HK1134821B - Amino derivatives of androstanes and androstenes as medicaments for cardiovascular disorders - Google Patents

Description

Amino derivatives of androstanes and androstenes as cardiovascular agents

Technical Field

The present invention relates to novel amino derivatives at position 3 of 5-and/or 6-and/or 7-substituted androstanes and androstenes, processes for their preparation, and to pharmaceutical compositions comprising them for the treatment of cardiovascular disorders such as heart failure and hypertension.

Background

Cardiovascular disease remains the first cause of morbidity and mortality in the western world; among them, hypertension and heart failure are two kinds of multiple diseases. Hypertension is one of the most important cardiovascular risk factors, and over one third of the population over the age of 60 suffer from this disease. Congestive heart failure affects 1-2% of the population, 10% of the very elderly; the ratio is expected to rise (Sharpe N., et al, The Lancet, 1998, 352, (suppl.1), 3-17). In addition, hypertension is probably one of the most important factors causing heart failure in the elderly (eur. heart j., 2001, 22, 1527-. Although a number of have been effectiveDrugs that can treat hypertension and heart failure are still under further investigation to find more effective and safe compounds. Several drugs are used in combination for the treatment of heart failure, among which digoxin is the most used digitalis cardiac glycoside that can improve cardiac performance. A well-known drawback of the digitalis class of drugs is their arrhythmogenic side-effects. Evidence of Digitalis toxicity (e.g., conduction interference and arrhythmias, both characteristic of Digitalis toxicity) occurs at serum concentrations two to three times higher than therapeutic doses (Hoffman, B.F.; Bigger, J.T., Digitalis and Allied Cardiac glycosides, in The pharmacological basis of Therapeutics, 8 ^thed., Goodman Gilman, A.; Nies, A.S.; Rall, T.W.; Taylor, P., eds.; Pergamon Press, New York, 1990, pp 814-839). The ability of natural digitalis compounds to increase myocardial contractility depends strictly on their cardiac glycoside structure of 17 β -lactone on the 14-hydroxy-5 β,14 β -androstane skeleton.

Description of the prior art

In the field of steroid derivatives, certain classes of compounds are reported to have inotropic properties or other activities related to the cardiovascular system.

In particular, the following literature is focused on pregnane derivatives.

GB868,303 discloses pregnane-20-one derivatives having progestational and anti-fibrillation effects.

Other aminoalkyl esters of 3 beta-hydroxypregna-5-en-20-one derivatives are disclosed in GB966,060 as having appetite suppressant, anti-arrhythmic and anti-atherosclerotic activity and in US3,013,009 as having harmonizing, anti-convulsive and anti-hypertensive activity.

US5,144,017 discloses "digitalis receptor binding compounds" including androstane and pregnane derivatives. According to the inventors, binding to the digitalis receptor is analogous to the ability to elicit a characteristic cellular response. The inventors have focused on the ability of different classes of steroids to form glycoside derivatives which have a typical digoxin-like action on heart and other tissues, which may be important in increasing the toxicity of such compounds. Although partial androstane derivatives have been reported, a more interesting compound is the 3-glycoside of a pregnane derivative.

Pregnane amidinohydrazones with cardiotonic action are reported in S.Et al, Arzneimittel-Forschung, 1969, 19, 69-75. Amidinohydrazone groups are particularly critical to the activity of these compounds, since "replacement of amidinohydrazone groups with other relevant residues can lead to loss of activity".

Other pregnen-20-one derivatives such as chlormadinone acetate and megestrol acetate are reported to inhibit Na⁺,K⁺-ATPase activity, but they "do not cause contractile action alone" (K.Temma, et al, research. Comm. chem. in Pathology and Pharmacology, 1983, 41, 51-63).

In the field of 5 α,14 α -androstanes, the following documents are of interest.

GB1,175,219 and US3,580,905 disclose "3- (aminoalkoxycarbonylalkyl-ene) steroid derivatives with digitalis-like activity" in which the ratio between the dose giving rise to the toxic symptoms (arrhythmic episodes) and the effective dose is comparable to the ratio measured with standard cardiac glycosides ". This highest proportion of compound produces the least contractile force, except for the lack of clear advantage over digitonin.

6-hydroxy and 6-oxoandrostane derivatives are disclosed as ligands and Na in EP0825197B1⁺,K⁺-inhibitors of atpase, and cardiotonic drugs with lower toxicity (assessed on the basis of acute toxicity in mice) compared to digoxin. The same compounds are also reported in s.de Munari, et al, j.med.chem.2003, 64, 3644-.

The evidence that high levels of Endogenous Ouabain (EO) (the very close isomer of ouabain) are associated with hypertension and cardiac hypertrophy in humans and heart failure has stimulated pharmaceutical research to develop novel antihypertensive drugs with ouabain antagonist action. The pathogenesis of increased EO levels affecting the cardiovascular system includes regulation of Na-K atpase, key enzymes responsible for sodium reabsorption from the renal tubular epithelium, and activation of signal transduction pathways involved in transcription of growth-related genes. After simultaneous studies in both genetic and experimental rat models of hypertension and comparison with humans, increased circulating EO levels and genetic polymorphisms in cytoskeletal protein adducin were demonstrated to be associated with hypertension and high renal Na-K pump activity. Ouabain itself induces hypertension and up-regulates renal Na-K pump (OS) when perfused into rats at low doses for a long period of time. In cultured kidney cells, both incubation with nanomolar concentrations of ouabain for several days and transfection with genetic variants of adducin in hypertension resulted in an increase in Na-K pumping. In addition, EO and adducin polymorphisms can affect cardiac complications associated with hypertension, the former being affected by activation of signal transduction pathways. Thus, compounds that interact with cellular and molecular level changes and are maintained by EO or mutant adducin may be useful as therapies for patients in whom these mechanisms are implicated (Ferrandi M., et al, Curr Pharm Des.2005;11(25): 3301-5).

As reported above, a key point of cardiotonic drugs is the ability to discriminate between efficacy, including elevation of myocardial contractility, and the onset of arrhythmia.

There is a continuing need for drugs that exhibit better therapeutic rates and/or longer duration of action, both of which are important factors in patient compliance. Preferably, the medicament is administered by the oral route.

Other substituted steroids are reported to have completely different pharmacological activities.

Dehydroepiandrosterone 3 β -amino ethers or amino ethers substituted with a ketone in position 7 or finally substituted alkoxy groups as cosmetic and therapeutic methods for skin disorders associated with keratinous disorders are disclosed in US2003/0054021 and WO03/035023a 1.

Dialkylaminoethers and dialkylaminosulfides of 3 β -hydroxy-6 α -methyl androstanes or 3 β -hydroxy-6-methyl-5-androstenes are disclosed in US3,210,386 as hypocholesterolemic and antiparasitic agents.

Disclosure of Invention

Summary of the invention

It has now been found that 3-amino derivatives of 5-and/or 6-and/or 7-substituted androstanes and androstenes meet the need for drugs with better therapeutic ratios and/or longer duration of action. Some of these compounds result from modifications of the compounds disclosed in EP0825197 and lead to unexpected pharmacological properties.

The compounds of the invention have the general formula (I):

wherein:

a is CHX，C=NO，CR⁷CH=CHCR⁷CH₂，CR⁸XC=O，CR⁸XC (= O) X', wherein the left-terminal carbon atom of any of these groups is in position 3 of the androstane skeleton;

x and X', which may be identical or different, are O, S (O)_xOr NR⁹，

R⁷Is hydrogen or hydroxy;

R⁸and R⁹Independently of each other is H, C₁-C₆An alkyl group;

x is an integer between 0 and 2;

b is C₁-C₆Straight or branched alkylene or C₃-C₆A cycloalkylene group, optionally containing a benzene ring;

r, which may be the same or different¹And R²Is H, C₁-C₆Alkyl, phenyl-C₁-C₄Alkyl or when R¹When it is hydrogen, R²Or may be C (= NR)¹⁰)NHR¹¹Or R¹And R²May be taken together with the nitrogen atom to form an unsubstituted or substituted saturated or unsaturated monoheterocyclic 4-, 5-or 6-membered ring, which optionally contains a further heteroatom selected from oxygen, sulfur or nitrogen, and R¹And R²Optionally substituted with one or more hydroxy, methoxy, ethoxy groups;

r, which may be the same or different¹⁰And R¹¹Is H, C₁-C₆Alkyl, or R¹⁰And R¹¹May form together with the nitrogen atom and the guanidine carbon atom an unsubstituted or substituted saturated or unsaturated mono-heterocyclic 5-or 6-membered ring, which optionally contains a further heteroatom selected from oxygen, sulphur or nitrogen;

R³is H, C₁-C₆Alkyl radical, ONO₂，OR¹²；

R¹²Is H, C₁-C₆Alkyl optionally substituted with one or more hydroxy, methoxy, ethoxy; or R ¹²Is allyl or propargyl;

when connecting the carbon atom at position 6 of androstane skeleton with R⁴Key ofWhen it is a double bond, R⁴Is NOR¹³Or CR¹⁴R¹⁵；

When connecting the carbon atom at position 7 of androstane skeleton with R⁵Key ofWhen it is a double bond, R⁵Is O representing a ketone group, or is NOR¹³Or CR¹⁴R¹⁵；

R¹³Is H, C₁-C₆Alkyl optionally substituted with one or more hydroxy, methoxy, ethoxy; or R¹³Is allyl or propargyl;

r, which may be the same or different¹⁴And R¹⁵Is H, C₁-C₆An alkyl group optionally substituted with one or more hydroxy, methoxy, ethoxy; or R, which may be the same or different¹⁴And R¹⁵Is allyl, propargyl, F, COOR¹⁶，CN，CONR¹⁷R¹⁸Or R is¹⁴And R¹⁵Together form a cycloalkylene substituent;

R¹⁶is H, substituted by one or more hydroxy, methoxyEthoxy optionally substituted C₁-C₆An alkyl group;

r, which may be the same or different¹⁷And R¹⁸Is H, C₁-C₆An alkyl group, or R¹⁷And R¹⁸May optionally form a heterocyclic group together with the nitrogen atom,

when connecting the carbon atom at position 6 of androstane skeleton with R⁴Key ofWhen it is a single bond, R⁴Is H, C₁-C₆Alkyl radical, vinyl radical, ethynyl radical, COOR radical¹⁶，CN，CONR¹⁷R¹⁸，ONO₂，NHCHO，NHCOCH₃，CH=NOH, spirocyclopropan, spirooxirane, wherein the alkyl group may be optionally substituted with one or more hydroxyl, methoxy, ethoxy groups;

When connecting the carbon atom at position 7 of androstane skeleton with R⁵Key ofWhen it is a single bond, R⁵Is H, C₁-C₆Alkyl radical, vinyl radical, ethynyl radical, COOR radical¹⁶，CN，CONR¹⁷R¹⁸，OR¹⁹，ONO₂，NHCHO，NHCOCH₃，CH=NOH, spirocyclopropan, spirooxirane, wherein the alkyl group may be optionally substituted with one or more hydroxyl, methoxy, ethoxy groups;

R¹⁶，R¹⁷and R¹⁸As defined above;

R¹⁹is H, optionally substituted by one or more hydroxy, methoxy, ethoxy groupsSubstituted C₁-C₆An alkyl group;

R⁶is H, C₁-C₆Alkyl radicals or C₂-C₆Acyl groups, the bond in position 17 of the androstane skeletonWhen it is a single bond, the remaining substituent at position 17 is H, when the bond at position 17 isR being a double bond representing a ketone group⁶Is absent;

when R is¹⁶，R¹⁷And R¹⁸May be the same or different when present at different positions of the same compound;

symbolRepresents an alpha or beta single bond, or when it is attached to a double bond, an E or Z diastereomer;

symbols in positions 4, 5, 6, 7 and 17Independently represents a single or double bond, and when it is a monocyclic external bond in positions 6, 7 and 17 it may be an alpha or beta single bond;

the conditions were as follows:

symbol in position 5-6Only double bonds, and the other symbols in positions 4-5 and 6-7 are single bonds, and R⁴Is methyl, A represents CHX, wherein when X is oxygen or sulfur, R ²R¹N is not dimethylamino or diethylamino or morpholino,

when A is CR⁸XC = O or CR⁸XC = OX', wherein R⁸When hydrogen, X is oxygen and X' is O or NH, and when A is CHX, wherein X is oxygen, when the symbol in position 5-6R being a double bond⁵Not oxygen, to position 7⁵Symbol ofIs a double bond, or R⁵Is not OR¹⁹And R is attached in position 7⁵Symbol ofIs a single bond, and is a single bond,

at least R³,R⁴And R⁵One of which is not hydrogen at the same time.

Wherein the compound of formula (I) may exhibit tautomerism, which formula is intended to encompass all tautomers; the present invention includes within its scope all possible stereoisomers, Z and E isomers, optical isomers and mixtures thereof, metabolites and metabolic precursors of the compounds of formula (I).

Pharmaceutically acceptable salts are also included within the scope of the invention. Pharmaceutically acceptable salts are salts which retain the biological activity of the base and are derived from known pharmaceutically acceptable acids (e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, fumaric, succinic, oxalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acids and other acids commonly used in the art).

The C is₁-C₆The alkyl group may be a branched or branched chain or cyclic group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl or cyclohexyl.

The C is₁-C₆The alkenyl group may be a branched or straight chain or cyclic group, for example, ethylene, trimethylene, propylene, tetramethylene, dimethylethylene, cyclopropene, cyclobutene, cyclopentene, cyclohexene.

The C is₂-C₆The acyl group may be a branched or straight chain or cyclic group, and is preferably acetyl, propionyl, butyryl, pivaloyl, cyclopentane-carbonyl.

In the context of the present invention, metabolites and metabolic precursors refer to active metabolites and metabolic precursors, i.e. compounds of formula (I) which are converted by a metabolic reaction, but which substantially retain or enhance pharmacological activity.

Examples of metabolites or metabolic precursors are hydroxylated, carboxylated, sulfonated, glycosylated, uronated, methylated or demethylated, oxidized or reduced derivatives of the compounds of formula (I).

Part of the compound of formula (I) may also be a prodrug of the active form.

A further object of the present invention is the use of said compounds of general formula (I) for the preparation of a medicament useful for the treatment of cardiovascular diseases, such as heart failure and hypertension.

Detailed Description

According to a first preferred embodiment of the invention, the symbols R in the compounds of formula (I)³And R⁵Represents H, the symbol R⁴Represents methylene, difluoromethylene, oxyimino, methoxyimino, as symbol in position 6 Connection R⁴And position17 represents a double bond, and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a second preferred embodiment of the invention, the symbol R in the compound of formula (I)³And R⁵Represents H, the symbol R⁴Represents alpha-methyl, alpha-carbamoyl, alpha-methoxycarbonyl, alpha-hydroxymethyl, alpha- (2-hydroxyethyl), alpha-methoxymethyl, alpha-nitrooxy, alpha-formylamino, alpha-ethynyl,symbol when in position 17Represents a double bond and the other symbols When represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a third preferred embodiment of the invention, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁵Represents H, symbolNumber R⁴Represents methylene, difluoromethylene, oxyimino, methoxyimino, as symbol in position 6Connection R⁴And in position 17 represents a double bond, and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR ⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In the fourth aspect of the present inventionIn a preferred embodiment, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁵Represents H, the symbol R⁴Represents alpha-methyl, alpha-carbamoyl, alpha-methoxycarbonyl, alpha-hydroxymethyl, alpha-methoxymethyl, alpha-nitrooxy, alpha-carboxamido, alpha-ethynyl, when the symbol in position 17Represents a double bond and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR ⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X isS, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

According to a fifth preferred embodiment of the invention, the symbol R in the compound of formula (I)³And R⁴Represents H, the symbol R⁵Represents methylene, difluoromethylene, oxyimino, methoxyimino, as symbol in position 7Connection R⁴And in position 17 represents a double bond, and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CH X wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a sixth preferred embodiment of the invention, the symbol R in the compound of formula (I)³And R⁴Represents H, the symbol R⁵Represents alpha-hydroxy, alpha-methyl, alpha-carbamoyl, alpha-methoxycarbonyl, alpha-hydroxymethyl, alpha-methoxymethyl, alpha-nitrooxy, alpha-carboxamido, alpha-ethynyl, alpha 0-hydroxy, alpha 1-methyl, alpha 2-carbamoyl, alpha 3-methoxycarbonyl, alpha 4-hydroxymethyl, alpha 5-methoxymethyl, alpha 6-nitrooxy, alpha 7-carboxamido, beta-ethynyl, as the symbol in position 17Represents a double bond and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR ⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a seventh preferred embodiment of the invention, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁴Represents H, the symbol R⁵Represents a methylene group, a hydroxyimino group, a methoxyimino group, a symbol in position 7Connection R⁵And in position 17 represents a double bond, and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CH X wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In an eighth preferred embodiment of the invention, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁴Represents H, the symbol R⁵Represents alpha-methyl, alpha-carbamoyl, alpha-methoxycarbonyl, alpha-hydroxymethyl, alpha-methoxymethyl, alpha-nitrooxy, alpha-formylamino, alpha-ethynyl, alpha 0-methyl, alpha 1-carbamoyl, alpha 2-methoxycarbonyl, alpha 3-hydroxymethyl, alpha 4-methoxymethyl, alpha 5-nitrooxy, beta-formylamino, beta-ethynyl, as the symbol in position 17Represents a double bond and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is ⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a ninth preferred embodiment of the invention, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁴And R⁵Symbol representing H, when in position 17Represents a double bond and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

In a tenth preferred embodiment of the invention, the symbol R in the compound of formula (I)³Represents hydroxy, the symbol R⁴Represents alpha-hydroxymethyl, and R⁵Represents alpha-hydroxy, ketone, symbol when position 17Represents a double bond and the other symbolsWhen represents a single bond, R¹R²N andas defined above, and the symbol a is C = NO, in particular 2-amino-ethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoximino, (R) -2-aminopropoxyimino, (S) -2-aminopropoxyimino, 3-amino-2-methyl-2-propoximino, or the symbol A is CR⁸XC = O, wherein R⁸And X is as defined above, in particular 3 β - (3-aminopropionyloxy), 3 β - (3-aminobutyryloxy), 3 β - (3-amino-2-methylpropionyloxy), or the symbol A is CR⁷CH=CHWherein R is⁷As defined above, in particular 3 α - (5-aminopent-1Z-enyl), 3 α - (4-aminobut-1Z-enyl) or A is CHX wherein X is S, in particular 3 α - (3-aminopropylthio), 3 α - (3-aminopropylsulfinyl).

Preferred examples of specific compounds (I) of the present invention are:

EZ3- (2-aminoethoxyimino) -6-methyleneandrostan-17-one,

EZ3- (3-aminopropoxyimino) -6-methyleneandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -6-methyleneandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -6-methyleneandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -6-methyleneandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -6-methyleneandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -6-methyleneandrostan-17-one,

3 beta- (3-aminopropionyloxy) -6-methyleneandrostan-17-one,

3 beta- (3-aminobutyryloxy) -6-methyleneandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -6-methyleneandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -6-methyleneandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -6-methyleneandrostan-17-one,

3 alpha- (3-aminopropylthio) -6-methylene androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -6-methylene androstane-17-one,

and the corresponding 6-difluoromethylene, 6-hydroxyimino and 6-methoxyimino derivatives;

EZ3- (2-aminoethoxyimino) -6 alpha-methylandrostan-17-one,

EZ3- (3-aminopropoxyimino) -6 alpha-methyl androstane-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -6 alpha-methylandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -6 alpha-methylandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -6 alpha-methylandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -6 alpha-methylandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -6 alpha-methylandrostan-17-one,

3 beta- (3-aminopropionyloxy) -6 alpha-methylandrostan-17-one,

3 beta- (3-aminobutyryloxy) -6 alpha-methylandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -6 alpha-methylandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -6 alpha-methylandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -6 alpha-methylandrostan-17-one,

3 alpha- (3-aminopropylthio) -6 alpha-methyl androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -6 alpha-methylandrostan-17-one,

and the corresponding 6 α -carbamoyl, 6 α -methoxycarbonyl, 6 α -hydroxymethyl, 6 α - (2-hydroxyethyl), 6 α -methoxymethyl, 6 α -nitrooxy, 6 α -formylamino, 6 α -ethynyl derivatives;

EZ3- (2-aminoethoxyimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ3- (3-aminopropoxyimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -5 alpha-hydroxy-6 alpha-methyl-androstan-17-one,

3 beta- (3-aminopropionyloxy) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

3 beta- (3-aminobutyryloxy) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

3 alpha- (3-aminopropylthio) -5 alpha-hydroxy-6 alpha-methyl androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -5 alpha-hydroxy-6 alpha-methylandrostan-17-one,

and the corresponding 6 α -carbamoyl, 6 α -methoxycarbonyl, 6 α -hydroxymethyl, 6 α -methoxymethyl, 6 α -nitrooxy, 6 α -formylamino, α -ethynyl derivatives;

EZ3- (2-aminoethoxyimino) -7-methyleneandrostan-17-one,

EZ3- (3-aminopropoxyimino) -7-methyleneandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -7-methyleneandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -7-methyleneandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -7-methyleneandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -7-methyleneandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -7-methyleneandrostan-17-one,

3 beta- (3-aminopropionyloxy) -7-methyleneandrostan-17-one,

3 beta- (3-aminobutyryloxy) -7-methyleneandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -7-methyleneandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -7-methyleneandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -7-methyleneandrostan-17-one,

3 alpha- (3-aminopropylthio) -7-methylene androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -7-methyleneandrostan-17-one,

and the corresponding 7-difluoromethylene, 7-oxo, 7-hydroxyimino and 7-methoxyimino derivatives;

EZ3- (2-aminoethoxyimino) -7 alpha-methylandrostan-17-one,

EZ3- (3-aminopropoxyimino) -7 alpha-methyl androstane-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -7 alpha-methylandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -7 alpha-methylandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -7 alpha-methylandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -7 alpha-methylandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -7 alpha-methylandrostan-17-one,

3 beta- (3-aminopropionyloxy) -7 alpha-methylandrostan-17-one,

3 beta- (3-aminobutyryloxy) -7 alpha-methylandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -7 alpha-methylandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -7 alpha-methylandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -7 alpha-methylandrostan-17-one,

3 alpha- (3-aminopropylthio) -7 alpha-methyl androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -7 alpha-methylandrostan-17-one,

and the corresponding 7 α -hydroxy, 7 α -carbamoyl, 7 α -methoxy-carbonyl, 7 α -hydroxymethyl, 7 α -methoxymethyl, 7 α -nitrooxy, 7 α -formylamino, 7 α -ethynyl derivatives and the corresponding 7 β -methyl, 7 β -hydroxy, 7 β -carbamoyl, 7 β -methoxycarbonyl, 7 β -hydroxymethyl, 7 β -methoxymethyl, 7 β -nitrooxy, 7 β -formylamino, 7 β -ethynyl derivatives;

EZ3- (2-aminoethoxyimino) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

EZ3- (3-aminopropoxyimino) -5 alpha-hydroxy-6-methylene androstane-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -5 alpha-hydroxy-6-methylene-androstan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -5 alpha-hydroxy-6-methylene-androstan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-6-methylene androstane-17-one,

EZ (S) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-6-methylene androstane-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -5 alpha-hydroxy-6-methylene-androstan-17-one,

3 beta- (3-aminopropionyloxy) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

3 beta- (3-aminobutyryloxy) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

3 alpha- (3-aminopropylthio) -5 alpha-hydroxy-6-methylene androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -5 alpha-hydroxy-6-methyleneandrostan-17-one,

and the corresponding 6-difluoromethylene, 6-hydroxyimino and 6-methoxyimino derivatives;

EZ3- (2-aminoethoxyimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ3- (3-aminopropoxyimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -5 alpha-hydroxy-7-methylene-androstan-17-one,

3 beta- (3-aminopropionyloxy) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

3 beta- (3-aminobutyryloxy) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -5 alpha-hydroxy-7 methylene androstan-17-one,

3 alpha- (3-aminopropylthio) -5 alpha-hydroxy-7-methylene androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -5 alpha-hydroxy-7-methyleneandrostan-17-one,

and the corresponding 7-hydroxyimino and 7-methoxyimino derivatives;

EZ3- (2-aminoethoxyimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ3- (3-aminopropoxyimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -5 alpha-hydroxy-7 alpha-methyl-androstan-17-one,

3 beta- (3-aminopropionyloxy) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

3 beta- (3-aminobutyryloxy) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

3 alpha- (3-aminopropylthio) -5 alpha-hydroxy-7 alpha-methyl androstane-17-one,

3 alpha- (3-aminopropylsulfinyl) -5 alpha-hydroxy-7 alpha-methylandrostan-17-one,

and the corresponding 7 α -carbamoyl, 7 α -methoxycarbonyl, 7 α -hydroxymethyl, 7 α -methoxymethyl, 7 α -nitrooxy, 7 α -formylamino, 7 α -ethynyl derivatives and the corresponding 7 β -methyl, 7 β -carbamoyl, 7 β -methoxycarbonyl, 7 β -hydroxymethyl, 7 β -methoxymethyl, 7 β -nitrooxy, 7 β -formylamino, 7 β -ethynyl derivatives;

EZ3- (2-aminoethoxyimino) -5 alpha-hydroxyandrostan-17-one,

EZ3- (3-aminopropoxyimino) -5 alpha-hydroxyandrostan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -5 alpha-hydroxyandrostan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -5 alpha-hydroxyandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -5 alpha-hydroxyandrostan-17-one,

EZ (S) -3- (2-aminopropoxyimino) -5 alpha-hydroxyandrostan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -5 alpha-hydroxyandrostan-17-one,

3 beta- (3-aminopropionyloxy) -5 alpha-hydroxyandrostan-17-one,

3 beta- (3-aminobutyryloxy) -5 alpha-hydroxyandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -5 alpha-hydroxyandrostan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -5 alpha-hydroxyandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -5 alpha-hydroxyandrostan-17-one,

3 alpha- (3-aminopropylthio) -5 alpha-hydroxyandrostan-17-one,

3 α - (3-aminopropylsulfinyl) -5 α -hydroxyandrostan-17-one;

EZ3- (2-aminoethoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ3- (3-aminopropoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ3- (2- (N-methylamino) ethoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ3- (3- (N-methylamino) propoxyiimino) -6 alpha-hydroxymethylandrostane-7, 17-dione,

EZ (R) -3- (2-aminopropoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ (S) -3- (2-aminopropoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

3 beta- (3-aminopropionyloxy) -6 alpha-hydroxymethyl androstane-7, 17-dione,

3 beta- (3-aminobutyryloxy) -6 alpha-hydroxymethylandrostane-7, 17-dione,

3 beta- (3-amino-2-methylpropionyloxy) -6 alpha-hydroxymethylandrostane-7, 17-dione,

3 alpha- (5-aminopent-1Z-enyl) -6 alpha-hydroxymethyl androstane-7, 17-dione,

3 alpha- (4-aminobut-1Z-enyl) -6 alpha-hydroxymethylandrostane-7, 17-dione,

3 alpha- (3-aminopropylthio) -6 alpha-hydroxymethyl androstane-7, 17-dione,

3 alpha- (3-aminopropylsulfinyl) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ3- (2-aminoethoxyimino) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

EZ3- (3-aminopropoxyimino) -6 alpha-hydroxymethyl-7 alpha-hydroxy-androstan-17-one,

EZ3- (2- (N-methylamino) ethoxyimino) -6 alpha-hydroxymethyl-6 alpha-hydroxy-androstan-17-one,

EZ3- (3- (N-methylamino) propoxyiimino) -6 alpha-hydroxymethyl-6 alpha-hydroxyandrostan-17-one,

EZ (R) -3- (2-aminopropoxyimino) -6 alpha-hydroxymethyl androstane-7, 17-dione,

EZ (S) -3- (2-aminopropoxyimino) -6 alpha-hydroxymethyl-7 alpha-hydroxy-androstan-17-one,

EZ3- (3-amino-2-methyl-2-propoxyiimino) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 beta- (3-aminopropionyloxy) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 beta- (3-aminobutyryloxy) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 beta- (3-amino-2-methylpropionyloxy) -6 alpha-hydroxymethyl-7 alpha-hydroxy-androstan-17-one,

3 alpha- (5-aminopent-1Z-enyl) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 alpha- (4-aminobut-1Z-enyl) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 alpha- (3-aminopropylthio) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

3 alpha- (3-aminopropylsulfinyl) -6 alpha-hydroxymethyl-7 alpha-hydroxyandrostan-17-one,

and the corresponding pure E and Z isomers of the EZ mixtures reported above.

The invention further provides a process for preparing the compounds of the formula (I) starting from compounds of the formula (II)

Wherein the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and when connecting the androstane skeleton carbon atom to R⁴Key ofR being a double bond⁴Is also O when connecting the androstane skeleton carbon atom to R ⁴Key ofR is a single bond⁴Is OR¹⁹And when it is a symbolY and Z together represent a ketone group (= O) or = N when together represent a double bondOBNR¹R²Or when a symbolWhen Z is hydrogen, Y is hydroxy, mercapto or NHR⁹，CHO，XBNR¹R²Or a leaving group, when Z is C₁-C₆Y being hydroxy, mercapto, NHR in the case of alkyl radicals⁹When Z is R⁷When Y is CH = CHBNR¹R²，CH₂BNR¹R²Or when Z is R⁸When Y is XC (= O) BNR¹R²，XC(=O)X’BNR¹R²And R is⁷And R⁸As defined above.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (III), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is C = NO, in the general formula (II)Y and Z together represent a ketone group (= O) when taken together as a double bond,

R²R¹N-B-ONH₂ (III)

in the general formula (III), R²，R¹And B has the above definition, in the form of a free base or a salt such as dihydrochloride, in a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, water or a mixture thereof, at a temperature ranging from 0 ℃ to reflux temperature. The reaction may be carried out in the presence of a base (e.g. sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g. hydrochloric acid, hydrobromic acid, acetic acid) or a salt (e.g. sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate).

The compounds of the general formula (I) can be obtained by reacting compounds of the general formula (II) with compounds of the general formulae (IV) and (V) in which the symbol R is¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CR⁷CH=CHCR⁷CH₂In the general formula (II)Y and Z together represent a ketone group (= O) when taken together as a double bond,

W-B-CH=CHMetT (IV) W-B-CH₂MetT (V)

in which B has the abovementioned meaning, Met is a metal atom and T is absent, halogen or a different metal atom, depending on the oxidation state of the Met metal atom, for example Li, MgCl, MgBr, MgI and CuLi, and W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹And R²Is alkyl or phenylalkyl, PG is a protective group, e.g. benzyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, which can bring R to the compound of the formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. The organometallic reaction may be carried out in a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, diethyl ether, hexane, toluene or mixtures thereof at a temperature ranging from-70 ℃ to reflux temperature. The reaction can be carried out on a transition metal salt (e.g., Li)₂CuCl₄，CeCl₃) In the presence of (a).

When W is R¹PGN or PG₂N, the protecting group can be removed after organometallic reaction according to procedures well established in organic chemistry to give compounds of general formula (I).

When W is N₃When this is the case, the azido group can be converted after organometallic reaction to give the compounds of the general formula (I) according to well established procedures in organic chemistry, for example catalytic hydrogenation, reduction with sodium borohydride and transition metal salts, treatment with triphenylphosphine and hydrolysis.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (VI), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CHX, wherein X is NR⁹In the general formula (II)Y and Z together represent a ketone group (= O) when taken together as a double bond,

W-B-NHR⁹(VI)

w, R in the general formula (VI)⁹And B has the above definition, the reaction is carried out in a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, water or a mixture thereof, at a temperature ranging from 0 ℃ to reflux temperature, and in the presence of a reducing agent (e.g., sodium borohydride or sodium cyanoborohydride). The reaction can be carried out in the presence of a base (e.g., sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g., hydrochloric acid, hydrobromic acid, acetic acid) or salt (e.g., sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate) until the desired pH is reached.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (VII), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CHX, wherein X is O, S or NR⁹In the general formula (II), when Z is hydrogen, Y is hydroxyl, mercapto or NHR⁹，

W-B-LG(VII)

Wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃LG is a leaving group, for example, chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy. This reaction can be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, dimethylsulfoxide, toluene, or a mixture thereof at a temperature ranging from 0 ℃ to the reflux temperature. The reaction may be carried out in the presence of a base (e.g. sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide) and optionally a salt (e.g. sodium or potassium iodide). The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (VIII), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CHX, wherein X is O, S or NR⁹Y in formula (II) is a leaving group, for example chlorine, bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, and Z is hydrogen,

W-B-X-H(VIII)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group such as benzyl, t-butoxycarbonyl, benzyloxycarbonyl, acetyl, X is O, S or NR⁹Wherein R is⁹As defined above, it can bring R to the compounds of the general formula (I) directly or after radical conversion¹PGN，PG₂N，N₃. This reaction can be carried out under the same reaction conditions as those reported above for the compound of formula (II) and the compound of formula (VII).

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (IX), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CR⁷CH=CHWherein R is⁷Is hydrogen, Y in the general formula (II) is CHO, Z is hydrogen,

W-B-P⁺R²⁰Hal^-(IX)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, e.g. benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, R²⁰Is C₁-C₆Alkyl or aryl, for example methyl, n-butyl, phenyl, o-phenyl, and Hal is halogen, for example chlorine, bromine, iodine. This reaction can be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, or a mixture thereof at a temperature ranging from-78 ℃ to reflux temperature. The reaction can be carried out in the presence of a base (e.g., sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide) In the presence of oxygen. The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (X), the symbol R in the general formula (I)¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CR⁸XC = O, wherein R⁸Is hydrogen or C₁-C₆An alkyl radical, X is O, S or NR⁹In the general formula (II), Y is hydroxyl, sulfydryl or NHR⁹And Z is hydrogen or C₁-C₆An alkyl group, a carboxyl group,

W-B-COOH (X)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. The reaction may be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, acetone, ethyl acetate, dichloromethane, chloroform, N, N-dimethylformamide, dimethyl sulfoxide, water or a mixture thereof at a temperature ranging from 30 ℃ to reflux temperature in a condensing agent (e.g., N, N '-dicyclohexylcarbodiimide, N-ethyl-N' - (3-dimethylamino-propyl) carbodiimide hydrochloride, SOCl ₂POCl₃Or PCl₅Or the compound of formula (X) may be previously substituted with SOCl₂，POCl₃，PCl₅Treatment), optionally in the presence of a base (e.g., sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine, pyridine, or 4-dimethyl-aminopyridine).

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (XI) in which the symbol R is¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CR⁸X (C = O) X', wherein R⁸Is hydrogen or C₁-C₆An alkyl radical, X is O, S or NR⁹And X' is NH, and in the general formula (II), Y is hydroxyl, mercapto or NHR⁹And Z is hydrogen or C₁-C₆An alkyl group, a carboxyl group,

W-B-NCO (XI)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. This reaction can be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, acetone, ethyl acetate, dichloromethane, chloroform, N-dimethylformamide, dimethyl sulfoxide, ethanol, methanol, water or a mixture thereof at a temperature ranging from-30 ℃ to reflux temperature.

The compounds of the general formula (I) can be obtained by reacting a compound of the general formula (II) with a compound of the general formula (XI) in which the symbol R is ¹，R²，R³，R⁴，R⁵，R⁶B andhas the above definition, and A is CR⁸X (C = O) X', wherein R⁸Is hydrogen or C₁-C₆An alkyl radical, X is O, S or NR⁹And X' is O, S, NR⁹In the general formula (II), Y is hydroxyl, sulfydryl or NHR⁹And Z is hydrogen or C₁-C₆An alkyl group, a carboxyl group,

W-B-X’-H (XII)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²B and X' are as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. This reaction can be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, acetone, ethyl acetate, dichloromethane, chloroform, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, using a carbonyl-donating group (e.g., carbonyldiimidazole, carbonyl chloride, tricarbonyl chloride) at a temperature ranging from-60 ℃ to reflux temperature, in the presence of a base (sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine, pyridine or 4-dimethylaminopyridine).

Compounds of the general formula (I) (wherein the symbol R¹，R²，R³，R⁴，R⁵，R⁶B andhas the above meaning, and A is CHX，CR⁸XC=O，CR⁸XC (= O) X ', wherein X and X' are NR⁹And R is⁹Is C₁-C₆Alkyl radical) can be substituted by C₁-C₆alkyl-LG (wherein LG is a leaving group, e.g. chloro, bromo, iodo, mesyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy) A compound of formula (I) (wherein A is CH) X，CR⁸XC=O，CR⁸XC (= O) X ', where X and X' are NH) is obtained after alkylation. Such reaction may be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, dimethylsulfoxide, toluene or a mixture thereof, at a temperature ranging from 0 ℃ to reflux temperature, optionally in the presence of a base (sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide), and optionally in the presence of a salt (e.g., sodium or potassium iodide). The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature.

Compounds of the general formula (I) (wherein the symbol R¹，R²，R³，R⁴，R⁵，R⁶B has the meaning indicated above,is a single bond, and A is CHX, wherein X is NR⁹And R is⁹Is C₁-C₆Alkyl radical) can be prepared by reacting a compound of the general formula (I) in which A is CHX, and X is NH) and CH₂O or C₁-C₅alkyl-CHO is obtained by reaction in a solvent (dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, water or a mixture thereof) at a temperature ranging from 0 ℃ to reflux temperature in the presence of a reducing agent (sodium borohydride or sodium cyanoborohydride). The reaction can be carried out in the presence of a base (e.g., sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g., hydrochloric acid, hydrobromic acid, acetic acid) or salt (e.g., sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate) until the desired pH is reached.

Compounds of the general formula (I) (wherein the symbol R¹，R²，R³，R⁴，R⁵，R⁶B andhas the above meaning, and A is CHX, wherein X is S (O)_xAnd x is 1 or 2) the compound of formula (I) wherein A is CH can be oxidized by using literature reported oxidizing agents (e.g., hydrogen peroxide, sodium metaperiodate, t-butyl hypochlorite, sodium chlorate, sodium hypochlorite, sodium perborate, N-methylmorpholine-N-oxide and tetrapropylammonium periodate, oxone and peracids)X, whereinX is S (O)_xAnd x is 0); depending on the reaction conditions, i.e. temperature and oxide equivalents, the oxidation may provide compounds of the general formula (I) above (wherein x is 1 or 2).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁴，R⁵，R⁶Andhaving the above-mentioned meaning) can be carried out with hydrogen or under hydrogen transfer conditions in a metal catalyst (e.g., Pd/C, PtO)₂Reduction of the corresponding compounds of the general formula (I) (wherein the symbols are as defined above) by catalytic hydrogenation in the presence of Pt, Pt/C, Raney nickelDouble bond). Ammonium formate, sodium hypophosphite or cyclohexadiene can be used as hydrogen transfer agent. The reaction can be carried out in a solvent (ethanol, methanol, ethyl acetate, dioxane, tetrahydrofuran, acetic acid, N-dimethyl-formamide, water or a mixture thereof) at a temperature ranging from 0 ℃ to reflux temperature, under a pressure ranging from atmospheric pressure to 10 atm. Depending on the substrate and conditions used, the hydrogenation can act selectively on one or more double bonds.

Compounds of the general formula (I) (wherein the symbols B, R¹，R²，R³，R⁴，R⁵，R⁶Andhas the above-mentioned meaning, and A is CR⁷CH=CHCR⁷CH2Wherein R is⁷Hydrogen) can be prepared by one of the methods reported in the literature for such reactions (e.g. reaction with thiocarbonyldiimidazole and tri-n-butyltin hydride, carbon disulfide in the presence of a base, followed by reaction with methyl iodide and reaction with tri-n-butyltin hydride, NaBH₃CN and ZnI₂NaBH in acetic acid₄Treatment) of compounds of the general formula (I) (where the symbol R⁷Is hydroxyl) to deoxidize.

Compounds of the general formula (I) (symbols A, B, R)³，R⁴，R⁵，R⁶Andhaving the above definition, R¹Is hydrogen and R²Is C (= NR)¹⁰)NHR¹¹Wherein R is¹⁰And R¹¹Having the above definition) can be represented by the general formula (I) (wherein R is¹And R²Hydrogen) with a compound of the general formula (XIII),

TC(=NR¹⁰)NHR¹¹ (XIII)

wherein R is⁹And R¹⁰Having the definition reported above, T is a leaving group, e.g., methylthio, 1-pyrazolyl. The reaction may be carried out in a solvent (dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethyl-formamide, water or a mixture thereof) at a temperature in the range from 0 ℃ to reflux temperature, optionally in the presence of a base (e.g. sodium or potassium hydroxide, triethylamine, diethylisopropylamine).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 and R are bonded⁴Key ofMay be a single bond orA double bond and connects the carbon atom in position 7 of the androstane skeleton to R⁵Key ofWhen it is a double bond, R⁴Is not NOR¹³，R⁵Is NOR¹³) Can be prepared from corresponding compounds of general formula (I) (wherein R⁴Is not NOR¹³，R⁵O) representing a ketone group is obtained by one of the methods reported in the literature for such a reaction, for example by reaction with a compound of the general formula H in the form of the free base or of a salt (e.g. hydrochloride)₂NOR¹³Compound of (2) (wherein R is¹³Having the above definition) in a solvent (e.g., dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, pyridine, water or a mixture thereof) at a temperature ranging from 0 ℃ to reflux temperature. The reaction may be carried out in the presence of a base (e.g. sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g. hydrochloric acid, hydrobromic acid, acetic acid) or a salt (e.g. sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 and R are bonded ⁴Key ofIs a double bond and is attached to position 7 of the androstane skeletonCarbon atom of (A) and R⁵Key ofWhen it may be a single bond or a double bond, R⁴Is NOR¹³，R⁵Is not NOR¹³) Can be prepared from corresponding compounds of the general formula (II) (wherein R⁴Is O, R representing a keto group⁵Is not NOR¹³) One of the methods reported in the literature for such reactions is obtained, for example, by reaction with a compound of the general formula H₂NOR¹³Is obtained by reaction of the compound (1).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when connecting the carbon atoms in positions 6 and 7 with R⁴And R⁵Key ofWhen each is a double bond, R⁴And R⁵Is NOR¹³) Can be prepared from corresponding compounds of the general formula (II) (wherein R⁴And R⁵O) for the representation of a keto group is obtained by one of the methods reported in the literature for such a reaction, for example by reaction with the general formula H₂NOR¹³By reaction of a compound of (a) to give

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 and R are bonded⁴And connecting the carbon atom in position 7 of the androstane skeleton to R⁵Key ofWhen it is a double bond, R⁴Is not CR¹⁴R¹⁵，R⁵Is CR¹⁴R¹⁵) Can be prepared from corresponding compounds of general formula (I) (wherein R⁴Is not CR¹⁴R¹⁵，R⁵O) representing a ketone group is obtained by one of the methods reported in the literature for such a reaction, for example by reaction with a compound of the general formula (XIV) or (XV),

R¹⁴R¹⁵CH-P⁺R₃ ²⁰Hal^- (XIV)

R¹⁴R¹⁵CH-P(=O)(OR²⁰)₂ (XV)

Wherein R is¹⁴，R¹⁵And R²⁰As defined above, Hal is a halogen, e.g., chlorine, bromine, iodine. The reaction with the compound of formula (XIV) or (XV) may be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, N, N-dimethylformamide, dimethylsulfoxide, N-pentane or a mixture thereof at a temperature ranging from-78 ℃ to reflux temperature. The reaction may be carried out in the presence of a base (e.g., sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide). The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature. The reaction with the compound of the formula (XV) can also be carried out in water or a mixture of the above solvents and water at a temperature ranging from 0 ℃ to reflux temperature. Such reactions can be carried out in the presence of a base (e.g., sodium hydroxide orPotassium, sodium or potassium bicarbonate, sodium or potassium carbonate, triethylamine, diisopropylethylamine), optionally in the presence of a salt (e.g., lithium chloride).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 and R are bonded⁴And connecting the carbon atom in position 7 of the androstane skeleton to R⁵Key ofWhen it may be a single bond or a double bond, R⁴Is CR¹⁴R¹⁵，R⁵Is not CR¹⁴R¹⁵) Can be prepared from corresponding compounds of the general formula (II) (wherein R⁴Is O, R representing a keto group⁵Is not CR¹⁴R¹⁵) Obtained by one of the methods reported in the literature for such reactions, for example, by reaction with a compound of formula (XIV) or (XV),

R¹⁴R¹⁵CH-P⁺R₃ ²⁰Hal^- (XIV)

R¹⁴R¹⁵CH-P(=O)(OR²⁰)₂ (XV)

wherein R is¹⁴，R¹⁵And R²⁰As defined above, Hal is halogen.

