxy-5-is>3, 4-Epoxy-6,7,17-trihydroxy-5-androstane (239) can be obtained from the intermediate product 10 in the synthesis of 3, 4, 6, 7,17-pentahydroxy-5-androstane (258) (scheme 60 provided in the end of the description). A solution of compound 10 (111 mg, 0,0234 mmol) in THF (4 ml) is transferred into a flask containing lithium metal in liquid ammonia (6.4 mg in 10 ml) at -78oC in argon atmosphere. After keeping for 30 minutes at -78oWith to destroy excess lithium add isoprene (0.5 ml). The mixture was then warmed to room temperature and the solvent is evaporated in vacuum.

The residue is dissolved in THF (5 ml), cooled to -78oAnd then add SR(O)(OEt)2(0,044 ml, 0.30 mmol) and the mixture is stirred for 1 hour. Add water and dichloromethane, the mixture is acidified and the aqueous layer was extracted with dichloromethane and Et2O. the combined organic layers washed with water and dried over gSO4. The crude product is purified by radial chromatography, receiving the connection 11 (85,1 mg, 0,139 mmol) with a yield of 59%.

The reduction of compound 11 with lithium in liquid ammonia in the presence of tert-butyl alcohol gives olefin 128. A solution of compound 11 (85,1 mg, 0,139 mmol) and tert-VION (0.05 ml) in THF (6 ml) is transferred into a flask containing metallic lithium (16 mg) in liquid water acidification model HC1 mixture is extracted with Et2O, then EtOAc and the combined organic layers washed with water and dried over MgSO4. The crude product is purified by radial chromatography, receiving the connection 128 (50,3 mg, 0,109 mmol) with a yield of 78%.

Epoxidation 128 m-chloroperbenzoic acid (m-SRV) in dichloromethane gives the epoxide 238. Compound 128 (50,3 mg, 0,109 mmol) dissolved in dry dichloromethane (1.5 ml) and add m-SRV (43,0 mg). The mixture is stirred at room temperature for 1.5 hours, and then transferred into a separating funnel and washed with 10% PA2S2ABOUT3saturated Panso3and water and dried over MgSO4. Filtration and evaporation of the filtrate gives the 238 connection with the release of 78% (52,0 mg, 0,109 mmol), which was used in the next stage without further purification.

Two-stage release connection 238 from the protective group using TBAF by boiling under reflux in THF and then acidic aqueous THF gives compound 239.

EXAMPLE 3

Steroid 3, 4, 6,7,17-pentahydroxy-5-androstane (241) can be synthesized according to the following reaction sequence (scheme 61 provided at the end of the description).

Synthesis of 3, 4, 6, 7,17-pentahydroxy-5-androstane (241) spend up to intermediate 238 used in the epoxy resin with simultaneous removal of the acetonide functionality (scheme 62, listed at the end of the description) carried out by heating with glacial acetic acid, when receiving the connection 146, which contains acetoxyvalerenic at C4. Into a flask containing compound 238 (18.5 mg, of 0.038 mmol), add acetic acid (0,30 ml). The mixture is stirred with heating at 60oC for 24 hours, then at room temperature for 2 days. Acetic acid is removed in vacuum, obtaining a connection 146 with the release of 93% (18 mg, being 0.036 mmol).

The release of the C4-hydroxyl protective group using the K2CO3in boiling under reflux methanol and release C17-hydroxyl protective group using TBAF gives pentahydroxyflavone 241.

EXAMPLE 4

6,7-Acetonide 3,4,6,7,17-pentahydroxy-5-androstane (246).

Steroid, 6,7-acetonide 3,4,6,7,17-pentahydroxy-5-androstane (246) can be synthesized according to the reaction sequence illustrated circuit 63 provided at the end of the description.

Connection 10 receives, as described in example 1 of section 1. Release 6,7 - and 17-hydroxyl parts from protective groups carry out 80% solution of acetic acid and, after suitable processing, re protection of these groups in the form of calilove stirring for 8 hours at room temperature. The residue is placed in dry DMF containing imidazole and TBDMSC1, and stirred for 20 hours at room temperature in a nitrogen atmosphere. Add a simple ether and the mixture is washed with 5% aqueous solution model HC1, saturated solution NHCO3and saturated NaCl solution. The organic mixture was dried over gS4, filtered and evaporated. Purification of the residue by chromatography on silica gel gives the connection 242.

Recovery-unsaturated ketone in the a-ring is performed with the use of lithium in a mixture of liquid ammonia/THF and catching enolate trimethylsilylpropyne. A solution of compound 242 in a mixture of 1:4 tert-BuOH and THF is transferred into a flask containing metallic lithium in a dry, distilled ammonia at -78oC. After curing for 20 minutes at -78oWith to destroy excess lithium add isoprene. The mixture was then warmed to room temperature and the solvent is evaporated in vacuum. The residue is dissolved in THF, cooled to -78oWith and add Et3N and TMSC1. The cooling bath removed and the mixture is stirred for 15 minutes. Add saturated Panso3and this aqueous layer was extracted with Et2O and dichloromethane. The combined organic layers are washed twice with saturated ratita 243.

C4-Hydroxyl enter gidroborudovaniya-oxidation salelologa ester enol 243. Compound 243 was dissolved in dry THF and cooled in an ice bath. Add borane (1.0 M complex in THF), the mixture is heated to room temperature and stirred for 45 minutes. Add more complex NR3-THF and stirring is continued for 2 hours. The mixture was then cooled in an ice bath and add 30% NaOH and 30% H2ABOUT2. Vigorous stirring is continued for 12 hours. The aqueous layer was then extracted with dichloromethane, then Et2O and the combined organic extracts are washed with 10% aqueous PA2S2ABOUT3then with saturated salt solution and dried over gS4. The crude product is purified using radial chromatography receiving connection 244.

Protection 3,4-diol compounds 244 performs processing 2,2-dimethoxypropane and a catalytic amount of (1S)-(+)-10-camphorsulfonic acid (CSA) to obtain 245. Connection 244 and a catalytic amount of CSA dissolved in dry DMF and 2,2-dimethoxypropane. The mixture is heated at 100oC for 0.5 hour. Add dichloromethane and the mixture is washed with a saturated solution Panso3. The organic layer is dried over MgSO4, Phi is Oh cleanup.

Connection 245 is then converted into the triol 246 using TBAF. So, trailerby ether 245 dissolved in THF and treated with tetrabutylammonium fluoride (TBAF) (1 M solution in THF) at room temperature under nitrogen atmosphere for 5 hours. The reaction mixture is poured into CH2CL2and washed with a saturated solution of salt, dried (MgSO4) and concentrated in vacuo. The residue is then purified flash chromatography (CH2Cl2/EtOAC, 3:1) to give compound 246.

SECTION 2

Synthesis 22,29-epoxy-15-on-steroids.

Steroids, which are 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-ONU (165), due to the presence of C15-ketone and cyclic polyacetylenes functionality in the steroid side chain (i.e. a C22-hydroxyl functionality, condenses with s aldehyde functionality, forms a ring tetrahydropyrane and s-hydroxyl group), it is possible to synthesize a number of ways. Key stage includes the introduction of a C15-oxygen, the synthesis of a suitable side chain (described in section 3) and attaching the side chain. As the original products, you can use a number of commercially available steroids containing either a ketone or acetyl part C17, such as pregnenolone).

One way (example 5, scheme 64) 17-ketone is treated with a Wittig reagent, obtained by the interaction of bromide ethyltriphenylphosphonium and tert-butoxide potassium in THF to give (Z)-17(20)-italianboy part. The interaction product of the Wittig with alteredstories connection, such as 5-acetoxy-3-(1'-methylethyl)Pentel (156, section 3, example 8, scheme 71) in the presence of a Lewis acid gives products that contain required C22-oxygen that is present as hydroxyl functionality, and s-oxygen-protected as acetate. Then the reaction Jena gives both stereoisomer at S22, the ratio of which depends on the reaction conditions and select the source of the aldehyde product. Therefore, it is possible to synthesize four possible diastereoisomer, based on the configuration of C22 and C24, utilizing either 3R or 3S-isomer connection 156.

The reaction Jena, described above, is formed16the carbon-carbon double bond, which can be used for the introduction of C15-oxygen by allyl oxidation. For example, after defending C22-hydroxyl group novogo product suitable protecting group such as tert-butyldimethylsilyl, allyl oxidation using a reagent such as comp/SUP>-double bond gives a steroid compound, which has a D-ring functionality is identical with 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-one (165).

Remove s-protective group, typically acetate part, with subsequent oxidation of the resulting primary alcohol gives the target aldehyde in s. Remove C22-protective group, typically tert-butyldimethylsilyloxy group, leads to the formation of polyacetylene part of the side chain found in connection 165.

The second strategy of accession required polyacetylenes side chain and C15-ketone functionality includes the introduction of C15-oxygen before joining the side chain (example 6, scheme 67). In this way the first stage involves the transformation of the 17-ketone functionality steroid intermediate product in the enol acetate treatment isopropenylacetate and p-toluensulfonate acid. The conversion of the enol acetate-unsaturated ketone perform the processing of palladium acetate and methoxide presence of TBT (scheme B, is given at the end of the description).

Introduction C15-oxygen then performed by using an attach type Michael to the northward through alkoxide derived from p-methoxybenzylthio alcohol, in the presence of the alcohol to oxidize in C15-ketone.

The transformation of the 17-ketone functionality in the acetyl group is a method that begins with the attack acetylide-anion. For this purpose you can use this reagent, as commercially available complex acetylide lithium-Ethylenediamine. Dehydration of the product gives the connection with the paired16the carbon-carbon double bond. Hydration of acetylene part of using such reagents as saturated with mercury resin Dowex in methanol, THF and water, forms an acetyl group at C17 (16, C20-ketone). 16The carbon-carbon double bond restore using dithionite of sodium and bicarbonate in the conditions of the transfer phase.

The ketone is then converted into epoxide by treatment with sulfur ridom derived from iodide trimethylsilane and n-utility in THF. The epoxide ring then stereoselective disclose using a Lewis acid such as athirat bromide of magnesium, getting C22-aldehyde. Alkyl anion formed by the reaction of exchange litigated of a suitable halogen such as iodide 284 (example 9, scheme 72), then use to influence steroid aldehyde to generate the same side chain in a protected form, as found in these two strategies are presented in examples 5 and 6, which follow below.

EXAMPLE 5

22,29-Epoxy-3,29-dihydroxy-14-stigmasta-15-he (260).

As an example of the first method, described in the introduction to section 2, a steroid, 22,29-epoxy-3,29-dihydroxy-14-stigmasta-15-he (260), can be synthesized according to the following reaction sequence depicted in scheme 64 provided at the end of the description.

Synthesis 22,29-epoxy-3,29-dihydroxy-14-stigmasta-15-she (260) can be performed in ten stages from dehydroisoandrosterone (247). Catalytic hydrogenation of5the carbon-carbon double bond in connection 247 network connection 250, which contains TRANS-condensed system of rings A/C. the Compound 247 was dissolved in EtOAc and add 10% Pd/C. the Mixture is stirred in an atmosphere of H2at room temperature over night. Filtration through celite and concentration gives compound 250, which can be used directly in the next reaction.

The Wittig reaction of compound 250 using phosphor ylides derived from bromide ethyltriphenylphosphonium and tert-butoxide potassium in THF, gives compound 251. Bromide ethyltriphenylphosphonium stirred in suspension in THF. In the stream of nitrogen was added tert-piperonyl potassium and Brazos anion in the form of a solution in THF. The mixture is refluxed for 2 hours in nitrogen atmosphere, then cooled to room temperature and quenched by adding dropwise water. Add saturated ammonium chloride, and this aqueous layer was extracted with EtOAc and the combined organic phases are washed with water and saturated salt solution and dried over MgSO4. Filtration and concentration gives the crude product is 251, which is purified using flash chromatography on silica with stepped gradient hexanol and EtOAc.

