Indene derivatives as pharmaceutical agents


FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of a separate stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers and their pharmaceutically acceptable salts. In formula (I) ring A, C or D is independently completely or partially saturated; each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms; each of C9 and C14 is independently substituted with a hydrogen atom; R1 represents -OR7 or -N(R7)2. Values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition with anti-inflammatory activity and contains an effective amount of the disclosed compound and to use of the said compounds to make a medicinal agent with anti-inflammatory activity.

EFFECT: disclosed compounds have anti-inflammatory activity.

23 cl, 47 ex

 

The technical field

The present invention relates to derivatives of indene, applications containing these derivatives and derivatives of pharmaceutical compositions.

The level of technology

Normal inflammatory response is a substantially localized reaction of the body to penetrate the microorganisms or tissue damage involving cells of the immune system. Inflammatory response allows the body to specifically recognize and eliminate the invading organism and/or to restore the damaged tissue. Classic signs of inflammation include redness (erythema), swelling (edema), pain and increased heat (pirea) at the site of damage. Many sharp changes at the site of inflammation directly or indirectly associated with a characteristic of the reaction mass influx of leukocytes (e.g. neutrophils, eosinophils, lymphocytes, monocytes). Leukocyte infiltration and accumulation in the tissues leads to the activation of leukocytes and subsequent release of inflammatory mediators, such as, for example, LTB4, prostaglandins, TNF-α, IL-1β, IL-8, IL-5, IL-6, histamine, proteases and reactive oxygen species.

Normal inflammation is a strictly regulated process that is tightly controlled at multiple levels for each type of cells involved in the reaction. the example the expression of the proinflammatory cytokine TNF-α is controlled at the level of gene expression, translation, posttranslational modification and release of the Mature form of the cell membrane. Proinflammatory reactions usually counteract by endogenous anti-inflammatory mechanisms, such as the generation of IL-10 or IL-4. A feature of the normal inflammatory reaction is that this reaction is of a temporary nature, with the subsequent phase resolution that returns the skin to its previous state. It is believed that the phase resolution includes increasing regulation of anti-inflammatory mechanisms, such as IL-10 and lower regulation of Pro-inflammatory processes.

Inflammatory disease occurs when the inflammatory response is initiated, which is inadequate and/or not allowed in the normal way, but rather persists and leads to a chronic inflammatory state. The disease may also involve the disturbance of cellular immune response, which leads to the recognition of proteins of the host body (antigens) as alien. Here, the inflammatory response is incorrect in relation to supply tissues with cells effectors aimed at specific organs or tissues, which often leads to irreversible violation. The aspect of recognition “its is the autoimmune disease is often reflected clonal expansion of T-cell subsets, characterized by specific subtype of receptor T cells (TCR) in the painful condition. Often inflammatory disease is also characterized by an imbalance in the levels of subpopulations of T-helper (Th) (i.e., Th1 cells versus Th2)cells. The inflammatory disease may be systemic (e.g., lupus), or localized to certain areas or organs (e.g., asthma) and affects a huge number of people, representing a heavy economic burden for society. Examples of some of the most common and problematic inflammatory diseases are asthma, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, psoriasis and atopic dermatitis.

Therapeutic approaches to cure inflammatory diseases are usually divided into two categories: (a) negative negative modulation processes, subject to increasing regulation in a morbid condition, or (b) increasing regulation of anti-inflammatory pathways in the affected cells or tissues. Most currently used in the clinic of medical schemes belongs to the first category. Some examples of such schemes include corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs).

Clarified many of the tissue, cellular and biochemical processes, which narechenny and in inflammatory disease, that helped to create experimental models or to carry out biological tests that mimic the disease state. These tests and models enable screening and selection of compounds characterized by a sufficient likelihood of therapeutic efficacy in these inflammatory diseases. Despite the use of such models for many inflammatory diseases have not been found effective medicines. There is a significant need for therapeutic means, effectively stopping or reverse progression of the disease with painful conditions or pathologies, such as asthma, chronic obstructive pulmonary disease, multiple sclerosis, psoriasis and inflammatory bowel disease.

The INVENTION

Compounds of the present invention are useful as anti-inflammatory drugs.

Thus, one aspect of the present invention relates to compounds of formula (I):

where

ring A, C or D is independently fully saturated, partially saturated or fully unsaturated;

each of C1, C4, C11, C12, C15 and C16 is independently substituted with two groups independently selected from the group comprising hydrogen, alkyl, -R8-OR7or-R8-N(R7) 2provided that C4 can not be substituted by two methyl groups;

each of C9 and C14 is independently substituted by hydrogen, alkyl, -R8-OR7or

-R8-N(R7)2;

R1means-OR7or-N(R7)2;

each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7regardless of ybiraut from the group including hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain;

in the form of a single stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers;

or a pharmaceutically acceptable salt, MES or prodrug of the compounds, in isolated form or in the form of a mixture.

According to another aspect of the invention concerns compounds of formula (II):

where

ring A, C or D is independently fully saturated, partially saturated or fully unsaturated;

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

(a) one of the following groups =O, =C(R14)2, =C=C(R14)2, -[C(R14)2]n- (where n = 2-6) and-O-[C(R14)2]m-O- (where m is 1-6); or

(b) two of the following independently selected groups: -R14, -OR15and-N(R16)2;

C3 is substituted by two of the following independently selected groups: -R14, -OR15and

-N(R16)2;

each of C5, C8, C9, C10, C13, C14 and C17 optionally independently substituted by one of the following groups: -R14, -OR15and-N(R16)2;

each of R11and R12independently selected from the group comprising hydrogen, halogen, =O, -OR15, -N(R16)2and C1-30organic group;

R13means R14, -OR15, -N(R16)2, =C(R14)2, =C=C(R14)2, -[C(R14)2]n- (where n is 2-5), or-O-[C(R14)2]m-O- (where m is 1-5);

each R14independently selected from the group comprising hydrogen, halogen and

C1-30organic group, where two genialnyh R14groups may form a ring together with the carbon to which attached;

each R15independently selected from the group including hydrogen, oxygen protective group, so-OR15means a protected hydroxy-group, the initiator of the leaving group, so-OR15means a leaving group, and C1-30-organic g is the SCP, which may optionally contain at least one heteroatom selected from the group comprising boron, halogen, nitrogen, oxygen, phosphorus, silicon and sulfur, where vicinal-OR15group together with the carbon to which they're attached, may form a cyclic structure which protects vicinal hydroxy-group, and where genialny-OR15group together with the carbon to which is attached, can form a cyclic structure which protects a carbonyl group;

each R16independently selected from the group comprising hydrogen, -OR17oxygen (so that the formed nitro - or oxime group) and C1-30organic group, which may optionally contain at least one heteroatom selected from the group comprising boron, halogen, nitrogen, oxygen, phosphorus, silicon and sulfur; or

two R16group together with the nitrogen to which the are attached, form a heterocyclic ring; and

each R17independently selected from hydrogen and C1-30-hydrocarbide; in the form of a single stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers;

or a pharmaceutically acceptable salt, MES or prodrug of the compounds, in isolated form or in the form of a mixture;

provided, however, that

(1) C4 cannot be substituted by two methyl group is AMI

(2) R13cannot mean =O or 6-methylhept-2-yl;

(3) when the C17 is substituted by hydrogen, R13can't mean-OH or-OC(O)R, where R is methyl, ethyl, phenyl or cyclohexyl;

(4) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-CH2C(O)H, R13may not mean a-C(CH3)HCH2CH2C(O)och3or-C(CH3)HCH2CH2C(CH2CH3)NC(CH3)2N;

(5) when each of C1, C2, C4, C11, C12 and C15 substituted with two hydrogens, C16 substituted with hydrogen and hydroxy, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, C3 is substituted with hydrogen and hydroxy, R11mean =O and R12means-CH2C(O)HE or-CH2C(O)OCH3, R13may not mean a-C(CH3)NH2CH2N(CH3)2- (CH3)HCH2CH2C(CH2CH3)NC(CH3)2H or-C(CH3)H-R (where R is 5-methylpiperidin-2-yl);

(6) when each of C1, C2, C11, C12 and C15 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, C4 substituted with two hydrogens or C4 is connected by a double bond with C3, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12oznacza the t-CH 2CN, R13may not mean a-C(O)OCH3;

(7) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12mean =CHC(O)H, R13may not mean a-C(CH3)NSNSNS(CH3)NC(CH3)2N;

(8) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-CH2CH3, R13may not mean a-C(CH3)HOC(O)CH3;

(9) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means hydroxy and R12mean =CHCH2OH, R13may not mean a-C(CH3)HCH2CH2C(CH2CH3)NC(CH3)2H or-C(CH3)NSNSNS(CH3)NC(CH3)2H, -C(CH3)HCH2CH2C(CH2)C(CH3)2H or-C(CH3)NSNS[CH2C(CH3)2N]H;

(10) when each of C1, C2, C4, C11, C12 and C15 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, C16 for the of Eden two hydrogens or one hydrogen and hydroxy, R11means hydroxy and R12means-CH2CH2OH, R13may not mean a-C(CH3)HCH2CH2C(CH2CH3)NC(CH3)2H, -C(CH3)HCH2HE, -CH2HE or-C(CH3)N-R (where R is 5-methylpiperidin-2-yl);

(11) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means hydroxy and R12means-CH2CH3, R13may not mean a-C(CH3)HCH2C(CH3)NC(CH3)2N or-S(HE)HCH3;

(12) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means hydroxy and R12means SNSN2, R13may not mean(HE)HCH3;

(13) when each of C1, C4, C11, C12, C15 and C16 substituted with two hydrogens, C2 substituted with hydrogen and hydroxy, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH and R13means- (CH3)NA () NA () NA(CH2CH3)NC(CH3)2N, R12cannot mean-CH2SH or-CH2SSCH2R (where R is hydrogen or C1-30about the organic group);

(14) when each of C1, C4, C11, C12, C15 and C16 substituted with two hydrogens, C2 substituted with two hydrogens or hydrogen and hydroxy, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH or-CH2OH and R12means-CH2OH, R13cannot mean-CH2HE, -C(CH3)NA () NA () NA(CH3)NC(CH3)2H or-C(CH3)NA () NA () NA(CH2CH3)NC(CH3)2N;

(15) when each of C1, C2, C11, C12 and C15 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, substituted C4 hydrogen and stands, or two hydrogens, each of C5 and C9 substituted by hydrogen, each of C8 and C14 substituted with hydrogen or each substituted stands, each of C10 and C13 substituted stands, C16 substituted with hydrogen and -- OC(O)CH3, R11means-C(O)H and R12means-C(O)H, R13cannot mean =C[C(O)HE]CH2CH2SNA(CH3)2or-C(CH3)HCH2CH2C(O)och3;

(16) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, C12 substituted with hydrogen and hydroxy, R11means-CH2C(O)OH or-CH2C(O)OCH3and R12means-NH2or-N(CH3)3, R13may not mean a-C(CH3)N the N 2CH2C(O)och3or-C(CH3)HCH2CH2With(ABOUT)HIM;

(17) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-NH2or-N(CH3)3and R12means-CH2C(O)OH or-CH2C(O)OCH3, R13may not mean a-C(CH3)HCH2CH2C(O)och3or-C(CH3)HCH2CH2With(ABOUT)HIM;

(18) where each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and hydroxy, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =NNHC(NH)NH2and R12means-CH2CH2C(O)OH, R13may not mean a-C(CH3)NNHC(NH)NH2;

(19a) when each of C1, C2, C4, C11 and C12 substituted with two hydrogens, C3 is substituted by =O, each of C8, C14 and C17 substituted by hydrogen, C9 substituted by hydrogen or hydroxy, each of C10 and C13 substituted stands, C15 substituted with two hydrogens or C15 substituted with hydrogen and is linked by a double bond with C16, C16 is substituted by hydrogen or hydroxy and is linked by a double bond to C15, or C16 substituted =CH2OH, R11mean =O and R12mean =CHC(O)OH, R13may not mean a-C(CH3)HC(O)CH2C(CH3)HC(CH3)2H;

(19b) when each of C1, C2, C4, C11 and C12 substituted with two hydrogens, a substituted C =O, C8 and C14 are connected to each other by a double bond, C9 substituted hydroxy, each of C10 and C13 substituted stands, C15 substituted with hydrogen and is linked by a double bond with C16, C16 substituted methoxy and associated dual connection with C15, C17 substituted by hydrogen, R11mean =O and R12means-CH2C(O)OCH3, R13may not mean a-C(CH3)HC(O)CH2C(CH3)HC(CH3)2H;

(20) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted by =O, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-CH2CN, R13may not be C(O)other (where R is 5-trifluoromethyl-2-tert-butylphenyl) or-C(O)OCH3;

(21) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted by =O, each of C8, C9, C14 and C17 substituted with hydrogen, C10 substituted stands or-CH2OC(O)H, C13 substituted stands, R11mean =O and R12means-CH2CH3or-CH2I, R13may not mean a-C(O)OCH3;

(22) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted by =O, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH and R12means-C(O)OH, R13may not mean a-C(CH3)HCH2CH2C(O)OH or-C(CH3)HCH2CH2CH3;

(23) when each of C1, C2, C4, C11, C12, C15 and C16 is substituted by two bodoro the AMI, C3 is substituted by =O, each of C5, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-CN and R12means =O, R13may not mean a-C(CH3)HCHCHC(CH3)HC(CH3)2H;

(24) when each of C1, C2, C4, C12 and C15 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3, C8, C9, each of C8, C9 and C14 substituted by hydrogen, C11 substituted with two hydrogens, hydrogen and hydroxy or hydrogen and-OC(O)CH3, C16 substituted with two hydrogens or =CH2, C17 substituted by hydrogen, hydroxy or-OC(O)CH3each of C10 and C13 substituted stands, R11means =O, and R12means-CH2C(O)OH, R13cannot mean-CH3, -CH2CH3, -C(O)CH3, Cyclopentanone, -C(CH3)HOC(O)R (where R is phenyl), -C(CH3)HCH2CH2C(O)OCH3, -C(O)CH2OC(O)CH3or-C(CH3)HCH2CH2C(CH2CH3)HC(CH3)2H;

(25) when each of C1, C2, C4, C11, C12 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C8 and C9 substituted by hydrogen, each of C10 and C13 substituted stands, C14 substituted stands, or-OC(O)CH3, C15 substituted with two hydrogens or =O, C17 substituted with hydrogen or OC(O)CH3, R11mean =O and R12means-CH2C(O)H, R13may not mean a-C(O)OCH3, -C(O)CH3or-CH3;

(26) when each of C1, C2, C4, C11, C12 and C15 substituted with two hydrogens, 3 substituted with hydrogen and -- OC(O)CH 3each of C8, C9 and C14 substituted by hydrogen, each of C10 and C13 substituted stands, C16 substituted with two hydrogens, or forms a double bond with C17, R11mean =O and R12means-CH2CN, R13may not mean a-C(O)CH3;

(27) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C8, C9, C14 and C17 substituted with hydrogen, C10 substituted by hydrogen or-CH2C(O)OH, C13 substituted stands, R11mean =O and R12means-CH2I or-CH2C(O)OCH3, R13cannot mean-O(O)CH3;

(28) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C8, C9, C14 and C17 substituted with hydrogen, C10 substituted by hydrogen or-CH2C(O)OH, C13 substituted stands, R11mean =O and R12means-CH2I, -CHCH2, -CCH, -C(O)OCH3or-CH2OCH3, R13may not mean a-C(CH3)HOC(O)CH3;

(29) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-CH2NCO, -CH2C(O)N3or-C(O)OH, R13may not mean a-C(CH3)HCH2CH2C(CH2CH3)HC(CH3)2H;

(30) when each of C1, C2, C4, C11, C12, C15 and C16 is substituted by two hydrogen and, C3 is substituted with hydrogen and -- OC(O)CH3each of C8, C9 and C14 substituted by hydrogen, each of C10 and C13 substituted stands, C17 is substituted by-OC(O)CH3, R11mean =O and R12means-CH2CHNNHR (where R is 2,4-dinitrophenyl), R13cannot mean-CH3;

(31) when each of C1, C4, C11, C12, C15 and C16 substituted with two hydrogens, C2 substituted with hydrogen and -- OC(O)CH3, C3 is substituted with hydrogen and -- OC(O)CH3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH and R12means-C(O)H, R13may not mean a-C(CH3)HCH2CH2CH2CH3;

(32) when each of C1, C4, C11, C12, C15 and C16 substituted with two hydrogens, C2 substituted with hydrogen and -- OC(O)CH3, C3 is substituted with hydrogen and -- OC(O)CH3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH or-C(O)OCH3and R12means-C(O)H, -CH2SSCH2R (where R is hydrogen or C1-30organic group), -CH2OS(O)2CH3or-CH2OH, R13may not mean a-C(CH3)HC[OC(O)CH3]HC[OC(O)CH3]HC(CH2CH3)HC(CH3)2H;

(33) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-C(O)OH and R12means-C(O)OH,R 13may not mean a-C(CH3)HCH2CH2C(O)OH;

(34) when each of C1, C2, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3, C4 substituted with hydrogen and the stands, each of C5, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-CH2C(O)H and R12means =O, R13may not mean a-C(CH3)HCH2CH2C(O)C(CH3)2H;

(35) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11and R12both mean-CHNOCH3or CHNOCH2CH3, R13may not mean a-C(CH3)HCH2CH2C(O)OCH3;

(36) when each of C1, C2, C4, C11, C12 and C15 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)CH3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, C16 substituted with hydrogen and -- OC(O)CH3, R11means-OC(O)CH3and R12means-CH2CH2OC(O)CH3, R13may not mean a-C(CH3)HR (where R is 5-methyl-1-acetylpiperidine-2-yl);

(37) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen, triisopropylsilane, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means

p> -CH2C(O)OH, -CH2C(O)H, -CH2CH2N3, -CH2CH2OH, -CH2CH2OS(O)2CH3or-CH2C(O)N3, R13may not mean a-C(O)N(CH2CH3)2;

(38) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen, triisopropylsilane, each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means

-CH2C(O)OH, -CH2C(O)H or-CH2C(O)Cl, R13may not mean a-C(O)OCH3;

(39) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen, triisopropylsilane, each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands and R11and R12both mean-CHNOCH3, R13may not mean a-C(CH3)HCH2CH2C(O)OCH3;

(40) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(O)R (where R is 4-nitrophenyl or 3,5-dinitrophenyl), each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-OH and R12means-CH2CH2OC(O)R (where R is 4-nitrophenyl or 3,5-dinitrophenyl), R13may not mean a-C(CH3)HCH2OC(O)R (where R is 4-nitrophenyl or 3,5-dinitrophenyl) or-C(CH3)HCH2CH2C(CH2CH3)HC(CH3)2H;

(41) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and-OCH2OCH3each of C5, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-CN and R12means-OH or =O,

R13may not mean a-C(CH3)HCHCHC(CH3)HC(CH3)2H;

(42) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and-OCH2OCH3each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-CH2C(O)OH,

R13cannot mean-OCH2CH2CH3;

(43) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted =NNHR (where R is 2,4-dinitrophenyl), each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands and R11and R12both means-C(O)OH, R13may not mean a-C(CH3)HCH2CH2C(O)OH;

(44) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and-OCH2R (where R is phenyl), each of C5, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means-CH2C(O)H and R12means =O, R13may not mean a-C(CH3)HCH2CH2C(CH3)HC(CH3)2H;

(45) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and-CH 3each of C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11mean =O and R12means-C(O)OH, R13cannot mean-OC(CH3)3; and

(46) when each of C1, C2, C4, C11, C12, C15 and C16 substituted with two hydrogens, C3 is substituted with hydrogen and -- OC(CH3)3each of C5, C8, C9, C14 and C17 substituted by hydrogen, each of C10 and C13 substituted stands, R11means hydroxy and R12means-CH2OH, R13cannot mean-OC(CH3)3.

According to another aspect of the invention concerns pharmaceutical compositions containing a pharmaceutically acceptable excipient and a compound of formula (I) or the compound of formula (II)as specified above.

According to another aspect of the invention is a method of treating an inflammatory condition or disease in a mammal, the method includes the introduction in need of such treatment to the mammal a therapeutically effective amount of the compounds of formula (I) or the compounds of formula (II)as specified above.

DETAILED description of the INVENTION

The present invention relates to pharmaceutical compositions and methods useful for the treatment and/or prevention of various illnesses. For example, one aspect of the present invention concerns a method of treating inflammation in a mammal, predpochtitelno person. The method includes the introduction in need of such treatment to the mammal a therapeutically effective amount of the compounds according to the invention or pharmaceutically acceptable salts of the compounds, or an effective amount of a pharmaceutical composition containing the compound according to the invention or a pharmaceutically acceptable salt of the compounds.

Before to explain the invention in more detail, here are some concepts used here, with appropriate definitions, as well as some of the conventions used.

Definition of terms

As used here, the singular number include the plural, if not inconsistent with the context. For example, "connection" means one or more of such compounds, while the "enzyme" includes a specific enzyme, as well as other family members and their respective equivalents, known to specialists in this field. As used in the description and the attached items, unless otherwise specified, the following terms have the following meanings.

"Alkyl" means linear or branched hydrocarbon radical consisting solely of carbon atoms and hydrogen, having no unsaturation and contains from one to seven carbon atoms, which is connected to the remainder of the molecule is a simple relationship is, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), etc.

"Alkenyl" means linear or branched hydrocarbon radical consisting solely of carbon atoms and hydrogen atoms, having at least one double bond and containing from two to seven carbon atoms, which is connected to the remainder of the molecule by a simple bond, for example ethynyl, prop-1-enyl, but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl etc.

"Quinil" means linear or branched hydrocarbon radical consisting solely of carbon atoms and hydrogen atoms, having at least one triple bond and containing from two to seven carbon atoms, which is connected to the remainder of the molecule by a simple relationship, such as ethinyl, prop-2-inyl, but-2-inyl, Penta-2-inyl, Penta-1,4-dienyl etc.

"Aryl" means an aromatic monocyclic or polycyclic hydrocarbon system cycles consisting solely of hydrogen and carbon and containing from 6 to 19 carbon atoms, where the cyclic system may be partially or fully unsaturated. Aryl groups include, but are not in order of limitation, groups such as fluorenyl, phenyl and naphthyl. Unless specified in the description of particularly, it is understood that the term "aryl" or the prefix "ar-" (such as in "aralkyl") include aryl radicals optionally C is displaced by one or more substituents, selected from the group including alkyl, alkenyl, halogen, halogenated, halogenoalkanes, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, -R8-OR7, -R8-N(R7)2, -R8-C(O)R7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-N(R9)C(O)OR9, -R8-N(R9)C(O)R9, -R8-N(R9)(S(O)tR9) (where t takes values from 1 to 2), -R8-S(O)POR9(where p takes values from 1 to 2), -R8-S(O)tR9(where t takes values from 0 to 2) and-R8-S(O)PN(R9)2(where p takes values from 1 to 2)where each of R7, R8and R9takes the values specified above in the section “summary of the invention”.

"Aralkyl" means a radical of the formula-RaRbwhere Rameans of the above alkyl radical and Rbmeans one or more of the aforementioned aryl radicals, for example benzyl, diphenylmethyl and the like, Aryl radicals optionally may be substituted as specified above.

"Aralkyl" means a radical of the formula-RcRbwhere Rcmeans above alkanniny radical and Rbmeans one or more of the aforementioned aryl radicals, which optionally can be substituted as indicated above.

"Alkylene" and "Allenova t the universi" means a linear or branched divalent hydrocarbon chain, connecting the remainder of the molecule to a radical group, consisting solely of carbon and hydrogen having no unsaturation and contains from one to seven carbon atoms, for example methylene, ethylene, propylene, n-butylene, etc. Allenova circuit can be connected with the remainder of the molecule and to the radical group through any two of carbons in the chain.

"Albaniles" and "Alcanena chain" means a linear or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, having at least one double bond and containing from two to seven carbon atoms, such as ethenylene, propylen, n-butylen etc. Alcanena circuit connected to the remainder of the molecule through a simple connection with the radical group by a double bond or a simple link. The connection points alkenylamine chain to the remainder of the molecule and to the radical group can serve any two of the carbon in the chain.

"Alkylidene" means linear or branched hydrocarbon radical group, consisting solely of carbon and hydrogen, having at least one double bond and containing from one to seven carbon atoms, which is connected with the remainder of the molecule by a double bond, for example, methylene, ethylidene, propylidene, n is utilized etc.

"Cycloalkyl" means a stable monocyclic or bicyclic hydrocarbon radical consisting solely of carbon atoms and hydrogen, containing from three to ten carbon atoms, which is saturated and is connected to the remainder of the molecule via a simple link, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decaline etc. Unless specified in the description of particularly, it is understood that the term "cycloalkyl includes cycloalkyl radicals, optionally substituted by one or more substituents independently selected from the group including alkyl, alkenyl, halogen, halogenated, halogenoalkanes, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, -R8-OR7, -R8-N(R7)2, -R8-C(O)R7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-N(R9)C(O)OR9, -R8-N(R9)C(O)R9, -R8-N(R9)(S(O)tR9) (where t takes values from 1 to 2), -R8-S(O)POR9(where p takes values from 1 to 2), -R8-S(O)tR9(where t takes values from 0 to 2) and-R8-S(O)PN(R9)2(where p takes values from 1 to 2)where each of R7, R8and R9takes the values specified above in the section “summary of the invention”.

"Cycloalkenyl" OZNA is anything radical of the formula-R aRdwhere Rameans of the above alkyl radical and Rdmeans above cycloalkenyl radical. Alkyl radical and cycloalkyl radical optionally may be substituted as specified above.

"Halogen" means bromine, chlorine, fluorine or iodine.

"Halogenated" means the above-mentioned alkyl radical, which is substituted by one or more halogen radicals, for example trifluoromethyl, deformity, trichloromethyl, 2,2,2-triptorelin, 1-vermeil-2-foretel, 3-bromo-2-forproper, 1-methyl bromide-2-bromacil etc.

"Halogenoalkanes" means the above alkanniny radical, which is substituted by one or more halogen radicals, for example 2-bromanil, 3-bromoprop-1-enyl etc.

"Galgenlieder" means the above alkylidene radical, which is substituted by one or more halogen radicals, for example deformation, dihlormetilen etc.

"Heterocyclyl" means stable 3-18-membered non-aromatic cyclic radical, consisting of carbon atoms and one to five heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. In the context of the present invention heterocyclyl radical can mean a monocyclic, bicyclic, tricyclic or tetracyclic system cycles, which may include condensed and containing bridging the communication C is licencie system; and atoms of nitrogen, carbon or sulfur in heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally Quaternary and heterocyclyl radical may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not in the order restrictions, DIOXOLANYL, decahydroquinoline, imidazolines, imidazolidinyl, isothiazolinones, isoxazolidine, morpholine, octahedrally, activitiesunder, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, oxazolidinyl, piperidinyl, piperazinil, 4-piperidinyl, pyrrolidinyl, pyrazolidine, thiazolidine, tetrahydrofuryl, tritional, tetrahydropyranyl, thiomorpholine, themorphological and themorphological. If the description does not specifically mentioned, it is understood that the term "heterocyclyl" includes the above heterocyclyl radicals, which are optionally substituted by one or more substituents selected from the group including alkyl, alkenyl, halogen, halogenated, halogenoalkanes, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, -R8-OR7, -R8-N(R7)2, -R8-C(O)R7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-N(R9)C(O)OR9, -R8-N(R9)C(O)R9, -R8-N(R9)(S(O)t R9) (where t takes values from 1 to 2), -R8-S(O)POR9(where p takes values from 1 to 2), -R8-S(O)tR9(where t takes values from 0 to 2) and-R8-S(O)PN(R9)2(where p takes values from 1 to 2)where each of R7, R8and R9takes the values specified above in the section “summary of the invention”.

"Geterotsiklicheskikh" means a radical of the formula-RaRewhere Rameans of the above alkyl radical and Remeans above heterocyclyl radical, and if heterocyclyl means of nitrogen-containing heterocyclyl, heterocyclyl can be connected to the alkyl radical at the nitrogen atom. Heterocyclyl radical optionally may be substituted as specified above.

"Heteroaryl" means 3-18-membered aromatic cyclic radical, consisting of carbon atoms and one to five heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. In the context of the present invention, heterocyclyl radical can mean a monocyclic, bicyclic, tricyclic or tetracyclic system cycles, which may include condensed and containing bridged cyclic communication system; and atoms of nitrogen, carbon or sulfur in heterocyclyl radical may be optionally oxidized; the nitrogen atom may be the e l e C optional Quaternary. Examples include, but are not in the order restrictions, azepine, acridines, benzimidazolyl, benzothiazolyl, bunzendahl, benzothiadiazoles, benzenepropanal, benzoxazolyl, benzodioxolyl, benzodioxolyl, benzopyranyl, benzopyranones, benzofuranyl, benzofurazanyl, benzothiazyl (benzothiophenes), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnoline, dibenzofurans, furanyl, furanones, isothiazolin, imidazolyl, indolyl, indazoles, isoindolyl, indolinyl, isoindolyl, indolizinyl, isoxazolyl, naphthyridine, oxadiazole, 2-oxoazetidin, oxazolyl, oxiranyl, phenazines, phenothiazines, phenoxazines, phthalazine, pteridine, purinol, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, hintline, honokalani, chinoline, hinokitiol, ethenolysis, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl. If the description does not specifically mentioned, it is understood that the term "heteroaryl" includes the aforementioned heteroaryl radicals are optionally substituted by one or more substituents selected from the group including alkyl, alkenyl, halogen, halogenated, halogenoalkanes, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, -R8-OR7, -R8-N(R7)2, -R8-C(O)R7, -R8 -C(O)OR7, -R8-C(O)N(R7)2, -R8-N(R9)C(O)OR9, -R8-N(R9)C(O)R9, -R8-N(R9)(S(O)tR9) (where t takes values from 1 to 2), -R8-S(O)POR9(where p takes values from 1 to 2), -R8-S(O)tR9(where t takes values from 0 to 2) and-R8-S(O)PN(R9)2(where p takes values from 1 to 2)where each of R7, R8and R9takes the values specified above in the section “summary of the invention”.

"Heteroaromatic" means a radical of the formula-RaRfwhere Rameans of the above alkyl radical and Rfmeans the above-mentioned heteroaryl radical. Heteroaryl radical optionally may be substituted as specified above.

"Heteroaromatic" means a radical of the formula-RbRfwhere Rbmeans above alkanniny radical and Rfmeans the above-mentioned heteroaryl radical. Heteroaryl radical optionally may be substituted as specified above.

As used here, connections, defined as "commercially available" may be obtained from standard commercial sources including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee Wl; including Sigma Chemical and Fluka), American Tissue Culture Collection (ATCC, Rockville, MD), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Corwall, U.K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), EM Industries, Inc. (Hawthorne, NY; World Wide Web), Fisher Scientific Co. (Pittsburgh PA), Fisher Scientific Co. (Hampton, NH), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH; www.lancaster.co.uk), Maybridge Chemical Co. Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz &Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford, IL), Praxair (Vancouver, B.C.), Riedel de Haen AG (Hannover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), Steraloids Inc. (Newport, RI), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA).

As used here, "suitable conditions" for the implementation stage of the synthesis, just listed here, or can be indicated by references to publications relating to the methods used in synthetic organic chemistry. The above manuals and monographs detailing the synthesis of the reagents used in obtaining the compounds of the present invention, also give conditions for the implementation stage of the synthesis that meets the present invention.

As used here, "the methods known to the person skilled in the art" can be installed using a variety of reference books and databases. Suitable reference books and monographs detailing the synthesis of the reagents used in obtaining the compounds of the present invention, or provide references to articles that describe the receipt, including the t, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-lnterscience, New York, 1992.

Specific and similar reagents can also be found in the index known chemical products obtained by Chemical Abstract Service of the American Chemical Society, available in most public and University libraries, and interactive database (the American Chemical Society, Washington, D.C., possible contacts for details). Chemical reagents known, but not available from commercial directories can be custom specializing in chemical synthesis firms, where many suppliers standard chemical products (such as those listed above) provide services for the synthesis order. Recommendations for obtaining and selection of pharmaceutical salts of the present invention described in P. H. Stahl &C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

As used here, the term C1-30organic group means a stable group of atoms consisting of at least one and not more than the maximum number of carbon specified in the interval, usually not more than 30 carbon atoms, and l is the God of the number of non-carbon atoms.

C1-30organic group may be a saturated or unsaturated hydrocarbonyl radical. Rich hydrocarbonyl radical is determined in accordance with the present invention as any radical consisting solely of carbon and hydrogen, is extremely simple connection used to join carbon atoms. Thus, any stable grouping of atoms of carbon and hydrogen, containing at least one atom of carbon is included in the concept of a saturated hydrocarbon radical of the present invention. Some special terminology, which can be used to identify specific groups of carbon atoms, is discussed below.

Carbon atoms can form specified here, the alkyl group. Carbon atoms can form found here cycloalkyl group. Additional groups included within the concept of "cycloalkyl are listed below polycyclohexylene group.

Polycyclohexylene group is a grouping of carbon atoms, where at least one carbon atom is part of at least two separately identifiable cycles. Polycyclohexylene group can contain bridge bond between two carbon atoms, where typical examples are bicyclo[1.1.0]bout the l, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[2.2.1.01]heptyl, norbornyl and PINANYL. Polycyclohexylene group can contain one or more condensed cyclic systems, where typical examples are decaline (radical decline) and perhydroanthracene. Polycyclohexylene group can contain spirostane, where a single atom is the only common member of two cycles. Typical examples include Spiro[3.4]octyl, Spiro[3.3]heptyl, Spiro[4.5]decyl.

In addition, saturated hydrocarbonyl radical can be any combination of two or more of the above mentioned groups, i.e. any combination of alkyl and cycloalkyl groups. Thus, C1-30organic group may be an alkyl group (e.g. methyl) cycloalkyl (for example, tsiklogeksilnogo) Deputy, so C1-30organic group means cyclohexylmethyl group. As another example, C1-30organic group may be cycloalkyl group (for example, cyclooctyl) with two alkyl substituents (e.g., methyl and ethyl Deputy), so C1-30organic group means metiletilchlorfos group. As a final example, C1-30organic group may be cycloalkyl group is alkyl Deputy where the alkyl substituent of substituted polycyclohexylene Deputy.

As stated above, C1-30organic group may mean unsaturated hydrocarbonyl radical. This C1-30organic group is defined as having such a carbon group, as mentioned above for saturated hydrocarbonrich radicals, further characterized in that at least one connection between any two carbon atoms does not apply to simple communication. An alkyl group containing at least one double bond is called here alkenylphenol group. An alkyl group containing at least one triple bond, called here alkenylphenol group.

Similarly, cycloalkyl group can contain one or more double or triple bonds and enter into the concept of saturated hidrocarburos radical according to the invention. Cycloalkenyl and cycloalkenyl are common names that meet the groups that have one loop on carbon basis with one double or triple bond in the cycle, respectively. Cycloalkenyl group mean cycloalkyl group with two double bonds contained in the cyclic structure. The double bond can be ekzoticheskoy in relation to the cycle, for example, the carbon atom of the cycle may be associated with =CH2group (i.e. methylidene the th group) or a higher homologue.

The cycle can be unsaturated, until aromatic, and still enter into the concept unsaturated hidrocarburos radical. Thus, the aryl group, as defined here, is the concept hydrocarbonrich groups. Because the combination of the above group, is also included in the concept unsaturated hidrocarburos radical, aralkyl (C1-30organic group is an alkyl group with at least one aryl Deputy, for example, benzyl) and alkylaryl (C1-30organic group is an aryl cycle with at least one alkyl Deputy, for example tolyl) group included in the scope of the concept C1-30-organic group. C6-arily are the preferred organic component groups according to the invention.

Also in the concept C1-30organic group include those organic groups that contain one or more heteroatoms. Heteroatoms according to the invention means any atom other than carbon and hydrogen. A preferred class of heteroatoms are naturally occurring atoms (other than carbon and hydrogen). Another preferred class are the non-metals (other than carbon and hydrogen). Another preferred class includes boron, nitrogen, oxygen, phosphorus, sulfur, selenium and halogen (EmOC is emer, fluorine, chlorine, bromine and iodine, with fluorine and chlorine are preferred). Another preferred class includes nitrogen, oxygen, sulfur and halogen. Another preferred class includes nitrogen, oxygen and sulfur. Preferred heteroatom is oxygen. Also preferred heteroatom is nitrogen.