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶And has the above definition when the carbon atoms in positions 6 and 7 are bonded to R⁴And R⁵When the bonds of (A) are each a double bond, R⁴And R⁵Is CR¹⁴R¹⁵) Can be prepared from corresponding compounds of the general formula (II) (wherein R⁴And R⁵O) both representing a keto group, are obtained by one of the methods reported in the literature for such a reaction, for example by reaction withA compound of formula (XIV) or (XV),

R¹⁴R¹⁵CH-P⁺R₃ ²⁰Hal^- (XIV)

R¹⁴R¹⁵CH-P(=O)(OR²⁰)₂ (XV)

wherein R is¹⁴，R¹⁵And R²⁰As defined above, Hal is halogen.

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 of the androstane skeleton is bonded to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R ⁴And R⁵Independently C substituted by hydroxy groups, especially hydroxymethyl₁-C₆Alkyl group) can be derived from the corresponding compounds of the general formula (I) wherein the carbon atom at position 6 in the androstane skeleton is connected to R⁴And the carbon atom in position 7 with R⁵Key ofR, which are identical or different from each other when they are double bonds⁴And R⁵Is CR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Hydrogen) can be obtained, for example, by reaction with a borane (e.g., borane or its complex with dimethylamine or dimethylsulfide, 9-borobicyclononane, diisopinocampheylborane, diisoprenylborane) in an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane) followed by treatment with an alkaline aqueous hydrogen peroxide or sodium perborate.

Conversion of the general formula (I)Compound (wherein symbols A, B, R¹，R²，R³，R⁶Andhaving the above definition, when the carbon atom at position 6 of the androstane skeleton is bonded to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently C substituted by hydroxy groups, especially hydroxyethyl₁-C₆Alkyl group) can be prepared from the corresponding compound of the general formula (I) (wherein the carbon atom at position 6 when connecting the androstane skeleton to R⁴And the carbon atom in position 7 with R ⁵Key ofR's, when being single bond, are the same or different from each other⁴And R⁵Is vinyl). A compound of the general formula (I) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, the substituent R⁴And R⁵Independently a vinyl group) can be prepared by reacting a corresponding compound of formula (I) (wherein R is⁴And R⁵Independently CHO) with methyltriphenylphosphonium chloride or bromide or iodide under the same conditions as described above in connection with the reaction of the compounds of formula (XIV) or (XV).

Compounds of the general formula (I) (wherein the symbols A, B, R¹，R²，R³，R⁴，R⁶Andhaving the above definition, when the carbon atom at position 7 of the androstane skeleton is bonded to R⁵Key ofWhen it is a double bond, R⁵O) representing a ketone group can be prepared from the corresponding compounds of the general formula (I) wherein the carbon atom at position 7 in the androstane skeleton is connected to R⁵Key ofWhen it is a single bond, R⁵As hydroxyl group) and reagents reported in the literature for such oxidations (e.g., iodoxybenzoic acid, Dess-Martin periodinane, oxalyl chloride and triethylamine, CrO in pyridine or in sulfuric acid and acetone₃Pyridine chlorochromate, pyridine dichromate).

The compounds of the general formula (II) as defined above can be prepared by reference to the general procedures listed below by known compounds having appropriate functional groups at different positions (e.g. 3. beta. -hydroxyandrost-5-en-17-one, 3. beta. -hydroxyandrost-5-en-7, 17-dione) reported in the literature or commercially available. The following list is illustrative of the compounds reported in the preparation of compound (II) and not limiting the scope of the invention: androstane-3, 6, 17-trione, androstane-3 α,6 β,17 β -triol, 6 α -hydroxyandrostane-3, 17-dione, 3 β,17 β -dihydroxyandrost-4-en-6-one, 3,3:17, 17-bis (ethylenedioxy) -androstane-6 α -ol, 3,3:17, 17-bis (ethylenedioxy) androstane-6 β -ol, 3,3:17, 17-bis (ethylenedioxy) androstane-6-one and 6 α,17 β -dihydroxyandrostane-3-one are reported in S.De Munari et al, J.Med.Chem., 2003, 3644, 3 β -acetoxyandrost-5-ene-7, 17-dione are reported in E.S.aroudes et al, Sterioi 407 41 68(2003), 3,3:17, 17-bis (ethylenedioxy) androst-5-en-7-one is reported in Pui-Kai Li and R.W.Brueggemieer, J.Med.chem.1990, 33, 101-.

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition, when a symbolWhen together represent a double bond, Y and Z together represent NOBNR¹R²Wherein R is¹，R²B andhaving the above definition) can be represented by the general formula (II) (wherein the symbols are as defined above)When together representing a double bond, Y and Z together represent a ketone group (= O)) with a compound of the general formula (III),

R²R¹N-B-ONH₂ (III)

wherein R is²，R¹And B has the above definition, in the form of a free base or a salt, and the same conditions as described above for obtaining the compound of formula (I) by reacting compound (III) with the compound of formula (II).

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition, when Z is R⁷When Y is CH = CHBNR¹R²，CH₂BNR¹R²Wherein R is⁷Is hydroxy or hydrogen, and the symbol R¹，R²B andhaving the above definition) can be represented by the general formula (II) (wherein the symbols are as defined above)Common generationIn the case of double bonds, Y and Z together represent a ketone group (= O)) with compounds of the general formulae (IV) and (V),

W-B-CH=CHMetT (IV) W-B-CH₂MetT (V)

in which B has the abovementioned meaning, Met is a metal atom and T is absent, halogen or a different metal atom, depending on the oxidation state of the Met metal atom, for example Li, MgCl, MgBr, MgI and CuLi, and W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹And R²Is alkyl or phenylalkyl, PG is a protective group, e.g. benzyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl, which can bring R to the compound of the formula (I) directly or after conversion of the group ¹PGN，PG₂N，N₃. The organometallic reaction may be carried out under the same conditions as described above for obtaining the compound of formula (I) from the reaction of compounds (IV) and (V) with the compound of formula (II), and the conversion of the protecting group or azido group may be carried out as described above.

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition, Y is XBN when Z is hydrogen¹R²Wherein X is O, S or NR⁹And R is¹，R²B andhaving the above definition) can be represented by the general formula (II) (wherein Y is hydroxy, mercapto, NHR when Z is hydrogen⁹) With a compound of the general formula (VII),

W-B-LG (VII)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, e.g. benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, ethylcarbonylAcyl which can bring R to the compound of the general formula (I) directly or after radical conversion¹PGN，PG₂N，N₃LG is a leaving group, for example, chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy. This reaction may be carried out under the same conditions as described above for obtaining the compound of formula (I) by reacting compound (VII) with the compound of general formula (II), and the conversion of the protecting group or the azido group may be carried out as described above.

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and Y is CR⁷CH=CHWherein R is ⁷Hydrogen) can be obtained by reacting a compound of formula (II) wherein Y is CHO and Z is hydrogen with a compound of formula (IX),

W-B-P⁺R²⁰Hal^- (IX)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, e.g. benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, R²⁰Is C₁-C₆Alkyl or aryl, for example methyl, n-butyl, phenyl, o-phenyl, and Hal is halogen, for example chlorine, bromine, iodine. This reaction may be carried out under the same conditions as described above for obtaining the compound of formula (I) by reacting compound (IX) with the compound of general formula (II), and the conversion of the protecting group or the azido group may be carried out as described above.

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and when Z is hydrogen or C₁-C₆Y being X (C = O) BNR in the case of alkyl radicals¹R²X is O, S or NR⁹And R is¹，R²And B has the above-mentioned definition) can be represented by the general formula (II) (wherein Y is hydroxy, mercapto, NHR)⁹Z is hydrogen or C₁-C₆Alkyl group) with a compound of the general formula (X),

W-B-COOH (X)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. This reaction may be carried out under the same conditions as described above for obtaining the compound of formula (I) by reacting compound (X) with the compound of general formula (II), and the conversion of the protecting group or the azido group may be carried out as described above.

Compounds of the general formula (I) (wherein the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and when Z is hydrogen or C₁-C₆When the alkyl radical Y isX(C=O)X’BNR¹R²X is O, S or NR⁹And R is¹，R²And B has the above definition, and X' is NH) may be represented by the general formula (II) (wherein Y is hydroxy, mercapto, NHR)⁹Z is hydrogen or C₁-C₆Alkyl group) with a compound of the general formula (XI),

W-B-NCO (XI)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²And B is as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group¹PGN，PG₂N，N₃. This reaction can be carried out under the same conditions as described above for obtaining the compound of formula (I) by reacting compound (XI) with the compound of general formula (II), and the conversion of the protecting group or the azido group can be carried out as described above.

Compounds of the general formula (II) (in which the symbol R³，R⁴，R⁵，R⁶B andhas the above definition, and when Z is hydrogen or C₁-C₆Y is X (C = O) X' BNR in the case of alkyl radicals¹R²X is O, S or NR⁹X' is O, S, NR⁹And R is¹，R²And B has the above-mentioned definition) can be represented by the general formula (II) (wherein Y is hydroxy, mercapto, NHR)⁹Z is hydrogen or C₁-C₆Alkyl group) with a compound of the general formula (XII),

W-B-X’-H (XII)

wherein W is R²R¹N，R¹PGN，PG₂N，N₃Wherein R is¹，R²B and X' are as defined above, PG is a protecting group, for example benzyl, tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, which may bring R to the compound of formula (I) directly or after conversion of the group ¹PGN，PG₂N，N₃. This reaction may be carried out under the same conditions as described above for obtaining the compound of formula (I) by reacting compound (XII) with the compound of general formula (II), and the conversion of the protecting group or azido group may be carried out as described above.

A compound of the general formula (II) (wherein R³And R⁵Independent of each otherIs C₁-C₆Alkyl) can be prepared by reacting a compound of formula (II) (wherein R is⁴Symbol attached to androstane skeletonIs a double bond, is⁵Symbol attached to androstane skeletonA single bond and symbols in positions 4-5, 5-6 and 6-7When it is a single bond, R³And R⁵Is hydrogen and R⁴Is oxygen) with a base (e.g., sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide, lithium diisopropylamide) in a solvent (e.g., diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, toluene, N, N-dimethylformamide, dimethyl sulfoxide or mixtures thereof) at a temperature in the range of-78 deg.C to reflux temperature, followed by treatment with C₁-C₆alkyl-LG (wherein LG is a leaving group, e.g., chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy) is terminated at a temperature in the range of-78 ℃ to reflux temperature. The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature.

A compound of the general formula (II) (wherein R⁴Is C₁-C₆Alkyl) can be derived from the corresponding compound of formula (II) (wherein R is substituted) by the same reaction reported above⁴Symbol attached to androstane skeletonIs a double bond, is⁵Symbol attached to androstane skeletonA single bond and symbols in positions 4-5, 5-6 and 6-7When it is a single bond, R⁴Is hydrogen and R⁵Oxygen).

A compound of the general formula (II) (wherein R³Is OR¹²) By reacting compounds of the general formula (II) in which the symbols in positions 4-5 and 5-6When it is a single bond, R³Is hydroxy) with the general formula R¹²Compounds of formula (i) -LG (wherein LG is a leaving group, e.g. chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy) are obtained after treatment. Such reaction may be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, dimethylsulfoxide, toluene or a mixture thereof, at a temperature ranging from 0 ℃ to reflux temperature, optionally in the presence of a base (sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium or potassium hydride, sodium or potassium methoxide, sodium or potassium tert-butoxide), and optionally in the presence of a salt (e.g., sodium or potassium iodide). The reaction can also be carried out in a mixture of organic solvents (e.g., dichloromethane, chlorobenzene, toluene, hexane, and water) in the presence of sodium or potassium hydroxide and a quaternary ammonium salt (e.g., tetrabutylammonium chloride or bromide or iodide or bisulfate) at a temperature ranging from 0 ℃ to reflux temperature.

A compound of the general formula (II) (wherein R⁵Is OR¹⁹) Can be prepared from the compounds of the general formula (II) (wherein the symbols in positions 4-5, 5-6 and 6-7 are as defined above) by the same reaction as reported aboveWhen it is a single bond, R⁵Is hydroxy) via the general formula R¹⁹The compound of-LG.

A compound of the general formula (II) (wherein R⁶Is C₁-C₆Alkyl group) can be derived from compounds of general formula (II) (wherein the symbol in position 17 is as defined above) by the same reaction reported aboveWhen it is a single bond, R⁶Is H) via a general formula C₁-C₆alkyl-LG compounds.

A compound of the general formula (II) (wherein R³，R⁴And R⁵Independently is ONO₂) Can be prepared from compounds of the general formula (II) (wherein the symbols in positions 4-5, 5-6 and 6-7When it is a single bond, R³，R⁴And R⁵Independently a hydroxyl group) by treatment with nitric acid in acetic anhydride or acetic acid, nitric acid and sulfuric acid in dichloromethane, nitrosyl fluoride in acetonitrile or tetrafluoro borate.

A compound of the general formula (II) (wherein R is⁴To the carbon atom at position 6 of the androstane skeleton and R⁵Bond to carbon atom at position 7 of androstane skeletonIs a double bond and is a symbol in positions 4-5, 5-6 and 6-7When it is a single bond, the substituent R⁴And R⁵Independently is NOR¹³) Can be prepared from compounds of the general formula (II) (wherein R are the same or different from each other⁴And R⁵Oxygen independently representing a ketone group) through formula H ₂NOR¹³Compound of (2) (wherein R is¹³Having the definition as defined above, in the form of a free base or a salt, e.g. hydrochloride, in a solvent (e.g. dioxane, tetrazine)Hydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N, N-dimethylformamide, water or a mixture thereof) at a temperature in the range of from 0 ℃ to the reflux temperature. The reaction may be carried out in the presence of a base (e.g. sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g. hydrochloric acid, hydrobromic acid, acetic acid) or a salt (e.g. sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate).

A compound of the general formula (II) (wherein R is⁴To the carbon atom at position 6 of the androstane skeleton and R⁵Bond to carbon atom at position 7 of androstane skeletonIs a double bond and is a symbol in positions 4-5, 5-6 and 6-7When it is a single bond, the substituent R⁴And R⁵Independently is CR¹⁴R¹⁵) Can be prepared from compounds of the general formula (II) (wherein R are the same or different from each other⁴And R⁵Independently oxygen representing a ketone group) with a compound of formula (XIV) or (XV),

R¹⁴R¹⁵CH-P⁺R₃ ²⁰Hal^- (XIV)

R¹⁴R¹⁵CH-P(=O)(OR²⁰)₂ (XV)

wherein R is¹⁴，R¹⁵And R²⁰Hal is halogen, e.g., chlorine, bromine, iodine, as defined above, under the same conditions as described above with respect to compounds of formula (XIV) or (XV).

A compound of the general formula (II) (wherein R is⁴To the carbon atom at position 6 of the androstane skeleton and R⁵Bond to carbon atom at position 7 of androstane skeletonWhen it is a double bond, the substituent R⁴And R⁵Independently a hydroxyl group, in particular hydroxymethyl-substituted C₁-C₆Alkyl group) can be derived from compounds of general formula (II) wherein the carbon atom at position 6 in the androstane skeleton is connected to R⁴And the carbon atom in position 7 with R⁵Key ofR, which are identical or different from each other when they are double bonds⁴And R⁵Is CR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Hydrogen) can be obtained, for example, by reaction with a borane (e.g., borane or its complex with dimethylamine or dimethylsulfide, 9-borobicyclononane, diisopinocampheylborane, diisoprenylborane) in an ether solvent (e.g., diethyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane) followed by treatment with an alkaline aqueous hydrogen peroxide or sodium perborate.

A compound of the general formula (II) (wherein R is⁴To the carbon atom at position 6 of the androstane skeleton and R⁵Bond to carbon atom at position 7 of androstane skeletonWhen it is a single bond, the substituent R⁴And R⁵Independently a hydroxyl group, in particular hydroxyethyl-substituted C ₁-C₆Alkyl group) can be prepared from the compound of the general formula (II) by the same method (wherein the carbon atom at position 6 when connecting the androstane skeleton with R⁴And the carbon atom in position 7 with R⁵R's are the same or different from each other when the bond(s) is a single bond⁴And R⁵Is vinyl).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, the substituent R⁴And R⁵Independently a vinyl group) can be prepared by reacting a corresponding compound of formula (II) (wherein R is⁴And R⁵Independently CHO) with methyltriphenylphosphonium chloride or bromide or iodide under the same conditions as described above in connection with the reaction of the compounds of formula (XIV) or (XV).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵When the bond of (A) is a single bond, the substituent R⁴And R⁵Independently a vinyl group) can be prepared by reacting a corresponding compound of formula (II) (wherein R is⁴And R⁵Independently CHO) with methyltriphenylphosphonium chloride or phosphonium bromide or phosphonium iodide at-78 deg.C to room temperature, and further treated with n-butyllithium.

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R ⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, the substituent R⁴And R⁵Independently is C₁-C₆Alkyl group) can be derived from the corresponding compounds of the general formula (II) wherein the carbon atom at position 6 in the androstane skeleton is connected to R⁴And the carbon atom in position 7 with R⁵Key ofR, which are identical or different from each other when they are double bonds⁴And R⁵Is CR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Is hydrogen or C₁-C₅Alkyl group) is obtained under similar conversion reaction conditions of the compounds of general formula (I) above, by one of the methods reported in literature for such reactions, for example by catalytic hydrogenation.

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently is C₁-C₆Alkyl radical) can be derived from compounds of the general formula (II) in which R are identical to or different from one another⁴And R⁵For hydroxymethyl and 2-hydroxyethyl) by one of the methods reported in the literature for such reactions (e.g., treatment with methanesulfonyl or toluenesulfonyl chloride in the presence of a base followed by reduction with a hydride (e.g., sodium borohydride lithium aluminum hydride)) or by one of the methods reported in the literature for such deoxygenation reactions (e.g., reaction with thiocarbonyl-diimidazole and tri-n-butyltin hydride, carbon disulfide, then methyl iodide, and with tri-n-butyltin hydride, NaBH in the presence of a base ₃CN and ZnI₂NaBH in acetic acid₄Treatment) reaction.

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently is COOR¹⁶Wherein R is¹⁶Is hydrogen) may be derived from compounds of the general formula (II) in which R are identical to or different from one another⁴And R⁵Hydroxymethyl) one of the reagents reported in the literature for this oxidation (for example iodoxybenzoic acid, Dess-Martin periodinane, oxalyl chloride and triethylamine and dimethyl sulfoxide in methylene chloride, CrO in pyridine or in sulfuric acid and acetone₃Pyridine chlorochromate, pyridine dichromate) to give an intermediate aldehyde (wherein R is⁴And R⁵Independently CHO) and then oxidized to carboxylic acid by one of the reagents reported in the literature for such oxidation (e.g., potassium permanganate, chromic anhydride in sulfuric acid/acetone, pyridine dichromate in N, N-dimethylformamide).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton is attached toR⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently is COOR¹⁶Or CONR¹⁷R¹⁸Wherein R is¹⁶Is C₁-C₆Alkyl radical, and R¹⁷And R¹⁸As defined above) may be represented by the general formula (II) wherein R is the same or different from each other ⁴And R⁵Is COOH) via diazomethane, trimethylsilyldiazomethane or of the formula R¹⁶OH or HNR¹⁷R¹⁸By one of the conversion methods reported in the literature (for example, in N, N '-dicyclohexylcarbodiimide, N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide hydrochloride, SOCl₂，POCl₃Or PCl₅By condensation in the presence of condensing agents), or the compound of formula (II) may be prepared beforehand as SOCl₂，POCl₃，PCl₅Optionally in the presence of a base (e.g., sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine, pyridine or 4-dimethylaminopyridine).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently is CONR¹⁷R¹⁸Wherein R is¹⁷And R¹⁸As defined above) may be represented by the general formula (II) wherein R is the same or different from each other⁴And R⁵Is COOR¹⁶Wherein R is¹⁶Is C₁-C₆Alkyl radical) via the general formula HNR¹⁷R¹⁸The compounds of (a) are obtained by one of the conversion methods reported in the literature, for example, in water, methanol or ethanol, finally in the presence of catalytic amounts of sodium methoxide at temperatures ranging from 0 ℃ to reflux temperature, and in sealed bottles Thus obtaining the product.

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently CH = NOH) may be represented by compounds of the general formula (II) (wherein R are the same or different from each other⁴And R⁵CHO) by treating the general formula hydroxylamine as a free base or in a salt form (e.g. hydrochloride, sulfate, phosphate) in a solvent (e.g. dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, water or mixtures thereof) at a temperature in the range of from 0 ℃ to reflux temperature. The reaction may be carried out in the presence of a base (e.g. sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate) or an acid (e.g. hydrochloric acid, hydrobromic acid, acetic acid) or a salt (e.g. sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate, sodium or potassium dihydrogen phosphate).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently CN) can be derived from a compound of formula (II) wherein the carbon atom at position 6 in the androstane skeleton is attached to R⁴And the carbon atom in position 7 with R ⁵Key ofIs a double bond and is a symbol in positions 4-5, 5-6 and 6-7R's, when being single bond, are the same or different from each other⁴And R⁵Oxygen, which is representative of a ketone group) is obtained by one of the transformation methods reported in the literature, for example, by treatment with tosylmethylisonitrile in the presence of a base.

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently NHCHO and NHCOCH₃) Can be prepared from compounds of the general formula (II) wherein the carbon atom at position 6 in the androstane skeleton is linked to R⁴And the carbon atom in position 7 with R⁵Key ofIs a double bond and is a symbol in positions 4-5, 5-6 and 6-7R's, when being single bond, are the same or different from each other⁴And R⁵Is NOR¹³Wherein R is¹³Hydrogen) by one of the reduction methods reported in the literature, for example, by lithium aluminium hydride, catalytic hydrogenation or treatment with sodium or lithium or magnesium in ethanol to give the corresponding amine, where R is⁴And R⁵Is NH₂And then formylated with formic acid or acetylated with acetic acid in the presence of a condensing agent (e.g., N '-dicyclohexylcarbodiimide, N-ethyl-N' - (3-dimethylamino-propyl) carbodiimide hydrochloride), or alternatively, acetoxylated with acetic anhydride in the presence of a base (e.g., triethylamine, pyridine, or 4-dimethylaminopyridine).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵When the bond of (A) is a single bond, R⁴And R⁵Independently isSpirooxirane) can be prepared from compounds of the general formula (II) in which the carbon atom at position 6 in the androstane skeleton is bonded to R⁴And the carbon atom in position 7 with R⁵Is a double bond, and when the symbols at positions 4-5, 5-6 and 6-7 are single bonds, R's which are the same or different from each other⁴And R⁵Is CR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Hydrogen) by reaction with one of the reagents reported in the literature for this reaction (e.g. perbenzoic acid, m-chloroperbenzoic acid, magnesium perphthalate, perphosphoric acid, peracetic acid or hydrogen peroxide and sodium hydroxide in acetonitrile).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵When the bond of (A) is a single bond, R⁴And R⁵Independently a spirooxirane) can be prepared from compounds of general formula (II) wherein the carbon atom in position 6 of the androstane skeleton when bound to R⁴And the carbon atom in position 7 with R⁵Is a double bond, and when the symbols at positions 4-5, 5-6 and 6-7 are single bonds, R's which are the same or different from each other⁴And R⁵O, which is a representative of a ketone group) is obtained by treating one of reagents reported in the literature for this reaction (e.g., trimethylsulfonium iodide or trimethylsulfoxonium iodide) in the presence of a base (e.g., sodium hydride, sodium methoxide, potassium tert-butoxide).

A compound of the general formula (II) (wherein the carbon atom at position 6 in the androstane skeleton when attached to R⁴And the carbon atom in position 7 with R⁵Key ofWhen it is a single bond, R⁴And R⁵Independently a spirooxirane) can be prepared from compounds of general formula (II) wherein the carbon atom in position 6 of the androstane skeleton when bound to R⁴And the carbon atom in position 7 with R⁵Is a double bond, and when the symbols at positions 4-5, 5-6 and 6-7 are single bonds, R's which are the same or different from each other⁴And R⁵Is CR¹⁴R¹⁵Wherein R is¹⁴And R¹⁵Hydrogen) reported in the literatureOne of the reagents used for this reaction (e.g., diiodomethane and diethyl tin or tin-copper alloy) is reacted.

A compound of formula (II) wherein the bond at position 17 in the androstane skeleton is attachedWhen it is a single bond, R⁶Is C₂-C₆Acyl radical) may be derived from compounds of the general formula (II) (wherein R is⁶Hydrogen) is obtained by one of the methods reported in the literature for this reaction, for example, with formula C₁-C₅alkyl-COOH compounds in the condensing agent (N, N '-dicyclohexylcarbodiimide, N-ethyl-N' - (3-dimethyl-aminopropyl) carbodiimide hydrochloride, SOCl₂POCl₃Or PCl₅) In the presence of (a) or of the formula C₁-C₅The compound of alkyl-COOH can be optionally preceded by SOCl in the presence of a base (sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine, pyridine or 4-dimethylaminopyridine) ₂，POCl₃，PCl₅And (6) processing.

Compounds of the general formula (II) (in which Y is mercapto, where the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and Z is hydrogen or C₁-C₆Alkyl group) can be obtained from a compound of general formula (II) wherein Y is hydroxyl by one of the methods reported in the literature for this reaction, for example, by reaction with a thiocarboxylic acid (e.g., thioacetic acid) in the presence of diethyl or diisopropyl azocarboxylate and tributylphosphine or triphenylphosphine, followed by cleavage of the thioester group with methanethiol or propanethiol ammonia, sodium.

A compound of the general formula (II) (wherein Y is NHR)⁹Wherein the symbol R³，R⁴，R⁵，R⁶，R⁹Andhaving the above definition and Z is hydrogen) can be represented by the general formula (II) whereinWhen together representing a double bond, Y and Z together represent a ketone group (= O)) is obtained by one of the methods reported in the literature for this reaction, for example, by reaction with the general formula NH₂R⁹In the presence of a reducing agent (e.g., sodium borohydride or sodium cyanoborohydride) at an appropriate pH.

A compound of the general formula (II) (wherein Y is NHR)⁹Wherein the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition, R⁹Is hydrogen and Z is hydrogen) may be derived from compounds of formula (II) wherein the symbols areWhen together representing a double bond, Y and Z together represent a ketone group (= O)) is obtained by one of the methods reported in the literature for this reaction, for example, by reaction with the general formula HONH ₂To give an oxime, which is then reduced with a reducing agent (e.g., sodium in ethanol, lithium aluminum hydride) or hydrogenated over a metal catalyst (e.g., Pt, Pd or raney nickel).

Compounds of the general formula (II) (in which Y is CHO, where the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition and Z is hydrogen) can be represented by the general formula (II) whereinWhen together representing a double bond, Y and Z together represent a ketone group (= O)) is obtained by one of the methods reported in the literature for this reactionObtained, for example, by reaction with methoxymethyltriphenylphosphonium chloride in the presence of a strong base (e.g., sodium hydride or potassium tert-butoxide) and then acidic hydrolysis of the intermediate methylenol ether; by reaction with methyltriphenylphosphonium iodide in the presence of a base (e.g.sodium hydride, sodium methoxide, potassium tert-butoxide) to give a methylene derivative which is treated with borane and sodium perborate or basic hydrogen peroxide to give a hydroxymethyl derivative which is treated with a reagent reported in the literature for such oxidation (e.g.iodoxybenzoic acid, Dess-Martin periodinane, oxalyl chloride and triethylamine, CrO in pyridine or in sulfuric acid and acetone) ₃Pyridinium chlorochromate, pyridinium dichromate) to obtain the target formaldehyde.

Compounds of the general formula (II) (in which Y is hydroxy, where the symbol R³，R⁴，R⁵，R⁶Andhas the above definition, and Z is C₁-C₆Alkyl radical) can be prepared from compounds of the general formula (II) (where the symbols are givenWhen together representing a double bond, Y and Z together represent a ketone group (= O)) is obtained by one of the methods reported in the literature for this reaction, for example, by reaction with the general formula C₁-C₆Compounds of alkylmett (where Met is a metal atom and T is a vacancy depending on the oxidation state of the Met metal atom, halogen or a different metal atom, for example, Li, MgCl, MgBr, MgI and CuLi) are reacted.

A compound of the general formula (II) (wherein Y is NHR)⁹Wherein the symbol R³，R⁴，R⁵，R⁶Andhaving the above definition, R⁹Is hydrogen and Z is hydrogen or C₁-C₆Alkyl group) can be obtained from a compound of general formula (II) wherein Y is hydroxyl by one of the methods reported in the literature for this reaction, for example, by reaction with cyanic acid in the presence of a strong acid (e.g., sulfuric acid) followed by hydrolysis of the intermediate formamide.

The compounds of the general formulae (III) to (XV) are commercially available or can be prepared by standard procedures from commercially available compounds.

In all the transformations described, any interfering reactive groups can be those described in Organic chemistry (see, for example, T.W.Greene and P.G.M.Wuts, "protective groups in Organic Synthesis", J.Wiley &Sons，Inc.，3^rdEd, 1999) and mature steps well known to those skilled in the art for protection and subsequent deprotection.

All the transformations described are described only in Organic Chemistry (see, for example, J.March "Advanced Organic Chemistry", J.Wiley&Sons，Inc.，4^thEd., 1992) and examples of maturation steps known to those skilled in the art.

We have found that the derivatives (I) and pharmaceutically acceptable salts thereof prepared according to the present invention are useful agents in the treatment of cardiovascular disorders, such as heart failure and hypertension. Furthermore the compounds show affinity and inhibit Na⁺,K⁺-an ATPase activity.

Since the compounds of the invention are shown to be able to antagonize the molecular effects of nanomolar ouabain concentrations on the Na-KATP enzyme, they are effective in the treatment of diseases caused by the hypertensive effects of endogenous ouabain.

According to a preferred embodiment of the invention, the diseases caused by the hypertensive effects of endogenous ouabain comprise renal failure progression in Autosomal Dominant Polycystic Kidney Disease (ADPKD), preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.

In Autosomal Dominant Polycystic Kidney Disease (ADPKD), the formation and enlargement of the bursa results from cell expansion and transepithelial secretion of fluid and leads to progressive impairment of renal function and renal failure. In 1 out of 1000 subjects, ADPKD was infected, which represents the first genetic cause of the renal failure mechanism. The renal Na-K ATPase is critical for ionic and liquid transport in ADPKD cells, and its translocation and altered function have been described in this pathology (Wilson PD et al Am J Pathol2000;156: 253-268). Ouabain (AN inhibitor of Na-K ATPase) inhibits fluid secretion in the ADPKD vesicles at micromolar concentrations (Grantham JJ et al I Clin. invest.1995;95: 195. sup. 202), whereas ouabain stimulates ADPKD cell proliferation but does not affect normal human kidney cell growth at nanomolar concentrations similar to circulating endogenous ouabain (Nguyen AN et al 2007;18: 46-57). Ouabain was shown to stimulate ADPKD proliferation by binding Na-K atpase with high affinity and triggering activation of the MEK-ERK pathway (Nguyen AN et al 2007;18: 46-57).

Preeclampsia is a potentially devastating disease of gestational hypertension, and effective treatment thereof remains lacking. Elevated circulating levels of cardenolides and bufogenin have been reported in preeclamptic patients and in rat models of this disease (Lopatin DA et al J. Hypertens.1999;17:1179-1187; Graves SV et al Am J Hypertens.1995;8:5-11; Adair CD et al Am J Nephrol.1996;16: 529-531). This existing data suggests that increased plasma concentrations of Na-K ATPase inhibitors lead to vasoconstriction and malignant hypertension in preeclampsia (Vu HV et al Am J Nephrol.2005;25: 520-. Recently, digoxin-specific Fab (digibind) has been shown to lower blood pressure and increase natriuresis in preeclamptic patients (Pullen MA al. JPETT2004; 310: 319-.

The proteinuria associated with glomerulosclerosis results from the destruction of the slit-void structure formed by the podocyte foot processes in the glomerulus. In particular, slit membrane proteins (e.g., nephrin, ZO1, podocyn, synaptopodin and others) and their function in the common signal transduction pathway are regulated by Fyn, a tyrosine kinase of Src family kinases (Benzing T.J Am Soc Nephrol2004;15: 1382-. Recently, the key role of the slit pore structure was attributed to beta adducin, a cytoskeletal protein under Fyn control (Gotoh BBRC2006;346: 600-. ACE-linked adducin polymorphisms were found to be associated with impaired renal function in both European and Chinese populations (Wang JG et al J Mol Med2004;82: 715-. As endogenous ouabain antagonists, Rosafuroxin and its analogs have been described as being capable of antagonizing the molecular effects of adducin polymorphisms on tyrosine kinase signaling (Ferrandi M. et al JBC,2004;279:33306-14; Ferrari et al Am J Physiol Regul2006;290: R529-535; Ferrari P. et al Med Hypophthes.2007; 68: 1307-1314).

The pharmaceutical compositions will contain at least one compound of formula (I) as an active ingredient in an amount sufficient to produce a significant therapeutic effect. The compositions encompassed by the present invention are all conventional compositions and can be prepared by methods commonly used in the Pharmaceutical industry, for example, as set forth in the latest edition of Remington's Pharmaceutical Science Handbook, Mack pub.N.Y. Depending on the route of administration chosen, the composition may be in solid or liquid form suitable for oral, parenteral or intravenous administration. The composition according to the invention comprises at least one pharmaceutically acceptable carrier or excipient in addition to the active ingredient. They may be particularly useful formulation adjuvants, for example, cosolvents, dispersants, suspending agents or emulsifiers.

Furthermore, the compounds of the invention have a contractile force enhancing feature, which can be seen in slow intravenous infusion of Cerri in anesthetized guinea pigs (Cerri a. et al, j.med.chem.2000, 43, 2332), and have lower toxicity compared to standard cardiotonic steroids (e.g. digoxin).

The following examples illustrate the invention without limiting it.

Detailed Description

Example 1

(E, Z)3- (2-aminoethoxyimino) -17-oxoandrostan-6 alpha-yl nitrate rich in Maleate (I-aa)

To a stirring solution of 3, 17-dioxoandrostane-6 α -yl nitrate (II-aa, preparation 1, 1.14g) in THF (30mL) was added 2-aminoethoxyamino dihydrochloride (223mg), Na, rapidly dropwise₂HPO₄.12H₂O (2.30g) in water (11.6 mL). After 1.5 hours, NaCl (1.8g) was added and the mixture was stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with THF (2 ×). The combined organic extracts were washed with Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) was used. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-aa (0.57g, 33%) as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 8.76(bb, 4H), 6.41(s, 1H), 4.98(m, 1H), 4.04(m, 2H), 3.16(m, 0.5H), 3.06(m, 0.5H), 2.98(m, 2H), 2.45-0.75(m, 19H), 0.98(s, 1.5H), 0.97(s, 1.5H), 0.80(s, 3H), in ppm of TMS.

Example 2

(E, Z)3- (2-aminoethoxyimino) -17-oxoandrostan-6 beta-yl nitrate rich in Maleate (I-ab)

Prepared as described in example 1, starting from 3, 17-dioxoandrostan-6 β -yl nitrate (II-ab, preparation 2) and 2-aminoethoxyamino dihydrochloride in 60% yield. ¹H-NMR(300MHz，DMSO-d₆δ 8.41(bb, 4H), 6.40(s, 2H), 5.23(m, 0.5H), 5.19(m, 0.5H), 4.03(m, 2H), 3.05(m, 1H), 2.96(m, 2H), 2.45-0.70(m, 19H), 1.00(s, 1.5H), 0.99(s, 1.5H), 0.80(s, 3H), in ppm of TMS。

Example 3

(E, Z)3- (2-aminoethoxyimino) -6 alpha-cyanoandrostan-17-one fumarate (I-ac)

Prepared as described in example 1, starting from 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) and 2-aminoethoxyamino dihydrochloride in 65% yield.¹H-NMR(300MHz，DMSO-d₆δ 9.07(bb, 4H), 6.40(s, 2H), 4.07(m, 2H), 3.24(m, 0.5H), 3.06(m, 0.5H), 2.99(m, 2H), 2.77(m, 1H), 2.45-0.70(m, 19H), 0.88(s, 1.5H), 0.87(s, 1.5H), 0.77(s, 3H), in ppm of TMS.

Example 4

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxyandrostan-17-one fumarate (I-ad)

To a stirring solution of 5 α -hydroxyandrostane-3, 17-dione (II-ad, preparation 4, 447mg) in THF (10mL) was added rapidly dropwise an aqueous solution of 2-aminoethoxyamino dihydrochloride (223mg) (5 mL). After 1.5 hours, NaCl (556mg) was added, and the mixture was stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with THF (2 ×). The combined organic extracts were washed with Na ₂SO₄Drying, filtration and evaporation gave an oily residue. The crude product was dissolved in CH₂Cl₂(10mL) and washed with saturated aqueous NaCl (3X). The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) was used. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-ad (420mg, 60%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.9.10 (bb, 4H), 6.40(s, 2H), 4.32(bb, 1H), 4.03(m, 2H), 2.96(m, 3H), 2.45-1.00(m，20H，0.97(s，3H)，0.76(s，3H)。

Example 5

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxy-6 beta-cyanoandrostan-17-one Fumarate (I-ae)

Prepared as described in example 1, starting from 5 α -hydroxy-6 β -cyanoandrostane-3, 17-dione (II-ae, preparation 5) and 2-aminoethoxyamino dihydrochloride in 50% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.50(bb, 5H), 6.35(s, 2H), 4.03(m, 2H), 3.30-0.95(m, 22H), 1.22(s, 3H), 0.81(s, 3H), in ppm of TMS.

Example 6

(E, Z) -3- (2-aminoethoxyimino) -7 alpha-methylandrostane-6- (E) -hydroxy-imine Base-17-keto hydrochloride (I-af)

Prepared as described in example 4, starting from 6- (E) -hydroxyimino-7 α -methylandrostane-3, 17-dione (II-af, preparation 6) and 2-aminoethoxyamino dihydrochloride in 64% yield. The crude product was reacted with Et ₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 10.30(s, 1H), 7.62(bb, 3H), 4.07(m, 2H), 3.08(m, 0.5H), 2.99(m, 2H), 2.95(m, 0.5H), 2.73(m, 0.5H), 2.68(m, 0.5H), 2.45-1.00(m, 17H), 1.08(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 7

(E, Z)3- (2-aminoethoxyimino) -6- (2-spiro-1, 3-dioxolane) androstane -17-Keto fumarate (I-ag)

Prepared as described in example 1 starting from 6, 6-ethylenedioxyandrostane-3, 17-dione (II-ag, preparation 7) and 2-aminoethoxyamino dihydrochloride in 53% yield. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) was used. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-ag.¹H-NMR(300MHz，DMSO-d₆δ 8.00(bb, 4H), 6.40(s, 2H), 4.05-3.65(m, 6H), 3.12(m, 0.5H)3.04(m, 0.5H)2.97(m, 2H)2.45-0.70(m, 19H), 0.97(s, 1.5H), 0.95(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 8

(E, Z)3- (2-aminoethoxyimino) -6-methyleneandrostane-17-one hydrochloride (I-ah)

Prepared as described in example 4, starting from 6-methyleneandrostane-3, 17-dione (II-ah, preparation 8) and 2-aminoethoxyamino dihydrochloride in 90% yield. The crude product was reacted with Et ₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 8.08(bb, 3H), 4.83(bs, 0.5H), 4.80(bs, 0.5H), 4.53(bs, 0.5H), 4.49(bs, 0.5H), 4.09(m, 2H), 3.15-2.95(m, 3H), 2.45-0.90(m, 19H), 0.77(s, 3H), 0.75(s, 3H), in ppm of TMS.

Example 9

(E)3- (2-aminoethoxyimino) -6-methylene androstane-17-one hydrochloride (I-ai)

Prepared as described in example 1, starting from 6-methyleneandrostane-3, 17-dione (II-ah, preparation 8) and 2-aminoethoxyamino dihydrochloride in 40% yield. The crude product (1.65g) was crystallized twice from EtOAc to give the title compound I-ai. H-NMR (300MHz, DMSO-d)₆δ 7.97(bb, 3H), 4.81(bs, 1H), 4.49(bs, 1H), 4.08(t, 2H), 3.10(m, 1H), 3.02(t, 2H), 2.45-0.85(m, 19H), 0.77(s, 3H), 0.75(s, 3H), in ppm of TMS.

Example 10

(E, Z)3- (2-aminoethoxyimino) -6 beta-hydroxymethyl androstane-17-one hydrochlorination Thing (I-aj)

Prepared as described in example 4, starting from 6 β -hydroxymethylandrostane-3, 17-dione (II-ai, preparation 9) and 2-aminoethoxyamino dihydrochloride in 85% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.14(bb, 3H), 4.42(t, 0.5H), 4.40(t, 0.5H), 4.08(m, 2H), 3.50-3.25(m, 2H), 3.05(m, 0.5H), 3.00(m, 2H), 2.91(m, 0.5H), 2.50-0.60(m, 20H), 0.84(s, 1.5H), 0.82(s, 1.5H), 0.80(s, 3H), in ppm of TMS.

Example 11

(E, Z)3- (2-aminoethoxyimino) -6 beta-methoxymethylandrostan-17-one salts Acidizing substance (I-ak)

Prepared as described in example 4, starting from 6 β -methoxymethylandrostane-3, 17-dione (II-aj, preparation 10) and 2-aminoethoxyamino dihydrochloride in 60% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.06(bb, 3H), 4.07(m, 2H), 3.35(m, 2H), 3.32(s, 3H),), 3.07(m, 0.5H), 3.02(m, 2H), 2.92(m, 0.5H), 2.45-0.62(m, 20H), 0.86(s, 1.5H), 0.85(s, 1.5H), 0.81(s, 3H), in ppm of TMS.

Example 12

(E, Z)3- (2-aminoethoxyimino) -6 alpha-vinyl androstane-17-one hydrochlorination Thing (I-al)

Prepared as described in example 4, starting from 6 α -vinyl androstane-3, 17-dione (II-ak, preparation 11) and 2-aminoethoxyamino dihydrochloride in 90% yield. 1H-NMR (300MHz, DMSO-d6, ppm from TMS). delta.7.95 (bb, 3H), 5.51(m, 1H), 4.98(m, 2H), 4.05(m, 2H), 3.06(m, 0.5H), 3.01(m, 2H), 2.97(m, 0.5H), 2.44-0.67(m, 20H), 0.91(s, 1.5H), 0.90(s, 1.5H), 0.78(s, 3H).