Protection of the 3-hydroxyl is carried out using tert-butyldimethylsilyloxy and imidazole in DMF to obtain 252. Compound 251 was dissolved in DMF and added imidazole. After adding TBDMSC1 the mixture is stirred over night at room temperature. Then add dichloromethane, the mixture is washed with water and the organic phase is dried over MgSO4. Filtration and concentration gives the crude product is 252, which can be used without further purification.

Connection 252 is then combined with the aldehyde 156 in the presence of a suitable Lewis acid to obtain a compound 253. Aldehyde 156 dissolved in dichloromethane and at -78oWith add Me2AlCl (1.0 M in hexane). After 5 minutes add raskladom to -78oC and quenched with a mixture of methanol/water. The layers are separated and the aqueous phase extracted with Et2O. the combined organic layers are then washed sequentially 1 N. model HC1, saturated aqueous Panso3and saturated salt solution and dried over MgSO4. After filtration and evaporation to dryness C22-isomers separated using flash chromatography on silica, receiving connection a and 253b.

Connection a (or 253b) is then dissolved in dry DMF and added imidazole. Then add TBDMSC1 and the mixture is stirred at room temperature for 14 hours, then at 60oC for 3 hours. The mixture was diluted with Et2O, washed with water and then dried over MgSO4. After filtration and evaporation the crude product is purified using flash chromatography on silica using mixtures of EtOAc and hexane as eluent, receiving the connection 254.

Allyl oxidation C15 connection 254 with SGAs3and 3,5-dimethylpyrazole in dichloromethane gives the connection 255. SGAs3and dichloromethane added to the flask, cooled to -20oWith and left under stirring at this temperature for 15 minutes. Add 3,5-dimethylpyrazol and then the reaction mixture is stirred for d is it. The mixture was then warmed to room temperature and filtered through silica gel, EtOAc washing. Evaporation of the solvent gives the crude product, which was purified using flash chromatography (EtOA/hexane) to give pure compound 255.

Recovery 16the carbon-carbon double bond in the compound 255 can then be carried out using hydrogen and palladium on coal in EtOAc. Compound 255 was dissolved in EtOAc and add a catalytic amount of 10% Pd/C. the Mixture is stirred in hydrogen atmosphere overnight, then filtered through celite and concentrated, obtaining after cleaning the connection 256.

Remove the acetate protective group in the side chain connections 256 can then be carried out using potassium carbonate in methanol (or NaOMe in Meon) for connection 257. Compound 256 was dissolved in methanol and added TO2CO3. The mixture is refluxed for 3 hours, cooled to room temperature and poured into dichloromethane. Add water (10%) NaHCO3and the layers separated. The aqueous layer was extracted with dichloromethane, the combined organic extracts washed with water and dried over gSO4. Filtration, evaporation and purification give soedinenii. Connection 257 and NaOAc stirred in dichloromethane and add the RCC. The mixture is stirred at room temperature for 3 hours and then filtered through celite. The filtrate is concentrated and the residue purified using flash chromatography, receiving the connection 258.

The release of both hydroxyl parts in connection 258 from the protective groups can be performed in one stage, using tetrabutylammonium fluoride. Connection 258 is dissolved in THF and added dropwise tetrabutylammonium fluoride in THF. The mixture is stirred over night at room temperature, then concentrated in vacuo and purified by receiving 22,29-epoxy-3,29-dihydroxy-14-stigmasta-15-he (248).

The epimerization of compound 248 at the C14 position using the line in the Meon gives 22,29-epoxy-3,29-dihydroxy-14-stigmasta-15-he (260). Connection 248 dissolved in Meon and add a solution of KOH in Meon (25 mg/ml). The mixture is refluxed for 15 minutes, then cooled to room temperature. Add water, aqueous suspension is extracted with chloroform and then dried over gSO4. Filtration and concentration gives the crude product, which contains epimeno mixture of compounds 248 and 260. Division 248 and 260 carried out using cue) includes obtaining-lactone in the side chain and subsequent Dibal-H reduction to obtain compound, containing s-polyacetylene functionality. For example, the hydroxyl in compound 251 protects as benzyloxybenzophenone and then carry out the standard reaction Jena, described in example 5. The removal of the protective group s-acetoxyl then carried out using sodium methoxide in methanol. The resulting diol 263 is then oxidised in-lactone using silver carbonate on celite in boiling under reflux benzene. Compound 263 was dissolved in benzene and added silver carbonate deposited on celite, and the mixture is refluxed for 12 hours. The reaction mixture was then filtered, evaporated and the residue purified flash chromatography, getting lactone 264. Allyl oxidation connection 264 using chromium trioxide and 3.5-dimethylpyrazole in dichloromethane introduces carbonyl part C15 (compound 265). Recovery of conjugated16the carbon-carbon double bond using hydrogen and palladium on coal in EtOAc, followed by removal benzoate groups using NaOMe in a mixture of 1:1 SNS3/Meon gives the product 266. Finally, protection C15-ketone in the form of atelectasia and subsequent selective reduction of the lactone in lactol, which then perform with eye 260.

EXAMPLE 6

As stated in the beginning of this section, the second method the introduction of a C15-oxygen involves using join Michael as described Cantral et al., J. Org. Chem. , 29:64, 1963. If you want, after selective removal of the protective group carried out the oxidation of the resulting secondary alcohol to the ketone at C15. Horita et al., Tetrahedron, 42(11):3021-3028, 1986, it was found that p-methoxybenzylamine protective group can be removed in the presence of many other protective groups including benzyl functionality, using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Therefore, the alkoxide derived from p-methoxybenzylthio alcohol in the pot used instead of similar benzylacrylamide used Cantral et al. Scheme 66 provided in the end of the description shows an example of this chemical transformations of Aenon in connection 270, which is obtained in three stages of trance dehydropiandrosterone (247) using methods described by Takahashi et al., Tetrahedron, 41(24):5747-5754, 1985.

Methods of reaction for joining Michael, is shown in scheme 67 provided at the end of the description following. Connection 270 is dissolved in p-methoxybenzylamine alcohol and add powdered KOH. The mixture is stirred under nitrogen atmosphere at room temperature for 4 hours is comfort. The crude residue purified using flash chromatography with step gradient (EtOA/hexane) with elution by receiving the connection 271.

Attaching the side chain can be performed on compounds containing C17-ketone functionality, using the method of Wittig/EN, as shown previously (example 5), or by using techniques that include compound containing a ketone at C17, such as ketone 275. Making connections with the C17-ketone functionality in methylketone derivatives perform chetyrehstvolnym way using the techniques described in the literature. An example of this methodology is illustrated in scheme 68 provided at the end of the description.

The first stage of the above method involves the conversion of compounds 271 in acetylene alcohol compound 272 using complex acetylide lithium/Ethylenediamine. Acetylene complex is suspended in THF and after cooling to - 20oTo add a solution of compound 271 in THF. The mixture is stirred at room temperature for 6 hours, cooled to 0oC and then quenched with water. The mixture is extracted with dichloromethane, then the combined organic extracts washed with saturated salt solution and is ographie on the silicon dioxide (EtOA/hexane, 1:6), when receiving the connection 272.

Dehydration of compound 272 forms a conjugated carbon-carbon double bond in the D-ring connection 273. Connection 272 dissolved in dry pyridine and added dropwise phosphorus oxychloride. The mixture is stirred for 30 minutes at room temperature and then poured onto a mixture of ice/water. The aqueous suspension is extracted with dichloromethane and the combined organic extracts washed with water Panso3and water and dried over MgSO4. After filtration and concentration the crude product is purified using flash chromatography on silica (EtOA/hexane, 1:6), when receiving the connection 273.

Then, to obtain a conjugated ketone 274 of the connection 273 use saturated mercury (2+) resin Dowex-50W in a solvent mixture of methanol, THF and water. Connection 273 dissolved in a mixture of methanol/THF (2:1) and add two drops of water. Add Nd2+/resin Dowex and the mixture was stirred at 60oWith during the night. Filtration and concentration gives the crude residue, which was purified flash chromatography on silica (EtOA/hexane, 1:2) to give ketone 274.

16The carbon-carbon double bond in connection 274 restore using diti is t catalyst transfer phases Aliquat336 and the mixture is refluxed for 3 hours. The mixture is extracted with dichloromethane and the organic phase is dried over gSO4. Filtration and concentration of the filtrate in vacuo gives the crude residue containing the compound 275.

Selective release of the 15-hydroxyl protective group 275 can be performed at this stage or after joining a suitable side chain according to the methods described Horita et al. (Tetrahedron, 1986, 42(11), 3021-3028), which include the oxidation of p-methoxybenzylthio simple ester of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in dichloromethane and water. Oxidation of the resulting 15-hydroxyl group in the ketone functionality can be performed using several methods, including the PCC in dichloromethane.

EXAMPLE 7

As described in the introduction to this section, the functionality polyacetylene side chain in compounds such as 165, you can enter using the methodology of the Grignard reagent. It first includes a two-stage transformation methylketones functionality from C17 to C22-aldehydebase connection. The methodology for such transformations illustrated in scheme 69 provided at the end of the description, has previously been described by several groups of researchers, including Ko the new chain to steroid aldehyde 278 is achieved by nucleophilic attack carb-anion. The connection 28 to receive the in situ treatment of iodide 284 tert-BuLi in Et2O at -78o(See section 3, example 9, scheme 72) and then add the aldehyde 278 Et2O. the Mixture is stirred for 1.5 hours at -78oC, then warmed to room temperature and add EtOAc. The organic layer is washed successively with water, 1 N. model HC1 and water, dried over gSO4. After filtration and concentration the crude product is purified using flash chromatography on silica, receiving the connection 281. Removing the protective groups of the side chain using standard techniques, such as 80% aqueous acetic acid at 60oWith, gives the target Polyacetal in the side chain.

SECTION 3

The synthesis of various carbon skeletons of the side chains to attach to the steroid ring.

Synthesis of compound 165 and these analogues convergent (i.e., highly functionalized side chain combined with functionalized steroid ring). Two methods used to attach the carbon skeleton of the side chain to the structure of the steroid rings were described in section 2. Below is a description of the production of carbon skeletons of the side chains, which are used in the reaction mix.species of primary alcohol 154 (derived from L-carvone, which is available, for example, from Aldrich Chemical Co., Milwaukee, WI). This sequence gives the connection 156 with S-configuration. The connection with the R-configuration are synthesized from D-carvone. Also worthy of attention that instead of the acetate ester to obtain the aldehyde compound, suitable for combination with the steroid by reaction Yong-type connection 252 and related steroids, you can use any suitable alcohol protective group.

The second method (scheme 72) includes the synthesis of compound 284 and related alkylhalogenide of carboxylic acids 282. This sequence forms the product (280) with S-configuration. And again, the enantiomer of compound 280 synthesized from D-carvone. As indicated above, instead of Catalinas functionality 280 for stages in obtaining carb-anion used in the reaction combinations (obtained by the reaction of lithium exchange/halide corresponding alkylhalogenide), you can use any suitable aldehyde protective group.