For example, C1-30organic group may mean the above hydrocarbonyl radical with at least one Deputy, containing at least one heteroatom. In other words, C1-30organic group may mean the above hydrocarbonyl radical, where at least one hydrogen atom substituted by a heteroatom. For example, if heteroatom means oxygen, the Deputy may represent a carbonyl group, i.e., two hydrogen on the same carbon atom substituted with oxygen, which leads to the formation of either a ketone or aldehyde group. Alternatively, one hydrogen may be replaced by oxygen atom that forms a hydroxy, alkoxy, aryloxy, aralkylated, alkylacrylate (where alkoxy, aryloxy, aralkylated, alkylacrylate are collectively called hidrocarburos), heteroaromatic, -OC(O)R, ketal, acetal, hemiketal, hemiacetal, epoxy and-OSO3M. Heteroatom can be a halogen. Heteroatom may indicate nitrogen, where the nitrogen is part of AMI is o-(-NH 2, -Other, -N(R)2), alkylamide, arylamide, arylalkylamine, alkylsilane-, nitro-, -N(R)SO3M or aminocarbonylmethyl group. Heteroatom may mean sulfur where the sulfur is part Tilney, thiocarbonyl, -SO3M, sulfonyloxy sulfonamidnuyu or sulfohydrazide group. The heteroatom can be a part of carbon-containing substituent, such as formyl, cyano, -C(O)OH, -C(O)OR, -C(O)OM, -C(O)R, -C(O)N(R)2, carbamate, carbohydrate and carbohidrazona acid.

In the above illustrative examples containing heteroatom substituents, R is the residue of C1-30organic group and M denotes a proton or metal ion. Preferred metal ions in combination with a counterion form a physiologically tolerant of 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 (Mg), calcium (Ca) and strontium (Sr)], or manganese (Mn), iron (Fe), zinc (Zn) or silver (Ag). Alkali metal or alkaline earth metal are preferred M groups. Sodium, potassium, magnesium and calcium form a preferred M groups. Sodium and potassium form a preferred M groups.

Another class C1-30organic groups izobretateley above gidrolabilna radicals, where the carbon atom in hydrocarbide substituted by at least one heteroatom. One of the examples of such organic groups are above heterocyclyl. In another example, such organic groups contain heteroatom, forming a bridge connection between (a) a moiety that is linked organic group, and (b) the residue of an organic group. Examples include alkoxy, aryloxy, arakaki and alkylacrylate-radicals, which are here the common name of hydrocarbonate-radicals or groups. Thus, -OR, is an example of C1-30organic groups according to the invention (where R is the remainder of the C1-30organic group). Another example is-other (where R is the rest

C1-30organic group). Other examples include-R8-OR7and R8-N(R7)2where R7and R8take the values specified above in the section “summary of the invention”, and R10means a chemical bond or a linear or branched alkylen, or albaniles.

Although C1-30organic group may contain up to 30 carbon atoms, the preferred organic groups according to the invention contain approximately less than 30 carbon atoms, for example up to 25 carbon atoms, more preferably up to 20 carbon atoms. The organic group may contain about 15 carbon atoms which, either 12 or 10 carbon atoms. A preferred category of organic groups contain approximately 8 or 6 carbon atoms.

It is implied that the term "prodrug" means a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound according to the invention. Thus, the term "prodrug" means a pharmaceutically acceptable metabolic precursor compounds according to the invention. A prodrug may be inactive during the introduction in need of such treatment to the patient, but turned in vivo into the active compound according to the invention. Prodrugs are typically rapidly transformed in vivo, giving the original connection according to the invention, for example, by hydrolysis in blood. Proletarienne connection often provides advantages of solubility, tissue compatibility or delayed release in the body of a mammal (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

Overview of prodrugs is provided in Higuchi, T., et. al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the contents of which are incorporated herein by reference.

It is also understood that the term "prodrug" includes any covalently associated media, releasing the active connection is according to the invention in vivo introduction of such prodrug to the mammal. Prodrugs of the compounds according to the invention can be obtained by modification of existing connection according to the invention the functional groups carried out in such a way that modifications hatshepsuts or conventional operations, or in vivo, with the formation of the initial compounds according to the invention. Prodrugs include compounds according to the invention, where the hydroxy-, amino - or mercapto-group chemically linked to any group that, with the introduction of prodrugs of the compounds according to the invention the mammal is cleaved, forming a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not in order of limitation, acetate, formiate and benzoate alcohol derivative or amino functional groups in the compounds according to the invention, etc.

Assume that the terms "stable compound" and "stable structure" means a connection that is stable enough to withstand isolation from the reaction mixture to a suitable purity and formulation in an effective therapeutic tool.

"Mammal" includes humans and domestic animals such as cats, dogs, pigs, cattle, sheep, goats, horses, rabbits, etc.

"Optional" or "optionally" means that consistently describes the outcome of events can have the place, and you may not have, and that the description includes instances when the specified event or condition occurs, and the cases when it doesn't. For example, "optionally substituted aryl" means aryl radical may or may not be substituted and that the description includes both substituted aryl radical, and aryl radical without substitution.

"Oxygen-protective group" means a radical, which protects and stores a hydroxy-group during the subsequent chemical transformations. Such groups include, but are not in the order restrictions, trialkylsilyl or diarylethylenes (for example, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like, the Protective group can be introduced or removed according to standard techniques, well known to experts in this field, and as specified in this description. The use of protective groups, in particular the oxygen-protective groups are described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2 nd Ed., Wiley-Interscience.

"The initiator of the leaving group" means a moiety which, together with oxygen, attached to the specified moiety that forms a leaving group, can be easily removed from the remainder of the molecule under the action of an appropriate nucleophile. Hydroxy radical is not easily removed from the group and must therefore be converted into a group, the cat heaven is cleaved. One way is to attach proton hydroxy-radical (with the aim of obtaining more acidic leaving group). Another is the transformation of the hydroxy in the reactive ester, most often in the ether sulfonic acids. We often use sulfoxylate ester group, as toilet, brasilit, nosrat and mesilate. Other leaving groups include hydronium ions, alkylphenolate, esters of ammonioalkyl, alkylphosphonate and fluorinated compounds - triflate and nonathlete.

"Pharmaceutically acceptable carrier, diluent or excipient" includes, but is not in order limitation any excipient, a carrier, a filler, a sliding agent, a sweetener, a diluent, preservative, dye/pigment, an intensifier of taste and fragrance, surfactant, moisturizer, dispersing agent, suspendisse agent, stabilizer, isotonic agent, solvent, or emulsifier approved by Management under the control over products and medicines of the United States as suitable for consumption by people or Pets.

"Pharmaceutically acceptable salt" includes both acidic and basic additive salt.

The term "pharmaceutically acceptable acid additive salt" means those salts which retain the biological will hinder the effectiveness and properties of the free bases, are not biologically or otherwise unacceptable and formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, 2,2-dichloracetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzolsulfonat acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, Caproic acid, Caprylic acid, carbonic acid, cinnamic acid, citric acid, reklamowa acid, modellerna acid, ethane-1,2-disulfonate acid, econsultancy acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactosemia acid, gentisic acid, glucoheptonate acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, somalina acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonate acid, mucus acid, naphthalene-1,5-disulfonate acid, naphthalene-2-AlfaNova acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamula acid, propionic acid, pyroglutamyl acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sabotinova acid, stearic acid, succinic acid, tartaric acid, titanova acid, p-toluensulfonate acid, triperoxonane acid, undecylenoyl acid, etc.

"Pharmaceutically acceptable basic additive salt" means those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise unacceptable. These salts are obtained by attaching an inorganic base or organic base to the free acid. Salts formed with inorganic bases include, but are not in order of limitation, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Preferred inorganic salts are ammonium salts, sodium, potassium, calcium and magnesium. Salts formed with organic bases include, but are not in order of limitation, salts of primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, so is x as ammonia, Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-Diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betainovuyu resin, benethamine, benzathine, Ethylenediamine, glucosamine, methylglucamine, teobrom, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the like, particularly preferred organic bases are Isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" means such amount of the compounds according to the invention that when administered to a mammal, preferably a human, is sufficient for effective treatment, as described below, an inflammatory disease in a mammal. The number of compounds according to the invention, constituting a "therapeutically effective amount"varies depending on the connection status and severity of this condition, and age of the mammal treatable, but can be installed using the standard method specialist in this field, taking into account personal experience and the description.

"Treatment", as used here, encompasses cures the disease or condition in the subject rassm trilemma disease or violation of any mammal, preferably human, and includes

(i) preventing a disease or condition in a mammal, in particular, when such mammal is predisposed to the condition, but the diagnosis of the presence of this condition is not installed;and

(ii) containment of the disease or condition, i.e. the suspension of development; or

(iii) removing the specified disease or condition, i.e. ensuring regression of the disease or condition.

Compounds according to the invention contain a Central core of three rings, shown here in A, C and D, as follows:

The carbon atoms of the Central cores are numbered as above. In this description, the carbon atom in position 1 of the Central nuclei labeled C1 and so on.

In the compounds according to the invention, unless otherwise stated, each of rings A, C and D is independently fully saturated, partially saturated or fully unsaturated. That is, the hydrogen atoms connected to any of the carbon atoms in positions 1-5, 8-17, can be omitted on the basis of what can be inferred about the unsaturation within the rings A, C, and D. for Example, when the carbon atoms numbered 5, 8, 9, 10, 13 and 14 are indicated as substituted by one hydrogen, and also indicated that each of rings A, C and D, independently, is a fully saturated, partially saturated or fully nanosys is authorized, one or more of any of the hydrogen atoms connected to the carbon atoms numbered 5, 8, 9 and 14 can be omitted, which indicates the unsaturation of the carbon atom.

Compounds according to the invention or pharmaceutically acceptable salts of these compounds can contain one or more asymmetric centers and can thus form the enantiomers, diastereomers, and other stereoisomeric forms that may be defined in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. Understood that this invention includes all such possible isomers, as well as the corresponding racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)and (L)-isomers may be obtained by application of chiral synthons or chiral reagents, or by selection according to standard techniques, such as GHUR with reversed phase. When these compounds contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, this means that the compounds include both E and Z geometric isomers. Similarly, it is understood that include all tautomeric forms.

The nomenclature used here for the compounds according to the invention is a modified form of the nomenclature of the IUPAC system, the cat is Roy compounds are named as derivatives of indene. Numbering the locations of various substituents indene cycle in the names of the compounds according to the invention is based on a standard numbering system location for indene cycles. In addition, the configuration of the substituents indicated in the names of compounds as "α", if the Deputy is located below the plane of the indene cycle, and "β", if the Deputy is located above the plane of the indene cycle. For example, the compound of formula (Ia) (reflecting the numbering of carbon atoms:

where each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogens; each of C9 and C14 is independently substituted with hydrogen; R1mean β-hydroxy; R2mean β-(2-hydroxyethyl); R3mean α-hydroxy; R4aand R4btogether form methylene; R5mean β-methyl and R6means hydrogen, i.e. the compound of the following formula:

which is here the name 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7αβ-methyl-1-methylenechloride.

Compounds according to the invention can, and typically this is done, to exist in the form of solid compounds, including crystalline solid, which can be crystallized from common solvents such as ethanol, N,N-dimethylformamide, water or the like, or mixtures of the above process is of Italy. The crystallization process may, depending on the crystallization conditions, lead to different polymorphic structures. In most cases it is more thermodynamically stable polymorph suitable for production on an industrial scale steroid compounds according to the invention and is the preferred form of connection.

Often the crystallization gives MES compounds according to the invention. As used here, the term "MES" means a unit that includes one or more compounds according to the invention and one or more solvent molecules. The solvent may be water, in this case, the MES is a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention can exist as a hydrate, including the monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and the like, as well as corresponding solvate forms. The connection according to the invention can be a true solvate, whereas in other cases, the connection according to the invention can simply hold an incremental amount of water or solvent, or a mixture of water and solvent.

As used here, "pharmaceutically acceptable MES" means the MES, which retains the biological effectiveness and properties of biological engineering the active compounds according to the invention. Examples of pharmaceutically acceptable solvate include, but are not in the order restrictions, water, isopropanol, ethanol, methanol, DMSO, EtOAc, acetic acid and ethanolamine. A qualified specialist in this field it is clear that the solvated forms are equivalent nonsolvated forms and are included in the scope of the present invention. Sykes, P. A., Guidebook to Mechanism in Organic Chemistry, 6th Ed (1986, John Wiley & Sons, N.Y.) is an example of a link that describes the solvate.

B.The pharmaceutical composition

The present invention relates to pharmaceutical compositions or compositions for veterinary use (hereafter have a common name pharmaceutical composition containing the above compound according to the invention in a mixture with a pharmaceutically acceptable carrier. The invention also relates to compositions, preferably pharmaceutical compositions containing an effective amount of the above compounds together with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention can be presented in a form that allows the introduction of the composition to the patient. For example, the composition may be in the form of solid, liquid or gas (aerosol). Typical routes of administration include, but are not in the order restrictions, oral, local, parenteral, sublingual,rectal, vaginal, ocular and intranasal. The term parenteral as used here, includes subcutaneous injection, intravenous, intramuscular, epigastric injection or infusion techniques. The pharmaceutical composition according to the invention are therefore to provide bioavailability contained in the specified composition of the active ingredient with the introduction of the composition to the patient. Enter the patient's compositions are in the form of one or more standard doses, where, for example, a tablet may be a single standard dose, and the container for the aerosol form of the compounds according to the invention can contain a number of standard doses.

Substances used to obtain pharmaceutical compositions should be pharmaceutically pure and non-toxic in the quantities used. For the person skilled in the art it is obvious that the optimal dosage of the active ingredient (ingredients) in the pharmaceutical composition depends on a number of factors. Relevant factors include, but are not in the order constraints subject type (e.g., human), the particular form of the active ingredient, route of administration and composition used.

In the General case, the pharmaceutical composition includes the compound, and refers to one or more of the above active compounds according to the invention in a mixture with one or more carriers. The carrier (s) can be, in particular, such that the compositions are, for example, in the form of tablets or powder. The carrier (s) may be liquid, while the compositions are, for example, in the form of a syrup for oral administration or injection of fluids. In addition, the carrier (s) may be gaseous, which provides aerosol composition, useful, for example, for administration by inhalation.

When intended for oral administration, the composition preferably exists either in solid or in liquid form, where semi-solid, semi-solid, suspension and gel forms are among the forms considered here either as a solid or as a liquid.

As solid compositions for oral administration, the composition may be formulated in the form of powder, granules, compressed tablets, pills, capsules, chewing gum, wafers or other Such solid composition should usually contain one or more inert diluent or edible carrier. In addition, the presence of one or more of the following adjuvants: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, dezintegriruetsja tools such as alginic acid, lgint sodium, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; a moving substances such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin, corrigenda, such as peppermint, methyl salicylate or orange extract, and dye.

When the composition is presented in the form of capsules, such as gelatin capsules, the composition may contain, in addition to the substances of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or fatty oil.

The composition may be presented in the form of a liquid, such as elixir, syrup, solution, emulsion or suspension. As two examples, the fluid may be intended for oral administration or for delivery by injection. If it is assumed oral administration, the preferred composition contains, in addition to the compounds, one or more sweeteners, preservatives, dyes/pigments and intensifiers taste and aroma. In a composition intended for administration by injection may be included in the amount of one or more surfactant, a preservative, a moisturizer, a dispersing agent, suspendisse agent, buffer, stabilizer and an isotonic agent.

Liquid pharmaceutical compo is icii according to the invention, regardless of whether it 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 solution, ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as a solvent or suspendida environment, glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and means for regulating toychest, such as sodium chloride or dextrose. The preparation for parenteral administration can be enclosed in ampoules, disposable syringes application or contains multiple dose vials made of glass or plastic.

Preferred auxiliary substance is saline. Pharmaceutical composition for injection is mostly sterile.

A liquid composition intended for either parenteral or oral administration should contain the such number of the compounds according to the invention, which can provide an acceptable dose. Usually this amount is equal to at least 0.01% of the compounds according to the invention in the composition. Preferred for oral administration, the compositions contain from 4% to 50% of the active compounds according to the invention. Preferred compositions and preparations according to the present invention receive so that standard parenteral dosage contains from 0.01 to 2 wt.% active connection.

The pharmaceutical composition may be intended for topical application, in this case it is convenient to include the media, which is the basis of a solution, emulsion, ointment or gel. The basis of, for example, may contain one or more of the following ingredients: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, and emulsifiers and stabilizers. In the pharmaceutical compositions for topical application may be available thickeners. If intended for transdermal use, the composition may include transdermal patch or device for iontophoresis. Compositions for topical application may contain the compound according to the formula of the invention in a concentration of from about 0.01 % to 10 wt./vol.% (mass per unit volume).

The composition may be intended for rectal use, in the form of, for example, with pository, which melts in the rectum and release the drug.

Composition for rectal application may contain oil-based as a suitable non-irritating excipient. Such bases include, but are not in the order restrictions, lanolin, cocoa butter and polyethylene glycol.

The composition may include a variety of substances which modify the physical form of a solid or liquid standard dosage units. For example, the composition may include substances that form around the active ingredients insulating sheath.

The materials forming the insulating sheath, are generally inert and can be selected, for example, from the group comprising sugar, shellac or other means, forming intersolubility coverage. Alternatively, the 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 component(s) and thereby contribute to the delivery of active ingredients. Suitable agents that may act in this capacity include monoclonal and polyclonal antibody, a protein or a liposome.

The pharmaceutical composition of the present invention may consist of a gaseous drug doses, for example, the composition may be presented in the form of an aerosol. The term AE is the open air is used to denote the number of systems, since systems of colloidal character and finishing systems, including an aerosol packaging. Delivery may be through a liquefied or compressed gas, or by using a system of sprinklers, dosing of the active ingredients. Aerosols compounds according to the invention can be produced in single-phase, two-phase or three-phase systems, ensuring delivery of the active ingredient (ingredient). Delivery of aerosol implies the necessary container, activators, valves, auxiliary compartments, distributors, etc. together forming a set. Preferred aerosols can be installed by a person skilled in the art without undue experimentation.

Regardless of what form it is, solid, liquid or gaseous, the pharmaceutical composition of the present invention may contain one or more known pharmacological agents used in the treatment of inflammation (including asthma, allergies, rheumatoid arthritis, multiple sclerosis etc), autoimmune diseases (including diabetes and lupus erythematosus), and proliferative disorders (malignant neoplasms).

The pharmaceutical compositions can be obtained by methods well known in the field of pharmacy.

The composition is intended for use by injection, may be the allowed to receive the merger of compounds according to the invention with water to obtain a solution. May be added a surfactant that facilitates the formation of a homogeneous solution or suspension. Surfactants are compounds that ecovalence interact with the connection according to the invention, promoting dissolution or formation of a homogeneous suspension of the active compound in the aqueous delivery system.

C.Applications

Compounds according to the invention or a pharmaceutical composition containing one or more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in methods of treating or preventing an inflammatory condition or disease in a patient, where the method includes the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent the inflammatory condition or disease in a patient.

The inflammatory condition or disease may include acute or chronic inflammation of bone and/or cartilage of the joints; the inflammatory condition or disease may indicate arthritis selected from the group comprising rheumatoid arthritis, gouty arthritis or juvenile rheumatoid arthritis; inflammatory condition may mean and what commune condition or disease; the inflammatory condition or disease may include inflammation of the Central nervous system (for example, where the disease of the Central nervous system is multiple sclerosis or where disease of the Central nervous system is Alzheimer's disease); the inflammatory condition or disease may indicate disease lupus erythematosus; inflammatory condition or disease may indicate inflammatory bowel disease (such as Crohn's disease or ulcerative colitis); the inflammatory condition or disease may indicate an inflammatory skin disease (e.g. psoriasis or dermatitis); the inflammatory condition or disease may indicate a graft-versus-host; the inflammatory condition or disease may be vascular (e.g., vasculitis); the inflammatory condition or disease may mean atherosclerotic disease; the inflammatory condition or disease may include respiratory inflammation (e.g., respiratory disease is asthma or where respiratory disease is chronic obstructive pulmonary disease; or where respiratory disease is emphysema); the inflammatory condition or disease may mean pulmonary sarcoidosis; the inflammatory condition or disease which may indicate ocular inflammation or allergies; the inflammatory condition or disease may indicate allergic rhinitis; the inflammatory condition or disease may be associated with infiltration by leukocytes; the inflammatory condition or disease may be associated with edema; the condition or disease may be associated with ischemic reperfusion violation; the condition or disease may be associated with elevated levels of inflammatory cytokines (for example, where the inflammatory cytokine mean IL-1, or where the inflammatory cytokine mean IL-2, or where the inflammatory cytokine mean IL-3, or where the inflammatory means cytokine interleukin (IL)-4, or where the inflammatory cytokine mean IL-5, or where inflammatory cytokine mean IL-6, or where the inflammatory cytokine mean IL-8, or where the inflammatory cytokine mean IL-9, or where the inflammatory cytokine mean IL-10, or where the inflammatory cytokine mean IL-12, or where the inflammatory cytokine mean IL-13, or where the inflammatory cytokine mean IL-18, or where the inflammatory cytokine mean TNF-α, or where the inflammatory cytokine means TGF-β, or where the inflammatory cytokine means GM-CSF, or where the inflammatory cytokine mean IFN-γ, or where inflammatory cytokine mean LTB4, or where the inflammatory cytokine is a member of the family of containerisation, or where inflammatory t is taken is regulated by the activation of normal T-cells, expressed and secreted (RANTES), or where the inflammatory cytokine means eotaxin-1, 2, or 3, or where the inflammatory cytokine means inflammatory macrophage protein (MIP)-1a, or where the inflammatory cytokine means macrophage chemotactic protein-1, 2, 3 or 4); the condition or disease may be associated with altered levels of inflammatory adhesion factors (for example, when the factor of adhesion is an immunoglobulin, such as the factor of adhesion of vascular cells (VCAM-1 or 2) or factor intercellular adhesion (ICAM-1 or 2); when the factor adhesion is integrin, such as very late antigen-4 (VLA-4) or Mac-1; when the factor of adhesion is a selectin, such as e-selectin).

In addition, the present invention relates to a method of treating or preventing a disease or condition in a patient, where the disease or condition is associated with pathological conditions involving infiltration by leukocytes, the method includes the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent a disease or condition caused by pathological conditions involving infiltration by leukocytes.

Further, the present invention relates to a method of treatment or prevention is rcrit the patient, including the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent arthritis in the patient.

Further, the present invention relates to a method of treating or preventing inflammatory bowel disease in a patient, including the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent inflammatory bowel disease in a patient.

Further, the present invention relates to a method of treating or preventing inflammatory bowel disease in a patient, including the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent psoriasis patient.

Further, the present invention relates to a method of treating or preventing atherosclerosis in a patient, including the introduction in need of such treatment the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent atherosclerosis in a patient.

According to the FPIC of the BU according to the present invention the compound according to the invention or pharmaceutical composition, containing one or more compounds according to the invention and a pharmaceutically acceptable carrier, diluent or excipient, may, although not necessarily, to achieve one or more of the following desired outcomes from the patient who entered the above compound according to the invention or a composition containing one of these compounds and a pharmaceutically acceptable carrier, diluent or filler:

1. Inhibition of infiltration of leukocytes (e.g. neutrophils, macrophages, etc.);

2. Inhibition of leucocyte activation;

3. The change in the ratio of lymphocytes (e.g., cells TH1 versus TH2);

4. The inhibition of the chemotaxis of leukocytes;

5. Inhibition of the production and/or release of TNF-α;

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

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

8. Inhibition of edema;

9. Inhibition of the production and/or release of the cytokine interleukin (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL6, IL-8, IL-9, IL10, IL-12, IL-13, IL-18);

10. Inhibition of release of mediators of inflammation (e.g., leukotrienes, tryptase, adenosine, etc.);

11. Inhibition of the symptoms of arthritis;

12. Inhibition of the symptoms of inflammatory bowel disease;

13. Inhibition of C is Tomov psoriasis;

14. Inhibition of the symptoms of atherosclerosis.

Described herein the compounds according to the invention or a pharmaceutical composition containing one or more of these compounds and a pharmaceutically acceptable carrier, diluent or excipient, may be used in the treatment or prevention of proliferative disorders in a patient, where the method includes the introduction in need of such therapy to the patient a certain amount of the compounds or compositions of the present invention, where the amount is effective to treat or prevent proliferative disorders in a patient.

As used here, proliferative disorders include, but are not in the order restrictions, all types of leukemia and solid tumors exposed to differentiation or apoptosis when the corresponding interrupt the cell cycle.

Thus, the method according to the invention can be used to treat inflammation, including both acute and chronic inflammation, as well as some of proliferative disorders (malignant neoplasms). As used here, the inflammation includes, but is not in order restrictions, arthritis (where the term covers more than 100 kinds of diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, gout, and synovitis), vospolenie the brain (including multiple sclerosis, Alzheimer's disease, mental disorder, AIDS, stroke, encephalitis, trauma and disease of Creutzfeldt-Jakob disease), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), irritable bowel syndrome, ischemic reperfusion disturbance, including myocardial infarction, sarcoidosis, psoriasis, reaction of the graft tissue/organ against the owner, systemic lupus erythematosus, juvenile diabetes, type I, vasculitis, arteriosclerosis, cardiomyopathy, autoimmune myocarditis, atopic dermatitis, asthma, allergies, allergic rhinitis and chronic obstructive pulmonary disease (including emphysema and bronchitis).

The method according to the invention provides for the introduction of therapeutically effective amounts of compounds according to the invention, including the corresponding salts, compositions, etc. As used here, the actual amount covered by the term "therapeutically effective amount" depends on the method of administration, type curable warm-blooded and physical characteristics specific to the considered warm-blooded. These factors and the impact of these factors on the determination of the number of well-known specialists in the field of medicine. The specified amount and method of administration can be selected to achieve optimal performance based on the factors such as weight, diet, competitive drug therapy and other factors known to experts in the field of medicine.

A therapeutically effective amount of a compound or pharmaceutical composition of the present invention should be sufficient to treat the inflammatory or proliferative diseases in warm-blooded animals such as man. Methods of administration of therapeutically effective amounts of anti-inflammatory drugs are well known in this area and include the introduction of inhalation, oral, or parenteral forms. Such dosage forms include, but are not in order of limitation, parenteral solutions, tablets, capsules, slow-release implants and systems for transdermal delivery; or inhalation of medicinal system, using inhalers dry powder or inhalation device containing multiple doses under pressure.

The amount of dosage and frequency of injection is chosen in such a way as to create a therapeutically effective level of the funds will have no adverse impact. This level typically corresponds to a range of doses from about 0.001 to 100 mg/kg/day, and typically from about 0.01 to 10 mg/kg/day, oral or intravenous. In addition, typically, from about 0.0001 to 10 mg/kg/day when Intrans the flax introduction or by inhalation.

D.Preferred embodiments of the invention

From among the compounds of formula (I)above in the section “summary of the invention”, the preferred group of compounds are compounds of formula (Ia):

where

ring A, C or D is independently fully saturated or partially saturated;

each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogens;

each of C9 and C14 is independently substituted with hydrogen;

R1means-OR7or-N(R7)2;

each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From this group of compounds is one of the preferred subgroup of compounds is that subgroup, where

R1means-OR7;

each of R2and R3independently selected from the group comprising-R8-OR7, -R8-C(O)R 9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optional samisen the th heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From this subgroup of compounds is one of the preferred classes of compounds is that class, where

R1means-OR7;

R2means R8-OR7;

R3selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bwho appoints a direct link to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

Of this class of compounds, one of the preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R8-OR7;

R3means R8-OR7;

each and the R 4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl;

R6means hydrogen;

each R7independently selected from the group comprising hydrogen, alkyl, substituted aryl or optionally substituted aralkyl; and

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine chain.

From the specified class of compounds, another preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R8-OR7;

R3means R10-N(R7)2;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

Rsup> 6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From the above preferred subgroup of another preferred class of compounds is that class, where

R1means-OR7;

R2means R10-N(R7)2;

R3selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N( 9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes EPI and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

Of this preferred class of compounds, one of the preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R10-N(R7)2;

R3means R8-OR7;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, not battelino substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From the specified preferred class of compounds, another preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R10-N(R7)2;

R3means R10-N(R7)2;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2the alkyl, optional what about the substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From the group of compounds listed above, another preferred subgroup of compounds is that subgroup, where

R1means-N(R7)2;

each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted g is triarylamines and optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

Of the preferred class of compounds, the above first, another preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R8-OR7;

R3means R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from g is uppy, includes direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

Of the preferred subgroup of the compounds mentioned above, another preferred class of compounds is that class, where

R1means-OR7;

R2selected from the group comprising-R8-OC(O)R9, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2, alkyl, alkenyl, optionally substituted aralkyl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic and optionally substituted heteroaromatic;

R3means R8-OR7or-R8-OC(O)R9;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans direct contact with the carbon in the state is C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R10independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

Of the preferred class of compounds, the above first, another preferred subclass of compounds is that subclass, where

R1means-OR7;

R2means R8-OR7;

R3OZNA is anything geterotsiklicheskikh, optionally substituted heteroaromatic, optionally substituted heteroaromatic or optionally substituted heteroaromatic;

each of R4aand R4bindependently selected from the group comprising hydrogen, alkyl, alkenyl or quinil;

or R4ameans hydrogen, alkyl, alkenyl or quinil and R4bmeans a direct bond to the carbon in position C16;

or R4aand R4btogether form alkylidene or halogenation;

R5means alkyl or R5means a direct bond to the carbon in position C14;

R6means hydrogen, -R8-OR7or-R8-N(R7)2;

each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted geterotsiklicheskikh, optionally substituted heteroaryl and optionally substituted heteroaromatic;

each R8independently selected from the group comprising a direct bond, linear or branched alkylenes chain and linear or branched alkenylamine circuit; and

each R9independently selected from the group comprising hydrogen, alkyl, aryl and aralkyl;

each R0 independently selected from the group including linear or branched alkylenes and linear or branched alkenylamine chain.

From the above preferred groups of compounds the most preferred compounds according to the invention are those compounds which are described in the section “examples of syntheses". From the above preferred groups of compounds the most preferred choices of the values of R1, R2, R3, R4a, R4b, R5, R6, R7, R8, R9and R10can be identified when considering the compounds described below in the section “examples of syntheses". For example, the most preferred choice of the values of R4aand R4bis when both Deputy together form methylene or ethylidene group. For example, the preferred choice of the values of R1is-R8-OR7where R8means a direct bond and R7means hydrogen. For example, the preferred choice of the values of R5is methyl. For example, the preferred choice of the values of R6is hydrogen. Such preferred embodiments of immediately visible from the following description and the attached items.

Method of treatment of an inflammatory condition or disease in recapitalise through the introduction of compounds according to the invention, as mentioned above in the section “summary of the invention”, the preferred route of administration of the compounds of formula (Ia). In addition, preferred is a method, where the inflammatory condition or disease selected from the following group, including arthritis (including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, gout, and synovitis), inflammation of the brain (including multiple sclerosis, Alzheimer's disease, mental disorder, AIDS, stroke, encephalitis, trauma and disease of Creutzfeldt-Jakob disease), inflammatory bowel disease (including Crohn's disease and ulcerative colitis), irritable bowel syndrome, ischemic reperfusion disorder (including myocardial infarction) sarcoidosis, psoriasis, reaction of the graft tissue/organ against the owner, systemic lupus erythematosus, juvenile diabetes, type I, vasculitis, arteriosclerosis, cardiomyopathy, autoimmune myocarditis, atopic dermatitis, asthma, allergies, allergic rhinitis and chronic obstructive pulmonary disease (including emphysema and bronchitis).

E.Obtaining the compounds according to the invention

Compounds according to the invention can be obtained by methods using stages, known to specialists in this field, or similar such stages.

General methods of implementing the mutual the action on steroids can be found in the "Steroid Reactions", C. Djerassi, Ed. Holden Day, San Francisco, Calif., 1963 and are there links. General synthetic methods can be found in Comprehensive Organic Transformations", R.C. Larock, VCH Publishers, New York, N.Y., 1989 and are there links. Additional literature references, useful for the synthesis of compounds according to the invention are as follows: T. Reichstein; C.H. Meystre, Helv. Chim. Act, 1932, 22, 728; H. Westmijze; H. Kleyn; P. Vermeer; L.A. van Dijck, Tet. Lett. 1980, 21, 2665; K. Prezewowsky; R Wiechert, Pat. U.S. No. 3682983; P. Kaspar; H. Witzel, J. Steroid Biochem. 1985, 23, 259; W.G. Dauben; T. Brookhart, J. Am. Chem. Soc. 1981, 103, 237; A.J. Manson et al., J. Med. Chem. 1963, 6, 1; R.O. Clinton et al, J. Am. Chem. Soc. 1961, 83, 1478; M.S. Ahmad; L.A. Khan, Acta. Chim. Acad. Sci. Hung. 1981, 106, 111.

In particular, the compounds according to the invention can be obtained according to the following schemes or reaction schemes, see “examples of syntheses”. Needless to say that other compounds according to the invention can be obtained in a similar way, as described below, or by methods known to a qualified specialist in this field. It is obvious that although the following “examples of syntheses aimed at obtaining a specific substituent on a particular carbon atom in the compounds, a specialist in this field, based on the instructions here and taking into account known information this area can get similar substituents on other carbon atoms of the compounds.

According to the diagram below, A ketone compounds is s 1 or connections, same as above, can be subjected to alkylation with the help of a number of alkylating groups, giving compounds according to the invention having, but not in the manner restrictions, alkyl, cycloalkyl, aryl and heteroaryl substitution. Alkylation of the 17-ketone 1 under the action of acetylene anion leads to the formation of 17α-ethinyl-17β-hydroxyl intermediate compound 2.

Handling of stereochemistry C17-substituents can be carried out by the original receipt methylsulfonate with subsequent treatment with silver nitrate(I) in tetrahydrofuran (THF) and water. Dehydration of compound 2 using POCl3in 2,4-lutidine gives compound 3. Processing using tetrabutylammonium removes the tert-butyldimethylsilyl groups, with the formation of compound 4.

Scheme And

i)KCCH; (ii) 2,4-lutidine (iii) Bu4NF

According to the diagram below B compounds according to the invention, with allene functionality can be obtained from the intermediate compounds similar to compound 2. A typical example is the interaction of compound 2 with LiAlH4and AlCl3in THF, leading to Allen 5. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound 6.

Circuit

According to the diagram below With the compounds according to the invention, having alkylamino functionality can be obtained from the intermediate arenovich compounds. An illustrative example is the processing of compounds 5 n-BuLi in THF, giving 17β-etinilnoy connection 7. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound8.

Scheme

According to the diagram below D compounds according to the invention, having alkenylphenol functionality can be obtained from the intermediate alkenovich compounds. An illustrative example is the controlled hydrogenation of compound 7 using Pd-CaCO3as a catalyst, leading to the formation of alkene 9. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound 10.

Scheme D

Compound 1 can be used in many reactions referirovanija, including reaction-type Wittig, leading to the compounds according to the invention, containing ekzoticeski olefin. For example, as illustrated by the following scheme E, compound 1 can be processed by ethyltriphenylphosphonium and tert-butyl potassium, which gives the connection 11, steriade the R 1=methyl and R2=hydrogen. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound 12.

By analogy with the synthesis shown in scheme E, ketones, such as compound 1, can be subjected to interaction with other reagents of the type Wittig, such as, but not in the manner restrictions, methyl-, propyl-, butyl-, pentyl or hexyltrichlorosilane, which leads to the formation of compounds according to the invention, similar to the connection 12, containing R2=hydrogen and R1=hydrogen, ethyl, propyl, butyl or pentyl.

Scheme E

Compounds according to the invention can contain ekzoticheskie double bond E and/or Z-geometry. For example, as illustratively shown in the following diagram F, Z-olefin 11 in cyclohexane can be treated with UV light in the presence of diphenyldisulfide that leads to isomerization to the E-olefin 13. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound 14.

Scheme F

Many of the compounds according to the invention, containing functionalityand side chains, can be obtained by applying methods such as promoted by Lewis acids in combination with aldehydes and acceptance of the Rami Michael. For example, as is illustrated in the following diagram G, compound 11 may be subjected to interaction with methylpropionate in the presence of diethylaluminium, which leads to the formation of compound 15. The double bond can be subjected to hydrogenation using a catalyst such as platinum, which gives the connection 16. Processing tetrabutylammonium removes the tert-butyldimethylsilyl group, which leads to the formation of compound 17.

Scheme G

The following specific examples are provided as guidelines to further the practical implementation of the invention, and are not considered as limiting the scope of the invention and the attached items.

Unless otherwise noted, flash chromatography and column chromatography, used in the following examples, can be performed using silica gel Merck 60 (230-400 mesh mesh). Flash chromatography can be performed according to methodology described in "Purification of Laboratory Chemicals", 3rd. edition, Butterworth-Heinemann Ltd., Oxford (1988), Eds. D. D. Perrin and W. L. F. Armarego, page 23. Column chromatography is a way where the speed of flow of eluent through the Packed material is determined by gravity. In all cases, flash chromatography and radial chromatography can be used interchangeably. Radial chromatography can be performed is using on silica gel Chromatotron Model No. 7924T (Harrison Research, Palo Alto, California). Unless otherwise noted, the recorded Rf values obtained by thin layer chromatography, using silica gel 60 F254(Merck KGaA, 64271, Darmstadt, Germany). A saturated solution of salt means a saturated solution of sodium chloride.