Example 13

(E, Z)3- (2-aminoethoxyimino) -6 alpha- (2-hydroxyethyl) androstan-17-one hydrochloride Compound (I-am)

Prepared as described in example 4, starting from 6 α - (2-hydroxyethyl) androstane-3, 17-dione (II-al, preparation 12) and 2-aminoethoxyamino dihydrochloride in 85% yield. 1H-NMR (300MHz, DMSO-d)₆δ 7.95(bb, 3H), 4.37(br, 1H), 4.08(m, 2H), 3.42(m, 2H), 3.22(m, 0.5H), 3.06(m, 0.5H), 3.02(m, 2H), 2.44-0.90(m, 22H), 0.88(s, 1.5H), 0.87(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 14

3- (E, Z) - (2-aminoethoxyimino) -17-oxoandrostane-6 alpha-carbaldehyde (E, Z) Oxime fumarate (I-an)

Prepared as described in example 1, starting from 3, 17-dioxoandrostane-6 α -carbaldehyde (E, Z) -oxime (II-am, preparation 13) and 2-aminoethoxyamino dihydrochloride in 52% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.72(bb, 0.5H), 10.46(bb, 0.5H), 8.00(bb, 4H), 7.10(d, 0.25H), 7.07(d, 0.25H), 6.42(d, 0.25H), 6.40(s, 2H), 6.38(d, 0.25H), 4.05(m, 2H), 3.02(m, 2H), 3.05(m, 1H), 2.88(m, 0.5H), 2.45-0.67(m, 19.5H), 0.91(s, 1.5H), 0.90(s, 1.5H), 0.77(s, 3H), in ppm of TMS.

Example 15

(E, Z)3- (2-aminoethoxyimino) -6 alpha-hydroxymethylandrostane-17-one hydrochlorination Substance (I-ao)

As described in example 4 from 6 alpha-hydroxymethyl androstaneAlkane-3, 17-dione (II-an, preparation 14) and 2-aminoethoxyamino dihydrochloride were prepared in 60% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.73(bb, 3H), 4.37(t, 1H), 4.06(m, 2H), 3.37(m, 2H), 3.16(m, 0.5H), 3.06(m, 0.5H), 3.02(m, 2H), 2.45-0.60(m, 20H), 0.89(s, 1.5H), 0.87(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 16

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetoxymethyl androstan-17-one Fumarate (I-ap)

Prepared as described in example 1, starting from 6 α -acetoxymethyl androstane-3, 17-dione (II-ao, preparation 15) and 2-aminoethoxyamino dihydrochloride in 30% yield. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH95/5/0.5) purifying the crude product. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-ap.¹H-NMR(300MHz，DMSO-d₆δ 8.00(bb, 4H), 6.40(s, 2H), 4.05-3.80(m, 4H), 3.05(m, 1H), 2.95(m, 2H), 2.45-0.58(m, 20H), 2.00(s, 3H), 0.89(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 17

(E)3- (2-aminoethoxyimino) -6 alpha-methoxymethyl androstane-17-one hydrochloride Compound (I-aq)

Prepared as described in example 1, starting from 6 α -methoxymethylandrostane-3, 17-dione (II-ap, preparation 16) and 2-aminoethoxyamino dihydrochloride in 33% yield. From Et₂The crude product was crystallized from O/EtOAc.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.82 (bb, 3H), 4.06(m, 2H), 3.22(m, 2H), 3.20(s, 3H), 3.05(m, 1H), 3.02(m, 2H), 2.45-0.60(m，20H)，0.89(s，3H)，0.78(s，3H)。

Example 18

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carboxy androstane-17-one hydrochloride (I-ar)

To a stirring solution of 6 α -carboxyandrostane-3, 17-dione (II-aq, preparation 17, 50mg) in dioxane (1mL) was added rapidly dropwise an aqueous solution of 2-aminoethoxyamino dihydrochloride (22mg) (0.5 mL). After 2 hours the mixture was lyophilized and treated with Et₂The residue was triturated to give the title compound I-ar (52mg, 80%).¹H-NMR(300MHz，DMSO-d₆δ 8.24(bb, 4H), 4.07(m, 2H), 3.01(m, 3H), 2.45-0.70(m, 20H), 0.90(s, 1.5H), 0.89(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 19

(Z)3- (2-aminoethoxyimino) -6 alpha-carbamoylandrostane-17-one hydrochlorination Substance (I-as)

Starting from 6 α -carbamoylandrostane-6, 17-dione (II-ar, preparation 18, 90mg), precipitation from THF gave the title compound I-as a white solid (46mg, 40%) according to the procedure described in example 1.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS) 7.78(3H, bb), 7.37(1H, s), 6.79(1H, s), 4.05(2H, m), 2.99(2H, m), 2.91(1H, m), 2.45-0.65(20H, m), 0.89(3H, s), 0.78(3H, s).

Example 20

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carbamoylandrostan-17-one fumaric acid Acid salt (I-at)

The residual mother liquor of the reaction of example 19 was evaporated and chromatographed by flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) purification.The residue of pure components was dissolved in methanol and treated with fumaric acid to give the title compound I-at (61mg, 40%) as a white solid.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS 8.00(4H, bb), 7.38(0.5H, s), 7.32(0.5H, s), 6.80(0.5H, s), 6.78(0.5H, s), 6.40(2H, s), 4.05(2H, m), 3.06(0.5H, m), 2.99(2H, m), 2.91(0.5H, m), 2.45-0.65(20H, m), 0.89(3H, s), 0.78(3H, s).

Example 21

(E, Z)3- (2-aminoethoxyimino) -6 alpha-methoxycarbonylandrostane-17-one hydrochloride Compound (I-au)

Prepared as described in example 1, starting from 6 α -methoxycarbonylandrostane-3, 17-dione (II-as, preparation 19) and 2-aminoethoxyamino dihydrochloride (43mg) in 62% yield using Et₂The crude product was washed with O/EtOAc and centrifuged.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS) 7.75(3H, bb), 4.06(2H, m), 3.60(3H, s), 3.07(0.5H, m, E isomer), 3.01(2H, m), 2.79(0.5H, m, Z isomer), 2.55-0.92(20H, m), 0.91(1.5H, s, E isomer), 0.90(1.5H, s, Z isomer), 0.78(3H, s).

Example 22

(E, Z)3- (2-aminoethoxyimino) -6- (E) -hydroxyiminoandrostan-17-one salts Acidized substance (I-av)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 400mg) and 2-aminoethoxyamino dihydrochloride (188mg), as described in example 1. The crude product was crystallized from MeOH/EtOAc to afford the title compound as a white solid (367mg, 70%).¹H-NMR(300MHz，DMSO-d₆δ 10.58(s, 0.5H), 10.51(s, 0.5H), 7.98(m, 3H), 4.08(m, 2H), 3.29(m, 1H), 3.13(m, 0.5H), 3.10(m, 0.5H), 3.02(m, 2H), 2.45-0.95(m, 18H), 0.79(s, 6H), in ppm of TMS.

Example 23

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -methoxyiminoandrostane-17- Ketone hydrochloride (I-aw)

Prepared as described in example 1, starting from 6- (E) -methoxyiminoandrostane-3, 17-dione (II-au, preparation 21) and 2-aminoethoxyamino dihydrochloride in 60% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.03(bb, 3H), 4.09(m, 2H), 3.75(s, 1.5H), 3.73(s, 1.5H), 3.24-3.05(m, 2H), 3.02(m, 2H), 2.45-0.95(m, 18H), 0.78(s, 3H), 0.77(s, 3H), in ppm of TMS.

Example 24

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -ethoxyiminoandrostane-17- Ketone hydrochloride (I-ax)

Starting from 6- (E) -ethoxyiminoandrostane-3, 17-dione (II-av, preparation 22, 80mg) and 2-aminoethoxyamino dihydrochloride (34mg), as described in example 1, was prepared by flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) to yield the title compound I-ax (81mg, 80%).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.85 (3H, bb), 4.07(2H, m), 4.00(1H, q), 3.98(1H, q), 3.20(1H, m), 3.10(1H, m), 3.03(2H, m), 2.46-0.98(18H, m), 1.17(1.5H, t), 1.16(1.5H, t), 0.78(6H, s).

Example 25

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -allyloxyiminoandrostane -17-Keto fumarate (I-ay)

6- (E) -allyloxyiminoandrostane-3, 17-dione (II-aw, preparation 23, 121mg) and 2-aminoethoxy as described in example 1Amine dihydrochloride (50mg) starting, can be purified by flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) to yield the title compound I-ay (134mg, 75%).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.9.01 (4H, bb), 6.40(2H, s), 5.93(1H, m), 5.18(2H, m), 4.49(2H, m), 4.05(2H, m), 3.22(1H, m), 3.09(1H, m), 2.98(2H, m), 2.44-0.98(18H, m), 0.78(6H, s).

Example 26

(E, Z)3- (2-aminoethoxyimino) -6 beta-methylandrostan-17-one hydrochloride (I-az)

Prepared as described in example 1 starting from 6 β -methylandrostane-3, 17-dione (II-ax, preparation 24) and 2-aminoethoxyamino dihydrochloride in 64% yield. The crude product was triturated with EtOAc.¹H-NMR(300MHz，DMSO-d₆δ 7.89(bb, 3H), 4.06(m, 2H), 3.07(m, 0.5H), 3.02(m, 2H), 2.81(m, 0.5H), 2.45-0.60(m, 20H), 0.96(s, 1.5H), 0.95(s, 1.5H), 0.91(d, 1.5H), 0.90(d, 1.5H), 0.81(s, 3H), in ppm of TMS.

Example 27

(E, Z)3- (2-aminoethoxyimino) -6 alpha-methylandrostan-17-one hydrochloride (I-ba)

Prepared as described in example 1, starting from 6 α -methylandrostane-3, 17-dione (II-ay, preparation 25) and 2-aminoethoxyamino dihydrochloride in 83% yield. The crude product was crystallized from MeOH/EtOAc to provide the title compound I-ba as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 7.83(bb, 3H), 4.07(m, 2H), 3.16(m, 0.5H), 3.06(m, 0.5H), 3.03(m, 2H), 2.45-0.55(m, 20H), 0.89(s, 1.5H), 0.87(s, 1.5H), 0.84(s, 1.5H), 0.81(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Practice ofExample 28

(E, Z) -3- (2-aminoethoxyimino) androstane-6 (S) - (spiro-2' -oxiranyl Alkyl) -17-keto hydrochloride (I-bb)

Prepared as described in example 1, starting from 6(S) - (spiro-2' -oxirane) androstane-3, 17-dione (II-az, preparation 26) and 2-aminoethoxyamino dihydrochloride in 40% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.80(bb, 3H), 4.06(m, 2H), 3.07(m, 0.5H), 3.01(m, 2H), 2.90(m, 0.5H), 2.76(d, 1H), 2.57(d, 1H), 2.45-0.75(m, 19H), 0.92(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 29

(E, Z) -3- (2-aminoethoxyimino) androstane-6 (R) - (spiro-2' -oxiranyl Alkyl) -17-keto hydrochloride (I-bc)

Prepared as described in example 1, starting from 6(R) - (spiro-2' -oxirane) androstane-3, 17-dione (II-ba, preparation 26) and 2-aminoethoxyamino dihydrochloride in 50% yield. The crude product was dissolved in water and lyophilized to give the title compound II-bc.¹H-NMR(300MHz，DMSO-d₆δ 7.75(bb, 3H), 4.06(m, 2H), 3.05(m, 0.5H), 2.99(m, 2H), 2.83(m, 0.5H), 2.75(d, 0.5H), 2.72(d, 0.5H), 2.30(d, 0.5H), 2.27(d, 0.5H), 2.45-0.90(m, 19H), 0.96(s, 1.5H), 0.94(s, 1.5H), 0.80(s, 3H), in ppm of TMS.

Example 30

(E, Z)3- (2-aminoethoxyimino) -6 alpha-ethynylandrostane-17-one hydrochlorination Thing (I-bd)

Prepared as described in example 1, starting from 6-ethynylandrostane-3, 17-dione (II-bb, preparation 27) and 2-aminoethoxyamino dihydrochloride in 76% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.90(bb, 3H), 4.06(m, 2H), 3.05(m, 3H), 2.98(d, 0.5H), 2.97(d, 0.5H), 2.61-0.66(m, 20H), 0.88(s, 1.5H), 0.87(s, 1.5H), 0.77(s, 3H), in ppm of TMS.

Example 31

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carboxamidoandrostan-17-one fumarate Acid salt (I-be)

Prepared as described in example 1, starting from 6 α -formamidoandrostane-3, 17-dione (II-bc, preparation 28) and 2-amino-ethoxyaminyl dihydrochloride in 59% yield. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) was used. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-be.¹H-NMR(300MHz，DMSO-d₆δ 8.20(m, 4H), 8.10(bd, 0.5H), 8.03(bd, 0.5H), 8.01(bd, 0.5H), 7.90(bd, 0.5H), 6.44(s, 2H), 4.05(m, 2H), 3.72(m, 1H), 3.16(m, 0.5H)3.06(m, 0.5H)3.00(m, 2H), 2.45-0.65(m, 19H), 0.93(s, 1.5H), 0.92(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 32

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetamido androstane-17-one hydrochloride Compound (I-bf)

Prepared as described in example 1, starting from 6 α -acetamido androstane-3, 17-dione (II-bd, preparation 29) and 2-aminoethoxyamino dihydrochloride in 84% yield. The crude product was triturated with EtOAc.¹H-NMR(300MHz，DMSO-d₆δ 7.87(bb, 3H), 7.83(d, 0.5H), 7.67(d, 0.5H), 4.07(m, 2H), 3.65(m, 1H), 3.15(m, 0.5H), 3.07(m, 0.5H), 3.03(m, 2H), 2.45-0.65(m, 19H), 1.81(s, 1.5H), 1.79(s, 1.5H), 0, in ppm of TMS.93(s，1.5H)，0.91(s，1.5H)，0.78(s，3H)。

Example 33

(E, Z)3- (2-aminoethoxyimino) -6- (E) -ethylideneandrostan-17-one hydrochloride Compound (I-bg)

Prepared as described in example 1, starting from 6(E) -ethyleneandrostane-3, 17-dione (II-be, preparation 30) and 2-aminoethoxyamino dihydrochloride in 71% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.01(bb, 3H), 5.01(q, 0.5H), 4.97(q, 0.5H), 4.08(m, 2H), 3.03(m, 3H), 2.69(m, 1H), 2.45-0.85(m, 21H), 0.77(s, 3H), 0.72(s, 3H), in ppm of TMS.

Example 34

(E, Z)3- (2-aminoethoxyimino) -6-difluoromethyleneandrostane-17-one hydrochloride Compound (I-bh)

Prepared as described in example 1, starting from 6-difluoromethyleneandrostane-3, 17-dione (II-bf, preparation 31) and 2-aminoethoxyamino dihydrochloride in 61% yield. The crude product was dissolved in water and freeze dried.¹H-NMR(300MHz，DMSO-d₆δ 7.62(bb, 3H), 4.07(m, 2H), 3.27(m, 0.5H), 3.07(m, 0.5H), 3.01(m, 2H), 2.45-0.80(m, 19H), 0.89(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 35

(E)3- (2-aminoethoxyimino) -17-oxoandrostan-6- (E) -ylidene acetonitrile salts Acidized substance (I-bi)

Prepared as described in example 1, starting from 3, 17-dioxoandrostan-6- (E) -ylideneacetonitrile (II-bg, preparation 32) and 2-aminoethoxyamino dihydrochloride in 61% yield. The crude product was dissolved in water and freeze dried.¹H-NMR(300MHz，DMSO-d₆δ 7.95(bb, 3H), 5.26(bs, 1H), 4.08(m, 2H), 3.04(m, 3H), 2.82(m, 1H), 2.45-1.00(m, 18H), 0.79(s, 3H), 0.75(s, 3H), in ppm of TMS.

Example 36

(E, Z)3- (2-aminoethoxyimino) -6- (E) - [ 2-hydroxyethylidene group]Androstan-17-one Hydrochloride (I-bj)

As described in example 1, from 6(E) - [ 2-hydroxyethylidene]Androstane-3, 17-dione (II-bh, preparation 33) and 2-aminoethoxyamino dihydrochloride were prepared starting in 70% yield. 1H-NMR (300MHz, DMSO-d) ₆δ 7.75(bb, 3H), 5.08(bt, 0.5H), 5.05(bt, 0.5H), 4.56(t, 0.5H), 4.53(t, 0.5H), 4.12-3.92(m, 4H), 3.05(m, 3H), 2.65(m, 1H), 2.45-0.85(m, 18H), 0.77(s, 3H), 0.75(s, 3H), in ppm of TMS.

Example 37

Methyl [3- (E, Z) - (2-aminoethoxyimino) -17-oxoandrostane-6- (E) -ylidene Base of]Acetic ester hydrochloride (I-bk)

Prepared as described in example 1, starting from (E) - (3, 17-dioxoandrostan-6-ylidene) methyl acetate (II-bi, preparation 34) and 2-aminoethoxyamino dihydrochloride in 87% yield. The crude product was triturated with EtOAc.¹H-NMR(300MHz，DMSO-d₆δ 8.09(bb, 3H), 5.45(s, 0.5H), 5.41(s, 0.5H), 4.10(m, 2H), 3.94(m, 1H), 3.62(s, 3H), 3.05(s, 3H), 2.50-1.00(m, 18H), 0.77(s, 3H), 0.75(s, 3H), in ppm of TMS.

Example 38

E, Z)3- (2-aminoethoxyimino) -6- (spirocyclopropane) androstan-17-one salts Acidized substance (I-bl)

As in the examples1, prepared in 92% yield starting from 6- (spirocyclopropan) androstane-3, 17-dione (II-bj, preparation 35) and 2-aminoethoxyamino dihydrochloride. 1H-NMR (300MHz, DMSO-d)₆δ 7.88(bb, 3H)4.06(m, 2H), 3.06(m, 0.5H), 3.00(m, 2H), 2.70(m, 0.5H), 2.43-0.89(m, 19H), 0.95(s, 3H), 0.79(s, 3H), 0.57-0.16(m, 4H), in ppm of TMS.

Example 39

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetamidomethylandrostan-17-one Hydrochloride (I-bm)

Prepared under the same reaction conditions as described in example 1, starting with 6 α -acetamidomethylandrostane-6, 17-dione (II-bk, preparation 36, 155mg) and 2-aminoethoxyamino dihydrochloride (49mg), the reaction mixture was quenched after 2 hours with brine and extracted with THF. The combined organic layers were washed with brine and then with Na₂SO₄Dry and evaporate the solvent to dryness. With EtOAc and Et₂O washing the resulting solid. After drying overnight in vacuo, the title compound I-bm (120mg, 61%) was obtained as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 7.92(0.5H, t), 7.82(3H, bb), 7.71(0.5H, t), 4.07(2H, m), 3.40(0.5H, m), 3.25-2.69(4.5H, m), 2.46-0.57(20H, m), 1.84(1.5H, s), 1.80(1.5H, s), 0.87(3H, s), 0.78(3H, s).

Example 40

(E, Z)3- (2-aminoethoxyimino) -6 alpha-formamidomethyl androstane-17-one Hydrochloride (I-bn)

Starting from 6 α -carboxamidomethylandrostane-3, 17-dione (II-bl, preparation 37, 65mg) and 2-aminoethoxyamino dihydrochloride (21mg) under the reaction conditions described in example 4, flash chromatography (SiO 2) ₂，CH₂Cl₂:MeOH:NH₃Titled formation after 9:1:0.1)Compound (50mg, 60%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.8.17-7.95 (2H, m), 7.85(3H, bb), 4.07(2H, m), 3.20-2.80(5H, m), 2.45-0.59(20H, m), 0.88(1.5H, s), 0.87(1.5H, s), 0.78(3H, s).

EXAMPLE 41

(E, Z) -3- (2-aminoethoxyimino) -5 alpha-hydroxy-6- (E) -hydroxyiminoandrostane -17-Keto fumarate (I-bo)

Prepared as described in example 1, starting from 5 α -hydroxy-6- (E) -hydroxyiminoandrostane-3, 17-dione (II-bm, preparation 38) and 2-aminoethoxyamino dihydrochloride in 77% yield. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) was used. To this concentrated fraction was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-bo. 1H-NMR (300MHz, DMSO-d)₆δ 10.68(bb, 1H), 9.01(bb, 4H), 6.41(s, 2H), 5.11(bb, 1H), 4.05(m, 2H), 3.26(d, 0.5H), 3.11(m, 1H), 3.01(m, 0.5H), 2.98(m, 2H), 2.63-1.13(m, 17H), 0.82(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 42

(E, Z) -3- (2-aminoethoxyimino) -5 alpha-hydroxy-6- (E) -methoxyimino androstane Stanol-17-one fumarate (I-bp)

Prepared as described in example 41, starting from 5 α -hydroxy-6- (E) -methoxyiminoandrostane-3, 17-dione (II-bn, preparation 39) and 2-aminoethoxyamino dihydrochloride in 50% yield. 1H-NMR (300MHz, DMSO-d)₆δ 8.00(bb, 4H), 6.40(s, 2H), 5.21(s, 1H), 4.05(m, 2H), 3.75(s, 3H), 3.25(d, 0.5H), 3.10-2.90(m, 3.5H), 2.62-1.04(m, 17H), 0.83(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 43

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxy-6-methyleneandrostan-17-one Hydrochloride (I-bq)

Prepared under reaction conditions as described in example 1 with 5 α -hydroxy-6-methyleneandrostane-3, 17-dione (II-bo, preparation 40, 500mg) and 2-aminoethoxyamino dihydrochloride (236 mg). The combined organic layers were washed with brine, and Na₂SO₄Dry and evaporate the solvent to dryness. With EtOAc/Et₂O washing the resulting solid. After drying overnight in vacuo, the title compound I-bq (483mg, 74%) was obtained.¹H-NMR(300MHz，DMSO-d₆δ 7.88(bb, 3H), 4.87(m, 0.5H), 4.83(m, 0.5H), 4.71(m, 0.5H), 4.66(m, 0.5H), 4.64(s, 0.5H), 4.55(s, 0.5H), 4.08(m, 2H), 3.20(d, 0.5H), 3.07(m, 0.5H), 3.03(m, 2H)2.61-1.11(m, 18H), 0.84(s, 1.5H), 0.83(s, 1.5H), 0.76(s, 3H), in ppm of TMS.

Example 44

(E, Z)3- (2-aminoethoxyimino) androstane-7, 17-dione fumarate (I-br)

Prepared as described in example 1 starting from androstane-3, 7, 17-trione (II-bp, preparation 41) and 2-aminoethoxyamino dihydrochloride in 50% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.86(bb, 4H), 6.40(s, 2H), 4.03(m, 2H), 3.09(m, 0.5H), 2.97(m, 2H), 2.93(m, 0.5H)2.66(m, 1H), 2.55-0.95(m, 18H), 1.13(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 45

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -hydroxyiminoandrostan-17-one Maleate (I-bs)

As described in example 1, from 7-(E) Starting with (II-bq, preparation 42) hydroxyiminoandrostan-17-one and 2-aminoethoxyamino dihydrochloride, was prepared in 50% yield. 1H-NMR (300MHz, DMSO-d)₆δ 10.37(bb, 1H), 8.85(bb, 4H), 6.40(s, 2H), 4.04(m, 1H), 3.02(m, 4H), 2.97-0.84(m, 18H), 1.01(s, 3H), 0.80(s, 3H), in ppm of TMS.

Example 46

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -methoxyiminoandrostane-17- Keto fumarate (I-bt)

Prepared as described in example 1 starting from 7- (E) -methoxyiminoandrostan-17-one (II-br, preparation 43) and 2-aminoethoxyamino dihydrochloride in 55% yield. ¹H-NMR(300MHz，DMSO-d₆δ 8.00(bb, 3H), 6.40(s, 2H), 4.02(m, 2H), 3.72(s, 3H), 2.97(m, 4H), 2.60-0.87(m, 18H)1.01(s, 3H), 0.80(s, 3H), in ppm of TMS.

Example 47

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -allyloxyiminoandrostane -17-Keto fumarate (I-bu)

Prepared as described in example 1, starting from 7- (E) -allyloxyiminoandrostane-3, 17-dione (II-bs, preparation 44) and 2-aminoethoxyamino dihydrochloride in 75% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.70(m, 4H), 6.39(s, 2H), 5.93(m, 1H), 5.23(m, 1H), 5.16(m, 1H), 4.46(m, 2H)4.02(m, 2H), 3.10-2.85(m, 4H), 2.60-0.89(m, 18H), 1.01(s, 3H), 0.80(s, 3H), in ppm of TMS.

Example 48

(E, Z)3- (2-aminoethoxyimino) -7 alpha-hydroxyandrostan-17-one fumarate (I-bv)

Prepared as described in example 1 starting from 7 α -hydroxyandrostane-3, 17-dione (II-bt, preparation 45) and 2-aminoethoxyamino dihydrochloride in 55% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.70(m, 4H), 6.40(s, 2H), 4.30(bb, 1H), 4.03(m, 2H), 3.74(m, 1H), 3.07(m, 0.5H), 2.98(m, 2H)2.77(m, 0.5H), 2.44-0.91(m, 19H), 0.85(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 49

(E, Z) -3- (2-aminoethoxyimino) -7 alpha-carboxamidoandrostane-3, 17-dione Hydrochloride (I-bw)

Prepared as described in example 1, starting from 7 α -formamidoandrostane-3, 17-dione (II-bu, preparation 46) and 2-aminoethoxyamin dihydrochloride in 70% yield. The crude product was reacted with Et₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 8.30-7.70(m, 5H), 4.07(m, 3H), 3.09(m, 0.5H), 3.03(m, 2H), 2.80(m, 0.5H), 2.43-0.95(m, 19H), 0.89(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 50

(E, Z)3- (2-aminoethoxyimino) -7-methyleneandrostan-17-one hydrochloride (I-bx)

Prepared as described in example 1, starting from 7-methyleneandrostane-3, 17-dione (II-bv, preparation 47) and 2-aminoethoxyamino dihydrochloride in 50% yield. The crude product was triturated with EtOAc.¹H-NMR(300MHz，DMSO-d₆δ 7.85(bb, 3H), 4.73(m, 1H), 4.68(m, 1H), 4.07(m, 2H), 3.07(m, 0.5H), 3.04(m, 2H), 2.93(m, 0.5H), 2.45-0.73(m, 19H), 1.00(s, 3H), 0.81(s, 3H), in ppm of TMS.

Example 51

(E, Z)3- (2-aminoethoxyimino) -7 beta-methylandrostane-17-dione hydrochlorination Thing (I-by)

Prepared as described in example 1, starting from 7-methylandrostane-3, 17-dione (II-bw, preparation 48) and 2-aminoethoxyamino dihydrochloride in 78% yield. The crude product was reacted with Et ₂O triturated then dissolved in water and lyophilized to give the title compound I-by.¹H-NMR(300MHz，DMSO-d₆δ 7.87(bb, 3H), 4.06(m, 2H), 3.07(m, 0.5H), 3.02(m, 2H), 2.86(m, 0.5H), 2.44-0.66(m, 20H), 0.98(d, 3H), 0.84(s, 3H), 0.79(s, 3H), in ppm of TMS.

Example 52

(E, Z)3- (2-aminoethoxyimino) -7 alpha-hydroxymethylandrostane-17-one hydrochlorination Thing (I-bz)

Prepared as described in example 1, starting from 7 α -hydroxymethylandrostane-3, 17-dione (II-bx, preparation 49) and 2-aminoethoxyamino dihydrochloride in 85% yield. The crude product was crystallized from EtOAc to give the title compound I-bz.¹H-NMR(300MHz，DMSO-d₆δ 7.90(bb, 3H), 4.33(t, 0.5H), 4.32(t, 0.5H), 4.07(m, 2H), 3.45(m, 2H), 3.07(m, 0.5H), 3.03(m, 2H), 2.82(m, 0.5H), 2.43-0.91(m, 20H), 0.89(s, 1.5H), 0.88(s, 1.5H), 0.76(s, 3H), in ppm of TMS.

Example 53

(E, Z)3- (2-aminoethoxyimino) -7 beta-hydroxymethylandrostane-17-one hydrochlorination Thing (I-ca)

Prepared as described in example 1, starting from 7 β -hydroxymethylandrostane-3, 17-dione (II-by, preparation 49) and 2-aminoethoxyamino dihydrochloride in 55% yield. The crude product was crystallized from EtOAc to give the title compound I-ca. ¹H-NMR(300MHz，DMSO-d₆δ 7.91(bb, 3H), 4.38(bb, 1H), 4.07(m, 2H), 3.39(m, 2H), 3.08(m, 0.5H), 3.12(m, 2H), 2.41-0.67(m, 20H), 0.83(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 54

(E, Z)3- (2-aminoethoxyimino) -7- (spirocyclopropane) androstan-17-one salts Acidizing substance (I-cb)

Prepared as described in example 1, starting from 7- (spirocyclopropan) -androstane-3, 17-dione (II-bz, preparation 50) and 2-aminoethoxyamino dihydrochloride in 85% yield. The combined organic extracts were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was reacted with Et₂O trituration followed by dissolution in water and freeze drying afforded the title compound I-cb. 1H-NMR (300MHz, DMSO-d)₆δ 7.67(bb, 3H)4.04(m, 2H), 3.08(m, 0.5H), 3.01(m, 2H), 2.79(m, 0.5H), 2.38-0.10(m, 23H), 0.93(s, 1.5H), 0.92(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 55

3- (E, Z) - (2-aminoethoxyimino) -6- (Z) -hydroxyimino-7 alpha-hydroxyandrostane -17-keto hydrochloride (I-cc)

Prepared as described in example 1, starting from 6- (Z) -hydroxyimino-7 α -hydroxyandrostane-3, 17-dione (II-ca, preparation 51) and 2-aminoethoxyamino dihydrochloride in 65% yield. The combined organic extracts were washed with Na ₂SO₄Dried, filtered and evaporated to dryness. The crude product was reacted with Et₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 10.72(s, 0.5H), 10.64(s, 0.5H), 7.84(bb, 3H), 5.15(d, 0.5H), 5.13(d, 0.5H), 5.02(m, 1H), 4.08(m, 2H), 3.09(m, 0.5H), 3.04(m, 2H), 2.99(m, 0.5H), 2.65-1.02(m, 17H), 0.77(s, 3H), 0.75(s, 1.5H), 0.5H, TMS ppm.74(s，1.5H)。

Example 56

(E, Z)3- (2-aminoethoxyimino) -6 alpha-hydroxymethylandrostane-7, 17-dione hydrochloric acid Compound (I-cd)

Prepared as described in example 1, starting from 6 α -hydroxymethylandrostane-3, 7, 17-trione (II-cb, preparation 52) and 2-aminoethoxyamino dihydrochloride in 65% yield. The combined organic extracts were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was reacted with Et₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 7.81(bb, 3H), 4.22(t, 0.5H), 4.20(t, 0.5H), 4.07(m, 2H), 3.53(m, 2H), 3.23-2.97(m, 3H), 2.75-0.97(m, 18H), 1.18(s, 1.5H), 1.17(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 57

(E, Z)3- (2-N-methylaminoethoxyimino) -6- (E) -methoxyimino androstane Alkane-17-ketone hydrochloride (I-ce)

Prepared as described in example 1, starting from 6- (E) -methoxyiminoandrostane-3, 17-dione (II-au, preparation 21) and 2-N-methylaminoethoxyamino dihydrochloride (III-a, preparation 53) in 60% yield. ¹H-NMR(300MHz，DMSO-d₆δ 8.77(bb, 2H), 4.15(m, 2H), 3.75(s, 1.5H), 3.73(s, 1.5H), 3.25-3.05(m, 4H), 2.55(s, 3H), 2.45-1.00(m, 18H), 0.78(s, 3H), 0.77(s, 3H), in ppm of TMS.

Example 58

(E, Z)3- (2-N-methylaminoethoxyimino) -5 alpha-hydroxy-6- (E) -hydroxyimino- Androstane-17-one hydrochloride (I-cf)

From 5 α -hydroxy-6- (E) -hydroxyimino as described in example 1Androstane-3, 17-dione (II-bm, preparation 38) and 2-N-methylaminoethoxyamino dihydrochloride (III-a, preparation 53) were prepared starting in 75% yield. 1H-NMR (300MHz, DMSO-d)₆δ 10.68(s, 0.5H), 10.65(s, 0.5H), 8.53(bb, 2H), 5.09(s, 0.5H), 4.97(s, 0.5H), 4.14(m, 2H), 3.24(d, 0.5H), 3.14(m, 3H), 3.05(m, 0.5H), 2.55(s, 3H), 2.44-1.13(m, 17H), 0.82(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 59

(E, Z)3- (2-N-methylaminoethoxyimino) -5 alpha-hydroxy-6-methyleneandrostane -17-keto hydrochloride (I-cg)

As described in example 1, fromPrepared in 70% yield starting from alpha-hydroxy-6-methyleneandrostane-3, 17-dione (II-bo, preparation 40) and 2-N-methylaminoethoxyamino dihydrochloride (III-a, preparation 53). The crude product was reacted with Et ₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 8.63(bb, 2H), 4.86(m, 0.5H), 4.84(m, 0.5H), 4.70(m, 0.5H), 4.66(m, 0.5H), 4.65(s, 0.5H), 4.59(s, 0.5H), 4.14(m, 2H), 3.19(d, 0.5H), 3.14(m, 2H), 3.04(m, 0.5H), 2.61-1.09(m, 18H), 2.96(s, 3H), 0.84(s, 1.5H), 0.83(s, 1.5H)0.76(s, 3H), in ppm of TMS.

Example 60

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (E) -hydroxyiminoandrostane -17-keto hydrochloride (I-ch)

Prepared from 6- (E) -hydroxy-iminoandrostane-3, 17-dione (II-at, preparation 20, 400mg) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54, 225mg) as described in example 1. The crude product was crystallized from MeOH/EtOAc to provide the title compound as a white solid (388mg, 7)0%)。¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.57 (s, 0.5H), 10.53(s, 0.5H), 8.70(bb, 2H), 3.96(m, 2H), 3.35-2.85(m, 4H), 2.51(s, 1.5H), 2.50(s, 1.5H), 2.45-0.97(m, 20H), 0.77(s, 6H).

Example 61

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (E) -methoxyimino androstane Alkane-17-ketone hydrochloride (I-ci)

Prepared as described in example 1 starting from 6- (E) -methoxyiminoandrostane-3, 17-dione (II-au, preparation 21) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 60% yield. ¹H-NMR(300MHz，DMSO-d₆δ 8.60(bb, 2H), 3.97(m, 2H), 3.75(s, 1.5H), 3.73(s, 1.5H), 3.19(dd, 1H), 3.05(m, 0.5H), 2.99(m, 0.5H), 2.90(m, 2H), 2.52(s, 3H), 2.45-0.99(m, 20H), 0.78(s, 1.5H), 0.78(s, 1.5H), 0.77(s, 3H), in ppm of TMS.

Example 62

(E)3- (3-N-methylaminopropoxyimino) -6-methyleneandrostan-17-one fumarate Acid salt (I-cj)

Starting from 6-methyleneandrostane-3, 17-dione (II-ah, preparation 8, 345mg) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54, 245mg) according to the procedure described in example 4, flash chromatography (SiO-S-O-S-O₂，CH₂Cl₂:MeOH:NH₃9:1:0.1), concentrate the fractions, add fumaric acid and filter to give the title compound I-cj as a white solid (310mg, 70%).¹H-NMR(300MHz，DMSO-d₆δ 6.41(2H, s), 4.80(1H, m), 4.49(1H, m), 3.96(2H, t), 3.01(1H, m), 2.80(2H, m), 2.46(3H, s), 2.45-0.90(21H, m), 0.77(3H, s), 0.75(3H, s).

Example 63

(E, Z)3- (3-N-methylaminopropoxyimino) -6-methyleneandrostan-17-one Fumarate salt (I-ck)

After the procedure described in example 62, the mother liquor was evaporated and filtered to give the title compound I-ck (90mg, 20%) as a beige solid. ¹H-NMR(300MHz，DMSO-d₆δ 6.41(2H, s), 4.82(0.5H, m), 4.80(0.5H, m), 4.52(0.5H, m), 4.49(0.5H, m), 3.96(2H, t), 3.01(0.5H, m), 2.96(0.5H, m), 2.80(2H, m), 2.46(1.5H, s), 2.45(1.5H, s), 2.45-0.90(21H, m), 0.77(3H, s), 0.75(3H, s).

Example 64

(E, Z)3- (3-N-methylaminopropoxyimino) -6-hydroxymethylandrostan-17-one Hydrochloride (I-cl)

Prepared as described in example 1 starting from 6 α -hydroxymethylandrostane-3, 17-dione (II-an, preparation 14) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 67% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.64(bb, 2H), 4.36(t, 1H), 3.96(m, 2H), 3.33(m, 2H), 3.16(m, 0.5H), 2.97(m, 0.5H), 2.89(m, 2H), 2.51(s, 3H), 2.45-0.60(m, 22H), 0.88(s, 1.5H), 0.87(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 65

(Z, E)3- (3-N-methylaminopropoxyimino) -6 alpha-methoxycarbonylandrostane-17- Ketone hydrochloride (I-cm)

Prepared from 6 α -methoxycarbonylandrostane-3, 17-dione (II-as, preparation 19, 325mg) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54, 171mg) under the same reaction conditions as described in example 1. After 1.5 hours the reaction mixture was extracted with THF, The organic layer was washed with brine, Na₂SO₄The solvent was dried and evaporated to dryness. With Et₂The resulting solid was washed and after centrifugation and drying, the title compound I-cm was obtained as a white powder (290mg, 65%).¹H-NMR(300MHz，DMSO-d₆δ 8.36(2H, bb), 3.95(2H, m), 3.61(1.5H, s), 3.60(1.5H, s), 2.98(0.5H, m), 2.87(2H, m), 2.77(0.5H, m), 2.53(1.5H, s), 2.52(1.5H, s), 2.44-0.72(22H, m), 0.91(3H, s), 0.78(3H, s).

Example 66

(Z, E)3- (3-N-methylaminopropoxyimino) -6 alpha-carbamoylandrostane-17- Ketone hydrochloride (I-cn)

Prepared from 6 α -carbamoylandrostane-6, 17-dione (II-ar, preparation 18, 500mg) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54, 265mg) under the same reaction conditions as described in example 1. After 2 hours the reaction mixture was extracted with THF, the organic layer was washed with brine, Na₂SO₄The solvent was dried and evaporated to dryness. With Et₂The resulting solid was washed and, after filtration and drying, the title compound I-cn was obtained as a white powder (570mg, 84%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS 8.53(2H, bb), 7.36(0.5H, bb), 7.32(0.5H, bb), 6.79(1H, bb), 3.95(2H, m), 2.89(3H, m), 2.54(1.5H, s), 2.51(1.5H, s), 2.45-0.65(22H, m), 0.89(3H, s), 0.78(3H, s).

Example 67

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-formamidoandrostane-17- Ketone hydrochloride (I-co)

Prepared as described in example 4 starting from 6 α -formamidoandrostane-3, 17-dione (II-bc, preparation 28) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 76% yieldThus obtaining the product. The crude product was dissolved in water and lyophilized to provide the title compound I-co.¹H-NMR(300MHz，DMSO-d₆δ 8.57(bb, 2H), 8.06-7.57(m, 2H), 3.96(m, 2H), 3.72(m, 1H), 3.07(m, 0.5H), 2.97(m, 0.5H), 2.88(m, 2H), 2.52(s, 3H), 2.46-0.65(m, 21H), 0.93(s, 1.5H), 0.92(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 68

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (spirocyclopropan) androstane -17-Ketone hydrochloride (I-cp)

Prepared as described in example 4, starting from 6- (spirocyclopropane) androstane-3, 17-dione (II-bj, preparation 35) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54), in 93% yield. Combining the organic extracts with Na₂SO₄Dried, filtered and evaporated to dryness to provide the title compound I-cp. 1H-NMR (300MHz, DMSO-d)₆δ 8.55(bb, 2H), 3.95(m, 2H), 2.96(m, 0.5H), 2.88(m, 2H), 2.62(m, 0.5H), 2.52(s, 3H), 2.43-0.70(m, 21H), 0.96(s, 1.5H), 0.95(s, 1.5H), 0.79(s, 3H), 0.52(m, 1H), 0.40(m, 1H), 0.25(m, 1H), 0.10(m, 1H), in ppm of TMS.

Example 69

(E, Z)3- (3-N-methylaminopropoxyimino) -6-ethynylandrostan-17-one Hydrochloride (I-cq)

Prepared as described in example 1 starting from 6-ethynylandrostane-3, 17-dione (II-bb, preparation 27) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 70% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.90(bb, 2H), 3.98(m, 2H), 3.44(m, 0.5H), 3.00(m, 0.5H), 3.01(d, 0.5H), 2.97(d, 0.5H), 2.86(m, 2H), 2.75-0.70(m, 22H), 2.49(s, 1.5H), 2.48(s, 1.5H), 0.87(s, 3H), in ppm of TMSH)，0.77(s，3H).

Example 70

(E, Z)3- (3-N-methylaminopropoxyimino) -5 α -hydroxy-6- (E) -hydroxyimino- Androstane-17-one hydrochloride (I-cr)

Prepared as described in example 4 starting from 5 α -hydroxy-6- (E) -hydroxyiminoandrostane-3, 17-dione (II-bm, preparation 38) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 57% yield. Combining the organic extracts with Na₂SO₄Dried, filtered and evaporated to dryness to provide the title compound I-cr.¹H-NMR(300MHz，DMSO-d₆δ 10.68(s, 0.5H), 10.66(s, 0.5H), 8.63(bb, 2H), 5.07(s, 0.5H), 5.04(s, 0.5H), 3.98(m, 2H), 3.15(d, 0.5H), 3.11(m, 1H), 2.97(m,0.5H), 2.88(m, 2H), 2.60-1.10(m, 19H), 2.49(s, 3H), 0.82(s, 1.5H), 0.81(s, 1.5H), 0.76(s, 3H), in ppm of TMS.

Example 71

(E, Z)3- (3-N-methylaminopropoxyimino) -5 alpha-hydroxy-6- (E) -methoxy-imino Amino-androstane-17-one fumarate (I-cs)

Prepared as described in example 1 starting from 5 α -hydroxy-6- (E) -methoxyiminoandrostane-3, 17-dione (II-bn, preparation 39) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 57% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.00(bb, 3H), 6.40(s, 2H), 5.20(s, 1H), 3.96(m, 2H), 3.77(s, 1.5H), 3.75(s, 1.5H), 3.12(d, 0.5H), 3.02(m, 1H), 2.95(m, 0.5H), 2.80(m, 2H), 2.44(s, 1.5H), 2.43(s, 1.5H), 2.60-1.09(m, 19H), 0.82(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 72

(E,Z)3- (3-N-methylaminopropoxyimino) -5 alpha-hydroxy-6-methylene-androstane Alkane-17-ketone hydrochloride (I-ct)

Prepared as described in example 1 starting from 5 α -hydroxy-6-methyleneandrostane-3, 17-dione (II-bo, preparation 40) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 70% yield. The crude product was reacted with Et₂And O, grinding.¹H-NMR(300MHz，DMSO-d₆δ 8.70(bb, 2H), 4.85(m, 0.5H), 4.83(m, 0.5H), 4.70(m, 0.5H), 4.65(m, 0.5H), 4.63(s, 1H), 3.97(m, 2H), 3.09(d, 0.5H), 2.97(m, 0.5H), 2.91(m, 2H), 2.60-1.08(m, 20H), 2.91(s, 1.5H), 2.90(s, 1.5H), 0.82(s, 1.5H)0.75(s, 3H), in ppm of TMS.