EXAMPLE 8

5-Acetoxy-3-(1'-methylethyl)pentanal (156)

The intermediate 5-acetoxy-3-(1'-methylethyl)pentanal (156) used in the Wittig reaction described in the previous sections, can be synthesized according to the reaction placenta is inania 154 perform according to published methods (Tetrahedron Letters, 1984, 25(41), 4685-4688). Protection of the primary alcohol in connection 154 is accomplished by conversion into the acetate ester. Compound 154 (207 mg, 1.10 mmol) was dissolved in pyridine (2 ml) and added DMAP (10 mg) and acetic anhydride (2 ml). The mixture is stirred at room temperature overnight and then diluted with Et2O. the Mixture is washed with 10% aqueous Panso3then water and dried over gSO4. Purification of the crude product is carried out using flash chromatography on silica (EtOAc/hexane, 1:4) to give compound 155 (249 mg, of 1.08 mmol) with a yield of 98%.

Remove Catalinas protective groups in Kitale 155 using 80% acetic acid gives the target aldehyde 156. Compound 155 (150 mg, 0,652 mmol) are suspended in 80% of the Asón (5 ml) and the mixture is heated at 70oC for 2 hours. The solvent is removed in vacuum and the residue is dissolved in Et2About (50 ml). The mixture was then washed with water Panso3and saturated salt solution and then dried over gSO4. Filtration and evaporation of the filtrate gives a pure compound 156 (110 mg, 0,591 mmol) with a yield of 91%.

EXAMPLE 9

The intermediate product 280 used in the reaction combinations in the previous sections, can be synthesized according to the reaction sequence, summing the standard literature methods (Tetrahedron Letters, 25(41), 4685-4688, 1984) and it is then made into 280 three-stage methodology. Compound 282 (1.04 g, 5,12 mmol) dissolved in dry CC14(120 ml) and add I2(to 2.57 g) and iodobenzaldehyde (IDBA) (3.28 g). The mixture is refluxed under lighting light bulb 100 W for 10 minutes. After cooling to room temperature, add 5% aqueous solution PA2S2ABOUT3(300 ml) until then, until the solution becomes colorless, then the layers separated. The organic phase is washed with water and dried over MgSO4. Cleaning gives a pure compound 283 (657 mg, 2,30 mmol, yield 45%).

For connection 284 of the connection 283 spend currency aldehyde protective group using 2,2-dimethyl-1,3-propane diol and p-toluensulfonate acid as catalyst. Compound 283 (42 mg, 0.18 mmol) dissolved in benzene (5 ml) and added dropwise 2,2-dimethyl-1,3-propandiol (300 mg) and p-toluensulfonate acid (3 mg). The mixture is heated at the boil under reflux overnight, then cooled and evaporated to dryness in a vacuum. The residue is purified using flash chromatography on silica (CH2CL2/hexane, 19:1) to give compound 284 (40 mg, 0.14 mmol, 80%).

Finally, reacti (52.1 mg, 0,160 mmol) in dry Et2O (2.0 ml) at -78oWith added tert-BuLi (1.7 M solution in pentane, 0.25 ml). The solution was stirred at -78oWith up until according to GC analysis will not remain the original product. This solution is used directly in the reaction combination with aldehyde 278 (example 7, scheme 70).

SECTION 4

Synthesis of 3,4,6,7-polyhydroxy-22,29-epoxy-15-on-steroids.

Synthesis polyhydroxylated steroids containing one or both of the C15-ketone and polyacetale side chain present in 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-one (165), can be performed using a combination of methods described in the first two sections. The synthesis can start with a functionalization of the rings a and b, then holding functionalization of D-rings and attach the side chain or the stage can be performed while the reverse order. In compounds containing C15-ketone and/or s-Polyacetal, a/b-ring may contain 2, 3 or 4 hydroxyl groups at carbons 3, 4, 6 and/or 7 in any combination and in any combination of configurations.

The following describes a synthetic route to compounds 22,29-epoxy-3,6,7,29-tetrahydroxy-14-stigmasta-15-she (304) and 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-she (165) and compliance and, which are synthetic transformations described in the first two sections, the same methodology can be used to obtain compounds containing other models hydroxylation at carbon 3, 4, 6 and 7 in the ring system And/Century

Below are also included synthetic path 22,29-epoxy-3,6,7,29-tetrahydrocannibinol (306), the compound that contains polyhydroxyalkane system of rings a/b and polyacetylene side chain, but has no C15-ketone functionality found in connection 165.

EXAMPLE 10

22,29-Epoxy-3,6,7,29-tetrahydroxy-14-stigmasta-15-he (304).

Steroid 22,29-epoxy-3,6,7,29-tetrahydroxy-14-stigmasta-15-he (304) can be synthesized according to the scheme 73 provided at the end of the description.

Steroid 22,29-epoxy-3,6,7,29-tetrahydroxy-14-stigmasta-15-he (304) can be synthesized based on commercially available steroid dehydroisoandrosterone (247). C17-ketone compounds 247 first protect in the form of ketala by treatment with ethylene glycol and a catalytic amount of p-toluensulfonate acid in boiling under reflux benzene. Protection of the 3-hydroxyl in the form salelologa ether then carried out using tert-butyldimethylsilyl chromium and 3,5-dimethylpyrazole introduces carbonyl part in the C7-position (compound 287). Chemoselective 1,2-recovery of the ketone using sodium borohydride and cerium chloride gives allyl alcohol 288 in the system of solvents THF-methanol.

Introduction C6-alcohol can be performed using the sequence described in example 1, or gidroborudovaniya with the use of a complex of borane-THF followed by oxidative hydrolysis of the basic hydrogen peroxide. The second method allyl alcohol in connection 288 first protect in the form of acetate using acetic anhydride and pyridine and the product 289 dissolved in dry THF and at 0oTo add a solution of 1.0 M borane in THF. The mixture was stirred at 0oC for 30 minutes and then at room temperature for 2.5 hours. Then added dropwise 3 n NaOH solution, followed by 30% aqueous H2ABOUT2. The mixture is stirred at room temperature for 16 hours and then poured into a saturated solution of sodium chloride. The aqueous suspension is extracted with chloroform and the combined organic layers dried over MgSO4. Filtration and evaporation of the filtrate gives the crude product, which was purified flash chromatography, receiving the connection 221.

Protection of vicinal 6,7-diol compounds 221 in the form of dibenzyline 221 dissolved in dimethylformamide and add sodium hydride. The mixture is stirred for 1 hour at room temperature, then add benzylbromide. Stirring is continued for 2.5 hours, then the reaction quenched by addition of water and stirring is continued for 30 minutes. The mixture is extracted with diethyl simple ether and then washed successively with 5% model HC1, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness. The resulting crude residue purified using flash chromatography, receiving the connection 291.

The release of C3-alcohol protective group in the compound 291 carried out using TBAF in THF boiling under reflux for 2 hours, obtaining a connection 292. Subsequent oxidation using PDC gives ketone 293. For carrying out this transformation 292 crude product was dissolved in CH2Cl2and add the PDC. The mixture is stirred at room temperature for 22 hours. Filtration through a layer of celite with subsequent cleaning of the evaporated filtrate using flash chromatography gives the product ketone 293 in the form of a white solid.

Selective recovery 293 network-hydroxyl group at C3 with access 83SUP>
and stirring is continued at -78oC for 1 hour in nitrogen atmosphere. Add the methanol and the reaction mixture is heated to room temperature. Standard processing and subsequent purification with flash chromatography gives the 294 connection with the release of approximately 80%. 3-Epimer is obtained in yield of approximately 10%. Protection of the hydroxyl group in the compound 294 is carried out in the form of benzyloxypropionic. So, the connection

294 dissolved in dimethylformamide and add sodium hydride. The mixture is stirred for 1 hour at room temperature, then add benzylbromide. Stirring is continued for 16 hours, then the reaction is quenched by slow addition of water and stirring is continued for 30 minutes. The mixture is extracted with diethyl simple ether and washed successively with 5% model HC1, saturated sodium bicarbonate and saturated sodium chloride. The organic layer is dried over magnesium sulfate, filtered and evaporated to dryness. The resulting crude residue purified using flash chromatography, receiving the connection 295.

The removal of the protective group C17-Catala in connection 295 using a mixture of acetic acid, water and acetone (2:1:2) for 14 hours at boiling reverse Ho is m ilide, obtained by treating the bromide ethyltriphenylphosphonium tert-piperonyl potassium in THF. Joining the carbon structure of the side chain is carried out using an aldehyde 156 (scheme 45) and a Lewis acid chloride dimethylamine in dichloromethane, to obtain after purification C22-epimeres a and 298b. The removal of the protective group s-acetoxyl then achieved using sodium methoxide in methanol. The resulting diol 299 is then oxidised in-lactone using silver carbonate on celite in boiling under reflux benzene. Compound 299 was dissolved in benzene and added silver carbonate deposited on celite, and the mixture is refluxed for 12 hours. The reaction mixture was then filtered, evaporated and the residue purified flash chromatography, getting lactone 300. Allyl oxidation 300 connection with the use of chromium trioxide and 3.5-dimethylpyrazole in dichloromethane introduces carbonyl part C15 (compound 301). Recovery conjugate16the carbon-carbon double bond using hydrogen and palladium on coal in EtOAc network connection 302. Remove benzoate groups in the ether 302 carry out joint epimerization at 14, getting trihydroxypropane 303, which szdest chromatography. Finally, protection C15-ketone in the form of atelectasia ((CH2OH)2, p-TsOH, benzene), followed by reduction of the lactone in lactol using DIBAL at -78oAnd removing the protective groups (80% Asón) can give 22,29-epoxy-3,6,7,29-tetrahydroxy-14-stigmasta-15-he (304).

Alternatively, the connection 221 can be treated for removal of all protective groups, for example, using 80% acetic acid. After this hydroxyl group in the b ring can be selectively protected. This can be done by using 2,2-dimethoxypropane and camphorsulfonic acid. Ketone group at the C17 can then be turned into ekzoticheskuyu double bond using chemical transformations by Wittig, for example, the use of bromide ethyldiphenylphosphine, tert-GFCF and THF provides ethylidene substitution at C17. Then the C3-hydroxyl group can oxidize in the carbonyl group, for example, oxalicacid, DMSO, Et3N in methylene chloride, followed by reduction of the received C3-carbonyl LS-Selectride(Aldrich Chemical Co. , Milwaukee, WI) to form 3-hydroxy-group. Removing the protective groups for hydroxyl groups in the b ring network connection 330. This is the way to connection 330, an alternative route shown in scheme is the sequences in scheme 74, listed at the end of the description.

Connection 306 can be synthesized from compounds of 300 two-stage method, the first stage is the removal of the protective groups for hydroxyl groups using hydrogen and palladium on coal in EtOAc and EtOH with simultaneous recovery 16the carbon-carbon double bond. The above mixture was stirred at room temperature for 12 days, filtered and purified flash chromatography, getting 305. Selective reduction of the lactone in lactol then perform the following way. Connection 305 is dissolved in THF and cooled to -78oC. Add DIBAL and the mixture was stirred at -78oC for 3 hours. Standard processing and purification using flash chromatography on silica gives 22,29-epoxy-3,6,7,29-tetrahydrocannibinol (306).

EXAMPLE 12

Reaction conditions described in the previous sections, can be used for the synthesis of compound 165, as shown in figure 75 is provided at the end of the description.

Synthesis 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-she (165) is conducted on the basis of commercially available steroid 4-androsten-3,17-dione (1). Synthesis from compounds 1 to the intermediate product 128 was already described (Prim techniques for connection with the side chain, described in the following examples (example 16, scheme 79), begins with the removal of the silyl group at C17 of the steroid 128. Compound 128 was dissolved in THF and added TBAF (1.0 M in THF). The mixture is heated at the boil under reflux for 2 hours and then concentrated in vacuo. The residue is purified flash chromatography, obtaining alcohol 129.