Also, unless otherwise noted, all chemicals and reagents are supplied in standard chemical firms-suppliers, such as Aldrich (Milwaukee, WI; www.aldrich.sial.com); EM Industries, Inc. (Hawthorne, NY); Fisher Scientific Co. (Hampton, NH) and Lancaster Synthesis, Inc. (Windham, NH). Gaseous substances Praxair supplies (Vancouver, B.C.). Cell lines, unless otherwise noted, are obtained from public sale or commercial sources, such as American Tissue Culture Collection (ATCC, Rockville, MD).

EXAMPLES SYNTHESIS

EXAMPLE 1

The connection 25, characterized by the connection according to the invention can be obtained according to reaction scheme 1. Any number of compounds related to compound 25 can be obtained using similar methods. The original connection 18 can be obtained by the methods outlined in U.S. patent 6046185.

Reaction scheme 1

In General, the hydrogenation of compounds 18, using Pd on coal as katalysator, network connection 19. Oxidation on the Bayer-Villager using 3-chloroperoxybenzoic acid (MCPBA) in CHCl3gives lactoovo connect the tion 20. The restoration of the lactone lydialydia in THF gives dialogue connection 21. Interaction of compound 21 with tert-butyldiphenylsilyl (TBDPSCl and imidazole in DMF protect the primary hydroxyl in compound 22. Treatment with 80% acetic acid removes ketal and tert-butyldimethylsilyl (TBS) group, which gives the connection 23. Rafinirovaniyu connection 23 with the use of methyltriphenylphosphonium and KOtBu in THF gives methylidene connection 24. Processing when heated to the boiling temperature under reflux solution Bu4NF in THF removes the TBDPS group that gives compound 25.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 19

A solution of compound 18 (2,03 g, to 4.41 mmol) in EtOAc (135 ml) was treated overnight with hydrogen (pressure cylinder) in the presence of catalytic amount of Pd on coal. The catalyst was removed by filtration and the solution concentrated to dryness. The residue is purified by chromatography on silica gel (hexane/EtOAc/CH2Cl2, 8:1:1)to give compound 19 (1,79 g, 88%) as a white solid.

Synthesis of compound 20

A mixture of compound 19 (2.38 g, 5,14 mmol) and MCPBA (3.11 g, or 10.3 mmol) in chloroform (26 ml) is heated to the boiling temperature under reflux for 4 hours. After cooling to ambient temperature cf the water, the reaction mixture was diluted with EtOAc (25 ml), washed with saturated Na2SO3(2×20 ml), saturated NaHCO3(2×20 ml) and saturated salt solution (2×20 ml), then dried over anhydrous MgSO4and concentrate to dryness. The crude compound 20 (2,43 g, white solid) is used for subsequent interactions without additional purification.

Synthesis of compound 21

To a solution of compound 20 (1,00 g of 2.09 mmol) in THF at 0°C add LiAlH4(21 ml of a 1M solution in THF, is 2.09 mmol). The reaction mixture was stirred at ambient temperature for one hour, then slowly add a saturated solution of salt (5 ml). The solution is extracted with CH2Cl2(2×15 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (EtOAc)to give compound 21 (of 0.786 g, 78%) as a white solid.

Synthesis of compound 22

A solution of compound 21 (0,93 g of 1.93 mmol), TBDPSCl (1.1 ml, 4.4 mmol) and imidazole (0,57 g, 8.5 mmol) in dry DMF (10 ml) is stirred over night. The reaction mixture was diluted with EtOAc (50 ml) and washed with saturated salt solution (2×20 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 3:1)to give compound 22 (1.22 g, 66%) as a white solid.

The synthesis of compounds 23

A mixture of compound 22 (1,00 g of 1.39 mmol) and 80% of the UKS the Noah acid (20 ml) was stirred at 50°C for 2 hours, then diluted with toluene (30 ml) and concentrated. The crude compound 23 is used for subsequent interactions without additional purification.

Synthesis of compound 24

The mixture KOtBu (0,487 g, 4,12 mmol) and MePPh3Br (1.47 g, 4,12 mmol) in THF (6 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add the connection 23 (0,773 g, 1.37 mmol) in THF (6 ml). The reaction mixture was stirred at ambient temperature overnight, then diluted with EtOAc (40 ml) and washed with saturated salt solution (2×30 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 1:1)to give compound 24 (0,606 g, 79%) as a white solid.

The synthesis of compounds 25

A solution of compound 24 (0.15 g, 0,267 mmol) and Bu4NF (0.4 ml of 1,0M solution in THF) in THF (5 ml) is heated to the boiling point under reflux in an argon atmosphere for 2 hours. The solvent is evaporated under reduced pressure and the residue purified by chromatography on silica gel (MeOH/EtOAc, 2:98)to give compound 25 (0,073 g, 82%) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 287,10; C20H31O.

EXAMPLE 2

The connection 29, characterized by the connection according to the invention, can be p is received according to the following reaction scheme 2. Any number of compounds related to compound 29 can be obtained using similar techniques. The original connection 20 can be obtained according to the procedures described above in example 1.

Reaction scheme 2

In General, processing lactoovo connection 20 with MeLi in THF gives compound lactol 26. Oxidation on the Bayer-Villager using MCPBA in CHCl3network connection 27. Treatment with 80% acetic acid removes ketal and TBS group that gives compound 28. Reconnection 28 using methyltriphenylphosphonium and KOtBu in THF introduces methylidene group and removes the acyl group that gives compound 29.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 26

To a solution of compound 20 (2.0 g, 4,18 mmol) at 0°C in dry THF (12 ml) is added dropwise MeLi (8,95 1 ml,4M solution in diethyl ether). The reaction mixture is stirred for 2 hours, then poured on ice and extracted with EtOAc (3×100 ml). The combined organic layer was washed with saturated salt solution (2×50 ml), then dried over Na2SO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 8:2)to give compound 26 (1,49 g, 72%) as a white solid.

inches connection 27

To a solution of compound 26 (1,49 g, 3.00 mmol) in chloroform added MCPBA (1.8 g, 6,00 mmol). The reaction mixture was stirred at ambient temperature for 20 hours, then diluted with EtOAc (200 ml). The solution is washed successively with 5% solution of NaHSO3(2×100 ml), a saturated solution of K2CO3(2×50 ml) and saturated salt solution (2×50 ml), then dried over Na2SO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 27 (1.3 g, 85%) as a white solid.

Synthesis of compound 28

A mixture of compound 27 (400 mg, 0,783 mmol) and 80% acetic acid (5 ml) was stirred at 50°C for 5 hours, then diluted with toluene (50 ml) and concentrated. The residue is purified by chromatography on silica gel (hexane/acetone, 1:1)to give compound 28 (322 mg, 86%) as a white solid.

Synthesis of compound 29

The mixture KOtBu (286 mg, 2.55 mmol) and MePPh3Br (911 mg, 2.55 mmol) in THF (2 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add the connection 28 (300 mg, 0.85 mmol) in THF (2 ml). The reaction mixture is heated to boiling point under reflux for 4 hours, then cooled to ambient temperature and diluted with water (5 ml). The solution is extracted with EtOAc (3×50 ml) and washing the Ute saturated salt solution (2×20 ml), then dried over Na2SO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 2:8)to give compound 29 (144 mg, 55%) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 273,01; C19H29O.

EXAMPLE 3

The connection 38, characterized by the connection according to the invention can be obtained according to the following reaction scheme 3. Any number of compounds related to compound 38 can be obtained using similar techniques. The original connection 30 can be obtained according to the procedures outlined in U.S. patent 6046185.

Reaction scheme 3

In General, dihydroxypropane connection 30 with the use of osmium tetroxide in pyridine gives the connection 31. Oxidative cleavage of the diol using leads to compounds, which lead in CH2Cl2network connection 32. Selective reduction of the aldehyde group using LiBEt3H in THF gives compound 33. Interaction of compound 33 with TBDPSCl and imidazole in DMF protect the free hydroxyl group, giving a connection 34. Recovery lydialydia ketone group gives compound 35. Treatment with 80% acetic acid removes ketal that gives compound 36. Refiniries using methyltriphenylphosphonium and KO tBu in THF gives methylidene connection 37. Processing when heated to the boiling temperature under reflux solution Bu4NF in THF removes the TBDPS group that gives compound 38.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 31

To a solution of compound 30 (0.45 g, 0.89 mmol) in pyridine (2.5 ml) is added OsO4(0.25 g, 0.98 mmol). The reaction mixture was stirred at 90°C overnight, then add a solution of Na2S2O3(0.5 g) in a mixture of water (8 ml) and pyridine. The reaction mixture is stirred for 20 minutes, then extracted with CH2Cl2(2×20 ml) and washed with saturated salt solution (30 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 4:1)to give compound 31 (0,249 g, 58%) as a white solid.

Synthesis of compound 32

To a solution of compound 31 (0.52 g, a 1.08 mmol) in CH2Cl2added Pb(OAc)4(0,527 g, 1,19 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes in an argon atmosphere. The precipitate is removed by filtration and the solvent is evaporated under reduced pressure. The residue is filtered through a layer of silica gel (hexane/EtOAc, 1:1)to give compound 32 (0,482 g, 58%) as a white solid.

Si is TEZ connection 33

To a solution of compound 32 (0,562 g at 1.17 mmol) in THF at 0°C add LiBEt3H (1,29 ml of 1M solution in THF). The reaction mixture was stirred at ambient temperature for 40 minutes in an argon atmosphere, then cooled in an ice bath and slowly add NaOH (1,29 ml, 1M) and H2O2(0.2 ml, 30%). The resulting solution was stirred at 0°C for another 5 minutes. The solution is extracted with CH2Cl2(2×15 ml) and the extracts dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 75:25 to 40:60)to give compound 33 (256 mg, 46%) as a white solid.

Synthesis of compound 34

A solution of compound 33 (0,185 g, 0,385 mmol), TBDPSCl (0,175 ml, 0,673 mmol) and imidazole (0.09 g, 1,161 mmol) in dry DMF (4 ml) is stirred over night. The reaction mixture was diluted with toluene (30 ml) and washed with saturated salt solution (2×15 ml), then dried over MgSO4filter and concentrate. The crude compound 34 is used for subsequent interactions without additional purification.

Synthesis of compound 35

To a solution of compound 34 (crude product, in 0.104 mmol) in THF at 0°C add LiAlH4(0.1 ml 1M solution in THF) in an argon atmosphere. The reaction mixture was stirred at 0°C for 1 hour, then slowly add a saturated solution of salt (5 ml). The solution is extracted with CH Cl2(2×15 ml), then the extracts dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 2:3)to give compound 35 (39 mg, 51% two steps) as a white solid.

Synthesis of compound 36

A mixture of compound 35 (120 mg, 0,197 mmol) and 80% acetic acid (1.5 ml) was stirred at ambient temperature overnight, then diluted with toluene (10 ml) and concentrated. The crude compound 36 is used for subsequent interactions without additional purification.

Synthesis of compound 37

The mixture KOtBu (60 mg, 0.54 mmol) and MePPh3Br (194 mg, 0.54 mmol) in THF (0.9 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add the connection 36 (97 mg, 0,17 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, then diluted with EtOAc (80 ml) and washed with saturated salt solution (2×30 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 2:3)to give compound 37 (63 mg, 65%) as a white solid.

Synthesis of compound 38

A solution of compound 37 (59 mg, 0,105 mmol) and n-Bu4NF (0.16 ml 1,0M solution in THF) in THF (0.35 ml) is heated to the boiling point under reflux in an argon atmosphere within 2 hours. The solvent is evaporated under reduced pressure and the residue purified by chromatography on silica gel (mixture of MeOH/EtOAc, 2:98),

receiving a connection 38 (38 mg) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 286,93; C20H31O.

EXAMPLE 4

The connection 45, characterized by the connection according to the invention can be obtained according to the following reaction scheme 4. Any number of compounds related to compound 45 can be obtained using similar techniques. The original connection 18 can be obtained according to the procedures outlined in U.S. patent 6046185.

Reaction scheme 4

In General, oxidative disclosure cycle connection 18 with the use of periodate sodium and catalytic amounts of ruthenium oxide network connection 39. Interaction with lydialydia in THF gives compound 40. Oxidative cleavage of the diol with the use of leads to compounds, which lead in CH2Cl2network connection 41. Treatment with MeLi in THF gives lactolose connection 42. Oxidation on the Bayer-Villager using MCPBA in CHCl3network connection 43. Treatment with 80% acetic acid removes ketal and TBS group that gives compound 44. Interaction of compound 44 with methyltriphenylphosphonium and KOt/sup> Bu in THF introduces methylidene group, and subsequent processing using the K2CO3in boiling methanol removes the acyl group, which leads to the formation of compound 45.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 39

To a solution of NaIO4(13,96 g, to 65.2 mmol) and RUO Li2·H2O (87 mg, 0.66 mmol) in water (120 ml) is added CCl4(80 ml) and acetone (100 ml). Then slowly add the connection 18 (crude product, 0.81 mmol) in a mixture of CCl4(40 ml) and acetone (60 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The solution is extracted with CH2Cl2(2×200 ml) and the combined organic layer was washed with saturated salt solution (200 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc/MeOH, 70:25:5)to give compound 39 (3,41 g, 37%) as a white solid.

Synthesis of compound 40

To a solution of compound 39 (0,509 g, 1.00 mmol) in THF is slowly added LiAlH4(3 ml of 1M solution in THF). The reaction mixture is stirred for 2 hours, then slowly add saturated NaHCO3(5 ml). The solution is extracted with CH2Cl2(2×20 ml) and the extracts dried over MgSO4filter and concentrate. The residue is purified by chromatography naselesele (a mixture of MeOH/EtOAc, 5:95)to give compound 40 (0.16 g, 32%) as a white glassy solid.

Synthesis of compound 41

To a solution of compound 40 (0.16 g, 0.32 mmol) CH2Cl2added Pb(OAc)4(0.156 g, 0.35 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes in an argon atmosphere. The precipitate is removed by filtration and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 41 (0,113 g, 87%) as a white glassy solid.

Synthesis of compound 42

To a solution of compound 41 (0.20 g, 0.43 mmol) in THF (3 ml) at 0°C is added MeLi (1.5 ml 1,4M solution in diethyl ether) in an argon atmosphere. The reaction mixture was stirred at ambient temperature for 2 hours, then quenched with saturated NH4Cl (15 ml) and extracted with EtOAc (2×15 ml), then dried over MgSO4filter and concentrate. The crude compound 42 is used for subsequent interactions without additional purification.

Synthesis of compound 43

A mixture of compound 42 (crude product, 0.43 mmol) and MCPBA (0.26 g, 57-86%and 1.51 mmol) in chloroform (3 ml) was stirred at ambient temperature for 1 day. The reaction mixture was diluted with EtOAc (15 ml) and washed sequentially with saturated Na2SO3(20 ml), saturated NaHCO3 (20 ml) and saturated salt solution (20 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 4:1)to give compound 43 (66 mg, 31% two steps) as a white solid.

Synthesis of compound 44

A mixture of compound 43 (0.40 g, 0.81 mmol) and 80% acetic acid (5 ml) was stirred at 50°C for 2 hours, then diluted with toluene (20 ml) and concentrated. The crude compound 44 is used for subsequent interactions without additional purification.

Synthesis of compound 45

The mixture KOtBu (0.45 g, of 4.05 mmol) and MePPh3Br (1.45 g, of 4.05 mmol) in THF (10 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add the connection 44 (crude product, 0.81 mmol) in THF (5 ml). The reaction mixture was stirred at ambient temperature overnight, then diluted with CH2Cl2(50 ml) and washed with saturated salt solution (2×30 ml), then dried over MgSO4filter and concentrate. The crude product is heated to the boiling point under reflux in the presence of K2CO3(0.34 g, 2,42 mmol) in THF (5 ml) for 3 hours. The solvent is removed and the residue purified by chromatography on silica gel (hexane/EtOAc/MeOH, 5:5:0.5), and receiving a connection 45 (of 0.13 g, 55% two steps) as white solids is: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 317,00; C18H30PAO3.

EXAMPLE 5

The connection 51, characterized by the connection according to the invention can be obtained according to the following reaction scheme 5. The original connection 46 can be obtained according to the procedures outlined in U.S. patent 6046185. Any number of compounds related to compound 51 can be obtained using similar methods.

Reaction scheme 5

In General, the interaction of compound 46 with periodates sodium in THF oxidative enzyme diol, which gives the connection 47. The interaction of the aldehyde groups with sodium borohydride gives the connection 48. Treatment with 80% acetic acid removes ketal and TBS group that gives compound 49. Interaction with TBSCl and imidazole in DMF protects the hydroxyl, which leads to the formation of compound 1. Rafinirovaniyu using methyltriphenylphosphonium and KOtBu in THF gives compound 50. Treatment with 80% acetic acid and subsequently boiling the solution Bu4NF in THF removes the TBS-group that gives compound 51.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 47

A solution of compound 46 (450 mg, of 0.94 mmol), NaIO4(240 mg, 1.12 mmol), water (2 ml) and THF (4 ml) peremeci is up during the night when the ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated salt solution, then dried over Na2SO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/hexane, 15:85)to give compound 47 (140 mg, 31%) as a white solid.

Synthesis of compound 48

A solution of compound 47 (1,32 g, was 2.76 mmol), NaBH4(229 mg, the 6.06 mmol), MeOH (17 ml) and CH2Cl2(3 ml) stirred at 0°C for 4 hours, then at ambient temperature overnight. The solvent is evaporated under reduced pressure, and the residue was diluted with EtOAc and washed with a saturated solution of salt. EtOAc layer is dried over Na2SO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of EtOAc/hexane, 2:3)that gives compound 48 (0.35 g, 26%) as a white solid.

Synthesis of compound 49

A mixture of compound 48 (350 mg, to 0.72 mmol) and 80% acetic acid (20 ml) is stirred overnight at ambient temperature. The solvent is evaporated under reduced pressure, and the residual solvent is removed by joint distillation with toluene, receiving the connection 49 (250 mg, 100%) as a yellow solid.

Synthesis of compounds 1

A solution of compound 49 (cleared to 0.72 mmol), TBSCl (382 mg, 2.54 mmol), imidazole (346 mg, 5.08 mmol) in dry DMF (15 ml) was stirred at which the temperature of the environment during the night. The reaction mixture was diluted with EtOAc (100 ml), washed with water, then dried over Na2SO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/hexane, 5:95)that gives compound 1 (374 mg, 78%).

Synthesis of compound 50

The mixture KOtBu (191 mg, 1.7 mmol) and MePPh3Br (600 mg, 1.7 mmol) in THF (1.5 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add the connection 1 (374 mg, 0,56 mmol) in THF (1.5 ml). The reaction mixture is heated to boiling point under reflux for 3 hours, then diluted with water (3 ml) and extracted with EtOAc (30 ml). EtOAc layer washed with water (10 ml) and saturated salt solution (10 ml), then dried over Na2SO4filter and concentrate. The residue is passed through silica gel (EtOAc/hexane, 1:99)to give compound 50 (354 mg, 95%) as a yellow oil.

Synthesis of compound 51

A mixture of compound 50 (350 mg, of 0.53 mmol) and 80% acetic acid (10 ml) heated to 50°C for 6 hours. The solvent is evaporated under reduced pressure, and the residual solvent is removed by joint distillation with toluene. The residue still contains a number of TBS-protected product, so the remainder absorb THF (1 ml) and Bu4NF (2.5 ml of 1,0M solution in THF)and the resulting solution is heated to boiling point with the reverse holodilniki is within 3.5 hours. The reaction mixture was diluted with EtOAc and washed with water and saturated salt solution, then dried over Na2SO4filter and concentrate. The residue is purified column chromatography on silica gel (EtOAc)to give compound 51 (119 mg, 70%) as a light yellow solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 305,16; C20H32O2, 287,19; C20H30O.

EXAMPLE 6

The connection 59, characterized by the connection according to the invention can be obtained according to the following reaction scheme 6. Any number of compounds related to compound 59, can be obtained using similar techniques. The original connection 27 can be obtained according to the procedures described above in example 2.

Reaction scheme 6

In General, the interaction of compound 27 with acetic anhydride and DMAP in pyridine gives the connection 52. Treatment with 80% acetic acid removes ketal and TBS group that gives compound 53. Interaction with methyltriphenylphosphonium and KOtBu in toluene enters methylidene group and it acyl group from a primary hydroxyl, resulting in the formation of compound 54. Processing TBSCl, DMAP and Et3N in DMF selectively protect the primary hydroxyl, giving the connection 55. The free hydroxyl of soedinenii 55 turn in bromide connection 56, using bromine, triphenylphosphine and Et3N in THF. Azide substitution of bromine with the use of sodium azide in NMP network connection 57. Interaction with lydialydia in THF restores azide and it acyl group, which gives the connection 58. Treatment with 80% acetic acid removes the TBS group and leads to the formation of salts with ammonium acetate, which gives the connection 59.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 52

A solution of compound 27 (is 3.08 g, by 5.87 mmol), acetic anhydride (1,12 ml, 11.7 mmol) and DMAP (50 mg, 0.41 mmol) in pyridine (25 ml) is stirred over night. Then the reaction mixture was quenched with a saturated salt solution (80 ml) and extracted with EtOAc (200 ml). EtOAc layer was washed with saturated salt solution (2×60 ml), then dried (MgSO4), filtered and concentrated. The crude compound 52 is used directly in the next stage.

Synthesis of compound 53

A mixture of compound 52 (crude product by 5.87 mmol) and 80% acetic acid (40 ml) was stirred at 50°C for 1 hour, and then distilled with toluene (3×50 ml) and concentrated. The crude compound 53 is used directly in the next stage.

Synthesis of compound 54

The mixture KOtBu (2,02 g, 18.0 mmol) and MePPh3Br (to 6.43 g, 18.0 mmol) in toluene (45 ml) was stirred at ambient temperature for 1 cha is in the atmosphere of argon, then add the connection 53 (crude product by 5.87 mmol) in toluene (10 ml). The reaction mixture was stirred at ambient temperature overnight, then diluted with a saturated solution of NH4Cl (100 ml) and extracted with EtOAc (100 ml). EtOAc layer was washed with saturated salt solution (80 ml), then dried (MgSO4), filtered and concentrated. The residue is passed through silica gel (hexane/acetone, 7:3)to give the purified compound 54.

The synthesis of compounds 55

A solution of compound 54 (cleared to 2.85 mmol), TBSCl (490 mg, 3.25 mmol), DMAP (58 mg, 0.47 mmol) and Et3N (600 μl, 4.3 mmol) in dry DMF (6 ml) is stirred for 5 hours. The reaction mixture was diluted with toluene (80 ml), washed with saturated solution of NaHCO3and a saturated solution of salt, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography on silica gel, receiving the connection 55 (480 mg, 45%).

Synthesis of compound 56

Bromine (80 μl, 1.6 mmol) are added to a solution of Ph3P (407 mg, 1.6 mmol) in THF (5 ml) at ambient temperature. After 5 minutes add Et3N (290 μl, 2.1 mmol) followed by a solution of compound 55 (480 mg, of 1.03 mmol) in THF (5 ml). After 1.5 hours the reaction mixture was diluted with EtOAc (100 ml) and washed with water and saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified chromate what graphy (hexane/EtOAc, 95:5)to give compound 56 (510 mg, 94%).

Synthesis of compound 57

A solution of compound 56 (510 mg, 0.97 mmol), NaN3(200 mg, 3.1 mmol) and NMP (8 ml) is heated to 55°C for 4 hours. The reaction mixture was diluted with toluene (100 ml) and EtOAc (30 ml) and washed with water and saturated salt solution, dried over MgSO4filter and concentrate. The residue is purified by chromatography (hexane/EtOAc, 98:2)to give compound 57 (197 mg, 41%).

Synthesis of compound 58

To a solution of compound 57 (197 mg, 0.40 mmol) in THF at ambient temperature is added LiAlH4(1 ml of 1,0M solution in diethyl ether). The reaction mixture was stirred at ambient temperature for 2.5 hours, then add Na2SO4·10H2O. the Solution is filtered and the solid product washed with MeOH and CH2Cl2. The filtrate is concentrated and the residue purified by chromatography on silica gel (mixture of CHCl3/MeOH/Et3N, 90:8:2)to give compound 58 (144 mg, 78%).

Synthesis of compound 59

A mixture of compound 58 (114 mg, 0.27 mmol) and 80% acetic acid (7 ml) is stirred overnight at ambient temperature. The solution was diluted with toluene (3×50 ml) and concentrate the receiving connection 59 (58 mg, 59%) as a yellow solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 307,92; C19H34NO2.

Connections 67 and 68, typical compounds according to the invention can be obtained according to the following reaction scheme 7. Any number of compounds related compounds 67 and 68, can be obtained using similar techniques. The original connection 21 can be obtained according to the procedures described above in example 1.

Reaction scheme 7

In General, treatment of compound 21 with acetic anhydride in pyridine (in order to protect the free hydroxyl) gives compound 60. Treatment with 80% acetic acid removes ketal and TBS group that gives compound 61. Processing TBSCl and imidazole in DMF protect the free hydroxyl in compound 62. Rafinirovaniyu connection 62 using methyltriphenylphosphonium and KOtBu in toluene enters methylidene group. In some cases, conditions referirovanija lead to the removal of acetate from the primary hydroxyl, which leads to the formation of compounds, such as 63. Primary acetate can be selectively hydrolysed by engagement with K2CO3in boiling methanol. The free hydroxyl in compound 63 in turn mesylate connection 64, using MsCl, pyridine. Sideropenia with the use of sodium azide in DMF gives etidocaine 65. The restoration of the azide lydialydia in THF gives and insidente 66. Treatment with 80% acetic acid removes the TBS group and leads to the formation of salts with ammonium acetate, which gives the connection 67.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 60

To a solution of compound 21 (China 0,686 g of 1.42 mmol) in pyridine (5 ml) is added acetic anhydride (0,94 ml, 9,94 mmol) and the reaction mixture was stirred at 50°C during the night. The solution was diluted with EtOAc (25 ml) and washed with saturated salt solution (2×20 ml), then dried over MgSO4filter and concentrate. The crude compound 60 is used for subsequent interactions without additional purification.

Synthesis of compound 61

A mixture of compound 60 (crude product of 1.42 mmol) and 80% acetic acid (15 ml) was stirred at 50°C for 2 hours, then diluted with toluene (2×20 ml) and concentrated. The residue is purified by chromatography on silica gel (hexane/EtOAc, 1:2)to give compound 61 (0,479 g, 87%) as a white solid.

Synthesis of compound 62

A solution of compound 61 (0,971 g of 2.38 mmol), TBSCl (0,716 g of 4.75 mmol) and imidazole (0,647 g of 9.51 mmol) in dry DMF (10 ml) is stirred for 3 hours. The reaction mixture was diluted with toluene (50 ml) and washed with saturated salt solution (2×20 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture g is Xan/EtOAc, 4:1)to give compound 62 (1,218 g, 98%) as a viscous light yellow oil.

Synthesis of compound 63

The mixture KOtBu (5,00 g of 42.3 mmol) and MePPh3Br (15,1 g of 42.3 mmol) in toluene (100 ml) was stirred at ambient temperature for 1 hour in an argon atmosphere, and then add a solution of compound 62 (crude product, 14.1 mmol) in 100 ml of toluene. The reaction mixture was stirred over night at ambient temperature, then quenched with saturated solution of NaHCO3(75 ml) and water (75 ml). The solution is further diluted with 100 ml of water and extracted with EtOAc (4×100 ml). The combined solution extracts washed with saturated salt solution (2×100 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 100:0, then 9:1, then 4:1), receiving diacetate compound (4.5 g, 62%) as a yellow oil and compound 63 (1.8 g, 27%) as a yellow oil. The solution diacetate compound (4.5 g, 8.6 mmol), K2CO3(4,78 g, 34.6 mmol) and methanol (100 ml) is heated to the boiling point under reflux in an argon atmosphere. After 75 minutes, the reaction mixture was cooled to ambient temperature and filtered through celite, elwira CH2Cl2. The filtrate is concentrated and dissolved in EtOAc (250 ml), then washed with water and dried over MgSO4filter and concentrate. The remainder of cidaut chromatography on silica gel (hexane/EtOAc, 100:0, then 19:1 then 9:1)to give compound 63 (3.2 g, 47%) as a yellow foam.

Synthesis of compound 64

To a solution of compound 63 (3,17 g, 6.62 mmol) in pyridine (50 ml) and CH2Cl2(0.5 ml) add methanesulfonanilide (of 1.02 ml, 13,2 mmol) and the reaction mixture is stirred in an argon atmosphere at ambient temperature for 3 hours. The reaction mixture was quenched with saturated solution of NaHCO3(60 ml) and extracted with EtOAc (3×80 ml). The combined solution of the extracts washed with water and saturated salt solution, then dried over MgSO4filter and concentrate. The residue concentrated from toluene, to give crude compound 64, which is used for subsequent interactions without additional purification.

Synthesis of compound 65

A solution of compound 64 (crude product, 6.62 mmol) and NaN3(646 mg, to 9.93 mmol) in DMF (40 ml) is heated in an argon atmosphere at 60°C over night. After cooling, the reaction mixture was diluted with water (100 ml) and extracted with diethyl ether (4×100 ml). The combined solution of the extracts washed with water and saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 100:0, then 98:2 then 95:5)to give compound 65 (2,56 g, 77% from 2 stages) as a yellow oil.

Synthesis of compound 66

A solution of LiAlH4(385 ml of 1,0M solution in THF) are added to a solution of compound 65 (647 mg, 1.28 mmol) in THF (15 ml) in an argon atmosphere. After 3 hours the reaction mixture was quenched with Na2SO4·10H2O and diluted with THF (10 ml). After 30 minutes the solution is filtered and concentrated. The residue is purified by chromatography on silica gel (mixture of CH2Cl2/Meon/Et3N, 100:0:0 then 95:5:0, then 90:10:0 then 95:5:2)to give compound 66 (324 mg, 58%) as a colourless oil.

Synthesis of compound 67

A solution of compound 66 (320 mg, 0,734 mmol) and 80% acetic acid (25 ml) is heated to 50°C for 3 hours. The residue is purified by chromatography on silica gel with reversed phase (H2O, the mixture is then H2O/Meon/AcOH 50:50:2). The concentration of a mixture of MeOH/MeCN gives compound 67 (244 mg, 87%) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 322,12; C20H36NO2.

Synthesis of compound 68

Using the techniques described for the synthesis of compounds 67, except referirovanija using EtPPh3Br, compound 68 (75 mg) are obtained in the form of a white solid with a yield of 22%, based on the connection 62. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 336,16; C21H38NO2.

EXAMPLE 8

Connection 77-81, typical compounds according to the invention can be obtained according to the following reaction scheme 8. Source connect the Oia, such as 69, can be obtained according to the procedures outlined in U.S. patent 6046185. Any number of compounds related compounds 77-81, may be obtained using similar methods.

Reaction scheme 8

a) AC2O, DMAP, pyridine; b) 80% AcOH; (c) NaBH4, MeOH, THF; (e) AC2O, DMAP, pyridine, g) NaN3, DMF: h) LiAlH4, THF; (i) 80% AcOH; (j) HCl, water, MeOH, 65°C.

In General, the interaction connection 69 with acetic anhydride and DMAP in pyridine gives the connection 70. Treatment with 80% acetic acid removes the acetonide group that gives compound 71. Interaction with periodates sodium in THF oxidative enzyme diol, giving the connection 72. The recovery of the aldehyde groups with sodium borohydride gives compound 73. Interaction with acetic anhydride and DMAP in pyridine selectively protects one of the primary hydroxyl, giving the connection 74. The free hydroxyl turn in mesilate connection 75, using MsCl, pyridine. Interaction with sodium azide in DMF gives etidocaine 76. Interaction with lydialydia in THF restores azide and removes acetyl groups, which leads to the formation of compound 77. Treatment with 80% acetic acid leads to the formation of compound 78 in the form of a salt with ammonium acetate. Interaction link is, such as 78 with HCl in water and MeOH, contributes to the displacement of the 18-methyl group to C17 with the formation of compounds, such as 79. Careful handling connection 77 with HCl in MeCN and water leads to the formation of salts of compound 77 with ammonium chloride (i.e. connection 80).

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 70

A solution of compound 69 (6,9 g of 19.1 mmol), acetic anhydride (3,62 ml, to 38.3 mmol) and DMAP (0,23 g, 1.9 mmol) in pyridine (50 ml) is stirred for 4.5 hours. The reaction mixture was diluted with cold water (150 ml), extracted with EtOAc (600 ml) and washed with saturated salt solution (2×200 ml), then dried over MgSO4filter and concentrate. The crude compound 70 are used directly in the next stage.

Synthesis of compound 71

A mixture of compound 70 (crude product of 19.1 mmol) and 80% acetic acid (50 ml) was stirred at 40°C for 2 hours. The solution is concentrated, give crude compound 71, which is used in the next stage without additional purification.

Synthesis of compound 72

A solution of compound 71 (crude product of 19.1 mmol), NaIO4(8,19 g, to 38.3 mmol), water (53 ml) and THF (106 ml) was stirred at ambient temperature for 3.5 hours. The reaction mixture was diluted with CH2Cl2and washed with saturated salt solution, then dried the hell MgSO 4, filtered and concentrated give crude compound 72, which is used in the next stage without additional purification.

Synthesis of compound 73

A solution of compound 72 (crude product of 19.1 mmol), NaBH4(1.45 g, to 38.3 mmol), THF (120 ml) and MeOH (40 ml) stirred at 0°C for 10 minutes, then at ambient temperature for 1 hour. The mixture is cooled with ice and slowly add 80% acetic acid (62 ml). The solution was stirred at ambient temperature for 10 minutes, then diluted with EtOAc (400 ml) and then washed with a saturated solution of salt. EtOAc layer is dried over MgSO4, filtered and concentrated give crude compound 73, which is used in the next stage without additional purification.

Synthesis of compound 74

A solution of compound 73 (crude product of 19.1 mmol), acetic anhydride (2.1 ml, 22,0 mmol) and DMAP (230 mg, 1.9 mmol) in pyridine (65 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was diluted with EtOAc (400 ml) and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc 5:1, then 4:1, then 7:3)to give compound 74 (4.9 g, 63%).

Synthesis of compound 75

To a solution of compound 74 (4.9 g, 12.1 mmol) in pyridine (40 ml) add methanesulfonyl is Lorig (1,68 ml, of 21.7 mmol) and the reaction mixture stirred at ambient temperature for 2 hours. The solution was diluted with EtOAc (400 ml) and washed with saturated salt solution, then dried over MgSO4, filtered and concentrated give crude compound 75, which is used for subsequent interactions without additional purification.

Synthesis of compound 76

A mixture of compound 75 (crude product, 12.1 mmol) and NaN3(1,57 g, 24,1 mmol) in DMF (100 ml) is heated in an argon atmosphere at 60°C over night. After cooling, the reaction mixture was diluted with toluene (400 ml) and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 8:2)to give compound 76 (4.8 g, 92% from 2 stages).

Synthesis of compound 77

A solution of LiAlH4(44,5 ml of 1,0M solution in Et2O) add ice to a solution of compound 76 (4.8 g, 11.1 mmol) in THF (111 ml). After 10 minutes the dissolution continued at ambient temperature for another 4 hours. The reaction mixture is cooled with ice and quenched with Na2SO4·10H2O. After 15 minutes the solution was diluted with EtOAc (100 ml), stirred for further 20 minutes at ambient temperature, then filtered. The filtrate is washed with saturated salt solution, then dried over MgSO4, filtered and concentrated, p is the best connection 77 (3.8 g, quantitatively) as a white solid.

Synthesis of compound 78

A solution of compound 77 (1,00 g of 2.93 mmol) and 80% acetic acid (15 ml) is heated to 40°C for 1 hour, then concentrated. Residual solvent is removed by joint distillation with toluene. The remainder proscout in diethyl ether and filtered, obtaining a connection 78 (923 mg, 83%) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 321,95; C20H36NO2.

Synthesis of compound 79

A solution of compound 78 (600 mg, 1.57 mmol), concentrated HCl (5 drops), water (1 ml) and MeOH (9 ml) was heated to 65°C for 5 days, then concentrate. The remainder proscout in MeCN and filtered, obtaining a connection 79 (504 mg, 90%) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 322,2; C20H36N02.

Synthesis of compound 80

To a suspension of compound 77 (0.1 g, 0.3 mmol) in MeCN (2 ml) is added HCl (337 μl of 1,0M solution in Et2O). After 15 minutes the solution is filtered, getting salt compound 77 with ammonium chloride, i.e. the connection 80 (76 mg, 72%) as a white powder.

