HK1134097B

HK1134097B - Amino derivatives of b-homoandrostanes and b-heteroandrostanes

Info

Publication number: HK1134097B
Application number: HK09111582.2A
Authority: HK
Inventors: A‧塞利; B‧摩洛; M‧多利; G‧卡扎纳; G‧毕安祺; M‧费兰迪; P‧费拉里; M‧P‧扎帕比纳; L‧班菲; G‧加卡罗内
Original assignee: 希格马托制药工业公司
Priority date: 2006-06-23
Filing date: 2007-05-31
Publication date: 2013-06-28

Description

Amino derivatives of B-homoandrostanes and B-heteroandrostanes

Technical Field

The present invention relates to novel substituted B-homoandrostanes and B-heteroandrostane derivatives having an aminoalkoxyimino group at the 3-position, their preparation and pharmaceutical compositions containing them for the treatment of cardiovascular diseases, such as heart failure and hypertension.

Background

Cardiovascular disease remains a leading cause of morbidity and mortality in the western world; of which hypertension and heart failure are the two highest. Hypertension is one of the most important cardiovascular risk factors, with more than one third of the population over the age of 60 suffering from the disease. Congestive heart failure affects 1-2%, even 10% of the very aging population; this percentage is expected to rise (Sharpe N., et al., The Lancet, 1998, 352, (suppl.1), 3-17). Furthermore, hypertension is probably one of the most important causes of heart failure in the elderly population (eur. heart j., 2001, 22, 1527-. While there are many effective drugs available for the treatment of hypertension and heart failure, further research is ongoing to find more effective and safe compounds. Several drugs are used in combination to treat heart failure, while among the agents that increase the force of muscle contraction, digoxin is the digitoxin most commonly prescribed, which can improve the performance of the myocardium. The best known disadvantage of digitalis drugs is their side effect causing arrhythmia. Signs of Digitalis toxicity, such as conduction disturbances and arrhythmia, which are characteristic of Digitalis toxicity, occur in serum concentrations 2-to 3-fold higher than therapeutic doses (Hoffman, B.F.; Bigger, J.T., Digitalis and Allied Cardiac glycosides, in the pharmaceutical)l Basis of Therapeutics，8^th ed.；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 is closely related to their cardiotonic steroid structures with 17 β -lactone on the 14-hydroxy-5 β, 14 β -androstane skeleton.

In the field of 5 α, 14 α -androstane derivatives, some compounds have been reported to have muscle contractile force enhancing properties.

3- (aminoalkoxycarbonylalkylene) steroid derivatives are disclosed in GB 1,175,219 and US 3,580,905 which have digitalis-like activity and have the property that the ratio between the dose giving rise to the toxic symptoms (onset of arrhythmia) and the effective dose corresponds to that measured for standard cardiac glycosides. In addition to no significant advantage over digitonin, having the highest proportion of the compound also produces the lowest contractile force.

EP 0825197B1 discloses 6-hydroxy and 6-oxoandrostane derivatives which are Na⁺，K⁺Ligands and inhibitors of ATPase and agents that increase the force of muscle contraction, as evaluated on the basis of acute toxicity in mice, are less toxic than digoxin. S.de Munari et al, j.med.chem.2003, 46(17), 3644-.

Evidence showing that high levels of Endogenous Ouabain (EO), closely related ouabain isomers, are involved in hypertension and cardiac hypertrophy and failure in humans has stimulated pharmacological studies to develop new antihypertensive agents with ouabain antagonist activity. The pathogenesis of the effects of elevated EO levels on the cardiovascular system involves the regulation of Na-K atpase, a key enzyme responsible for tubular sodium reabsorption and activation of signal transduction pathways involved in gene transcription involved in growth. By studying genetic and experimental rat models of hypertension and comparing with humans, it has been demonstrated that elevated circulating EO levels and genetic polymorphisms of cytoskeletal protein adducin are associated with hypertension and high renal Na-K pumping power. Ouabain itself induces hypertension and up-regulation of renal Na-K pumping when slowly instilled in rats (OS) at low doses. In cultured kidney cells, Na-K pumping results were improved whether cultured with nanomolar concentrations of ouabain for several days or transfected with hypertensive adducin gene variants. Furthermore, both EO and adducin polymorphisms affect cardiac complications associated with hypertension, the former through activation of signal transduction pathways. As a result, compounds that are capable of interacting with cells and molecules maintained by EO or mutant adducin may represent an appropriate treatment modality for those patients affected by these mechanisms (Ferrandi M. et al, Curr Pharm Des.2005; 11 (25): 3301-5).

As reported above, the key point of the agent that increases the force of myocardial contraction is the ability to distinguish the efficacy of the inducing increase in force of myocardial contraction from the onset of arrhythmia.

There is a continuing need to prepare available drugs that exhibit better therapeutic ratios and/or longer duration of action, both of which are important factors in patient compliance. Preferably, such a medicament should be suitable for oral administration.

It is reported that different steroids with B ring enlarged and/or one carbon atom substituted by a heteroatom have different pharmacological activities and are active against Na⁺，K⁺ATPases have some action, or act as diuretics.

3-hydroxy and 3-keto B-plus-androstane derivatives are disclosed in JP 45023140 as anabolic and anti-androgenic steroids and in U.S. Pat. No. 3,000, 3059019 and J.J.Ringold J.Am.chem.Soc., 1960, 82, 961-propan 963 as anabolic and anti-gonadotropic compounds.