Hydroxyl part in alcohol 129 is converted into a ketone using oxalicacid in CH2Cl2. Compound 129 was dissolved in CH2Cl2and added to a solution of oxalicacid in CH2Cl2at -78oC. After stirring at -78oC for 15 minutes, add triethylamine and stirring is continued for 5 minutes. Standard processing and clearing network connection 142 in the form of a white solid product.

The transformation of compound 142 in connection 145 is performed by using the same techniques described in example 3 (scheme 61) for the conversion of compound 128 in connection 241. Epoxidation of compound 142 using m-SRVA in dichloromethane to obtain the epoxide 143 and subsequent ring opening of the epoxide with acetic acid gives 3,6,7-trihydroxy-4-acetoxysilane 144 and the removal of the acetate groups attached to s 165 of the connection 145 is performed using the same types of reactions as described in the previous sections. Compound 145 in turn ethylidene 157 using ylides derived from the bromide utiltity-phosphonium and tert-butoxide potassium in THF. Four of the hydroxyl group is then protected in the form of benzyl parts, getting tetramethylhexadecane 158. Attaching the side chain is performed by using an aldehyde 156 (scheme 71) and a Lewis acid such as chloride dimethylamine in dichloromethane, receiving a connection 159. Release s-acetoxyl from the protective groups are then carried out using sodium methoxide in methanol. The resulting diol is then oxidised in-lactone 161 using silver carbonate on celite in benzene. Allyl oxidation connection 161 using chromium trioxide and 3.5-dimethylpyrazole in dichloromethane introduces carbonyl part 15 with simultaneous oxidation of benzyl groups in benzoate group (compound 162). Recovery of conjugated16the carbon-carbon double bond using hydrogen and palladium on coal in EtOAc and EtOH gives compound 163. Remove benzoate groups in the ester 163 carried out using basic conditions (for example, the line in the Meon) with simultaneous epimerization at C14, getting the product 164, which Casita C15-ketone in the form of atelectasia ((CH2OH)2, p-TsOH, benzene) and subsequent selective reduction of the lactone in lactol using DIBAL at -78oAnd removing the protective groups (80% Asón) can give 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-he (165) and C14-epimer gives 22,29-epoxy-3,4,6,7,29-pentahydroxy-14-stigmasta-15-he.

SECTION 5

Additional examples of the synthesis of new polyhydroxylated steroids with biological activity

In addition to the compounds described in the previous sections, has obtained a series of related compounds with biological activity. They include, among others, compounds containing the model 3,6,7-hydroxylation with variable functionality at the C17 position, as well as compounds containing model 3, 6, 7-hydroxylation with variable functionality at the C17 position. Some of the techniques used to obtain these compounds are described in the following examples.

EXAMPLE 13

A number of 3,6,7-hydroxylated compounds can be obtained from the intermediate connection 221. As described in scheme 73, the connection 221 can be obtained from commercially available starting product, dehydroisoandrosterone (247). Specifically, the compound 247 (20,0 g and 69.3 mmol) dissolved in benzene (200 ml) in truhanovoy acid (0,501 g, of 2.64 mmol), followed by ethylene glycol (20 ml) and the mixture is refluxed for 4.5 hours. The mixture is cooled to room temperature and diluted with diethyl simple ether (200 ml). The organic layer was washed with saturated sodium bicarbonate (2100 ml), then saturated sodium chloride (2100 ml). The organic layer is dried over gSO4, filtered and evaporated to dryness, obtaining the product 285 (of 22.8 g of 68.6 mmol, 99%), which is used in the next reaction without further purification. Protection of the 3-hydroxyl in compound 285 as salelologa ether can be carried out as follows. Compound 285 (22,5 g of 67.7 mmol) dissolved in a mixture of dimethylformamide (112,5 ml) and dichloromethane (112,5 ml). Add imidazole (11.3 g, 166,0 mmol) and then tert-butyldimethylsilyl (15,8 g to 104.8 mmol). The mixture is stirred at room temperature for 6 hours in an atmosphere of argon, then diluted with diethyl simple ether (675 ml). The organic mixture was washed with aqueous 5% model HC1 (2135 ml), then saturated sodium bicarbonate (2135 ml), then saturated sodium chloride (2135 ml). The organic layer is dried MgS4, filtered and evaporated to dryness, obtaining the crude product is 286. The crude product is then recrystallized from a mixture of ethyl acetate/methanol (3:2), receiving soedinenii carbonyl part of the C7-position (compound 287). Compound 286 (15.0 g, 33.6 mmol) dissolved in cyclohexane (60 ml) and add N2(7.3 ml). Add the hydrate chloride, ruthenium (III) (0,0561 g, 0.27 mmol), then added dropwise tert-butylhydroperoxide (37.6 ml). The mixture is stirred at room temperature for 24 hours and then diluted with ethyl acetate (376 ml). The organic mixture was washed with saturated sodium chloride (2188 ml), then 25% sodium thiosulfate (2188 ml). The organic layer is dried over MgSO4, filtered and evaporated to dryness, to give crude product. The crude product is recrystallized from ethyl acetate, receiving the connection 287 (8.6 g, to 18.7 mmol, 56%). Chemoselective 1,2-recovery ketone in connection 287 can give 288. Thus, compound 287 (14,7 g, 31.9 per mmol) dissolved in tetrahydrofuran (118 ml) and add heptahydrate cerium chloride (III) (17.6 g, to 47.2 mmol) in methanol (35 ml). The mixture is cooled using an ice bath and slowly add borohydride sodium (2.5 g, of 66.1 mmol). The mixture is heated to room temperature and then stirred for 2.5 hours. Then to the mixture slowly add water 5% model HC1 (44 ml), then ethyl acetate (588 ml). The reaction mixture is washed with aqueous 5% model HC1 (120 ml), then saturated sodium bicarbonate (120 ml), then saturated sodium chloride (120 ml). Org next reaction without further purification. Compound 288 (14.8 g) is then dissolved in pyridine (30 ml) and added dropwise acetic anhydride (15 ml) and a catalytic amount of 4-dimethylaminopyridine (30 mg). The mixture is stirred at room temperature for 16 hours and then diluted with ethyl acetate (300 ml). The organic mixture was washed with saturated sodium bicarbonate (260 ml), then saturated sodium chloride (260 ml). The organic layer is dried with MgSO4, filtered and evaporated to dryness, to give crude product. Recrystallization from methanol gives compound 289 (12,6 g 25,0 mmol, yield 78% in two stages). Hydroporinae connection 289 network model 6,7-hydroxylation. So, the connection 289 (8,4 g of 16.6 mmol) dissolved in dry THF (50 ml) and the mixture cooled to 0oC. Add 1.0 M solution of borane in THF (20 ml) and the mixture was stirred at 0oC for 30 minutes and then at room temperature for 2.5 hours. Then added dropwise aqueous 10 n NaOH solution (10 ml), then 30% aqueous H2ABOUT2(10 ml). The mixture is stirred at room temperature for 18 hours and then poured into a saturated solution of sodium chloride (200 ml). The aqueous suspension is extracted with methylene chloride (2250 ml) and the combined organic layers washed with aqueous 25% solution of sodium thiosulfate (2250 is th purified flash chromatography on silica gel (hexane/ethyl acetate, 3:1) to give compound 221 (5.9 g, 12.3 mmol, 74%).

The circuit 76 is provided at the end of the description illustrates the synthesis of compounds 326 and 327 of the connection 221. Compound 221 (1.2 g, 2.4 mmol) dissolved in acetic anhydride (3 ml) and add pyridine (3 ml) and a catalytic amount of 4-dimethylaminopyridine (40 mg). The mixture is stirred at room temperature for 3 hours, then diluted with ethyl acetate (100 ml). The organic mixture was washed with aqueous 5% model HC1, then with saturated sodium bicarbonate (100 ml) and saturated sodium chloride (100 ml). The organic layer is dried gSO4, filtered and evaporated to dryness, obtaining the product 321 (1.3 g), which is used in the next reaction without further purification. The removal of the silyl protective group using TBAF in THF gives compound 322, which contains the 3-hydroxyl group. The crude product 321 dissolved in THF (10 ml) and added 1.0 M tetrabutylammonium fluoride (4 ml). The mixture is refluxed for 1 hour, cooled to room temperature, then poured into a saturated solution of sodium chloride (50 ml). The aqueous suspension is extracted with methylene chloride (540 ml) and the organic layer dried over gSO4. Filtration and evaporation of the filtrate gives the crude product, which chisle two stages). Inversion of the stereochemistry at C3 then carry out the oxidation using PDC in CH2Cl2receiving ketone 323, followed by reduction with L-Selectrideto obtain predominantly the 3-hydroxyl connection 324. So, the connection 322 (0.84 g, 1.9 mmol) dissolved in CH2Cl2(15 ml) and added PDC (1.2 g, 3.2 mmol). The mixture is stirred for 40 hours at room temperature and then diluted with diethyl simple ether (50 ml). Filtration and evaporation to dryness giving the crude product, which was purified flash chromatography on silica gel (hexane/ethyl acetate, 9:1) to give compound 323 (0,81 g, 1.8 mmol, 95%). Compound 323 (0.34 g, 0.75 mmol) and then dissolved in THF (10 ml) and then cooled to -78oC. Added L-Selectride (1.0 M in THF, 1.6 ml) and the mixture was stirred at -78oC for 1 hour. The mixture is heated to room temperature and then added dropwise aqueous 10 n NaOH solution (1 ml) and then 30% aqueous H2ABOUT2(1 ml). The mixture is stirred at room temperature for 1 hour and then poured into ethyl acetate (50 ml). The organic mixture was washed with aqueous 5% model HC1 (225 ml), then saturated sodium bicarbonate (225 ml) and saturated sodium chloride (225 ml). The organic layer is dried gSO4filter, viparis the imposition of 324 (0,214 g, 0.48 mmol, 64%).

Then you can delete acetate protective group. Compound 324 (0.25 g, 0,56 mmol) dissolved in methanol (10 ml) and add sodium methoxide (250 mg). The mixture is stirred at room temperature for 3 hours and then diluted with ethyl acetate (50 ml). The organic mixture was washed with aqueous 5% model HC1 (225 ml), then saturated sodium bicarbonate (225 ml) and saturated sodium chloride (225 ml). The organic layer is dried gSO4, filtered, evaporated to dryness and purified using flash chromatography on silica gel (ethyl acetate) to give compound 325 (0,185 g, 0.51 mmol, 91%). Connection 325 (141 mg, 0,385 mmol) is then dissolved in 80% acetic acid (10 ml) and stirred at 70oC for 14 hours. The mixture is diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (225 ml) and saturated sodium chloride (225 ml). The organic layer is dried with MgSO4, filtered, evaporated to dryness and purified using flash chromatography on silica gel (ethyl acetate) to give compound 326 (0,054 g, 0,17 mmol, 44%). Finally, the recovery of the ketone 326 (0,023 g, 0,072 mmol) NaBH4(0,034 g) in 95% ethanol (1 ml) at room temperature for 2 hours gives tetrahydrogestrinone 327 (0,018 g 0,056 mmol, 78%).

Five-322 two-stage method. The acetate removal of the protective groups is carried out by stirring with ether 322 in sodium methoxide and methanol for 15 hours at room temperature. Then do demetalization connection 328 using 80% acetic acid, getting trihydroxystilbene 329.

EXAMPLE 15

Compound 329 can also be obtained directly from compounds 221 in one stage, using 80% of the Asón, as shown in figure 78 is provided at the end of the description. So, ketal 221 (1.3 g, 2.7 mmol) was dissolved in 80% aqueous acetic acid (20 ml) and the mixture is stirred for 3 hours at room temperature. Evaporation to dryness gives compound 329 (0,79 g, 2.5 mmol, 93%), which is used in the following reactions without further purification.