Synthesis of compound 81

Using the methods described for the synthesis of compound 80, compound 81 (0,646 g) are obtained in the form of a white powder with a yield of 37%, based on utilize the new connection, similar to the connection 69. Stage of formation of salt differs in that connection produce through co-distillation of the residual acid solution, using MeOH: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 335,89; C21H38NO2.

EXAMPLE 9

Connections 88 and 89, typical compounds according to the invention can be obtained according to the following reaction scheme 9. Any number of compounds related compounds 88-89, can be obtained using similar techniques. The original connection 73 can also be obtained according to the procedures described above in example 8.

Reaction scheme 9

In General, the interaction connection 73 with TBSCl and imidazole in DMF gives the connection 83. Interaction with acetic anhydride and DMAP in pyridine protects the remaining free hydroxyl, giving a connection 84. Interaction with tetrabutylammonium removes the TBS-group, resulting in the formation of compound 85. The free hydroxyl turn in mesilate connection 86 using MsCl, pyridine. Interaction with sodium azide in DMF gives etidocaine 87. Interaction with lydialydia in THF restores azide and removes the acyl group, giving a connection 88. Treatment with 80% acetic acid leads to the formation is aniu salt with ammonium acetate, that gives compound 89.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 83

A solution of compound 73 (2.9 g, a 7.92 mmol), TBSCl (1,32 g, 8,76 mmol), imidazole (813 mg, to 11.9 mmol) and DMF (20 ml) was stirred at ambient temperature for 1.5 hours. The solution was diluted with water (50 ml) and extracted with toluene (100 ml). Toluene layer was washed with saturated salt solution (40 ml), then dried over MgSO4, filtered and concentrated give crude compound 83, which is used in the next stage without additional purification.

Synthesis of compound 84

A solution of compound 83 (crude product of 7.96 mmol), acetic anhydride (2.25 ml of 23.9 mmol) and DMAP (100 mg, 0.82 mmol) in pyridine (25 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The crude compound 84 is used in the next stage without additional purification.

Synthesis of compound 85

A solution of compound 84 (crude product g of 7.96 mmol), Bu4NF (12 ml of 1,0M solution in THF) and THF stirred at ambient temperature for 2 hours and at 40°C for 30 minutes. The reaction mixture is filtered through silica gel and concentrated. The residue is purified by chromatography on silicagel is e (a mixture of EtOAc/hexane 3:7), receiving a connection 85 (of 2.06 g, 64%).

Synthesis of compound 86

To a solution of compound 85 (1.06 g, 2,61 mmol) in pyridine (12 ml) add methanesulfonanilide (400 μl, 5,16 mmol) and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was quenched with water and extracted with EtOAc. The solution was washed with saturated salt solution, then dried over MgSO4, filtered and concentrated give crude compound 86, which is used for subsequent interactions without additional purification.

Synthesis of compound 87

A mixture of compound 86 (crude product, 2,61 mmol) and NaN3(1.0 g, 15 mmol) in DMF (15 ml) is heated in an argon atmosphere at 95°C during the night. After cooling, the reaction mixture is diluted with toluene and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel, receiving the connection 87 (575 mg, 89%).

Synthesis of compound 88

A solution of LiAlH4(3.2 ml 1,0M solution in THF) is added to cooled with ice to a solution of compound 87 (274 mg, 0,635 mmol) in THF (3 ml). After 10 minutes the dissolution continued at ambient temperature for another 3 hours. The reaction mixture is cooled with ice and quenched with Na2SO4·10H2O. After 15 minutes the solution is filtered, and the filtrate is washed with saturated salt solution,then dried over MgSO 4filter and concentrate. Purification by chromatography on silica gel (mixture of EtOAc/MeOH/H2O/NH4OH 7:2:1:0.15 in, then 7:2:1:0,2, then 7:2:1:0,3)that gives compound 88 (135 mg, 66%).

Synthesis of compound 89

A solution of compound 88 (135 mg, 0.42 mmol) and 80% acetic acid (3 ml) is heated to 40°C for 30 minutes, then concentrated. Residual solvent is removed by joint distillation with methanol, receiving the connection 89 (158 mg, 99%) as a pale yellow foam. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 322,11; C20H36NO2.

EXAMPLE 10

Compounds 100 and 101, the characteristic of the compounds according to the invention can be obtained according to the following reaction scheme 10. Any number of compounds related compounds 100 and 101, can be obtained using similar techniques. The original connection 60 can also be obtained according to the procedures described above in example 7.

Reaction scheme 10

In General, selective hydrolysis of the primary acetate in connection 60 with the use of K2CO3network connection 90. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 91. Substitution of nelfinavir on phenylsilane network connection 92. Oxidative elimination and with the use of hydrogen peroxide gives olefinic compound 93. Ominirovaniya gives dihydroxypropane connection 94, which is then subjected to oxidative decomposition under the action leads to compounds, which lead that gives compound 95. The recovery of the sodium borohydride gives the alcohol connection 96. Sideropenia using diisopropylcarbodiimide (DIAD), diphenylphosphinite (DPPA) and PPh3in THF gives etidocaine 97. Interaction with lydialydia in THF restores azide and removes the acyl group that gives compound 98. Treatment with HCl removes as TBS-group and a cyclic ketal, which leads to the formation of compound 99. Rafinirovaniyu using methyltriphenylphosphonium and KOtBu in THF gives compound 100. The treatment with acetic acid leads to the formation of salts with ammonium acetate that gives compound 101.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 90

A mixture of compound 60 (12.7 g, of 22.4 mmol), K2CO3, (9,38 g, and 67.2 mmol), MeOH (250 ml) and water (94 ml) was stirred at 55°C for 2 hours, cooled to ambient temperature, then concentrated. The residue is dissolved in EtOAc, washed twice with saturated solution of NaHCO3, then twice with saturated salt solution, dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (mixture g is Xan/EtOAc), receiving a connection 90 (10,16 g, 86%) as a white foam.

Synthesis of compound 91

To a solution of compound 90 (10,14 g, and 19.3 mmol) in pyridine (50 ml) at 0°C add methanesulfonanilide (2,69 ml, 34.8 mmol). The mixture is stirred at 0°C for 10 minutes, then at ambient temperature for 2 hours. The mixture was diluted with EtOAc (200 ml) and washed with water (2×50 ml). Carry back extraction combined aqueous portions with EtOAc (50 ml). The combined organic layers washed with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate. The residue is dissolved in toluene and concentrated, obtaining compound 91 (11.3 g, 97%) as a white foam, which is used for subsequent interactions without additional purification.

Synthesis of compound 92

To stir the mixture diphenyldisulfide (? 7.04 baby mortality g, 22,1 mmol) and EtOH (100 ml) at 0°C is added in portions over a period of 7 minutes, NaBH4(1,69 g, a 44.2 mmol), then after 5 minutes, the mixture is allowed to warm to ambient temperature and stirred for further one hour. The resulting solution was added via cannula to a suspension of compound 91 in EtOH (175 ml), rinsing EtOH (25 ml). The mixture is stirred at 50°C for 35 minutes. The mixture is cooled, water is added (70 ml)and the mixture concentrated. The residue is dissolved in EtOAc (400 ml) and washed with water (100 ml), then saturated salt solution (100 is l). Carry back extraction combined wash water with EtOAc (3×75 ml). The combined organic layers washed with saturated salt solution (2×100 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc)to give compound 92 (10.6 g, 87%) as a yellow foam.

Synthesis of compound 93

A mixture of compound 92 (10.2 g, to 15.4 mmol) and 30% solution of H2O2in THF (4500 ml) was stirred at ambient temperature for 50 minutes, then at 65°C for 40 minutes. After cooling, the mixture was diluted with EtOAc (500 ml) and washed with saturated salt solution (200 ml), then with saturated solution of NaHCO3(200 ml). Carry back extraction combined aqueous portions with EtOAc (2×100 ml). The combined organic portion was washed with saturated salt solution (2×200 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 3:1; EtOAc)to give compound 93 (5,86 g, 75%) as a white foam.

Synthesis of compound 94

To a solution of compound 93 (to 4.81 g, 9,49 mmol) in THF (90 ml),tBuOH (30 ml) and water (9 ml) was added NMO (1,72 g of 14.2 mmol) and OsO4(3.0 ml of a 4% solution in water, 0.47 mmol). The reaction mixture was stirred at ambient temperature overnight, then add a solution of Na2S2O3 ·5H2O (1,75 g) in water (30 ml). The mixture is stirred for 30 minutes, then diluted with saturated salt solution (350 ml) and extracted with CH2Cl2(200 ml, 2×125 ml 75 ml). The combined organic layers washed with saturated salt solution (2×150 ml), dried over anhydrous MgSO4and concentrate, receiving the connection 94 (5,70 g) as a light brown foam, which is used for subsequent interactions without additional purification.

Synthesis of compound 95

To a solution of compound 94 (5,70 g) in CH2Cl2(100 ml) was added Pb(OAc)4(4,43 g, 9,49 mmol). The reaction mixture was stirred at ambient temperature for 35 minutes, then filtered through a layer of silica and concentrated. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1, 4:1), receiving a connection 95 (4,21 g, 85% based on INT1660) as a white foam.

Synthesis of compound 96

To a stirred solution of compound 95 (300 mg, 0.59 mmol) in a mixture of MeOH/THF (2 ml/7 ml) at 0°C is added NaBH4(45 mg, 1.2 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature, add an additional amount of NaBH4(89 mg, 2.4 mmol), in portions over 4 hours. The mixture is cooled to 0°C and the reaction quenched with water (1 ml). The mixture was diluted with EtOAc (200 ml), washed twice with saturated salt solution, dried and concentrated. Statomat column chromatography (hexane/EtOAc, 6:4)to give compound 96 with the release of 82%.

Synthesis of compound 97

Using the methods described below in the method the method In example 12 for the synthesis of compound 116, the connection 97 is produced from compound 96. The crude compound 97 purified column chromatography (hexane/EtOAc, 8:2) and used in the next stage without additional purification.

Synthesis of compound 98

To mix the solution of purified compound 97 (0.59 mmol) in THF (20 ml) at 0°C is added dropwise 1M LAH in THF (5.8 ml, 5.8 mmol). After 25 min at 0°C the mixture was stirred at ambient temperature for 3 hours. The mixture is again cooled to 0°C and add portions of solid Na2SO4·10H2O (1.86 g, 5.8 mmol). The mixture is stirred at 0°C for 5 min and then at ambient temperature for another 20 min, and then filtered through celite. The filtrate is concentrated, and the residue is purified column chromatography (mixture of EtOAc/MeOH/Et3N, 9:1:0.5), and receiving a connection 98 (150 mg, 59% (based on compound 96) in the form of a transparent resin.

Synthesis of compound 99

A mixture of compound 98 (150 mg, 0.32 mmol) and 80% HOAc (5 ml) was stirred at 40°C for 7 hours. The solvents are removed by rotational evaporation and dried in vacuum. The crude compound 99 is used in the next stage without additional purification.

Synthesis of compound 100

The mixture MePPh 3Br (1.26 g, 3.5 mmol) and KOtBu (395 mg, 3.5 mmol) in THF (15 ml) was stirred at ambient temperature for 2 hours and then added to the mixture previously obtained compound 99 in THF (5 ml) and DMF (1 ml). The reaction mixture was stirred at ambient temperature for 2 days and then quenched with saturated NH4Cl (0.25 ml). The mixture was diluted with EtOAc (20 ml) and MeOH (5 ml) and filtered through celite. The filtrate is concentrated, and the residue is purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 6:3:0,5:0,5), receiving a connection 100 (47 mg, 47% (based on compound 98).

Synthesis of compound 101

A solution of compound 100 (47 mg, 0.15 mmol) in 80% HOAc was stirred at ambient temperature for several minutes, and then the solvents are removed by rotational evaporation. The residue is evaporated several times together with MeOH. The residue is dissolved in a small amount of MeOH and treated with a small amount of acetonitrile. The product is separated by sedimentation and the supernatant is removed with a pipette. The obtained solid product is dried in vacuum, obtaining the connection 101 (35 mg, 62%) as a light powder: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 308,06; C19H34NO2.

EXAMPLE 11

Connection 107-108, typical compounds according to the invention can be obtained according to the SNO following reaction scheme 11. Any number of compounds related compounds 107-108, can be obtained using similar techniques. The original connection 33 may also be obtained according to the procedures described above in example 3.

Reaction scheme 11

a) MsCl, pyridine; (b) NaN3, DMF, 40°C; c) NaBH4, MeOH, THF; d) PPh3H2O, THF, 40°C; e) 2 N HCl, THF; (f) MePPh3Br, KOtBu, THF, DMF; (g) 80% AcOH.

In General, the engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 102. Substitution of nelfinavir on azide using sodium azide in DMF network connection 103. The sodium borohydride selectively restore carbonyl, receiving a connection 104. The restoration of the azide using PPh3and water in THF gives compound 105. Treatment with HCl removes the TBS-group and a cyclic ketal, which leads to the formation of compound 106. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 107. The treatment with acetic acid leads to the formation of salts with ammonium acetate, which gives the connection 108.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 102

To a solution of compound 33 (15.0 g, and 31.2 mmol) in pyridine (100 ml) at 0°C add methanesulfonanilide (4.35 m is, 56.2 mmol). The reaction mixture was stirred at 0°C for 10 minutes, then at ambient temperature for 4 hours. The mixture was diluted with EtOAc (400 ml), washed with water (2×100 ml) and then with saturated salt solution (2×100 ml), then dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 3:1, 1:1), that gives compound 102 (12.8 g, 78%) as a white foam.

Synthesis of compound 103

A mixture of compound 102 (0.800 to g, of 1.43 mmol) and NaN3(0,190 g, 2.89 mmol) in dry DMF (15 ml) was stirred at 50°C for 3 hours, then at 40°C during the night. After cooling to ambient temperature the mixture is diluted with water (80 ml) and extracted with Et2O (3×30 ml). The organic portion was washed with saturated salt solution (2×20 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane; hexane/EtOAc, 19:1, 9:1, 4:1), that gives compound 103 (0,476 g, 66%) as a yellow oil.

Synthesis of compound 104

To a stirred solution of compound 103 (0,473 g, 0,935 mmol) in THF (15 ml) and MeOH (5 ml) at 0°C is added NaBH4(0,286 g of 7.48 mmol), in portions, over a period of 5 minutes. The resulting mixture was stirred at 0°C for 10 minutes, then at ambient temperature overnight. The reaction mixture was quenched with water (50 ml), then extracted with EtOAc (30 ml, 2×20 ml The organic extracts are washed with saturated salt solution (2×20 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1, 4:1), that gives compound 104 (0,349 g, 73%) as a white foam.

Synthesis of compound 105

A mixture of compound 104 (0,346 g, 0,681 mmol), PPh3(0,542 g, 2.04 mmol), water (1 ml) and THF (20 ml) was stirred at 40°C overnight and then concentrated. The residue is purified by chromatography on silica gel (mixture of CH2Cl2/MeOH, 19:1; a mixture of CH2Cl2/Meon/Et3N, 9:1:0,2)to give compound 105 (0,336 g, quantitative) as a colourless glassy mass.

Synthesis of compound 106

A mixture of compound 105 (0,050 g, 0.10 mmol) and 2n. HCl (1 ml, 2 mmol) in THF (3 ml) was stirred at ambient temperature for 2 hours, then concentrated. To a solution of the residue in CH2Cl2/MeOH (1:1.8 ml) is added macroporous polystyrene-bound carbonate (0,105 g, 0,300 mmol) and the mixture was stirred at ambient temperature for 3 hours. The mixture is filtered, rinsing with a mixture of CH2Cl2/MeOH (1:1, 3×5 ml) and the filtrate is concentrated and receiving connection 106 (0,032 g, 94%) as a colourless oil.

Synthesis of compound 107

The mixture KOtBu (0,339 g, 2,87 mmol) and MePPh3Br (1,02 g, 2,87 mmol) in THF (12 ml) was stirred at ambient temperature for 2.5 cha is s, then add a solution of compound 106 (0,116 g, 0,359 mmol) in THF (6 ml) and DMF (2 ml). The reaction mixture was stirred at ambient temperature overnight, then quenched with saturated solution of NH4Cl (4 ml), diluted with MeOH (10 ml), filtered and the filtrate concentrated. The residue was washed with EtOAc (3×10 ml) and MeOH (2×10 ml). The combined wash water concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH; a mixture of EtOAc/MeOH/H2O/Et3N)to give compound 107 (0,024 g, 21%) as a colourless glassy mass.

Synthesis of compound 108

A mixture of compound 107 (0.035 g, 0.11 mmol) and 80% acetic acid (5 ml) was stirred at ambient temperature for 45 minutes, then concentrated. The residue is dissolved in MeOH and concentrated three times. The deposition of a mixture of ACN/MeOH network connection 108 (0.036 g, 86%) as a yellow solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 322,24; C20H36NO2.

EXAMPLE 12

Connection 119-120, typical compounds according to the invention can be obtained according to the following reaction scheme 12. Any number of compounds related compounds 119-120, can be obtained using similar techniques. The original connection 102 can be obtained according to the procedures described above in example 11.

The reaction is ionic scheme 12

In General, the substitution of nelfinavir on phenylsilane network connection 109. Oxidative elimination using hydrogen peroxide gives olefinic compound 110. The recovery of the sodium borohydride gives the alcohol connection 111. Interaction with acetic anhydride and DMAP in pyridine gives the connection 112. Ozonation gives aldehyde compound 113. The recovery of the sodium borohydride network connection 114. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 115. Azide substitution nelfinavir with the use of sodium azide in DMF network connection 116. Interaction with lydialydia in THF restores azide and deletes both the acyl group and the TBS-group that gives compound 117. Treatment with HCl removes the cyclic ketal, leading to the formation of compound 118. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 119. The treatment with acetic acid leads to the formation of salts with ammonium acetate, which gives the connection 120.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 109

To stir the mixture diphenyldisulfide (of 7.25 g of 22.8 mmol) and EtOH (100 ml) at 0°C add portions NaBH4(1,74 g of 45.5 mmol), after 5 minutes the mixture datagrams to ambient temperature and stirred for another hour. The resulting solution was added via cannula to a suspension of compound 102 in EtOH (175 ml), rinsing with EtOH (25 ml). The mixture was stirred at ambient temperature for 30 minutes, then at 50°C for 45 minutes. The mixture is cooled, add water (80 ml) and the mixture concentrated. The residue is dissolved in EtOAc (500 ml) and washed with saturated salt solution (2×100 ml). Carry back extraction combined wash water with EtOAc (200 ml), and EtOAc-part washed with saturated salt solution (2×50 ml). The combined organic extracts dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 109 (8,9 g, 75%) as a pale yellow solid.

Synthesis of compound 110

A mixture of compound 109 (0,907 g of 1.46 mmol) and 30% solution of H2O2in THF (60 ml) was stirred at ambient temperature for 1 hour, then at 65°C for 1 hour. After cooling, the mixture was diluted with EtOAc (60 ml) and washed with saturated salt solution (30 ml), then with saturated solution of NaHCO3(40 ml). Carry back extraction combined aqueous portions with EtOAc (2×20 ml). The combined organic portion was washed with saturated salt solution (2×40 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica compound is barely (hexane; hexane/EtOAc, 7:1)to give compound 110 (0,447 g, 66%) as a white solid.

Synthesis of compound 111

To a stirred solution of compound 110 (3,82 g, compared to 8.26 mmol) in THF (75 ml) and MeOH (25 ml) at 0°C is added NaBH4(1.06 g, 27.7 mmol), in portions over 20 minutes. The resulting mixture was stirred at 0°C for 10 minutes, then at ambient temperature overnight. The reaction mixture was cooled to 0°C and quenched with water (200 ml), then extracted with EtOAc (3×100 ml). The organic extracts are washed with saturated salt solution (2×100 ml), dried over anhydrous MgSO4and concentrate, receiving the connection 111 (3,76 g, 98%) as a white foam.

Synthesis of compound 112

To a solution of compound 111 (are 5.36 g, 11.5 mmol) and DMAP (0,282 g, 2,31 mmol) in pyridine (85 ml) is added acetic anhydride (10.9 ml, 115 mmol). The resulting mixture was stirred at 50°C overnight, then cooled to ambient temperature, diluted with EtOAc (350 ml) and washed with water (120 ml). Carry back extraction of the aqueous portion with EtOAc (2×50 ml). The combined organic layers washed with saturated salt solution (2×125 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 112 (lower than the 5.37 g, 92%) as a white foam.

Synthesis of compound 113

A solution of compound 112 (4,84 g of 9.55 mmol who) in CH 2Cl2(75 ml) and MeOH (25 ml) is treated with ozone at -78°C for 3.5 hours. Bubbled nitrogen at -78°C for 10 minutes, then add the dimethyl sulphide (12 ml, 164 mmol), and the mixture was stirred at -78°C for 10 minutes, then at ambient temperature for 2 hours. The mixture is concentrated, then the residue is dissolved in EtOAc (200 ml), washed with water (2×50 ml) and then with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate, receiving the connection 113 (4.59 g, 94%) as a white foam.

Synthesis of compound 114

To a stirred solution of compound 113 (300 mg, 0.59 mmol) in a mixture of MeOH/THF (2 ml/7 ml) at 0°C is added NaBH4(64 mg, 1.7 mmol). After 15 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then add an additional amount of NaBH4(20 mg, of 0.53 mmol). The mixture is stirred for a further 50 minutes, then cooled to 0°C and the reaction quenched with water (5 ml). The mixture was diluted with EtOAc (200 ml), washed twice with saturated salt solution, dried and concentrated, to give crude compound 114 (299 mg, 99%). The product is used in the next stage without additional purification.

Synthesis of compound 115

To a stirred solution of compound 114 (103 mg, 0.2 mmol) in pyridine at 0°C is added dropwise MsCl (0.1 ml, 0.9 mmol). The resulting mixture was stirred at the temperature of the environment is the first environment for 8 hours, then diluted with EtOAc (200 ml), washed with saturated salt solution, dried and concentrated, to give crude compound 115, which is used in the next stage without additional purification.

Synthesis of compound 116

The way A

The mixture obtained earlier connection 115 and NaN3(46 mg, 0.7 mmol) in DMF (1.6 ml) was stirred at 60°C over night. The reaction mixture was diluted with toluene (150 ml) and washed with a saturated solution of salt. Wash water are combined and extracted with toluene. The organic extracts are combined and washed with saturated salt solution, dried and concentrated. The residue is purified column chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 116 (45 mg, 43% based on INT1861), in the form of a transparent resin.

Method In

To a stirred solution of compound 114 (293 mg, or 0.57 mmol) in THF (6 ml) at 0°C add Ph3P (329 mg, 1.25 mmol), DIAD (0.25 ml, of 1.27 mmol) and DPPA (0,27 ml, 1.25 mmol). After 10 min at 0°C the mixture was stirred at ambient temperature overnight. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc. EtOAc extracts are combined and washed with saturated NaHCO3saturated salt solution, dried and concentrated. The residue is purified column chromatography (hexane/EtOAc, 9:1)to give compound 116 (275 mg, 89%) as a transparent resin.

Synthesis connected to the I 117

To a stirred solution of compound 116 (128 mg, 0.24 mmol) in THF (5 ml) at 0°C is added dropwise 1M LAH in THF (0.95 ml, 0.95 mmol). After 10 min at 0°C the mixture was stirred at ambient temperature for 4.5 hours. The mixture is again cooled to 0°C and add portions of solid Na2SO4·10H2O (308 mg, 0.95 mmol). The mixture is stirred at 0°C for 10 min and then at ambient temperature for another 20 min, and then filtered through celite. The filtrate was diluted with EtOAc (200 ml), washed with saturated salt solution, dried (Na2SO4) and concentrate. The residue is purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 7:2:0,5:0,5), receiving a connection 117 (45 mg, 53%).

Synthesis of compound 118

A mixture of compound 117 (45 mg, 0.13 mmol) and 2n. HCl (1 ml) in THF (3 ml) was stirred at ambient temperature overnight. The solvent is removed by rotational evaporation and the residue purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 7:2:0,5:0,5), receiving a connection 118 (50 mg, mixed with traces Et3N).

Synthesis of compound 119

The mixture MePPh3Br (457 mg, 1.28 mmol) and KOtBu (144 mg, 1.28 mmol) in THF (6 ml) was stirred at ambient temperature for 1 hour 40 min and then added to the mixture of compound 118 (50 mg, 0.16 mmol) in THF (3 ml) and DMF (1 ml). The reaction mixture paramashiva the t at ambient temperature overnight and then quenched with saturated NH 4Cl (2 ml). After stirring for several minutes the mixture is concentrated by rotational evaporation. The residual pasty mass is repeatedly extracted with EtOAc and filtered. The filtrates are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 7:2:0,5:0,5), receiving a connection 119 (24 mg, 63% (based on compound 117).

Synthesis of compound 120

To a stirred solution of compound 119 (43 mg) in MeOH (~2 ml) add 80% HOAc (0.5 ml) and the mixture is then concentrated to dryness. The residue re-dissolved in a small amount of MeOH and treated with a small amount of acetonitrile. The mixture is concentrated again and the precipitate is dried in vacuum, obtaining the connection 120 (53 mg, 100%) as a light powder: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 308,11; C19H34NO2.

EXAMPLE 13

Connection 132-133, typical compounds according to the invention can be obtained according to the following reaction scheme 13. Any number of compounds related compounds 132-133, can be obtained using similar techniques. The original connection 121 receive according to the methods described in U.S. patent 6046185.

Reaction scheme 13

In General, rafinirovaniyu using (EtO) P(O)CHF2and sitedisability (LDA) in THF gives compound 122. Tetrabutylammonium in THF removes the TBS-group that gives compound 123. Interaction with acetic anhydride in pyridine gives the connection 124. Treatment with 80% acetic acid removes the acetonide group, which leads to the formation of compound 125. Oxidation using NaIO4gives dialdehyde connection 126. The recovery of the sodium borohydride network connection 127. Interaction with acetic anhydride in pyridine gives the connection 128. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 129. Azide substitution nelfinavir with the use of sodium azide in DMF network connection 130. The restoration of the azide using PPh3and water in THF gives compound 131. The methanolysis of acetates network connection 132. Treatment with HCl leads to the formation of a salt of compound 133.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 122

Freshly prepared LDA (3.4 ml, 2.4 mmol) is added to at -78°C solution of F2CHPO(OEt)2(and 0.40 ml, 2.5 mmol) in dry THF (3 ml) in an argon atmosphere. After 20 minutes, add a solution of compound 121 (0,30 g to 0.63 mmol) in dry THF. The interaction is carried out for 1 hour, then slowly heated to a temperature OK usausa environment over a period of time of 2 hours and finally, heated to 60°C for 3 hours. The reaction mixture was cooled to ambient temperature, then quenched with 0.5 ml of water. The solution is diluted with EtOAc and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 4% EtOAc/hexane)to give compound 122 (0,145 g, 45%) as a white solid.

Synthesis of compound 123

A solution of compound 122 (0.65 g, 1.3 mmol), Bu4NF (2,7 ml of 1M solution in THF) and THF (10 ml) heated to 50°C for 3 hours. The reaction mixture was concentrated and the residue purified column chromatography on silica gel (mixture of 30% EtOAc/hexane)to give compound 123 (0.54 g, quantitatively).

Synthesis of compound 124

A solution of compound 123 (0.54 g, 1.3 mmol), acetic anhydride (to 0.24 ml, 2.5 mmol) and pyridine (5 ml) was stirred at ambient temperature for 3 days. The solution was diluted with EtOAc, washed with saturated salt solution, then dried over MgSO4filter and concentrate. The crude compound 124 used in the next stage without additional purification.

Synthesis of compound 125

A solution of compound 124 (crude product, 1.3 mmol) and 80% acetic acid (10 ml) heated to 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residual solvents del whom have joint by distillation with toluene. The crude compound 125 is used in the next stage without additional purification.

Synthesis of compound 126

The solution NaIO4(0.54 g, 2.5 mmol) and water (4 ml) are added to a solution of compound 125 (crude product, 1.3 mmol) and THF (10 ml). After 3 hours the solution was diluted with CH2Cl2and washed with saturated salt solution, then dried over MgSO4filter and concentrate. Raw connection 126 is used in the next stage without additional purification.

Synthesis of compound 127

Sodium borohydride (48 mg, 1.3 mmol) are added to a solution of compound 126 (crude product, 1.3 mmol), THF (6 ml) and MeOH (2 ml). After 3 hours the reaction mixture was quenched with water (15 ml) and the solution extracted using 2×15 ml EtOAc. The combined extracts dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 30% EtOAc/hexane)to give compound 127 (0,38 g, 75%) as a white solid.

Synthesis of compound 128

A solution of compound 127 (0,38 g, 0.95 mmol), acetic anhydride (and 0.09 ml, 1 mmol) and pyridine (5 ml) is stirred overnight at ambient temperature. The reaction mixture was diluted with water and extracted with 2×15 ml EtOAc. The combined extracts dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel, receiving the connection 128 (0.32 g, 76%) is the form of a white solid.

Synthesis of compound 129

A solution of compound 128 (0.32 g, to 0.72 mmol), MsCl (of 0.11 ml, 1.4 mmol) and pyridine (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was quenched with water and extracted with EtOAc (2×25 ml). The combined extracts washed with saturated salt solution, then dried over MgSO4filter and concentrate. The crude compound 129 use in the next stage without additional purification.

Synthesis of compound 130

A solution of compound 129 (crude product, to 0.72 mmol), NaN3(0,83 g, 3.6 mmol) and DMF (5 ml) is heated overnight to 55°C. the Reaction mixture was cooled to ambient temperature and diluted with water (10 ml), then extracted with toluene. Toluene solution is dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 20% EtOAc/hexane)to give compound 130 (0,30 g, 89%) as a white foam.

Synthesis of compound 131

A solution of compound 130 (of 0.13 g, 0.28 mmol), PPh3(0.15 g, 0,56 mmol), THF (3 ml) and water (0.3 ml) is stirred in an argon atmosphere for 3 days. The reaction mixture was concentrated, and the residue is purified column chromatography on silica gel (mixture of EtOAc/MeOH/Et3N 9:1:0.5), and receiving a connection 131 (98 mg, 79%) as a white solid.

Synthesis of compound 132

A solution of compound 131 (0.28 g, of 0.65 mmol), NaOMe (0.5 to ml% solution in MeOH) and MeOH (5 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and the residue purified column chromatography (mixture of EtOAc/MeOH/NH4OH 9:1:0,6)to give compound 132 (0.21 g, 89%) as a white solid.

Synthesis of compound 133

A solution of compound 132 (0.24 g, of 0.68 mmol), HCl (1,36 ml of 1M solution in Et2O) and MeOH (3 ml) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated and the residue proscout in EtOAc (5 ml). The obtained white solid is filtered and dried over night under high vacuum and temperature of 56°C, when receiving the connection 133 (0.21 g, 78%): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 358,14; C20H34F2NO2.

EXAMPLE 14

Connection 143, characterized by the connection according to the invention can be obtained according to the following reaction scheme 14. Any number of compounds related to compound 143, can be obtained using similar techniques. The original connection 121 receive according to the methods described in U.S. patent 6046185.

Reaction scheme 14

In General, rafinirovaniyu using (EtO)2P(O)CCl3and LDA in THF gives compound 134. Treatment with 80% acetic acid removes both the TBS group and the acetonide group, which leads to the formation of compound 135. Processing TBSCl and imida the I in DMF selectively protects one hydroxyl, what network connection 136. Oxidation using NaIO4gives dialdehyde connection 137. The recovery of the sodium borohydride gives compound 138. Processing TBSCl and imidazole in DMF selectively protects one hydroxyl that gives compound 139. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 140. Azide substitution nelfinavir with the use of sodium azide in DMF gives the connection 141. The restoration of the azide using PPh3and water in THF gives compound 142. Treatment with HCl removes the TBS group and leads to the formation of a salt of compound 143.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 134

CCl3P(O)(OEt)2(1,12 ml, 6 mmol) are added to at -78°C solution of freshly prepared LDA (6 mmol) in dry THF (20 ml) in an argon atmosphere. After 5 minutes add the connection 121 (954 mg, 2 mmol). The interaction lasts for 1 hour, then the reaction mixture is slowly heated to ambient temperature for 2 hours and finally stirred at ambient temperature overnight. The reaction is quenched with 0.5 ml of water. The solution was diluted with EtOAc and washed with water, then dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 3% EtOA/hexane), receiving a connection 134 (109 mg, 10%) as a pale yellow foam.

Synthesis of compound 135

A solution of compound 134 (288 mg, of 0.53 mmol) in 2 ml of THF and 80% acetic acid (8 ml) is heated to 50°C for 2 hours. The reaction mixture was concentrated under reduced pressure and the residual solvent removed by joint distillation with toluene. The crude compound 135 use in the next stage without additional purification.

Synthesis of compound 136

A solution of compound 135 (crude product, of 0.53 mmol) in DMF (3 ml), imidazole (108 mg, 1.6 mmol) and TBSCl (160 mg, 1.1 mmol) was stirred at ambient temperature for 2 hours. The reaction mixture is diluted with 50 ml of water and extracted with 100 ml EtOAc. The extracts are dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel, receiving a connection 136 (243 mg, 91%) as a pale yellow foam.

Synthesis of compound 137

The solution NaIO4(205 mg, 0.96 mmol) and water (2 ml) are added to a solution of compound 136 (243 mg, 0.48 mmol) and THF (6 ml). After 3 hours, the solution was diluted with CH2Cl2and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The crude compound 137 used in the next stage without additional purification.

Synthesis of compound 138

Sodium borohydride (36 mg, 0.96 mmol) are added to a solution of soy is inane 137 (crude product, 0.48 mmol), THF (3 ml) and MeOH (1 ml). After 3 hours the reaction is quenched with water (30 ml) and the solution extracted using 2×50 ml EtOAc. The combined extracts dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 30% EtOAc/hexane)to give compound 138 (201 mg, 83%) as a pale yellow oil.

Synthesis of compound 139

A solution of compound 138 (201 mg, 0.4 mmol), imidazole (136 mg, 2 mmol), TBSCl (110 mg, 0.73 mmol) and DMF (3 ml) is stirred for 1 hour at ambient temperature. The reaction mixture is diluted with 30 ml of water and extracted with 2×40 ml EtOAc. The combined extracts dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel, receiving a connection 139 (230 mg, 93%) as a pale yellow oil.

Synthesis of compound 140

A solution of compound 139 (216 mg, 0.35 mmol), MsCl (of 0.14 ml, 1.8 mmol) and pyridine (3.5 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with 30 ml of water and extracted with EtOAc (2×40 ml). The combined extracts washed with saturated salt solution, then dried over MgSO4filter and concentrate. The crude compound 140 is used in the next stage without additional purification.

Synthesis of compound 141

A solution of compound 140 (crude product, 0.35 mmol), NaN3(178 mg, 2.7 mmol) and DMF (3 ml) and n is grebaut over night at 55°C. The reaction mixture was cooled to ambient temperature, diluted with water (30 ml), then extracted with toluene. Toluene solution is dried over MgSO4filter and concentrate. The residue is purified column chromatography on silica gel (mixture of 5% EtOAc/hexane)to give compound 141 (202 mg, 89%) as a pale yellow oil.

Synthesis of compound 142

A solution of compound 141 (202 mg, 0.31 mmol), PPh3(320 mg, 1.2 mmol), THF (4 ml) and water (0.3 ml) is stirred under argon atmosphere overnight, then heated to 50°C for 4 hours. The reaction mixture is concentrated and the residue purified 2 g SCX ion-exchange resin (6 volumes of MeOH, 3 volume mixture of 5% ammonia/MeOH)to give compound 142 as a pale yellow foam (during this process partially lost TBS-group).

Synthesis of compound 143

A solution of compound 142 (crude product, 0.31 mmol), HCl (1 ml, 1M solution in Et2O), THF (3 ml) and water (0.5 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was kept at 4°C for 1 hour. The obtained white solid was filtered and washed with EtOAc, then dried over night under high vacuum and temperature of 56°C, when receiving the connection 143 (122 mg, 92%): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 390,06; C20H34Cl2NO2.

EXAMPLE 15

Connected to the I 157-158, typical compounds according to the invention can be obtained according to the following reaction scheme 15. The original connection 144 may be obtained according to the procedures outlined in U.S. patent 6046185. Any number of compounds related compounds 157-158, can be obtained using similar methods.

The reaction scheme 15

a) TBSCl, imidazole, DMF; (b) BH3·THF, H2O2, THF; c)n-Pr4N(RUO Li4), NMO, 4Å molecular sieves, CH2Cl2; d) MePPh3Br, KOtBu, THF; (e) n-Bu4NF, THF; (f) Ac2O, DMAP, pyridine; (g) 80% AcOH; (h) NalO4, THF, H2O; (i) NaBH4, MeOH, THF; (j) Ac2O, DMAP, pyridine; (k) MsCl, pyridine; (l) NaN3, DMF; (m) LiAlH4, THF; (n) 80% AcOH.