Example 73

(E, Z)3- (3-N-methylaminopropoxyimino) androstane-7, 17-dione fumaric acid Salt (I-cu)

Prepared as described in example 1, starting from androstane-3, 7, 17-trione (II-bp, preparation 41) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54), in 50% yield.¹H-NMR(300MHz，DMSO-d₆δ 9.00(bb, 3H), 6.40(s, 2H), 3.96(m, 2H), 3.01(m, 0.5H), 2.84(m, 0.5H), 2.80(m, 2H)2.46(m, 3H), 2.74-0.98(m, 21H), 1.13(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 74

(E, Z)3- (3-N-methylaminopropoxyimino) -7- (spirocyclopropan) androstane -17-keto hydrochloride (I-cv)

Prepared as described in example 1 starting from 7- (spirocyclopropane) -androstane-3, 17-dione (II-bz, preparation 50) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 65% yield. The combined organic extracts were washed with Na₂SO₄DryingFiltered and evaporated to dryness. The crude product was reacted with Et₂O trituration followed by dissolution in water and freeze drying afforded the title compound I-cv. 1H-NMR (300MHz, DMSO-d)₆δ 8.44(bb, 2H), 3.95(m, 2H), 2.98(m, 0.5H), 2.89(m, 2H), 2.68(m, 0.5H), 2.53(s, 3H)2.37-0.10(m, 25H), 0.93(s, 1.5H), 0.92(s, 1.5H), 0.78(s, 3H), in ppm of TMS.

Example 75

(E, Z)3- (3-N-methylaminopropoxyimino) -7 beta-hydroxymethylandrostan-17-one Hydrochloride (I-cw)

Prepared as described in example 1 starting from 7 β -hydroxymethylandrostane-3, 17-dione (II-by, preparation 49) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 80% yield. The crude product was crystallized from EtOAc to give the title compound I-cw.¹H-NMR(300MHz，DMSO-d₆δ 8.43(bb, 2H), 4.37(t, 1H), 3.96(s, 2H), 3.41(m, 2H), 2.99(m, 0.5H), 2.90(m, 2H), 2.55(s, 3H)2.41-0.67(m, 22H), 0.83(s, 3H), 0.78(s, 3H), in ppm of TMS.

Example 76

(E, Z)3- (3-N-methylaminopropoxyimino) -7- (E) -hydroxyiminoandrostane -17-Keto fumarate (I-cx)

Prepared as described in example 1 starting from 7- (E) -hydroxyiminoandrostan-17-one (II-bq, preparation 42) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 55% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.38(bb, 1H), 8.80(bb, 3H), 6.40(s, 2H), 3.96(m, 2H), 3.00(m, 4H), 2.50-0.70(m, 20H), 2.49(s, 3H), 1.02(s, 3H), 0.80(s, 3H), in ppm of TMS.

Example 77

(E, Z) -3- (cis-4-aminocyclohexyloxyimino) -6- (E) -hydroxyiminoandrostane -17-keto hydrochloride (I-cy)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 615mg) and cis-4-aminocyclohexyloxyamino dihydrochloride (III-c, preparation 55, 406mg) as described in example 1. Subjecting the crude product to flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) purification. To the concentrated fraction was added 5M HCl in EtOAc. With Et₂After dilution, the solid was collected by filtration to give the title compound I-cy (540mg, 60%).¹H-NMR(300MHz，DMSO-d₆δ 10.50(bb, 1H), 7.84(3H, bb), 4.10(1H, m), 3.15(0.5H, m, E isomer), 3.03(0.5H, m, Z isomer), 3.01(1H, m), 2.55-1.20(14H, m), 0.79(4.5H, s), 0.78(1.5H, s, Z isomer), in ppm of TMS.

Example 78

(E, Z)3- (cis-2-Aminocyclopentyloxyimino) -6- (E) -hydroxyiminoandrostane -17-keto hydrochloride (I-cz)

Prepared from cis-2-aminocyclopentoxyamino dihydrochloride (III-d, preparation 56, 250mg) and 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 515mg) as a white solid (470mg, 71%) by the procedure described in example 1.¹H-NMR(300MHz，DMSO-d₆δ 10.40(bb, 1H), 9.10(3H, bb), 4.49(1H, m), 3.47(1H, m), 3.19(1H, m), 2.60-1.20(25H, m), 0.79(6H, s).

Example 79

(E, Z)3- (trans-2-aminocyclopentyloxyiimino) -6- (E) -hydroxyimino-androstane Alkane-17-one hydrochloride (I-da)

As described in example 1 from 6- (E) -hydroxyiminoandrostane-3, 17-Diketone (II-at, preparation 20, 280mg) and trans-2-aminocyclopentyloxyamino dihydrochloride (III-e, preparation 57, 137mg) gave the title compound I-da as a white solid after precipitation from THF (220mg, 56%).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.98 (3H, bb), 4.42(1H, m), 3.42(1H, m), 2.99(0.5H, m, E isomer), 2.94(0.5H, m, Z isomer), 2.60-1.20(25H, m), 0.78(6H, s).

Example 80

3 beta- (5-Aminopentyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-db)

3 beta- (5-Aminopentyl) androstane-6, 17-dione (preparation 58, 0.39g) and NH as described in example 1₂Oh. hcl. The crude residue was purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1 followed by CH₂Cl₂:MeOH:NH₃90:10:1) purification. To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. After addition of EtOAc, the precipitate was filtered to give 0.18g (47%) of the title compound I-db as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 10.40(1H, s), 7.98(3H, bb), 6.35(2H, s), 3.28(1H, m), 2.73(2H, m), 2.50-0.85(29H, m), 0.77(3H, s), 0.63(3H, s), in ppm of TMS.

Example 81

3 beta- (5-Aminopent-1- (Z) -alkenyl) -6- (E) -hydroxyiminoandrostan-17-one fumaric acid Salt (I-dc)

Prepared from (Z)3 β - (5-aminopent-1-enyl) androstane-6, 17-dione (preparation 59, 385mg) as described in example 1 in 40% yield as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 10.36(1H, s), 7.80(3H, bb), 6.35(2H, s), 5.25(2H, m), 3.28(1H, m), 2.73(2H, m), 2.55-1.05(25H, m), 0.78(3H, s), 0.67(3H, s), in ppm of TMS.

Example 82

3 beta- (4-Aminobutyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-dd)

Prepared from 3 β - (4-aminobutyl) androstane-6, 17-dione (preparation 60, 290mg) as described in example 1 as a white solid in 44% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.30 (1H, s), 7.80(3H, bb), 6.35(2H, s), 3.28(1H, m), 2.74(2H, m), 2.50-0.85(27H, m), 0.77(3H, s), 0.63(3H, s).

Example 83

3 beta- (4-Aminobut-1- (Z) -enyl) -6- (E) -hydroxyiminoandrostan-17-one fumaric acid Salt (I-de)

Prepared from (Z)3 β - (4-aminobut-1-enyl) androstane-6, 17-dione (preparation 61, 415mg) as described in example 1 in 44% yield as a white solid.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS) 10.25(1H, s), 7.80(3H, bb), 6.35(2H, s), 5.38(1H, m), 5.23(1H, m), 3.29(1H, m), 2.75(2H, m), 2.55-1.10(23H, m), 0.78(3H, s), 0.67(3H, s).

Example 84

3 α - (5-Aminopentyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-df)

Prepared from 3 α - (5-aminopentyl) androstane-6, 17-dione (preparation 62, 60mg) as described in example 1 in 59% yield as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 10.20(1H, s), 7.70(3H, bb), 6.35(2H, s), 3.29(1H, m), 2.73(2H, m), 2.50-1.10(29H, m), 0.77(3H, s), 0.67(3H, s), in ppm of TMS.

Example 85

3 alpha- (5-aminopent-1- (Z) -alkenyl) -6- (E) -hydroxyiminoandrostan-17-one fumaric acid Salt (I-dg)

Prepared from (Z)3 α - (5-aminopent-1-enyl) androstane-6, 17-dione (preparation 63, 250mg) as described in example 1 in 34% yield as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 10.36(1H, s), 8.00(3H, bb), 6.35(2H, s), 5.77(1H, m), 5.27(1H, m), 3.29(1H, m), 2.74(3H, m), 2.54-1.09(24H, m), 0.77(3H, s), 0.69(3H, s).

Example 86

3 α - (4-Aminobutyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-dh)

Prepared from 3 α - (4-aminobutyl) androstane-6, 17-dione (preparation 64, 55mg) as described in example 4 as a white solid in 60% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.35(1H, s), 7.79(3H, bb), 6.35(1H, s), 3.28(1H, m), 2.74(2H, m), 2.50-1.15(27H, m), 0.77(3H, s), 0.67(3H, s), in ppm of TMS.

Example 87

3 alpha- (4-Aminobut-1- (Z) -enyl) -6- (E) -hydroxyiminoandrostan-17-one fumaric acid Salt (I-di)

Prepared from (Z)3 α - (4-aminobut-1-enyl) androstane-6, 17-dione (preparation 65, 60mg) as described in example 1 in 53% yield as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 10.30(1H, s), 7.80(3H, bb), 6.35(2H, s), 5.84(1H, m), 5.28(1H, m), 3.29(1H, m), 2.74(3H, m), 2.55-1.10(22H, m), 0.78(3H, s), 0.70(3H, s).

Example 88

3 alpha- (6-aminohexane)-1- (Z) -alkenyl) -6- (E) -hydroxyiminoandrostan-17-one fumaric acid Salt (I-dj)

Prepared from (Z)3 α - (6-aminohex-1-enyl) androstane-6, 17-dione (preparation 66, 133mg) as described in example 4 as a white powder in 40% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.25(1H, s), 7.73(3H, bb), 6.35(1H, s), 5.71(1H, m), 5.26(1H, m), 3.29(1H, m), 2.74(3H, m), 2.56-1.12(26H, m), 0.78(3H, s), 0.69(3H, s).

Example 89

3 alpha- (5-aminopent-1- (Z) -alkenyl) -5 alpha-hydroxyandrostan-17-one fumarate (I-dk)

The title compound I-dk was prepared from 5- (5 α -hydroxy-17-keto-androstan-3 α -yl) pent-4- (Z) -en-1-ylcarbamic acid 9H-fluoren-9-ylmethyl ester (preparation 67) in 95% yield, by reference to the procedure for the preparation of 3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane (preparation 46). The crude product was purified by flash chromatography (SiO) ₂，CH₂Cl₂/MeOH90/10/NH₃) And (5) purifying. To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Addition of EtOAc/Et₂After 1/1 mixture of O, the precipitate was filtered to give the title compound I-dk.¹H-NMR(300MHz，DMSO-d₆δ 8.00(m, 4H), 6.40(s, 2H), 6.10(m, 1H), 5.05(m, 1H), 3.55(s, 1H), 2.73(m, 2H), 2.66(m, 1H), 2.42-0.99(m, 25H), 0.90(s, 3H), 0.76(s, 3H), in ppm of TMS.

Example 90

3 beta- (2-aminoacetoxy) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride (I-dl)

Prepared from 3 beta- (2-Aminoacetoxy) androstane-6, 17-dione fumarate (preparation 68, 290mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-dl in 75% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.40 (1H, s), 8.00(3H, bb), 4.67(1H, m), 3.49(2H, s), 3.27(1H, m), 2.55-1.15(19H, m), 0.78(3H, s), 0.69(3H, s).

Example 91

3 beta- (3-aminopropionyloxy) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride (I-dm)

Prepared from 3 β - (3-aminopropionyloxy) androstane-6, 17-dione fumarate (preparation 69, 260mg) and hydroxylamine hydrochloride (41mg) according to the procedure described in example 1, the title compound I-dm was prepared by flash chromatography (SiO) ₂;CH₂Cl₂MeOH9:1) (168mg, 75%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.42 (1H, s), 8.13(3H, bb), 4.63(1H, m), 3.27(1H, m), 2.98(2H, t), 2.64(2H, t), 2.45-0.95(19H, m), 0.77(3H, s), 0.69(3H, s).

Example 92

3 beta- (4-aminobutyryloxy) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride (I-dn)

Prepared from 3 β - (4-aminobutyryloxy) androstane-6, 17-dione fumarate (preparation 70, 290mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-dn in 75% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.35 (1H, s), 7.93(3H, bb), 4.89(1H, m), 3.28(1H, m), 2.78(2H, t), 2.50-1.15(23H, m), 0.78(3H, s), 0.69(3H, s).

Example 93

3 beta- [3(R, S) -aminobutyryloxy]-6- (E) -hydroxyiminoandrostane-17-one hydrochloride Compound (I-do)

Prepared from 3 β - (3R, S-aminobutyryloxy) androstane-6, 17-dione fumarate (preparation 71, 200mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-do in 75% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.30(1H, s), 8.00(bb, 3H)4.63(m, 1H), 3.47(m, 1H), 3.28(1H, m), 2.78-1.12(m, 21H), 1.21(d, 3H), 0.78(s, 3H), 0.70(s, 3H), in ppm of TMS.

Example 94

3 beta- [2(R, S) -methyl-3-aminopropionyloxy]-6- (E) -hydroxyimino-androstane-17- Ketone hydrochloride (I-dp)

Prepared from 3 β - (3R, S-aminobutyryloxy) androstane-6, 17-dione fumarate (preparation 72, 240mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-dp in 55% yield.¹H-NMR(300MHz，DMSO-d₆In ppm of TMS,. delta.10.30 (1H, s), 7.98(bb, 3H)4.61(m, 1H), 3.26-1.03(m, 23H), 1.15(d, 1.5H), 1.14(d, 1.5H), 0.78(s, 3H), 0.70(s, 3H).

Example 95

3 beta- [ N- (2-aminoethyl) carbamoyloxy]-6- (E) -hydroxyiminoandrostan-17-one Hydrochloride (I-dq)

By the procedure described in reference example 4, starting from 3 β - [ N- (2-aminoethyl) carbamoyloxy]Androstane-6, 17-dione fumarate (preparation 73, 190mg) prepared by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt at 45%The title compound I-dq was obtained in yield.¹H-NMR(300MHz，DMSO-d₆δ 10.30(1H, s), 7.57(3H, bb), 7.20(1H, t), 4.42(1H, m), 3.27(1H, m), 3.17(2H, m), 2.78(2H, t), 2.50-1.15(19H, m), 0.78(3H, s), 0.68(3H, s).

Example 96

3 beta- (4-aminobutanamide) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride (I-dr)

Prepared from 3 β - (4-aminobutanamide) androstane-6, 17-dione fumarate (preparation 74, 220mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-dr in 57% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.25(1H, s), 7.85(1H, d), 7.76(3H, bb), 3.45(1H, m), 3.26(1H, m), 2.76(2H, m), 2.45-1.15(23H, m), 0.78(3H, s), 0.66(3H, s), in ppm of TMS.

Example 97

3 beta- (3-aminopropionylamino) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride (I-ds)

Prepared from 3 beta- (3-aminopropionylamino) androstane-6, 17-dione fumarate (preparation 75, 190mg) by the procedure described in example 4, and purified by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1) and formation of the hydrochloride salt gave the title compound I-ds in 62% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.30 (1H, s), 8.01(1H, d), 7.76(3H, bb), 3.48(1H, m), 3.28(1H, m), 2.96(2H, m), 2.45-1.15(21H, m), 0.78(3H, s), 0.67(3H, s).

Example 98

3 beta- (3-N-methylaminopropoxy)]-6- (E) -hydroxyiminoandrostan-17-one fumarate (I-dt)

Reacting 3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]A solution of-6-hydroxyiminoandrostane-17- (2-spiro-1, 3-dioxolane) (preparation 76, 105mg) in THF (5mL) was treated with 5M HCl in EtOAc (0.2mL) and stirred at 0 ℃ for 1.5 h. After evaporation, by flash chromatography (SiO)₂;CH₂Cl₂:MeOH:NH₃9:1:0.1) and adding fumaric acid to the concentrated fraction to give compound I-dt (61mg, 62%) as a white solid.¹H-NMR(300MHz，DMSO-d₆In ppm of TMS,. delta.10.43 (1H, bb), 9.00(3H, bb), 6.45(2H, s), 3.55-2.80(6H, m), 2.49(3H, s), 2.45-0.89(21H, m), 0.76(3H, s), 0.65(3H, s).

Example 99

3 beta- (3-N-methylaminopropoxy) -6 alpha-hydroxymethylandrostan-17-one fumarate (I-du)

Reacting 3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]A solution of-6 α -hydroxymethylandrostane-17- (2-spiro-1, 3-dioxolane) (preparation 77, 100mg) in THF (5mL) was treated with 5M HCl in EtOAc (0.15mL) and stirred at 0 ℃ for 1.5 h. Evaporating the mixture and purifying by flash chromatography (SiO)₂;CH₂Cl₂:MeOH:NH₃9:1:0.1) purifying the residue. After addition of fumaric acid to the concentrated fractions, Compound I-du (100mg, 85%) was obtained as a white solid.¹H-NMR(300MHz，DMSO-d₆In ppm of TMS,. delta.10.00 (3H, bb), 6.41(2H, s), 4.33(1H, bb), 3.50-2.80(7H, m), 2.49(3H, s), 2.45-0.55(23H, m), 0.77(6H, s).

Example 100

3 alpha- (2-aminoethylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-dv)

Stirring to the right3 α - (2-trifluoroacetamidoethylthio) -6- (E) -hydroxyiminoandrostan-17-one (preparation 78, 115mg) in MeOH/H₂O95/5 solution (7mL) K was added₂CO₃(159 mg). The mixture was refluxed for 1.5 hours, then concentrated, washed with water and CH₂Cl₂Extracting and adding Na₂SO₄And (5) drying. Fumaric acid (27mg) was added and the resulting solution was evaporated to dryness. The residue was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₃9/1/0.1). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. The resulting solution was concentrated and the resulting mixture was centrifuged. With Et₂O/EtOH9/1(0.8mL) washed the solid to give the title compound I-dv (53mg, 50%) after centrifugation.¹H-NMR(300MHz，DMSO-d₆δ 10.45(1H, s), 8.10(3H, m), 6.35(2H, s), 3.29(1H, dd), 3.22(1H, m), 2.86(2H, t), 2.67(1H, m), 2.60(2H, t), 2.50-0.80(20H, m), 0.76(3H, s), 0.67(3H, s), in ppm of TMS.

Example 101

3 alpha- (3-aminopropylthio) -6- (E) -hydroxyiminoandrostan-17-one hemi-fumarate (I-dw)

The title compound was prepared in 50% yield starting from 3 α - (3-trifluoroacetamidopropyl thio) -6- (E) -hydroxy-iminoandrostan-17-one (preparation 79, 53mg) as described in reference to example 100. ¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.39 (1H, s), 8.00(4H, bb), 6.35(2H, s), 3.29(1H, dd), 3.21(1H, m), 2.70(2H, m), 2.50-0.90(23H, m), 0.76(3H, s), 0.68(3H, s).

Example 102

3 alpha- (4-aminobutylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-dx)

The title compound was prepared from 3 α - (4-trifluoroacetamide as described in reference to example 100Prepared starting with phenylbutylthio) -6- (E) -hydroxy-iminoandrostan-17-one (preparation 80, 120mg) in 53% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.43 (1H, s), 8.00(3H, m), 6.35(2H, s), 3.28(1H, dd), 2.73(2H, m), 2.64(1H, m), 2.50-1.15(25H, m), 0.78(3H, s), 0.68(3H, s).

Example 103

3 alpha- (3-N-methylaminopropylthio) -6- (E) -hydroxyiminoandrostan-17-one hemifumarate Salt (I-dy)

The title compound was prepared in 50% yield starting from 3 α - (3-N-methyltrifluoroacetamidopropylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one (preparation 81, 115mg) as described in example 100.¹H-NMR(300MHz，DMSO-d₆δ 10.43(1H, s), 8.00(3H, m), 6.35(1H, s), 3.28(1H, dd), 3.22(1H, m), 2.67(2H, m), 2.35(3H, s), 2.50-0.80(23H, m), 0.76(3H, s), 0.67(3H, s), in ppm of TMS.

Example 104

3 α - (3-Aminopropylthio) -6-methyleneandrostan-17-one fumarate (I-dz)

To a stirred solution of 3 α - (3-N-trifluoroacetamidopropylsulfanyl) -6-methylene-androstan-17-one (preparation 82, 85mg) in MeOH/H₂O8/2 solution (5mL) Ambersep900OH (1.4g) was added and the resulting mixture was stirred at room temperature overnight. The resin was filtered and the solvent was evaporated to a smaller volume. Fumaric acid (20mg) was added and the solution was evaporated to dryness. With Et₂The resulting solid was washed, filtered and dried to give the title compound I-dz (80mg, 90% yield) as a white powder.¹H-NMR(300MHz，DMSO-d₆δ 9.50(4H, bb), 6.38(2H, s), 4.73(1H, m), 4.41(1H, m), 3.24(1H, m), 2.81(2H, m), 2.56-0.84(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Example 105

3 alpha- (3-N-methylaminopropylthio) -6-methyleneandrostan-17-one fumarate (I-ea)

The title compound was prepared in 60% yield starting from 3 α - (3-N-methyltrifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one (preparation 83, 75mg) as described in reference example 80.¹H-NMR(300MHz，DMSO-d₆δ 8.00(3H, bb), 6.40(2H, s), 4.73(1H, m), 4.41(1H, m), 3.25(1H, m), 2.80(2H, m), 2.50-0.89(24H, m), 2.45(3H, s), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Example 106

3 alpha- [ (S) -3-aminopropylsulfinyl group]-6-methyleneandrostan-17-one fumarate (I-eb)

The title compound was synthesized from 3 α - [ (S) -3-trifluoroacetamidopropyl sulfonyl as described in example 104]-6-Methyleneandrostan-17-one (preparation 84, 100mg) was prepared starting with 90% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.98(3H, bb), 6.42(2H, s), 4.72(1H, m), 4.41(1H, m), 3.24(3H, m), 2.50-0.86(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Example 107

3 alpha- [ (R) -3-aminopropylsulfinyl group]-6-methyleneandrostan-17-one fumarate (I-ec)

The title compound was synthesized from 3 α - [ (R) -3-trifluoroacetamidopropyl sulfonyl as described in example 104]-6-Methyleneandrostan-17-one (preparation 85, 70mg) prepared starting in 90% yield.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.98 (3H, bb), 6.42(2H, s), 4.70(1H, m), 4.41(1H, m), 3.24(3H, m), 2.50-0.86(24H, m), 0.75(3H,s)，0.65(3H，s)。

example 108

(E, Z)3- (2-aminoethoxyimino) -7 alpha-methoxymethylandrostan-17-one salts Acidized substance (I-ed)

Starting from 7 α -methoxymethylandrostane-3, 17-dione (preparation 86) and 2-aminoethoxyamino dihydrochloride as described in example 1, a white powder was prepared in 80% yield. ¹H-NMR(300MHz，DMSO-d₆δ 7.95(3H, bb), 3.35(3H, s), 3.15(2H, m), 2.53-0.75(25H, m), 0.85(3H, s), 0.78(3H, s), in ppm of TMS.

Example 109

(E, Z)3- (2-aminoethoxyimino) -7 alpha-methoxyandrostan-17-one hemifumarate Acid salt (I-ee)

Prepared from 7 α -methoxyandrostane-3, 17-dione (preparation 87) and 2-aminoethoxyamino dihydrochloride as described in example 1. In flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1), the fractions were concentrated, fumaric acid was added and filtered to give the title compound as a white powder in 75% yield.¹H-NMR(300MHz，DMSO-d₆δ 7.98(3H, bb), 6.42(1H, s), 3.35(3H, s), 2.58-1.00(25H, m), 0.86(3H, s), 0.78(3H, s), in ppm of TMS.

Example 110

3 beta- (2-aminoethylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-ef)

To a stirred solution of 3 β - (2-trifluoroacetamidoethylthio) -6- (E) -hydroxyiminoandrostan-17-one (preparation 88, 120mg) in MeOH/H₂O95/5 solution (7mL) K was added₂CO₃(170 mg). The mixture was refluxed for 1.5 hours, thenAfter concentration, washing with water and CH₂Cl₂Extracting and adding Na₂SO₄And (5) drying. Fumaric acid (30mg) was added and the resulting solution was evaporated to dryness. The residue was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₃9/1/0.1). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. The resulting solution was concentrated and the resulting mixture was centrifuged. With Et ₂O/EtOH9/1(1mL) washed the solid to give the title compound (55mg, 50%) after centrifugation.¹H-NMR(300MHz，DMSO-d₆δ 10.45(1H, s), 8.10(3H, m), 6.35(2H, s), 3.30(1H, dd), 3.22(1H, m), 2.86(2H, t), 2.67(1H, m), 2.60(2H, t), 2.50-0.80(20H, m), 0.76(3H, s), 0.67(3H, s), in ppm of TMS.

Example 111

3 beta- (3-aminopropylthio) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-eg)

The title compound was prepared in 50% yield starting from 3 β - (3-trifluoroacetamidopropylsulfanyl) -6- (E) -hydroxy-iminoandrostan-17-one (preparation 89, 53mg) as described in example 110.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.39 (1H, s), 8.00(4H, bb), 6.35(2H, s), 3.31(1H, dd), 3.22(1H, m), 2.70(2H, m), 2.50-0.90(23H, m), 0.76(3H, s), 0.68(3H, s).

Example 112

3 beta- (4-aminobutylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one fumarate (I-eh)

The title compound was prepared in 53% yield starting from 3 β - (4-trifluoroacetamidobutylsulfanyl) -6- (E) -hydroxy-iminoandrostan-17-one (preparation 90, 120mg) as described in example 110.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS). delta.10.43 (1H, s), 8.00(3H, m), 6.35(2H, s), 3.3 1(1H，dd)，2.73(2H，m)，2.66(1H，m)，2.50-1.15(25H，m)，0.78(3H，s)，0.68(3H，s)。

Example 113

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-hydroxymethylandrostane-7, 17- Diketofumarate (I-ei)

Prepared as described in example 1 starting from 6 α -hydroxymethylandrostane-3, 7, 17-trione (II-cb, preparation 52) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 80% yield. The crude product was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26%NH₄OH 90/10/1). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. The precipitate was filtered to give the title compound.¹H-NMR(300MHz，DMSO-d₆δ 8.44(2H, bb), 6.40(2H, s), 4.37(1H, t), 3.96(2H, m), 3.41(2H, m), 2.80(2H m), 2.50(3H, s), 2.40-1.10(21H, m), 0.98(3H, s), 0.82(3H, s).

Example 114

(E, Z)3- (2-aminoethoxyimino) -6 alpha-hydroxymethyl-7 alpha-hydroxy-androstane-17- Ketone hydrochloride (I-ej)

Prepared as described in example 1, starting from 6 α -hydroxymethyl-7 α -hydroxyandrostane-3, 17-dione (preparation 91) and 2-aminoethoxyamino dihydrochloride in 85% yield. The combined organic extracts were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was reacted with Et₂O was triturated, then dissolved in water and lyophilized to give the title compound. ¹H-NMR(300MHz，DMSO-d₆δ 8.02(3H, bb), 4.35(1H, t), 4.26(1H, d), 3.96(2H, m), 3.86(1H, m), 3.40(2H, t), 2.97(2H, m), 2.40-1.10(19H, m), 0.99(3H, s), 0.82(3H, s).

Example 115

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-hydroxymethyl-7 alpha-hydroxy-androstane Alkane-17-ketone hydrochloride (I-ek)

Prepared as described in example 1 starting from 6 α -hydroxymethyl-7 α -hydroxyandrostane-3, 17-dione (preparation 91) and 3-N-methylaminopropoxyamino dihydrochloride (III-b, preparation 54) in 80% yield. The combined organic extracts were washed with Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was reacted with Et₂O was triturated, then dissolved in water and lyophilized to give the title compound.¹H-NMR(300MHz，DMSO-d₆δ 8.44(2H, bb), 4.35(1H, t), 4.26(1H, d), 3.96(2H, m), 3.86(1H, m), 3.40(2H, m), 2.80(2H, m), 2.50(2H, m), 2.40-1.10(21H, m), 0.99(3H, s), 0.85(3H, s), in ppm of TMS.

Example 116

(E, Z) -3- [ (S) -2-aminopropoxyimino group]Androstane-6- (E) -hydroxyimino-androstanes Alkane-17-one hydrochloride (I-el)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 500mg) and (S) -2-aminopropoxyamino dihydrochloride (preparation 92, 257mg), as described in example 1. The crude product was crystallized from MeOH/EtOAc to afford the title compound as a white solid. (503mg, 75%). NMR (300MHz, DMSO-d) ₆δ 10.50(1H, s), 7.98(3H, m), 3.97(2H, m), 3.40(1H, m), 3.11(0.5H, m), 3.05(0.5H, m), 2.54-1.15(22H, m), 0.79(3H, s), 0.78(3H, s).

Example 117

(E, Z) -3- [ (R) -2-aminopropoxyimino group]Androstane-6- (E) -hydroxyimino-androstanes Alkane-17-one hydrochloride (I-em)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 500mg) and (R) -2-aminopropoxyamino dihydrochloride (preparation 93, 257mg), as described in example 1. The crude product was crystallized from MeOH/EtOAc to afford the title compound as a white solid. (503mg, 75%).¹H-NMR(300MHz，DMSO-d₆δ 10.50(1H, s), 7.98(3H, m), 3.97(2H, m), 3.40(1H, m), 3.11(0.5H, m), 3.05(0.5H, m), 2.54-1.15(22H, m), 0.79(3H, s), 0.78(3H, s).

Example 118

(E, Z)3- (2-amino-2-methylpropoxyimino) -6- (E) -hydroxyimino-androstane -17-keto hydrochloride (I-en)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 500mg) and 2-amino-2-methyl-1-propoxyamino dihydrochloride (preparation 94, 279mg), as described in example 1. The crude product was crystallized from MeOH/EtOAc to afford the title compound as a white solid. (485mg, 70%). NMR (300MHz, DMSO-d) ₆From the ppm of TMS,. delta.10.50 (1H, s), 7.84(3H, m), 3.16(0.5H, m), 3.08(0.5H, m), 2.54-1.21(21H, m), 1.20(6H, s), 0.79(3H, s), 0.77(3H, s).

Example 119

(E, Z)3- (3-amino-2-methyl-2-propoxyiimino) -6- (E) -hydroxyimino-androstane Alkane-17-ketone hydrochloride (I-eo)

Prepared from 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20, 500mg) and 3-amino-2-methyl-2-propoxyamino dihydrochloride (preparation 95, 279mg), as described in example 1. The crude product was crystallized from MeOH/EtOAc to afford the title compound as a white solid (519mg, 75%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS) delta 10.35(1H, bb), 7.50(3H, bb), 4.08(m, 2H), 3.30-2.80(5H，m)，1.22(6H，s)，0.79(6H，s)。

Example 120

(E, Z)3- (2-aminoethoxyimino) -7-difluoromethyleneandrostane-17-one hydrochloride Compound (I-ep)

Prepared from 7-difluoromethyleneandrostane-3, 17-dione (preparation 96, 150mg) and 2-aminoethoxyamino dihydrochloride (66mg), as described in example 1. The residue was taken up in THF/Et₂O9/1. Filtration and drying in vacuo afforded the title compound (88mg, 50%) as a yellow solid.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.45 (3H, bs), 4.05(2H, m), 3.10-0.95(22H, m), 0.98(3H, s), 0.80(3H, s).

Example 121

3 beta- [3- (N-methylamino) propionyloxy]-6- (E) -hydroxyiminoandrostan-17-one fumarate Acid salt (I-eq)

3 β - [3- (N-benzyloxycarbonyl-N-methylamino) propionyloxy ] contained in EtOH (7mL)]Mixture of-6- (E) -hydroxyiminoandrostan-17-one (preparation 97, 160mg) and 10% Pd/C (10mg) in H₂Stirred for 1 hour at atmospheric pressure. The mixture was filtered through celite. The filtrate was treated with the theoretical amount of fumaric acid and evaporated to dryness. The residue was reacted with EtOAc/Et₂O9/1, and filtering to obtain 3 beta- [3- (N-methylamino) propionyloxy]-6- (E) -hydroxyiminoandrostan-17-one fumarate (129mg, 84%).¹H-NMR(300MHz，DMSO-d₆δ 10.30(s, 1H), 7.83(m, 3H), 6.40(s, 2H), 4.60(m, 1H), 3.00-1.10(m, 24H), 2.42(s, 3H), 0.78(s, 3H), 0.71(s, 3H), in ppm of TMS.

Example 122

3 beta- [ (2, 2-dimethyl) -3-aminopropionyloxy]-6- (E) -hydroxyimino-androstane-17- Ketofumarate salt(I-er)

Preparation of 3 beta- [ (2, 2-dimethyl) -3- (N-benzyloxycarbonyl) aminopropionyloxy) as described in example 121]-6- (E) -hydroxyimino-androstan-17-one (preparation 98, 500mg) was prepared as a white solid (397mg, 80%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.20 (1H, s), 7.98(4H, bb), 6.40(2H, s), 4.58(1H, m), 3.00-1.10(20H, m), 0.78(3H, s), 0.72(3H, s).

Preparation 1

3, 17-dioxoandrostane-6 alpha-yl nitrate (II-aa)

To acetic anhydride (2.53mL) cooled to 0 ℃ and 65% HNO₃(0.592mL) 3,3:17, 17-bis (ethylenedioxy) androstane-6 α -ol (2.5g) was added to the solution. After 2 hours ice and 5% NaHCO were carefully added₃Aqueous solution to inhibit the mixture, and CH₂Cl₂(3X) extraction. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -androstan-6 α -yl nitrate as a white solid (2.50g, 89%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.4.94 (m, 1H), 3.94-3.75(m, 8H), 2.24-0.74(m, 20H), 0.98(s, 3H), 0.85(s, 3H).

3,3:17, 17-bis (ethylenedioxy) androstane-6-alpha-yl nitrate (2.50g) and pTSA. H₂A solution of O (6.05g) in acetone (150mL) was stirred at room temperature for 1.5 hours. Add 5% NaHCO₃The solution was neutralized with an aqueous solution and the acetone was evaporated off. By CH₂Cl₂The aqueous phase was extracted (3X 50 mL). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/acetone/CH₂Cl₂70/15/15) to give the title compound II-aa (1.66g, 75%) as a white solid.¹H-NMR (300MHz, acetone-d) ₆From ppm of TMS). delta.5.09 (ddd, 1H), 2.60-0.95(m, 17H), 1.25(s, 3H), 0.90(s, 3H).

Preparation 2

3, 17-dioxoandrostane-6 beta-yl nitrate (II-ab)

3,3:17, 17-bis (ethylenedioxy) androstan-6 β -yl nitrate was prepared in 50% yield from 3,3:17, 17-bis (ethylenedioxy) androstan-6 β -ol as described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) androstan-6 α -yl nitrate (preparation 1).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.5.16 (m, 1H), 3.93-3.76(m, 8H), 2.20-0.77(m, 20H), 1.00(s, 3H), 0.85(s, 3H).

The preparation procedure described above for 3, 17-dioxoandrostan-6 α -yl nitrate (II-aa, preparation 1) was prepared from 3,3:17, 17-bis (ethylenedioxy) androstan-6 α -yl nitrate in 75% yield. The crude product was purified by flash chromatography (SiO)₂cyclo-hexane/acetone/CH₂Cl₂70/15/15) to obtain II-ab.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS), delta 5.24(ddd, 1H), 2.72(dd, 1H), 2.57-0.96(m, 19H), 1.25(s, 3H), 0.90(s, 3H).

Preparation 3

6 alpha-cyanoandrostane-3, 17-dione (II-ac)

To be at N₂While stirring, a solution of toluene-4-sulfonylmethylisonitrile (2.23g) in anhydrous DMSO (13mL) was added potassium tert-butoxide (3.55 g). After stirring for 5 min, anhydrous MeOH (0.40mL) was added dropwise and after 10 min 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (3.27g) was added. After 72 hours at room temperature, the reaction was quenched by addition of water, the mixture was neutralized by addition of 1N HCl and extracted with EtOAc (3 ×). With water, 5% NaHCO ₃The combined organic extracts were washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-Hexane/EtOAc 70/30) to obtain 6 alpha-cyano-3, 3:17, 17-bis (ethylenedioxy) androstaneAlkane (1.05g, 31%).¹H-NMR (300MHz, acetone-d)₆δ 3.95-3.70(m, 8H), 2.60(m, 1H), 2.14-0.74(m, 20H), 0.89(s, 3H), 0.82(s, 3H), in ppm of TMS.

6 alpha-cyano-3, 3:17, 17-bis (ethylenedioxy) androstane (1.05g) and pTSA. H₂A solution of O (2.46g) in acetone (105mL) was stirred at room temperature for 3 hours. Add 5% NaHCO₃The solution was neutralized with an aqueous solution and the acetone was evaporated off. By CH₂Cl₂(3X) extracting the aqueous suspension. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-Hex/EtOAc 70/30) to yield the title compound II-ac (0.62mg, 75%) as a white solid.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.2.82 (ddd, 1H), 2.87-0.80(m, 20H), 1.16(s, 3H), 0.87(s, 3H).

Preparation 4

5 alpha-hydroxyandrostane-3, 17-dione (II-ad)

To stirring cooled to 0 deg.C 3 beta-hydroxyandrost-5-en-17-one (0.81g) in CH₂Cl₂Solution (7.4mL) mCPBA (0.77mg) in CH was added dropwise ₂Cl₂Solution (13.6 mL). After 0.5 hour at 0 ℃ and 0.5 hour at room temperature, 10% Na was added₂SO₃An aqueous solution. With 5% NaHCO₃Neutralizing the mixture with CH₂Cl₂(3X 100 mL). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 60/20/20) to give 3 β -hydroxy-5 α,6 α -epoxyandrostan-17-one (0.64g, 75%).¹H-NMR(300MHz，DMSO-d₆δ 4.62(d, 1H), 3.52(m, 1H), 2.87(d, 1H), 2.44-0.56(m, 19H), 1.00(s, 3H), 0.72(s, 3H), in ppm of TMS.

To N₂LiAlH under stirring₄(0.247mg) of THF suspension (10.5mL) A solution of 3 β -hydroxy-5 α,6 α -epoxyandrostan-17-one (0.64g) in THF (20mL) was added dropwise and the mixture was stirred at reflux for 8 h. The suspension was cooled with an ice bath and quenched by careful addition of water (1mL) and 4N NaOH (0.20 mL). The mixture was filtered through a pad of celite and the filter cake was washed with THF (3 × 10 mL). With Na₂SO₄The filtrate was dried and evaporated to dryness and purified by flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 40/30/30) to give androstane-3 β,5 α,17 β -triol (0.48g, 74%).¹H-NMR(300MHz，DMSO-d₆δ 4.37(d, 1H), 4.19(d, 1H), 3.78(m, 1H), 3.62(s, 1H), 3.39(m, 1H), 1.87-0.80(m, 21H), 0.86(s, 3H), 0.59(s, 3H), in ppm of TMS.

A solution of androstane-3 β,5 α,17 β -triol (0.48g) and IBX (0.72g) in DMSO (8mL) was stirred at-15 ℃ overnight and then quenched by addition of water (40mL) at room temperature. After stirring for 15 min, the mixture was filtered and the filter cake was washed with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (3X 40 mL). With Na₂SO₄The combined organic extracts were dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 60/20/20) to afford the title compound II-ad (0.36g, 75%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.48 (s, 1H), 2.72(d, 1H), 2.60-1.18(m, 20H), 1.23(s, 3H), 0.86(s, 3H).

Preparation 5

5 alpha-hydroxy-6 beta-cyanoandrostane-3, 17-dione (II-ae)

A mixture of 3 β -hydroxyandrost-5-en-17-one (13.0g) and IBX (25.3g) in THF (260mL) was heated at reflux with stirring for 4 hours. After cooling to rt, the mixture was filtered and the solid was washed with EtOAc (3 × 50 mL). The filtrate was evaporated to dryness. The residue is charged into CH₂Cl₂And the suspension was filtered. The filtrate was evaporated to dryness and reacted with Et₂O/MeOH9/1(65mL) triturates the residue. Filtration and vacuum drying gave 5-androstene-3, 17-dione (8.68g, 67%). ¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.40 (m, 1H), 3.41(m, 1H), 2.76-1.06(m, 18H), 1.29(s, 3H), 0.91(s, 3H).

A toluene solution (530mL) of 5-androstene-3, 17-dione (4.72g), ethylene glycol (37mL), and pTSA (0.219g) was stirred at reflux in a Dean-Stark trap for 12 hours. After cooling to room temperature, with 5% NaHCO₃The mixture is neutralized with an aqueous solution. The organic layer was separated, washed with water (2X 350mL), and Na₂SO₄Dried and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -5-androstene (6.11g, 99%) as a white solid.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.5.25 (m, 1H), 3.93-3.76(m, 8H), 2.72(d, 1H), 2.46(m, 1H), 2.12-0.80(m, 18H), 1.04(s, 3H), 0.85(s, 3H).

3,3:17, 17-bis (ethylenedioxy) -5 α,6 α -epiandrostane was prepared from 3,3:17, 17-bis (ethylenedioxy) -5-androstene in a yield of 45% according to the procedure for preparation of 3 β -hydroxy-5 α,6 α -epiandrostane-17-one (preparation 4) above. The crude product was purified by flash chromatography (SiO)₂n-hexane/EtOAc 80/20).¹H-NMR (300MHz, acetone-d)₆δ 3.92-3.75(m, 8H), 2.68(m, 1H), 2.56(d, 1H), 1.99-1.06(m, 18H), 1.09(s, 3H), 0.78(s, 3H), in ppm of TMS.

In N₂To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) -5 α,6 α -epoxyandrostane (2.26g) in dry toluene (20mL) was added dropwise 1MEt in toluene (10.4mL)₂And (4) AlCN. After 24 h at room temperature, EtOAc (20mL), KF (23.5g) and water (1.4mL) were added. The mixture was filtered and the filter cake was washed with EtOAc. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 80/10/10) to afford 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6 β -cyanoandrostane (1.39g, 57%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.4.45 (s, 1H)4.07-3.75(m, 8H), 2.73(dd, 1H), 2.31(d, 1H), 2.00-2.21(m, 18H), 1.24(s, 3H), 0.98(s, 3H).

The title compound II-ai was prepared in 82% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6 β -cyanoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). By flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 60/20/20) to yield the title compound II-ae.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.4.27 (s, 1H), 3.21(d, 1H), 2.92(m, 1H), 2.62-1.24(m, 18H), 1.50(s, 3H), 0.93(s, 3H).