EXAMPLE 16

Steroid 3, 6, 7 trihydroxy-17(20)-pregnen (330) can be synthesized according to the reaction sequence shown in scheme 79 provided at the end of the description.

Connection 330 can be obtained from compound 10 (as shown in scheme 79). A solution of compound 10 (0,82 g of 1.73 mmol) in diethyl simple ether (15 ml) is transferred into a flask containing metallic lithium (55 mg) in liquid ammonia (30 ml) at -78oC in argon atmosphere. After 30 minutes at -78oTo add NH4C (225 ml) and the combined organic layers washed with water (25 ml) and dried over magnesium sulfate. After filtration and evaporation to dryness the residue is dissolved in CH2Cl2(15 ml) and added PDC (600 mg, of 1.59 mmol). The mixture is stirred at room temperature for 18 hours, then filtered through a layer of celite. The filtrate is then purified using flash chromatography on silica gel (hexane/ethyl acetate 5: 1) to give compound 13 (653 g of 1.40 mmol, 81%).

The ketone 13 then restore the following procedure. Compound 13 (1.2 g, 2,53 mmol) dissolved in THF (30 ml), the mixture is then cooled to -78oWith and added L-Selectride(1.0 M in THF, 3.8 ml). The mixture was stirred at -78oC for 2.5 hours and then heated to 0oC. Add 10% NaOH (10 ml), then 30% H2ABOUT2(10 ml). After stirring for 2 hours, add water (20 ml) and the aqueous suspension extracted with CH2Cl2(4100 ml). The combined organic extracts are then washed with 10% PA2S2ABOUT3(2100 ml) and saturated sodium chloride (2100 ml). The organic layer is dried with magnesium sulfate, filtered and evaporated to dryness, obtaining the product 14, which is used in the next stage without further purification. 3-Gidroksilnuyu group then protect as acetate using acetic anhydride and pyridine, getting acetate is owls. Add ethyl acetate and diethyl simple ether (1: 1, 150 ml) and the mixture washed with 5% model HC1 (250 ml), then saturated sodium bicarbonate (250 ml). The organic layer is dried with magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 10:1) to give compound 15 (0,89 g of 1.73 mmol, 68% after two steps). Remove silloway protective group at C17 connection 15 of 0.85 g of 1.63 mmol) performed by boiling under reflux in THF (30 ml) and TBAF (1.0 M in THF, 3.6 ml) for three hours, followed by evaporation to dryness. The residue is then dissolved in CH2Cl2(100 ml) and washed with H2Oh (330 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 1: 1) to give compound 16 (0,59 g, 1,45 mmol, 89%). Oxidation C17-hydroxyl in compound 16 is then carried out using oxalicacid in DMSO. So, the connection 16 (0,57 g of 1.40 mmol) dissolved in CH2Cl2(5 ml) and added to a solution of oxalicacid (0.15 ml, 1,68 mmol) and DMSO (of 0.24 ml, to 3.36 mmol) in CH2Cl2(10 ml) at -78oC. After stirring at -78oC for 15 minutes, add triethylamine (0,98 ml) and continue stirring the content of inorganic fillers layer was washed with 5% model HC1 (25 ml), then saturated sodium bicarbonate (25 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 2:1) to give compound 17 (0.54 g, of 1.33 mmol, 95%).

The Wittig reaction of compound 17 using phosphor ylides derived from bromide ethyltriphenylphosphonium and tert-butoxide potassium in THF gives compound 18. Add tert-piperonyl potassium (0,59 g, 5,23 mmol) in a stream of nitrogen to a suspension of bromide ethyltriphenylphosphonium (1,94 g, 5,23 mmol) in THF (15 ml) and the mixture is stirred at room temperature for 1 hour. Compound 17 (0,53 g of 1.31 mmol) dissolved in THF (10 ml) and the solution is added to the ylides in THF. The resulting mixture is refluxed under nitrogen atmosphere for 12 hours, then cooled to room temperature. The mixture is filtered through celite and the filtrate is evaporated to dryness. The residue is dissolved in CH2Cl2(100 ml) and washed with saturated solution of NH4C1 (230 ml) and N2On (230 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 3:1) to give compound 18 (0.33 g, 0.88 mmol, 67%).

Finally, you(1.5 ml) and stirred at 60oC for 1 hour. The mixture is evaporated to dryness, obtaining the connection 330 (17,8 mg, 0,053 mmol, 99%).

EXAMPLE 17

A number of compounds with important biological activity can be synthesized from compounds 329. For example, the connection 333, which contains the model 3,6, 7-hydroxylation and etiogenesis balance at C17, get in three stages from compound 329 (scheme 80 provided at the end of the description). So, the connection 329 (1,81 g, 5.6 mmol) was dissolved in 2,2-dimethoxypropane (25 ml) and add a catalytic amount camphorsulfonic acid (CSA) (0.03 g) and the mixture is stirred at room temperature for 3 hours. Add ethyl acetate (200 ml) and the mixture washed with 5% aqueous model HC1 (50 ml), then saturated sodium bicarbonate (2100 ml) and saturated sodium chloride (2100 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 1:1) to give compound 331 (1.54 g, 4.3 mmol, 76%). The Wittig reaction of compound 331 using phosphor ilide, described in the previous sections, the network connection 332. So, tert-piperonyl potassium (7,15 g of 63.7 mmol) is added in a stream of nitrogen to a stirred solution of bromide ethyltriphenylphosphonium (23.7 g, of 63.7 mmol) in toluene (360,2 mmol) in toluene (210 ml). The mixture is stirred at room temperature for 24 hours in a nitrogen atmosphere, and then quenched by adding dropwise water (120 ml). The mixture is diluted with ethyl acetate (900 ml) and washed with saturated sodium bicarbonate (2200 ml), sodium chloride (2200 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 2:1) to give compound 332 (7.2 g, 19.2 mmol, 90%). The release of hydroxyl groups in the compound 332 from the protective groups are then carried out by mixing 332 in 80% acetic acid. So, the connection 332 (7.2 g, 19.2 mmol) was dissolved in 80% acetic acid (115 ml) and the mixture is stirred at room temperature for 3 hours. Evaporation to dryness followed by purification with flash chromatography on silica gel (CH2CL2/Meon, 9:1) gives compound 333 (of 5.81 g of 17.4 mmol, 90%).

Compounds containing a ketone at C3 and model of 6,7-hydroxylation, can be obtained from the connection 332. For example, the oxidation of compounds 332 using Swern conditions gives compound 334, which can be freed from the protective groups for conversion in connection 335 (scheme 81 provided at the end of the description). Compound 332 (1.01 g, 2,70 mmol) dissolved in CH2ClC. After stirring at -78oC for 15 minutes, add triethylamine (4.6 ml) and stirring is continued for 15 minutes, followed by stirring at room temperature for 30 minutes. The mixture is diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate (250 ml), then saturated sodium chloride (250 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (pretreated with 1% triethylamine in hexano) (hexane/ethyl acetate, 19:1) to give compound 334 (0,77 g 2,07 mmol, 77%). The release of hydroxyl groups in the compound 334 from the protective groups is carried out, as in the previous examples, by mixing the compound 334 (11 mg, 0,030 mmol) in 80% aqueous acetic acid (1.25 ml) at room temperature for 1 hour, obtaining, after evaporation to dryness and purification with flash chromatography on silica gel (ethyl acetate), the connection 335 (9.8 mg, 0,029 mmol, 97%).

EXAMPLE 19

A byproduct of oxidation under Swern on the circuit 81 is chlorinated 336. Connection 336 can be freed from the protective groups by treatment with 80% acetic acid as shown in scheme 82 provided at the end of the description. So, the connection 336 (0,028 the hour. The mixture is evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 3: 2) to give compound 337 (0,024 g, O,067 mmol, 94%).

EXAMPLE 20

As described in an earlier section, the connection 330 can be obtained by recovering the C3 carbonyl in compound 334 (e.g., using L-Selectride, Aldrich Chemical Co. , Milwaukee, WI) to form 3-hydroxy-group, followed by removal of protective groups. So, the connection 334 of 0.85 g, 2.3 mmol) dissolved in THF (25 ml) and cooled to -78oC. Add LS-Selectride (1.0 M in THF, 3.0 ml) and the mixture was stirred at -78oC for 3 hours. Add water 10 N. NaOH (2 ml) and 30% H2ABOUT2(2 ml) and the mixture is heated to 0oC. the Mixture is diluted with ethyl acetate (150 ml) and washed with saturated sodium bicarbonate (250 ml), then saturated sodium chloride (250 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica (hexane/ethyl acetate, 3:1) to give compound 338 (0,703 g, 1.88 mmol, 80%). Then the release of hydroxyl groups in the b ring of the protective group gives compound 330 (scheme 83 provided at the end of the description). So, the connection 338 (1.44 g, of 3.85 mmol) was dissolved in 80% aqueous acetic acid (25 ml)5 g, 3,74 mmol, 97%). This is the way to connection 330, the alternative path is shown in scheme 79.

EXAMPLE 21

Compounds containing ethyl residue or a different alkyl chain at C17, can be obtained from the corresponding compounds containing ekzoticheskuyu double bond at C17. For example, the connection 339 produced by the catalytic hydrogenation of the C17-C20-double bond of compound 338 with the subsequent removal of the protective groups as described below. So, the connection 338 (0.15 g, 0.40 mmol) dissolved in a mixture of 1:1 acetic acid and ethanol (4 ml) and add 10% Pd/C (15 mg). The mixture is stirred in an atmosphere of H2for 16 hours, followed by filtration and evaporation, obtaining the target product 339 (0,115 g, 0,340 mmol, 85%) (scheme a provided at the end of the description). If the hydrogenation reaction is carried out in ethyl acetate (scheme 84b provided at the end of the description), I get the intermediate 17-ethyl-6,7-acetonide 361. So, the connection 338 (0,019 g 0,050 mmol) is dissolved in ethyl acetate (5 ml) and add 10% Pd/C (9 mg). The mixture is stirred in an atmosphere of H2for 14 hours, followed by filtration and evaporation, obtaining the target product 361 (0,018 g 0,048 mmol, 96%).

Similarly, the connection 332 in acetic acid hydronaut using Halternative alkyl groups at C17 can be obtained using other reagents Wittig. For example, the connection 342 easily get Wittig reaction similar to the reaction described previously, but using h3RVG as the Wittig reagent, and not EtPh3PBr, with the subsequent release of Tirol 341 of protective groups, as shown in the diagram 86 provided at the end of the description. So, bromide methyltriphenylphosphonium (1.97 g, 5.51 mmol) and tert-GFCF (0,61 g, 5.4 mmol) stirred in THF (10 ml) for 1 hour. To the ilide add ketone 331 (0,411 g to 1.14 mmol) in THF (5 ml) and the mixture refluxed for 3 hours. After standard processing, as described previously, the crude product is purified using flash chromatography on silica gel (hexane/ethyl acetate, 3:1) to give compound 341 (of 0.332 g, 0,920 mmol, 81%). Product 341 (0,204 g, 0,567 mmol) then treated with 80% solution of acetic acid (4 ml) for 1.5 hours at room temperature. The mixture is evaporated in vacuum, obtaining the target triol 342 (0,173 g, 0,540 mmol, 95%). Appropriate C17-methylpropane then obtained by hydrogenation of compound 341 (0,023 g 0,063 mmol) and 10% Pd/C (15 mg) in ethyl acetate (5 ml) in the atmosphere2followed after filtration and evaporation to dryness, removing the protective groups of the 80% solution of acetic acid (2.5 ml) to give compound 343 (0,018 g 0,056 mmol, 88%)e in C3, it is possible to synthesize a number of different ways. One example includes a modified method of Burton (Robins et al., J. Am. Chem. Soc., 105:4059-4065, 1983), as shown in figure 88. Alcohol 332 (0.10 g, 0.27 mmol) is treated with familiarisation (0.45 ml, 3.3 mmol) in pyridine (2 ml) and methylene chloride (3 ml) at room temperature for 2 hours. The mixture is evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate 30:1) to give tenoever 344 (0.12 g, 0.22 mmol, 84%). Ether 334 (0,091 g, 0,17 mmol) then treated with n-VI3Sn (60 μl, 0.22 mmol) and a catalytic amount of A1BN (4 mg) in toluene (3 ml) at 75oC for 3 hours in an inert atmosphere. The mixture is evaporated to dryness and the compound 345 (0.035 g, 0.1 mmol, 57%) was obtained after purification using flash chromatography on silica gel (hexane/ethyl acetate 30: 1). The process of joining 345 (0.025 g, 0,069 mmol) of 80% aqueous acetic acid (2 ml) for 1 hour at room temperature followed by evaporation and purified flash chromatography on silica gel (hexane/ethyl acetate, 3:1) gives the diol 346 (0,021 g of 0.066 mmol, 96%) (scheme 88 provided at the end of the description).