In General, the interaction connection 144 with TBSCl and imidazole in DMF gives compound 145. Hydroporinae using complex borane-tetrahydrofuran in THF, followed by oxidation under the action of NaOH and H2O2makes the connection 145 to the secondary alcohol compound 146. The oxidation catalytic amount of Tetra-n-propylammonium (TPAP and NMO in CH2Cl2network connection 147. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives the alkene 148. Tetrabutylammonium removes TBS group, Yes the flanged connection 149. Interaction with acetic anhydride in pyridine gives the connection 150. Treatment with 80% acetic acid removes the acetonide group, giving a connection 151. Oxidation using NaIO4gives dialdehyde connection 152. The recovery of the sodium borohydride gives compound 153. Interaction with acetic anhydride in pyridine selectively protects one hydroxyl, giving connection 154. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 155. Azide substitution nelfinavir with the use of sodium azide in DMF gives the connection 156. Interaction with lydialydia in THF restores azide and remove acetates, giving connection 157. Treatment with 80% acetic acid leads to the formation of AMMONIATING salt compound 158.

Synthesis of compound 145

A solution of compound 144 (10.0 g, 26,7 mol), TBSCl (6,22 g, 40,1 mmol) and imidazole (3,67 g, with 53.4 mmol) in dry DMF (178 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was diluted with water (250 ml) and extracted with toluene (3×250 ml). The combined toluene extracts are washed with saturated salt solution (250 ml), dried over MgSO4filter and concentrate. The crude compound 145 (12.5 g, 96%) use in the next stage without additional purification.

Synthesis of compound 146

To a solution of connection is drop-145 (12.5 g, 25.6 mmol) in dry THF (150 ml) is added a complex of borane-tetrahydrofuran (46 ml of 1,0M solution in THF)and the reaction mixture stirred at ambient temperature for 1 hour. Slowly add 10% aqueous NaOH (180 ml). The mixture is cooled with ice and slowly add 30% aqueous solution of H2O2(120 ml). The mixture was stirred at ambient temperature for 1 hour and then extracted with EtOAc (3×250 ml). The combined EtOAc extracts are washed with 10% aqueous Na2S2O3(200 ml), saturated salt solution (200 ml), dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of CH2Cl2/EtOAc, 95:5, then 85:15 hexane/EtOAc, 90:10, then 85:15)to give compound 146 (10.7 g, 83%) as a white solid.

Synthesis of compound 147

To a mixture of compound 146 (8,50 g, a 16.8 mmol), NMO (2,23 g, 18.5 mmol), 4 Å molecular sieves (5.3g) in CH2Cl2(85 ml) was added TPAP (152 mg, 0.42 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then filtered through silica gel filled in the funnel of porous glass (elute with hexane/EtOAc, 1:1) and concentrate to dryness. The crude product 147 use in the next stage without additional purification.

Synthesis of compound 148

The mixture KOtBu (5,69 g, 48.1 mmol) and MePPh3Br (17,2 g, 48.1 mmol) in THF (160 ml) is remediat at ambient temperature for one hour in an argon atmosphere, then type connection 147 (8,10 g, 16,1 mmol). The reaction mixture was stirred at ambient temperature for 4 hours, diluted with saturated salt solution (150 ml), extracted with EtOAc (3×200 ml). The combined EtOAc extracts are washed with saturated salt solution (200 ml), dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 96:4, then 10:1, then 4:1)to give compound 148 (6.3 g, 79%) as a white foam.

Synthesis of compound 149

A solution of compound 148 (6.3 g, 12.5 mmol) and n-Bu4NF (18.8 ml 1,0M solution in THF) in THF (125 ml) is heated to the boiling point under reflux in an argon atmosphere for 1 hour. The solvent is evaporated under reduced pressure, and the residue purified by chromatography on silica gel (hexane/EtOAc, 2:1 then 1:1)to give compound 149 (4.8 g, 99%) as a white solid.

Synthesis of compound 150

A solution of compound 149 (4.8 g, 12.4 mmol), acetic anhydride (2.3 ml, of 24.7 mmol) and DMAP (151 mg, 1,24 mmol) in pyridine (60 ml) was stirred at ambient temperature overnight. The reaction mixture was diluted with EtOAc (300 ml) and washed with saturated salt solution (2×100 ml). EtOAc layer is dried over MgSO4filter and concentrate. The crude compound 150 is used directly in the next stage.

Synthesis of compound 151

CME is ü connection 150 (crude product, 12.4 mmol) and 80% acetic acid (90 ml) was stirred at 40°C for 1 hour. The solution is concentrated and receiving connection 151, which is used in the next stage without additional purification.

Synthesis of compound 152

A solution of compound 151 (2.20 g, 5,63 mmol), NaIO4(2,43 g, 11.3 mmol), water (23 ml) and THF (46 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with CH2Cl2(200 ml) and washed with saturated salt solution (3×75 ml). CH2Cl2the layer is dried over MgSO4filter and concentrate the receiving connection 152, which is used in the next stage without additional purification.

Synthesis of compound 153

A solution of compound 152 (crude product, 5,63 mmol), NaBH4(538 mg, 14.1 mmol), THF (36 ml) and MeOH (12 ml) was stirred at 0°C for 10 minutes, then at ambient temperature for 2 hours. The mixture is cooled with ice and slowly add 80% acetic acid (23 ml). The solution was stirred at ambient temperature for 10 minutes, then diluted with EtOAc (200 ml) and washed with saturated salt solution (3×75 ml). EtOAc layer is dried over MgSO4, filtered and concentrated give crude compound 153, which is used in the next stage without additional purification.

Synthesis of compound 154

A solution of compound 153 (crude product, 5,63 mm is l), acetic anhydride (0,58 ml of 6.20 mmol) and DMAP (69 mg, 0,56 mmol) in pyridine (22 ml) was stirred at ambient temperature for 1.5 hours. The reaction mixture was diluted with EtOAc (200 ml) and washed with saturated salt solution (3×75 ml). EtOAc layer is dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 5:1, then 4:1, then 7:3)to give compound 154 (1.6 g, 65% from 5 furlongs).

Synthesis of compound 155

To a solution of compound 154 (1.60 g, 3,68 mmol) in pyridine (15 ml) add methanesulfonanilide (0,600 ml, 7,37 mmol)and the reaction mixture stirred at ambient temperature for 4 hours. The solution was diluted with EtOAc (200 ml) and washed with saturated salt solution (3×70 ml), then dried over MgSO4, filtered and concentrated give crude compound 155, which is used in the next stage without additional purification.

Synthesis of compound 156

A mixture of compound 155 (crude product, 3,68 mmol) and NaN3(479 mg, 7.36 mmol) in DMF (25 ml) is heated in an argon atmosphere at 60°C over night. After cooling, the reaction mixture was diluted with toluene (300 ml) and washed with saturated salt solution (3×75 ml), then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1 then 8:2)to give compound 156 (1.6 g, 95% from 2 article is Dios) as a white foam.

Synthesis of compound 157

A solution of LiAlH4(to 13.9 ml of 1,0M solution in THF) are added to a cooled with ice to a solution of compound 156 (1.60 g, a 13.9 mmol) in THF (35 ml) and stirred for 15 minutes. Stirring is continued at ambient temperature for 3 hours. The reaction mixture is cooled with ice, quenched with Na2SO4·10H2O and stirred for 10 minutes. Then the mixture is stirred further for 30 minutes at ambient temperature, diluted with EtOAc and then filtered. The filtrate is washed with saturated salt solution, dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH/H2O/Et3N, 70:20:10:0, then 70:20:10:3)to give compound 157 (0.8 g, 66%) as a white solid.

Synthesis of compound 158

A solution of compound 157 (0.800 to g, to 2.29 mmol) and 80% acetic acid (20 ml) is heated to 40°C for 1 hour and then concentrated. Residual solvent is removed by joint distillation with acetonitrile. The remainder proscout in diethyl ether and filtered, obtaining a connection 158 (700 mg, 75%) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 350,12; C22H40NO2.

EXAMPLE 16

Connection 163, characterized by the connection according to the invention, can b is to be obtained according to the following reaction scheme 16. Any number of compounds related to compound 163, can be obtained using similar techniques. The original connection 21 can be obtained according to the procedures described above in example 1.

Reaction scheme 16

a) 80% of the Asón, 55°C; (b) TBSCI, imidazole, DMF; (C) TsNHNH2, toluene, heated to the boiling temperature under reflux; (d) LDA, THF; (e) 80% AcOH.

In General, treatment with 80% acetic acid removes the TBS group, giving a connection 159. Interaction with TBSCl and imidazole in DMF gives the connection 160. Interaction with tailgatenation in toluene gives compound 161. Interaction with LDA gives the product of elimination, the connection 162. Treatment with 80% acetic acid removes the TBS-group, resulting in the formation of compound 163.

Synthesis of compound 159

A mixture of compound 21 (1.19 g, 2,46 mmol) and 80% acetic acid (20 ml) was stirred at 55°C for 3 hours, then concentrated. The residue is dissolved in toluene and concentrated three times. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH, 49:1)to give compound 159 (0,747 g, 93%) as a white foam.

Synthesis of compound 160

A mixture of compound 159 (0,747 g, 2,30 mmol), TBSCl (2,08 g of 13.8 mmol) and imidazole (1.88 g, 27.6 mmol) in dry DMF (12 ml) was stirred at ambient temperature for 3 hours, then diluted the ode (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers washed with saturated salt solution (2×30 ml), dried over anhydrous Na2SO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 7:3)to give compound 160 (1,11 g, 93%) as a white foam.

Synthesis of compound 161

A mixture of compound 160 (0,500 g, 0,904 mmol) and TsNHNH2(0,236 g of 1.27 mmol) in toluene (20 ml) is heated to the boiling temperature under reflux for 1 hour, then stirred at ambient temperature overnight, then heated to the boiling temperature under reflux for a further one hour.

After cooling, the mixture is concentrated. To the residue add CH2Cl2and the mixture is cooled with ice. The precipitate was separated by filtration, rinsing chilled CH2Cl2, then dried, obtaining a connection 161 (0,588 g, 90%) as a white solid.

Synthesis of compound 162

The LDA solution is produced by addingnBuLi (2 ml, 2.5m solution in hexane, 5.0 mmol) to a solution ofiPr2NH (of 0.77 ml, 5.5 mmol) in THF (4,23 ml) at 0°C, then stirred solution at 0°C for 30 minutes. To a solution of compound 161 (0,550 g, 0,763 mmol) in THF (4 ml) at ambient temperature is added a solution of LDA (6,4 ml 0,71M solution, 4.6 mmol). The reaction mixture was stirred at ambient temperature overnight. A mixture of razbam Aut saturated salt solution (50 ml) and extracted with EtOAc (3×50 ml). The combined organic layers washed with saturated salt solution (2×30 ml), dried over anhydrous Na2SO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 19:1, 9:1), receiving a connection 162 (0.062 g, 15%) as a yellow gel.

Synthesis of compound 163

A mixture of compound 162 (0,062 g, 0.11 mmol) and 80% acetic acid (2 ml) was stirred at ambient temperature for 3 hours and then concentrated. The residue is dissolved in toluene and concentrated. The residue is purified by chromatography on silica gel (EtOAc/MeOH, 19:1)to give compound 163 (0,022 g, 65%) as a pale yellow solid.

EXAMPLE 17

The 178 connection typical connection according to the invention can be obtained according to the following reaction scheme 17. Any number of compounds related to compound 178, can be obtained using similar techniques. The original connection 164 may be obtained according to the procedures outlined in U.S. patent 6046185.

The reaction scheme 17

a) MsCl, pyridine; (b) LiBr, DBU, DMF, 150°C; (c) NMO, OsO4H2O,tBuOH, THF; d) MePPh3Br, KOtBu, THF; (e) Ac2O, DMAP, pyridine; (f) 80% AcOH; (g) NalO4H2O, THF; (h) NaBH4, MeOH, THF; (i) TBSCl, imidazole, DMF; (j) MsCl, pyridine; (k) NaN3, DMF, 40°C l) K 2CO3H2O, MeOH; (m) PPh3H2O, THF, 40°C; n) 80% AcOH.

In General, the engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 165. Treatment with LiBr and DBU in DMF gives compound 166 as the elimination product. Ominirovaniya network connection 167. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 168. Interaction with acetic anhydride and DMAP in pyridine gives compound 169. Treatment with 80% acetic acid removes the acetonide group, giving connection 170. Oxidation using NaIO4gives dialdehyde connection 171. The recovery of the sodium borohydride gives the connection 172. Processing TBSCl and imidazole in DMF selectively protects one hydroxyl that gives compound 173. The engagement of the free hydroxyl using MsCl and pyridine gives mesylate connection 174. Azide substitution nelfinavir with the use of sodium azide in DMF gives compound 175. Basic hydrolysis of the acetates network connection 176. The restoration of the azide using PPh3and water in THF gives compound 177. Treatment with 80% acetic acid removes the TBS group and leads to the formation of a salt of the compound 178.

The following are typical examples of the compounds obtained as described above.

Sint is C connection 165

To a solution of compound 164 (4,00 g, 11,03 mmol) in pyridine (20 ml) was added MsCl (1,28 ml, 16,55 mmol). The reaction mixture was stirred at ambient temperature for one hour in an argon atmosphere, then diluted with EtOAc (100 ml), washed with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate to dryness. Raw received a connection 165 is used for the next interaction without additional purification.

Synthesis of compound 166

A mixture of crude compound 165 (2.00 g, of 4.54 mmol), literotica (0,59 g, for 6.81 mmol) and DBU (2 ml, 13,62 mmol) in dry DMF (50 ml) is heated to 150°C for 1.5 hours. After cooling, to the reaction mixture are added toluene (120 ml) and water (60 ml). The layers are separated and the aqueous phase is extracted with toluene (80 ml). The combined toluene solution was washed with saturated salt solution (100 ml), dried over anhydrous MgSO4and concentrate to dryness. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9/1)to give the purified compound 166 (1,09 g, 70%) as a white solid.

Synthesis of compound 167

To a solution of compound 166 (1,00 g, 2,90 mmol) in a mixture of THF (15 ml) and tert-BuOH (5 ml) is added water (2.5 ml), followed by addition of NMO (of 0.60 ml, 50% in H2O) and OsO4(0,89 ml, 4% in H2O). The reaction mixture was stirred at ambient temperature for 3 hours, C is the add a solution of Na 2S2O3(0.5 g) in water (15 ml). The reaction mixture is stirred for 20 minutes, then extracted with CH2Cl2(2×30 ml), washed with saturated salt solution (50 ml), dried over anhydrous MgSO4and concentrate to dryness. The residue is purified by chromatography on silica gel (hexane/EtOAc, 1:1)to give compound 167 (0.65 g, 60%) as a white solid.

Synthesis of compound 168

The mixture KOtBu (2,88 g of 32.9 mmol) and MePPh3Br (11.8 g, from 32.9 mmol) in THF (40 ml) was stirred at ambient temperature for 1 hour, then add the connection 167 (4.15 g, 11.0 mmol) in THF (10 ml) and the mixture was stirred at ambient temperature overnight. Add a saturated solution of NaHCO3(50 ml) and the mixture is stirred for 15 minutes, then diluted with water (50 ml) and extracted with EtOAc (4×50 ml). The combined organic layers washed with saturated salt solution (2×60 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc/MeOH, 1:1:0,02), obtaining the mixture containing the compound 168 (6,29 g) as a light brown foam.

Synthesis of compound 169

To a solution of the mixture containing the compound 168 (6,29 g, 11.0 mmol) and DMAP (0,128 g, 1.05 mmol) in pyridine (40 ml) is added acetic anhydride (4,15 ml, to 44.0 mmol). The mixture was stirred at ambient temperature over night the, then diluted with EtOAc (100 ml), washed with saturated solution of NaHCO3(50 ml), water (50 ml) and saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 1:3)to give compound 169 (4.12 g, 81% based on INT395) as a white foam.

Synthesis of compound 170

A mixture of compound 169 (1.97 g, to 4.28 mmol) and 80% acetic acid (15 ml) was stirred at ambient temperature for 3 hours and then concentrated. The residue is purified by chromatography on silica gel, receiving the connection 170 (1.35 g, 75%) as a yellow foam.

Synthesis of compound 171

A mixture of compound 170 (1.29 g, of 3.07 mmol) and NaIO4(1,32 g, 6,13 mmol) in THF (20 ml) and water (10 ml) was stirred at ambient temperature. After 1.5 hours, add 0.20 g (0,92 mmol) NaIO4. After 3 hours total reaction time the mixture was diluted with water (20 ml) and extracted with CH2Cl2(60 ml). The organic portion was washed with saturated salt solution (30 ml), dried over anhydrous MgSO4and concentrate give crude compound 171, which is used for subsequent interactions without additional purification.

Synthesis of compound 172

To a solution of crude compound 171 (of 3.07 mmol) in THF (15 ml) and MeOH (5 ml) at 0°C is added NaBH4(0,232 g, 6,14 mmol). Then mix paramesh what happens at 0°C for 15 minutes, and then at ambient temperature for 1.5 hours. The mixture is cooled to 0°C and slowly add 80% acetic acid (10 ml). The mixture was stirred at ambient temperature for 10 minutes, then diluted with EtOAc (80 ml) and washed with saturated salt solution (2×30 ml). The organic portion is dried over anhydrous MgSO4and concentrate, receiving the connection 172 (1,23 g, 95% (based on compound 170) as a pale yellow foam.

Synthesis of compound 173

A mixture of compound 172 (1,23 g, only 2.91 mmol), imidazole (0,600 g, 8,73 mmol) and TBSCl (0,585 g, 3,76 mmol) in DMF (15 ml) was stirred at ambient temperature for 35 minutes, then diluted with water (140 ml) and extracted with Et2O (4×50 ml). The combined organic layers washed with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane; hexane/EtOAc, 9:1, 4:1, 3:1), receiving a connection 173 (0,992 g, 64%) as a white foam.

Synthesis of compound 174

To a solution of compound 173 (0,990 g of 1.84 mmol) in pyridine (10 ml) add methanesulfonanilide (0,257 ml of 3.32 mmol). The reaction mixture was stirred at ambient temperature for 1.5 hours, then diluted with EtOAc (50 ml), washed with water (20 ml), then saturated salt solution (20 ml), dried over anhydrous MgSO4and concentrate, p is the best crude compound 174 (1,17 g, white foam), which is used for subsequent interactions without additional purification.

Synthesis of compound 175

A mixture of crude compound 174 (of 1.84 mmol) and NaN3(0,242 g, 3,68 mmol) in dry DMF (15 ml) was stirred at 40°C during the night. After cooling to ambient temperature the mixture is diluted with water (150 ml) and extracted with Et2O (4×50 ml). The combined organic layers washed with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane; hexane/EtOAc, 9:1, 4:1), receiving a connection 175 (0,708 g, 69% (based on compound 173) as a white foam.

Synthesis of compound 176

A mixture of compound 175 (0,397 g to 0.645 mmol), K2CO3(0,446 g of 3.23 mmol), water (5 ml) and MeOH (15 ml) was stirred at ambient temperature for 4 hours, then diluted with water (100 ml) and extracted with CH2Cl2(3×50 ml). The combined organic layers washed with saturated salt solution (2×50 ml), dried over anhydrous MgSO4and concentrate, receiving the connection 176 (0,284 g, 92%) as a white solid, which is used for subsequent interactions without additional purification.

Synthesis of compound 177

A mixture of compound 176 (0,284 g, 0,594 mmol), triphenylphosphine (0,472 g, 1.78 mmol), water (1 ml) and THF (15 ml) was stirred at 40°C in t is the significance of the night and then concentrated. The residue is purified by chromatography on silica gel (CH2Cl2; CH2Cl2/Me0H, 19:1, 12:1; CH2Cl2/Meon/Et3N, 9:1:0,3), receiving the connection 177 (0,241 g, 90%) as a white solid.

Synthesis of compound 178

A mixture of compound 177 (0,234 g, 0,518 mmol) and 80% acetic acid (20 ml) was stirred at ambient temperature overnight and then concentrated. The residue three times, dissolved in MeOH and concentrated. The deposition of a mixture of ACN/MeOH (20 ml) gives compound 178 (0,223 g, quantitative) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 338,26; C20H36NO3.

EXAMPLE 18

Connection 182-185, typical compounds according to the invention can be obtained according to the following reaction scheme 18. Any number of compounds related compounds 182-185, can be obtained using similar techniques. The original connection 95 receive according to the procedures described above in example 10.

The reaction scheme 18

a) KOtBu, Me2NCH2CH2PPh3Br, THF; (b) LAH, THF; c) 80% AcOH; (d) MePPh3Br, KOtBu, THF; (e) 80% AcOH.

In General, rafinirovaniyu using Me2NCH2CH2PPh3Br and KOtBu in THF gives soedinenie. Recovery lydialydia removes the acyl group, which leads to the formation of compound 180. Treatment with 80% acetic acid removes the cyclic group Catala that gives compound 181. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 182. Treatment with 80% acetic acid leads to the formation of a salt of compound 183.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 179

The mixture KOtBu (101 mg, 0.9 mmol) and (2-dimethylaminoethyl)triphenylphosphonium (373 mg, 0.9 mmol) in THF (10 ml) was stirred at ambient temperature for 1 hour and 20 minutes, Add a solution of compound 95 (154 mg, 0.3 mmol) in THF (5 ml)and the mixture stirred at ambient temperature overnight. Add saturated NH4Cl (1 ml)and the mixture was diluted with EtOAc (100 ml), washed with saturated NaHCO3saturated salt solution, dried and concentrated. The crude product is purified column chromatography (mixture of EtOAc/MeOH, 9:1)to give compound 179 (118 mg, 69%).

Synthesis of compound 180

To a stirred solution of compound 179 (118 mg, 0.21 mmol) in THF (10.5 ml) at 0°C is added dropwise 1M LAH in THF (0.63 ml, was 0.63 mmol). After 30 min at 0°C, the mixture was stirred at ambient temperature for 3 hours. The mixture is again cooled to 0°C and we use the t portions of solid Na 2SO4·10H2O (203 mg, to 0.63 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 45 min and then filtered through celite and washed with EtOAc. The filtrate is concentrated, and the thus obtained crude compound 180 is used in the next stage without additional purification.

Synthesis of compound 181

The solution previously obtained crude compound 180 in 80% HOAc (5 ml) was stirred at 40°C for 7 hours and 20 minutes the Solvent is removed by rotational evaporation and the residue purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 7:2:0,5:0,5), receiving a connection 181 (73 mg, 96% (based on compound 179).

Synthesis of compound 182

The mixture Ph3PMeBr (357 mg, 1.0 mmol) and KOtBu (112 mg, 1.0 mmol) in THF (5 ml) was stirred at ambient temperature for 1 hour and 20 minutes, Add a solution of compound 181 (73 mg, 0.2 mmol) in THF (3 ml)and the mixture stirred at ambient temperature overnight. The reaction is quenched with saturated NH4Cl (0.5 ml)and the mixture was diluted with EtOAc (150 ml), washed with saturated NaHCO3saturated salt solution, dried and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 7:2:0,5:0,5, then EtOAc/MeOH/Et3N of 7.5:2:0.5), and receiving a connection 182 (57 mg, 79%).

Synthesis of compound 183

A solution of compound 182 (57 mg, 0.16 mmol)in 80% HOAc (1 ml) was stirred at 40°C for several minutes and then the solvents are removed by rotational evaporation and the residue is dried in vacuum. The product is dissolved in a small amount of MeOH and treated with a small amount of diethyl ether. Salt is separated by precipitation and dried in vacuum, obtaining the compound 183 (68 mg, Quant.) in the form of a light powder. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 362,09; C23H40NO2.

Synthesis of compound 184

Using the techniques described for the synthesis of compound 183, except referirovanija (4-chlorbenzyl)triphenylmethylchloride receive connection 184 (34 mg) in 51%yield, based on connection 95. Other significant exceptions include the use of HCl in MeOH for impact on stage disilylgermane/demetalizarea (when receiving intermediate compounds similar to the compound 181) and enable the subsequent stage of the hydrogenation of the double bond. The intermediate connection similar to the connection 181, treated with a catalytic amount of 10% Pd on coal in THF and MeOH in the atmosphere of H2. The catalyst is separated by filtration, and the filtrate concentrated. The crude intermediate compound is treated with 80% HOAc, receiving the acetate salt of compound 184: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 434,68; C26H41ClNO2.

Synthesis of compound 185

Stage 1: synthesis of (3-pyridylmethyl)triphenylmethylchloride

To stir a solution of 3-(chloromethyl)pyridinecarboxamide (of 5.17 g, to 31.5 mmol) in water (8 ml) is added by portions K2CO3(4,34 g of 31.5 mmol). The resulting mixture was thrice extracted with diethyl ether. The extracts are combined and washed twice with saturated salt solution, dried and concentrated. The residue (3.25 g, 25.5 mmol) is dissolved in xylene (30 ml) and add Ph3P (6,70 g, 25.5 mmol). The mixture is heated to 133-134°C overnight and then cooled to ambient temperature. The solid product was filtered, washed with toluene and dried in vacuum, obtaining (3-pyridylmethyl)triphenylphosphorane (5,86 g, 48%) as a pinkish solid.

Stage 2: synthesis of compound 185

Using the methodology described above for the synthesis of compound 184, except replacing the (3-pyridylmethyl)triphenylmethylchloride, compound 185 (19 mg) obtained in yield of 20%, based on the connection 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 384,15; C25H38NO2.

EXAMPLE 19

Compound 189 typical connection according to the invention can be obtained according to the following reaction scheme 19. Any number of compounds related to compound 189, can be obtained using similar techniques. The original connection 93 can be obtained according to the procedures described above in example 10.

The reaction scheme 19

In the General terms catalytic hydrogenation of the double bond gives compound 186. Recovery lydialydia removes the acyl group, giving the connection 187. Treatment with 80% acetic acid removes both the TBS-group and a cyclic group of ketala, giving connection 188. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 189.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 186

A mixture of compound 93 (98 mg, 0,19 mmol), 10% Pd/C (10 mg) in EtOH (4 ml) stirred in an atmosphere of H2(1 ATM) overnight. The catalyst was removed by filtration, and the filtrate concentrated. The crude compound 186 (98 mg) used in the next stage without additional purification.

Synthesis of compound 187

To a stirred solution of compound 186 (98 mg, 0,19 mmol) in THF (9 ml) at 0°C is added dropwise 1M LAH in THF (0,86 ml, 0.86 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 6 hours. The mixture is again cooled to 0°C and add portions of Na2SO4·10H2O (275 mg, 0.86 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then filtered through celite. The filtrate is concentrated, and the crude product is purified column chromatography (hexane/EtOAc, 1:1)to give compound 187.

Synthesis of compound 188

The solution obtained earlier connection 187 in 80% HOAc (5 ml) was stirred at 40°C for 7.5 hours. The solvents are removed by rotational evaporation, and the residue is purified column chromatography (EtOAc/hexane, 8:2, then 9:1)to give compound 188 (35 mg, 59% (based on compound 186).

Synthesis of compound 189

The mixture Ph3PMeBr (196 mg, 0.55 mmol) and KOtBu (62 mg, 0.54 mmol) in THF (5 ml) was stirred at ambient temperature for 1.5 hours. Add a solution of compound 188 (35 mg, 0.11 mmol) in THF (2 ml)and the mixture stirred at ambient temperature overnight. The reaction is quenched with saturated NH4Cl (1 ml)and the mixture was diluted with EtOAc (150 ml), washed with saturated salt solution, dried and concentrated. The residue is purified column chromatography (mixture of EtOAc/hexane, 7:3)to give compound 189 (37 mg, Quant.). LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 324,74; C20H38NO2.

EXAMPLE 20

Connection 192, characterized by the connection according to the invention can be obtained according to the following reaction scheme 20. Any number of compounds related to compound 192, can be obtained using similar methods.

The reaction scheme 20

In General, catalyzed by palladium combination of olefin 93 with Ari is a halide 4-BrC 6H4OEt network connection 190. Treatment with 80% acetic acid removes both the TBS-group and a cyclic group of ketala, giving connection 191. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 192.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 190

A mixture of compound 93 (100 mg, 0.2 mmol), 4-bromophenetole (0.04 ml, 0.28 mmol), three(orthotopic)phosphine (12 mg, 0.04 mmol), Pd(OAc)2(2.3 mg, 0.01 mmol), Et3N (0.06 ml) in acetonitrile (2 ml) is heated to 80°C during the night. The solvents were removed and the residue purified column chromatography (hexane/EtOAc, 9:1, then 85:15)to give compound 190 (61 mg, 49%).

Synthesis of compound 191

A solution of compound 190 in 80% HOAc (5 ml) was stirred at 40°C for 7.5 hours. The solvents are removed by rotational evaporation, and the residue is purified column chromatography (EtOAc/hexane, 8:2)to give compound 191 (27 mg, 60%).

Synthesis of compound 192

The mixture Ph3PMeBr (114 mg, 0.32 mmol) and KOtBu (36 mg, 0.32 mmol) in THF (3 ml) was stirred at ambient temperature for 1.5 hours. Add a solution of compound 191 (27 mg, 0,064 mmol) in THF (1 ml) and the mixture was stirred at ambient temperature overnight. The reaction is quenched with saturated NH4Cl (1 ml) and the mixture was diluted with EtOAc (150 ml), protivotumanki salt solution, dry and concentrate. The residue is purified column chromatography (mixture of EtOAc/hexane, 1:1)to give compound 192 (13 mg, 43%). LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OSA 3:7 water and MeCN) 484,69; C30H46NO4.

EXAMPLE 21

Connection 195-201, typical compounds according to the invention can be obtained according to the following reaction scheme 21. Any number of compounds related compounds 195-201, can be obtained using similar techniques. The original connection 85 can be obtained according to the procedures described above in example 9.

The reaction scheme 21

In General, catalyzed TPAP oxidation of free alcohol gives compound 193. Rafinirovaniyu using (2-pyridylmethyl)triphenylmethylchloride and KOtBu in THF gives compound 194. Recovery lydialydia removes acetyl groups, which makes the connection 195.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 193

To a solution of compound 85 (11.6 g, 28.4 mmol) in CH2Cl2(100 ml) at 0°C is added TPAP (1.50 g, 4.26 deaths mmol) and NMO (9,98 g of 85.2 mmol). The mixture is stirred at 0°C for 10 minutes, then at ambient temperature for 3 hours. The mixture is concentrated to dryness, and the residue is purified of chromatogra what s on silica gel (hexane/EtOAc, 3:2, 1:1; EtOAc)to give compound 193 (8,61 g, 75%) as a white solid.

Synthesis of compound 194

Stage 1. Synthesis of (2-pyridylmethyl)triphenylmethylchloride

To a stirred solution of 2-(chloromethyl)pyridinecarboxamide (8.0 g, 48.8 mmol) in water (20 ml) is added by portions K2CO3(6,74 g of 48.7 mmol). The resulting mixture was extracted four times with diethyl ether. The extracts are combined and washed twice with saturated salt solution, dried and concentrated. The residue (5,78 g of 45.3 mmol) dissolved in 1,4-dioxane (19 ml) and add Ph3P (11,89 g of 45.3 mmol). The mixture is heated to 110°C overnight and then cooled to ambient temperature. The solid product was filtered, washed with diethyl ether and dried in vacuum, obtaining (2-pyridylmethyl)triphenylphosphorane (15,78 g, 83%) as a light solid.

Stage 2. Synthesis of compound 194

The mixture KOtBu (132 mg, 1.2 mmol) and (2-pyridylmethyl)triphenylmethylchloride (460 mg, 1.2 mmol) in THF (15 ml) was stirred at ambient temperature for 1.5 hours. Add a solution of compound 193 (195 mg, 0.48 mmol) in THF (5 ml) and the mixture was stirred at ambient temperature overnight. Add saturated NH4Cl (1 ml) and the mixture was diluted with EtOAc (150 ml), washed with saturated salt solution, dried and concentrated. The crude product is purified column x is omatography (a mixture of EtOAc/hexane, 1:1)to give compound 194 (207 mg, 90%).

Synthesis of compound 195

To a stirred solution of compound 194 (207 mg, 0.43 mmol) in THF (15 ml) at 0°C is added dropwise 1M LAH in THF (1.9 ml, 1.9 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was again cooled to 0°C and add portions of Na2SO4·10H2O

(623 mg, 1.9 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH, 95:5)to give compound 195 (135 mg, 79%): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 396,43; C26H38NO2.

Synthesis of compound 196

Using the techniques described for the synthesis of compounds 195, except referirovanija (3-pyridylmethyl)triphenylmethylchloride receive connection 196 (90 mg) with a yield of 61%, based on the connection 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 396,17; C26H38NO2.

Synthesis of compound 197

Using the techniques described for the synthesis of compounds 195, except referirovanija hexyltrichlorosilane receive connection 197 (Z of the measures 124 mg) with a yield of 85%, based on the connection 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 405,86; C26H48NO2.

The synthesis of compounds 198 and 201

Using the techniques described for the synthesis of compounds 195, except referirovanija (3-benzyloxyphenyl)triphenylphosphorane, the connection 198 (Z-isomer, 114 mg, 68%) and the connection 201, the product dibenzylamine (Z-isomer, 10 mg, 7%), receive, based on the connection 193. Compound 198: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 452,57; C30H44O3. Compound 201: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 363,15; C23H39O3.

Synthesis of compound 199

Using the techniques described for the synthesis of compounds 195, except referirovanija (2-dimethylaminoethyl)triphenylphosphonium and obtain a salt with acetic acid, the compound 199 (Z-isomer, 93 mg) obtained in yield 57%, based on the connection 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 376,06; C24H42NO2.

Synthesis of compound 200

Using the techniques described for the synthesis of compounds 195, except referirovanija (4-chlorbenzyl)triphenylmethylchloride, the connection 200 (118 mg) get with what hodom 74%, based on the connection 193.

EXAMPLE 22

Connection 203, characterized by the connection according to the invention can be obtained according to the following reaction scheme 22. Any number of compounds related to compound 203, can be obtained using similar techniques. The original connection 193 can be obtained according to the procedures described above in example 21.

The reaction scheme 22

In General, rafinirovaniyu using methyl(triphenylphosphonium)acetate in THF gives compound 202. Recovery lydialydia ester group gives compound 203.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 202

A mixture of compound 193 (300 mg, of 0.74 mmol) and methyl(triphenylphosphonium)acetate (742 mg, 2.2 mmol) in THF (30 ml) was stirred at 67°C overnight and then at 80°C for one day. The solvent is removed and the residue purified column chromatography (hexane/EtOAc, 8:2)to give compound 202 (328 mg, 96%).

Synthesis of compound 203

To a stirred solution of compound 202 (179 mg, 0,39 mmol) in THF (15 ml) at 0°C is added dropwise 1M LAH in THF (2.2 ml, 2.2 mmol). After 5 min at 0°C, the mixture was stirred at ambient temperature for 6 hours and 10 minutes, the Reaction mixture was again cooled d is 0°C and add portions of Na 2SO4·10H2O (715 mg, 2.2 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH, 95:5)to give compound 203 (66 mg, 49%): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 331,06; C22H35O2.

EXAMPLE 23

Connection 210-212 can be obtained according to the following reaction scheme 23. Any number of compounds related compounds 210-212 may be obtained using similar techniques. The original connection 90 can be obtained according to the procedures described above in example 10.

The reaction scheme 23

a) NMO, TPAP, CH2Cl2; (b) (4 Chlorobenzyl)triphenylphosphonium, KOtBu, THF; (C) LiAlH4, THF; (d) 80% AcOH, MeOH, THF, 40°C; e) MePPh3Br, KOtBu, THF.

In General, catalyzed TPAP oxidation of free alcohol network connection 205. Rafinirovaniyu using (4-chlorbenzyl)triphenylmethylchloride and KOtBu in THF gives compound 206 and E-isomeric compound 207. Recovery lydialydia removes the acyl group that network connection 208. Processing 80% vinegar is Oh acid removes the TBS-group and a cyclic Catala, what network connection 209. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 210.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 205

To a solution of compound 204 (at 8.60 g, 16.4 mmol) in CH2Cl2(100 ml) at 0°C is added TPAP (0,86 g, 2.5 mmol) and NMO (USD 5.76 g, and 49.2 mmol). The mixture is stirred at 0°C for 5 minutes, then at ambient temperature. After 3 hours add TPAP (0,29 g, 0.83 mmol) and NMO (1.92 g, 16.4 mmol) and continue stirring. After a total reaction time of 5.5 hours, the mixture is concentrated to dryness. The residue is purified by chromatography on silica gel (hexane/EtOAc, 49:1, 19:1, 9:1, 4:1), receiving a connection 205 (5,13 g, 60%) as a white solid.