Preparation 6

6- (E) -Hydroxyimino-7 alpha-methylandrostane-3, 17-dione (II-af)

To a stirred dry THF solution (3mL) of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (0.20g) cooled to-78 deg.C was added dropwise a THF solution of 1.5M LDA (0.41 mL). After 15 minutes CH was added dropwise₃I (0.13 mL). The mixture was stirred at-20 ℃ for 3 hours, then 39% NH was carefully added₄Stopping with aqueous Cl solution and using CH₂Cl₂(2X 50 mL). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 90/5/5) to afford 3,3:17, 17-bis (ethylenedioxy) -7 α -methylandrostan-6-one (0.91g, 44%).¹H-NMR (300MHz, acetone-d)₆δ 3.95-3.78(m, 8H), 2.76(dd, 1H), 2.30(m, 1H), 2.08-1.17(m, 17H), 1.09(s, 3H), 0.84(s, 3H), 0.76(s, 3H), in ppm of TMS.

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) -7 α -methyl-androstan-6-one (1.10g) in THF (22mL) was added NH₂OH.HCl(0.332g)，Na₂HPO₄.12H₂O (1.71g) aqueous solution (7.2 mL). ChamberAfter stirring overnight at room temperature, NaCl was added and the mixture was extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, and Na₂SO₄Dried, filtered and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyimino-7 α -methylandrostane (1.08g, 93%). ¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.34 (s, 1H), 3.88-3.71(m, 8H), 3.16(dd, 1H), 2.22-0.86(m, 21H), 0.74(s, 3H), 0.64(s, 3H).

The title compound II-af was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -6- (E) -hydroxyimino-7 α -methylandrostan-6-one by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS). delta.3.05 (dd, 1H), 2.64-1.09(m, 21H), 1.01(s, 3H), 0.89(s, 3H).

Preparation 7

6, 6-Ethoxy androstane-3, 17-dione (II-ag)

To androstane-3 beta, 6 alpha, 17 beta-triol (3.00g) CH₂Cl₂acetone/-H₂O solution (300/150/6mL) activated MnO was added three times over 8 hours₂(30.0g, 345 mmol). The mixture was stirred at 45 ℃ overnight. After cooling to room temperature, the mixture was filtered through celite. Evaporating the filtrate and flash chromatography (SiO)₂，CH₂Cl₂n-Hexane/i-PrOH 10/5/1) to give 3 beta, 17 beta-dihydroxyandrostan-6-one (0.89g, 30%).¹H-NMR(300MHz，DMSO-d₆δ 4.54(d, 1H), 4.48(d, 1H), 3.45(m, 1H), 3.30(m, 1H), 2.27(dd, 1H), 2.08-0.90(m, 19H), 0.62(s, 3H), 0.61(s, 3H), in ppm of TMS.

6, 6-Ethanedioxyandrostane-3 beta, 17 beta-diol the 3 beta-androstene-5-diol was prepared according to the procedure described above for the preparation of 3,3:17, 17-bis (Ethanedioxy) preparation 517 beta-dihydroxyandrostan-6-one was prepared in 70% yield. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness to give 6, 6-ethylenedioxyandrostane-3 β,17 β -diol.¹H-NMR(300MHz，DMSO-d₆δ 4.45(d, 1H), 4.41(d, 1H), 3.90-3.57(m, 4H), 3.41(m, 1H), 3.29(m, 1H), 1.87-0.53(m, 20H), 0.84(s, 3H), 0.60(s, 3H), in ppm of TMS.

In N₂Down to CH of 6, 6-Ethoxyandrostane-3 beta, 17 beta-diol (0.216g)₂Cl₂Solution (8.7mL) NMNO (0.217g), TPAP (10.8mg) andmolecular sieves (0.30 g). The mixture was stirred for 1 hour, then SiO was added₂. By flash chromatography (SiO)₂n-Hex/EtOAc 50/50) to yield the title compound II-ag (0.154g, 72%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.4.04-3.70 (m, 4H), 2.52-0.82(m, 20H), 1.18(s, 3H), 0.88(s, 3H).

Preparation 8

6-Methyleneandrostane-3, 17-dione (II-ah)

At 0 ℃ and N₂While stirring a suspension of methyltriphenylphosphonium bromide (9.50g) in dry THF (77mL) was added potassium tert-butoxide (2.91 g). After stirring for 10 minutes, a solution of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (2.60g) in dry THF (77mL) was added dropwise over 0.5 hour at room temperature. After 0.5 hour at room temperature, 5% NaH was added ₂PO₄The mixture was quenched with aqueous solution and Et₂O (2X 60 mL). With 5% NaH₂PO₄The combined organic extracts were washed with aqueous, brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtOAc 85/15) to give 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane (2.66g, 97%).¹H-NMR(300MHz, acetone-d₆From ppm of TMS,. delta.4.68 (m, 1H), 4.36(m, 1H), 3.88-3.71(m, 8H), 2.27-0.78(m, 20H), 0.74(s, 3H), 0.62(s, 3H).

The title compound II-ah was prepared from 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane in 87% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 4.85(m, 1H), 4.50(m, 1H), 2.63-1.02(m, 20H), 0.92(s, 3H), 0.86(s, 3H), in ppm of TMS.

Preparation 9

6 beta-hydroxymethyl androstane-3, 17-dione (II-ai)

At 0 ℃ and N₂While stirring a solution of 3,3:17, 17-bis (ethylenedioxy) -6-methylene-androstane (preparation 8, 2.89g) in dry THF (29mL) 1M BH in THF (5.21mL) was added₃A THF complex. After the addition was complete, the mixture was stirred at 0 ℃ for 3 hours. Water (2.3mL) was carefully added dropwise followed by 3N NaOH (3mL) and 9.8M H ₂O₂(0.91 mL). After stirring overnight at room temperature, H was added₂O (20 mL). The mixture was extracted with EtOAc (2X 20 mL). The combined organic extracts were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 45/55) to give 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxymethylandrostane (2.86g, 95%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.94-3.75 (m, 8H), 3.52(m, 2H), 3.36(t, 1H), 2.05-0.65(m, 21H), 0.84(s, 3H), 0.81(s, 3H).

The title compound II-ai was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxymethylandrostane in 85% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with waterWith Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 3.71-3.47(m, 3H), 2.82-0.79(m, 21H), 1.08(s, 3H), 0.89(s, 3H), in ppm of TMS.

Preparation 10

6 beta-methoxymethyl androstane-3, 17-dione (II-aj)

At 0 ℃ and N₂While stirring a solution of 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxy-methylandrostane (preparation 9, 0.80g) in dry THF (11mL) NaH (60% dispersion, 96mg) was added. The mixture was stirred at 0 ℃ for 1 hour, and CH was added ₃I (144. mu.L). After stirring overnight at room temperature, H was added₂O (10 mL). The mixture was extracted with EtOAc (2X 20 mL). With Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂Hexane/acetone 90/10) to give 3,3:17, 17-bis (ethylenedioxy) -6 β -methoxymethylandrostane (0.70g, 84%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.94-3.73 (m, 8H), 3.32(m, 2H), 3.24(s, 3H), 1.98-0.65(m, 21H), 0.84(s, 3H), 0.83(s, 3H).

The title compound II-aj was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 β -methoxymethylandrostane in 90% yield according to the procedure for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 70/10/20) was purified.¹H-NMR (300MHz, acetone-d)₆δ 3.45(m, 2H), 3.27(s, 3H), 2.80-0.80(m, 21H), 1.10(s, 3H), 0.89(s, 3H), in ppm of TMS.

Preparation 11

6 alpha-Vinylandrostane-3, 17-dione (II-ak)

To a DMSO solution (6mL) of 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxymethyl-androstane (preparation 9, 0.63g) was added IBX (0.87g) and stirred at room temperature for 1 hour. Addition of H ₂O (30mL) and Et₂The mixture was quenched with O (30 mL). After stirring for 15 min, the mixture was filtered and treated with Et₂O washing the filter cake. Separate the layers and use Et₂O (3X) extract the aqueous phase. The combined organic extracts were washed with brine, Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 75/35) to give 3,3:17, 17-bis (ethylenedioxy) -6 β -formylandrostane (0.52g, 83%).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.9.92 (d, 1H), 3.96-3.75(m, 8H), 2.32-0.68(m, 21H), 0.81(s, 3H), 0.77(s, 3H).

MeOH (57mL) in 3,3:17, 17-bis (ethylenedioxy) -6-beta-formylandrostane (0.61g), K₂CO₃(0.90g) the mixture was stirred at room temperature overnight. After evaporation, with H₂The residue was treated with O (20mL) and EtOAc (3)30 mL). The combined organic extracts were washed with brine (3X 20mL) and Na₂SO₄Dried and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6 α -formylandrostane (0.57g, 94%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.9.41 (d, 1H), 3.95-3.72(m, 8H), 2.24-0.73(m, 21H), 0.90(s, 3H), 0.84(s, 3H).

3,3:17, 17-bis (ethylenedioxy) -6 α -vinylandrostane was prepared in 70% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -formylandrostane by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane (preparation 8). The crude product was purified by flash chromatography (SiO) ₂n-hexane/EtOAc 88/12).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.47 (m, 1H), 4.91(m, 2H), 3.94-3.73(m, 8H), 2.00-0.67(m, 21H), 0.88 (ms，3H)，0.83(s，3H)。

The title compound II-ak was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -vinyl androstane in 92% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 5.51(m, 1H), 4.97(m, 2H), 2.53-0.82(m, 21H), 1.14(s, 3H), 0.98(s, 3H),

preparation 12

6 alpha- (2-hydroxyethyl) androstane-3, 17-dione (II-al)

3,3:17, 17-bis (ethylenedioxy) -6 α - (2-hydroxyethyl) androstane was prepared in 96% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -vinyl androstane (preparation 11) by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxymethyl-androstane (preparation 9). The crude product was purified by flash chromatography (SiO)₂N-hexane/acetone 80/20).¹H-NMR(300MHz，DMSO-d₆δ 4.25(t, 1H), 3.86-3.70(m, 8H), 3.35(m, 2H), 1.91-0.42(m, 23H), 0.75(s, 3H), 0.74(s, 3H), in ppm of TMS.

The title compound II-al was prepared in 100% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α - (2-hydroxyethyl) androstane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，dmso-d₆δ 4.32(t, 1H), 3.39(m, 2H), 2.46-0.54(m, 23H), 0.98(s, 3H), 0.79(s, 3H), in ppm of TMS.

Preparation 13

3, 17-dioxoandrostane-6 α -carboxaldehyde (EZ) -oxime (II-am)

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) -6 α -formyl-androstane (preparation 11, 0.50g) in pyridine (10mL) was added NH₂OH. HCl (0.16 g). After stirring overnight at room temperature, the solution was evaporated. With H₂O treatment of the residue with CH₂Cl₂(2X) extraction. The combined organic extracts were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) androstane-6 α -carboxaldehyde- (EZ) -oxime in 87% yield.¹H-NMR(300MHz，DMSO-d₆δ 10.58(s, 0.15H), 10.35(s, 0.85H), 6.98(d, 0.85H), 6.28(d, 0.15H), 3.90-3.68(m, 8H), 2.89(m, 0.15H), 2.04(m, 0.85H), 1.93-0.55(m, 20H), 0.79(s, 3H), 0.76(s, 3H), in ppm of TMS.

The title compound II-am was prepared in 80% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-6 α -carbaldehyde- (E, Z) -oxime using the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 40/20/20) to give the title compound II-am.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.72 (s, 0.1H), 10.44(s, 0.9H), 7.05(d, 0.9H), 6.35(d, 0.1H), 2.50-0.72(m, 21H), 1.03(s, 3H), 0.80(s, 3H).

Preparation 14

6 alpha-hydroxymethyl androstane-3, 17-dione (II-an)

To a stirred mixture of 3,3:17, 17-bis (ethylenedioxy) -6 α -formyl-androstane (preparation 11, 0.52g) in dioxane/H₂O9/1 suspension (25mL) NaBH was added₄(0.049g), and the mixture was stirred at room temperature overnight. NaCl was added to the solution and the layers were separated. The aqueous phase was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, Na₂SO₄Dried and evaporated to dryness to give 3,317, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostane (0.45g, 86%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.94-3.75 (m, 8H),3.57-3.25(m, 3H), 1.98-0.60(m, 21H), 0.86(s, 3H), 0.83(s, 3H).

The title compound II-an was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostane in 85% yield according to the procedure for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.50 (m, 3H), 2.52-0.74(m, 21H), 1.11(s, 3H), 0.88(s, 3H).

Preparation 15

6 alpha-acetoxymethyl androstane-3, 17-dione (II-ao)

DMAP (1mg) and Ac were added to a stirred solution of 6 α -hydroxymethylandrostane-3, 17-dione (II-an, preparation 14, 42mg) in pyridine (1.5mL) at 0 deg.C₂And O. After stirring overnight at room temperature, the solution was evaporated. The residue was treated with 1N HCl and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, and Na₂SO₄Dried, filtered and evaporated to dryness to give the title compound II-ao (91%).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.3.97 (m, 2H), 2.53-0.80(m, 21H), 1.99(m, 3H), 1.13(s, 3H), 0.88(s, 3H).

Preparation 16

6 alpha-methoxymethyl androstane-3, 17-dione (II-ap)

3,3:17, 17-bis (ethylenedioxy) -6 α -methoxymethylandrostane was prepared in 84% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostane (preparation 14) according to the procedure for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6 β -methoxymethylandrostane (preparation 10) described above. With H₂The combined extracts were washed with Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtO₂80/20) purifying the residue to obtain 3,3:17, 17-bis (ethylenedioxy) -6 α -methoxymethylandrostane.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):3.92-3.70(m，8H)，3.25(dd，1H)，3.23(s，3H)，3.14(dd，1H)，1.97-0.59(m，21H)，0.85(s，3H)，0.82(s，3H)。

the title compound II-ap was prepared in 88% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -methoxymethylandrostane according to the procedure for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.25 (s, 3H), 3.24(m, 2H), 2.53-0.75(m, 21H), 1.11(s, 3H), 0.87(s, 3H).

Preparation 17

6 alpha-carboxy androstane-3, 17-dione (II-aq)

6 α -formylandrostane-3, 17-dione was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -formylandrostane (preparation 11) according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness to give 6 α -formylandrostane-3, 17-dione.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.9.50 (d, 1H), 2.56-0.82(m, 21H), 1.16(s, 3H), 0.88(s, 3H).

To stirring at t-ButOH (35mL) and 5% Na₂HPO₄Suspension of 6 alpha-formylandrostane-3, 17-dione (1.77g) in aqueous solution (21.5mL) was added KMnO₄Aqueous solution (35 mL). 5 minutes at room temperatureAfter that, 40% NaHSO was added₃The aqueous solution terminates the mixture. The suspension was filtered, washed with water and the filtrate was freeze-dried. The residue was poured into water (50mL) and extracted with EtOAc (4X 70 mL). With Na₂SO₄The combined organic extracts were dried and evaporated to dryness to give the title compound II-aq (1.80g, 96%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.11.99 (bb, 1H), 2.46-0.73(m, 21H), 1.01(s, 3H), 0.79(s, 3H).

Preparation 18

6 alpha-carbamoylandrostane-3, 17-dione (II-ar)

To a stirred suspension of 6 α -carboxyandrostane-3, 17-dione (II-aq, preparation 17, 600mg) in dry toluene (12mL) was added SOCl₂(623. mu.L). After stirring at 85 ℃ for 5.5 hours, the solution was cooled to 0 ℃ and 2M NH was added₃MeOH (2.97 mL). After stirring overnight at room temperature, the solution was evaporated to dryness. With CH₂Cl₂And H₂Treating the residue with CH₂Cl₂And (4) extracting. With 10% K₂CO₃The combined organic extracts were washed with aqueous, brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO) ₂N-hexane/acetone 50/50) to give the title compound II-ar (90mg, 15%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.27 (bs, 1H), 6.78(bs, 1H), 2.50-0.72(m, 21H), 1.00(s, 3H), 0.80(s, 3H).

Preparation 19

6 alpha-methoxycarbonylandrostane-3, 17-dione (II-as)

6 alpha-Carboxyandrostane-3, 17-dione (II-aq, preparation 17, 34mg) in CH with stirring at 0 deg.C₂Cl₂To the solution (1.5mL) were added MeOH (8. mu.L), DMAP (1mg) and EDAC (39.4 mg). After stirring overnight at room temperature, H was added₂O and with CH₂Cl₂Extract the mixture (2 ×). By H₂The combined organic extracts were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/EtOAc 60/40) to provide the title compound II-as (25mg, 70%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.3.59 (s, 3H), 2.53-0.75(m, 21H), 1.02(s, 3H), 0.79(s, 3H).

Preparation 20

6(E) -Hydroxyiminoandrostane-3, 17-dione (II-at)

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (1.10g) in THF (22mL) was added NH₂OH.HCl(0.33g)，Na₂HPO₄.12H₂O (1.71g) aqueous solution (7.2 mL). After stirring overnight at rt, NaCl was added and the mixture was extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, and Na ₂SO₄Dried, filtered and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyimino-androstane (1.08g, 93%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.34 (s, 1H), 3.88-3.71(m, 8H), 3.16(dd, 1H), 2.22-0.86(m, 19H), 0.74(s, 3H), 0.64(s, 3H).

The title compound II-at was prepared from 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane in 70% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂N-hexane/acetone 70/30).¹H-NMR(300MHz，DMSO-d₆δ 10.61(s, 1H), 3.29(dd, 1H), 2.61-1.03(m, 19H), 0.88(s, 3H), 0.79(s, 3H), in ppm of TMS.

Preparation 21

6(E) -Methoxyiminoandrostane-3, 17-dione (II-au)

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (1.00g) in pyridine (20mL) was added NH₂OCH₃HCl (0.39 g). After stirring overnight at room temperature, the solution was evaporated, the residue was treated with water and CH₂Cl₂(2) And (4) extracting. The combined organic extracts were washed with brine, and Na₂SO₄Dried, filtered and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6(E) -methoxyiminoandrostane (1.04g, 97%). ¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.94-3.76 (m, 8H), 3.73(s, 3H), 3.22(dd, 1H), 2.29-0.95(m, 19H), 0.82(s, 3H), 0.75(s, 3H).

The title compound II-au was prepared in 70% yield from 3,3:17, 17-bis (ethylenedioxy) -6(E) -methoxyiminoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.78 (s, 3H), 3.37(dd, 1H), 2.68-1.14(m, 19H), 1.01(s, 3H), 0.98(s, 3H).

Preparation 22

6(E) -ethoxyiminoandrostane-3, 17-dione (II-av)

3,3:17, 17-bis (ethylenedioxy) -6(E) -ethoxyiminoandrostane prepared in 90% yield from 3,3:17, 17-bis (ethylenedioxy) androstan-6-one and NH as described above in preparation 21₂OCH₂CH₃Preparation of HCl.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.99 (2H, q), 3.92 to 3.75(8H, m), 3.25(1H, dd), 2.25(1H, m), 1.99 to 0.94(18H, m), 1.17(3H, t),0.82(3H，s)，0.75(3H，s)。

the title compound II-av was prepared from 3,3:17, 17-bis (ethylenedioxy) -6(E) -ethoxyiminoandrostane in 100% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 4.03(2H, q), 3.40(1H, dd), 2.70-1.12(19H, m), 1.20(3H, t), 1.01(3H, s), 0.87(3H, s), in ppm of TMS.

Preparation 23

6(E) -allyloxyiminoandrostane-3, 17-dione (II-aw)

Using the same reaction conditions as described in preparation 21 and starting from 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (250mg) and O-allylhydroxylamine hydrochloride (140mg), 3:17, 17-bis (ethylene-dioxide) -6- (E) -allyloxyiminoandrostane (260mg, 91%) was obtained.¹H-NMR (300MHz, acetone-d)₆δ 5.97(m, 1H), 5.22(m, 1H), 5.11(m, 1H), 4.47(m, 2H), 3.94-3.76(m, 8H), 3.28(dd,1H), 2.26(m,1H), 2.03-0.95(m, 18H), 0.82(s, 3H), 0.75(s, 3H), in ppm of TMS.

The title compound II-aw was prepared in 70% yield from 3,3:17, 17-bis (ethylenedioxy) -6(E) -allyloxyiminoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 5.99(1H, m), 5.25(1H, m), 5.14(1H, m), 4.52(2H, m), 4.42(1H, dd), 2.68-1.15(19H, m), 1.01(3H, s), 0.88(3H, s), in ppm of TMS.

Preparation 24

6 beta-methyl androstane-3, 17-dione (I)I-ax)

To N₂Stirring under 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxy-methylandrostane (preparation 9, 90mg) and DMAP (5mg) in CH₂Cl₂TCDI (78mg) was added to the solution (3 mL). After stirring for 2 hours at 40 ℃, water is added and CH is added₂Cl₂Extract the mixture (2 ×). The combined organic extracts were washed with brine, and Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 70/15/15) to obtain O- [3,3:17, 17-bis (ethylenedioxy) androstan-6 beta-ylmethyl]Imidazole-1-thioformate (95mg, 83%).¹H-NMR(300MHz，DMSO-d₆δ 8.43(dd, 1H), 7.76(dd, 1H), 7.08(dd, 1H), 4.82(dd, 1H), 4.68(dd, 1H), 3.90-3.70(m, 8H), 2.17-0.89(m, 21H), 0.84(s, 3H), 0.79(s, 3H), in ppm of TMS.

Ph under stirring in Ar₃AIBN (5mg) was added to a dry toluene solution (2mL) of SnH (193 mg). After stirring for 20 minutes at 90 ℃ O- [3,3:17, 17-bis (ethylenedioxy) androstan-6 beta-ylmethyl was added dropwise]Imidazole-1-thioformate (95mg) in dry toluene (2 mL). After stirring for 2 hours at 110 ℃ the mixture was evaporated to dryness and purified by flash chromatography (SiO)₂hexane/EtOAc 98/2) to give 3,3:17, 17-bis (ethylenedioxy) -6 β -methylandrostane (30mg, 42%). ¹H-NMR (300MHz, acetone-d)₆δ 3.92-3.78(m, 8H), 2.10-0.62(m, 21H), 0.92(s, 3H), 0.88(d, 3H), 0.85(s, 3H), in ppm of TMS.

The title compound II-ax was prepared in 94% yield from 3,3:17, 17-bis (ethylenedioxy) -6 β -methylandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.2.77 to 0.75(m, 21H), 1.18(s, 3H), 0.98(d, 3H), 0.90(s, 3H).

Preparation 25

6 alpha-methylandrostane-3, 17-dione (II-ay)

In N₂To a stirred mixture of DABCO (0.55g) and 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostane (preparation 14, 1.00g) in dry CH at 0 deg.C₂Cl₂Solution (20mL) p-TSCl (0.703g) was added. After stirring for 2 hours at room temperature, the mixture was filtered and taken up with CH₂Cl₂The filter cake is washed. The organic layer was washed with brine, and Na₂SO₄Dried, filtered and evaporated to dryness. The crude product was triturated with n-hexane/EtOAc (60/40) and filtered. Vacuum drying at 40 deg.C to obtain 3,3:17, 17-bis (ethylene-dioxy) -6 alpha- [ (4-methyl) benzenesulfonyloxymethyl]Androstane (1.11g, 80%). ¹H-NMR (300MHz, acetone-d)₆δ 7.82(m, 2H), 7.49(m, 2H), 4.00-3.74(m, 10H), 2.46(s, 3H), 1.97-0.57(m, 21H), 0.82(s, 3H), 0.80(s, 3H), in ppm of TMS.

In N₂NaBH being stirred in the interior in 15 minutes₄(0.15g) in dry DMSO (90mL) 3,3:17, 17-bis (ethylenedioxy) -6 α - [ (4-methyl) benzenesulfonyloxy-methyl-was added portionwise]Androstane (1.11 g). After stirring at 80 ℃ for 3 hours, the mixture was quenched by careful addition of water (200mL) at room temperature. With Et₂O extracting the suspension. The combined organic extracts were washed with brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 90/10) to give 3,3:17, 17-bis (ethylenedioxy) -6 α -methylandrostane (0.70g, 90%).¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.94-3.72 (m, 8H), 1.98-0.53(m, 21H), 0.85(s, 3H), 0.83(s, 3H), 0.79(d, 3H).

The title compound II-ay was prepared from 3,3:17, 17-bis (ethylenedioxy) -6-methylandrostane in 94% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. ¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.2.77 to 0.75(m, 21H), 1.18(s, 3H), 0.98(d, 3H), 0.90(s, 3H).

Preparation 26

6- (S) -Spiro- (2' -Oxirane) androstane-3, 17-one (II-az) and6- (R) -Spiro-Ring - (2' -Oxirane) androstane-3, 17-one (II-ba)

6-Methyleneandrostane-3, 17-dione (II-ah, preparation 8, 0.76g) in CH with stirring at 0 deg.C₂Cl₂To the solution (44mL) was added mCPBA (0.933mg) in three portions over 5 hours. After stirring at room temperature for 3 hours, 5% NaHCO was used₃Aqueous solution, 40% NaHSO₃Aqueous solution, 5% Na₂HPO₄The mixture was washed with aqueous solution and brine. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂Toluene/acetone 95/5) to give the title compounds II-az (30%) and II-ba (15%).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS, II-az: delta 2.79(dd, 1H), 2.59(d, 1H), 2.53-0.94(m, 20H), 1.16(s, 3H), 0.88(s, 3H), II-ba: delta 2.70-0.96(m, 22H), 1.17(s, 3H), 0.90(s, 3H).

Preparation 27

6 alpha-ethynylandrostane-3, 17-dione (II-bb)

To a stirred solution of (chloromethyl) triphenylphosphonium chloride (1.20g) in dry THF (20mL) at-78 deg.C under argon was added dropwise 1.6M n-butyllithium in n-hexane (1.5 mL). After 30 minutes at room temperature, a solution of 3,3:17, 17-bis (ethylenedioxy) -6 α -formylandrostane (preparation 11, 0.28g) in dry THF (7mL) was added dropwise. The mixture was heated at 70 ℃ for 1 hour and then cooled to room temperature. The mixture was quenched by addition of brine and then extracted with EtOAc (3 ×). With Na ₂SO₄The combined organic extracts were dried and evaporated to dryness. Subjecting the crude product to a distillationDissolved in dry THF (20mL) and stirred at-78 ℃. To the resulting solution was added dropwise a 1.6M n-butyllithium solution in n-hexane (2.24mL) under argon. After 1 hour at room temperature, the mixture was quenched by addition of brine and Et₂O (3X) extraction. With Na₂SO₄The combined organic extracts were dried and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6 α -ethynylandrostane (160mg, 46%) which was pure in composition and used in the next step without further purification.¹H-NMR (300MHz, acetone-d)₆δ 3.85(m, 8H), 2.46(d, 1H), 2.30-0.67(m, 21H), 0.82(s, 3H), 0.86(s, 3H), in ppm of TMS.

The title compound II-bb was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -ethynylandrostane in 46% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/CH₂Cl₂/acetone 80/10/10) was purified.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS) delta 2.69-0.78(m, 22H), 1.12(s, 3H), 0.87(s, 3H).

Preparation 28

6 alpha-carboxamidoandrostane-3, 17-dione (II-bc)

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyimino-androstane (preparation 20, 0.88g) in n-PrOH (26mL) was added small pieces of Na (2.0g) over 20 minutes. The mixture was stirred at reflux for 2 hours. After cooling to room temperature, the mixture was quenched by careful addition of MeOH. Water was carefully added to the solution and the organic solvent was evaporated. With CH₂Cl₂Extract the mixture (3 ×). The combined organic extracts were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂，CHCl₃/MeOH/26%NH₄OH90/10/1) to obtain 3,3:17, 17-bis (ethylene glycol)Oxy) -6 α -aminoandrostane (0.45g, 53%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.3.87-3.70 (m, 8H), 2.29(m, 1H), 1.98-0.50(m, 22H), 0.75(s,3H), 0.74(s, 3H).

CHCl conversion to formic acid at 0 deg.C₃Solution (0.67mL) DCC (106mg) in CHCl was added dropwise₃And (3) solution. The mixture was stirred for an additional 5 minutes, then an ice-cooled solution of 3,3:17, 17-bis (ethylenedioxy) -6 α -aminoandrostane (100mg) in pyridine (0.70mL) was added over 30 minutes. The mixture was then stirred in an ice bath for 4 hours. Evaporation of the solvent and addition of Et₂And O. The precipitate was removed by filtration and taken up in Et ₂And O washing. The combined organic extracts were evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6 α -carboxamidoandrostane (100mg, 95%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.98-7.43 (m, 2H), 3.89-3.00(m, 9H), 1.93-0.50(m, 20H), 0.81(s,3H), 0.77(s, 3H).

The title compound II-bc was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -carboxamidoandrostane in 96% yield according to the procedure for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.8.02 to 7.56(m, 2H), 3.74(m, 1H), 2.54 to 0.70(m, 20H), 1.04(s,3H), 0.80(s, 3H).

Preparation 29

6 alpha-acetamido androstane-3, 17-dione (II-bd)

At 0 ℃ and N₂A solution of 3,3:17, 17-bis (ethylenedioxy) -6 α -amino-androstane (preparation 28, 100mg) in dry pyridine (0.5mL) was added dropwise (CH) with stirring₃CO)₂O (48. mu.L). The mixture was stirred at room temperature for 1.5 hours and the solution was evaporated to dryness. The residue was poured into water and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, Na₂SO₄Dried, filtered and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6 α -acetamido androstane (103mg, 94%). ¹H-NMR(300MHz，DMSO-d₆δ 7.55(d, 1H), 3.88-3.70(m, 8H), 3.53(m, 1H), 1.92-0.81(m, 20H), 1.75(s, 3H), 0.80(s,3H), 0.75(s, 3H), in ppm of TMS.

The title compound II-bd was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -acetamido androstane in 96% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，DMSO-d₆δ 7.61(d, 1H), 3.67(m, 1H), 2.51-0.68(m, 20H), 1.78(s, 3H), 1.04(s, 3H), 0.80(s,3H), in ppm of TMS.

Preparation 30

6(E) -Ethyleneandrostane-3, 17-dione (II-be)

3,3:17, 17-bis (ethylenedioxy) -6(E) -ethylideneandrostane was prepared in 96% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-6-one and (ethyl) triphenylphosphonium bromide, according to the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane (preparation 8). The mixture was purified by flash chromatography (SiO)₂cyclohexane/EtOAc 85/15).¹H-NMR (300MHz, acetone-d)₆δ 4.91(m, 1H), 3.93-3.78(m, 8H), 2.69(m, 1H), 2.10-0.85(m, 22H), 0.81(s, 3H), 0.66(s, 3H), in ppm of TMS.

The title compound II-be was prepared from 3,3:17, 17-bis (ethylenedioxy) -6(E) -ethyleneandrostane in 96% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.4.99 (m, 1H), 2.86(dd, 1H), 2.61-1.01(m, 19H), 1.66 (m)，3H)，0.93(s，3H)，0.86(s，3H)。

Preparation 31

6-Difluoromethylene androstane-3, 17-dione (II-bf)

Diethyldifluoromethylenephosphonate (0.6) stirred at-78 ℃ under argonμ L) of DME (5.75mL) and n-pentane (1.1mL) was added dropwise a 1.5M solution of pentane in t-butyllithium (2.75 mL). After 15 minutes at the same temperature, a solution of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (500mg) in DME (4.5mL) and n-pentane (1.25mL) was added dropwise. The mixture was stirred at-78 ℃ for a further 30 minutes and warmed to room temperature. N-pentane was distilled off, after heating at 80 ℃ for 4 hours, the mixture was quenched with water and CH₂Cl₂(3X) extraction. With Na₂SO₄The combined organic extracts were dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/Et₂O70/30) to give 3,3:17, 17-bis (ethylenedioxy) -6-difluoromethyleneandrostane (470mg, 85%). ¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.85 (m, 8H), 2.52-0.80(m, 20H), 0.83(s, 3H), 0.84(s, 3H).

The title compound II-bf was prepared in 99% yield from 3,3:17, 17-bis (ethylenedioxy) -6-difluoromethyleneandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.2.85-0.95 (m, 20H), 1.12(s, 3H), 0.88(s, 3H).

Preparation 32

3, 17-dioxoandrostane-6- (E) -ylideneacetonitrile (II-bg)

To a stirred suspension of NaH (60% dispersed in mineral oil, 204mg) in THF (6mL) at room temperature was added diethyl cyanomethylphosphonate (895 μ L). After stirring for 0.5 h, 3:17, 17-bis (ethylenedioxy) androstan-6-one (200mg) was added to the yellow mixture. After stirring at reflux for 2 hours, the mixture was quenched by addition of brine and then Et₂O (3X) extraction. With Na₂SO₄The combined organic extracts were dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 70/20/20) to give 3,3:17, 17-bis (ethylene-dioxy) androstan-6- (E) -ylideneacetonitrile (150mg, 71%). ¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.03 (t, 1H), 3.95-3.78(m, 8H), 2.90(dd, 1H), 2.33(m, 1H), 2.10-0.99(m, 18H), 0.84(s, 3H), 0.73(s, 3H).

The title compound II-bg was prepared in 87% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-6- (E) -ylideneacetonitrile according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.15 (s, 1H), 3.04(dd, 1H), 2.71-1.17(m, 19H), 1.01(s, 3H), 0.90(s, 3H).

Preparation 33

6- [ 2-hydroxy- (E) -ethylidene E]Androstane-3, 17-dione (II-bh)

At-78 ℃ and N₂Stirring under dry CH of 3,3:17, 17-bis (ethylenedioxy) androstan-6- (E) -ylideneacetonitrile (preparation 35, 214mg)₂Cl₂Solution (10mL) was added 1M DIBAH CH₂Cl₂Solution (1.56 mL). The mixture was stirred at-78 ℃ for 1 hour and then quenched by the careful addition of 2M isopropanol in toluene (0.80 mL). After 1 hour, H was added₂O (70. mu.L) and THF (2.8mL) and after another hour, SiO was added₂(0.76g) and Na₂SO₄(1.52g) In that respect The mixture was stirred for 1 hour, filtered through a pad of celite and the filter cake was washed with EtOAc. With Na ₂SO₄The filtrate was dried and evaporated to give 3,3:17, 17-bis (ethylenedioxy) androstan-6- (E) -ylideneacetaldehyde (0.18g, 55%).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.9.98 (dd, 1H), 5.46(d, 1H), 3.91-3.70(m, 8H), 3.35(dd, 1H), 2.31-0.91(m, 19H), 0.75(s, 3H), 0.64(s, 3H).

To a stirred suspension of 3,3:17, 17-bis (ethylenedioxy) androstan-6- (E) -ylideneacetaldehyde (110mg) in MeOH (2.5mL) at 0 deg.C was added NaBH₄(5mg), and the mixture was stirred for 1 hour. Acetone (100 μ L) was added and the mixture was evaporated. With H₂The residue was treated with O and extracted with EtOAc. The combined organic extracts were washed with brine, Na₂SO₄Dried and evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6- (E) - (2-hydroxyethylidene) androstane (100mg, 90%).¹H-NMR (300MHz, acetone-d)₆δ 5.07(m, 1H), 4.11(m, 2H), 3.95-3.75(m, 8H), 3.41(d, 1H), 2.67(m, 1H), 2.14-0.84(m, 18H), 0.80(s, 3H), 0.69(s, 3H), in ppm of TMS.

The title compound II-bh was prepared from 3,3:17, 17-bis (ethylenedioxy) -6- (E) - (2-hydroxyethylidene) androstane in 60% yield by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂N-hexane/acetone 70/30).¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm delta 5.14(m, 1H), 4.17(m, 2H), 3.53(t, 1H), 2.84(dd, 1H), 2.65-1.01(m, 20H), 0.97(s, 3H) and 0.85(s, 3H).

Preparation 34

Methyl (3, 17-dioxoandrostane-6 (E) -ylidene) acetate (II-bi)

To 0 ℃ and N₂Trimethyl phosphorus under stirringA DME solution (5.75mL) of acetic acid (5.17mL) was added dropwise to a 1.5M n-pentane solution of tert-butyllithium (18.5 mL). After 15 minutes at the same temperature, a solution of 3,3:17, 17-bis (ethylenedioxy) androstan-6-one (1.00g) in DME (15mL) was added dropwise. After stirring for 8h at 110 ℃ and cooling, water was added to stop and extracted with EtOAc (3 ×). With Na₂SO₄The combined organic extracts were dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 80/10/10) to provide [3,3:17, 17-bis (ethylenedioxy) androstan-6 (E) -ylidene]Methyl acetate (400mg, 35%).¹H-NMR (300MHz, acetone-d)₆The TMS consists of the components with the ppm ratio delta 5.34(s, 1H), 4.05-3.75(m, 9H), 3.62(s, 3H), 2.28(m, 1H), 2.00-0.97(m, 18H), 0.82(s, 3H) and 0.72(s, 3H).

The title compound II-bi can be prepared from [3,3:17, 17-bis (ethylenedioxy) androstane-6 (E) -ylidene by the procedure described above for the preparation of 6 α -cyano-androstane-3, 17-dione (II-ac, preparation 3)]Methyl acetate was prepared in 70% yield. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (n-hexane/CH)₂Cl₂/acetone 75/15/15) was purified.¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm of delta 5.42(bs, 1H), 4.16(dd, 1H), 3.66(s, 3H), 2.73-1.16(m, 19H), 0.99(s, 3H) and 0.87(s, 3H).

Preparation 35

6- (spirocyclopropane) androstane-3, 17-dione (II-bj)

To N₂While stirring a solution of 3,3:17, 17-bis (ethylenedioxy) -6-methylene-androstane (preparation 8, 200mg) in dry toluene (10mL) 1M Et was added₂Zn in n-hexane (2.5 mL). After heating at 60 ℃ CH was added portionwise over 15 minutes₂I₂(0.42 mL). After 26 hours, the mixture was cooled and then quenched by careful addition of 1N HCl. With Et₂O extracting the suspension. With 5% NaHCO₃Aqueous solution,The combined organic extracts were washed with brine, and Na₂SO₄Dried and evaporated to dryness. The crude product was dissolved in acetone (20mL) and pTSA. H was added₂O (39mg), and the solution was stirred at room temperature for 1 hour. Add 5% NaHCO ₃The solution was neutralized with an aqueous solution and the acetone was evaporated. The aqueous suspension was extracted with EtOAc. The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂EtOAc90/5/5) to provide the title compound II-bj (78mg, 48%).¹H-NMR (300MHz, acetone-d)₆The TMS consists of the ppm of delta 2.51-0.83(m, 20H), 1.17(s, 3H), 0.88(s, 3H), 0.60(m, 1H), 0.41(m, 1H), 0.34(m, 1H), -0.08(m, 1H).

Preparation 36

6 alpha-acetamidomethyl androstane-6, 17-dione (II-bk)

3,3:17, 17-bis (ethylenedioxy) androstane-6 α -carboxaldehyde- (E, Z) -oxime (preparation 13, 1.94g) was dissolved in dry THF (60mL) and LiAlH was added rapidly at 0 deg.C₄(1.23 g). After stirring at reflux for 2 hours, the slurry was cooled to 0 deg.C and water (1.25mL), NaOH30% (1.25mL) and water (3.75mL) were added sequentially. The mixture was extracted with THF. The organic layer was washed with brine, Na₂SO₄Drying, evaporation drying gave 3,3:17, 17-bis (ethylenedioxy) -6 α -aminomethyl-androstane (1.87g, 100%).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.3.90-3.68 (8H, m), 2.67(1H, dd), 2.54(1H, dd), 1.92-0.49(23H, m), 0.76(3H, s), 0.55(3H, s).

3,3:17, 17-bis (ethylenedioxy) -6 α -aminomethylandrostane (250mg) was dissolved in dry pyridine (1.25mL) and acetic anhydride (0.12mL) was added at 0 ℃. After stirring for 2h at rt, the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with water and Na₂SO₄Dried and evaporated to dryness to provide 3,3:17, 17-bis (ethylenedioxy) -6 α -acetamidomethyl-androsta as a white solidStanol (215mg, 78%) was used directly in the next step.¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.59 (1H, t), 3.90-3.67(8H, m), 3.03-2.79(2H, m), 1.92-0.48(21H, m), 1.77(3H, s), 0.75(6H, s).

The title compound II-bk was prepared in 100% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -acetamidomethylandrostane (210mg) by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.67 (1H, t), 3.10(1H, m), 2.78(1H, dd), 2.60-1.00(21H, m),1.78(3H, s), 0.97(3H, s), 0.79(3H, s).

Preparation 37

6 alpha-carboxamidomethylandrostane-3, 17-dione (II-bl)

DCC (203mg) in CHCl at 0 deg.C₃The solution (0.7mL) was added to CHCl₃2M HCOOH (1.3 mL). After 5 minutes at this temperature 3,3:17, 17-bis (ethylenedioxy) -6 α -aminomethylandrostane (preparation 36, 200mg) in pyridine (1.5mL) was added dropwise. After 1h the solvent was evaporated, the precipitate filtered off and the filtrate evaporated to dryness to give 3,3:17, 17-bis (ethylenedioxy) -6 α -carboxamidomethyl-androstane (194mg, 92%). ¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.97 (1H, d), 7.87(1H, m), 3.78(8H, m), 2.97(2H, m), 1.94-0.51(21H, m), 0.76(3H, s), 0.75(3H, s).

The title compound II-bl was prepared in 92% yield from 3,3:17, 17-bis (ethylenedioxy) -6 α -carboxamidomethylandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.7.99 (0.9H, s), 7.94(0.9H, m), 7.88(0.1H, d), 7.67(0.1H, m), 3.15(1H, m), 2.87(1H, m), 2.40-1.00(21H, m), 0.98(3H, s), 0.79(3H, s).

Preparation 38

5 alpha-hydroxy-6- (E) -hydroxyiminoandrostane-3, 17-dione (II-bm)

To stirring cooled to 0 deg.C 3 beta-hydroxyandrost-5-en-17-one (0.81g) in CH₂Cl₂Solution (7.4mL) mCPBA (0.77mg) in CH was added dropwise₂Cl₂Solution (14 mL). After 0.5 hour at 0 ℃ and 0.5 hour at room temperature, 10% Na was added₂SO₃An aqueous solution. Add 5% NaHCO₃Neutralizing the mixture with an aqueous solution and adding CH₂Cl₂(3 × 100 mL). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness to give 5 α,6 α -epoxyandrostan-17-one and 5 β,6 β -epoxyandrostan-17-one as white foams (1/1 mixture; 1.24g, 97%). ¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS), 3 beta-hydroxy-5 alpha, 6 alpha-epoxy androstane-17-one delta 3.26(d, 1H), 2.96(d, 1H), 2.70-1.12(m, 18H), 1.36(s, 3H), 0.83(s, 3H), 3 beta-hydroxy-5 beta, 6 beta-epoxy androstane-17-one delta 2.98(d, 1H), 2.93(d, 1H), 2.71-1.13(m, 18H), 1.06(s, 3H), 0.84(s, 3H).