Natural or synthetic brassinolide (2, 3-dihydroxy-6-keto-7-oxa-7 a-carbo-addition derivatives) is reported to be a plant growth regulator (CS 274530), some of which are Na⁺，K⁺Inhibitors or stimulators of ATPase (L.Starka et al, Sbionik Lekarski, 1997, 98, 21-25).

US 3,328,408 claims 6-azaestrane as a diuretic and hypoglycemic agent and therefore useful in the treatment of congestive heart failure.

Compounds structurally similar to steroids with an oxygen atom in the B ring are inactive or almost inactive agents in hypertensive rats, even at very high doses (10mg/kg), as reported by r.k.razdan et al in j.med.chem., 1976, 19, 719-721.

Description of the invention

It has now been found that 3-aminoalkoxyimino derivatives of substituted B-homoandrostanes and B-heteroandrostanes meet the need to provide compounds with better therapeutic ratios and/or longer duration of action. The compounds of the invention have the general formula (I):

wherein:

a is a divalent group selected from:whereinThe symbol represents an alpha or beta single bond linking the a group to the androstane skeleton at position 5 or 8;

b is oxygen or NR⁴；

R³Is H or C₁-C₆An alkyl group;

x is oxygen, sulfur or NOR⁵；

R⁴Is H, C₁-C₆Alkyl, or when A isOrWherein B is NR⁴When R is⁴Is a formyl group;

R⁵is H or C₁-C₆An alkyl group;

R¹is H, C₁-C₆Alkyl or C₂-C₆Acyl group, in which case the bond at position 17 of the androstane skeletonIs a single bond; or

R¹Absent, this time the key at position 17Is a double bond;

R²is DNR⁶R⁷Or group

Wherein the group D or Z is attached to an oxygen atom;

d is C₂-C₆Straight or branched alkylene or C₃-C₆Cycloalkylene, optionally containing a phenyl ring;

R⁶and R⁷Identical or different is H, C₁-C₆Alkyl, phenyl-C₁-C₄Alkyl, or when R is⁶When it is hydrogen; or

R⁷Is C (═ NR)⁹)NHR¹⁰(ii) a Or

R⁶And R⁷And together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated or unsaturated monocyclic 4-, 5-or 6-membered ring, optionally containing another heteroatom selected from oxygen, sulfur or nitrogen; r⁶And R⁷Optionally substituted with one or more hydroxy, methoxy, ethoxy;

R⁸is H, C₁-C₆Straight or branched alkyl, optionally substituted with one or more hydroxy, methoxy, ethoxy, or C (═ NR)⁹)NHR¹⁰；

R⁹And R¹⁰Identical or different is H, C₁-C₆A linear or branched alkyl group; or

R⁹And R¹⁰Together with the nitrogen atom and the guanidine carbon atom form an unsubstituted or substituted saturated or unsaturated monocyclic 5-or 6-membered ring, optionally containing a further heteroatom selected from oxygen, sulphur or nitrogen;

z is C₁-C₄A linear or branched alkylene group or a single bond;

y is CH₂Oxygen, sulfur or NR¹¹；

R¹¹Is H, C₁-C₆An alkyl group;

n is 0, 1, 2 or 3;

m is 0, 1, 2 or 3;

symbol on 17 bitIndependently a single or double bond, and when it is an exocyclic single bond at position 17, it is an alpha or beta single bond.

In the case where the compound of formula (I) is capable of exhibiting tautomerism, this formula is intended to cover all tautomers; the present invention includes within its scope all possible stereoisomers, Z and E isomers, optical isomers (R and S) 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 pharmacologically acceptable acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, fumaric, succinic, oxalic, malic, tartaric, maleic, citric, methanesulfonic or benzoic acid and other acids commonly used in the art.

Said C₁-C₆The alkyl group may be a branched or straight chain or cyclic group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentyl or cyclohexyl.

Said C₂-C₆Alkylene groups may be branched or straight chain groups such as ethylene, trimethylene, propylene, tetramethylene, methylpropylene, dimethylethylene.

Said C₃-C₆The cycloalkylene group may be a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, or a cyclohexylene group.

Said C₂-C₆The acyl group may be a branched, straight chain or cyclic group, preferably acetyl, propionyl, butyryl, pivaloyl, cyclopentane-carbonyl.

Preferably, A is selected fromAnd

preferably, R⁶And R⁷Same or different, selected from H and C₁-C₆An alkyl group.

In the context of the present invention, metabolites and metabolic precursors mean active metabolites and metabolic precursors, i.e. compounds of formula (I) which are converted by metabolic reactions, but which substantially retain or enhance the 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).

Some compounds of formula (I) may also be prodrugs of the active form.