The synthesis of compounds 206 and 207

The mixture KOtBu (0,136, 1.15 mmol) and (4-chlorbenzyl)triphenylmethylchloride (0,496 g, 1.15 mmol) in THF (10 ml) was stirred at ambient temperature for 1 hour, then add a solution of compound 205 (0.20 g, 0.38 mmol) in THF (5 ml). The reaction mixture was stirred at ambient temperature overnight, then quenched with saturated solution of NH4Cl (1 ml), diluted with EtOAc (150 ml), washed with saturated salt solution (2×25 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, receiving a connection 206 (0,093 g, 39%) as a colourless glass mass and the connection 207 (0.126 g, 53%) as a colourless glass mass.

Synthesis of compound 208

To a solution of compound 206 (0.15 mmol) in THF (10 ml) is added LiAlH4(0,59 ml of 1M solution in THF, 0.59 mmol). The mixture was stirred at ambient temperature overnight, then quenched with Na2SO4·10H2O and stirred for 30 minutes. The mixture is filtered, rinsing EtOAc, and concentrated to dryness give crude compound 208 (0,089 g, colorless glass mass), which is used in the next stage without additional purification.

Synthesis of compound 209

The crude compound 208 (0.15 mmol) is dissolved in 80% acetic acid (10 ml) with THF (1 ml) and MeOH (1 ml) and stirred at 40°C for 4.5 hours, then at ambient temperature overnight. The mixture is concentrated, give crude compound 209 (0,074 g) as a colorless glass mass, which is used in the next stage without additional purification.

Synthesis of compound 210

The mixture KOtBu (0,122 g of 1.03 mmol) and MePPh3Br (0,368 g of 1.03 mmol) in THF (5 ml) was stirred at ambient temperature for 1 hour, then add a solution of compound 209 (0,074 g, 0,17 mmol) in THF (5 ml). The reaction mixture was stirred at ambient temperature overnight, then quenched with saturated RA is tworoom NH 4Cl (1 ml), diluted with EtOAc (100 ml), washed with saturated salt solution (2×20 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 3:1, 1:1), receiving a connection 210 (0.035 g, 21% (based on connection 205) as a white solid after concentration of CH2Cl2. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 411,14; C27H36ClO.

Synthesis of compound 211

Using the procedure described for the synthesis of compounds 208, the connection 207 (0.126 g, 0,200 mmol) is subjected to interaction with LiAlH4(0,80 ml of 1M solution in THF, 0.80 mmol)to give the alcohol intermediate (0,121 g, colorless glass mass). Using the procedure described for the synthesis of compound 209, alcohol intermediate compound (0.20 mmol) is transformed into ketone intermediate compound (0.104 g g, colorless glass mass). Using the procedure described for the synthesis of compound 210, except that used a different solvent system by chromatography on silica gel (hexane/EtOAc, 4:1, 7:3, 3:2, 1:1), ketone intermediate compound (0.20 mmol) turn in alkene. The concentration of CH2Cl2network connection 211 (0,058 g, 36% (based on connection 205) as a light yellow solid: LC/MS (direct injection, electrorash ylenia +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 411,09; C27H36ClO.

Synthesis of compound 212

Using the procedure described for the synthesis of compound 206, except that used a different solvent system by chromatography on silica gel (mixture of EtOAc/MeOH, 9:1; EtOAc/MeOH/Et3N, 9:0,75:0,25), compound 205 (0.20 g, 0.38 mmol) is subjected to interaction with (2-dimethylaminoethyl)triphenylphosphonium (0,485 g, 1.15 mmol)to give amine intermediate connection (0,204 g, 93%, yellow oil). Using the procedure described for the synthesis of compounds 208, except that after 2.5 hours add 0,76 ml solution of LiAlH4(1M in THF, from 0.76 mmol) and the total reaction time is 5.5 hours, the amine intermediate compound (0.35 mmol) is subjected to interaction with LiAlH4(0,76 ml of 1M solution in THF, from 0.76 mmol)to give the alcohol intermediate compound (0,203 g, colorless glass mass). Using the procedure described for the synthesis of compound 209, except that THF and MeOH is not added and the reaction mixture is not heated, the alcohol intermediate compound (0.35 mmol) is transformed into ketone intermediate compound in the form of salts with acetic acid (0,189 g, colorless glass mass). Using the procedure described for the synthesis of compound 210, except that they use 0,331 g (2,80 mmol) KOtBu, of 1.00 g (2,80 mmol) MePPh33N, 9:0,9:0,1, 9:0,75:0,25), ketone intermediate compound (0.35 mmol) turn in alkene. A mixture of alkene, 80% AcOH (1 ml) and MeOH (5 ml) concentrate by rotational evaporation. Deposition of Et2O network connection 212 (0,072 g, 43% (based on connection 205) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 375,98; C24H42NO2.

EXAMPLE 24

Connection 219-222, typical compounds according to the invention can be obtained according to the following reaction scheme 24. Any number of compounds related compounds 219-222, may be obtained using similar techniques. The original connection 35 can be obtained according to the procedures described above in example 3.

The reaction scheme 24

a) AC2Oh, DMAP, pyridine; b) HCl, H2O, THF, 60-65°C; (C) MePPh3Br, KOtBu, THF; (d) TBAF, THF, 70°C; (e) NMO, TPAP, CH2Cl2; (f) (2-dimethylaminoethyl)triphenylphosphonium, KOtBu, THF; (g) LiAlH4, THF; (h) 80% AcOH, MeOH.

In General, the interaction with acetic anhydride and DMAP in pyridine gives compound 213. Treatment with HCl and water in THF removes the group is ilichevskogo Catala, what network connection 214. Rafinirovaniyu using MePPh3Br and KOtBu in THF gives compound 215. Tetrabutylammonium removes the tert-butyldiphenylsilyl group, which leads to the formation of compound 216. Catalyzed TPAP oxidation of free alcohol gives compound 217. Rafinirovaniyu using (2-dimethylaminoethyl)triphenylphosphonium and KOtBu in THF gives compound 218. Recovery lydialydia removes acetyl groups, which makes the connection 219. Treatment with 80% acetic acid leads to the formation of salt connection 220.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 213

To a solution of compound 35 (67 mmol) in pyridine (150 ml) at 0°C add DMAP (1.0 g, 8.2 mmol) and acetic anhydride (12,7 ml, 134 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction is quenched with water and the reaction mixture was diluted with EtOAc, then concentrated to dryness, to give crude compound 213, which is used for subsequent interactions without additional purification.

Synthesis of compound 214

A mixture of compound 213 (67 mmol), HCl (20 ml), water (50 ml) and THF (150 ml) was stirred at 60-65°C for 2 hours, then cooled to ambient temperature. With K2CO3the pH value of the mixture is avodat to pH=7,0-8,0, then add water and CH2Cl2. The mixture is dried over anhydrous MgSO4and concentrate. Precipitation from EtOAc gives the crude mixture containing the compound 214 (white solid), which is used in the next stage without additional purification.

Synthesis of compound 215

The mixture KOtBu (9,43 g of 83.9 mmol) and MePPh3Br (30.0 g, of 83.9 mmol) in THF (200 ml) was stirred at ambient temperature, then add raw connection 214 (67 mmol) and the mixture was stirred at ambient temperature for another 2 hours. The reaction is quenched with chilled water and the reaction mixture extracted with EtOAc. Organic part concentrate to dryness, then the residue is treated with a mixture of hexane/EtOAc (4:1), filtered, and the filtrate concentrated to dryness. The residue is dissolved in pyridine and added dropwise acetic anhydride. The mixture was stirred at ambient temperature for 2 hours, then quenched with water and extracted with EtOAc. Organic part concentrate to dryness give crude compound 215, which is used in the next stage without additional purification.

Synthesis of compound 216

A mixture of crude compound 215 (67 mmol) and TBAF (30 ml of 1M solution in THF, 30 mmol) in THF (80 ml) was stirred at ambient temperature for 2 hours, then at 70°C for 1 hour. The mixture is concentrated, and the residue purified by chromatography on silica gel, recip what I connection 216 (6,12 g, 22% (based on compound 35) as a white solid.

The synthesis of compound 217

To a solution of compound 216 (6.0 g, 15 mmol) in CH2Cl2(50 ml) was added TPAP (0,052 g, 0.15 mmol) and NMO (4.4 g, 38 mmol). The mixture was stirred at ambient temperature. After 2 hours add an additional amount of TPAP (0,052 g, 0.15 mmol) and continue stirring. After 3 hours total reaction time the mixture is concentrated. The residue is purified by chromatography on silica gel (hexane/EtOAc, 9:1)to give compound 217 (2.9 g, 48%) as a white solid.

Synthesis of compound 218

The mixture KOtBu (of) 0.157, of 1.33 mmol) and (2-dimethylaminoethyl)triphenylphosphonium (0,563 g of 1.33 mmol) in THF (10 ml) was stirred at ambient temperature for 1 hour, then add a solution of compound 217 (0.20 g, 0.49 mmol) in THF (5 ml). The reaction mixture was stirred at ambient temperature overnight, then quenched with saturated solution of NH4Cl (1 ml), diluted with EtOAc (150 ml), washed with saturated salt solution (2×25 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH, 9:1; EtOAc/MeOH/Et3N, 9:0,75:0,25), receiving the connection 218 (0,197, 88%) as a white foam.

Synthesis of compound 219

To a solution of compound 218 (0,197 g, 0,428 mmol) in THF (10 ml) is added LiAlH4 (0,98 ml of 1M solution in THF, 0.98 mmol). The mixture was stirred at ambient temperature for 4 hours, then quenched with Na2SO4·10H2O and stirred for 30 minutes. The mixture is filtered, rinsing EtOAc, and concentrated to dryness. The residue is purified by chromatography on silica gel (mixture EtAc/MeOH, 9:1; a mixture of EtOAc/MeOH/Et3N, 9:0,75:0,25, 9:0,5:0,5), receiving a connection 219 in the form of a white solid, which is used for further interaction.

Synthesis of compound 220

A mixture of compound 219, 80% AcOH (1 ml) and MeOH (5 ml) concentrate by rotational evaporation. The concentration of CH2Cl2network connection 220 (0,154 g, 72% (based on connection 217) as a white foam: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 375,96; C24H42NO2.

The synthesis of compounds 221 and 222

Using the procedure described for the synthesis of compound 218, with the exception that a different system of solvents used in chromatography on silica gel (hexane/EtOAc, 3:1, 3:2), compound 217 (0.20 g, 0.49 mmol) is subjected to interaction with (3-pyridylmethyl)triphenylmethylchloride (0,519 g of 1.33 mmol)to give a mixture alkenovich intermediate compounds of € 0.195 g, colorless glass mass). Using the procedure described for the synthesis of compound 219, with the exception that the reaction time of the composition is scored for 3 hours and other systems of solvents used in chromatography on silica gel (mixture of EtOAc/MeOH and

CH2Cl2/acetone), the mixture alkenovich intermediates (0.41 mmol) is subjected to interaction with LiAlH4(0,81 ml of 1M solution in THF, 0.81 mmol)to give compound 221 (Z-isomer) (0.037 g, 19% (based on connection 217) as a white foam, after concentration of CH2Cl2and the connection 222 (E-isomer) (0,047 g, 24% (based on connection 217) as a white solid after precipitation from Et2O. Compound 221: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 395,98; C26H38NO2. Compound 222: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 395,96; C26H38NO2.

EXAMPLE 25

Connection 225, characterized by the connection according to the invention can be obtained according to the following reaction scheme 25. Any number of compounds related to compound 225, can be obtained using similar techniques. The original connection 76 may be obtained according to the methods presented above reaction scheme 8.

The reaction scheme 25

In General, the interaction of compound 76 with triphenylphosphine and water in THF restores azide group that gives compound 223. The amino group is transformed into sulfonamidnuyu connection 224 using MsCl and triethylamine in CH2Cl2 . Treatment with potassium carbonate in methanol and water gives compound 225.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 223

A solution of compound 76 (6,00 g, a 13.9 mmol), PPh3(5,85 g of 22.3 mmol), water (and 3.72 ml, 206 mmol) and THF (100 ml) is heated overnight to 40°C. the Reaction mixture was concentrated, and the residue purified by chromatography on silica gel (mixture of EtOAc/MeOH/Et3N 90:10, then 90:10:3)to give compound 223 (4.59 g, 81%) as a white foam.

Synthesis of compound 224

A solution of compound 223 (250 mg, 0,616 mmol), MsCl (72 μl, of 0.92 mmol), Et3N (258 μl, of 1.84 mmol) and CH2Cl2stirred at ambient temperature in an argon atmosphere for 1.5 hours. The reaction is quenched with saturated solution of NaHCO3(3 ml) and water (2 ml). The solution is further diluted with water (5 ml) and extracted with 100 ml EtOAc. EtOAc solution washed with water and saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc 3:1, then 1:1)to give compound 224 (310 mg, quantitative) as a white foam.

Synthesis of compound 225

A solution of compound 224 (223 mg, 0.46 mmol), K2CO3(255 mg, of 1.84 mmol), water (3 ml) and methanol (6 ml) is heated to the boiling temperature under reflux for 2 hours. The reaction mixture conc tryout, then dissolved in water and CH2Cl2and extracted with CH2Cl2(240 ml). CH2Cl2the solution is washed with water and saturated salt solution, then dried over MgSO4filter and concentrate.

The residue is purified by chromatography on silica gel (mixture of CH2Cl2/MeOH 100:0, then 19:1 then 9:1). The remainder of the purified fractions of the concentrate from the minimum amount of MeOH and acetonitrile (5 ml)to give compound 225 (132 mg, 72%) as a white powder: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 381,90; C21H35NO3S, 363,85; C21H33NO2S.

EXAMPLE 26

Connection 227, characterized by the connection according to the invention can be obtained according to the following reaction scheme 26. Any number of compounds related to compound 227, can be obtained using similar techniques. The original connection 77 can be obtained according to the procedures described above in example 8.

The reaction scheme 26

In General, the interaction of compound 77 with acetic anhydride and DMAP in pyridine leads to acylation of the hydroxyl and amino groups, which gives the connection 226. Selective recovery of acetates by lydialydia network connection 227.

The following are typical examples of the compounds obtained as is shown above.

Synthesis of compound 226

A solution of compound 77 (208 mg, 0,647 mmol), acetic anhydride (214 μl, of 2.27 mmol), DMAP (17 mg) and pyridine (5 ml) is stirred overnight at ambient temperature. The reaction is quenched with saturated salt solution and the reaction mixture extracted with EtOAc. EtOAc solution was washed with saturated salt solution, then dried over MgSO4filter and concentrate. Residual solvent is removed by joint distillation with toluene. The residue is purified by chromatography on silica gel (EtOAc)to give compound 226 (235 mg, 81%).

Synthesis of compound 227

A solution of LiAlH4(of 1.57 ml of 1,0M solution in THF) is added to cooled with ice to a solution of compound 226 (235 mg, 0,525 mmol) in THF (10 ml). After 10 minutes the dissolution continued at ambient temperature for another 2 hours. The reaction is quenched with Na2SO4·10H2O. After 1 hour add MgSO4and the solution is filtered and concentrated. The resulting crystalline solid proscout, consistently rubbing with Et2O, CH2Cl2, EtOAc and MeOH, which gives compound 227 (128 mg, 67%) as white solid powder. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 386,48; C22H37NNaO3.

EXAMPLE 27

Connections 229 and 231-233, typical compounds according to the invention can be obtained according to the following the respective reaction scheme 27. Any number of compounds related compounds 229 and 231-233, can be obtained using similar techniques. The original connection 223 can be obtained according to the procedures described above in example 25.

The reaction scheme 27

In General, the interaction of amino compounds, such as compound 223, with benzoyl chloride gives the amide compound 230. The restoration of the amide and the acetates lydialydia network connection 231. Treatment with 80% acetic acid leads to the formation of salt 232 connection.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 230

A solution of compound 223 (405 mg, 1.00 mmol), benzoyl chloride (0.17 ml of 1.46 mmol), DMAP (15 mg), pyridine (4 ml) and CH2Cl2(6 ml) is stirred for 2 hours at ambient temperature. The reaction mixture was diluted with EtOAc (250 ml) and washed with saturated solution of NaHCO3and saturated salt solution, then dried over NaSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/hexane 45:55)to give compound 230 (490 mg, 96%) as a colourless syrup.

Synthesis of compound 231

A solution of LiAlH4(6×4.8 ml 1,0M solution in THF) add 3 days to the solution of compound 230 (490 mg, 0.96 mmol) in THF (20 ml) and heated to the andsinging under reflux in an argon atmosphere. The reaction mixture is cooled with ice and quenched with Na2SO4·10H2O. After 20 minutes the solution is filtered and concentrated. The residue is purified by chromatography (mixture of EtOAc/MeOH 95:5)to give compound 231 (395 mg, 39%) as a crystalline solid.

Synthesis of compound 232

A solution of compound 231 (150 mg, 0.36 mmol) and 80% AcOH is heated to 40°C for 10 minutes. The solution is concentrated and receiving connection 232 (162 mg, 94%) as a white foam. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 412,16; C27H42NO2.

Synthesis of compound 233

Using the techniques described for the synthesis of compound 232, except for the replacement on cyclopropanecarboxylate, the connection 233 (231 mg) obtained as white solid with a yield of 67%, based on the connection 223: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 376,35; C24H42NO2.

Synthesis of compound 229

Using the techniques described for the synthesis of compound 232 connection 229 (549 mg) obtained as a glassy solid with a yield of 36%, based on connection 226. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 350,63; C22H40NO2.

EXAMPLE 28

Connection 235-236, typical compounds according to the invention, can be by the researchers according to the following reaction scheme 28. Any number of compounds related compounds 235-236, can be obtained using similar techniques. The original connection 223 can be obtained according to the procedures described above in example 25.

The reaction scheme 28

In General, the interaction of amino compounds, such as compound 223, with an aldehyde, such as formaldehyde, and regenerating agent such as

NaBH3CN gives tertiary aminosilane, such as the connection 234. Reducing agent, such as socialogical use to restore a secure complex with ether, hydroxyl, receiving the connection 235. Treatment with 80% acetic acid leads to the formation of AMMONIATING salt compound 236.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 234

NaBH3CN (2×25 mg, 0.8 mmol) is added over a period of 25 minutes to have the ambient temperature to a solution of compound 223 (99 mg, 0.24 mmol), 37% CH2O in water (0.1 ml) and acetonitrile (2 ml). After 15 minutes the pH of the solution was adjusted to pH 7 by adding dropwise 80% acetic acid. After 1 hour the reaction mixture was diluted with EtOAc (150 ml) and washed with saturated solution of NaHCO3and saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified what cromatografia on silica gel (mixture of EtOAc/MeOH 95:5), receiving a connection 234 (104 mg, 98%).

Synthesis of compound 235

A solution of LiAlH4(5.5 ml 1,0M solution in THF) is added to cooled with ice to a solution of compound 234 (492 mg, 1.1 mmol) in THF (15 ml) in an argon atmosphere. After 25 minutes the cooling bath is removed and the interaction continue to make for 4 hours at ambient temperature. The reaction mixture is cooled with ice and the reaction quenched with Na2SO4·10H2O. After 10 minutes at ambient temperature, the solution is filtered, rinsing with EtOAc, and the filtrate is washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH/H2O 16:3:1)to give compound 235 (294 mg, 74%) as a crystalline solid.

Synthesis of compound 236

A solution of compound 235 (287 mg, 0.82 mmol) and 80% AcOH (10 ml) was stirred at 40°C for 10 minutes, then concentrated. Re-concentration of small amounts of methanol in acetonitrile gives compound 236 (287 mg, 85%) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 350,69; C22H40NO2.

EXAMPLE 29

Connection 240-241, typical compounds according to the invention can be obtained according to the following reaction scheme 29. Any number of the number of connections, related compounds 240-241, can be obtained using similar techniques. The original connection 223 can be obtained according to the procedures described above in example 25.

The reaction scheme 29

In General, aminosidine can be converted to a sulfonamide, such as by communicating connection 223 with sulphonylchloride, such as 2-nitrobenzenesulfonamide that gives compound 237. Nitrogen sulfonamida in the connection, such as 237, may then be subjected to alkylation using an electrophile, such as methyliodide that gives aminosidine, such as 238. The sulfonamide can be split by interaction with the nucleophile, such as anion thiophenolate that gives compound 239. Acetates can be removed by basic hydrolysis, which gives the connection 240. Treatment with 80% acetic acid leads to the formation of AMMONIATING salt compound 241.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 237

2-Nitrobenzenesulfonamide (194 mg, 0.88 mmol) is added to cooled with ice to a solution of compound 223 (296 mg, 0.73 mmol), Et3N (180 μl, 1.3 mmol) and CH2Cl2(5 ml) in an argon atmosphere. After 30 minutes the cooling bath is removed and the interaction continues the t to exercise for 1 hour at ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated solution of NaHCO3and saturated salt solution, then dried over MgSO4, filtered and concentrated, obtaining the compound 237 (433 mg, 100%) as a pale yellow solid.

Synthesis of compound 238

MeI (60 μl 2×30 μl 1.9 mmol) is added over 7 hours to a solution of compound 237 (431 mg, 0.73 mmol), K2CO3(232 mg, 1.7 mmol) and DMF (3 ml) in an argon atmosphere. After stirring overnight at ambient temperature the reaction mixture was diluted with EtOAc and washed with saturated salt solution, then dried over MgSO4, filtered and concentrated give crude compound 238, which is used in the next stage without additional purification.

Synthesis of compound 239

A solution of compound 238 (crude product, 0.73 mmol), PhSH (225 μl, 2,19 mmol), CsCO3(714 mg, 2,19 mmol) and acetonitrile (6 ml) is heated to 55°C in argon atmosphere for 1.5 hours. The reaction mixture at ambient temperature diluted with EtOAc and washed with saturated salt solution, then dried with MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/hexane 1:1, then EtOAc/MeOH/Et3N 90:10:2)to give compound 239 (268 mg, 88%) as a pale yellow oil.

Synthesis of compound 240

A solution of compound 239 (268 mg, 0,639 mmol, 10% KOH in water (1 ml) and MeOH (5 ml) is heated to 55°C for 4 hours. The reaction mixture at ambient temperature diluted with EtOAc (80 ml) and washed with saturated salt solution, then dried over MgSO4filter and concentrate. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH/H2O/NH4OH 80:15:5:1,5, then 70:20:10:2)to give compound 240 (182 mg, 85%) as a white foam.

Synthesis of compound 241

A solution of compound 240 (182 mg, 0,542 mmol) and 80% AcOH is heated to 40°C for 15 minutes, then concentrated. Residual solvent is removed by joint distillation with methanol, receiving the connection 241 (210 mg, 98%) as a pale yellow foam. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 336,08; C21H38NO2.

EXAMPLE 30

Connection 242, characterized by the connection according to the invention can be obtained according to the following reaction scheme 30. Any number of compounds related compounds 242, can be obtained using similar techniques. The original connection 77 can be obtained according to the procedures described above in example 8.

The reaction scheme 30

a) pyrazole-1-carboximetilceluloza

In General, the interaction of amino compounds, such as 77, pyrazole-1-carboximetilceluloza the m and diisopropylethylamine (DIEA) in methanol gives compound 242.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 242

A solution of compound 77 (106 mg, 0.33 mmol), pyrazole-1-karboksimetilirovaniya (51 mg, 0.35 mmol), DIEA (61 μl, 0.35 mmol) and MeOH (165 μl) was stirred at ambient temperature in an argon atmosphere for 3 days. The suspension is triturated with Et2O, dicontinue the solvent, giving a white powder.

Then the solid is recrystallized from 3 ml of a mixture of EtOAc/MeOH/Et2O, when receiving the connection 242 (64 mg, 48%) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 364,06; C21H38N3O2.

EXAMPLE 31

Connection 243-250, typical compounds according to the invention can be obtained according to the following reaction scheme 31. Any number of compounds related compounds 243-250, can be obtained using similar techniques. The original connection 77 can be obtained according to the procedures described above in example 8.

The reaction scheme 31

a) IU2SEINO, NaB(OAc)3H, 4Å molecular sieves, 1,2-dichloroethane; (b) 80% AcOH.

In General, reductive amination of the amino compounds, such as compound 77, with the help of a ketone or aldehyde, such as isobut aldehyd, gives amine, such as connection 243. Treatment with 80% acetic acid salt gives the connection 244.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 243

To a stirred mixture of compound 77 (100 mg, 0.31 mmol) in 1,2-dichloroethane (5 ml) and EtOH (1 ml) add Isobutyraldehyde (of 0.14 ml, 1.5 mmol), 4Å molecular sieves (100 mg) and NaB(OAc)3H (197 mg, of 0.93 mmol). The mixture was stirred at ambient temperature for three days and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH, 9:1 then 8:2), which gives compound 243 (79 mg, 67%).

Synthesis of compound 244

A solution of compound 243 (79 mg) in 80% HOAc (2 ml) was stirred at 40°C for a few and then concentrated by rotational evaporation. The residue is repeatedly subjected to co-distillation with MeOH and dried in vacuum. The product is dissolved in a small amount of MeOH and treated with a small amount of acetonitrile. The solvents were removed and the product dried in vacuum, obtaining the compound 244 (91 mg, 99%): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 378,21; C24H44NO2.

Synthesis of compound 245

Using the techniques described for the synthesis of compound 244, the exception is the group of replacing 1-methyl-4-piperidone, compound 245 (183 mg) are obtained with a quantitative yield based on compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 419,21; C26H47N2O2.

Synthesis of compound 246

Using the techniques described for the synthesis of compound 244, except for the replacement of 3-nitrobenzaldehyde, the connection 246 (58 mg) receive 35% yield based on compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 457,22; C27H41N2O4.

Synthesis of compound 247

Using the techniques described for the synthesis of compound 244, except for the replacement on piperonal, compound 247 (161 mg) receive 99% yield based on compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc

in a mixture of 3:7 water and MeCN) 456,12; C28H42NO4.

Synthesis of compound 248

Using the techniques described for the synthesis of compound 244, except for the replacement on pyrrol-2-carboxaldehyde, compound 248 (131 mg) are obtained from 91% yield based on compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc

in a mixture of 3:7 water and MeCN) 401,15; C25H41N2O2.

Synthesis of compound 249

Using the techniques described for the synthesis of compound 244, except for replacing 2-furaldehyde, the connection is giving 249 (88 mg) receive from 61% yield, proceeding from compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 402,23; C25H40NO3.

Synthesis of compound 250

Using the techniques described for the synthesis of compound 244, except for the replacement of 3-pyridinecarboxamide, compound 250 (59 mg) receive a 40% yield based on compound 77: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 413,22; C26H41N2O2.

EXAMPLE 32

Connection 252-261, typical compounds according to the invention can be obtained according to the following reaction scheme 32. Any number of compounds related compounds 252-261, can be obtained using similar techniques. The original connection 193 can be obtained according to the procedures described above in example 9.

The reaction scheme 32

a) pyrrolidin, NaB(OAc)3H, 4Å molecular sieves, 1,2-dichloroethane; (b) LAH, THF; c) 80% AcOH.

In General, reductive amination of a ketone or aldehyde compounds, such as compound 193, with an amine, such as pyrrolidine gives amine, such as connection 251. Recovery lydialydia removes acetyl groups, which leads to the formation of compound 252. Treatment with 80% acetic acid salt gives with the Association 253.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 251

To a stirred solution of compound 193 (150 mg, and 0.37 mmol) in 1,2-dichloroethane (7.5 ml) add pyrrolidine (of 0.18 ml, 2.2 mmol), 4Å molecular sieves (150 mg) and NaB(OAc)3H (314 mg, 1.5 mmol). The mixture was stirred at ambient temperature for three days and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH/Et3N, 8:2:0.5), and receiving a connection 251 (155 mg, 91%).

Synthesis of compound 252

To a stirred solution of compound 251 (155 mg, 0.34 mmol) in THF (15 ml) at 0°C is added dropwise 1M LAH in THF (1.7 ml, 1.7 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 5 hours 40 minutes, the Reaction mixture was again cooled to 0°C, add portions of solid Na2SO4.10H2O (536 mg, 1.7 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 8:1:0,5:0,5), receiving a connection 252 (121 mg, 92%).

Synthesis of compound 253

A solution of compound 252 (121 mg) in 80% HOAc (2 ml) stirred the ri 40°C for several minutes and then concentrated by rotational evaporation. The residue is subjected to co-distillation with MeOH several times, and dried in vacuum. The product is dissolved in a small amount of MeOH and treated with a small amount of acetonitrile. The solvents were removed and the product dried in vacuum, obtaining the compound 253 (147 mg, Quant.): LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 376,24; C24H42NO2.

Synthesis of compound 254

Using the techniques described for the synthesis of compound 253, except for the replacement of ethanolamine, the connection 254 (84 mg) receive from 51% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 366,13; C22H40NO3.

Synthesis of compound 255

Using the techniques described for the synthesis of compound 253, except replacing the N,N-dimethylethylenediamine, compound 255 (38 mg) receive a 20% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 393,11; C26H49N2O4.

Synthesis of compound 256

Using the techniques described for the synthesis of compound 253, except for the replacement on cyclohexylamin, compound 256 (154 mg) receive from 87% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 404,28; C26H 46NO2.

Synthesis of compound 257

Using the techniques described for the synthesis of compound 253, except replacing the 3-(aminomethyl)pyridine, compound 257 (122 mg) receive from 65% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 413,15; C26H41N2O2.

Synthesis of compound 258

Using the techniques described for the synthesis of compound 253, except for the replacement on furfurylamine, the connection 258 (83 mg) receive from 47% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 402,20; C25H40NO3.

Synthesis of compound 259

Using the techniques described for the synthesis of compound 253, except for the replacement of 3-ftoranila and absence of salt formation stage, the connection 259 (86 mg) receive from 57% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 416,08; C26H39FNO2.

Synthesis of compound 260

Using the techniques described for the synthesis of compound 259, except for the replacement of 3-aminopyridine, connection 260 (42 mg) receive from 28% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 399,20; C25H39N2 2.

Synthesis of compound 261

Using the techniques described for the synthesis of compound 259, except for the replacement for m-toluidine, connection 261 (91 mg) receive 60% yield based on compound 193: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 412,20; C27H42NO2.

EXAMPLE 33

Connection 270, characterized by the connection according to the invention can be obtained according to the following reaction scheme 33. Any number of compounds, related to the connection 270 may be obtained using similar techniques. The original connection 262 can be obtained according to the methods described in U.S. patent 6046185.

The reaction scheme 33

a) TBSCl, imidazole, DMAP, DMF, THF; b) NalO4H2O, THF; c) NaBH4, MeOH, THF; d) Ac2O, DMAP, pyridine; (e) MsCl, pyridine; (f) NaH, imidazole, DMF; (g) LAH, THF; (h) HOAc.

In General, processing TBSCI and imidazole in DMF selectively protects one hydroxyl that gives compound 263. Oxidation using NaIO4gives dialdehyde connection 264. Recovery using detribalized network connection 265. Interaction with acetic anhydride and DMAP in pyridine selectively protects one hydroxyl, which gives the connection 266. The engagement of the free hydroxyl of the application of MsCl and pyridine gives mesylate connection 267. Substitution nelfinavir anion imidazole in DMF gives the connection 268. The removal of acetyl groups by lydialydia gives compound 269. Treatment with 80% acetic acid removes the TBS-group that gives compound 270.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 263

To a solution of crude compound 262 (86,3 mmol) in DMF (90 ml) and THF (150 ml), cooled in a bath of cold water, add DMAP (0.50 g, 4.1 mmol), imidazole (11.8 g, 173 mmol) and TBSCl (15.6 g, 104 mmol). The mixture was stirred at ambient temperature for 2.5 hours, then cooled in a bath of cold water. Add water (100 ml) and EtOAc (100 ml). The layers are separated and the carry back extraction of the aqueous portion with EtOAc (50 ml). The combined organic layers washed with saturated salt solution (2×250 ml), dried over anhydrous MgSO4and concentrate to dryness, obtaining the compound 263 (38.0 g, quantitative) as a white foam.

Synthesis of compound 264

To a solution of compound 263 (38.0 g, 86,3 mmol) in THF (250 ml), cooled in a bath of cold water, add the suspension NaIO4(36,9 g, 173 mmol) in water (120 ml). The reaction mixture was stirred at ambient temperature for 1.5 hours, then add water (150 ml) and EtOAc (150 ml). The layers are separated and the carry back extraction of the aqueous portion with EtOAc (100 ml). The combined organic layers washed with saturated salt solution (200 ml), dried over anhydrous MgSO4and concentrate to dryness give crude compound 264, which is used in the next stage without additional purification.

Synthesis of compound 265

To a solution of crude compound 264 (86,3 mmol) in THF (125 ml) and MeOH (125 ml) at 0°C add portions NaBH4(6,53 g, 173 mmol). The mixture is stirred at 0°C for 15 minutes, then at ambient temperature for 1 hour. The mixture is cooled in a bath of cold water and quenched with 80% acetic acid, leading to pH=7.0. Add water (100 ml) and EtOAc (150 ml). The layers are separated and the carry back extraction of the aqueous portion with EtOAc (100 ml). The combined organic layers washed with saturated salt solution (200 ml), dried over anhydrous MgSO4and concentrate to dryness. The residue is stirred with hexane (150 ml) for 2 hours, then the precipitate was separated by filtration, rinsing with hexane (2×25 ml). The solid product is dried, receiving the connection 265 (19,8 g, 52% (based on compound 263) as a white solid.

Synthesis of compound 266

To a solution of compound 265 (17.0 g, for 38.9 mmol) in CH2Cl2(25 ml) and pyridine (50 ml), cooled in a bath of cold water, add DMAP (0.50 g, 4.1 mmol), and then, dropwise, acetic anhydride (4.0 ml, 43 mmol). The mixture was stirred at the temperature of the environment within 1.5 hours. Add a saturated solution of salt (120 ml) and EtOAc (250 ml). The layers are separated and the carry back extraction of the aqueous portion with EtOAc (100 ml). The combined organic layers washed with saturated salt solution (2×150 ml), dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel (hexane/EtOAc, 49:1, 19:1, 9:1, 4:1), receiving a connection 266 (11,0 g, 59%) as a white solid.

Synthesis of compound 267

To a stirred solution of compound 266 (2.4 g, 5.0 mmol) in pyridine (20 ml) is added dropwise MsCl (of 0.39 ml, 5.0 mmol). The resulting mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with EtOAc (300 ml), washed with saturated salt solution and wash water are combined and extracted with EtOAc. The organic extracts are combined and washed with saturated salt solution, dried and concentrated, obtaining the compound 267 (2.8 g, 100%) as a light solid.

Synthesis of compound 268

To a stirred solution of imidazole (66 mg, 0.97 mmol) in DMF (6 ml) at ambient temperature is added NaH (39 mg, 60% in mineral oil, 0.97 mmol). After stirring for 1 hour at ambient temperature the mixture becomes transparent, and then add in a solid compound 267 (200 mg, 0.36 mmol). The mixture is stirred at 60°C for 3 hours is 45 min and then left at ambient temperature overnight. The mixture is diluted with toluene (200 ml), washed with saturated salt solution, dried and concentrated. The crude compound 268 used in the next stage without additional purification.

Synthesis of compound 269

To a stirred solution of compound 268 (0.36 mmol) in THF (15 ml) at 0°C is added dropwise 1M LAH in THF (0,57 ml, or 0.57 mmol). After 5 minutes at 0°C the mixture was stirred at ambient temperature for 5 hours. the reaction mixture was again cooled to 0°C and add portions of solid Na2SO4.10H2O (184 mg, or 0.57 mmol). After 5 minutes at 0°C the mixture was stirred at ambient temperature for 1 hour, and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The crude compound 269 used in the next stage without additional purification.

Synthesis of compound 270

A solution of crude compound 269 (0.36 mmol) in 80% HOAc (4 ml) was stirred at 40°C for 6.5 hours. The solvents were removed and the residue purified column chromatography (mixture of EtOAc/MeOH/Et3N, 8:1,5:0,5), receiving the connection 270 (110 mg, 82% (based on connection 267). LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 372,87; C23H37N2O2.

EXAMPLE 34

Connection 276-277, typical compounds according to the invention can be obtained according to the ACLs the following reaction scheme 34. Any number of compounds related compounds 276-277, can be obtained using similar techniques. The original connection 267 can be obtained according to the procedures described above in example 33.

The reaction scheme 34

a) NaN3, DMF; (b) K2CO3, MeOH, H2O; c) NMO, TPAP, CH2Cl2; (d) cyclopentylamine, NaB(OAc)3H, 4Å molecular sieves, 1,2-dichloroethane; (e) LAH, THF; (f) 80% AcOH; (g) 80% AcOH.

In General, azide substitution nelfinavir with NaNO3in DMF gives compound 271. Basic hydrolysis of the acetate gives compound 272. Catalyzed TPAP oxidation of the hydroxyl group gives compound 273. Reductive amination using cyclopentylamine network connection 274. The restoration of the azide lydialydia network connection 275. Treatment with 80% acetic acid removes the TBS-group that gives compound 276. After purification on a column of additional treatment with 80% acetic acid to give a salt of the compound 277.