To an acetone solution (38mL) of a mixture of 3 β -hydroxy-5 α,6 α -epiandrostan-17-one and 3 β -hydroxy-5 β,6 β -epiandrostan-17-one (2.10g, 6.90mmol) in 1/1 was added dropwise Jones reagent (8.35mL) and the temperature was kept below 40 ℃. After 5 minutes of complete addition, i-PrOH (10mL) was added and after a further 10 minutes the suspension was filtered and the filtrate was evaporated to dryness. By H₂The residue was treated with O (300mL) and EtOAc (3)100mL) was extracted. By H₂O(100mL)，5%NaHCO₃Aqueous solution (100mL), H₂The combined organic extracts were washed with O (100mL) and Na₂SO₄Dried and evaporated to dryness to give 5 α -hydroxyandrostan-3, 6, 17-trione (1.65g, 75%) as a white solid.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.5.00 (s, 1H), 2.85(m, 2H), 2.45-1.25(m, 17H), 1.06(s, 3H),0.88(s，3H)。

5 alpha-hydroxyandrostane-3, 6, 17-trione (2.23g) and pTSA. H₂A solution of O (80mg) in 2-methyl-2-ethyl-1, 3-dioxolane (29mL) was stirred at 40 ℃ for 6 hours. Adding 5% Na ₂HPO₄The solution was neutralized with aqueous solution and extracted with EtOAc. The combined organic extracts were washed with brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/acetone/CH₂Cl₂80/10/10) to afford 3,3:17, 17-bis (ethylene-dioxy) -5 α -hydroxyandrostan-6-one (1.56g, 55%).¹H-NMR (300MHz, acetone-d)₆The TMS consists of the ppm of delta 4.36(s, 1H), 4.07-3.74(m, 8H), 2.64(m, 1H), 2.10-1.17(m, 18H), 0.82(s, 3H) and 0.78(s, 3H).

3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6- (E) -hydroxyiminoandrostane was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxyandrostan-6-one according to the procedure for preparation of 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20) above. By flash chromatography (SiO)₂cyclohexane/acetone/CH₂Cl₂70/15/15) purifying the crude product.¹H-NMR(300MHz，DMSO-d₆The TMS consists of the ppm of delta 10.45(s, 1H), 4.33(s, 1H), 3.96-3.69(m, 8H), 2.96(dd, 1H), 2.02-1.08(m, 18H), 0.74(s, 3H) and 0.71(s, 3H).

The title compound II-bm was prepared in 80% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6- (E) -hydroxyiminoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/acetone/CH₂Cl₂60/20/20) purifying the residue.¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm of delta 10.72(s, 1H), 5.35(s, 1H), 3.12(dd, 1H), 2.85-1.09(m, 18H), 0.94(s, 3H) and 0.78(s, 3H).

Preparation 39

5 alpha-hydroxy-6- (E) -methoxyiminoandrostane-3, 17-dione (II-bn)

3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6- (E) -methoxyiminoandrostane was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxyandrostan-6-one (preparation 38) according to the procedure for the preparation of 6- (E) -hydroxyiminoandrostane-3, 17-dione (II-at, preparation 20) above. By flash chromatography (SiO)₂cyclohexane/acetone/CH₂Cl₂70/15/15) purifying the crude product.¹H-NMR (300MHz, acetone-d)₆The TMS consists of the ppm of delta 4.31(s, 1H), 4.05-3.76(m, 8H), 3.75(s, 3H), 3.00(dd, 1H), 2.15-1.15(m, 18H) and 0.82(s, 6H).

The title compound II-bn was prepared in 80% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6- (E) -methoxyiminoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/acetone/CH₂Cl₂60/20/20) purifying the residue.¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm delta 5.47(s, 1H), 3.75(s, 3H), 3.02(dd, 1H), 2.79(d, 1H), 2.45-1.13(m, 17H), 0.95(s, 3H) and 0.77(s, 3H).

Preparation 40

5 alpha-hydroxy-6-methylene androstane-3, 17-dione (II-bo)

At 0 ℃ and N₂While stirring a suspension of methyltriphenylphosphonium bromide (14.1g) in dry THF (240mL) was added potassium tert-butoxide (4.31 g). After stirring for 10 min, a solution of 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxyandrostan-6-one (preparation 38, 4.00g) in dry THF (77mL) was added dropwise over 0.5 h at room temperature. After 2 hours at room temperature, 5% NaH was added₂PO₄The mixture was quenched with aqueous solution and extracted with EtOAc (2X 100 mL). With 5% NaH₂PO₄The combined organic extracts were washed with aqueous, brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 80/10/10) to afford 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6-methyleneandrostane (2.40g, 60%).¹H-NMR(300MHz，DMSO-d₆δ 4.69(m, 1H), 4.51(m, 1H), 4.10(s, 1H), 3.83(m, 8H), 2.18-1.05(m, 19H), 0.73(s, 3H), 0.72(s, 3H), in ppm of TMS.

The title compound II-bo was prepared in 78% yield from 3,3:17, 17-bis (ethylenedioxy) -5 α -hydroxy-6-methyleneandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，DMSO-d₆δ 4.93(s, 1H), 4.83(m, 1H), 4.60(m, 1H), 2.83(d, 1H), 2.90-1.10(m, 18H), 0.95(s, 3H), 0.77(s, 3H), in ppm of TMS.

Preparation 41

Androstane-3, 7, 17-trione (II-bp)

A mixture of 3 β -acetoxyandrost-5-ene-7, 17-dione (7.97g) in EtOH (0.5L) and 10% Pd/C (0.80g) in H₂And stirred at atmospheric pressure for 2 hours. The mixture was filtered through celite and the filtrate was evaporated to dryness. From Et₂The crude product was crystallized from O to give 3 β -acetoxyandrostane-7, 17-dione (4.75g, 60%).¹H-NMR (300MHz, acetone-d)₆δ 4.57(m, 1H), 2.66-0.96(m, 20H), 1.96(s, 3H), 1.05(s, 3H), 0.77(s, 3H), in ppm of TMS.

To a solution of 3 β -acetoxyandrostane-7, 17-dione in MeOH (156mL) was added 5N NaOH (54 mL). After stirring for 10 minutes at room temperature, the solution is evaporated and taken up with CH₂Cl₂(2X) extraction residueAnd (4) remaining. The combined organic extracts were washed with brine, and Na ₂SO₄Dried, filtered and evaporated to dryness to give 3 β -hydroxyandrostane-7, 17-dione (1.70g, 95%).¹H-NMR (300MHz, acetone-d)₆δ 4.56(d, 1H), 3.35(m, 1H), 2.66-0.87(m, 20H), 1.02(s, 3H), 0.76(s, 3H), in ppm of TMS.

To N₂3 beta-hydroxyandrostane-7, 17-dione (1.65g), TPAP (0.100g), NMNO (1.40g) in a stirred CH₂Cl₂Solution (90mL) addition molecular sieves typePowder (2.6 g). After 0.5 h the mixture was filtered and purified by flash chromatography (SiO)₂，CH₂Cl₂) The filtrate was purified to give the title compound II-bp (1.32g, 81%).¹H-NMR (300MHz, acetone-d)₆δ 2.82-1.12(m, 20H), 1.39(s, 3H), 0.88(s, 3H), in ppm of TMS.

Preparation 42

7(E) -Hydroxyiminoandrostane-3, 17-dione (II-bq)

3,3:17, 17-bis (ethylenedioxy) androstan-7-one was prepared from 3,3:17, 17-bis (ethylenedioxy) -5-androsten-7-one in 82% yield by substituting EtOAc for EtOH, according to the procedure described above for the preparation of 3 β -acetoxyandrostan-7, 17-dione (preparation 41). By flash chromatography (SiO)₂n-hexane/EtOAc 6/4) was purified.¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm of delta 3.96-3.75(m, 8H), 2.54-1.10(m, 20H), 1.13(s, 3H) and 0.83(s, 3H).

3,3:17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane was prepared in 95% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-7-one according to the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane (preparation 20). With H₂The combined extracts were washed with Na₂SO₄Drying and evaporating to dryness. By flash chromatography (SiO)₂，CH₂Cl₂MeOH9/1) purify the crude product.¹H-NMR(300MHz，DMSO-d₆The TMS consists of the ppm of delta 10.17(s, 1H), 3.88 to 3.70(m, 8H), 2.89(m, 1H), 2.23 to 0.71(m, 19H), 0.90(s, 3H) and 0.77(s, 3H).

The title compound II-bq was prepared in 50% yield from 3,3:17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane by the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). By flash chromatography (SiO)₂n-hexane/EtOAc 6/4) was purified.¹H-NMR(300MHz，DMSO-d₆The TMS consists of the ppm of delta 10.37(s, 1H), 2.99(m, 1H), 2.58-0.67(m, 19H), 1.12(s, 3H) and 0.82(s, 3H).

Preparation 43

7(E) -Methoxyiminoandrostane-3, 17-dione (II-br)

3,3:17, 17-bis (ethylenedioxy) -7(E) -methoxyiminoandrostane was prepared in 90% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-7-one, according to the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane (preparation 20). The crude product was purified by flash chromatography (SiO) ₂，CH₂Cl₂/MeOH 9/1).¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm of delta 3.88-3.70(m, 8H), 3.69(s, 3H), 2.79(m, 1H), 2.28-0.72(m, 19H), 0.89(s, 3H) and 0.77(s, 3H).

The title compound II-br was prepared from 3,3:17, 17-bis (ethylenedioxy) -7(E) -methoxyiminoandrostane in 55% yield according to the procedure for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. By flash chromatography (SiO)₂n-hexane/EtOAc 6/4) was purified.¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm of delta 3.72(s, 3H), 2.89(m, 1H), 2.63-0.93(m, 19H), 1.12(s, 3H) and 0.82(s, 3H).

Preparation 44

7(E) -allyloxyiminoandrostane-3, 17-dione (II-bs)

3,3:17, 17-bis (ethylenedioxy) -7- (E) -allyloxyiminoandrostane was prepared in 86% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-7-one according to the procedure described above for preparation of 3,3:17, 17-bis (ethylenedioxy) -6- (E) -hydroxyiminoandrostane (preparation 20). The crude product was purified by flash chromatography (SiO)₂n-hexane/EtOAc 6/4).¹H-NMR (300MHz, acetone-d)₆The TMS consists of the ppm of delta 5.98(m, 1H), 5.23(m, 1H), 5.12(m, 1H), 4.48(m, 2H), 3.84(m, 8H), 2.98(m, 1H), 2.39-0.89(m, 19H), 1.00(s, 3H) and 0.84(s, 3H).

The title compound II-bs was prepared from 3,3:17, 17-bis (ethylenedioxy) -7(E) -allyloxyiminoandrostane in 76% yield according to the procedure for the preparation of 8 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3) above. By flash chromatography (SiO)₂n-hexane/EtOAc 6/2) was purified.¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm delta 5.99(m, 1H), 5.25(m, 1H), 5.14(m, 1H), 4.51(m, 2H), 3.10(m, 1H), 2.75-1.04(m, 19H), 1.26(s, 3H) and 0.90(s, 3H).

Preparation 45

7 alpha-hydroxyandrostane-3, 17-dione (II-bt)

At-78 ℃ and N₂While stirring a solution of 3,3:17, 17-bis (ethylenedioxy) androstan-7-one (preparation 42, 762mg) in dry THF (21mL) 1M lithium tripentyl borohydride (lithium selectride) in THF (2.34mL) was added. After the addition was complete, the mixture was stirred at-78 ℃ for 0.5 h. After warming to-50 ℃ H was carefully added dropwise₂O (7.8mL), then 6N NaOH (18.7mL) and 9.8M H were added₂O₂(3.0 mL). After stirring at room temperature for 1 hour, brine (20mL) was added. With CH₂Cl₂The mixture was extracted (2X 20 mL). Washing with brineOrganic extract of Na₂SO₄Dried, filtered and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 60/40) to give 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxyandrostane (578mg, 75%). ¹H-NMR(300MHz，DMSO-d₆δ 4.17(d, 1H), 3.79(m, 8H), 3.59(m, 1H), 1.95-1.01(m, 20H), 0.72(s, 6H), in ppm of TMS.

The title compound (II-bt) was prepared in 89% yield from 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxyandrostane according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，DMSO-d₆δ 4.34(d, 1H), 3.75(m, 1H), 2.50-1.00(m, 20H), 0.96(s, 3H), 0.78(s, 6H), in ppm of TMS.

Preparation 46

7 alpha-carboxamidoandrostane-3, 17-dione (II-bu)

3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane was prepared from 3,3:17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane (preparation 42, 1.61g) by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6 α -aminomethylandrostane (preparation 36). With H₂The combined extracts were washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂，CH₂Cl₂/MeOH/NH₄OH90/10/1) to obtain a mixture of 3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane and 3,3:17, 17-bis (ethylenedioxy) -7 β -aminoandrostane (1.19 g, ratio 35/65).

To a stirred mixture of 3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane and 3,3:17, 17-bis (ethylenedioxy) -7 β -aminoandrostane (1.17g, ratio 35/65) and Et ₃CH for N (1.67mL)₂Cl₂Solution (35mL) at 0 ℃ and N₂With the addition of 9-fluorenylMethoxycarbonyl chloride (1.39 g). After stirring overnight at room temperature, water was added and CH added₂Cl₂The mixture is extracted. With 5% NaHCO₃The organic phase is washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-Hexane/EtOAc 70/30) purifying the residue to obtain [3,3:17, 17-bis (ethylenedioxy) -androstan-7 a-yl]Carbamic acid 9H-fluoren-9-ylmethyl ester (505mg, 28%)¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.90-6.90 (m, 9H), 4.46-4.10(m, 3H), 3.90-3.60(m, 9H), 1.90-1.00(m, 20H), 0.75(s, 6H).

[3,3:17, 17-bis (ethylenedioxy) androstan-7 alpha-yl group at 0 ℃ with stirring]A solution of 9H-fluoren-9-ylmethyl carbamate (464mg) in dry THF (29mL) was added 1M tetrabutylammonium fluoride in THF (5.21 mL). After stirring for 4 hours at room temperature, the solution was concentrated to a smaller volume and subjected to flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26%NH₄OH92/8/0.8) to give 3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane (247mg, 84%)¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS, delta 3.77(m, 8H), 2.84(m, 1H), 1.90-1.05(m, 22H), 0.74(s, 6H).

3,3:17, 17-bis (ethylenedioxy) -7 α -carboxamidoandrostane was prepared in 92% yield from 3,3:17, 17-bis (ethylenedioxy) -7 α -aminoandrostane by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6 α -carboxamidoandrostane (II-bc, preparation 28). ¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm delta 8.23(dd, 1H), 7.97(d, 1H), 4.00-3.70(m, 8H), 1.85-1.05(m, 20H), 0.76(s, 3H) and 0.74(s, 3H) of TMS.

The title compound II-bu was prepared from 3,3:17, 17-bis (ethylenedioxy) -7 α -carboxamidoandrostane in 97% yield according to the procedure described above for the preparation of 70 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). By flash chromatography (SiO)₂N-hexane/acetone 70/30).¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm of delta 8.18(dd, 1H), 7.97(d, 1H), 4.13(m, 1H) and 2.90-0.95(m，20H)，1.00(s，3H)，0.79(s，3H)。

Preparation 47

7-Methyleneandrostane-3, 17-dione (II-bv)

3,3:17, 17-bis (ethylenedioxy) -7-methyleneandrostane was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) androstane-7-one (preparation 42) by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane (preparation 8). With H₂The combined extracts were washed with Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆δ 4.67(m, 1H), 4.60(m, 1H), 3.86(m, 8H), 2.12-0.75(m, 20H), 0.97(s, 3H), 0.86(s, 3H), in ppm of TMS.

The title compound II-bv can be prepared from 3,3:17, 17-bis (ethylenedioxy) -6-methyleneandrostane in 87% yield by reference to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). By H ₂The combined organic extracts were washed with Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.4.78 (m, 1H), 4.76(m, 1H), 2.53-0.88(m, 20H), 1.23(s, 3H), 0.91(s, 3H).

Preparation 48

7 beta-methyl androstane-3, 17-dione (II-bw)

Will be contained in CH₂Cl₂(52mL) of a mixture of 3,3:17, 17-bis (ethylenedioxy) -7-methyleneandrostane (II-bw, preparation 47) (520mg) and (1, 5-cyclooctadiene) (pyridine) (tricyclo-hexylphosphine) iridium (1) -hexafluorophosphate (Crabtree catalyst) (75mg) in H₂And stirred at atmospheric pressure for 4 hours. The mixture was evaporated to dryness and purified by flash chromatography (SiO)₂n-Hexane/EtOAc 85/15) to give 3,3:17, 17-bis (ethylenedioxy) -7 β -methylandrostane (287mg, 55%).¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.3.48 (m, 8H), 1.95-0.65(m, 21H), 0.97(d, 3H),0.84(s, 3H), 0.81(s, 3H).

The title compound II-bw was prepared from 3,3:17, 17-bis (ethylenedioxy) -7 β -methylandrostane in 90% yield according to the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d) ₆From ppm of TMS,. delta.2.50-0.82 (m, 21H), 1.07(d, 3H),1.06(s, 3H), 0.88(s, 3H).

Preparation 49

7 alpha-hydroxymethyl androstane-3, 17-dione (II-bx) and 7 beta-hydroxymethyl-androstane-3, 17- Diketones (II-by)

3,3:17, 17-bis (ethylenedioxy) -7 β -hydroxymethylandrostane and 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxymethylandrostane were prepared in 10% and 70% yields, respectively, from 3,3:17, 17-bis (ethylenedioxy) -7-methyleneandrostane (preparation 48) by the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6 β -hydroxymethyl-androstane (preparation 9). By flash chromatography (SiO)₂hexane/EtOAc 60/40) purification of the residue 3,3:17, 17-bis (ethylenedioxy) -7 β -hydroxy-methylandrostane:¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.84 (m, 8H), 3.58(m, 2H), 3.32(t, 1H), 1.94-0.68(m, 21H), 0.85(s, 3H), 0.81(s, 3H). 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxymethylandrostane:¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.3.83 (m, 8H), 3.67(m, 2H), 3.34(t, 1H), 1.97-0.91(m, 21H), 0.87(s, 3H), 0.81(s, 3H).

7 α -Hydroxymethylandrostane-3, 17-dione (II-bx) was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxymethylandrostane according to the procedure described above for the preparation of 6 α -cyano-androstane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.4.30 (t, 1H), 3.48(m, 2H), 2.46-0.95(m, 21H), 1.00(s, 3H), 0.78(s, 3H)

7 β -hydroxymethylandrostane-3, 17-dione (II-by) was prepared in 85% yield from 3,3:17, 17-bis (ethylenedioxy) -7 β -hydroxymethylandrostane according to the procedure described above for the preparation of 6 α -cyano-androstane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with water and Na₂SO₄Dried and evaporated to dryness.¹H-NMR (300MHz, acetone-d)₆From ppm of TMS,. delta.3.66 (m, 2H), 3.64(t, 1H), 2.51-0.80(m, 21H), 1.07(s, 3H), 0.89(s, 3H).

Preparation 50

7- (Spirocyclopropane) androstane-3, 17-dione (II-bz)

7- (Spirocyclopropane) androstane-3, 17-dione (II-bz) was prepared in 45% yield from 3,3:17, 17-bis (ethylenedioxy) -7-methyleneandrostane (preparation 47) according to the procedure for preparation of 6- (spirocyclopropane) androstane-3, 17-dione (II-bj, preparation 35) above. By flash chromatography (SiO)₂n-hexane/EtOAc/acetone 10/1/1).¹H-NMR (300MHz, acetone-d)₆The TMS consists of ppm of delta 2.52-0.03(m, 24H), 1.15(s, 3H) and 0.87(s, 3H).

Preparation 51

6- (Z) -hydroxyimino-7 alpha-hydroxyandrostane-3, 17-dione (II-ca)

A dry THF solution (15mL) of trimethylchlorosilane (3.7mL) and LDA (15.6mL, 1.5M in THF) was added dropwise over 30 minutes at-78 deg.C under nitrogen to a THF solution (15mL) of 3,3:17, 17-bis (ethylenedioxy) -androstan-6-one (1.43g) at-78 deg.C. After 2 hours at the same temperature, TEA (7.3mL) was added and after 30 minutes solid NaHCO was added₃Finally extracted with EtOAc (3 ×). Washing the combined with brineOrganic extract (3X), with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtOAc 90/10) to yield 3,3:17, 17-bis (ethylenedioxy) -6-trimethylsiloxy androst-6-ene (1.35g, 80%).¹H-NMR (300MHz, acetone-d)₆δ 4.67(1H, m), 3.94-3.76(8H, m), 2.31(1H, m), 2.00-0.90(17H, m), 0.86(3H, s), 0.83(3H, s), 0.17(9H, s), in ppm of TMS.

To 3,3:17, 17-bis (ethylenedioxy) -6-trimethyl-siloxan androst-6-ene (940mg) in CH with stirring at-15 deg.C₂Cl₂Solution (50mL) solid NaHCO was added₃(683mg) then mCPBA (550mg, 70%) was added. After 1 hour TBAF (2.56g) was added and the mixture was warmed to room temperature. After 1 hour the mixture was quenched with brine and CH₂Cl₂And (4) extracting. The combined organic extracts were washed with water and Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 60/40) to give 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxyandrostan-6-one (660mg, 80%).¹H-NMR(300MHz，dmso-d₆From the ppm of TMS,. delta.5.63 (1H, d), 3.90-3.70(8H, m), 3.53(1H, m), 3.13(1H, m), 2.00-1.00(17H, m), 0.74(3H, s), 0.62(3H, s).

3,3:17, 17-bis (ethylenedioxy) -6- (Z) -hydroxyiminoandrostan-7 α -ol (628mg, 92%) was prepared from 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxyandrostan-6-one (660mg) according to the procedure for preparation of 3,3:17, 17-bis (ethylenedioxy) -6- (E) -hydroxyiminoandrostane (preparation 20) above. With H₂The combined organic extracts were washed with Na₂SO₄Dried and evaporated to dryness. The residue was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.42 (1H, s), 4.90(1H, d), 4.80(1H, m), 3.90-3.75(8H, m), 2.75(1H, m), 1.90-1.00(17H, m), 0.73(3H, s), 0.61(3H, s).

The title compound II-ca (500mg, 60%) was found to refer to 6- (E) -hydroxyiminoandrostanePreparation of the stanol-3, 17-dione (II-h, preparation 18) prepared from 3,3:17, 17-bis (ethylenedioxy) -6- (Z) -hydroxyimino-7 α -hydroxyandrostan-6-one (628 mg). The combined organic extracts were washed with brine, Na ₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/acetone/CH₂Cl₂40/30/30) purifying the residue.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.76 (1H, s), 5.14(1H, d), 5.02(1H, m), 2.84(1H, m), 2.70-1.10(17H, m), 0.85(3H, s), 0.78(3H, s).

Preparation 52

6 alpha-hydroxymethyl androstane-3, 7, 17-trione (II-cb)

3,3:17, 17-bis (ethylenedioxy) -7-trimethylsiloxyandrost-6-ene (1.82g, 84%) was prepared from 3,3:17, 17-bis (ethylenedioxy) androstan-7-one (1.86g) according to the procedure described above for the preparation of 3,3:17, 17-bis (ethylenedioxy) -6-trimethylsiloxyandrost-6-ene (preparation 51). With H₂The combined extracts were washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 92/8) to yield 3,3:17, 17-bis (ethylenedioxy) -6-trimethylsiloxy androst-6-ene (1.35g, 80%).¹H-NMR(300MHz，DMSO-d₆δ 4.35(1H, m), 3.90-3.70(8H, m), 2.20-2.05(1H, m), 1.90-0.90(17H, m), 0.79(3H, s), 0.69(3H, s), 0.15(9H, s) in ppm TMS.

To a solution of 2, 6-diphenylphenol (3.8g) in DCM (50mL) was added trimethylaluminum (4mL, 2M in hexanes). After 1 hour the temperature was adjusted to 0 ℃ and a solution of trioxane (231mg) in DCM (1mL) was added. After 1 hour the mixture was cooled to-78 ℃ and a solution of 3,3:17, 17-bis (ethylenedioxy) -7-trimethylsiloxy-androst-6-ene (1.21g) in DCM (15mL) was added. After stirring overnight at-20 ℃ NaHCO was added ₃The reaction was terminated with saturated aqueous solution. The mixture was filtered through a pad of celite and washed with DCM. The filtrate was washed with water and Na₂SO₄Dried and evaporated to a smaller volume. TBAF (2.8mL of 1M in THF) was added and the mixture was stirred at room temperature for 1.5 h. The solution was washed with water and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂hexane/EtOAc 30/70) to give 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostan-7-one (783mg, 72%).¹H-NMR(300MHz，DMSO-d₆δ 4.05(1H, t), 3.90-3.70(8H, m), 3.50(2H, m), 2.45-2.28(2H, m), 2.10-1.95(1H, m), 1.90-1.10(16H, m), 1.05(3H, s), 0.75(3H, s), in ppm of TMS.

The title compound II-cb (570mg, 92%) was prepared from 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostan-7-one (780mg) by following the procedure described above for the preparation of 6 α -cyanoandrostane-3, 17-dione (II-ac, preparation 3). The combined organic extracts were washed with brine, and Na₂SO₄Dried and evaporated to dryness. The residue was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆δ 4.25(1H, t), 3.55(2H, m), 2.51(2H, m), 2.10(1H, m), 1.90-1.10(16H, m), 0.95(3H, s), 0.80(3H, s), in ppm of TMS.

Preparation 53

3-N-Methylaminoethoxyamine dihydrochloride (III-a)

To a vigorously stirred DMSO suspension (200mL) of potassium hydroxide (19.7g) was added benzophenone oxime (20.2 g). A DMSO solution (40mL) of N-methyl-2-chloroethylamine hydrochloride (5.2g) was added dropwise. After 2.5 h at room temperature, the reaction was poured into ice/water (400mL), acidified to pH2.5 with 37% HCl, and Et₂And O washing. The aqueous layer was treated with powdered KOH to pH10 and Et₂Extracting for three times; the combined organic layers were washed with water, brine, and Na₂SO₄Dry and evaporate the solvent to dryness. By flash chromatography (SiO)₂，CHCl₃MeOH AcOH purification from 9:1:0.1 to 7:3:0.3) gave benzophenone O- (2-N-methylaminoethyl) oxime (4.65g, 62%) as a thick oil.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.51-7.25 (10H, m), 4.13(2H, t), 2.72(2H, t), 2.26(3H, s), 1.60(1H, bb).

Benzophenone O- (2-N-methylaminoethyl) oxime (4.65g) was suspended in 6N HCl (24mL), and the mixture was refluxed for 2 hours. The reaction was cooled and Et₂And (4) extracting. The aqueous layer was evaporated to dryness to give the title compound III-a (1.78g, 80%) as a hygroscopic white solid.¹H-NMR(300MHz，DMSO-d₆In ppm TMS,. delta.10.5 (5H, bb), 4.26(2H, t), 3.22(2H, t), 2.55(3H, s).

Preparation 54

3-N-methylaminopropoxyamino dihydrochloride (III-b)

Benzophenone O- (3-N-methylaminopropyl) oxime was prepared from benzophenone oxime and N-methyl-3-chloropropylamine hydrochloride in a yield of 62% according to the above-mentioned preparation procedure of benzophenone O- (2-N-methylaminoethyl) oxime (preparation 53).¹H-NMR(300MHz，DMSO-d₆In ppm TMS,. delta.9.20 (2H, bb), 7.37(10H, m), 4.14(2H, t), 2.70(2H, t), 2.36(3H, s), 1.87(2H, m), 1.83(3H, s).

The title compound III-b was prepared from benzophenone O- (3-N-methylaminopropyl) oxime in 80% yield according to the above-mentioned preparation method of 2-N-methylaminoethoxyamino dihydrochloride (III-a, preparation 53).¹H-NMR(300MHz，DMSO-d₆δ 11.08(3H, bb), 9.10(2H, bb), 4.10(2H, t), 2.91(2H, m), 2.50(3H, s), 1.96(2H, m), in ppm of TMS.

Preparation 55

Cis-4-aminocyclohexyloxyamino dihydrochloride (III-c)

To a solution of trans-4-aminocyclohexanol hydrochloride (2.00g) and triethylamine (3.90mL) cooled to 0 deg.C in MeOH (20mL) was added di-tert-butyl dicarbonate (3.12 g).After stirring at room temperature for 6 hours, the solvent was evaporated to dryness. By CH₂Cl₂The residue was dissolved, washed with water and the organic phase was evaporated to dryness. The crude trans-4- (tert-butoxycarbonyl) aminocyclohexanol (2.51g, 90%) was used directly in the next step. ¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.64 (1H, d), 4.47(1H, d), 3.28(1H, m), 3.12(1H, m), 1.73(4H, m), 1.35(9H, s), 1.13(4H, m).

To a solution of trans-4- (tert-butoxycarbonyl) aminocyclohexanol (2.50g), triphenylphosphine (6.55g) and N-hydroxyphthalimide (1.63g) in THF (130mL) cooled to 0 deg.C was added diisopropyl azocarboxylate (5.4mL) dropwise. After stirring for 6 hours, the solvent is evaporated and flash chromatography (SiO)₂Hexane EtOAc7:3) purification of the crude product to obtain tert-butyl cis-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy]Cyclohexyl carbamate (2.00g, 50%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.84 (4H, m), 6.88(1H, d), 4.25(1H, m), 3.31(1H, m), 1.40-2.00(8H, m), 1.36(9H, s).

To tert-butyl cis-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy)]-Cyclohexylcarbamate (2.00g) in MeOH (23mL) hydrazine (26% in water, 1.1mL) was added. After stirring at room temperature for 30 minutes, the mixture was filtered. The filtrate was evaporated to dryness and purified by flash chromatography (SiO)₂，CH₂Cl₂MeOH9:1) gave cis-4- (tert-butoxycarbonyl) aminocyclohexyloxyamino (0.80g, 63%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.73 (1H, d), 5.75(2H, bb), 3.45(1H, m), 3.21(1H, m), 1.30-1.90(8H, m), 1.36(9H, s).

Cis-4- (tert-butoxycarbonyl) aminocyclohexylamino (0.80g) was dissolved in 5M HCl in EtOAc (20 mL). After 1 hour the solvent was removed under reduced pressure to give the title compound III-c as a white solid (0.64g, 99%).¹H-NMR(300MHz，DMSO-d₆δ 11.03(3H, bb), 8.08(3H, bb), 4.26(1H, m), 3.02(1H, m), 1.50-2.10(8H, m), in ppm of TMS.

Preparation 56

cis-2-Aminocyclopentyl-1-aminooxy dihydrochloride (III-d)

With reference to the procedure described in preparation 55, trans-2- (tert-butoxycarbonyl) aminocyclopentan-1-ol (9.20g, 97%) was obtained starting from trans-2-aminocyclopentan-1-ol hydrochloride (3.00g), which was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.70 (1H, d), 4.59(1H, d), 3.75(1H, m), 3.47(1H, m), 1.36(9H, s), 1.20-1.90(6H, m).

Starting from trans-2- (tert-butoxycarbonyl) aminocyclopentan-1-ol (2.50g) flash chromatography (SiO) was carried out according to the procedure described for preparation 55₂，CH₂Cl₂Then CH₂Cl₂EtOAc from 99:1 to 98:2) to yield tert-butyl cis-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy]Cyclopentyl carbamate (3.50g, 83%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.85 (4H, m), 6.66(1H, d), 4.63(1H, m), 3.78(1H, m), 1.31(9H, s), 1.30-2.00(6H, m).

With reference to the procedure described in preparation 55, starting from tert-butyl cis-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy]Cyclopentyl carbamate (2.50g) can be initially purified by flash chromatography (SiO)₂，CH₂Cl₂EtOAc95:5) to yield cis-2- (tert-butoxycarbonyl) amino-1-cyclopentyl-oxoamine (1.36g, 63%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.49 (1H, d), 5.92(2H, bb), 3.80(1H, m), 3.69(1H, m), 1.37(9H, s), 1.30-1.80(6H, m).

Starting from cis-2- (tert-butoxycarbonyl) amino-1-cyclopentyloxyamino (1.36g), the title compound III-d was obtained as a white solid (1.10g, 92%) following the procedure described for preparation 55.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS) delta 9.00-12.00(6H,bb)，4.59(1H，m)，3.63(1H，m)，1.50-2.00(6H，m)。

preparation 57

Trans-2-aminocyclopentyloxyamino dihydrochloride (III-e)

To a THF solution (90mL) of trans-2- (tert-butoxycarbonyl) aminocyclopentan-1-ol (preparation 47, 3.00g) triphenylphosphine (5.90g) and 4-nitrobenzoic acid (2.50g) was added diisopropyl azocarboxylate (4.50mL) at 0 ℃. After stirring for 4 hours, the solvent was evaporated and purified by flash chromatography (SiO)₂，CH₂Cl₂Acetone 99:1) to give cis-2- (tert-butoxycarbonyl) amino-1- (4-nitrobenzoyloxy) cyclopentane (3.70g, 70%). ¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.8.33 (2H, d), 8.23(2H, d), 7.08(1H, d), 5.25(1H, m), 3.92(1H, m), 1.40-2.10(6H, m), 1.28(9H, s).

To a solution (20mL) of cis-2- (tert-butoxycarbonyl) amino-1- (4-nitrobenzoyl-oxy) cyclopentane (3.70g) in a mixture of methanol/water 1:1 was added potassium carbonate (2.37g) at room temperature and stirred overnight. Water was added and the mixture was extracted with diethyl ether. The combined organic layers were separated over Na₂SO₄Dried and evaporated to dryness to give cis-2- (tert-butoxycarbonyl) amino-cyclopentan-1-ol (1.94g, 91%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.09 (1H, d), 4.54(1H, bb), 3.86(1H, m), 3.53(1H, m), 1.30-1.80(6H, m), 1.37(9H, s).

Starting from cis-2- (tert-butoxycarbonyl) aminocyclopentan-1-ol (0.97g) flash chromatography (SiO) was performed according to the procedure described for preparation 55₂，CH₂Cl₂Acetone 99:1) to obtain tert-butyl trans-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy]Cyclopentyl carbamate (1.30g, 78%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.84 (4H, m), 6.95(1H, d), 4.59(1H, m), 3.93(1H, m), 1.30-2.10(6H, m), 1.17(9H,s)。

with reference to the procedure described in preparation 55, starting from tert-butyl trans-4- [ (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) oxy ]Cyclopentyl carbamate (1.30g) can be initially purified by flash chromatography (SiO)₂，CH₂Cl₂Methanol 99:1) trans-2- (tert-butoxycarbonyl) amino-1-cyclopentyl-aminoxy (0.75mg, 100%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.6.86 (1H, d), 4.25(1H, m), 3.73(1H, m), 1.30-1.90(6H, m), 1.77(3H, s), 1.73(3H, s), 1.36(9H, s).

Starting from trans-2- (tert-butoxycarbonyl) amino-1-cyclopentyloxyamino (745mg) according to the procedure described for preparation 55, flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) to yield the title compound III-e (0.51g, 90%).¹H-NMR(300MHz，DMSO-d₆δ 11.00(3H, bb), 8.48(3H, bb), 4.66(1H, m), 3.60(1H, m), 1.50-2.10(6H, m), in ppm of TMS.

Preparation 58

3 beta- (5-aminopentyl) androstane-6, 17-dione hydrochloride

With reference to the procedure of EP0825197A2, starting from androstane-3, 6, 17-trione (3.90g) flash chromatography (SiO₂;CH₂Cl₂EtOAc9:1) obtained after isolation 3 beta-formylandrostane-6, 17-dione (2.40g, 62%) and 3 alpha-formylandrostane-6, 17-dione (0.78g, 20%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. beta. -isomers,. delta.9.57 (1H, d), 2.45-1.10(21H, m), 0.78(3H, s), 0.63(3H, s);. alpha. -isomers,. delta.9.56 (1H, bs), 2.60-0.95(21H, m), 0.76(3H, s), 0.60(3H, s).

Et under nitrogen atmosphere₂Potassium hydride (20% in mineral oil, 245mg) was carefully washed. Anhydrous THF (4mL), 1,1,1,3,3, 3-hexamethyldisilylamine (200mg), and (4-azido-butyl) triphenylphosphonium bromide (537mg) were added at-78 ℃. Completion of dissolutionThereafter, a solution of 3 β -formylandrostane-6, 17-dione (350mg) in THF (8mL) was added and the reaction mixture was warmed from-78 deg.C to room temperature over 5 hours. The mixture was poured into 5% NaHCO₃Aqueous and extracted with EtOAc. The combined organic layers were dried, evaporated to dryness and subjected to flash chromatography (SiO)₂Hexane, CH₂Cl₂Acetone 70:15:15) to give (Z)3 β - (5-azidopent-1-enyl) androstane-6, 17-dione (215mg, 50%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.5.31 (2H, m), 3.34(2H, t), 2.50-1.15(25H, m), 0.87(3H, s), 0.76(3H, s).

A suspension of (Z)3 β - (5-azidopent-1-enyl) androstane-6, 17-dione (160mg) and 5% Pd/C (10mg) in absolute EtOH (10mL) and 1N hydrochloric acid (0.4mL) was stirred at room temperature under 1 atmosphere of hydrogen for 1 hour. The mixture was filtered through celite and the filtrate was evaporated to dryness. With EtOAc and Et₂The crude product was washed with O to purify to give 120mg (75%) of 3 β - (5-aminopentyl) androstane-6, 17-dione hydrochloride as a white solid. ¹H-NMR(300MHz，DMSO-d₆δ 7.68(2H, bb), 2.73(2H, m), 2.50-0.85(29H, m), 0.77(3H, s), 0.63(3H, s), in ppm of TMS.

Preparation 59

(Z)3 beta- (5-aminopent-1-enyl) androstane-6, 17-dione hydrochloride

To a solution of (Z)3 β - (5-azidopent-1-enyl) androstane-6, 17-dione (preparation 58, 145mg) in THF (7mL) was added triphenylphosphine (100mg) and water (11 μ L), and the mixture was stirred at room temperature for 2 days. Evaporating to obtain crude product and performing flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1 followed by CH₂Cl₂:MeOH:NH₃7:3:0.3) purification. The solvent was evaporated to reduce volume to remove ammonia, then 1N hydrochloric acid: the precipitate was obtained and filtered to give (Z)3 β - (5-aminopent-1-enyl) androstane-6, 17-dione hydrochloride (115mg, 85%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.78 (3H, bb), 5.25(2H, m), 2.73 (b) ((2H, m))2H，m)，2.55-1.05(25H，m)，0.78(3H，s)，0.67(3H，s)。

Preparation 60

3 beta- (4-aminobutyl) androstane-6, 17-dione hydrochloride

Starting from (3-azidopropyl) triphenylphosphonium bromide (520mg) the procedure described in reference to preparation 58 was carried out in flash chromatography (SiO)₂N-hexane and CH₂Cl₂Acetone 70:15:15) to give (Z)3 β - (4-azidobut-1-enyl) androstane-6, 17-dione (292mg, 72%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.5.36 (2H, m), 3.33(2H, t), 2.50-1.20(25H, m), 0.87(3H, s), 0.76(3H, s).

3 β - (4-amino-butyl) androstane-6, 17-dione hydrochloride (290mg), 3 β - (4-amino-butyl) androstane-6, 17-dione hydrochloride (228mg, 74%) was obtained as a white solid starting with (Z)3 β - (4-azidobut-1-enyl) androstane-6, 17-dione hydrochloride (290 mg).¹H-NMR(300MHz，DMSO-d₆δ 7.76(3H, bb), 2.74(2H, m), 2.50-0.85(27H, m), 0.77(3H, s), 0.63(3H, s), in ppm of TMS.

Preparation 61

(Z)3 beta- (4-aminobut-1-enyl) androstane-6, 17-dione hydrochloride

Prepared starting from (Z)3 β - (4-azidobut-1-enyl) androstane-6, 17-dione (preparation 60, 415mg) by the procedure described with reference to preparation 59. After evaporation of the solvent, purification by flash chromatography (SiO)₂;CH₂Cl₂MeOH9:1 followed by CH₂Cl₂:MeOH:NH₃6:4:0.4) the crude product. The solvent was evaporated to reduce the volume and 1N HCl was added. The precipitate was filtered to give the title compound (300mg, 71%). 1H-NMR (300MHz, DMSO-d)₆From ppm of TMS,. delta.7.80 (3H, bb), 5.38(1H, m), 5.23(1H, m), 2.75(2H, m), 2.55-1.10(23H，m)，0.78(3H，s)，0.67(3H，s)。

Preparation 62

3 alpha- (5-aminopentyl) androstane-6, 17-dione hydrochloride

To a solution of (4-azidobutyl) triphenylphosphonium bromide (750mg) in THF (5mL) was added lithium bis (trimethylsilyl) amide (1M in THF, 1.7mL) at-5 deg.C, and the reaction mixture was stirred to complete the dissolution. 3 α -formylandrostane-6, 17-dione (preparation 46, 490mg) was added and the reaction mixture was warmed from-78 ℃ to room temperature over 5 hours. The mixture was poured into 5% NaHCO ₃Aqueous and extracted with EtOAc. The combined organic layers were washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂Hexane, CH₂Cl₂Acetone 70:15:15) to give (Z)3 α - (5-azidopent-1-enyl) androstane-6, 17-dione (265mg, 43%).¹H-NMR (300MHz, acetone-d)₆δ 5.79(1H, m), 5.34(1H, m), 3.35(2H, t), 2.85(1H, m), 2.60-1.20(24H, m), 0.87(3H, s), 0.79(3H, s), in ppm of TMS.

Starting with (Z)3 α - (5-azidopent-1-enyl) androstane-6, 17-dione (60mg) following the procedure described for preparation 58 gave the title compound as a white solid (45mg, 75%).¹H-NMR(300MHz，DMSO-d₆δ 7.70(3H, bb), 2.73(2H, m), 2.50-1.10(29H, m), 0.77(3H, s), 0.67(3H, s), in ppm of TMS.

Preparation 63

(Z)3 alpha- (5-Aminopent-1-enyl) androstane-6, 17-dione

Starting with (Z)3 α - (5-azidopent-1-enyl) androstane-6, 17-dione (preparation 62, 250mg), starting with the procedure described in preparation 59, the title compound was obtained as a white solid (220mg, 86%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS) < delta > 7.87(3H, bb), 5.74(1H，m)，5.26(1H，m)，2.74(3H，m)，2.55-1.10(24H，m)，0.78(3H，s)，0.69(3H，s)。

Preparation 64

3 alpha- (4-aminobutyl) androstane-6, 17-dione hydrochloride

Starting from (3-azidopropyl) triphenylphosphonium bromide (713mg), flash chromatography (SiO) can be performed according to the procedure described in preparation 58 ₂N-hexane CH₂Cl₂Acetone 70:15:15) to obtain (Z)3 α - (4-azidobut-1-enyl) androstane-6, 17-dione (350mg, 60%) as a solid.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.88 (1H, m), 5.38(1H, m), 3.35(2H, t), 2.98(1H, m), 2.60-1.20(22H, m), 0.87(3H, s), 0.79(3H, s).

Starting with (Z)3 α - (4-azidobut-1-enyl) androstane-6, 17-dione (35mg) following the procedure described in preparation 58 gave 3 α - (4-aminobutyl) androstane-6, 17-dione hydrochloride (32mg, 89%) as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 7.79(3H, bb), 2.74(2H, m), 2.50-1.15(27H, m), 0.77(3H, s), 0.67(3H, s), in ppm of TMS.