EXAMPLE 24

Compounds containing a methylene carbon at 17, can be obtained by chemical transformation, similar to prewire salelologa ether by treatment of tert-butyldimethylsilyloxy (0,095 g, to 0.63 mmol) and imidazole (0,057 g, 0.84 mmol) in dimethylformamide (4 ml) at room temperature for 4 hours. The mixture is diluted with diethyl simple ether (75 ml) and washed with saturated sodium bicarbonate (225 ml), then N2(225 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica (hexane/ethyl acetate, 9: 1) to give compound 347 (0.18 g, 0.38 mmol, 90%) (scheme 89 provided at the end of the description). Ketone function compounds 347 then restore sociallyengaged in diethyl simple broadcast, receiving 17-alcohol 348. So, the connection 347 (0.18 g, of 0.37 mmol) dissolved in diethyl simple ether (5 ml), cooled tooWith and add sociallyengaged (0,018 g, 0.48 mmol). The mixture was stirred at 0oC for 30 minutes and then added dropwise saturated sodium bicarbonate (1 ml). The mixture is diluted with diethyl simple ether (50 ml) and washed with saturated sodium bicarbonate (215 ml), then N2(215 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 4:1) to give compound 348 (0.15 g, 0.31 mmol, 85%). Using reaction type BCI. So, the connection 348 (0,052 g, 0.11 mmol) dissolved in THF (5 ml) and add NaH (17,4 mg (60% in oil), 0.43 mmol) and imidazole (5 mg, 0,074 mmol). The mixture is stirred at room temperature for 30 minutes, then add carbon disulfide (0.2 ml) and stirring is continued for 2 hours, followed by boiling under reflux for 30 minutes. Add MeI (0.2 ml) and boiled under reflux continued for an additional 30 minutes. Added dropwise N2O (1 ml) and the mixture diluted with diethyl simple ether (100 ml), washed with 5% model HC1 (230 ml), then saturated sodium bicarbonate (230 ml) and then N2On (230 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate 15:1) to give compound 349 (0,054 g, 0.09 mmol, 85%). In the next reaction as the radical initiator is usually used A1BN. So, the connection 349 (0.05 g, 0,087 mmol) dissolved in toluene (15 ml) and add n-V3Sn (0,051 g, 0,17 mmol) and a catalytic amount A1BN (10 mg), the mixture is refluxed for 22 hours in an inert atmosphere. The mixture is cooled to room temperature, evaporated to dryness and purified using flash groudinine 350 (0,010 g, to 0.022 mmol) of 80% acetic acid (2 ml) for 18 hours at room temperature followed by evaporation to dryness and purified using flash chromatography on silica gel (SNS3/Meon, 20:1) gives compound 351 (0,0065 g 0,021 mmol, 96%).

EXAMPLE 25

Compounds with higher alkyl chains attached to the C17, can be obtained using chemical transformation similar to the transformation described in the previous examples. For example, the connection 354 can be obtained in 4 steps from commercially available cholesterolaemia (228), as shown in the diagram 90 is provided at the end of the description. The previously described methodology, including C7-oxidation using RuCl3and tert-Vjoon with subsequent restoration C7-ketone using the N4/l3gives alcohol 352. Acetylation of compound 352 subsequent gidroborudovaniya (and then treatment with an alkaline peroxide) gives the target connection 354.

Specifically, the connection 228 (0,431 g, 1.01 mmol), RuCl3(0,020 g, 0,098 mmol), cyclohexane (5 ml), water (0.25 ml) and 70% tert-VION in water (1.5 ml, 11.0 mmol) is stirred for 24 hours at room temperature. The mixture is diluted with ethyl acetate (125 ml) and washed with aqueous solution of 10% PA2SO337H2On (2.00 g, 5,368 mmol) in methanol (5 ml) are added to a solution of ketone 229 (1,11 g, 2,52 mmol) in THF (5 ml) and the mixture cooled to 0oC. Add NaBH4(0,119 g, 5,14 mmol) and the mixture was stirred at 0oC for 1 hour followed by heating to room temperature and continued stirring for 2 hours. The mixture was carefully quenched with aqueous 5% model HC1 (10 ml) and diluted with ethyl acetate (250 ml). The emulsion is then washed with aqueous 5% model HC1 (2100 ml), saturated aqueous Panso3(2100 ml) and saturated aqueous NaCl (2100 ml). The organic phase is dried MgSO4and evaporated to dryness. The residue is purified flash chromatography on silica gel with a mixture of hexane/ethyl acetate, 9:1, receiving alcohol 352 (0,850 g, at 1.91 mmol, 76%). Then do the protecting groups and hydroporinae. So, the connection 352 (0,850 g, at 1.91 mmol), pyridine (5 ml) and acetic anhydride (5 ml) was stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate (150 ml) and washed with aqueous 5% model HC1 (350 ml), saturated aqueous Panso3(250 ml) and saturated aqueous NaCl (250 ml). The organic phase is dried MgSO4and evaporated to dryness. The residue is purified flash chromatography on sitll (5 ml) cooled to 0oWith and add NR3in THF (1.0 M, 2.5 ml, 2.5 mmol). The mixture is stirred for 3 hours at 0oWith, then carefully quenched with aqueous 10 N. NaOH solution (1 ml) and aqueous 30% solution of H2ABOUT2(1 ml). The resulting mixture is stirred for 16 hours, diluted with ethyl acetate (100 ml) and washed with aqueous 10% solution of PA2SO3(250 ml), a saturated solution Panso3(250 ml) and saturated NaCl solution (250 ml). The organic layer is dried over MgS4and evaporated to dryness. Purification with flash chromatography on silica gel (hexane/ethyl acetate, 3: 1) to give the product, 3-acetoxy-6,7-dihydroxy-5-cholestan (0,032 g, 0,069 mmol, 13%), which is freed from the protective groups by treatment with sodium methoxide (obtained from metallic sodium (0,262 grams, or 11.4 mmol) and methanol (10 ml) at room temperature for 1.5 hours. The mixture is diluted with ethyl acetate (30 ml) and then washed with saturated aqueous Panso3(215 ml) and saturated aqueous NaCl (215 ml). The organic layer is dried gSO4and evaporated to dryness. The residue is purified flash chromatography on silica gel with a mixture of hexane/ethyl acetate, 1:1, receiving triol 354 (0,029 g, 0,069 mmol, 99%).

EXAMPLE 26

Compounds containing additional functional groups in the a-Col is the first synthesis of compound 335, as shown in figure 91. Acetylation of compound 335 with acetic anhydride and pyridine and DMAP gives diacetoxyscirpenol 355. So, the connection 335 (1.5 g, 4.5 mmol), pyridine (10 ml), acetic anhydride (5 ml) and 4-dimethylaminopyridine (0,028 g, 0.23 mmol) was stirred at room temperature for 12 hours. The mixture is diluted with ethyl acetate (300 ml) and washed with aqueous 5% model HC1 (350 ml), saturated aqueous Panso3(350 ml) and N2O (350 ml). The organic phase is dried gS4and evaporated to dryness, obtaining the crude residue 355 (1.9 grams), which is used in the next reaction without further purification. Thus, the crude product 355 (0.800 to g, 1.9 mmol) dissolved in Asón and add 10% Pd/C (80 mg). The mixture was then stirred in an atmosphere of H2for 16 hours at room temperature. The mixture is filtered and evaporated to dryness, to give crude residue, which was purified flash chromatography on silica gel (hexane/ethyl acetate 5:1) to give compound 356 (0,702 g, 1,67 mmol, 88%). The oxime 357 then obtained by boiling under reflux connection 356 with HONH2-HCl in the solution Meon-pyridine. So, the connection 356 (0.05 g, 0.12 mmol) dissolved in a mixture of pyridine (2 ml) and methanol (2 ml) and add HONH2-HCl (0,017 g, 0.24 mmol). The mixture is refluxed in Atria (315 ml) and then N2(315 ml). The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness, obtaining the compound 357 (0,052 g, 0.12 mmol, 99%), which is used in the next reaction without further purification. Product 357 (0,071 g, 0.16 mmol) and then dissolved in pyridine (13 mg) in acetic anhydride (3 ml), cooled to 0oWith and add acetylchloride (15,5 mg, 0.20 mmol). The mixture was then heated for 8 hours at 100oC. Add N2About (0.5 ml) and heating continued for 30 minutes. The mixture was then cooled to room temperature, diluted 2O (10 ml) and extracted with CH2Cl2(315 ml). The combined organic extracts are then washed2(210 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the residue purified flash chromatography on silica gel (hexane/ethyl acetate, 2:1) to give compound 358 (0,41 g 0,086 mmol, 52%). C3-Ketone in 358 (0,020 g 0,042 mmol) then restore NaBH4(2.4 mg) in THF (2 ml) at room temperature for 1 hour. Add Asón (2 drops), the mixture is diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (215 ml), then N2O (250 ml). The organic layer is dried over magnesium sulfate, filtered, evaporated to dryness and the crude product 359 dissolve the achievements pH 6 type ion-exchange resin Amberlite IR-120. The mixture is filtered and evaporated to dryness and purified flash chromatography on silica gel (SNS3/Meon, 10: 1) to give compound 360 (0,010 g 0,028 mmol, 67% over two stages) (scheme 91 provided at the end of the description).

The following examples are provided for illustration and not for limitation.

Examples of use

The compounds described above are used in the treatment of allergies and asthma, arthritis and/or thrombosis. Used herein, the term "treatment of allergies and asthma, arthritis and/or thrombosis" refers to the treatment of allergies and asthma, arthritis and thrombosis and to prevent the development of allergic reactions, bronchostenosis, inflammation and blood clots that cause thrombosis and associated diseases. For the treatment of allergies, asthma, arthritis or thrombosis in a warm-blooded animal, such as man, using the effective amount of the compounds or compositions of the present invention. Methods of administration of effective amounts of anti-allergic, anti-asthma, antiarthritic and antithrombotic agents are well known in this area and include the introduction of inhalation, oral, or parenteral forms. Such dosage forms include, but are not limited to, printer inhalation dosed system, using inhalers dry powder, or under pressure device for inhalation with many doses. Typically, for the treatment of arthritis and thrombosis preferably orally or intravenously, whereas oral or inhaled/intranasal introduction preferable for asthma and allergies. Metered quantity and frequency of injection is chosen to ensure the effective level of the agent without harmful effects. They will usually vary from a dose of about 0.01 to 100 mg/kg / day, typically from about 0.1 to 10 mg/kg / day, when administered orally or intravenously for antiallergic, anti-asthma, antiarthritic or antithrombotic actions. In addition, the dose range is usually from about 0.01 to 1 mg/kg / day when administered intranasally or by inhalation for anti-asthma and anti-allergic effects.