The following are typical examples of the compounds obtained as described above.

Synthesis of compound 271

A mixture of compound 267 (1.8 g, 3.2 mmol) and NaN3(420 mg, 6.5 mmol) in DMF (26 ml) was stirred at 60°C over night. The mixture is cooled to ambient temperature and diluted with toluene (300 m is), washed with saturated salt solution, dried and concentrated, obtaining the compound 271 (1.56 g, 95%).

Synthesis of compound 272

A mixture of compound 271 (1.35 g, 2.68 mmol), K2CO3(2.9 g, 21 mmol) in a mixture of MeOH/THF/water (50 ml/50 ml/39 ml) was stirred at ambient temperature overnight. A large part of the solvent is removed by rotational evaporation and the residue diluted with water (250 ml) and extracted with EtOAc. EtOAc extracts are combined and washed with saturated salt solution, dried and concentrated. The crude product is purified column chromatography (hexane/EtOAc, 85:15)to give compound 272 (856 mg) with a yield of 69%.

Synthesis of compound 273

To a stirred solution of compound 272 (892 mg, of 1.93 mmol) in CH2Cl2(35 ml) was added NMO (333 mg, 2,84 mmol) and TPAP (57 mg, 0.16 mmol). The mixture was stirred at ambient temperature for 2 hours 15 min and then the solvent is removed by rotational evaporation. The residue is purified column chromatography (hexane/EtOAc, 9:1)to give compound 273 (769 mg) with a yield of 87%.

Synthesis of compound 274

To a stirred solution of compound 273 (170 mg, of 0.37 mmol) in 1,2-dichloroethane (8 ml) add cyclopentylamine (of 0.18 ml, 1.8 mmol), 4Å molecular sieves (170 mg) and NaB(OAc)3H (331 mg, 1.56 mmol). The mixture was stirred at ambient temperature for 28 hours and stemphylium through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The residue is filtered through a column with silica using a mixture of EtOAc/MeOH (9:1)and the crude compound 274 used in the next stage without additional purification.

Synthesis of compound 275

To a stirred solution of compound 274 (from 0.37 mmol) in THF (15 ml) at 0°C is added dropwise 1M LAH in THF (1.9 ml, 1.9 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 5.5 hours. The reaction mixture was again cooled to 0°C and add portions of Na2SO4.10H2O (596 mg, 1.9 mmol). After 5 min at 0°C the mixture was stirred at ambient temperature for 1 hour and then filtered through celite and washed with EtOAc. The filtrate and wash water are combined and concentrated. The crude compound 275 used in the next stage without additional purification.

Synthesis of compound 276

A solution of crude compound 275 (of 0.37 mmol) in 80% HOAc (5 ml) was stirred at 40°C for 7.5 hours. The solvents were removed and the residue purified column chromatography (mixture of EtOAc/MeOH/water/Et3N, 6,5:2,5:0,5:0,5), receiving a connection 276 (74 mg, 52% (based on compound 273).

Synthesis of compound 277

A solution of compound 276 (74 mg) in 80% HOAc (0.5 ml) was stirred at ambient temperature for several minutes, and then the solvents are removed by the method rotationg the evaporation. The residue is evaporated several times together with MeOH and dried in vacuum. The product is dissolved in a small amount of MeOH and treated with a small amount of acetonitrile. The solvents were removed and the product dried in vacuum, obtaining the compound 277 (90 mg, 93%) as not quite white powder: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 388,98; C25H45N2O.

EXAMPLE 35

Connection 282-306 typical compounds according to the invention can be obtained according to the following reaction scheme 35. Any number of compounds related compounds 282-306 can be obtained using similar techniques. The original connection 113 may be obtained according to the procedures described above in example 12.

The reaction scheme 35

a) isobutylamine, NaB(OAc)3H, 4Å MS, DCE; (b) LiAIH4, THF; c) 80% AcOH, 40°C; d) MePPh3Br, KOtBu, THF; (e) 80% AcOH.

In General, reductive amination of a ketone or aldehyde compounds, such as compound 113, with an amine, such as isobutylamine gives amine, such as connection 278. Recovery lydialydia removes the acyl group that gives compound 279. Treatment with 80% acetic acid removes both the TBS-group and a cyclic group of ketala that gives compound 280. Olaf the plan using MePPh 3Br and KOtBu in THF gives compound 281. Treatment with 80% acetic acid leads to the formation of a salt of compound 282.

The following are typical examples of the compounds obtained as described above.

The synthesis of compound 278

A mixture of compound 113 (0.18 g, 0.35 mmol), isobutylamine (of 0.18 ml, 1.8 mmol) and 4Å molecular sieves (0.15 g) in DCE (5 ml) was stirred at ambient temperature for 1 hour. Added NaB(OAc)3H (0,395 g, 1.77 mmol) and the mixture was stirred at ambient temperature for 5 days. The reaction mixture was diluted with MeOH and filtered through a layer of celite, rinsing EtOAc. The filtrate was washed with a saturated solution of NaHCO3, then twice with saturated salt solution, dried over anhydrous MgSO4and concentrate. The residue is purified by chromatography on silica gel, receiving a mixture of compound 278 and Imin connection 278 (0,240 g) as a pale yellow oil, which was used in the next stage without additional purification.

Synthesis of compound 279

To a solution mixture of compound 278 and the corresponding imine (0.33 mmol) in THF (10 ml) is added LiAlH4(0,99 ml of 1M solution in THF, 0,99 mmol). The mixture was stirred at ambient temperature overnight, then quenched with Na2SO4·10H2O and stirred for 30 minutes. The mixture is filtered, rinsing EtOAc, and concentrated to dryness, recip what I crude compound 279 (0,137 g) as a colorless glass mass which is used in the next stage without additional purification.

Synthesis of compound 280

The crude compound 279 (0.33 mmol) is dissolved in 80% acetic acid (7 ml) and stirred at 40°C overnight, then concentrated. The residue partially purified by chromatography on silica gel, receiving a connection 280 (0.083 g) in the form of colorless glass mass.

Synthesis of compound 281

The mixture KOtBu (0,184 g, 1.56 mmol) and MePPh3Br (0,557 g, 1.56 mmol) in THF (6 ml) was stirred at ambient temperature for 1.5 hours, then add a solution of compound 281 (0.083 g, 0.20 mmol) in THF (4 ml). The reaction mixture was stirred at ambient temperature overnight, then quenched with saturated solution of NH4Cl and concentrate. The residue partially purified by chromatography on silica gel, receiving the connection 281, which is used for further interaction.

The synthesis of compound 282

A mixture of compound 281 (0.2 mmol), 80% AcOH and MeOH concentrate by rotational evaporation. The residue is dissolved in water and washed with CH2Cl2(5×5 ml), then concentrated. Precipitation from hexane gives compound 282 (0,042 g, 28% based on connection 113) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 364,22; C23H42NO2.

The synthesis of the is placed 283

Using the procedure described for the synthesis of compound 278, with the exception that they use 0,329 g (1,47 mmol) of NaB(OAc)3H and the reaction time is 4 days, compound 113 (0.25 g, 0.49 mmol) is subjected to interaction with 3-(aminomethyl)pyridine (0.25 ml, 2.5 mmol), receiving Eminova intermediate connection (0,225 g, 77%, white foam). Using the procedure described for the synthesis of compound 279, with the exception that the reaction time is 5 hours, Eminova intermediate connection (0,376 mmol) is subjected to interaction with LiAlH4(1.50 ml 1M solution in Et2O, 1.50 mmol)to give crude alcohol intermediate compound with a split TBS group (rate £ 0.162 g, yellow foam). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% AcOH and recovery is carried out at ambient temperature, the crude mixture containing the alcohol intermediate compound (0,376 mmol) is transformed into ketone intermediate connection (0,095 g, colorless glass mass). Using the procedure described for the synthesis of compound 281, with the exception that they use 0,163 g (1.38 mmol) KOtBu and 0,492 g (1.38 mmol) MePPh3Br and after quenching the reaction mixture was filtered through celite, the ketone intermediate compound (0.23 mmol) turn in alkene. Deposition of Et2O gives compound 283 (0,014 g, 7% is based n the connection 113) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 397,75; C25H38N2O2.

Synthesis of compound 284

Using the procedure described for the synthesis of compound 278, compound 113 (0.18 g, 0.35 mmol) is subjected to interaction with ethanolamine (of 0.11 ml, 1.8 mmol)to give amine intermediate connection (0,053 g, 27%, yellow oil). Using the procedure described for the synthesis of compound 279, amine intermediate connection (0,096 mmol) is subjected to interaction with LiAlH4(0,19 ml of 1M solution in THF, 0,19 mmol)to give the alcohol intermediate compound with some TBS-banding (0,040 g, colorless glass mass). Using the procedure described for the synthesis of compound 280, except that they use 6 ml of 80% acetic acid and the remainder is not subjected to purification, the crude mixture containing the alcohol intermediate compound is converted into the ketone intermediate compound in the form of acetate salt level (0.041 g, colorless glass mass). Using the procedure described for the synthesis of compound 281, ketone intermediate connection (0,096 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, with the exception that the remainder is not washed with CH2Cl2, crude alkene is transformed into acetic acid salt. Deposition from a mixture of hexane/CH2Cl2the AET connection 284 (0.015 g, 10% is based on connection 113) as a yellow solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 352,12; C21H38NO3.

Synthesis of compound 285

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.20 g of 4Å molecular sieves, the interaction will be performed from 0.395 g (1.77 mmol) of NaB(OAc)3H, then, after 2 days, add to 0.263 g (1.18 mmol) of NaB(OAc)3H, and the total reaction time is 6 days, compound 113 (0,30 g, 0.59 mmol) is subjected to interaction with furfurylamine (with 0.27 ml, 3.0 mmol), and receiving the mixture of amine and iminovogo intermediates (0,283 g, white foam). Using the procedure described for the synthesis of compound 279, with the exception that the reaction time is 5 hours, the mixture of intermediate compounds Amin/Amin (0.48 mmol) is subjected to interaction with LiAlH4(of 1.44 ml of a 1M solution in Et2O, 1.44 mmol)to give crude alcohol intermediate compound with mostly derived TBS-groups (0,248 g, yellow oil). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% Asón, the interaction is carried out at ambient temperature, and the residue after deposition dissolved in THF (6 ml) and treated with 2n. HCl (2 ml) at ambient temperature T. the value of the night, and then concentrated, the crude mixture containing the alcohol intermediate compound (0,481 mmol)is converted into the ketone intermediate compound in the form of HCl salts (0,146 g, yellow oil). Using the procedure described for the synthesis of compound 281, with the exception that they use 0,236 g (2.00 mmol) KOtBu and 0,715 g (2.00 mmol) MePPh3Br add DMF (0.5 ml) and after quenching the reaction mixture was filtered through celite, the ketone intermediate compound (0.33 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, crude alkene is transformed into acetic acid salt. Deposition of Et2O gives compound 285 (0,013 g, 14% based on connection 113) as a light brown solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 388,16; C24H38NO3.

Synthesis of compound 286

Using the procedure described for the synthesis of compound 278, except that the balance is not purified, interact compound 113 (0.18 g, 0.35 mmol) with N,N-dimethylethylenediamine (0,20 ml, 1.8 mmol), and receiving the mixture of amine and iminovogo intermediates (0,192 g, colorless oil). Using the procedure described for the synthesis of compound 279, the mixture of intermediate compounds Amin/Amin (0.33 mmol) is subjected to interaction with LiAlH4(0,99 ml of 1M rest the RA in THF, 0,99 mmol)to give crude alcohol intermediate compound (0,137 g, colorless glass mass). Using the procedure described for the synthesis of compound 280, except that the balance is not subjected to purification, the crude alcohol intermediate compound converted into the ketone intermediate compound in the form of acetate salt (0,147 g, colorless glass mass). Using the procedure described for the synthesis of compound 281, ketone intermediate compound (0.33 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, with the exception that the remainder is not washed with CH2Cl2, crude alkene is transformed into acetic acid salt. The concentration of CH2Cl2gives compound 286 (0,072 g, 47% based on connection 113) as a light yellow solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 379,03; C23H43N2O2.

Synthesis of compound 287

Using the procedure described for the synthesis of compound 278, compound 113 (0.18 g, 0.35 mmol) is subjected to interaction with 2-(1-cyclohexenyl)ethylamine (0.25 ml, 1.8 mmol)to give amine intermediate connection (0,165 g, 77%, yellow oil). Using the procedure described for the synthesis of compound 279, amine intermediate compound (0.27 mmol) is subjected to interaction with LiAlH42O (4×5 ml) instead of CH2Cl2, crude alkene is transformed into acetic acid salt. Deposition from a mixture of hexane/CH2Cl2gives compound 287 (0,051 g, 31% based on connection 113) as a white solid: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 416,26; C27H46NO2.

Synthesis of compound 288

Using the procedure described for the synthesis of compound 278, except that the balance is not purified, interact compound 113 (0.18 g, 0.35 mmol) with 4-(2-amino-ethyl)morpholine (0,23 ml, 1.8 mmol)to give amine intermediate connection (0,205 g, 94%, colorless oil). Using the procedure described for the synthesis of compound 279, Minogue intermediate compound (0.33 mmol) is subjected to interaction with LiAlH 4(0,66 ml of 1M solution in THF, 0.66 mmol)to give crude alcohol intermediate compound (0,150 g, colorless glass mass). Using the procedure described for the synthesis of compound 280, except that use 8 ml of 80% acetic acid and the remainder is not subjected to purification, the crude alcohol intermediate compound converted into the ketone intermediate compound in the form of acetate salt (0,203 g, brown oil). Using the procedure described for the synthesis of compound 281, ketone intermediate compound (0.33 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, with the exception that the residue is purified by chromatography on silica gel after washing, the crude alkene is transformed into acetic acid salt. Deposition of Et2O gives compound 288 (to 0.108 g, 64% based on connection 113) in the form of not-quite-white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 421,16; C25H45N2O3.

Synthesis of compound 289

Using the procedure described for the synthesis of compound 278, with the exception that they use 0,125 g of 4Å molecular sieves, the interaction will be performed with 0,329 g (1,47 mmol) of NaB(OAc)3H, then, after 2 days, add another 0,219 g (0,982 mmol) of NaB(OAc)3H, and the total reaction time is 6 days, the is giving 113 (0.25 g, 0.49 mmol) is subjected to interaction with m-toluidine (with 0.27 ml, 2.5 mmol)to give amine intermediate connection (0,240 g, yellow oil). Using the procedure described for the synthesis of compound 279, with the exception that the reaction time is 5 hours, the amine intermediate compound (0.400 mmol) is subjected to interaction with LiAlH4(0,80 ml of 1M solution in Et2O, 0.80 mmol)to give crude alcohol intermediate compound with, for the most part, derived TBS-groups (0,224 g, yellow oil). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% AcOH and interaction is carried out at ambient temperature, the crude mixture containing the alcohol intermediate compound (0.400 mmol) is transformed into ketone intermediate connection is 0.135 g, light brown solid). Using the procedure described for the synthesis of compound 281, with the exception that they use 0,238 g (a 2.01 mmol) KOtBu and 0,719 g (a 2.01 mmol) MePPh3Br and after quenching the reaction mixture was filtered through celite, the ketone intermediate compound (0.34 mmol) turn in alkene. The concentration of CH2Cl2gives compound 289 (0,095 g, 49% based on connection 113) as a yellow foam.

Synthesis of compound 290

Using the procedure described for the synthesis of compound 278, except that IP is result of 0.10 g of 4Å molecular sieves and 6 ml of DCE, interaction begin with 0,165 g (0,740 mmol) of NaB(OAc)3H, then, after 8 hours, add another 0.083 g (0,37 mmol) of NaB(OAc)3H, and the total reaction time is 2 days, compound 113 (0,197 g, 0,387 mmol) is subjected to interaction with benzylamine (of 0.21 ml, 1.9 mmol)to give amine intermediate connection (0,171 g, 73%, colorless resin). Using the procedure described for the synthesis of compound 279, with the exception that they use 6 ml THF and the reaction time is 5 hours, the amine intermediate compound (0.28 mmol) is subjected to interaction with LiAlH4high (0.56 ml of a 1M solution in THF, 0,56 mmol)to give crude alcohol intermediate compound with, for the most part, derived TBS-groups (0,132 g, colorless resin). Using the procedure described for the synthesis of compound 280, with the exception that the alcohol is treated with 2n. HCl (2 ml) in THF (6 ml) instead of 80% acetic acid and the interaction is carried out at ambient temperature, the crude mixture containing the alcohol intermediate compound (0.28 mmol) is transformed into ketone intermediate connection (0,095 g, colorless glassy mass). Using the procedure described for the synthesis of compound 281, with the exception that the use rate £ 0.162 g (1.44 mmol) KOtBu 0,514 g (1.44 mmol) MePPh3Br and 13 ml of THF, and after quenching the reaction mixture was diluted with EtOAc (20 ml) and MeOH (10 ml), ZAT is filtered through celite, ketone intermediate compound (0.24 mmol) turn in alkene. The deposition of the ACN network connection 290 (0,063 g, 41% based on connection 113) as a white solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 382,06; C25H36NO2.

Synthesis of compound 291

Using the techniques described for the synthesis of compound 282, with the exception of the replacement of 3-forbindelsen, the connection 291 (0,039 g) obtained as yellow solid with a 23% yield based on compound 95: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 416,21; C26H39FNO2.

Synthesis of compound 292

Using the techniques described for the synthesis of compound 282, with the exception of replacing the morpholine, compound 292 (0,089 g) obtained as a light pink solid with 58% yield based on compound 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 378,12; C23H40NO3.

Synthesis of compound 293

Using the techniques described for the synthesis of compound 282, with the exception of replacing the 3,4-(methylenedioxy)aniline, the compound 293 (0,068 g) are obtained in the form of a white solid with a 45% yield, based on connection 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 428,37; C 26H38NO4.

Synthesis of compound 294

Using the techniques described for the synthesis of compound 282, with the exception of replacing isobutylamine, the connection 294 (0,111 g) obtained as orange solids with 75% yield, based on connection 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 364,12; C23H42NO2.

Synthesis of compound 295

Using the techniques described for the synthesis of compound 282, with the exception of the replacement cyclohexylamine, compound 295 (0,029 g) obtained as orange solids with 18% yield, based on connection 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAC mixture in 3:7 water and MeCN) 390,12; C25H42NO2.

Synthesis of compound 296

Using the techniques described for the synthesis of compound 282, with the exception of substitution by N-methylaniline, compound 296 (0,040 g) obtained as orange solids with 28% yield, based on connection 95. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 397,86; C26H40NO2.

Synthesis of compound 297

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.20 g of 4Å molecular sieves and 7 ml of DCE, the mixture is stirred for 1 hour before adding the NaB(OAc)3H, the reaction BP is me is 3 days, and the residue purified by chromatography on silica gel (hexane/EtOAc, 1:1; a mixture of EtOAc/MeOH, 9:1), compound 95 (0.25 g, 0.49 mmol) is subjected to interaction with 3-(aminomethyl)pyridine (0.25 ml, 2.5 mmol)to give amine intermediate connection (0,266 g, 90%, colorless glass mass). Using the procedure described for the synthesis of compound 279, with the exception that the reaction time is 1 night, amine intermediate compound (0.44 mmol) is subjected to interaction with LiAlH4(0,98 ml of 1M solution in Et2O, 0.98 mmol)to give the alcohol intermediate compound (0,255 g, yellow foam). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% AcOH, the interaction is carried out at ambient temperature for 4 days and the residual product was then purified by chromatography on silica gel (mixture of EtOAc/MeOH/H2O/Et3N, 9:1:0,25:0,25), alcohol intermediate compound (0.46 mmol) is transformed into ketone intermediate compound in the form of free amine (0,039 g, light brown solid). Using the procedure described for the synthesis of compound 281, with the exception that they use 0,069 g (of 0.58 mmol) KOtBu, 0,209 g (0,585 mmol) MePPH3Br and 7 ml of THF, the reaction mixture is stirred for 1 hour, then add a solution of ketone intermediate compounds, and the reaction time, the composition of AET 2 days, ketone intermediate connection (0,097 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, with the exception that the residue is not cleaned chromatography, the crude alkene is converted into a compound 297 (0,011 g, 5% based on INT1703) as a yellow glassy mass. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 399,16; C25H39N2O2.

Synthesis of compound 298

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.20 g of 4Å molecular sieves and 7 ml of DCE, the mixture is stirred for 1 hour, then added NaB(OAc)3H, the reaction time is 3 days, and the residue purified by chromatography on silica gel (hexane/EtOAc, 3:2, 1:1), compound 95 (0.25 g, 0.49 mmol) is subjected to interaction with furfurylamine (0,23 ml, 2.5 mmol), which gives the amine intermediate connection (0,269 g, 93%, yellow foam). Using the procedure described for the synthesis of compound 279, with the exception that the amine intermediate compound (0.46 mmol) is subjected to interaction with LiAlH4(0,98 ml of 1M solution in Et2O, 0.98 mmol) overnight, then further add to 1.96 ml solution of LiAlH4(1M in Et2Oh, a 1.96 mmol), followed by further interaction during the night, get alcohol intermediate connection of the tell (0,228 g, white foam). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% Asón and interaction is carried out at ambient temperature for 3 days, alcohol intermediate compound (0.42 mmol) is transformed into ketone intermediate compound in the form of acetate salt (0,229 g, yellow glass mass). Using the procedure described for the synthesis of compound 281, with the exception that add 0.2 ml of DMF, the ketone intermediate compound (0.42 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, crude alkene is transformed into acetic acid salt. Deposition of Et2O gives compound 298 (0,088 g, 40% based on compound 95) as an orange solid. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 388,05; C24H38NO3.

The synthesis of compounds 299

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.20 g of 4Å molecular sieves and 7 ml of DCE, the mixture is stirred for 1 hour, then added NaB(OAc)3H, the reaction time is 3 days, and the residue purified by chromatography on silica gel (EtOAc; a mixture of EtOAc/MeOH/Et3N, 9:1:0,3), compound 95 (0.25 g, 0.49 mmol) is subjected to interaction with ethanolamine (0.15 ml, 2.5 mmol)to give amine premiato the Noah connection (0,274 g, quantitatively, yellow foam). Using the procedure described for the synthesis of compound 279, amine intermediate compound (0.49 mmol) is subjected to interaction with LiAlH4(0,98 ml of 1M solution in Et2O, 0.98 mmol) overnight, then further add to 0.98 ml of a solution of LiAlH4(1M in Et2Oh, 0.98 mmol), followed by further interaction during the night, get alcohol intermediate compound (0,224 g, colorless glass mass). Using the procedure described for the synthesis of compound 280, except that use 20 ml of 80% Asón and interaction is carried out at ambient temperature for 3 days, alcohol intermediate compound (0.44 mmol) is transformed into ketone intermediate compound in the form of acetate salt (0,216 g, colorless glass mass). Using the procedure described for the synthesis of compound 281, with the exception that add 0.5 ml of DMF, the ketone intermediate compound (0.44 mmol) turn in crude alkene. Using the procedure described for the synthesis of compound 282, with the exception that the remainder is not purified by chromatography, the crude alkene is transformed into acetic acid salt. The concentration of the

CH2Cl2gives compound 299 level (0.041 g, 20% based on compound 95) as a yellow solid. LC/MS (direct injection, electrotactile the e +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 352,06; C21H38NO3.

Synthesis of compound 300

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.10 g of 4Å molecular sieves, the reaction time is 2.5 days and the residue purified by chromatography on silica gel (hexane/EtOAc, 8:2), compound 95 (0.10 g, 0.20 mmol) is subjected to interaction with m-toluidine (0.10 ml, of 0.93 mmol)to give amine intermediate connection (0,091 g, 77%, yellowish resin). Using the procedure described for the synthesis of compound 279, with the exception that use 8 ml of THF, a solution of LiAlH4added at 0°C and the mixture was stirred at 0°C for 20 minutes, then stirred at ambient temperature and the reaction time is 3.5 hours, the amine intermediate compound (0.15 mmol) is subjected to interaction with LiAlH4(0,45 ml of 1M solution in THF, 0.45 mmol)to give crude alcohol intermediate connection. Using the procedure described for the synthesis of compound 280, except that they use 4 ml of 80% Asón and interaction is carried out for 5 hours, the crude alcohol intermediate compound (0.15 mmol) is transformed into crude ketone intermediate connection. Using the procedure described for the synthesis of compound 281, with the exception that they use 7 ml of THF and 0.5 ml of DMF, and after clearing MES diluted with EtOAc (20 ml) and MeOH (5 ml), and then filtered through celite, the ketone intermediate compound (0.15 mmol) turn in alkene (0,021 g, transparent resin). Using the procedure described for the synthesis of compound 282, with the exception that the remainder is not purified by chromatography, alkene converted into acetic acid salt. The deposition of a mixture of ACN/MeOH gives compound 300 (0,020 g, 21% based on compound 95) as a yellow foam.

Synthesis of compound 301

Using the procedure described for the synthesis of compound 278, with the exception that the use of 0.10 g of 4Å molecular sieves, the reaction time is 2.5 days and the residue purified by chromatography on silica gel (mixture of EtOAc/MeOH, 9:1), compound 95 (0.10 g, 0.20 mmol) is subjected to interaction with pyrrolidine (0.10 ml, 1.2 mmol)to give amine intermediate connection (0,090 g, 82%, transparent resin). Using the procedure described for the synthesis of compound 279, with the exception that use 8 ml of THF, a solution of LiAlH4added at 0°C, the mixture was stirred at 0°C for 20 minutes, followed by stirring at ambient temperature, and the reaction time is 3.5 hours, the amine intermediate compound (0.16 mmol) is subjected to interaction with LiAlH4(0,45 ml of 1M solution in THF, 0.45 mmol)to give crude alcohol intermediate connection. Using the procedure described for the synthesis of compound 280, excluding the rising, using 4 ml of 80% AcOH and the reaction time is 5 hours, the crude alcohol intermediate compound (0.16 mmol) is transformed into crude ketone intermediate connection. Using the procedure described for the synthesis of compound 281, with the exception that they use 7 ml of THF and 0.5 ml of DMF and after quenching the mixture was diluted with EtOAc (20 ml) and MeOH (5 ml), then filtered through celite, the ketone intermediate compound (0.16 mmol) turn in alkene (0,029 g resin). Using the procedure described for the synthesis of compound 282, with the exception that the residue is not cleaned chromatography, alkene turn in explicilty salt. The deposition of a mixture of ACN/MeOH gives compound 301 (0,038 g, 42% based on INT1703) not quite white foam. LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 362,18; C23H40NO2.

Synthesis of compound 302

Using the techniques described for the synthesis of compound 282, with the exception of replacing the N,N-dimethylethylenediamine, compound 302 (0,067 g) obtained as orange solids with 39% yield based on compound 205: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 393,03; C24H45N2O2.

Synthesis of compound 303

Using the techniques described for the synthesis of compound 282, with the exception of replacing the 3,4-(meth is landice)aniline, compound 303 (0,055 g) obtained as orange solids with 33% yield based on compound 205: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 441,95; C27H40NO4.

Synthesis of compound 304

Using the techniques described for the synthesis of compound 282, with the exception of the replacement cyclohexylamine, compound 304 (0,022 g) obtained as light yellow solids with a 12% yield based on compound 205: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 404,05; C26H46NO2.

Synthesis of compound 305

Using the techniques described for the synthesis of compound 282, with the exception of the replacement of 3-triptorelin, compound 305 (0,096 g) are obtained in the form of a white solid with a 54% yield based on compound 205: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4OAc mixture in 3:7 water and MeCN) 465,45; C27H38F3NO2.

Synthesis of compound 306

Using the techniques described for the synthesis of compound 282, with the exception of replacing isobutylamine, the connection 306 (0.035 g) are obtained in the form of a white solid with 21% yield based on compound 205: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 378,08; C24H44NO2.

EXAMPLE 36

Connection 08-310, typical compounds according to the invention can be obtained according to the following reaction scheme 36. Any number of compounds related compounds 308-310, can be obtained using similar techniques. The original connection 217 can be obtained according to the method described above in example 24.

The reaction scheme 36

a) pyrrolidin, NaB(OAc)3H, 4Å MS, DCE; (b) LiAlH4, THF; c) 80% AcOH, MeOH.

In General, reductive amination of compound 217 network connection 307. Reducing agent, such as socialogical use to restore a secure complex with ether, hydroxyl, receiving a connection 305. Treatment with 80% acetic acid gives AMMONIATING Sol connection 309.

Synthesis of compound 307

A mixture of compound 217 (0.20 g, 0.49 mmol), pyrrolidine (of 0.18 ml, 2.2 mmol) and 4Å molecular sieves (0.20 g) in DCE (5 ml) was stirred at ambient temperature for 30 minutes. Added NaB(OAc)3H (0,297 g of 1.33 mmol), rinsing with DCE (2 ml)and the mixture stirred at ambient temperature overnight. The reaction mixture was diluted with MeOH (3 ml) and filtered through a layer of celite, rinsing with EtOAc (25 ml). The filtrate was washed with a saturated solution of NaHCO3(10 ml), then saturated salt solution (2×5 ml), dried over anhydrous is MgSO 4and concentrate, receiving the connection 307 (0,235 g, quantitative) as a colorless glass mass, which is used in the next stage without additional purification.

Synthesis of compound 308

To a solution of compound 307 (0.49 mmol) in THF (10 ml) is added LiAlH4(0,88 ml of 1M solution in THF, 0.88 mmol). The mixture was stirred at ambient temperature overnight, then quenched with Na2SO4·10H2O and stirred for 1 hour. The mixture is filtered, rinsing with EtOAc, and concentrated to dryness. The residue is purified by chromatography on silica gel (mixture of EtOAc/MeOH, 9:1; a mixture of EtOAc/MeOH/Et3N, 9:0,75:0,25), receiving the connection 308 in the form of a white solid, which is used for further interaction.

Synthesis of compound 309

A mixture of compound 308, 80% AcOH (1 ml) and MeOH (5 ml) concentrate by rotational evaporation. The concentration of CH2Cl2gives compound 309 (has 0.168 g, 79% based on INT5) as a white foam: LC/MS (direct injection, elektrorazpredelenie +ve, 10 mm NH4SLA in a mixture of 3:7 water and MeCN) 375,95; C24H42NO2.

Synthesis of compound 310

Using the techniques described for the synthesis of compound 309, except for the replacement for m-toluidine, connection 310 (0.20 g) obtained as yellow foam with 69% yield, based on connection 217. LC/MS (direct injection, elektrorazpredelenie +ve, 10 the M NH 4OAC mixture in 3:7 water and MeCN) 412,01; C27H42NO2.

The following compounds according to the invention receive according to the above examples.

The connection 25; 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-1-methylenechloride;

The connection 29; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Compound 38; 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-(2-hydroxyethyl)-7aβ-methyl-1-methylenechloride;

The connection 45; 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

The connection 51; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-hydroxymethyl-7aβ-methyl-1-methylenechloride;

Connection 59; salt 5-(1β-methyl-4β-amino-2β-hydroxymethylcellulose)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 67; salt 5-(1β-methyl-4β-hydroxy-2β-(2-amino-ethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

The connection 68; salt 5-(1β-methyl-4β-hydroxy-2β-(2-amino-ethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-ethylidenecyclopentane-ammonium acetate;

Connection 77; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7aβ-methyl-1-methylenechloride;

The connection 78; salt 5-(1β-methyl-4β-hydroxy-2β-hydroximate the cyclohexyl)-

4α-aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 79; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-1,1-dimethyl-2,3,4,5,6,7-hexahydro-1H-inden-ammonium chloride;

The connection 80; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7aβ-methyl-1-methylenechloride-ammonium chloride;

Connection 81; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1-ethylidenecyclopentane-ammonium chloride;

The connection 88; 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-

4α-hydroxymethyl-7aβ-methyl-1-methylenechloride;

Connection 89; salt 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-

4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 100; 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 101; salt 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 107; 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-(2-amino-ethyl)-7aβ-methyl-1-methylenechloride;

The connection 108; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-(2-amino-ethyl)-7αβ-methyl-1-methylenechloride-ammonium acetate;

Connection 119; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-amino shall ethyl-7aβ-methyl-1-methylenechloride;

Connection 120; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 132; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1-deformitiesaccutane;

Connection 133; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1-deformitiesaccutane-ammonium chloride;

Connection 143; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1-dichlorohydroquinone-ammonium chloride;

Connection 157; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1β-(propen-2-yl)octahedron;

Connection 158; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1β-(propen-2-yl)octahedron-ammonium acetate;

Connection 163; 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7aβ-methyl-3a,4,5,6,7,7a-hexahydro-3H-inden;

Connection 178; salt 5-(1β-methyl-4α,5α-dihydroxy-2β-hydroxymethylcellulose)-

4α-aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 182; 5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-enyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 183; salt 5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-enyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 184; salt 5-(1β-methyl-4β-hydroxy-2β-(2-(4-chlorophenyl)ethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 185; salt 5-(1β-methyl-4β-hydroxy-2β-(2-pyridin-3-retil)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 189; 5-(1β-methyl-4β-hydroxy-2β-ethylcyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 192; 5-(1β-methyl-4β-hydroxy-2β-(2-(4-ethoxyphenyl)ETH-1-EN-1-yl)cyclohexyl)-

α-acetoxy-7aβ-methyl-1-methylenechloride;

Connection 195; 5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-2-yl)ETH-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7aβ-methyl-1-methylenechloride;

Connection 196; 5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-3-yl)ETH-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 197; 5-(1β-methyl-4β-hydroxy-2β-(hept-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 198; 5-(1β-methyl-4β-hydroxy-2β-(4-benzyloxy-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Compound 199; salt 5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;

The connection 200; 5-(1β-methyl-4 is-hydroxy-2β-(2-(4-chlorophenyl)ethynyl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 201; 5-(1β-methyl-4β-hydroxy-2β-(4-hydroxyben-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 203; 5-(1β-methyl-4β-hydroxy-2β-(3-hydroxyprop-1-EN-1-yl)cyclohexyl)-

4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 210; 5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2Z-EN-1-yl)cyclohexyl)-

4α-hydroxy-7β-methyl-1-methylenechloride;

Connection 211; 5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2E-EN-1-yl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

The connection 212; 5-(1β-methyl-4β-hydroxy-2β-(4-dimethylamino-1-EN-1-yl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 219; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(4-dimethylamino-

2Z-EN-1-yl)-7aβ-methyl-1-methylenechloride;

Connection 220; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(4-dimethylamino-

2Z-EN-1-yl)-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 221; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(3-pyridin-3-rprop-2Z-EN-1-yl)-7aβ-methyl-1-methylenechloride;

Connection 222; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(3-pyridin-3-rprop-2E-EN-1-yl)-7aβ-methyl-1-methylenechloride;

Connection 225; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-methylsulphonyl)

aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 227; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(acetyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 229; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(ethyl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 231; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(benzyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 232; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(benzyl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 233; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(cyclopropylmethyl)

aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 235; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-

4α-(dimethyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 236; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(dimethyl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 240; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(methyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 241; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(methyl)aminomethyl-7aβ-methyl-1-methylenechloride-acetate and mania;

Connection 242; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(guanidino)methyl-7aβ-methyl-1-methylenechloride-ammonium chloride;

Connection 243; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-

(2-methylpropyl " aminomethyl-7β-methyl-1-methylenechloride;

Connection 244; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose) -4α-(2-methylpropyl " aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;

Connection 245; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(1-methylpiperidin-4-yl)aminomethyl-7β-methyl-1-methylenechloride-ammonium diacetate;

Connection 246; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(3-nitrobenzyl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 247; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(piperonyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;

Connection 248; salt 5-(1β-methyl-4(3-hydroxy-2(3-hydroxymethylcellulose)

-4α-(pyrrol-2-ylmethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;

Compound 249; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(furfuryl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;

Connection 250; salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(pyridine-3-metil)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;

Connection 252; 5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)

-4α-hydroxymethyl-7β-methyl-1-methylenechloride;

Connection 253; salt 5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)

-4α-hydroxymethyl-7aβ-methyl-methylenechloride-ammonium acetate;

Compound 254; salt 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 255; salt 5-(1β-methyl-4β-hydroxy-2β-(2-dimethylaminoethyl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 256; salt 5-(1β-methyl-4β-hydroxy-2β-(cyclohexyl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 257; salt 5-(1β-methyl-4β-hydroxy-2β-(pyridine-3-ylmethyl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 258; salt 5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 259; 5-(1β-methyl-4β-hydroxy-2β-(3-forfinal)aminoethylthiomethyl

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride;

Connection 260; 5-(1β-methyl-4β-hydroxy-2β-(pyridin-3-yl)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-met is l-1-methylenechloride;

Connection 261; 5-(1β-methyl-4β-hydroxy-2β-(3-were)aminoethylthiomethyl)

-4α-hydroxymethyl-7aβ-methyl-1-methylenechloride;

Connection 270; 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)

-4α-(imidazol-1-yl)methyl-7aβ-methyl-1-methylenechloride;

Connection 276; 5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminoethylthiomethyl)

-4α-aminomethyl-7aβ-methyl-1-methylenechloride;

Compound 277; salt 5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminoethylthiomethyl)

-4α-aminomethyl-7aβ-methyl-1-methylenechloride-ammonium diacetate;

Connection 282; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-methylpropyl " aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 283; 5-(1β-methyl-2β,4β-dihydroxytoluene)-

4α-(pyridine-3-ylmethyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 284; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(2-hydroxyethyl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 285; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(furfuryl)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 286; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-dimethylaminoethyl)

aminomethyl-7aβ-methylethylenediamine-ammonium acetate;

Compound 287; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4 is-(2-cyclohex-1-EN-1-

retil)aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 288; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-morpholine-4-retil)

aminomethyl-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 289; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(3-were)

aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 290; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(benzyl)aminomethyl-7aβ-methyl-1-methylenechloride;

Connection 291; salt 5-(1β-methyl-4β-hydroxy-2β-(3-terbisil)aminoethylthiomethyl)-4α

-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 292; salt 5-(1β-methyl-4β-hydroxy-2β-(morpholine-4-yl)

methylcyclohexyl)-4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 293; 5-(1β-methyl-4β-hydroxy-2β-(1,3-benzodioxol-5-yl)aminoethylthiomethyl)-4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 294; salt 5-(1β-methyl-4β-hydroxy-2β-(2-methylpropyl " aminoethylthiomethyl)-4α-

hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 295; salt 5-(1β-methyl-4β-hydroxy-2β-(cyclohexyl)aminoethylthiomethyl)-4α-

hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 296; 5-(1β-methyl-4β-hydroxy-2β-(N-phenyl-N-methylamino)methylcyclohexyl)-4α-

hydroxy-7aβ-methyl-1-melanotheron the Yong;

Compound 297; salt 5-(1β-methyl-4β-hydroxy-2β-(pyridine-3-ylmethyl)aminoethylthiomethyl)-4α-

hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 298; salt 5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminoethylthiomethyl)-4α-

hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Compound 299; salt 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminoethylthiomethyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 300; salt 5-(1β-methyl-4β-hydroxy-2β-(3-were)aminoethylthiomethyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 301; salt 5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 302; salt 5-(1β-methyl-4β-hydroxy-2β-(2-(2-dimethylaminoethyl)aminoethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 303; 5-(1β-methyl-4β-hydroxy-2β-(2-(1,3-benzodioxol-5-yl)aminoethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride;

Connection 304; salt 5-(1β-methyl-4β-hydroxy-2β-(2-(cyclohexyl)aminoethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 305; 5-(1β-methyl-4β-hydroxy-2β-(2-(3-triptoreline)aminoethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-m is teleactivities;

Connection 306; salt 5-(1β-methyl-4β-hydroxy-2β-(2-(2-methylpropyl " aminoethyl)cyclohexyl)-

4α-hydroxy-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 308; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(2-pyrrolidin-1-retil)-7aβ-methyl-1-methylenechloride;

Connection 309; salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(2-pyrrolidin-1-retil)-7aβ-methyl-1-methylenechloride-ammonium acetate;

Connection 310; 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-

(2-(3-were)aminoethyl)-7aβ-methyl-1-methylenechloride.