Preparation 65

(Z)3 alpha- (4-aminobut-1-enyl) androstane-6, 17-dione hydrochloride

Starting with (Z)3 α - (4-azidobut-1-enyl) androstane-6, 17-dione (preparation 64, 60mg) following the procedure described in preparation 59 gave the title compound as a white solid (50mg, 80%).¹H-NMR(300MHz，DMSO-d₆δ 7.77(3H, bb), 5.84(1H, m), 5.28(1H, m), 2.74(3H, m), 2.55-1.10(22H, m), 0.78(3H, s), 0.70(3H, s), in ppm of TMS.

Preparation 66

(Z)3 alpha- (6-aminohex-1-enyl) androstane-6, 17-dione hydrochloride

Starting from (3-azidopentyl) triphenylphosphonium bromide (600mg), flash chromatography (SiO) can be performed according to the procedure described in preparation 58₂Hexane: CH₂Cl₂Acetone 70:15:15) to obtain (Z)3 α - (4-azidohex-1-enyl) androstane-6, 17-dione (240mg, 40%) as a solid.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.5.75 (1H, m), 5.34(1H, m), 3.34(2H, t), 2.92-1.21(27H, m), 0.87(3H, s), 0.79(3H, s).

The title compound was prepared starting from (Z)3 α - (6-azidohex-1-enyl) androstane-6, 17-dione (133mg) by the procedure described for preparation 58. The crude product was purified by flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃92:8:0.8) purifying; the eluate was concentrated to reduce volume, acidified with 1N HCl and the solvent evaporated to dryness. (Z)3 α - (6-aminohex-1-enyl) androstane-6, 17-dione hydrochloride was obtained as a white solid (60mg, 44%).¹H-NMR(300MHz，DMSO-d₆δ 7.73(3H, bb), 5.71(1H, m), 5.26(1H, m), 2.74(3H, m), 2.56-1.12(26H, m), 0.78(3H, s), 0.69(3H, s), in ppm of TMS.

Preparation 67

5- (5 alpha-hydroxy-17-keto-androstan-3 alpha-yl) pent-4- (Z) -en-1-ylcarbamic acid 9H- Fluoren-9-ylmethyl ester

Referring to the 5 α -hydroxyandrostan-3, 17-dione (II-ad, preparation 4) preparation procedure, starting from 17,17- (ethylenedioxy) -5-androsten-3 β -ol, after epoxidation with mCPBA, reduction with LAH and oxidation with IBX, 17- (ethylenedioxy) -5 α -hydroxyandrostan-3-one can be obtained in 55% yield. ¹H-NMR(300MHz，DMSO-d₆δ 4.29(s, 1H), 3.78(m, 4H), 2.69-1.10(m, 21H), 1.07(s, 3H), 0.76(s, 3H), in ppm of TMS.

17,17- (Ethoxydioxy) -3-methylene-androstan-5 α -ol was obtained in 98% yield starting with 17,17- (Ethoxy) -5 α -hydroxyandrostan-3-one and following the procedure for the preparation of 3,3:17, 17-bis (Ethoxy) -6-methyleneandrostane (preparation 8) above.¹H-NMR(300MHz，DMSO-d₆δ 4.62(m, 1H), 4.50(m, 1H), 3.78(m, 4H), 3.42(s, 1H), 2.36-1.03(m, 21H), 0.93(s, 3H), 0.75(s, 3H), in ppm of TMS.

17,17- (Ethoxydioxy) -3 α -hydroxymethylandrostane-5 α -ol was obtained in 98% yield starting with 17,17- (Ethoxy) -3-methyleneandrostane-5 α -ol according to the procedure described above for the preparation of 3,3:17, 17-bis (Ethoxy) -6 β -hydroxymethylandrostane (preparation 9).¹H-NMR(300MHz，DMSO-d₆δ 4.44(t, 1H), 3.81(s, 1H), 3.76(m, 4H), 3.58(m, 1H), 3.39(m, 1H), 1.91-0.97(m, 22H), 0.87(s, 3H), 0.74(s, 3H), in ppm of TMS.

A DMSO solution of 17,17- (ethylenedioxy) -3 α -hydroxymethylandrostan-5 α -ol (1.04g) and IBX (1.20g) (14.3mL) was stirred at room temperature for 1 hour, then H was added at room temperature₂The reaction was stopped with O (250 mL). After stirring for 15 minutes, the mixture was filtered and washed with H ₂The filter cake was washed with O (3X50mL) and acetone/MeOH 1/1. With Et₂O/EtOAc70/30(3X50mL) extracted the aqueous phase. With Na₂SO₄The combined organic extracts were dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 80/10/10) to give 17,17- (ethylenedioxy) -5 α -hydroxyandrostane-3 α -carboxaldehyde hemiacetal (0.90g, 88%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.5.87 (d, 1H), 4.96(d, 1H), 3.77(m, 4H), 1.98-1.01(m, 22H), 0.84(s, 3H), 0.73(s, 3H).

Reference was made to the above-mentioned preparation of 6-methyleneandrostane-3, 17-dione (II-ah, preparation 8) starting from 17,17- (ethylenedioxy) -5 α -hydroxyandrostane-3 α -carboxaldehyde hemiacetal and triphenyl-3-cyanopropylphosphonium bromide. By flash chromatography (SiO)₂n-hexane/CH₂Cl₂Acetone 80/10/10) the crude product was purified to give 17,17- (ethylenedioxy) -3 α - (4-cyanobutyl-1- (Z) -enyl) androstan-5 α -ol and 17,17- (ethylenedioxy) -3 α - (4-cyanobutyl-1- (E) -enyl) androstan-5 α -ol (85/15 mixture) in 73% yield.¹H-NMR(300MHz，DMSO-d₆δ 6.21(m, 1H), 5.07(m, 1H), 3.78(m, 4H), 3.47(s, 1H), 2.73-1.00(m, 26H), 0.88(s, 3H), 0.74(s, 3H), in ppm of TMS.

To a stirred solution of 17,17- (ethylenedioxy) -3 α - (4-cyanobutyl-1- (Z) -alkenyl) androstan-5 α -ol and 17,17- (ethylenedioxy) -3 α - (4-cyanobutyl-1- (E) -alkenyl) androstan-5 α -ol (85/15 mixture, 1.00g) in absolute EtOH (100mL) was added a small piece of Na (5.56g) at reflux over 2.45 hours. The mixture was continued to reflux for 3 hours. After cooling to 0 ℃ 5% NaH was carefully added ₂PO₄The mixture was quenched with aqueous solution and then adjusted to pH 8 by the addition of 1N HCl. With CH₂Cl₂The mixture was extracted (2x300 mL). The combined organic extracts were washed with brine, dried, filtered and evaporated to dryness to give 17,17- (ethylenedioxy) -3 α - (5-aminopent-1- (Z) -enyl) androstan-5 α -ol and 17,17- (ethylenedioxy) -3 α - (5-aminopent-1- (E) -enyl) androstan-5 α -ol (85/15 mixture, 0.93g, 92%).¹H-NMR(300MHz，DMSO-d₆δ 6.05(m, 1H), 5.08(m, 1H), 3.77(m, 4H), 3.44(s, 1H), 2.73-0.99(m, 30H), 0.87(s, 3H), 0.74(s, 3H), in ppm of TMS.

Reference is made to the above-mentioned [3,3:17, 17-bis (ethylenedioxy) androstan-7 alpha-yl group]Preparation of 9H-fluoren-9-ylmethyl carbamate (preparation 46) A procedure was performed from 17,17- (ethylenedioxy) -3 α - (5-aminopent-1- (Z) -enyl) androstan-5 α -ol and 17,17- (ethylenedioxy) -3 α - (5-aminopent-1- (E) -enyl) androstan-5 α -ol (85/15 mixture). By flash chromatography (SiO)₂n-Hexane/EtOAc 80/20) purification of the crude product gave 5- [17,17- (ethylenedioxy) -5 α -hydroxyandrostan-3 α -yl in 69% yield]Pent-4- (Z) -en-1-ylcarbamic acid 9H-fluoren-9-ylmethyl ester.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.92-7.22 (m, 9H), 6.05(m, 1H), 5.05(m, 1H), 4.22(m, 3H), 3.76(m ，4H)，3.42(s，1H)，3.03-0.97(m，28H)，0.83(s，3H)，0.74(s，3H)。

Reference is made to the procedure for the preparation of 6 alpha-cyanoandrostane-3, 17-dione (II-ac, preparation 3) starting from 5- [17,17- (ethylenedioxy) -5 alpha-hydroxyandrostan-3 alpha-yl]Pent-4- (Z) -en-1-ylcarbamic acid 9H-fluoren-9-ylmethyl ester was prepared. The combined organic extracts were washed with brine, Na₂SO₄Drying, filtration and evaporation to dryness gave 5- (5 α -hydroxy-17-keto-androstan-3 α -yl) pent-4- (Z) -en-1-ylcarbamic acid 9H-fluoren-9-ylmethyl ester in 87% yield.¹H-NMR(300MHz，DMSO-d₆δ 8.00-7.20(m, 9H), 6.05(m, 1H), 5.05(m, 1H), 4.23(m, 3H), 3.48(s, 1H), 3.02-1.00(m, 28H), 0.86(s, 3H), 0.75(s, 3H), in ppm of TMS.

Preparation 68

3 beta- (2-Aminoacetoxy) androstane-6, 17-dione fumarate

To a stirred DMSO solution (160mL) of 3 β -tert-butyldisiloxyandrostane-6 α,17 β -diol (EP0825197A2, 6.21g) was added IBX (16.45g) at room temperature. After 1.5 hours H was added at room temperature₂The mixture was quenched with O (300 mL). After 15 minutes the mixture was filtered and washed with H₂O washing the filter cake. With Et₂O (4 ×) extract the filter cake. With Na₂SO₄The combined organic extracts were dried and evaporated to dryness to give 3 β -tert-butyl-disilyloxy-androstane-6, 17-dione (0.36g, 75%). ¹H-NMR(300MHz，DMSO-d₆The TMS consists of ppm delta 3.54(m, 1H), 2.47-1.08(m, 20H), 0.84(s, 9H), 0.77(s, 3H), 0.66(s, 1H) and 0.01(s, 6H).

To a stirring solution of 3 β -tert-butyldisiloxyandrostane-6, 17-dione (2.00g) in EtOH (20mL) was added 37% HCl (40 μ L). After 3 hours, 5% NaHCO was used₃The aqueous solution adjusted the solution to a pH of 7. Evaporating the organic solvent and reacting with CH₂Cl₂The aqueous phase was extracted (4X 350 mL). With saturated NH₄Aqueous Cl solution, brine,H₂The combined organic extracts were washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtOAc 90/10) to give 3 β -hydroxy-androstane-6, 17-dione (1.25g, 86%).¹H-NMR(300MHz，DMSO-d₆δ 4.56(d, 1H), 3.31(m, 1H), 2.45-1.15(m, 20H), 0.77(s, 3H), 0.65(s, 3H), in ppm of TMS.

To a THF solution (8mL) of 3 β -hydroxyandrostane-6, 17-dione (0.40g) were added N- (9-fluorenylmethoxycarbonyl) glycine (0.43g), N, N' -dicyclohexylcarbodiimide (0.32g) and 4-dimethylaminopyridine (16mg), and the reaction mixture was stirred at room temperature for 1 hour. After evaporation to dryness, by flash chromatography (SiO)₂EtOAc: N-hexane 6:4) purification of the residue to obtain 3 β - {2- [ N- (9-fluorenylmethoxycarbonyl) ]Aminoacetoxy } androstane-6, 17-dione (0.73mg, 95%).¹H-NMR (300MHz, acetone, ppm from TMS) < delta > 7.93-7.30(8H, m), 6.86(1H, t), 4.71(1H, m), 4.40-4.20(3H, m), 3.91(2H, d), 2.55-1.25(20H, m), 0.87(3H, s), 0.78(3H, s).

To 3 beta- {2- [ N- (9-fluorenylmethoxycarbonyl)]A THF solution (5mL) of amino-acetoxy } androstane-6, 17-dione (690mg) was added 1M tetrabutylammonium fluoride in THF (2.3mL) and stirred for 45 min. Evaporation of the solvent and flash chromatography (SiO)₂，CH₂Cl₂:MeOH:NH₃9:1:0.1) purifying the crude product. The collected fractions were evaporated and the residue was dissolved in EtOAc and treated by fumaric acid to give 3 β - (2-aminoacetoxy) androstane-6, 17-dione fumarate (366mg, 65%) after filtration.¹H-NMR (300MHz, DMSO, ppm from TMS). delta.8.00 (4H, bb), 6.40(2H, s), 4.66(1H, m), 3.49(2H, s), 2.55-1.15(20H, m), 0.78(3H, s), 0.69(3H, s).

Preparation 69

3 beta- (3-aminopropionyloxy) androstane-6, 17-dione fumarate

Reference is made to the above preparationsPreparation of 3 β - {3- [ N- (9-fluorenyl-methoxycarbonyl) starting from N- (9-fluorenylmethoxycarbonyl) - β -alanine (0.45g) according to the preparation step 68]-aminopropionyloxy } androstane-6, 17-dione (0.77mg, 98%). ¹H-NMR (300MHz, acetone, ppm from TMS). delta.7.90-7.25 (8H, m), 6.56(1H, t), 4.67(1H, m), 4.38-4.16(3H, m), 3.42(2H, m), 2.55-1.00(22H, m), 0.87(3H, s), 0.80(3H, s).

Referring to the preparation procedure in preparation 68 above, starting from 3 β - {3- [ N- (9-fluorenylmethoxycarbonyl)]Propionyloxy } androstane-6, 17-dione (770mg) was initially prepared to give the title compound (420mg, 67%).¹H-NMR (300MHz, DMSO, ppm from TMS). delta.8.00 (4H, bb), 6.42(2H, s), 4.61(1H, m), 2.95(2H, t), 2.59(2H, t), 2.55-1.15(20H, m), 0.78(3H, s), 0.69(3H, s).

Preparation 70

3 beta- (4-aminobutyryloxy) androstane-6, 17-dione hydrochloride

Referring to the preparation procedure in preparation 68 above, starting from 4- (tert-butoxycarbonylamino) butanoic acid (147mg), by flash chromatography (SiO)₂;CH₂Cl₂MeOH99:1) purification to prepare 3 beta- [4- (N-tert-butoxycarbonyl) aminobutyryloxy]Androstane-6, 17-dione (230mg, 73%).¹H-NMR (300MHz, DMSO, ppm from TMS):6.82(1H，t)，4.56(1H，m)，2.90(2H，m)，2.50-1.15(24H，m)，1.35(9H，s)，0.77(3H，s)，0.68(3H，s)。

treatment of 3 β - [4- (N-tert-butoxycarbonyl) aminobutyryloxy with 5M HCl in EtOAc (0.3mL)]A solution of-androstane-6, 17-dione (230mg) in THF (8mL) and stirred at 0 ℃ for 1.5 h. The solid was filtered off to give the title compound (200mg, 94%). ¹H-NMR (300MHz, DMSO, ppm from TMS): delta 7.93(3H, bb), 4.89(1H, m), 2.78(2H, t), 2.50-1.15(24H, m), 0.78(3H, s), 0.69(3H, s)，s)。

Preparation 71

3 beta- (3R, S-aminobutyryloxy) androstane-6, 17-dione hydrochloride

3 β -hydroxyandrostane-6, 17-dione (preparation 68, 60.15mg), EDAC (75.7mg), 3R, S- (N-tert-butoxycarbonyl) aminobutyric acid (50.7mg), DMAP (1.2mg) in THF (1.9mL) and H₂The O (100. mu.L) solution was stirred at room temperature overnight. The mixture was diluted with THF, Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtOAc 10/90) to yield 3 β - (3R, S- (N-tert-butoxycarbonyl) aminobutyryloxy) androstane-6, 17-dione (49mg, 55%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.95(d，1H)，4.64(m，1H)，3.30-1.12(m，23H)，1.35(s，9H)，1.21(d，3H)，0.78(s，3H)，0.69(s，3H)。

the title compound was prepared in 55% yield starting from 3 β - (3R, S- (N-tert-butoxycarbonyl) aminobutyryloxy) androstane-6, 17-dione by reference to the preparation procedure in preparation 70 above. 1H-NMR (300MHz, DMSO-d)₆δ 8.00(bb, 3H)4.63(m, 1H), 3.47(m, 1H), 2.78-1.12(m, 22H), 1.21(d, 3H), 0.78(s, 3H), 0.70(s, 3H), in ppm of TMS.

Preparation 72

3 beta- (2R, S-methyl-3-aminopropionyloxy) androstane-6, 17-dione hydrochloride (I-cv)

68, 3 β - (2R, S-methyl-3- (N-tert-butoxycarbonyl) aminopropionyloxy) androstane-6, 17-dione was prepared in 63% yield starting from 3 β -hydroxyandrostane-6, 17-dione (preparation 68) and 2R, S-methyl-3- (N-tert-butoxycarbonyl) aminopropionic acid with reference to the preparation procedure described above for preparation 68.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.86(t，1H)，4.62(m，1H)，3.15-1.05(m，23H)，1.35(s，9H)，1.15(d，3H)，0.78(s，3H)，0.70(s，3H)。

the title compound was prepared in 63% yield starting from 3 β - (2R, S-methyl-3- (N-tert-butoxycarbonyl) aminopropionyloxy) androstane-6, 17-dione by reference to the preparation procedure in preparation 70 above. 1H-NMR (300MHz, DMSO-d)₆δ 7.98(bb, 3H)4.61(m, 1H), 3.26-1.03(m, 23H), 1.15(d, 1.5H), 1.14(d, 1.5H), 0.78(s, 3H), 0.70(s, 3H), in ppm of TMS.

Preparation 73

3 beta- [ N- (2-aminoethyl) carbamoyloxy]Androstane-6, 17-diones

To a solution of 3 β -hydroxyandrostane-6, 17-dione (preparation 68, 300mg) in THF (8mL) was added 1, 1' -carbonyldiimidazole (340mg), and the resulting mixture was stirred under reflux for 4 hours. After cooling, the solvent was evaporated. Dissolving the residue in CH₂Cl₂And washed with water. With Na₂SO₄The organic layer was dried and evaporated to dryness to give 3 β - (1-imidazolylcarbonyloxy) androstane-6, 17-dione (360mg, 90%). ¹H-NMR(300MHz，CDCl₃From the ppm of TMS,. delta.8.24 (1H, bs), 7.45(1H, bs), 7.12(1H, bs), 4.94(1H, m), 2.60-1.25(23H, m), 0.90(3H, s), 0.87(3H, s).

N- (tert-Butoxycarbonyl) ethylenediamino (0.20mL) was added to CH of 3 β - (1-imidazolylcarbonyloxy) androstane-6, 17-dione (200mg)₂Cl₂(10mL) and 2-propanol (1 mL). After heating at reflux for 9 hours, the mixture was cooled to room temperature and water was added. Separating the organic layer with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂;CH₂Cl₂EtOAc1:1) purifying the residue toTo give 3 beta- [ N- (2-tert-butoxycarbonylaminoethyl) -carbamoyloxy]Androstane-6, 17-dione (184mg, 76%).¹H-NMR(300MHz，CDCl₃In ppm of TMS,. delta.5.02 (1H, bb), 4.84(1H, bb), 4.56(1H, m), 3.27(4H, m), 2.50-1.20(20H, m), 1.45(9H, s), 0.87(3H, s), 0.80(3H, s).

Reference is made to the procedure described in preparation 70 and using 3 β - [ N- (2-tert-butoxycarbonylaminoethyl) carbamoyloxy]Androstane-6, 17-dione (260mg) gave initially 3 β - [ N- (2-aminoethyl) carbamoyloxy as a yellow solid]Androstane-6, 17-dione (158mg, 70%).¹H-NMR(300MHz，DMSO-d₆δ 7.57(3H, bb), 7.20(1H, t), 4.42(1H, m), 3.17(2H, m), 2.78(2H, t), 2.50-1.15(20H, m), 0.78(3H, s), 0.68(3H, s), in ppm of TMS.

Preparation 74

3 beta- (4-aminobutanamide) androstane-6, 17-dione hydrochloride

Starting from 6 α -hydroxyandrostan-3, 17-dione (5.00g) and hydroxyll amine hydrochloride (5.80g), filtration from THF, following the procedure described in example 4, gave (E, Z) 3-hydroxyimino-6 α -hydroxyandrostan-17-one (3.93g, 75%).¹H-NMR(300MHz，DMSO-d₆δ 10.10(0.5H, s), 10.07(0.5H, s), 4.47(0.5H, d), 4.44(0.5H, d), 3.47(0.5H, m), 3.24(1H, m), 3.03(0.5H, m), 2.60-0.60(19H, m), 0.85(3H, s), 0.77(3H, s), in ppm of TMS.

In a Parr shaker at 3.5atm and room temperature, at PtO₂Hydroxide (2.3g) CHCl for hydrogenation of (E, Z) 3-hydroxyimino-6 alpha-hydroxyandrostan-17-one (3.10g)₃(23mL) and MeOH (355 mL). After 24 hours, the mixture was filtered and washed with CHCl₃And water washing the filter cake. The organic layer was separated, dried and evaporated to dryness. By flash chromatography (SiO)₂;CH₂Cl₂:MeOH:NH₃8:2:0.2) purifying the residue. The two fractions were collected and evaporated to dryness. The residue of the first group (1.00g) was dissolvedAfter MeOH, the theoretical amount of fumaric acid was added and evaporated to dryness to give 3 α -aminoandrostane-6 α,17 β -diol fumarate (1.39g, 34% yield). The same procedure was repeated with the residue of the second fraction (1.5g) to give 3 β -aminoandrostane-6 α,17 β -diol fumarate (2.05g, 50%). ¹H-NMR(300MHz，DMSO-d₆From ppm TMS) 3 α -isomer:7.97(4H, bb), 6.40(2H, s), 4.45(2H, bb), 3.50-3.10(3H, m), 2.05-0.55(20H, m), 0.72(3H, s), 0.60(3H, s);3 β -isomer:7.88(4H，m)，6.40(2H，s)，4.43(2H，bb)，3.50-2.75(3H，m)，2.20-0.55(20H，m)，0.73(3H，s)，0.40(3H，s)。

IBX (2.00g) was added to a solution of 3 β -aminoandrostane-6 α,17 β -diol fumarate (1.50g) in dimethylsulfoxide (10mL) and trifluoroacetic acid (0.54 mL). After stirring overnight at room temperature, water was added and CH added₂Cl₂The mixture is extracted. The organic layer was washed with brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂;CHCl₃:MeOH:NH₃9:1:0.1) purification of the residue: the fractions were evaporated and treated with 5M HCl in EtOAc to give 3 β -aminoandrostane-6, 17-dione hydrochloride (780mg, 65%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.8.04 (3H, bb), 2.94(1H, m), 2.50-1.15(20H, m), 0.78(3H, s), 0.66(3H, s).

Treatment of 3 beta-aminoandrostane-6, 17-dione hydrochloride (150mg) with powdered KOH (25mg)₂Cl₂The solution was stirred for 15 minutes. 4- (tert-Butoxycarbonylamino) butyric acid (98mg), EDAC (168mg) and 4-dimethylaminopyridine (8mg) were added at 0 ℃. The reaction temperature was raised to room temperature and stirred for 24 hours. With water (2X10mL) and 5% NaHCO₃The mixture was washed (10 mL). The organic layer was dried and evaporated to dryness. By flash chromatography (SiO₂;CH₂Cl₂:MeOH:NH₃9:1:0.1) purifying the residue to obtain 3 β - [4- (tert-butoxycarbonyl-amino) butyrylamino]Androstane-6, 17-dione (161mg, 75%).¹H-NMR(300MHz，DMSO-d₆δ 7.68(1H, d), 6.77(1H, t), 3.46(1H, m), 2.87(2H, m), 2.45-1.10(24H, m), 1.36(9H, s), 0.78(3H, s), 0.66(3H, s), in ppm of TMS.

Reference is made to the procedure described in preparation 70 and using 3 β - [4- (tert-butoxycarbonylamino) butyrylamino]Androstane-6, 17-dione (110mg) initially gave 3 β - (4-aminobutanamide) androstane-6, 17-dione hydrochloride as a white solid (62mg, 65%).¹H-NMR(300MHz，DMSO-d₆δ 7.85(1H, d), 7.76(3H, bb), 3.45(1H, m), 2.76(2H, m), 2.45-1.15(24H, m), 0.78(3H, s), 0.66(3H, s), in ppm of TMS.

Preparation 75

3 beta- (3-aminopropionylamino) androstane-6, 17-dione hydrochloride

Starting from 3 beta-aminoandrostane-6, 17-dione hydrochloride (180mg) and N- (tert-butoxycarbonyl) -beta-alanine (preparation 61, 110mg) by the same reaction conditions described in preparation 74, was purified by flash chromatography (SiO 2)₂;CH₂Cl₂MeOH95:5) to give 3 beta- [3- (tert-butoxy-carbonylamino) -N-propionamido group]Androstane-6, 17-dione (138mg, 55%).¹H-NMR(300MHz，DMSO-d₆δ 7.74(1H, d), 6.72(1H, t), 3.46(1H, m), 3.08(2H, m), 2.45-1.10(22H, m), 1.36(9H, s), 0.78(3H, s), 0.66(3H, s), in ppm of TMS.

Reference is made to the procedure described in preparation 70 and using 3 β - [3- (tert-butoxycarbonylamino) propionamido]Androstane-6, 17-dione (120mg) initially gave 3 β - (3-aminopropionylamino) androstane-6, 17-dione hydrochloride (67mg, 65%) as a white solid.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.8.01 (1H, d), 7.76(3H, bb), 3.48(1H, m), 2.96 (m)2H，m)，2.45-1.15(22H，m)，0.78(3H，s)，0.67(3H，s)。

Preparation 76

3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6-hydroxyiminoandrostanes Alkane-17- (2-spiro-1, 3-dioxolane)

To a solution of 3 β -hydroxyandrost-5-en-17-one (10.00g) in pyridine (66mL) at 0 ℃ with stirring was added toluene-4-sulfonyl chloride (13.20g) and DMAP (10 mg). The reaction was warmed to room temperature and stirred for 15 hours. After dilution with EtOAc (300mL), the mixture was poured into ice-water. Separating the organic layer with 1N H₂SO₄Washed with water and brine, dried and evaporated to dryness to give a white solid. 3 beta- (p-toluenesulfonyloxy) androst-5-en-17-one (14.70g, 96%)¹H-NMR (300MHz, acetone-d)₆δ 7.81(2H, m), 7.48(2H, m), 5.35(1H, m), 4.26(1H, m), 2.46(3H, s), 2.54-0.93(19H, m), 1.05(3H, s), 0.85(3H, s).

3 β - (p-toluenesulfonyloxy) androst-5-en-17-one (12.00g) was added to a suspension of propane-1, 3-diol (61mL) and PTSA (610mg) at 95 ℃. After stirring for 40 min, the mixture was cooled to room temperature, poured into water (800mL) and washed with 5% NaHCO ₃The pH was adjusted to 7. After 3 hours the solid was dissolved filtered and dissolved in CH₂Cl₂. With Na₂SO₄The solution was dried and evaporated to dryness under reduced pressure to give 3 β - (3-hydroxypropoxy) androst-5-en-17-one (9.10g, 97%) which was used without purification.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.5.35 (1H, m), 4.34(1H, t), 3.43(4H, m), 3.06(1H, m), 2.45-0.85(21H, m), 0.96(3H, s), 0.79(3H, s).

Ethylene glycol (15.0mL) and PTSA (470mg) were added to a toluene solution (370mL) of 3 β - (3-hydroxypropoxy) androst-5-en-17-one (9.10 g). The reaction mixture was stirred at reflux for 3 hours. After cooling to room temperature, water (200mL) was added with 5% NaHCO₃The pH was adjusted to 7. Extracted with EtOAc (3X100mL)The mixture was taken. The combined organic layers were dried and evaporated to dryness. By flash chromatography (SiO)₂n-Hexane EtOAc55:45) to yield 3 β - (3-hydroxypropoxy) androst-5-ene-17- (2-spiro-1, 3-dioxolane) (10.2g, 100%).¹H-NMR(300MHz，DMSO-d₆δ 5.31(1H, m), 4.34(1H, t), 3.78(4H, m), 3.43(4H, m), 3.05(1H, m), 2.35-0.80(21H, m), 0.93(3H, s), 0.77(3H, s), in ppm of TMS.

To the cooled to 0 deg.C 3 beta- (3-hydroxypropoxy) androst-5-ene-17- (2-spiro-1, 3-dioxolane) (2.00g) and triethylamine (0.82mL) in CH ₂Cl₂To the solution (30mL) was added methanesulfonyl chloride (0.41 mL). After stirring for 3 hours at room temperature, the mixture was poured into ice water and added with CH₂Cl₂And (4) extracting. With 5% NaHCO₃The organic phase was washed with water, brine, dried and evaporated to give an oil which was left to solidify overnight in a refrigerator. With Et₂The resulting solid was crystallized from O to give 3 β - (3-methanesulfonyloxypropoxy) -17- (2-spiro-1, 3-dioxolane) androst-5-ene (2.33g, 97%) as a yellow solid.¹H-NMR(300MHz，DMSO-d₆δ 5.31(1H, m), 4.22(2H, t), 3.78(4H, m), 3.48(2H, t), 3.15(3H, s), 3.09(1H, m), 2.36-0.81(21H, m), 0.94(3H, s), 0.77(3H, s), in ppm of TMS.

3 β - (3-Methanesulfonyloxypropoxy) -17- (2-spiro-1, 3-dioxolane) androst-5-ene (1.90g) was dissolved in 2.23M methylamine in MeOH (53mL) and the solution was heated in a steel cylinder at 120 ℃ for 4 hours. After cooling to room temperature, CHCl was added₃And with 5% NaHCO₃The mixture was washed with water, brine. The organic layer was dried and evaporated to dryness to give a pale green residue 3 β - (3-N-methylaminopropoxy) -17- (2-spiro-1, 3-dioxolane) androst-5-ene (1.60g, 100%) which was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆δ 5.30(1H, m), 3.78(4H, m), 3.41(2H, t), 3.05(1H, m), 2.46(2H, t), 2.23(3H, s), 2.33-0.80(22H, m), 0.93(3H, s), 0.77(3H, s), in ppm of TMS.

With reference to the protection procedure for N-tert-butoxycarbonyl in preparation 55, starting from 3 β - (3-N-methylaminopropoxy) -17- (2-spiro-1, 3-dioxo-lane) androst-5-ene (1.60g) by flash chromatography (SiO)₂N-Hexane EtOAc85:15) to yield 3 β - (3-N-tert-butoxycarbonyl-N-methyl-aminopropoxy) -17- (2-spiro-1, 3-dioxolane) androst-5-ene (1.60g, 80%).¹H-NMR(300MHz，DMSO-d₆δ 5.30(1H, m), 3.78(4H, m), 3.37(2H, t), 3.18(2H, t), 3.06(1H, m), 2.74(3H, s), 2.36-0.80(21H, m), 1.37(9H, s), 0.93(3H, s), 0.77(3H, s).

With reference to the hydroboration procedure in preparation 9, starting from 3 β - (3-N-tert-butoxycarbonyl-N-methylaminopropoxy) -17- (2-spiro-1, 3-dioxolane) androst-5-ene (1.50g) by flash chromatography (SiO)₂Hexane EtOAc1:1) purification gave 3 β - [3- (N-tert-butoxy-carbonyl-N-methyl) -aminopropoxy]-17- (2-spiro-1, 3-dioxolane) androstan-6 β -ol (1.20g, 76%).¹H-NMR(300MHz，DMSO-d₆δ 4.30(1H, d), 3.77(4H, m), 3.45-3.00(6H, m), 2.74(3H, s), 2.27-0.50(22H, m), 1.37(9H, s), 0.74(3H, s), 0.71(3H, s), in ppm of TMS.

Reference IBX Oxidation step in preparation 11 from 3 β - [3- (N-tert-Butoxycarbonyl-N-methyl) aminopropoxy ]-17- (2-Spiro-1, 3-dioxolane) androstan-6-alpha-ol (180mg) starting by flash chromatography (SiO)₂Hexane EtOAc6:4) purification gave 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-17- (2-spiro-1, 3-dioxolane) -androstan-6-one (160mg, 90%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.3.78 (4H, m), 3.42 to 3.05(5H, m), 2.74(3H, s), 2.33 to 1.07(22H, m), 1.37(9H, s), 0.75(3H, s), 0.62(3H, s).

By following the procedure described in example 4, starting from 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]Starting from (120mg) of (E) -17- (2-spiro-1, 3-dioxolane) androstan-6-one, 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6-hydroxyimino-androstane-17- (2-spiro)Cyclo-1, 3-dioxolane) (110mg, 90%) which was used directly in the next step.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.34 (1H, s), 3.78(4H, m), 3.40-3.07(6H, m), 2.74(3H, s), 1.96-0.83(21H, m), 1.37(9H, s), 0.74(3H, s), 0.62(3H, s).

Preparation 77

3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6 alpha-hydroxy-methylandrostane Stanol-17- (2-spiro-1, 3-dioxolane)

Referring to the procedure for the Wittig reaction in preparation 8, starting from 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) amino-propoxy ]-17- (2-Spiro-1, 3-dioxolane) androstan-6-one (preparation 66, 500mg) starting by flash chromatography (SiO)₂N-Hexane EtOAc75:25) to obtain 3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) amino-propoxy ] ethyl acetate]-6-methylene-androstane-17- (2-spiro-1, 3-dioxolane) (470mg, 94%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):4.69(1H，m)，4.40(1H，m)，3.78(4H，m)，3.42-3.10(5H，m)，2.74(3H，s)，2.27-0.77(22H，m)，0.73(3H，s)，0.60(3H，s)。

reference was made to the hydroboration procedure in preparation 9 from 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6-methylene-androstane-17- (2-spiro-1, 3-dioxolane) (450mg) starting from flash chromatography (SiO)₂Purification of N-hexane EtOAc1:1) gave 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6 β -hydroxymethyl-androstane-17- (2-spiro-1, 3-dioxolane) (281mg, 60%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):4.24(1H，t)，3.78(4H，m)，3.45-1.05(7H，m)，2.74(3H，s)，1.90-0.50(23H，m)，1.37(9H，s)，0.77(3H，s)，0.68(3H，s)。

with reference to the IBX oxidation procedure described in example 11, starting from 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]Starting with (280mg) 6 β -hydroxymethylandrostane-17- (2-spiro-1, 3-dioxolane) 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy was obtained as a glassy solid]-6 β -formylandrostane-17- (2-spiro-1, 3-dioxolane) (274mg, 100%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.9.83 (1H, bs), 3.78(4H, m), 3.45-3.10(5H, m), 2.75(3H, s), 2.40-0.60(23H, m), 1.37(9H, s), 0.73(3H, s), 0.63(3H, s).

With reference to the epimerization procedure described in example 11, starting from 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6 β -formylandrostane-17- (2-spiro-1, 3-dioxolane) (220mg) 3 β - [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy initially obtained as an oil]-6 α -formylandrostane-17- (2-spiro-1, 3-dioxolane) (186mg, 85%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.41(1H，d)，3.78(4H，m)，3.40-3.05(5H，m)，2.73(3H，s)，2.21-0.61(23H，m)，1.37(9H，s)，0.77(3H，s)，0.75(3H，s)。

reference is made to NaBH described in example 14₄A reduction step of reacting 3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy]-6 α -formyl-androstane-17- (2-spiro-1, 3-dioxolane) (180mg) starting by flash chromatography (SiO)₂N-Hexane EtOAc55:45) to obtain 3 beta- [3- (N-tert-butoxycarbonyl-N-methyl) aminopropoxy) as a glassy solid]-6 β -hydroxymethyl-androstane-17- (2-spiro-1, 3-dioxolane) (110mg, 65%).¹H-NMR(300MHz，DMSO-d₆δ 4.20(1H, t), 3.78(4H, m), 3.41-3.00(7H, m), 2.74(3H, s), 1.97-0.48(23H, m), 1.37(9H, s), 0.75(3H, s), 0.74(3H, s), in ppm of TMS.

Preparation 78

3 alpha- (2-trifluoroacetamidoethylthio) -6- (E) -hydroxyiminoandrostan-17-one

To a solution of triphenylphosphine (2.38g) in THF (140mL) at 0 deg.C was added dropwise diisopropyl azocarboxylate (1.79 mL). After stirring for 30 minutes, thioacetic acid (0.65mL) and androstane-3 β,6 α,17 β -triol (2.00g) were added. After 2 hours at 0 ℃, rt overnight and addition of EtOAc. The mixture was washed with water and the organic layer was evaporated to dryness. By flash chromatography (SiO) ₂Cyclohexane: EtOAc55:45) to yield 3 α -acetylthiaandrostane-6 α,17 β -diol (1.60g, 66%).¹H-NMR(300MHz，DMSO-d₆δ 4.42(1H, bb), 4.28(1H, bb), 3.91(1H, bb), 3.42(1H, m), 3.11(1H, m), 2.28(3H, s), 2.00-0.80(20H, m), 0.74(3H, s), 0.60(3H, s), in ppm of TMS.

To a stirred CH of 3 alpha-acetylthioandrostane-6 alpha, 17 beta-diol (1.40g)₂Cl₂Suspension (50mL) NMNO (1.37g), TPAP (68mg) and powdered molecular sieves were added at room temperature(2.1 g). After 2 hours NMNO (0.7g), TPAP (34mg) and molecular sieves were again added(1g) The reaction was stirred for an additional 1.5 hours. By flash chromatography (SiO)₂Cyclohexane: EtOAc7:3) to yield 3 α -acetylthiaandrostane-6, 17-dione (1.07g, 76%).¹H-NMR (300MHz, acetone-d)₆In ppm TMS,. delta.3.99 (1H, bb), 2.55-1.20(23H, m), 0.86(3H, s), 0.79(3H, s).

To a suspension of 3 α -acetylthiaandrostane-6, 17-dione (1.07g) in MeOH (30mL) was added sodium propylmercaptide (0.28g), and the reaction was stirred at room temperature for an additional 20 minutes. The mixture was neutralized with 1N HCl. Water was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine and Na ₂SO₄Dried and evaporated to dryness to give 3 α -mercaptoandrostane-6, 17-dione (943mg, 100%), which was used without further purification.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.3.54 (1H, m), 2.77(1H, m), 2.54(1H, d), 2.45-1.10(19H, m), 0.78(3H, s), 0.66(3H, s).

To a stirred solution of 3 α -mercaptoandrostane-6, 17-dione (253mg) in dry DMF (3mL) was added NaH60% (32mg) in oil at 0 ℃. After 5 minutes, a solution of 2-N-methyltrifluoroacetamidoethyl chloride (216mg) in DMF (1mL) was added dropwise at room temperature over 30 minutes. After 2 hours, 5% NaH was added₂PO₄And (3) solution. The phases were separated and the aqueous phase was extracted with EtOAc. The organic layer was washed with brine, and Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂cyclohexane/EtOAc 65/35) to yield 3 α - (2-N-methyltrifluoroacetamido-ethylsulfanyl) androstane-6, 17-dione (265mg, 68%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.25(1H，t)，3.29(3H，m)，2.67(1H，m)，2.60(2H，t)，2.50-1.10(20H，m)，0.77(3H，s)，0.68(3H，s)。

the procedure described with reference to example 1 was started from 3 α - (2-N-methyltrifluoroacetamidoethylthio) androstane-6, 17-dione (220mg) by flash chromatography (SiO)₂，CH₂Cl₂acetone/N-hexane 2/2/6) gave 3 α - (3-N-methyltrifluoroacetamidoethylsulfanyl) -6(E) -hydroxyimino-androstan-17-one (186mg, 85%) as an oil. ¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.30(1H，s)，9.40(1H，t)，3.23(4H，m)，2.55-0.90(21H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 79

3 alpha- (3-trifluoroacetamidopropylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one

Starting from 3 α -mercaptoandrostane-6, 17-dione (preparation 65, 865mg) and 3-N-trifluoroacetamidopropyl bromide (695mg) the same reaction conditions as in preparation 78 gave 3 α - (3-trifluoroacetamidopropylsulfanyl) -androstane-6, 17-dione as a white solid (1.18g, 93%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.42(1H，t)，3.23(3H，m)，2.70-1.17(24H，m)，0.77(3H，s)，0.68(3H，s)。

starting from 3 α - (3-trifluoroacetamido-propylthio) androstane-6, 17-dione (394mg) and hydroxylamine hydrochloride (64mg) the procedure described in example 1 gave 3 α - (3-trifluoroacetamido-propylthio) -6- (E) -hydroxyiminoandrostane-17-one (203mg, 50%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.39(1H，s)，9.42(1H，t)，3.23(4H，m)，2.55-0.90(23H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 80

3 alpha- (4-trifluoroacetamido butylthio) -6- (E) -hydroxyiminoandrostan-17-one

Starting from 3 α -mercaptoandrostane-6, 17-dione and 4-N-trifluoroacetamido-butyl bromide using the same reaction conditions as in preparation 78, without any purification, 3 α - (4-trifluoroacetamido butylsulfanyl) androstane-6, 17-dione was obtained as a white solid (0.68g, 85%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.9.40 (1H, t), 3.20(3H, m), 2.75-1.10(26H, m), 0.77(3H, s), 0.68(3H, s).

With reference to the procedure described in example 1, from3 α - (4-trifluoroacetamido butylsulfanyl) androstane-6, 17-dione and hydroxylamine hydrochloride gave 3 α - (4-trifluoroacetamido butylsulfanyl) -6- (E) -hydroxyiminoandrostane-17-one (238mg, 40%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.35(1H，s)，9.40(1H，t)，3.20(4H，m)，2.55-0.90(25H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 81

3 alpha- (3-N-methylaminopropylthio) androstane-6, 17-dione fumarate

Starting from 3 α -mercaptoandrostane-6, 17-dione (preparation 65, 253mg) and 3- (N-methyl) trifluoro-acetamidopropyl chloride (216mg) the same reaction conditions as in preparation 78 gave 3 α - (3-N-methyltrifluoroacetamido-propylthio) androstane-6, 17-dione as a white solid (265g, 68%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):3.43(2H，m)，3.24(1H，m)，3.07(1.8H，q)，2.93(1.2H，bs)，2.70-1.15(24H，m)，0.77(3H，s)，0.68(3H，s)。

starting from 3 α - (3-N-methyltrifluoroacetamidopropylsulfanyl) androstane-6, 17-dione (265mg) and hydroxylamine hydrochloride (41mg), 3 α - (3-trifluoroacetamidopropylsulfanyl) -6- (E) -hydroxyiminoandrostane-17-one (116mg, 43%) was obtained using the same reaction conditions as in example 1.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.39(1H，s)，3.44(2H，m)，3.26(2H，m)，3.07(1.8H，q)，2.94(1.2H，bs)，2.56-0.93(23H，m)，0.77(3H，s)，0.68(3H，s)。

preparation 82

3 alpha- (3-trifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one

To a stirred THF solution (8mL) of 3 α -acetylthioandrostane-6, 17-dione (preparation 78, 600mg) cooled to-50 ℃ were added a dried THF solution of ylide prepared from methyltriphenylphosphorus bromide (1.47g) at-50 ℃ (8mL) and potassium tert-butoxide (484 mg). After 2 hours the temperature was raised to room temperature. Adding 5% NaH ₂PO₄The mixture was quenched with aqueous solution and extracted with EtOAc (2X 60 mL). With 5% NaH₂PO₄The combined organic extracts were washed with aqueous, brine, and Na₂SO₄Dried and evaporated to dryness. The residue was purified by flash chromatography (n-hexane/EtOAc 9/1) to give 3 α -acetylthio-6-methyleneandrostan-17-one (210mg, 35% yield) and 3 α -mercapto-6-methyleneandrostan-17-one (208mg, 35% yield).¹H-NMR(300MHz，DMSO-d₆From ppm TMS) 3 α -acetylthio-6-methyleneandrostan-17-one:4.73(1H, m), 4.39(1H, m), 3.96(1H, m), 2.44-0.84(20H, m), 2.29(3H, s), 0.75(3H, s), 0.66(3H, s), 3 alpha-mercapto-6-methyleneandrostan-17-one, delta 4.73(1H, m), 4.38(1H, m), 3.57(1H, m), 2.52(1H, d), 2.45-0.95(20H, m), 0.76(3H, s), 0.63(3H, s).