Introduction compounds or compositions of the present invention can be implemented in combination with other agents. For example, it may be desirable introduction bronchodilator or glucocorticoid agent to influence asthma, glucocorticoid for effects on arthritis or antihistamine for impact on allergies. Asteroid which you can use in combination with the steroid compounds of the invention to provide therapy for one or more diseases of asthma, allergies, arthritis and thrombosis.

For example, below are some examples of the biological activity of the various compounds described in the examples of syntheses, sections 1-5.

Anti-thrombotic agents activity polyhydroxylated steroids

The present invention has been described that polyhydroxyalkane steroids and intermediates described in the previous sections, inhibited platelet aggregation induced by platelet activating factor (PAF). PAF is a local mediator of thrombosis, and prevention of blood clots takes a direct part in the treatment of thrombosis and associated cardiovascular diseases. The system of analysis used to assess the ability of compounds to inhibit platelet aggregation in response to exogenous stimuli, is an indicator of antithrombotic or thrombolytic activity.

Platelets were isolated from the blood of rabbits and cooked at a density 2,4108cells/ml in Tyrodes buffer (pH of 7.2), containing CA2+. Platelets were incubated with each compound for 5 minutes at 37oWith prior stimulation. Platelets stimulated with 1 nm by platelet activating factor (PAF; EC75)methylsulfoxide (DMSO) and aggregation was measured as a percentage of the response to 1 nm PAF, obtained in the presence of an appropriate concentration of DMSO. The degree of inhibition caused by each sample was calculated using the control reaction in the presence of DMSO equal to 100%.

Table 1 shows some examples of compounds which inhibit the reaction of platelets in response to PAF.

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

Anti-allergic effects of different polyhydroxylated steroids of the present invention was evaluated by measuring their effect on antigen-induced secretion of hexosaminidase from passively sensitized line fat cells of rats (RBL-2H3) and line the fat cells of mice (MC/9). The ability of agents to inhibit the release of the contents of the granules of mast cells, such as histamine and hexosaminidase, is an indicator of anti-allergic and/or anti-asthma activity.

Hexosaminidase released from the granules of mast cells with histamine and other mediators during antigenic stimulation. Cells RBL-2H3 and MC/9 were grown in culture and passively took senzibilizirani to dinitrophenol (DNP) using human antibodies to DNP (IgE). The cells were incubated with the E. 15 minutes. An aliquot of supernatant was removed and used to measure the amount of hexosaminidase released during stimulation by antigen. The number of hexosaminidase present in the supernatant was determined colorimetrically by monitoring the enzymatic metabolism of p-nitrophenyl-N-acetyl--D-glucosaminide (p-NAG) during the period of 1 hour at 410 nm. The effect of each compound was determined as the percentage of antigen-induced reactions (minus background release) obtained in the presence of only DMSO, as shown in tables 2 and 3. These values are used to determine the degree of inhibition of antigen-induced release of hexosaminidase of cells.

The effect of selected compounds on allergen-induced contraction of smooth muscle of the ileum

The ability of compounds to inhibit allergen-induced contraction of the ileum sensitized animals is an indicator of anti-allergic activity. The ileum is sensitized Guinea pigs are especially suitable for the measurement of immediate allergic reactions.

The terminal ileum of Guinea pigs were used to assess the ability of compounds to inhibit the Indus the NOC was senzibilizirani intraperitoneal injection of 100 mg of ovalbumin and intramuscular injection of 50 mg of ovalbumin on day 0, followed second by intramuscular injection of 50 mg of ovalbumin on day 1. It was found that twenty days after the initial immunization the animals were sensitized, was obtained anaphylactic reaction to allergen stimulation. Segments of ileum were obtained and suspended, and the muscle contraction was measured in the longitudinal plane in Tyrode's buffer at 37oWith and aeronavali 5% CO2in O2. Fabric suspended when off-load voltage 2 g and isometric contractions were measured using transducers force-displacement connected to a polygraph. Tissue stimulated with 3 μm of histamine 3 times to ensure reproducible cuts. The tissue is then incubated with each compound (30 μm) or 0.15% dimethyl sulfoxide (DMSO) as a control for 20 minutes, after this time the fabric was subjected to antigenic stimulation with 100 μg/ml of ovalbumin. The magnitude of the contraction induced OA in the presence of each compound was expressed as the percentage reduction obtained at 3 μm histamine. Protective effect of various compounds on OA-induced contraction of the ileum of Guinea pigs from sensitized animals is summarized in table 4.

The effect of selected compounds on allergen-induced Brenes were evaluated for anti-asthma activity. The ability of compounds to inhibit allergen-induced increase in lung function in sensitized Guinea pigs in response to allergen stimulation is an indicator of anti-asthma activity. This model system is particularly useful when assessing the potential effects of compounds in the treatment of early asthmatic reaction (EAR), when there is heavy bronchostenosis.

Guinea pigs were exposed sprayed with 1% solution of ovalbumin (OA) in saline solution for 15 minutes. After 10 days it was discovered that the animals were sensitized, i.e., tracheal tissue reacted with anaphylactic bronchospasm in subsequent stimulation with antigen (OA). It was found that the trachea of these animals responded similarly to the situation in vivo. Tracheal rings were received and placed in a bath of a solution of Krebs-Henseleit at 37oWith and aeronavali 5% CO2in O2. Fabric suspended when off-load voltage 2 g and the isometric contraction was measured using transducers force-displacement connected to a polygraph. Tissues were incubated with each compound or 0.1% DMSO (control) for 20 minutes, after which tissue was added polyhistorian, tissue stimulated with 100 µm methacholine, which caused the maximum reduction in the trachea. The magnitude of the reduction caused by OA in the presence of each compound was expressed as a percentage of the maximum contraction obtained with the use of methacholine (100 μm). Protective effect of various compounds on OA-induced contraction of tracheal tissue are summarized in tables 5-7.

In addition, the effect of the compounds of the invention to the lung in vivo were determined in sensitized animals as follows.

Female Guinea pigs Cam Hartley (350-400 g) were senzibilizirani to ovalbumin, exposing Guinea pigs to the impact of the sprayed solution of 1% ovalbumin in saline solution for 15 minutes. After 10-12 days, it was found that the animals were really sensitized to the allergen (ovalbumin). Animals were treated by oral feeding with a weak anesthesia with halothane gas, 300 μl of polyethylene glycol-200 (PEG) or 5 mg/kg of the test compound in 300 μl of PEG. Animals were treated once daily for 4 days with the final dose, introduced for 2 hours before stimulation with allergen. Alternative compounds were delivered by inhalation using a Hudson sprayer, acting under Yes"ptx2">

Animal during the surgical procedure was anestesiologi using ketamine (50 mg/ml, intraperitoneally) and xylazine (10 mg/kg, intraperitoneally) and 1% halothane gas. Performed the tracheotomy, and water-filled esophageal cannula was inserted prior to placing the animal in plethysmograph for registration of changes in the volume of the organs of the body. The tracheal cannula was connected with a fixed tracheal cannula in pletismography. Cardiac function was monitored using electrocardiography. The animal was paralyzed with the use of pancuronium bromide (0.8 mg/kg, intramuscularly) and ventolinbuy 3 ml alternating inhales and exhales with a Harvard apparatus for artificial ventilation of the lungs of the animals at the rate of 60 breaths per minute. Data of pulmonary resistance and dynamic lung volume changes were obtained from signals volume, flow and repair of pressure, using multipoint analysis.

Pulmonary function is continuously controlled throughout the experiment and the measurement of lung resistance and changes in the volume of the lungs is carried out in different points of time (for example, 0, 1, 2, 3, 4, 5, 10, 20 and 30 min) after antigenic stimulation. Data are collected on a connected with to aliroot using software ANADAT, designed for measuring respiratory mechanics. This software was obtained from RHT-InfoDat Inc., Montreal, Quebec, Canada.

After getting the measurements of the base resistance and the change of volume of the lungs, the animal is stimulated to respond 6 breaths salt solution. After 10 minutes, during which there should be changes in lung function, animal to stimulate response 6 breaths 2 or 3% ovalbumin in saline solution (as antigenic stimulus). Saline and antigen delivered with each breath using a Hudson sprayer. Protective effect of compound 330, administered orally, on OA-induced contraction of tracheal tissue, is summarized in the following tables 8 and 9.

Protective effect of compound 330, introduced by inhalation, in OA-induced contraction of tracheal muscle is summarized in the following tables 10-11.

Protective effect of compound 339, administered orally, on OA-induced contraction of tracheal muscle is summarized in the following tables 12-13.

Protective effect of compounds 342, administered orally, on OA-induced contraction of tracheal tissue, summer the pneumonia

The ability of compounds to inhibit allergen-induced accumulation of inflammatory cells infiltration, such as eosinophils and neutrophils, in the washing liquid derived from sensitized animals is an indicator of anti-asthma activity. When evaluating the effect of compounds on treatment podnebesnoi reactions asthma, when it is obvious inflammation of the lungs and the second phase of bronchostenosis, particularly useful model system.

Male rats Brown Norway (200-250 g) sensibiliser to ovalbumin intraperitoneal injection of 1 mg of ovalbumin and 100 mg of aluminum hydroxide in 1 ml of sterile saline. After 21 days, it was found that animals sensitized to ovalbumin. Animals treated with drug or excipient (0.3 ml PEG-200) once a day for 4 days by oral feeding. Animals stimulated by processing, in a period of 60 minutes, sprayed with a solution of 0.5% ovalbumin in saline solution, generated using spray Devillbis. The final dose of the drug given 24 hours after stimulation. At 48 hours after stimulation animals painlessly killed by an overdose of halothane gas and light washed 72 mantripukhri at 1200 rpm to separate cells from supernatant. Cells subjected to rapid action buffer Tris/chloride of ammonium, pH of 7.3, to remove any red blood cells and washed with phosphate buffered saline. Products cytocentrifugation each sample cells were obtained and stained for the presence of cells containing peroxidase, and to determine the number of eosinophils and neutrophils. The number of cells of the inflammatory infiltrate was expressed as a percentage of the total number of cells allocated in the wash liquid. Protective effect of compound 330 on allergen-induced lung inflammation is summarized in table 16.

The effect of selected compounds in an allergic model of asthma sheep

It was investigated the effect of selected compounds in an allergic model of asthma sheep.

Used allergic sheep model, because it shows the main characteristics associated with asthma. This model shows natural allergies, early (acute) bronchostenosis, bronchostenosis in the late stage, the inflammation of the lungs and bronchial hypersensitivity. The model is conscious animals breathing spontaneously, which allows the measurement of bronchostenosis respiratory tract and acute hypersensitivity of the respiratory tract.

The proximal end of the endotracheal tube was connected with pheumothorax Fleisch to measure changes in flow. Pulmonary resistance (Rt) was calculated from measurements repair pressure, tidal volume (from digital integration of signal flow) and flow method of low flow. SRLwas calculated as RLVtg(Vtg=volume of gas in the chest).