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

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostane-7, 17-dione hydrochloride;

(E, Z)3- (3-N-methylaminopropoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione fumarate;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-7 a-carbaandrostane-7, 17-dione fumarate;

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carb-7-thiaandrostan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostan-17-one dihydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-7 a-carbaandrostan-17-one dihydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-aza-6-formyl-7 a-homoandrostan-17-one hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-6-formyl-7 a-homoandrostan-17-one hydrochloride;

3- (E, Z) - (2-aminoethoxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostan-17-one hydrochloride;

3- (E, Z) - (3-N-methylaminopropoxyimino) -6-aza-7 a-carb-o-7- (Z) -hydroxyimino-androstan-17-one hydrochloride;

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyimino-androstan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carb-7- (Z) -methoxyimino-androstan-17-one hydrochloride;

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-7 a-carb-7- (Z) -methoxyimino-androstan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-homoandrostane-7, 17-dione hydrochloride;

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-aza-7 a-carbaandrostane-7, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-carbaandrostane-7, 17-dione hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-homoandrostan-17-one difumarate;

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-aza-7 a-carbaandrostan-17-one difumarate;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-carbaandrostan-17-one difumarate;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-formyl-7 a-homoandrostan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-oxa-7 a-homoandrostane-7, 17-dione fumarate;

(E, Z)3- (2-aminoethoxyimino) -7-oxa-7 a-homoandrostane-6, 17-dione hydrochloride;

(E, Z) -3- (3-N-methylaminopropoxyimino) -7-oxa-7 a-carbaandrostane-6, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7-oxa-7 a-carbaandrostane-6, 17-dione hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-oxa-7 a-homoandrostane-7, 17-dione hydrochloride;

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-oxa-7 a-carbaandrostane-7, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-oxa-7 a-carbaandrostane-7, 17-dione hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-oxa-7 a-homoandrostane-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-homoandrostane-17-one hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-homoandrostan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-oxa-5 β -androstane-7, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-azaandrostane-7, 17-dione hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -B-homoandrostane-17-one hydrochloride;

(E, Z) -3- [3- (R) -pyrrolidinyl ] oxyimino-B-homoandrostan-17-one hydrochloride;

(E, Z) -3- (3-N-methylaminopropoxyimino) -6-oxa-7 a-carbaandrostane-7, 17-dione fumarate;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-oxa-7 a-carbaandrostane-7, 17-dione fumarate;

(E, Z) -3- (2-aminoethoxyimino) -6-oxa-7 a-homoandrostane-17-one hydrochloride;

(E, Z) -3- (2-aminoethoxyimino) -7 a-oxa-7 a-homoandrostane-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-azaandrostane-7, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-azaandrostane-7, 17-dione fumarate;

and the corresponding pure E and Z isomers of the EZ mixtures described above, and the S diastereomer of the R diastereomer described above, as well as RS mixtures.

In particular, the following pure E and Z isomers were prepared:

(E)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostane-7, 17-dione fumarate;

(Z)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostane-7, 17-dione fumarate;

(Z)3- (2-aminoethoxyimino) -6-aza-6-methyl-7 a-homoandrostane-7, 17-dione hydrochloride; and

(E)3- (2-aminoethoxyimino) -6-aza-6-methyl-7 a-homoandrostane-7, 17-dione hydrochloride.

The compounds of formula (I) can be prepared from readily available starting materials using the following general methods and procedures. It is to be understood that, unless otherwise indicated, where general or preferred test conditions (i.e., reaction temperatures, times, molar amounts of reagents, solvents, etc.) are given, other test conditions may also be used. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

The invention further provides a method for preparing the compound of the general formula (I) by taking the compound of the general formula (II) as a raw material,

wherein, the symbol A, R¹Andhaving the above meaning, the process is: reacting a compound of formula (II) with a compound of formula (III) as a free base or as a salt, e.g. as a dihydrochloride salt, in a polar solvent, e.g. dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, pyridine, water or mixtures thereof at a temperature of 0 ℃ to reflux temperature

R²ONH₂ (III)

Wherein R is²Have the above-mentioned meanings. The reaction may be carried out in the presence of a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, or in the presence of an acid, such as hydrochloric acid, hydrobromic acid, acetic acid, or a salt, such as sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium hydrogen phosphate, sodium or potassium dihydrogen phosphate.

In which R is⁶And R⁸Being hydrogenReaction of the corresponding compounds of the formula (I) with compounds of the formula (IV)

TC(＝NR⁹)NHR¹⁰ (IV)

Wherein R is⁹And R¹⁰Having the above-mentioned meaning and T is a leaving group, such as methylthio or 1-pyrazolyl, the following compounds of the general formula (I) can be obtained: a, R therein¹Andhas the above-mentioned meaning, and R²Is DNR⁶R⁷Or the following groups

Wherein R is⁷Or R⁸Is C (═ NR)⁹)NHR¹⁰Wherein R is⁹And R¹⁰Have the above-mentioned meanings. The reaction can be carried out in a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, water or a mixture thereof, at a temperature of 0 ℃ to reflux temperature, optionally in the presence of a base such as sodium or potassium hydroxide, triethylamine, diethylisopropylamine.

Commercially known compounds having suitable functionality at different positions, such as 3 β,17 β -dihydroxyandrost-5-ene-7-one and 3 β -hydroxyandrost-5-ene-7, 17-dione, or compounds already reported in the literature, such as 3, 3: 17, 17-bis (ethylenedioxy) androstan-6-one, 6 α -hydroxyandrostan-3, 17-dione (both reported in j.med.chem., 2003, 46(17), 3644, s.demmunari et al), or 3, 3: 17, 17-bis (ethylenedioxy) androst-5-en-7-one (Pui-Kai Li and R.W.Brueggemeer, reported in J.Med.chem.1990, 33, 101-105) to prepare the compounds of formula (II) defined above. The above-reported series of compounds are only examples of the reported preparation method of the compound (II), and do not limit the scope of the present invention.