All connections according to the invention, obtained as described above, existing in the form of free base or acid, can be converted into the corresponding pharmaceutically acceptable salt by treatment with the appropriate inorganic or organic base or an inorganic or organic acid. Salts of the compounds obtained as described above, can be converted into the corresponding free base or acid using standard techniques.

EXAMPLES of USE

An EXAMPLE of A

The influence of compounds on ear oedema model in mice TH1 hypersensitivity of the delayed type, caused by chemical hapten.

Model of delayed-type hypersensitivity represent a T-cell-dependent response. Used the first type of chemical hapten can skew T-cell response, mainly in the direction of TH1 - or TH2 polarization. Oxazole and dinitrochlorobenzene (DNCB) induce TH1-dominant immune response.

Mice sensibiliser at day 0 by applying to the surface of the shaved skin of the abdomen 100 μl of 3% solution of oxazolone in 95% ethanol. This procedure is repeated on day 1. Six days after sensitization (i.e. day 5) mice injected provocative test by local applications, applying 25 μl of 0.8% solution of oxazolone in 95% ethanol on both sides of the right ear and 25 ál of 95% ethanol to the left ears. On day 6 (after 24 hours after infection) mice hammer, remove both ears and immediately prepare standard tissue discs from each ear, using cortical Bor. You should pay attention to the fact that the tissue samples were selected from the same ear zone. Immediately measure the mass of the tissues of the ear disks. Compound administered orally at the dose of 5 mg/kg once daily for 7 days (from day 0 to day 6), introducing the last dose 2 hours prior to driving.

Alternatively, mice sensibiliser at day 0 by applying to the surface of the shaved skin of the abdomen 50 µl of 1% solution of dinitrochlorobenzene (DNCB) in a mixture of acetone:olive oil at a ratio of 4:1. This procedure is repeated on day 5. Starting from the eleventh day after the initial sensitization, the mice injected provocative test, 3 times (on days 10, 11 and 12)by double the first application, applying 25 μl of 0.5% DNCB, dissolved in a mixture of acetone:olive oil at a ratio of 4:1, on both sides of the right ear and 25 μl of the solvent left ears. Twenty-four hours after stimulation, mice score, as described above. Compound administered orally at the dose of 10 mg/kg once daily for 5 days (from day 8 to day 12), entering the last dose 2 hours before infection.

Ear oedema expressed through weight gain ear and calculated by subtracting the weight of the left ear (infection of the solvent) of the weight of the right ear (infection chemical hapten). The percentage suppression of ear swelling drugs calculated using the following equation: 100-((edema drug/average control swelling)·100).

Compounds according to the invention can be evaluated by this test in order to determine the ability to inhibition caused by oxazolone and DNCB skin inflammation.

The EXAMPLE IN

The influence of compounds in ear oedema model in mice TH2 hypersensitivity of the delayed type, caused fluoresceinisothiocyanate.

Mice sensibiliser at day 0 by applying to the surface of the skin shaved belly 50 µl of 0.5% solution fluoresceinisothiocyanate (FITC) in a mixture of 1:1 acetone and dibutyl phthalate. This procedure is repeated at day 7. Fourteen days after sensitization (i.e. on day 13) mice injected provocative test is houtem local applications applying 25 μl of 0.5% FITC dissolved in a mixture of 1:1 acetone and dibutyl phthalate, on both sides of the right ear and 25 μl of a solution of a mixture of 1:1 acetone and dibutyl phthalate on the left ears. On day 14 (after 24 hours after infection) mice hammer, remove both ears and immediately prepare standard tissue discs from each ear, using cortical Bor. You should pay attention to the fact that the tissue samples were selected from the same ear zone. Immediately measure the mass of the tissues of the ear disks. Compound (5-10 mg/kg) or solvent administered orally once daily for 3 days (from day 11 to day 13) for 2 hours before infection.

Ear oedema expressed through weight gain ear and calculated by subtracting the weight of the left ear (infection of the solvent) of the weight of the right ear (infection FITC). The percentage suppression of ear swelling drugs calculated using the following equation: 100-((edema drug/average control swelling)·100).

It is shown that the compounds according to the invention, the evaluation according to this test, inhibit FITC-induced skin inflammation at doses less than 20 mg/kg

EXAMPLE WITH

The effect of compounds on LPS-induced peritonitis in mice

Mice injected the drug (5 mg/kg) or solvent orally every day for four days, entering the last dose 2 hours before infection. N is day 4 mice stimulated with either saline, or lipopolysaccharide (LPS), dissolved in physiological solution (4 mg/kg) via intraperitoneally injection. At 24 h or 48 h after stimulation, animals anaesthetize and apply euthanasia by transthoracic cardiac exsanguination. The peritoneal cavity was washed with ice EDTA-containing phosphate buffered saline (PBS). Peritoneal wash fluid and centrifuged to remove the supernatant. The precipitate in the test tube resuspending in PBS at 4°C. Cytopenia samples receive and paint manual for differentiation and enumeration of cell types. In addition, resuspending wash liquid to analyze the absolute number of cells and cell differentials using a Hematology analyzer CellDyn 3700SC (Abbott Laboratories Inc.).

It is shown that the compounds according to the invention, the evaluation according to this test, inhibit LPS-induced peritoneal inflammation at doses less than 20 mg/kg

EXAMPLE D

The influence of compounds on the destruction of cartilage in mice

This model is used to study the effects of new compounds on the destruction of cartilage induced natural inflammatory reaction caused by the implantation of a foreign body. Activity in this model may indicate activity against arthritis.

Zavodny Grudin the initial cartilage promptly remove rats scored with the help of CO2, washed with hibitane and rinse it with sterile phosphate buffered saline. From the sternum remove disks with a diameter of 4 cm using the biopsy forceps skin stainless steel, No. 4, and cut in half. Each half before implantation weighed and wrapped in a pre-weighed, wet, sterile cotton wool. A piece of cartilage wrapped in cotton wool, implanted subcutaneously in each dorsolateral surface shot females CD/1 mice (age 6-8 weeks) through an incision of 1 cm along the dorsal midline (day 0). Mice injected the samples oral way 3-17 days. On day 18 mice hammer, remove the wool and cartilage, and the cartilage separates from wool. Weigh as cartilage and wool and calculate the difference between the masses before and after implantation. Wool washed with 1 ml buffer, receive cytopenia products and paint for differentiation and enumeration of cell types. In addition, resuspending wash liquid to analyze the absolute number of cells and cell differentials using a Hematology analyzer CellDyn 3700SC (Abbott Laboratories Inc.).

Carry out the fermentation of cartilage over night in a solution of papain and testingground at 65°C, analysis of the content remaining in the cartilage glycosaminoglycan spectrophotometric method and races is citybeat as %GAG/mg of decomposed cartilage (refer to the mass of cartilage prior to implantation).

Compounds according to the invention can be evaluated by this test in order to determine the ability to inhibition of cartilage destruction.

EXAMPLE E

The influence of compounds on induced irritant ear oedema in mice

The number of mice uniquely identify, applying a label with an indelible marker on the tail. Mice administered orally 15 mg/kg of the test compound in 100 μl of 45% β-cyclodextrin in saline. Anaesthetize mice for a short time with 2% halothane gas, and 2 µg of phorbol-12-myristate-13-acetate (PMA) in 25 μl of acetone applied on the inner and outer sides of the left ear of the mice. Acetone is applied in the same way on the right ear of mice, which serves as a control with the solvent. Control animals subjected to the same treatment, but without the test compound. 3 hours later mice slaughtered by their necks, and a standard size specimen for biopsy from each ear and weighed with an accuracy up to 1/10 mg. analyze Data differences between each left ear and the right ear and then calculate % inhibition of edema by the formula (((average Rx/average of the stimulus))×100)-100.

Compounds according to the invention can be evaluated by this test in order to identify the ability to inhibition of PMA-induced skin edema.

EXAMPLE F

The influence of compounds on the CIT is CIN-induced transendothelial leukocyte migration

Test with flow cells allows in vitro studies of the influence of the tested compounds on the adhesion of leukocytes in relation to the endothelium of human. Using a parallel flow chamber tablet carry out perfusion of human blood with physiological velocities through inflamed HUVEC monolayer.

HUVEC monolayers were obtained when 3 passage in a Petri dish 35 mm, coated with 2% gelatin and 5 mg/ml fibronectin. After 3 days confluent monolayers treated with 25 μg/ml TNF-α for 4 hours. Add test connection, if necessary, under appropriate incubation time (10 min or 4 h). Blood taken from healthy adult, trying to enter into vacuum tubes containing heparin sodium, and stored at 37°C. the Blood is treated with the test compound at various concentrations for 10 min at 37°C. Then perform the perfusion of whole blood through a flow chamber for 2 min at a shear of 10 Dyne/cm2. After which the monolayers are washed with HBSS at 37°C for approximately 6 min at 10 Dyne/cm2. First wash period produce a video layers on the magnetic tape. During the last 5 min wash period, moving, sticking and transmigrasi leukocytes counted manually under the microscope lens 20X, within two fields of view, every min the. Adhesive leukocytes are defined as remaining motionless for at least 10 seconds. The data for each minute average and expressed through the percentage of inhibition relative to solvent-treated TNF-α-stimulated sample. The effectiveness of the drug compared with zolototovarnoye the control sample, obtained by treatment of HUVEC monolayer using antibodies against E-selectin human (10 μg/ml) and blood antibody rats against human CD18 (20 μg/ml), and the other for 10 minutes at 37°C.

It is shown that the compounds according to the invention, the evaluation according to this test, inhibit TNF-α-induced leukocyte migration at concentrations of less than 20 microns.

EXAMPLE G

The influence of compounds on allergen-induced lung inflammation in rats

The ability of compounds to inhibit allergen-induced accumulation of cells in areas of inflammation, such as eosinophils and neutrophils, in the washing liquid derived from sensitized animals, testifies to the activity of the compounds against asthma. In particular, this model system is useful in evaluating the effects of the test compounds in the treatment response in the late phase of asthma, when it is evident pneumonia and the second phase of bronchoconstriction, and allergies, particularly when struck by the Republic of iratory system. The test is carried out as follows.

Male rats Brown Norway sensibiliser the ovalbumin by a single intraperitoneally injection of 1 mg of ovalbumin adsorbed on 100 mg Al(OH)3(alum), in 1 ml of sterile physiological solution (rats group control saline injected sterile saline) on day 1, and leave to sensitize until day 21. Compound administered orally each day for three days before stimulation (days 19, 20, 21) and one day after stimulation (day 22), introducing the third dose 2 hours prior to stimulation, and the dose of the fourth day after 24 hours of stimulation (volume=300 μl/dose). Rats injected provocative test in 5% ovalbumin in saline solution, treating spray Devillbis'a for 5 min on day 21.

Forty-eight hours after stimulation slaughtered by overdose administered intraperitoneally-injected pentobarbitalaboutLa sodium and spend the lung lavage using 2×7 ml of chilled phosphate buffered saline. The extracted wash liquid is placed on the ice. Bronchoalveolar wash liquid and centrifuged to remove the supernatant. The precipitate in the test tube resuspended in phosphate buffered saline at 4°C. Cytopenia samples and get okras shall provide for differentiation and enumeration of cell types. It is shown that the compounds according to the invention inhibit allergen-induced lung inflammation at doses less than 20 mg/kg

EXAMPLE H

The influence of compounds on allergen-induced bronchoconstriction in mice

Model hyperreactive respiratory tract of rats (AHR) Buxco, well described by numerous researchers, simulates a strong narrowing of the Airways in response to aerosol stimulation characterizing sensitized animals compared to desencibiliziruuchee animals. The Buxco system used method, called General plethysmography, which quantify due to breathing pressure changes in the chamber, using the correlation between the increased resistance of the Airways and an increased ratio of the time of expiration/respiratory pause, to calculate the degree of narrowing of the Airways (Penh). After allergen sensitization and inhalation stimulation of the respiratory tract Penh increases compared to minimalinvasive, mnemotrauma animals. Thus, the effectiveness of potential anti-inflammatory agents can be established by assessing the impact of this tool on ovalbumin-induced AHR.

Female Balb/c mice sensibiliser on day 1 and 14 by I.P. injection of 100 μl of sterile saline, sod is rasego 20 μg of ovalbumin and 2.25 mg Al(OH) 3. Minimalinvasive mice injected with 100 μl of sterile saline. Compound (5 mg/kg) administered orally by forced feeding through a tube for five consecutive days, two days before stimulation (days 26 and 27) and within three days of stimulation with ovalbumin (days 28, 29 and 30, for 2 hours before stimulation). Mice injected provocative test by spraying the aerosol of ovalbumin (5% in saline) for 20 min on days 28, 29 and 30. On day 31 mice are placed in chambers for a total plethysmography combined Buxco system and measure airway reactivity in relation to stimulation of aerosol PBS and methacholine (MCh; 0,78, 1,56, 3,125, 6,25, 12,5, 25, 50 mg/ml), expressed through Penh.

It is shown that the compounds according to the invention, the evaluation according to this test, inhibit allergen-induced Hyper-reactivity of the respiratory tract at doses less than 20 mg/kg

EXAMPLE I

The effect of compounds on LPS-induced acute lung inflammation in rats.

Rats injected drug (1-20 mg/kg) or solvent orally every day for four days before infection. On day 4 rats stimulated with either saline or LPS dissolved in physiological solution (2 mg/kg), through intraperitoneally instillation. Slaughtered by overdose entrap rivelino-enter pentobarbital sodium 3 hours after stimulation and spend the lung lavage using 14 ml of phosphate buffered saline (PBS). Lung wash fluid is centrifuged at 300 g for 3 min and remove supernatant. The precipitate in the test tube resuspended in 1-3 ml of PBS at 4°C depending on the sediment size and the number of total leukocytes. The amount of the final cell suspension, containing approximately 240,000 cells, add the appropriate volume of PBS at 4°C, receiving the final volume of 220 μl and a final concentration of 1×106cells/ml (final cytopenia suspension). A sample of 100 µl (100,000 cells) are placed on cytocentrifuge and spin for 4 minutes at 55 g. Get two microscopic preparation for leaching test, fix and paint in DifQuik. In addition, resuspending wash liquid to analyze the absolute number of cells and cell differentials using a Hematology analyzer CellDyn 3700SC (Abbott Laboratories Inc.).

It is shown that the compounds according to the invention, the evaluation according to this test, inhibit LPS-induced lung inflammation at doses less than 20 mg/kg

EXAMPLE J

The effect of compounds on LPS-induced acute lung inflammation in mice

Rats injected drug (1-20 mg/kg) or solvent orally every day for four days before infection. On day 4 rats stimulated with either saline or LPS dissolved in physiological solution (0.15 mg/kg) e the PTO intratracheal instillation. Slaughtered by overdose administered intraperitoneally-injected pentobarbitalaboutLa sodium later, 6 hours after stimulation. After thoracotomy spend lung lavage using a 3×0.75 ml PBS. Bronchoalveolar wash liquid is centrifuged, and remove supernatant. The precipitate in the test tube resuspending in PBS at 4°C. Cytopenia products are obtained and stained for differentiation and enumeration of cell types. In addition, resuspending wash liquid to analyze the absolute number of cells and cell differentials using a Hematology analyzer CellDyn 3700SC (Abbott Laboratories Inc.).

It is shown that the compounds according to the invention can be evaluated by this test in order to determine the ability to inhibition of LPS-induced lung inflammation.

EXAMPLE FOR

The influence of compounds on the synthesis of prostaglandin E2

Prostaglandin E2 (PGE2) is the primary product of the metabolism of arachidonic acid (AA). Like most eicosanoids PGE2 does not exist in advance in cellular reservoirs. The PGE2 synthesis is catalyzed by the cyclooxygenase-2 (COX-2), inducible enzyme, which is activated by inflammatory stimuli, cytokines and mitogens. Activation of COX-2 leads to increased production of PGE2. Reported the presence of high concentrations of PGE2 in chronic inflammatory States, still is as rheumatoid arthritis and asthma. Inhibition of the synthesis of COX-2 and PGE2 is the main goal of therapy of the future, aimed at treatment of inflammatory arthropathy.

Endothelial cells of the umbilical vein of a person (HUVEC-C) are grown to confluence in a coated gelatin Petri dishes in the presence of endothelial culture medium (EGM-2). When tested EGM-2 replace with medium RPMI-1640 containing 2% serum fetal calf (FBS). HUVEC-Cs incubated with compounds for 1 hour before stimulation with IL-1β for 24 hours. Exogenous AA added over a period of 15 minutes and determine the concentration of PGE2 in supernatant cell culture method competitive enzyme immunoassay (EIA).

Compounds are dissolved at a concentration of 20 mm in DMSO and explore the analytical method at the 5 and 1 μl with a final concentration of DMSO of 0.05%. Use triplicate analytical samples. Controls included in each experiment are intact cells treated with IL-1β cells treated with NS-398/IL-1β cells and a standard curve of known concentrations of PGE2. NS-398 is a selective inhibitor of COX-2. The concentration of PGE2 calculated using the appropriate software for log-logit transformation curve and correlating the data with PGE2 concentration on the standard curve.

The percentage inhibition calculated as follows: % I=100-[PGE2]C/[PGE2]Co×100, where [PGE2]C means the concentration of PGE2 in the mixture connection/processed IL-1β sample and [PGE2]Comeans the concentration of PGE2 in the processed IL-1β in the sample.

It is shown that the compounds according to the invention inhibit the synthesis of PGE2 at concentrations less than 10 mg/kg

All of the above U.S. patents, published patent applications U.S. patent application U.S., foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application instructions, fully incorporated herein by reference.

It follows from the above that, although specific embodiments of the invention described herein for purposes of illustration, can be implemented with various modifications, is not beyond the nature and scope of the invention. Therefore, the invention is not limited by anything except the enclosed items.

1. The compound of formula (I)

where ring a, C or D is independently fully or partially saturated;
each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms;
each of C9 and C14 is independently substituted by hydrogen atom;
R1means-OR7or-N(R7)2;
each of R2and R3independently selected from the group comprising: -R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R )C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl,
substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, Fe is Il, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain;
in the form of a single stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers;
or pharmaceutically acceptable salt of the compounds.

2. The compound according to claim 1, where
R1means ORsup> 7;
each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl,
substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4Aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10 -N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

3. The compound according to claim 2, where
R1oz ACHAT-OR 7;
R2means R8-OR7;
R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl, substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position 16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR 9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

4. The compound according to claim 3, br/> R1means-OR7;
R2means R8-OR7;
R3means R8-OR7;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position 16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl;
R6means hydrogen;
each R7independently selected from the group including hydrogen, C1-C6alkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2;
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain.

5. The compound according to claim 4, selected from the group including
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)diclohexal)-4α-hydroxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-hydroxyethyl)-7β-methyl-1-meth is inactiveborder;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-hydroxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-hydroxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)cyclohexyl)-4α-hydroxy-7β-methyl-3A,4,5,6,7,7a-hexahydro-3H-inden;
5-(1β-methyl-4β-hydroxy-2β-(4-benzyloxy-1-EN-1-yl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(4-hydroxyben-1-EN-1-yl)diclohexal)-4α-hydroxymethyl-7β-methyl-1-methylenechloride and
5-(1β-methyl-4β-hydroxy-2β-(3-hydroxyprop-1-EN-1-yl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride.

6. The compound according to claim 3, where
R1means-OR7;
R2means R8-OR7;
R3means R10-N(R7)2;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group including hydrogen, R 10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

7. Soedinenie claim 6, selected from the group including
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-ethylidenecyclopentane-ammonium chloride;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-methylenechloride-ammonium chloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-amino-ethyl)-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-amino-ethyl)-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-aminomethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-deformitiesaccutane;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-deformitiesaccutane-ammonium chloride;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-dichlorohydroquinone-ammonium chloride;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1β-(propen-2-yl)octahedron;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxym titikaveka)-4α-aminomethyl-7β-methyl-1β-(propen-2-yl)octahedron-ammonium acetate;
salt 5-(1β-methyl-4α,5α-dihydroxy-2β-hydroxymethylcellulose)-4α-aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(4-dimethylamino-2Z-EN-1-yl)-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(4-dimethylamino-2Z-EN-1-yl)-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(ethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(benzyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(cyclopropylmethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(dimethyl)aminomethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(dimethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(methyl)aminomethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(methyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(2-methylpropyl " aminoet the l-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(2-methylpropyl " aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(1-methylpiperidin-4-yl)aminomethyl-7β-methyl-1-methylenechloride-ammonium diacetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(3-nitrobenzyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(piperonyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(pyrrol-2-ylmethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(furfuryl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(pyridine-3-ylmethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-methylpropyl " aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(pyridine-3-ylmethyl)aminomethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-hydroxyethyl)aminomethyl-7β-methyl-1-methylenechloride-acetate AMM is tion;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(furfuryl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-dimethylaminoethyl)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-cyclohex-1-EN-1-retil)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-morpholine-4-retil)aminomethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(3-were)aminomethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(benzyl)aminomethyl-7β-methyl-1-methylenechloride and
5-(1β-methyl-2β,4β-dihydroxyphenyl)-4α-(2-(3-were)aminoethyl)-7β-methyl-1-methylenechloride.

8. The compound according to claim 2, where
R1means-OR7;
R2means R10-N(R7)2;
R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-
With6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkene is-phenyl, substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms is selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

9. The connection of claim 8, where
R1means-OR7;
R2means R10-N(R7)2;
R3means R8-OR7;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-sub> 6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
ka is every R 10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

10. The compound of claim 9 selected from the group including
salt 5-(1β-methyl-4β-hydroxy-2β-(2-amino-ethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-amino-ethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-ethylidenecyclopentane-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-enyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-enyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(3-dimethylaminopropyl-1-EN-1-yl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(-dimethylamino-1-EN-1-yl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-dimethylaminoethyl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydrxy-2β-(cyclohexyl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(pyridine-3-ylmethyl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(3-forfinal)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(pyridin-3-yl)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(3-were)aminoethylthiomethyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(3-terbisil)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(1,3-benzodioxol-5-yl)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-methyl is ropyl)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(cyclohexyl)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(N-phenyl-N-methylamino)methylcyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(pyridine-3-ylmethyl)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(furfuryl)aminoethylthiomethyl)-4α-hydroxy-7β-
methyl-1-methylisothiazoline-acetate ammonia;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-hydroxyethyl)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(3-were)aminoethylthiomethyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-(2-dimethylaminoethyl)aminoethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(2-(1,3-benzodioxol-5-yl)aminoethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-(cyclohexyl)aminoethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-(2-(3-triptoreline)aminoethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride and
salt 5-(1β-methyl-4β-hydroxy-2β-(2-(2-methylpr who drank)aminoethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate.

11. The connection of claim 8, where
R1means-OR7;
R2means R10-N(R7)2;
R3means R10-N(R7)2;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2C1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered hetaeras the aryl with 1 heteroatom, selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

12. Connection claim 11, selected from the group including
5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminoethylthiomethyl)-4α-aminomethyl-7β-methyl-1-methylenechloride and
salt 5-(1β-methyl-4β-hydroxy-2β-(cyclopentyl)aminoethylthiomethyl)-4α-aminomethyl-7β-methyl-1-methylenechloride-ammonium diacetate.

13. The compound according to claim 1, where
R1means-N(R7)2;
each of R2and R3independently selected from the group comprising R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-the 6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl,
substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-Fe is Il, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

14. The connection 13, namely, salt 5-(1β-methyl-4β-amino-2β-hydroxymethylcellulose)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate.

15. The compound according to claim 3, where
R1means-OR7;
R2means R8-OR7;
R3means R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is avno 1 or 2), R10-N(R9)C(NR9)N(R9)2;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatom and 1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

16. The connection 15, selected from the group including
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(methylsulphonyl)aminomethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(acetyl)aminomethyl-7β-methyl-1-methylenechloride and
salt 5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(guanidino)methyl-7β-methyl-1-methylenechloride-ammonium chloride.

17. The compound according to claim 2, where
R1means-OR7;
R2selected from the group comprising-R8-OC(O)R9, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-dryer is l, substituted with halogen, C2-C6alkenyl-phenyl, substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
R3means R8-OR7or-R8-OC(O)R9;
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, not battelino substituted with halogen or NO 2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

18. The connection 17, selected from the group including
salt 5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-4α-hydroxy-7β-methyl - 1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-(4-chlorophenyl)ethyl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate;
salt 5-(1β-methyl-4β-hydroxy-2β-(2-pyridin-3-retil)cyclohexyl)-4α-hydroxy-7β-ethyl-1-methylenechloride-ammonium acetate;
5-(1β-methyl-4β-hydroxy-2β-ethylcyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-(4-ethoxyphenyl)ETH-1-EN-1-yl)cyclohexyl)-4α-acetoxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-2-yl)ETH-1-EN-1-yl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-(pyridin-3-yl)ETH-1-EN-1-yl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(hept-1-EN-1-yl)diclohexal)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(2-(4-chlorophenyl)ethynyl)cyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2Z-EN-1-yl)cyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride;
5-(1β-methyl-4β-hydroxy-2β-(3-(4-chlorophenyl)prop-2E-EN-1-yl)diclohexal)-4α-hydroxy-7aβ-methyl-1-methylenechloride;
salt 5-(1β-methyl-4β-hydroxy-2β-(pyrrolidin-1-yl)methylcyclohexyl)-4α-hydroxymethyl-7β-methyl-1-methylenechloride-ammonium acetate and
salt 5-(1β-methyl-4β-hydroxy-2β-(morpholine-4-yl)methylcyclohexyl)-4α-hydroxy-7β-methyl-1-methylenechloride-ammonium acetate.

19. The compound according to claim 3, where
R1means-OR7;
R2means R8-OR7;
R3means1-C6alkyl-(5-6-membered saturated heterocyclyl or 2 heteroatoms, selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position 16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroa the Ohm and C 1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain.

20. The connection according to claim 19, selected from the group including
5-(1β-methyl-4β-hydroxy-2β-hydroxymethylcellulose)-4α-(imidazol-1-yl)methyl-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(3-pyridin-3-rprop-2Z-EN-1-yl)-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(3-pyridin-3-rprop-2E-EN-1-yl)-7β-methyl-1-methylenechloride;
5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-pyrrolidin-1-retil)-7β-methyl-1-methylenechloride and
salt 5-(1β-methyl-2β,4β-dihydroxytoluene)-4α-(2-pyrrolidin-1-retil)-7β-methyl-1-methylenechloride-ammonium acetate.

<> 21. Pharmaceutical composition having anti-inflammatory activity, containing a pharmaceutically acceptable excipient and an effective amount of a compound according to claim 1

where ring a, C or D is independently fully or partially saturated;
each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms;
each of C9 and C14 is independently substituted by hydrogen atom;
R1means-OR7or-N(R7)2;
each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl, substituted-R8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
l is Bo R 4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O and N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group, enabling the th direct link, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain;
in the form of a single stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers;
or pharmaceutically acceptable salt of the compounds.

22. The use of the compounds of formula (I)

where ring a, C or D is independently fully or partially saturated;
each of C1, C4, C11, C12, C15 and C16 is independently substituted with two hydrogen atoms;
each of C9 and C14 is independently substituted by hydrogen atom;
R1means-OR7or-N(R7)2;
each of R2and R3independently selected from the group comprising-R8-OR7, -R8-OC(O)R9, -R10-N(R7)2, -R10-N(R9)C(O)R9, -R10-N(R9)S(O)tR9(where t is 1 or 2), -R10-N(R9)C(NR9)N(R9)2C1-C6alkyl, C2-C6alkenyl, C1-C6alkyl-phenyl, substituted by halogen, C2-C6alkenyl-phenyl, Zam is on-R 8-OR7or halogen, With1-C6alkyl-(5-6-membered saturated heterocyclyl with 1 or 2 heteroatoms selected from O or N), C1-C6alkyl-(5-6-membered heteroaryl with 1 or 2 N atoms as heteroatoms) and (C2-C6alkenyl-(6-membered heteroaryl with one N atom as the heteroatom);
each of R4aand R4bindependently selected from hydrogen and C2-C6alkenyl;
or R4ameans hydrogen, and R4bmeans a direct bond to the carbon in position C16;
or R4aand R4btogether form a C1-C6alkylidene or halogen-C1-C6alkylidene;
R5means C1-C6alkyl, or R5means a direct bond to the carbon in position C14;
R6means hydrogen or R8-OR7;
each R7independently selected from the group comprising hydrogen, -R10-OR9, -R10-N(R9)2C1-C6alkyl, C3-C7cycloalkyl, partially saturated or saturated C1-C6alkyl-C3-C6cycloalkyl, phenyl, optionally substituted C1-C6by alkyl, halogen or halogen-C1-C6the alkyl, C1-C6alkyl-phenyl, optionally substituted with halogen or NO2With1-C6alkyl-(6-membered heterocyclyl with 1 or 2 heteroatoms selected from O Is N, optionally substituted C1-C6by alkyl), 6-membered heteroaryl with 1 nitrogen atom as heteroatoms, and C1-C6alkyl-(5-6-membered heteroaryl with 1 heteroatom selected from O and N), 9-membered heteroaryl with 2 oxygen atoms as heteroatoms and C1-C6alkyl-(9-membered heteroaryl with 2 oxygen atoms as heteroatoms);
each R8independently selected from the group comprising a direct bond, linear or branched C1-C6alkylenes chain and linear or branched C2-C6alkenylamine chain;
each R9independently selected from hydrogen and C1-C6of alkyl; and
each R10independently selected from the group including linear or branched C1-C6alkylenes and linear or branched C2-C6alkenylamine chain;
in the form of a single stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers;
or pharmaceutically acceptable salts of the compounds
to obtain drugs having anti-inflammatory activity.

23. The application of article 22, where the drug is intended for treatment of allergen-induced inflammation.



 

Same patents:

FIELD: medicine.

SUBSTANCE: present invention concerns lysine compounds of formula (I) or its pharmaceutically acceptable salts, a based pharmaceutical compositions and application for treatment or prevention of HIV-infection. The compounds of formula (I) where n is equal to 3 or 4, where X and Y identical or different are chosen from the group consisting of H, F, Cl, Br, I and -NR4R5, where R6 is chosen from the group consisting of unbranched alkyl group, containing 1 to 6 carbon atoms, and branched alkyl group containing 3 to 6 carbon atoms, where R3 is chosen from the group consisting of the group of formula R3A-CO-, and R3a is chosen from the group consisting of unbranched or branched alkyl group containing 1 to 6 carbon atoms, alkyloxygroup containing 1 to 6 carbon atoms, and 4-morpholinyl, where R4 and R5 are identical and represent H, where R2 is chosen from the group consisting of diphenylmethyl group, naphthyl-1-CH2-group, and naphthyl-2-CH2-group, where X' and Y' are identical and represent H, and where R1 is chosen from the group consisting of from (HO)2P(O) and (MO)2P(O), where M represents alkaline metal.

EFFECT: lysine compounds representing effective inhibitors of aspartyl-protease.

15 cl, 3 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel bioisosteres of actinonin of general formula (I) , as well as to pharmaceutically acceptable salts thereof and pharmaceutical compositions based on said compounds, with peptide deformylase (PDF) inhibitory activity, as well as to use of the compounds or pharmaceutical compositions based on said compounds to prepare medicinal agents. In general formula (I) R1 is a hydrogen atom, R2 is a hydrogen atom, (C1-C6)alkyl residue, hetero(C1-C6)alkylphenyl residue, where the heteroatom is sulphur, R3 is a hydrogen atom, R4 is (C1-C6)alkyl residue, (C3-C7)cycloalkyl residue, R6 is a hydrogen atom, n is 1, 2 or 3. Values of substitute R5 are given in the formula of invention.

EFFECT: new compounds have useful biological activity.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: pharmacy.

SUBSTANCE: invention relates to novel crystalline water-soluble salts of (2S,3S)-enantiomer of 2-[α-(2-ethoxyphenyl)benzyl]-morpholine that are its fumarate and succinate salts. Also, invention relates to a method for their preparing and their using in preparing pharmaceutical composition possessing property of selective inhibitor of reverse uptake of norepinephrine, and to a pharmaceutical composition comprising thereof.

EFFECT: improved and valuable properties of drug.

7 cl, 6 tbl, 5 dwg, 3 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

The invention relates to thiosulfonate formulas

< / BR>
< / BR>
or

< / BR>
< / BR>
< / BR>
where R1represents a radical having a length greater than the saturated chain of four carbon atoms, and shorter than the saturated chain from eighteen carbon atoms, and in rotation around the axis passing through the position 1, associated with the SO2and position 4 6-membered ring or through position 1, associated with the SO2group and associated with the Deputy position 3 or 5 of the 5-membered ring, defines a three-dimensional volume, the largest size in which the width is approximately one phenyl ring up to three phenyl rings in a direction transverse to the axis of rotation; R2means hydrido,1-C6alkyl, phenyl-C1-C4alkyl, heteroaryl-C1-C4alkyl, C2-C4alkyl substituted amino; C2-C4alkyl, substituted monosubstituted amino or disubstituted amino, where-C6) alkyl, C5-C8cycloalkyl and C1-C6alkylsulphonyl, or where two of the substituent and the nitrogen to which they are attached, together form pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, and other pyrimidinyl

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

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

25 cl, 1 tbl, 14 ex

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals

The invention relates to the separation and purification of 2-methylimidazole, which is an intermediate for the synthesis of antitrichomonas, protivoallergennogo drug metronidazole and accelerator curing epoxy resins
The invention relates to methods for C-alkylimidazole, in particular 2-substituted imidazoles

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

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