To a solution of 3 α -acetylthio-6-methyleneandrostan-17-one (210mg) in MeOH (3mL) was added 1N NaOH (0.6 mL). After 1 hour at room temperature 5% NaH was added₂PO₄Aqueous solution and Et₂The mixture was extracted with O (2X 20 mL). The combined organic extracts were washed with brine, Na₂SO₄Dried and evaporated to dryness to afford 3 α -mercapto-6-methyleneandrostan-17-one (185mg, 100%).

Starting from 3 α -mercapto-6-methyleneandrostan-17-one (100mg) and N-trifluoroacetamidopropyl bromide (147mg) by using the same reaction conditions as in preparation 78, on flash chromatography (S) iO₂n-Hexane/EtOAc 75/25) gave 3 α - (3-trifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one (104mg, 70%) as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 9.43(1H, bb), 4.72(1H, m), 4.41(1H, m), 3.24(3H, m), 2.50-0.86(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Preparation 83

3 alpha- (3-N-methyltrifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one

Starting from 3 α -mercapto-6-methyleneandrostan-17-one (preparation 69, 140mg) and N-methyltrifluoroacetamidopropyl bromide (178mg) by using the same reaction conditions as in preparation 78, on flash chromatography (SiO)₂N-Hexane/EtOAc 75/25) gave 3 α - (3-N-methyltrifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one (105mg, 60%) as a white solid.¹H-NMR(300MHz，DMSO-d₆δ 4.73(1H, m), 4.41(1H, m), 3.44(2H, m), 3.25(1H, m), 3.07(2.0H, br), 2.94(1.0H, br), 2.50-0.89(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Preparation 84

3 alpha- [ (S) -3-trifluoroacetamidopropylsulfinyl]-6-methyleneandrostan-17-one

To 3 α - (3-trifluoroacetamidopropylsulfanyl) -6-methyleneandrostan-17-one (preparation 82, 286mg) in dry CH ₃CN solution (14mL) was added NMO (213mg) and molecular sieves (Mole280mg) and then TPAP (10.6mg) was added. After 1 hour at room temperature the mixture was evaporated to dryness. By flash chromatography (SiO)₂N-hexane/acetone 65/35) to give 3 α - [ (S) -3-trifluoroacetamidopropylsulfinyl]-6-methylene-androstan-17-one (100mg, 34% yield).¹H-NMR(300MHz，DMSO-d₆δ 9.43(1H, bb), 4.72(1H, m), 4.41(1H, m), 3.24(3H, m), 2.50-0.86(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Preparation 85

3 alpha- [ (R) -3-trifluoroacetamidopropylsulfinyl group]-6-methyleneandrostan-17-one

The title compound was obtained from the second fraction of the column described in preparation 84 (70mg, 24% yield).¹H-NMR(300MHz，DMSO-d₆δ 9.43(1H, bb), 4.70(1H, m), 4.41(1H, m), 3.24(3H, m), 2.50-0.86(24H, m), 0.75(3H, s), 0.65(3H, s), in ppm of TMS.

Preparation 86

7 alpha-methoxymethyl androstane-3, 17-dione

The title compound was obtained in 70% yield starting from 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxymethylandrostane (preparation 49) (2.00g) with the procedure described in reference preparation 10.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.3.30 (3H, s), 3.28(2H, m), 2.53-0.75(21H, m), 1.13(3H, s), 0.90(3H, s).

Preparation 87

7 alpha-methoxyandrostane-3, 17-dione

The title compound was obtained in 68% yield starting from 3,3:17, 17-bis (ethylenedioxy) -7 α -hydroxyandrostane (preparation 45) (1.5g) with the procedure described in reference preparation 10.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.3.35 (3H, s), 2.58-1.00(21H, m), 0.96(3H, s), 0.78(3H, s).

Preparation 88

3 beta- (2-trifluoro-2)Acetylamidoethylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one

To PPh₃A THF solution (250mL) of (15.0g) and DIAD (9.0mL) was added androstane-3 β,6 α,17 β -triol (5.0g) and formic acid (2.1mL) at 0 deg.C and the mixture was stirred for 1 hour. The solvent was evaporated to dryness by flash chromatography (SiO)₂n-hexane/EtOAc 1/1) the crude product was purified to give 3 α -formyloxy androstane-6 α,17 β -diol as a white solid in 50% yield.¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.8.20 (1H, s), 5.10(1H, bs), 4.35(1H, d), 4.24(1H, d), 3.40(1H, m), 3.15(1H, m), 2.10-0.80(20H, m), 0.74(3H, s), 0.60(3H, s).

To a stirred CH of 3 alpha-formyloxy androstane-6 alpha, 17 beta-diol (2.50g)₂Cl₂Solution (100mL) was supplemented with NMO (2,7g) and molecular sieves (M3.8g) and then TPAP (270mg) was added. After stirring for 2 hours at room temperature, the solvent was removed and the mixture was purified by flash chromatography (SiO) ₂n-hexane/EtOAc 65/35) the mixture was purified to give 3 α -formyloxy androstane-6, 17-dione as a white solid in 90% yield.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.8.15 (1H, s), 5.12(1H, bs), 2.40-0.90(20H, m), 0.77(3H, s), 0.66(3H, s).

To a solution of 3 α -formyloxy androstane-6, 17-dione (2.20g) in MeOH (100mL) was added K₂CO₃(2.70g) and the mixture was stirred at room temperature for 10 min, then HCl1N (20mL) was added, the phases were separated and the aqueous phase was extracted with EtOAc (2X). By H₂The combined organic extracts were washed with Na₂SO₄Dried and evaporated to dryness to give 3 α -hydroxyandrostane-6, 17-dione (quantitative yield), which was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆δ 4.35(1H, d), 3.40(1H, m), 2.40-0.95(20H, m), 0.80(3H, s), 0.69(3H, s), in ppm of TMS.

3 α -methanesulfonyloxy androstane-6, 17-dione was obtained in quantitative yield with reference to the procedure described in preparation 76.¹H-NMR (300MHz, acetone-d)₆δ 5.05(1H, m), 3.10(3H, s), 2.70-1.30(20H, m), 0.88(3H, s), 0.79(3H, s), in ppm TMS.

To a dry DMF solution (25mL) of 3 α -methanesulfonyloxy androstane-6, 17-dione (2.00g) was added potassium thioacetate (1.20 g). The mixture was heated at 70 ℃ for 3 hours. After cooling, 5% NaH was added ₂PO₄And extracted with EtOAc (3 ×). The organic extract was washed with brine, Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂n-hexane/EtOAc 8/2) the residue was purified to give 3 β -acetylthioandrostane-6, 17-dione as a yellow solid in 55% yield.¹H-NMR (300MHz, acetone-d)₆From the ppm of TMS,. delta.4.50 (1H, m), 3.10(3H, s), 2.50-0.90(20H, m), 0.88(3H, s), 0.77(3H, s).

Starting from 3 beta-acetylthioandrostane-6, 17-dione, the procedure described in reference preparation 78 gave 3 beta-mercaptoandrostane-6, 17-dione in 80% yield.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.2.70-1.00 (22H, m), 0.78(3H, s), 0.67(3H, s).

The procedure described in reference preparation 78 was initiated with 3 β -mercaptoandrostane-6, 17-dione and 2-N-trifluoroacetamidoethyl chloride by flash chromatography (SiO)₂N-hexane/EtOAc 7/3) was purified to give 3 β - (2-N-trifluoroacetamidoethylthio) androstane-6, 17-dione in 70% yield.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.25(1H，t)，3.29(3H，m)，2.67(1H，m)，2.60(2H，t)，2.50-1.10(20H，m)，0.77(3H，s)，0.68(3H，s)。

reference example 1 the procedure described is carried out using 3 beta- (2-N-methyltrifluoroacetamidoethylthio) androstane-6, 17-dione (2)20mg) in flash chromatography (SiO)₂，CH₂Cl₂acetone/N-hexane 2/2/6) gave 3 α - (2-N-trifluoroacetamidoethylsulfanyl) -6(E) -hydroxyimino-androstan-17-one in 85% yield. ¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.30(1H，s)，9.40(1H，t)，3.23(4H，m)，2.55-0.90(21H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 89

3 beta- (3-trifluoroacetamidopropylsulfanyl) -6- (E) -hydroxyiminoandrostan-17-one

Starting from 3 β -mercaptoandrostane-6, 17-dione (preparation 88, 870mg) and 3-N-trifluoroacetamidopropyl bromide (700mg) the same reaction conditions as in preparation 78 gave 3 β - (3-trifluoro-acetamidopropylthio) androstane-6, 17-dione as a white solid (1.2g, 93%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.40(1H，t)，3.23(3H，m)，2.70-1.17(24H，m)，0.77(3H，s)，0.68(3H，s)。

starting from 3 β - (3-trifluoroacetamidopropylsulfanyl) androstane-6, 17-dione (395mg) and hydroxylamine hydrochloride (65mg) the procedure described in example 1 gave 3 β - (3-trifluoroacetamidopropylsulfanyl) -6- (E) -hydroxyiminoandrostane-17-one (200mg, 50%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.40(1H，s)，9.42(1H，t)，3.23(4H，m)，2.55-0.90(23H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 90

3 beta- (4-trifluoroacetamido butylthio) -6- (E) -hydroxyiminoandrostan-17-one

Starting from 3 β -mercaptoandrostane-6, 17-dione and 4-N-trifluoroacetamido-butyl bromide using the same reaction conditions as in preparation 78, 3 β - (4-trifluoroacetamido butylsulfanyl) androstane-6, 17-dione was obtained as a white solid (0.70g, 85%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.39(1H，t)，3.20(3H，m)，2.75-1.10(26H，m)，0.77(3H，s)，0.68(3H，s)。

starting from 3 β - (4-trifluoroacetamidobutylsulfanyl) androstane-6, 17-dione and hydroxylamine hydrochloride, 3 β - (4-trifluoroacetamidobutylsulfanyl) -6- (E) -hydroxyiminoandrostane-17-one (240mg, 40%) was obtained according to the procedure described in example 1.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.35(1H，s)，9.40(1H，t)，3.20(4H，m)，2.55-0.90(25H，m)，0.76(3H，s)，0.67(3H，s)。

preparation 91

6 alpha-hydroxymethyl-7 alpha-hydroxyandrostane-3, 17-dione

To a stirring solution of 3,3:17, 17-bis (ethylenedioxy) -6 α -hydroxymethylandrostan-7-one (preparation 52) (2.00g) in MeOH (100mL) at 0 deg.C was added NaBH₄(270 mg). The temperature was raised to room temperature. After 1 hour 5% NaH was added₂PO₄Terminating the reaction with CH₂Cl₂And (4) extracting. The combined organic extracts were washed with brine, and Na₂SO₄Dried and evaporated to dryness. The residue was dissolved in dioxane (25mL), 1N HCl (8mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. After evaporation to dryness, by flash chromatography (SiO)₂n-hexane/CH₂Cl₂/acetone 50/25/25) the residue was purified to give the title compound in 73% yield.¹H-NMR(300MHz，DMSO-d₆δ 4.36(1H, t), 4.26(1H, d), 3.86(1H, m), 3.43(2H, m), 2.40-1.10(19H, m), 0.99(3H, s), 0.79(3H, s), in ppm of TMS.

Preparation 92

(S) -2-aminopropoxyamino dihydrochloride

To a solution of (S) - (+) -2-amino-1-propanol (2.00g) and triethylamine (4.27mL) in MeOH (20mL) was added di-tert-butyl dicarbonate (6.42g) at 0 deg.C. After stirring at room temperature for 12 hours, the solvent was evaporated. Dissolving the residue in CH₂Cl₂The organic phase was washed with water and evaporated to dryness to give (S) -2- (tert-butoxycarbonyl) amino-1-propanol (4.6g, 100%) which was used in the next step without purification. ¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.40(1H，d)，4.51(1H，m)，3.64(1H，m)，3.10(1H，m)，3.34(1H，m)，1.46(9H，s)，1.02(3H，d)。

to a THF solution (130mL) of (S) -2- (tert-butoxycarbonyl) amino-1-propanol (4.95g), triphenylphosphine (11.12g) and N-hydroxyphthalimide (6.91g) was added diisopropylazocarboxylate (8.36g) at 0 ℃. After stirring for 3 hours at room temperature, the solvent was evaporated and purified by flash chromatography (SiO)₂n-Hexane EtOAc1:1) to give (S) -2- (tert-butoxycarbonyl) amino-1-phthalimidopropane (7.69g, 85%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):7.81(4H，m)，4.40(1H，m)，3.82(1H，m)，3.61(1H，m)，1.24(9H，s)，1.10(3H，d)。

to a solution of S) -2- (tert-butoxycarbonyl) amino-1-phthalimido-propane (7.69g) in MeOH (70mL)Hydrazine hydroxide (3.5mL) was added. After 1 hour the white solid was filtered, the solvent was evaporated and purified by flash chromatography (SiO)₂，CH₂Cl₂MeOH95:5) to give (S) -2- (tert-butoxycarbonyl) aminopropoxyamino (3.40g, 75%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.65(1H，bb)，5.96(2H，bs)，3.71(1H，m)，3.32(2H，m)，1.32(9H，s)，0.96(3H，d)。

to an EtOAc solution (30mL) of (S) -2- (tert-butoxycarbonyl) aminopropoxyamino (3.40g) was added a 5.9M EtOAc solution (10mL) of HCl at 0 ℃. After 30 minutes the white solid was filtered to give the title compound (2.40 g.82%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):11.12(2H，bs)，8.48(2H，bs)，4.08(2H，m)，3.52(1H，m)，1.25(3H，m)。

preparation 93

(R) -2-aminopropoxyamino dihydrochloride

Starting from (R) - (-) -2-amino-1-propanol (2.02g) with reference to the procedure in preparation 92 above, (R) -2- (tert-butoxycarbonyl) -aminopropanol (4.24g, 90%) was obtained, which was used in the next step without purification. ¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.40(1H，d)，4.51(1H，m)，3.64(1H，m)，3.10(1H，m)，3.34(1H，m)，1.46(9H，s)，1.02(3H，d)。

reference was made to the procedure in preparation 92 above, starting from (R) -2- (tert-butoxycarbonyl) aminopropanol (4.12g) and following flash chromatography (SiO)₂N-hexane CH₂Cl₂Acetone 6:3:1) to obtain (R) -2- (tert-butoxycarbonyl)Amino-1-phthalimidopropane (6.10g, 81%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):7.81(4H，m)，4.40(1H，m)，3.82(1H，m)，3.61(1H，m)，1.24(9H，s)，1.10(3H，d)。

reference was made to the procedure in preparation 92 above, starting from (R) -2- (tert-butoxycarbonyl) amino-1-phthalimidopropane (6.00g) in MeOH (40mL) and following flash chromatography (SiO)₂，CH₂Cl₂MeOH97.5:2.5) gave (R) -2- (tert-butoxycarbonyl) aminopropoxyamino (1.80g, 51.5%) as a green oil.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):6.65(1H，bb)，5.96(2H，bs)，3.71(1H，m)，3.32(2H，m)，1.32(9H，s)，0.96(3H，d)。

starting from (R) -2- (tert-butoxycarbonyl) aminopropoxyamino (1.80g) with reference to the procedure in preparation 92, (R) -2-aminopropoxyamino dihydrochloride (1.20g, 80%) was obtained as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):11.12(2H，bs)，8.48(2H，bs)，4.08(2H，m)，3.52(1H，m)，1.25(3H，m)。

preparation 94

3-amino-2-methyl-1-propoxyamino dihydrochloride

To a dry DMSO solution (40mL) of potassium tert-butoxide (2.78g) was added tert-butyl-N-hydroxycarbamate (3.00 g). After 5 minutes 2-bromoisobutyric acid (2.97g) in DMSO (50mL) was added dropwise, maintaining the temperature below 30 ℃. After 0.5 h at room temperature, the reaction was poured into ice/water (120mL) and extracted three times with EtOAc. Washing with water and brine And organic layer of Na₂SO₄The solvent was dried and evaporated to dryness to give methyl 2- (tert-butyl-N-hydroxycarbamoyl) isobutyrate (5.04g, 96%), which was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):9.53(1H，s)，3.66(3H，s)，1.40(9H，s)，1.33(6H，s)。

at-78 ℃ and N₂Methyl 2- (tert-butyl-N-hydroxycarbamoyl) -isobutyrate (2.00g) in stirring dried CH₂Cl₂Solution (20mL) CH of 1M DIBAH was added dropwise₂Cl₂Solution (17.14 mL). The mixture was stirred at-78 ℃ for 3 h, MeOH (28mL), Et was added carefully₂The reaction was stopped with O (30mL) and saturated aqueous sodium potassium tartrate (30 mL). After 1 hour Et₂The mixture was extracted three times. The combined organic layers were washed with water, brine, and Na₂SO₄Drying, the solvent was evaporated to dryness to give 2- (tert-butyl-N-hydroxycarbamoyl) -isobutyraldehyde (1.23g, 71%).¹H-NMR(300MHz，DMSO-d₆Ppm from TMS):10.02(1H，s)，9.58(1H，s)，1.38(9H，s)，1.17(6H，s)。

to a solution of 2- (tert-butyl-N-hydroxycarbamoyl) isobutyraldehyde (1.20g) in MeOH (15mL) in N₂Bottom additionMolecular sieves (120mg) and 4-methoxybenzylamino group (0.846 mL). After 1 hour, sodium cyanoborohydride (650mg) was added, and the resulting mixture was stirred at room temperature for 1 hour. The molecular sieve was filtered and the solvent was evaporated to dryness. The crude product was dissolved in 5% NaHCO₃Aqueous solution, with Et ₂O (3X), and washed with a saturated aqueous solution of NaCl. The organic layer was washed with Na₂SO₄Dried and evaporated to dryness. By flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26%NH₄OH94/6/0.6) to give 1- (tert-butyl-N-hydroxycarbamoyl) -2-methyl- [ N- (4-methoxybenzyl)]-2-propylamino (627mg, 32%)¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.9.85 (1H, bs), 7.21(2H, m), 6.84(2H, m), 3.71(2H, s), 3.57(2H, m), 2.38(2H, s), 1.38(9H, s), 1.09(6H, s).

Reacting 1- (tert-butyl-N-hydroxycarbamoyl) -2-methyl- [ N- (4-methoxybenzyl)]-2-propylamino (334mg) and 20% Pd (OH)₂Solution of a mixture of/C (83mg) in MeOH (4.66mL) and acetic acid (0.117mL) in H₂Stirred for 5 hours at medium 55psi pressure. The mixture was filtered through celite and the filtrate was evaporated to dryness. The crude product was dissolved in Et₂O (30mL) in 2N HCl, stirred overnight and concentrated. The crude product was filtered and washed with EtOH/Et₂O1/9 was washed and triturated with EtOAc overnight to give the title compound (0.110g, 60%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS). delta.7.90 (4H, bs), 3.03(2H, s), 6.84(2H, m), 1.23(6H, s).

Preparation 95

3-amino-2-methyl-2-propoxylamino-hydrochloride

To a solution of 2-methyl-2-propen-1-ol (0.856g) triphenylphosphine (4.67g) and N-hydroxyphthalimide (2.90g) in THF (90mL) at 0 deg.C was added diisopropylazocarboxylate (3.51 mL). After stirring for 2 hours, the solvent was evaporated and purified by flash chromatography (SiO) ₂cyclohexane/EtOAc 85/15) to yield 2- (2-methylallyloxy) isoindole-1, 3-dione (2.13g, 83%).¹H-NMR(300MHz，DMSO-d₆From ppm of TMS,. delta.7.80 (4H, bs), 5.02(2H, d), 4.54(2H, s), 1.83(3H, s).

To 2- (2-methylallyloxy) isoindole-1, 3-dione (0.705g) chloroacetonitrile (0.61mL) in CH₃COOH solution (0.56mL) at 0 deg.C 98% H was added₂SO₄(3.5 mL). After 1.5 hours ice was carefully added to stop the reactionThe reaction is carried out with 5% NaHCO₃Adjusting pH to 7 with CH₂Cl₂(3X) extraction. By H₂The combined organic extracts were washed with Na₂SO₄Drying and evaporating to dryness to give 2-chloro-N- [2- (1, 3-dioxo-1, 3-dihydroisoindol-2-yloxy) -1, 1-dimethyl-ethyl]Acetamide (0.93g, 92%) which was used directly in the next step.¹H-NMR(300MHz，DMSO-d₆In ppm TMS,. delta.7.75 (4H, bb), 4.32(2H, s), 3.87(2H, s), 1.35(6H, s).

2-chloro-N- [2- (1, 3-dioxo-1, 3-dihydroisoindol-2-yloxy) -1, 1-dimethylethyl]Acetamide (0.49g) in 6N HCl (10mL) was refluxed for 1.5 hours and then concentrated. The crude product was dissolved in water and Et₂And O washing. The aqueous solution was evaporated to dryness and the crude product was triturated with EtOH overnight to give the title compound.¹H-NMR(300MHz，DMSO-d₆From ppm of TMS). delta.11.02 (2H, bs), 8.31(2H, bs), 4.05(2H, s), 1.23(6H, s).

Preparation 96

7-Difluoromethylene androstane-3, 17-dione

Starting from 3,3:17, 17-bis (ethylenedioxy) androstan-7-one (preparation 42, 353mg) using the same reaction conditions as in preparation 31, flash chromatography (SiO 2)₂Cyclohexane CH₂Cl₂Acetone 8:1:1) gave 3,3:17, 17-bis (ethylenedioxy) -7-difluoromethyleneandrostane (115mg, 30%).¹H-NMR (300MHz, acetone-d)₆Ppm from TMS):3.85(8H，m)，2.10-0.9(20H，m)，0.96(3H，s)，0.83(3H，s)。

starting from 3,3:17, 17-bis (ethylenedioxy) -7-difluoromethyleneandrostane (135mg) using the same reaction conditions as in preparation 31, by flash chromatography (SiO)₂n-hexane/Et₂O1/1) to give the title compound (96 mg)，90%)。¹H-NMR(300MHz，DMSO-d₆δ 2.61-1.10(m, 20H), 1.22(s, 3H), 0.89(s, 3H), in ppm of TMS.

Preparation 97

3 beta- [3- (N-benzyloxy) -benzeneCarbonyl radical-N-methylamino) propionyloxy]-6- (E) -hydroxyiminoandrostanes Alk-17-ones

Referring to the procedure in preparation 38, starting from 3 β -hydroxyandrostane-6, 17-dione (preparation 68, 0.50g) and N-benzyloxycarbonyl-N-methyl-3-aminopropionic acid (0.39g) by flash chromatography (SiO)₂EtOAc-N-hexane 6:4) purification afforded 3 β - (N-benzyloxycarbonyl-N-methyl-3-aminopropionyloxy) androstane-6, 17-dione (0.79g, 90%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.7.32 (5H, m), 5.05(2H, s), 4.56(1H, m), 3.50-0.90(27H, m), 0.77(3H, s), 0.67(3H, s).

Reference to the procedure in preparation 20, preparation was carried out starting from 3 β - (N-benzyloxycarbonyl-N-methyl-3-aminopropionyloxy) androstane-6, 17-dione (0.70g) and hydroxylamine hydrochloride. By flash chromatography (SiO)₂N-hexane/acetone 60/40) to give the title compound (0.43g, 60%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.31 (1H, s), 7.30(5H, m), 5.05(2H, s), 4.56(1H, m), 3.50-0.87(27H, m), 0.78(3H, s), 0.68(3H, s).

Preparation 98

3 beta- [ (2, 2-dimethyl) -3- (benzyloxycarbonylamino) propionyloxy]-6- (E) -Hydroxyiminos Androstane-17-one

Referring to the procedure in preparation 68, from 3 β -hydroxyandrostane-6, 17-dione (preparation 68, 0.50g) and 3- (benzyloxycarbonylamino) -2, 2-dimethylpropionic acid (0.41g), by flash chromatography (SiO)₂Purification of EtOAc (n-hexane, 6:4) to obtain 3 beta- [ (2, 2-dimethyl) -3- (benzyloxycarbonylamino) propionyloxy]Androstane-617-dione (0.81g, 90%).¹H-NMR(300MHz，DMSO-d₆δ 7.34(5H, m), 5.07(2H, s), 7.01(1H, m), 4.57(1H, m), 2.50-1.10(22H, m), 1.10(6H, s), 0.78(3H, s), 0.70(3H, s), in ppm of TMS.

Reference procedure in preparation 20, starting from 3 β - [ (2, 2-dimethyl) -3-N-benzyloxycarbonylaminopropionyloxy ]Androstane-6, 17-dione (0.80g) starting from flash chromatography (SiO)₂N-hexane/acetone 60/40) to give the title compound (0.49g, 60%).¹H-NMR(300MHz，DMSO-d₆From the ppm of TMS,. delta.10.34 (1H, s), 7.34(5H, m), 5.07(2H, s), 7.01(1H, m), 4.57(1H, m), 3.00-1.10(22H, m), 1.10(6H, s), 0.78(3H, s), 0.72(3H, s).

Biological results

To detect Na⁺,K⁺Inhibition of the enzymatic activity of ATPases, Na was purified with reference to Jorghensen (Jorghensen P., BBA, 1974, 356, 36) and Erdmann (Erdmann E. et al, Arzneim. Forsh., 1984, 34, 1314)⁺,K⁺ATPase, and the inhibition can be determined in the presence or absence of the test compound³²Percent hydrolysis of P-ATP (MallF. et al, biochem. Pharmacol., 1984, 33, 47; see Table 1).

TABLE 1 dog Kidney Na ⁺ ,K ⁺ -ATPase inhibition

TABLE 1 dog Kidney Na ⁺ ,K ⁺ -ATPase inhibition (continuance)

Furthermore, the compounds of the invention have a contractile force enhancing feature, which can be seen in slow intravenous infusion of Cerri in anesthetized guinea pigs (Cerri a. et al, j.med.chem.2000, 43, 2332), and have lower toxicity (i.e. better therapeutic ratio) compared to standard cardiotonic steroids (e.g. digoxin).

Compared to compound 22b ((EZ)3- (2-aminoethoxyimino) androstane-6, 17-dione hydrochloride) reported in j.med.chem.2003, 64, 3644-3654 by s.de Munari et al, the compounds of the present invention have higher potency and/or better therapeutic ratio and/or longer duration of action. The activity of a portion of the compounds of formula (I) was determined in the above test and the results are shown in table 2 below. Contractile activity was shown as the greatest increase in contractile force (E) _maxMeasured as + dP/dT_max) Dose inducing maximal positive contractility (ED)_max) Shrinkage Efficacy (ED)₈₀Improved by 80% + dP/dT_maxThe dose of (c); toxicity is shown as the ratio of lethal dose to contractile potential, or as a safe ratio, (calculated in dead animals); maximum infusion dose in surviving animals; the duration of contraction is shown as ED measured 20 minutes after completion of infusion_maxThe effect of (c) is reduced.

TABLE 2 contractile action and lethal dose in anesthetized guinea pigs

As reported in table 2, these compounds showed positive contractile effect while having a higher safety ratio than digoxin and compound 22 b. Lethal dose/ED when virtually no animals die₈₀The ratio may be higher or even undetectable; value ofIt is noted that some of the compounds had lower animal mortality than digoxin and compound 22 b. In addition, some compounds showed longer duration of action, which was shown by the duration of contractile action after cessation of infusion (20 minutes after infusion by E)_maxReduction of%) of the sample. When no animals died, higher doses were not tested since the maximum increase in contractility was already comparable to or higher than digoxin and compound 22 b.

Additional data for the longer duration of action of the compounds of the invention have also been generated and the results are shown in Table 3, where the results of the metabolism of the compound in fresh rat hepatocytes (from Sprague Dawley, male, body weights in the range of 285-295 g; viability 80-90%; concentration: 2590000-3084000 hepatocytes/ml; test substance nominal concentration: 45. mu.M) are reported and compared with compound 22b (almost completely metabolized within 60 minutes).

TABLE 3 metabolism in rat hepatocytes

Ferrari et al, in Cardiovasular Drug Reviews, 1999, 17, 39-57, suggest that the compounds of the invention also have antihypertensive activity, demonstrate an effect on Na⁺,K⁺Compounds of the ATPase enzyme can lower blood pressure in models of hypertension.

The ability of these compounds to lower blood pressure was tested in animal models with induced hypertension (in particular in hypertensive rats generated by chronic infusion of ouabain, see Ferrari p., et al, j.

The procedure used to test the antihypertensive activity of this compound in the above model was as follows: systolic Blood Pressure (SBP) and Heart Rate (HR) were measured by indirect tail-cap method. The effect of lowering blood pressure was examined in hypertensive ouabain sensitive rats. The compound was suspended in Methocel0.5% (w/v) and administered orally at a dose of 10 μ g/kg/day for four weeks daily. SBP and HR were measured weekly 6 hours after treatment. For comparison, ouabain-sensitive rats (OS rats) and non-hypertensive rats (controls), both treated with Methocel0.5% (w/v) only, were used. As shown in Table 4 below, the blood pressure (170mm Hg) of OS rats treated with the compound of the present invention was reduced almost to the level of control rats (150mm Hg).

TABLE 4 systolic blood pressure drop in hypertensive ouabain-sensitive rats (OS rats)

Claims (15)

1. A compound of formula (I)

Wherein:

a isWherein the left-hand carbon atom of the group is in position 3 of the androstane skeleton;

b is C₁-C₆Straight or branched alkylene or C₃-C₆A cyclic alkylene group;

r, which may be the same or different¹And R²Is H, C₁-C₆Alkyl, optionally and R¹And R²Optionally substituted by one or more hydroxy, methoxy, ethoxy groups;

R³is H, OR¹²；

R¹²Is H, C₁-C₆Alkyl optionally substituted with one or more hydroxy, methoxy, ethoxy;

when connecting the carbon atom at position 6 of androstane skeleton with R⁴Key ofWhen it is a double bond, R⁴Is composed ofOr CR¹⁴R¹⁵；

When connecting the carbon atom at position 7 of androstane skeleton with R⁵Key ofWhen it is a double bond, R⁵Is O representing a ketone group, orOr CR¹⁴R¹⁵；

R¹³Is H, C₁-C₆Alkyl optionally substituted with one or more hydroxy, methoxy, ethoxy; or R¹³Is allyl or propargyl;

r, which may be the same or different¹⁴And R¹⁵Is H, C₁-C₆An alkyl group optionally substituted with one or more hydroxy, methoxy, ethoxy; or R, which may be the same or different¹⁴And R¹⁵Is allyl, propargyl, F, COOR¹⁶，CN，CONR¹⁷R¹⁸；R¹⁶Is H, C optionally substituted by one or more hydroxy, methoxy, ethoxy₁-C₆An alkyl group;

r, which may be the same or different ¹⁷And R¹⁸Is H, C₁-C₆An alkyl group, a carboxyl group,

when connecting the carbon atom at position 6 of androstane skeleton with R⁴Key ofWhen it is a single bond, R⁴Is H, C₁-C₆Alkyl radical, vinyl radical, ethynyl radical, COOR radical¹⁶，CN，CONR¹⁷R¹⁸，ONO₂，NHCHO，NHCOCH₃，Spirocyclic cyclopropane, spirocyclic oxirane, wherein the alkyl group may be optionally substituted with one or more hydroxy, methoxy, ethoxy groups;

when connecting the carbon atom at position 7 of androstane skeleton with R⁵When the bond of (A) is a single bond, R⁵Is H, C₁-C₆Alkyl radicals, OR¹⁹NHCHO, spirocyclopropan wherein the alkyl group may be optionally substituted with one or more hydroxy, methoxy, ethoxy;

R¹⁶，R¹⁷and R¹⁸As defined above;

R¹⁹is H, C optionally substituted by one or more hydroxy, methoxy, ethoxy₁-C₆An alkyl group;

R⁶is H, C₁-C₆Alkyl radicals or C₂-C₆Acyl groups, the bond in position 17 of the androstane skeletonWhen it is a single bond, the remaining substituent at position 17 is H, when the bond at position 17 isR6 is absent when it is a double bond representing a ketone group;

when R is¹⁶，R¹⁷And R¹⁸May be the same or different when present at different positions of the same compound;

symbolRepresents an alpha or beta single bond, or when it is attached to a double bond, an E or Z diastereomer;

symbols in positions 4, 5, 6, 7 and 17 Independently represents a single or double bond, and when it is a monocyclic external bond in positions 6, 7 and 17 it may be an alpha or beta single bond;

the conditions were as follows:

R³，R⁴and R⁵When the catalyst is not hydrogen at the same time,

their stereoisomers and mixtures thereof, and pharmaceutically acceptable salts.

2. The compound of claim 1, wherein the symbol R³And R⁵Represents H, R¹R²N and B are as defined above, wherein when R is attached in position 6⁴Symbol ofAnd symbol of position 17When representing a double bond and all other symbols represent a single bond, R⁴Represents methylene, difluoromethylene, oxyimino, methoxyimino or ethoxyimino, or when the symbols in position 17, excluding double bonds, all represent single bonds, R⁴Represents alpha-methyl, alpha-carbamoyl, alpha-methoxycarbonyl, alpha-hydroxymethyl, alpha-methoxymethyl, α -nitrooxy, α -formylamino, α -ethynyl, spirocyclic oxirane or spirocyclic cyclopropyl; their stereoisomers and mixtures thereof and pharmaceutically acceptable salts.

3. The compound of claim 1, wherein the symbol R³Represents hydroxy, the symbol R⁵Represents H and when R is attached in position 6⁴Symbol ofAnd symbol of position 17When representing a double bond and all other symbols represent a single bond, R ⁴Represents a methylene, hydroxyimino or methoxyimino group, or the symbol when in position 17When representing a double bond and all other symbols simultaneously represent a single bond, R⁴And R⁵Represents H, their stereoisomers and mixtures thereof and pharmaceutically acceptable salts.

4. The compound of claim 1, wherein the symbol R³And R⁴Represents H when R is attached in position 7⁵Symbol ofRepresents a double bond with all other symbolsWhen represents a single bond, the symbol R⁵Represents O, methylene, difluoromethylene, oxyimino or methoxyimino representing a ketone, or a symbol when in position 17When representing a double bond and all other symbols represent a single bond, the symbol R⁵Represents alpha-methyl, alpha-hydroxy, alpha-hydroxymethyl, alpha-methoxymethyl, alpha-carboxamido, beta-methyl, beta-hydroxymethyl, beta-methoxymethyl, or spirocyclopropyl, their stereoisomers and mixtures thereof and pharmaceutically acceptable salts thereof.

5. The compound of any one of claims 2-4, wherein a-B-NR¹R²Selected from the group consisting of 2-aminoethoxyimino, 3-aminopropoxyimino, 2- (N-methylamino) ethoxyimino, 3- (N-methylamino) propoxyiimino, their stereoisomers and mixtures thereof and pharmaceutically acceptable salts.

6. The compound of claim 1, selected from:

(E, Z)3- (2-aminoethoxyimino) -17-oxoandrostan-6 alpha-yl nitrate fumarate,

(E, Z)3- (2-aminoethoxyimino) -17-oxoandrostan-6 beta-yl nitrate fumarate,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-cyanoandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxyandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxy-6 beta-cyanoandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -6- (2-spiro-1, 3-dioxolane) androstan-17-one fumarate,

3- (E, Z) - (2-aminoethoxyimino) -17-oxoandrostane-6 alpha-carboxaldehyde (E, Z) -oxime fumarate,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetoxymethyl androstane-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carbamoylandrostan-17-one fumarate,

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -allyloxyiminoandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carboxamidoandrostan-17-one fumarate,

(E, Z) -3- (2-aminoethoxyimino) -5 alpha-hydroxy-6- (E) -hydroxyiminoandrostan-17-one fumarate,

(E, Z) -3- (2-aminoethoxyimino) -5 alpha-hydroxy-6- (E) -methoxyimino androstan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) androstane-7, 17-dione fumarate,

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -hydroxyiminoandrostan-17-one fumarate,

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -methoxyiminoandrostan-17-one fumarate,

(E, Z) -3- (2-aminoethoxyimino) -7- (E) -allyloxyiminoandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -7 alpha-hydroxyandrostan-17-one fumarate,

(E)3- (3-N-methylaminopropoxyimino) -6-methyleneandrostane-17-one fumarate,

(E, Z)3- (3-N-methylaminopropoxyimino) -6-methyleneandrostan-17-one fumarate,

(E, Z)3- (3-N-methylaminopropoxyimino) -5 alpha-hydroxy-6- (E) -methoxy-imino-androstan-17-one fumarate,

(E, Z)3- (3-N-methylaminopropoxyimino) androstane-7, 17-dione fumarate,

(E, Z)3- (3-N-methylaminopropoxyimino) -7- (E) -hydroxyiminoandrostan-17-one fumarate,

(E, Z)3- (2-aminoethoxyimino) -7 alpha-methoxyandrostan-17-one hemifumarate,

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-hydroxymethylandrostane-7, 17-dione fumarate.

7. The compound of claim 1, selected from:

(E, Z) -3- (2-aminoethoxyimino) -7 alpha-methylandrostane-6- (E) -hydroxy-imino-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6-methyleneandrostane-17-one hydrochloride,

(E)3- (2-aminoethoxyimino) -6-methylene androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 beta-hydroxymethylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 beta-methoxymethylandrostan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha- (2-hydroxyethyl) androstan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-hydroxymethylandrostane-17-one hydrochloride,

(E)3- (2-aminoethoxyimino) -6 alpha-methoxymethyl androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-carboxy androstane-17-one hydrochloride,

(Z)3- (2-aminoethoxyimino) -6 alpha-carbamoylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-methoxycarbonylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride,

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -methoxyiminoandrostan-17-one hydrochloride,

(E, Z) -3- (2-aminoethoxyimino) -6- (E) -ethoxyimino androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 beta-methylandrostan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-methylandrostan-17-one hydrochloride,

(E, Z) -3- (2-aminoethoxyimino) androstane-6 (S) - (spiro-2' -oxirane) -17-one hydrochloride,

(E, Z) -3- (2-aminoethoxyimino) androstane-6 (R) - (spiro-2' -oxirane) -17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-ethynylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetamido androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6- (E) -ethylideneandrostan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6-difluoromethyleneandrostane-17-one hydrochloride,

(E)3- (2-aminoethoxyimino) -17-oxoandrostane-6- (E) -ylideneacetonitrile hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6- (E) - [ 2-hydroxyethylidene ] androstane-17-one hydrochloride,

methyl [3- (E, Z) - (2-aminoethoxyimino) -17-oxoandrostan-6- (E) -ylidene ] -acetic acid ester hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6- (spirocyclopropane) androstan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-acetamidomethyl androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-formamidomethyl androstane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -5 alpha-hydroxy-6-methyleneandrostane-17-one hydrochloride,

(E, Z) -3- (2-aminoethoxyimino) -7 alpha-formamidoandrostane-3, 17-dione hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7-methyleneandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7 beta-methylandrostane-17-dione hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7 alpha-hydroxymethylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7 beta-hydroxymethylandrostane-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7- (spirocyclopropane) androstan-17-one hydrochloride,

3- (E, Z) - (2-aminoethoxyimino) -6- (Z) -hydroxyimino-7 alpha-hydroxyandrostan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -6 alpha-hydroxymethylandrostane-7, 17-dione hydrochloride,

(E, Z)3- (2-N-methylaminoethoxyimino) -6- (E) -methoxyimino androstan-17-one hydrochloride,

(E, Z)3- (2-N-methylaminoethoxyimino) -5 alpha-hydroxy-6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z)3- (2-N-methylaminoethoxyimino) -5 alpha-hydroxy-6-methyleneandrostane-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (E) -methoxyimino androstan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-hydroxymethylandrostan-17-one hydrochloride,

(Z, E)3- (3-N-methylaminopropoxyimino) -6 alpha-methoxycarbonylandrostan-17-one hydrochloride,

(Z, E)3- (3-N-methylaminopropoxyimino) -6 alpha-carbamoylandrostan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-formamidoandrostane-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6- (spirocyclopropane) androstan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -6 alpha-ethynylandrostan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -5 alpha-hydroxy-6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -5 alpha-hydroxy-6-methylene-androstan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -7- (spirocyclopropane) androstan-17-one hydrochloride,

(E, Z)3- (3-N-methylaminopropoxyimino) -7 beta-hydroxymethylandrostan-17-one hydrochloride,

(E, Z)3- (cis-4-aminocyclohexyloxyimino) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride,

(E, Z)3- (cis-2-aminocyclopentyloxyiimino) -6- (E) -hydroxyiminoandrostan-17-one hydrochloride,

(E, Z)3- (trans-2-aminocyclopentyloxyiimino) -6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z) -3- [ (S) -2-aminopropoxyimino ] androstane-6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z) -3- [ (R) -2-aminopropoxyimino ] androstane-6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z)3- (2-amino-2-methylpropoxyimino) -6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z)3- (3-amino-2-methyl-2-propoxyiimino) -6- (E) -hydroxyimino-androstan-17-one hydrochloride,

(E, Z)3- (2-aminoethoxyimino) -7-difluoromethyleneandrostane-17-one hydrochloride.

8. A process for the preparation of a compound according to claim 1, comprising the reaction of a compound of formula (II) with a compound of formula (III),

the symbol R in the general formula (II)³，R⁴，R⁵，R⁶Andas defined in claim 1, Y and Z together represent a keto group (═ O),

in the general formula (III)

R²R¹N-B-ONH₂(III)

R²，R¹And B is as defined in claim 1.

9. A process for preparing a compound of claim 1, wherein R, which are the same or different from each other⁴And R⁵Representing oximesThe method comprises the step of reacting a compound of a general formula (I) with a compound of a general formula H₂NOR¹³Of the compound of the general formula (I) as defined in claim 1, wherein R, which are the same or different from each other ⁴And R⁵To represent O of a keto group, in which process the group is to be converted into an oxime, formula H₂NOR¹³In R¹³Have the meaning of claim 1.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 7, in admixture with at least one pharmaceutically acceptable carrier and/or excipient.

11. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of a cardiovascular disorder.

12. The use according to claim 11, wherein the cardiovascular disorder is heart failure and/or hypertension.

13. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for inhibiting Na⁺，K⁺-ATPUse of an enzymatic activity of an enzyme in a medicament.

14. Use of a compound according to any one of claims 1-7 in the manufacture of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain.

15. The use according to claim 14, wherein the disease caused by the hypertensive effects of endogenous ouabain comprises renal failure progression in autosomal dominant polycystic kidney disease, preeclamptic hypertension and proteinuria and renal failure progression in patients with adducin polymorphisms.