Wherein A isOrAnd X is oxygen, by reacting the corresponding A withIs converted into the corresponding cyanohydrin (cyanidrin), which is then reduced to the amino alcohol, and finally diazotized.

The cyanohydrin (cyanohydrin) can be obtained by reaction with sodium cyanide or potassium cyanide in a solvent such as ethanol, dioxane, dimethyl sulfoxide, water or a mixture thereof in the presence of an acid such as sulfuric acid or acetic acid at 0 ℃ to room temperature, or by treatment of the ketone with another cyanohydrin, such as acetone cyanohydrin, in a solvent such as one of ethanol, dioxane, dimethyl sulfoxide, water or a mixture thereof, or with the cyanohydrin itself as a solvent at 0 ℃ to room temperature. The cyanohydrins can also be obtained by treating cyanotrimethylsilane in the presence of a Lewis acid or base, followed by hydrolysis of the silyl ether.

Can be used in metal catalysts, such as Pd/C, PtO₂The cyanohydrin is reduced to the corresponding amino alcohol by catalytic hydrogenation in the presence of Pt, Pt/C or Raney nickel with hydrogen or under hydrogen transfer conditions. Ammonium formate, sodium hypophosphite or cyclohexadiene can be used as hydrogen transfer agent. The reaction can be carried out in a solvent such as ethanol, methanol, ethyl acetate, dioxane, tetrahydrofuran, acetic acid, N-dimethylformamide, water, or a mixture thereof, at 0 ℃ to reflux temperature, atmospheric pressure-10 atm. The hydroxylation may also be carried out with a reducing agent such as lithium aluminium hydride in an inert solvent such as diethyl ether, tetrahydrofuran or dioxane at temperatures from 0 ℃ to refluxAnd (4) reducing the nitrile.

Conversion of an aminoalcohol to where A is a salt of sodium nitrite or potassium nitrite can be accomplished by diazotization with an acid such as sulfuric acid, hydrochloric acid or acetic acid in a solvent such as one of ethanol, dioxane, dimethyl sulfoxide, water or mixtures thereof at a temperature of 0 deg.C to room temperatureOrAnd X is oxygen.

Also in Lewis acids, e.g. BF₃·Et₂In the presence of O in a solvent such as diethyl ether, tetrahydrofuran or dichloromethane at a temperature of-70 ℃ to reflux temperature by treating with diazomethane or trimethylsilyldiazomethane wherein A isTo a compound of (a) wherein a isAnd X is oxygen.

In a solvent such as toluene or acetonitrile at a temperature of from 0 ℃ to reflux temperature, wherein A isOrAnd X is oxygen with Lawesson's reagent or P₂S₅The reaction can obtain the compound in which A isOrAnd X is sulfur.

Formula H as a free base or as a salt, e.g. as a hydrochloride salt, in a solvent, e.g. dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, pyridine, water or mixtures thereof at a temperature of 0 ℃ to reflux temperature₂NOR⁵Wherein R is⁵As described above, treating wherein A isOrA compound of the general formula (II) in which the substituent A isOrAnd X is NOR⁵A compound of the general formula (II). The reaction may be carried out in the presence of a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, or in the presence of an acid, such as hydrochloric acid, hydrobromic acid, acetic acid, or in the presence of a salt, such as sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium phosphate.

Treating with a base such as sodium or potassium hydroxide, sodium or potassium ethoxide, or Na dissolved in an alcohol, potassium butoxide dissolved in DMSO, in a solvent such as ethanol, butanol, pentanol, 1, 2-ethanediol at a temperature of from 0 ℃ to reflux temperatureOrWherein R is^WIs H, C₆H₅Tosyl group, wherein the substituent A isA compound of the general formula (II). The same reaction can be carried out with a reducing agent, for example lithium aluminium hydride in tetrahydrofuran, sodium cyanoborohydride in methanol or ethanol, at temperatures from 0 ℃ to reflux, optionally in the presence of a Lewis acid such as zinc chloride, or sodium borohydride in methanol or ethanol. At a temperature of from 0 ℃ to the reflux temperature, of the general formula H₂NNR^WAs a solvent, or in a solvent such as one of ethanol, dioxane, dimethyl sulfoxide, water or mixtures thereof, such that A isOrOf the general formula (II) and of the general formula H₂NNR^WBy reaction of a compound of (a) to obtain a compound of (b) wherein A isOrWherein R is^WIs H, C₆H₅And a methanesulfonyl compound.

In a solvent such as ethanol, water or dioxane or mixtures thereof, at temperatures from 0 ℃ to reflux temperature, with, for example, Raney-nickel pairs where A isOrBy catalytic hydrogenation of a compound of (a) to obtain a compound of (a) whereinA compound of the general formula (II). In a solvent such as diethyl ether, tetrahydrofuran or dioxane at 0 deg.C to reflux temperatureOrWith HS (CH)₂)_2-3SH and Lewis acids, e.g. BF₃·Et₂O reaction can obtain the compound in which A isOrThe compound of (1).