Aerosols generated using the available spray directed to the T-section connected in series with a Harvard respirator and tracheal tube. Aerosol delivery of regulated using a dosing system consisting of a solenoid valve and compressed air (1,406 kg/cm2, 20 psi), activated at the beginning of each cycle of inhalation. Aerosols were delivered in respiratory-expiratory volume and was diluted in saline solution. Animals received either 400 mg/kg of the compound for 30 minutes before stimulation and after 4 hours after stimulation, or 400 μg/kg of the compound for 4 days with the last dose 2 hours prior to stimulation. Extract of Ascaris suum was diluted in phosphate buffered saline to a concentration of 82000 of protein nitrogen units/ml and delivered by aerosol for 20 min Carbachol was dissolved in PBS (phosphate buffered saline) to concentrations 0,25, 0,5, 1,0, 2,0 4,0% (weight/volume). Each animal served as its own control throughout the study.

Specific lung resistance (SRL) was measured every 60 minutes within 8 hours after stimulation by antigen. Hypersensitivity of the respiratory tract to carbachol was measured 24 hours after initial stimulation.

Protective effect of compound 330 entered urgent (within 30 minutes before stimulation and 4 hours after stimulation, 400 µg/kg), specific pulmonary resistance and hypersensitivity summarized in tables 17-18.

Further studies demonstrating a protective effect of compound 330, introduced during 4 days (400 µg/kg), specific pulmonary resistance and hypersensitivity are summarized in A

The hallmark of a number of chronic inflammatory diseases is the activation of several genes, which, as is known, the integral (integral) participate in the maintenance of inflammation. Among them (the products of these genes) are cytokines, chemokines, adhesion molecules, transcription factors and proteases. Essential for induced the expression of many of these Pro-inflammatory molecules is a class of proteins called transcription factors. One family of transcription factors that are known to be key for the Pro-inflammatory state, is NF-kB. A number of clinical conditions, diseases associated with elevated levels of activated NF-kB. These include atherosclerosis, cancer, infectious disease and various diseases based on inflammation, including asthma, inflammatory bowel disease, arthritis, ischemia/perfusion and inflammatory skin conditions. It was found that the compounds described in this invention, cause the inhibition of activation of NF-kB induced esters of phorbol (activators NF-kB).

Tests for bias in the gel used for the study of the action of selected compounds of the invention on the activation of NF-kB by defining ur the NF-kB, noted the following procedure. 5 μl of the oligonucleotide NF-kB (8.9 pmol), 2 μl of 10x buffer T4-polynucleotide kinase, and 10 units of T 4 polynucleotide kinase and 1 mm-P-32-d (10 µci) was diluted using H2On a final volume of 20 µl. The reaction mixture was incubated at 37oC for 30 minutes. After this time the reaction was suppressed 2 μl of 0.5 M EDTA and 2 μl of 3 M NaOAc (pH 5.2). Added 2.5 x volume of 100% EtOH and the resulting mixture was centrifuged at 15000 g (microcentrifuge eppendorf) for 10 minutes. The precipitate after centrifugation then washed several times in 70% ethanol, dried in air at room temperature for 10 minutes and resuspendable in double-distilled H2(The final concentration of 0.75 pmol/2 μl). Cells (RBL-2H3 and a-549) were washed twice in phosphate buffered saline (PBS) at room temperature. They scraped from cups to tissue cultures in 5 ml of PBS using a scraper for cells and centrifuged (1500 rpm at room temperature, centrifuge Beckman GPR). After removal of the supernatant the cells resuspendable 2 volume (volume of sediment after centrifugation) of buffer A (0.25 M sucrose, 20 mm HEPES (pH of 7.9), 10 mm KS1, 1.5 mm MgCl2, 0.5 mm DTT (dithiothreitol), of 0.5 mm spermidine, 0.15 mm spermine). Suspensive be incubated at room temperature for 5 minutes. Added lysolecithin (10 mg/ml in buffer A) to a final concentration of 400 μg/ml (4 µl/100 µl buffer A) and the suspension is incubated with a cautious rolling more than 90 seconds. Lysis of cells was quickly stopped by addition of two volumes of ice buffer containing 3% BSA. Nuclei were collected by centrifugation at 4000 rpm for 1 min at 4oWith microcentrifuge. The supernatant was removed and the residue resuspendable in buffer a containing 3% BSA, before centrifugation at 30,000 rpm for 60 seconds atoWith (Beckman TL-100). Kernel resuspendable in ice buffer (20 mm HEPES (pH of 7.9), 25% (vol./about.) glycerol, 0.6 M KS1, 1.5 mm MgCl2, 0.2 mm EDTA, 0.5 mm DTT, 0, 5 mm PMSF) at a density of approximately 107nuclei/ml Kernel tore at keeping on ice by sonication with 2 heartbeats five seconds (the intensity of subsidence 40%, MICROSON: Ultrasonic cell disrupter). The homogenate on ice gently stirred for 30 minutes before centrifugation at 25000 g and at 4oWith in a Beckman TL-100. The supernatant was then removed and frozen at -70oIf not used immediately. Determination of DNA-binding activity of NF-kB was carried out as follows: 2 μl of 10x buffer for binding {20 mm HEPES (pH 7.5), 50 mm KS1, 5 mm MgCl2, 200 MS 5 μg protein, isolated from cell nuclei. The resulting mixture was brought to a final volume of 20 μl with distilled H2O. It then incubated on ice for 5 minutes to carry out the binding. Further incubation was performed (20 to 30 minutes) at room temperature. The samples are then loaded onto a 4.5% acrylamide gel {6 ml (29:1) acrylamide: bis, 2 ml 5x TBE buffer, 800 μl of 50% glycerol, 31 ml of distilled H2O, 150 ál of 10% APS (ammonium persulfate), 40 µl TEMED}. Through acrylamide gels previously missed 0.25 x TBE buffer for 1.5 hours (10 At/cm), followed by the replacement buffer before loading and deletion (electrophoresis) of these samples.

The effect of selected compounds of the present invention on the activity of NF-kB, as determined by analysis of the binding of the shift in the gel, is provided in table 21.

All publications and patent applications mentioned in this description are included here as a reference to the same extent as if each individual publication or patent application was specifically and individually incorporated by reference.

From the foregoing it should be apparent that although a specific embodiment of the invention have been described herein for purposes of illustration, the tx2">

1. 6,7-oxygenated steroids of General formula

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including their pharmaceutically acceptable salt and solvate,

where the rings a, b, C and D are fully saturated;

C3 is substituted by = O, or two of R4and-OR1, each of which is independently selected, where R4is H and R1represents H or a protective group;

or each of R3 and R4 is substituted OR1where R1represents H or a protective group, so that the adjacent-OR1groups together form a cyclic structure which protects the adjacent-OR1group; or C3 and C4 are connected to the same oxygen atom with the formation of rings of oxirane;

C6 and C7 each substituted OR1where R1represents H or a protective group, so that the adjacent-OR1groups may together form a cyclic structure that protects the adjacent-OR1group;

C15 is substituted by = O, or two R4, where R4is N;

C17 is substituted according to any of the following:

(a) -R4;

(b) -OR1;

(c) one of: = O; W = C(R2) (R3), where R2and R3independently selected from N or C1-4alkyl; and-C(R4) (R4) ((R4)(R4))n-, where n is the number from 1 to 6, subject to the Deputy C7-OR1has the beta configuration, then R17 is not replaced by any of the following groups:

< / BR>
or

< / BR>
(d) the cyclic structure of the formula

< / BR>
if C3 and C4 are not replaced simultaneously by hydroxyl or protected hydroxyl, or

(e) two hydrogen atoms if C3 is not replaced by a carbonyl group;

R1represents H or a protective group, so-OR1represents a protected hydroxyl group;

R2, R3and R4in each case, independently, selected from H and C1-4the alkyl.

2. Connection on p. 1 having a formula selected from

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< / BR>
including their pharmaceutically acceptable salt and solvate.

3. Connection on p. 2 having the formula

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4. Connection on p. 2 having the formula

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5. Connection on p. 1, where C11 and C12, each substituted only by hydrogen.

6. Connection on p. 1, where R17 is substituted by the Deputy, is selected from C1-C7hydrocarbon radical.

7. Connection on p. 1, where R17 is substituted by the Deputy selected from formula = C(C1-C4)2and = CH(C1-C4).

8. Connection on p. 1, where R17 is substituted by the Deputy, selected from carbonyl, hydroxyl and samisen the seal hydroxyl.

10. Connection on p. 1, where C3 and C4, both are replaced by oxygen and together form an epoxide, acetal or ketal.

11. Connection on p. 1, where C6 and C7 are each substituted with hydrogen.

12. Connection on p. 1, where C6 and C7, both, are replaced by hydroxyl groups.

13. Connection on p. 1 having the formula

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14. Connection on p. 1 having the formula

< / BR>
15. Connection on p. 1 having the formula

< / BR>
16. Connection on p. 1 having the formula

< / BR>
17. Connection on p. 1 having the formula

< / BR>
18. Connection on p. 1 having the formula

< / BR>
19. Connection on p. 1 having the formula

< / BR>
20. Connection on p. 1 having the formula

< / BR>
21. Connection on p. 1 having the formula

< / BR>
22. Connection on p. 1 having the formula

< / BR>
23. Connection on p. 1 having the formula

< / BR>
24. Connection on p. 1 having the formula

< / BR>
25. Connection on p. 1 having the formula

< / BR>
26. Connection on p. 1 having the formula

< / BR>
27. Connection on p. 1 having the formula

< / BR>
28. Connection on p. 1 having the formula

< / BR>
29. Connection on p. 1 having the formula

< / BR>
30. Connection on p. 1 having the formula

< / BR>
31. Connection on p. 1 having the formula

< / BR>
PR is

 

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The invention relates to Bioorganic chemistry, in particular to methods for the production of steroidal glycosides from plant material

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

The invention relates to new steroid, namely steroid with a 17-spermatocelectomy group having the General formula I, where R1is O, (H, H), (H, or), or NOR, and R is selected from H, (1-6C) alkyl and (1-6C) acyl; R2is H, (1-6C)akilam arbitrarily substituted with halogen, (2-6C)alkenyl arbitrarily substituted with halogen, (2-6C)quinil arbitrarily substituted with halogen, or halogen; R2is H; or R'2together with R2is (1-6C)alkylidene group or (2-6C)allenylidene group; or R'2together with R3are bond; R3is N, if R'2is not a bond; R4is (1-6C)alkyl; one of R5and R6is hydrogen and the other is hydrogen or (1-6C) alkyl; X is (CH2)nor (CnH2n-2), where n is 2 or 3, which is arbitrarily substituted with hydroxyl, halogen, (1-6C)alkyl, (1-6C)acyl, (7-9C)phenylalkyl, phenyl group which may be substituted (1-6C)alkyl, (1-6C)alkoxyl, hydroxyl or halogen; Y is O or (H, HE) and dashed lines show a random link, and at least one of the links 4-5, 5-10 and 9-10 is a double bond

-lactone 3(7-acetylthio-17-hydroxy-3 - oxoandrosta-4-en-17-yl)propionic acid" target="_blank">

The invention relates to pharmaceutical chemistry, and in particular to an improved method for producing a potassium-sparing diuretic such as spironolactone (verospiron, aldactone) of the available raw materials - Starinov of plant and animal origin

The invention relates to new derivatives of 17,20-epoxides Pregnana, to a method for their production and to their use as intermediates in the synthesis of biologically active products, specifically to derived 17,20-epoxides of General formula I

< / BR>
where R-=0,-OH, and In the remains of

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and K=O, or group

< / BR>
or

< / BR>
where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers

The invention relates to the synthesis of biologically active substances, in particular to the synthesis of ecdysteroids, specifically to the synthesis of SIDACTION found in very small amounts in some species, for example Blehnum niponicum and Vitex canescens

The invention relates to new steroid derivatives of the androstane series and pregnane, as well as to pharmaceutical preparations and methods for modulation of excitability of the brain

The invention relates to the field of organic chemistry, the method of production of monoether from 17-oxosteroid and succinic anhydride
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