In compatible solvents, for example methanol, ethanol, water and diethyl ether or tetrahydrofuran suitable for the former, with metal hydrides, for example sodium borohydride or lithium aluminium hydride, with sodium dissolved in alcohols, for example ethanol or methanol, or in solvents such as ethanol, methanol, ethyl acetate, dioxane, tetrahydrofuran, acetic acid, N-dimethylformamide, water or mixtures thereof, by reaction with, for example, Pd/C, PtO₂Pt, Pt/C or Raney nickel catalytic hydrogenation wherein A isOrA compound of the general formula (II) in which the substituent A isAnd R is³A compound of formula (II) which is hydrogen. All the reactions can be carried out at 0 ℃ to reflux temperature, atmospheric pressure-10 atm.

Wherein the substituent A isAnd R is³Is C₁-C₆The compounds of the general formula (II) of alkyl radicals can be prepared from those in which A isAnd R is³A compound of the formula (II) and of the formula R which is hydrogen³Compounds of LG, wherein LG is a leaving group, such as chloro, bromo, iodo, methanesulfonyloxy, p-methanesulfonyloxy, trifluoromethanesulfonyloxy. The reaction may be carried out at a temperature of from 0 ℃ to reflux temperature, optionally in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium or potassium hydride, sodium or potassium cyanide, sodium or potassium methoxide, sodium or potassium tert-butoxide, and optionally in the presence of a salt such as sodium or potassium iodide, in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, dimethyl sulfoxide, toluene or mixtures thereof. The reaction can also be carried out in the presence of sodium or potassium hydroxide and a quaternary ammonium salt, such as tetrabutylphosphonium chloride or bromide or iodide or ammonium bisulfate, in a mixture of organic solvents, such as dichloromethane, chlorobenzene, toluene, hexane and water, at a reflux temperature of 0 ℃ to the mixture.

Treating the corresponding with a peroxide, e.g. hydrogen peroxide, or a peroxy acid, e.g. m-chloroperbenzoic acid or peroxytrifluoroacetic acid or peroxyacetic acidThe derivatives can be obtained inThe substituent A isOrAnd B and X are oxygen. The reaction may be carried out at a temperature of from 0 ℃ to reflux temperature, optionally in the presence of a buffer, e.g. disodium hydrogen phosphate, in a solvent such as dichloromethane, chloroform, toluene or mixtures thereof. Treatment of the secoandrostane 5-keto-6-oic acid B derivative with sodium borohydride followed by acidification may also be obtained wherein the substituent A isAnd B and X are oxygen. The 5-androstene derivative can be treated with ozone, potassium permanganate or sodium periodate to obtain 5-keto-6-acid B secoandrostane derivative.

At temperatures from 0 ℃ to reflux, depending on the nature of the reagents, in solvents such as toluene, dichloromethane, pyridine, or using said solvents as solvents, with, for example, SOCl₂2, 4, 6-trichloro-1, 3, 5-triazine, methanesulfonyl chloride, P₂O₅、POCl₃、H₂SO₄By treating 6-or 7-hydroxyiminoandrostane derivatives, which are obtained by reaction of the substituents AOrB is NR⁴Wherein R is⁴The compound of formula (II) which is hydrogen and X is oxygen is optionally subsequently treated with a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine, pyridine in a solvent, such as methanol, ethanol, or water or a mixture of said solvents, at room temperature to reflux temperature.

With the general formula R⁴Compounds of formula (I) -LG, wherein LG is ionoBy a radical, e.g. chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, in which the substituent A isOrB is NR⁴Wherein R is⁴Corresponding compounds of the general formula (II) in which the substituent A is hydrogen and X is oxygen are obtainedOrB is NR⁴Wherein R is⁴Is C₁-C₆Alkyl, X is oxygen. The reaction may be carried out in a solvent such as diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, N-dimethylformamide, dimethyl sulfoxide, toluene or a mixture thereof, at from 0 ℃ to reflux temperature, optionally in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, sodium or potassium hydride, sodium or potassium cyanide, sodium or potassium methoxide, sodium or potassium tert-butoxide, and optionally in the presence of a salt such as sodium or potassium iodide. The reaction can also be carried out in a mixture of organic solvents such as dichloromethane, chlorobenzene, toluene, hexane and water, in the presence of sodium or potassium hydroxide and a quaternary ammonium salt, for example tetrabutylphosphonium chloride or bromide or iodide or ammonium bisulfate, at a reflux temperature of 0 ℃ to the mixture.

At temperatures from 0 ℃ to reflux in a Lewis acid, e.g. BF₃·Et₂Reduction with mixed hydrides, for example sodium borohydride or lithium aluminium hydride, in solvents such as diethyl ether, tetrahydrofuran or dioxane, in the presence of O, or catalytic hydrogenation on Pd/C in alcohols, from which A isAnd B and X are oxygen, to obtain compounds of the general formula (II) in which the substituent A isOrAnd B is oxygen.

By reduction of a mixed hydride in which the substituent A isAnd compounds of formula (II) wherein B and X are oxygen, then give the corresponding diols which can be converted into the desired ethers by treatment with methanesulfonyl chloride or thionyl chloride in a solvent such as diethyl ether, toluene, dichloromethane, pyridine, in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine at temperatures from 0 ℃ to reflux temperature, whereby compounds can be obtained wherein substituent A is oxygenOrAnd B is O.

Reduction of a compound wherein A isOrWherein B is NR⁴X is oxygen and R⁴Is hydrogen or C₁-C₆Alkyl compounds of the general formula (II) from which they are obtainableA isOrWherein B is NR⁴And R is⁴Is hydrogen or C₁-C₆Alkyl compounds of the general formula (II).

In a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, pyridine, water or a mixture thereof at 0 ℃ to reflux temperatureOrWherein B is oxygen or NR⁴，R⁴Is hydrogen or C₁-C₆Compounds of the formula (II) in which X is sulfur and H in the form of the free base or of a salt, for example the hydrochloride₂NOR⁵Wherein R is⁵As described above, the reaction is carried out to obtain a compound wherein A isOrAnd B is oxygen or NR⁴，R⁴Is hydrogen or C₁-C₆Alkyl, X is NOR⁵A compound of the general formula (II). The reaction may be carried out in the presence of a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, or an acid, such as hydrochloric acid, hydrobromic acid, acetic acid, or a salt, such as sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium hydrogen phosphate, sodium or potassium dihydrogen phosphate.

At a temperature of from 0 ℃ to reflux temperature, optionally in the presence of water and a base, such as sodium bicarbonate, sodium acetate or sodium phosphateIn which A isWith KMnO in tert-butanol₄Or NaIO₄By reaction with RuCl or in a solvent, for example ethyl acetate, carbon tetrachloride, acetonitrile and water or mixtures of said solvents₃Or RuO₂And NaIO₄Or NaBrO₃Wherein A isAnd B and X are oxygen.

With KMnO in tert-butanol at temperatures from 0 ℃ to reflux temperature, optionally in the presence of water and a base, such as sodium bicarbonate, sodium acetate or sodium phosphate₄Or NaIO₄By reaction with RuCl in a solvent such as ethyl acetate, carbon tetrachloride, acetonitrile and water or mixtures of said solvents₃Or RuO₂And NaIO₄Or NaBrO₃After reaction with ammonia, an ammonium salt, e.g. ammonium acetate or ammonium formate, or with compounds of the formula H₂NR⁴To give the methanolamide, from which A isA compound of the general formula (II) in which A isAnd B is NR⁴，R⁴Is hydrogen or C₁-C₆Alkyl, X is oxygen. The latter are dehydrated with dehydrating reagents, e.g. thionyl chloride, phosphorus oxychloride, p-toluenesulfonic acid, and the enamines are catalytically hydrogenated to give compounds in which A isAnd B isNR⁴，R⁴Is hydrogen or C₁-C₆Alkyl, X is oxygen.

By reaction with H in the form of the free base or a salt, for example the hydrochloride salt, in a solvent such as dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, methanol, ethanol, N-dimethylformamide, pyridine, water or mixtures thereof at temperatures from 0 ℃ to reflux temperature₂NOR⁵Wherein R is⁵The reaction of a compound as described above, from which A isWherein B is oxygen or NR⁴，R⁴Is hydrogen or C₁-C₆A compound of the general formula (II) in which A isAnd B is oxygen or NR⁴，R⁴Is hydrogen or C₁-C₆Alkyl, X is NOR⁵A compound of the general formula (II). The reaction may be carried out in the presence of a base, such as sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, or an acid, such as hydrochloric acid, hydrobromic acid, acetic acid, or a salt, such as sodium or potassium acetate, sodium or potassium phosphate, disodium or dipotassium hydrogen phosphate, sodium or potassium dihydrogen phosphate.

At temperatures from 0 ℃ to reflux in a Lewis acid, e.g. BF₃·Et₂By reduction with mixed hydrides, for example sodium borohydride or lithium aluminium hydride, in a solvent such as diethyl ether, tetrahydrofuran or dioxane, in the presence of O, or by catalytic hydrogenation on Pd/C in an alcohol, it being possible to obtain compounds of the formulaAnd B and X are oxygen, to obtain compounds of the general formula (II) in which the substituent A isAnd B is oxygen.

By reduction of a mixed hydride in which the substituent A isCompounds of formula (II) wherein B and X are oxygen give the corresponding diols which are converted to the desired ethers by treatment with tosyl chloride or thionyl chloride in the presence of a base such as pyridine, triethylamine, 4-dimethylaminopyridine in solvents such as diethyl ether, toluene, dichloromethane, pyridine at temperatures from 0 ℃ to reflux temperature, it is also possible to obtain compounds wherein substituent A is oxygenAnd B is O.

Reduction of a compound in which A isWherein B is NR⁴Wherein R is⁴Is hydrogen or C₁-C₆Compounds of the general formula (II) in which A is alkyl and X is oxygen are obtainedAnd B is NR⁴Wherein R is⁴Is hydrogen or C₁-C₆Alkyl compounds of the general formula (II).

At a temperature of from 0 ℃ to reflux temperature, wherein A isOrWherein B is oxygen or NR⁴Which isIn R⁴Is hydrogen or C₁-C₆Alkyl, corresponding compounds of the general formula (II) in which X is O, with Lawesson's reagent or P₂S₅The reaction can obtain the compound in which A isOrB is oxygen or NR⁴Wherein R is⁴Is hydrogen or C₁-C₆A compound of the general formula (II) wherein X is sulfur.

In the presence of a condensing agent, for example N, N '-carbonyldiimidazole, optionally in the presence of a base, for example triethylamine, diethylisopropylamine, 4-dimethylaminopyridine, pyridine, in a solvent such as dichloromethane, chloroform, acetone, tetrahydrofuran, dioxane, N' -dimethylformamide, with formic acid or formic acid, for example dissolved in acetic anhydrideOrAnd B is NR⁴Wherein R is⁴The formylation of compounds of the general formula (II) in which A is hydrogenOrAnd B is NR⁴Wherein R is⁴A compound of formula (II) which is a formyl group.

In all of the variants described, any interfering reactive groups can be protected before being reacted with the organic compounds described (see, for example, T.W. Greene) and P.G.M.Wuts“Protective Groups in Organic Synthesis”，J.Wiley&Sons，Inc.，3^rdEd, 1999) are well established and well known procedures to those skilled in the art for deprotection.

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

The compounds of formula (III) and (IV) are commercially available or can be prepared from commercially available compounds via standard procedures.

One aspect of the present invention is represented by a method of treating a mammal suffering from a cardiovascular disease comprising administering a therapeutically effective amount of a compound of formula (I) as described above. The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent required to treat, alleviate a target disease or condition, or to exhibit a detectable therapeutic effect.

For any compound, the therapeutically effective dose can be estimated initially in cell culture assays or in animal models, typically mouse, rat, guinea pig, rabbit, dog or pig.

Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the dosage and route of administration available to a human.

The precise effective dose for a human patient will depend upon the severity of the disease state, the general health of the patient, the age, body weight and sex of the patient, diet, time and frequency of administration, drug combination, response sensitivity, and tolerance/response to therapy. This amount can be determined by routine experimentation, within the judgment of the clinician. Generally, an effective dose is 0.01mg/kg to 100mg/kg, preferably 0.05mg/kg to 50 mg/kg. The compositions may be administered to the patient alone or in combination with other agents, drugs or hormones.

For administration of the therapeutic agent, the medicament may also contain a pharmaceutically acceptable carrier. Such vectors include antibodies and other polypeptides, genes, and other therapeutic agents, such as liposomes, provided that the vector itself does not induce the production of antibodies that are detrimental to the absorption of the composition by the individual, and that administration of the vector does not result in excessive toxicity.

Suitable carriers may be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive viral particles.

A detailed discussion of pharmaceutically acceptable carriers can be found in Remington's pharmaceutical Sciences (Mack pub. Co., N.J.1991).

The pharmaceutically acceptable carrier in the therapeutic composition may additionally contain liquids such as water, saline, glycerol and ethanol. In addition, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances and the like may also be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for ingestion by a patient.

Once formulated, the compositions of the present invention can be administered directly to a patient. The patient to be treated may be an animal; in particular, human patients may be treated.

The agents of the present invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intraventricular, transdermal or transdermal administration, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intrathecal, rectal means or topical administration at the diseased tissue post-operatively.

The dose treatment may be a single dose schedule or a multiple dose schedule.

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.

Since the compounds of the present invention are shown to antagonize the molecular effects on Na-K atpase induced by nanomolar ouabain, 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 disease caused by the hypertensive effects of endogenous ouabain comprises: exacerbation of renal failure in Autosomal Dominant Polycystic Kidney Disease (ADPKD), preeclamptic hypertension, and exacerbation of proteinuria and renal failure in patients with adducin polymorphisms.

In Autosomal Dominant Polycystic Kidney Disease (ADPKD), cyst formation and enlargement are due to cell proliferation and transepithelial secretion of fluids, thereby leading to increased damage to renal function and renal failure. In 1 of 1000 subjects, ADPKD was affected, which represents the first genetic cause of renal failure. Renal Na-K ATPases are required for the transport of ions and fluids in ADPKD cells, and mislocation (mislocalization) and functional alterations have been described in this pathology (Wilson PD et al, Am J Pathol 2000; 156: 253-268). Ouabain is a Na-KATP enzyme inhibitor, micromolar concentrations of ouabain inhibit fluid secretion in ADPKD cysts (Grantham J J et al, I Clin. invest.1995; 95: 195- "202), in contrast to nanomolar concentrations of ouabain which are similar to circulating endogenous ouabain, which stimulate ADPKD cell proliferation but do not affect normal human renal cell growth (Nguyen AN et al, 2007; 18: 46-57). Ouabain has been shown to stimulate ADPKD proliferation by binding with high affinity to Na-KATP enzymes and triggering activation that stimulates the MEK-ERK pathway (Nguyen ANet al, 2007; 18: 46-57).

Preeclampsia is a potentially devastating disease of gestational hypertension for which there is still a lack of effective treatment. Increased circulating levels of casinoside and bufadienolides (bufodienolides) 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). Available data indicate that elevated plasma concentrations of Na-K ATPase inhibitors lead to vasoconstriction and malignant hypertension in the pre-eclamptic phase (Vu HV et al, Am J Nephrol.2005; 25: 520-528). It has recently been shown that the digoxin-specific Fab (digibind) is capable of lowering blood pressure and increasing urinary sodium excretion in preeclamptic patients (Pullen MA al. JPET 2004; 310: 319-.

Proteinuria associated with glomerulosclerosis is caused by an impairment of the structure of the hiatus formed by podocyte processes in the glomerulus. In particular, the membrane proteins of the cleft, such as phenylephrine, ZO1, podocyn, synaptopodin, etc., in addition to their structural functions, are involved in the general signaling pathway regulated by the tyrosine kinase Fyn of Src family kinases (Benzing T.J Am Soc Nephrol 2004; 15: 1382-. Recently, it was thought that a key role in the structure of the split pore is β adducin, a cell scaffold protein controlled by Fyn (Gotoh BBRC 2006; 346: 600-. The ACE-linked adducin polymorphism has been found to be associated with renal function impairment in European and Chinese populations (Wang JG et al, J MolMed 2004; 82: 715-. Rosafuroxin and analogs as ouabain antagonists have been described as being able to antagonize 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 Regul 2006; 290: R529-535; Ferrari P.et al, Med Hypothes.2007; 68; 1307-1314).

A further object of the present invention is a pharmaceutical composition containing one or more compounds of formula (I) as described previously, together with excipients and/or pharmacologically acceptable diluents.

The compositions in question may all contain known active effects together with the compounds of formula (I).

A further embodiment of the present invention is a process for the preparation of a pharmaceutical composition, characterized in that one or more compounds of formula (I) are mixed with suitable excipients, stabilizers and/or pharmaceutically acceptable diluents.

The invention will now be illustrated in more detail by way of non-limiting examples.

Examples

The following examples report the synthesis of some compounds of formula (I), while the preparations report the synthesis of useful intermediates.

Example 1

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione hydrochloride (I-aa)

To a stirred solution of 6-aza-7 a-plus-carbaandrostane-3, 7, 17-trione (II-a, preparation 1, 1.028g) in THF (58mL) was added 2-aminoethoxyamine dihydrochloride (0.482g) and Na rapidly dropwise₂HPO₄·12H₂H of O (2.32g)₂O (14mL) solution. After 4h, NaCl (0.5g) was added and the mixture was stirred for 10 min. The phases were separated and the aqueous phase was extracted with 1/1 THF/tBuOH (3X) followed by tBuOH (3X). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. The crude product was triturated with EtOAc for 4h and the precipitate was filtered to give the title compound I-aa (1.247g, 93%) as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.97(bb, 3H), 7.26(d, 0.5H), 7.22(d, 0.5H), 4.09(m, 2H), 3.52(m, 1H), 3.15(m, 0.5H), 3.02(m, 2H), 2.93(m, 0.5H), 2.45-1.00(m, 18H), 0.84(s, 3H), 0.79(s, 3H).

Example 2

(E, Z)3- (2-N-methylaminoethoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione fumarate (I-ab)

The product was prepared in 51% yield as described in example 1 starting from 6-aza-7 a-carbaandrostane-3, 7, 17-trione (II-a, preparation 1, 70mg) and 2-N-methylaminoethoxyamine dihydrochloride (III-a, preparation 15, 36 mg). The crude product was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 85/15/1.5). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. 1/1 EtOAc/Et was added₂The mixture was then filtered to give the title compound I-ab as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.00(bb, 3H), 7.25(d, 0.5H), 7.22(d, 0.5H), 6.40(s, 2H), 4.09(m, 2H), 3.49(m, 1H), 3.11(m, 0.5H), 3.01(m, 2H), 2.91(m, 0.5H), 2.47(s, 3H), 2.30-1.00(m, 18H), 0.83(s, 3H), 0.79(s, 3H).

Example 3

(E, Z)3- (3-N-methylaminopropoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione fumarate (I-ac)

The product was prepared in 76% yield as described in example 1 starting from 6-aza-7 a-carba-androstane-3, 7, 17-trione (II-a, preparation 1, 382mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 213 mg). The crude product was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 85/15/1.5). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. 1/1 EtOAc/Et was added₂The mixture was then filtered to give the title compound I-ac.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 8.00(bb, 3H), 7.21(d, 0.5H), 7.19(d, 0.5H), 6.42(s, 2H)H)，3.97(m，2H)，3.50(m，1H)，3.10-2.80(m，3H)，2.47(s，3H)，2.30-1.00(m，20H)，0.83(s，3H)，0.79(s，3H)。

Example 4

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-7 a-carbaandrostane-7, 17-dione fumarate (I-ad)

The product was prepared in 88% yield as described in example 1 starting from 6-aza-7 a-carbaandrostane-3, 7, 17-trione (II-a, preparation 1, 334mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 171 mg). The crude product was purified by flash chromatography (SiO)₂，CHCl₃/MeOH/26％NH₄OH 85/15/1.5). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. 1/1 EtOAc/Et was added₂The mixture was then filtered to give the title compound I-ad.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 10.00(bb, 3H), 7.22(d, 1H), 6.42(s, 2H), 4.74(m, 1H), 3.51(m, 1H), 3.35-3.00(m, 4.5H), 2.86(m, 0.5H), 2.50-0.97(m, 20H), 0.83(s, 3H), 0.79(s, 3H).

Example 5

(E, Z)3- (2-aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ae)

The product was prepared in 40% yield as described in example 1 starting from 6-aza-6-methyl-7 a-carbaandrostane-3, 7, 17-trione (II-b, preparation 2, 90mg) and 2-aminoethoxyamine dihydrochloride (40 mg). The phases were separated and the aqueous phase was extracted with THF (3 ×). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. With Et₂The crude product was triturated and filtered to give the title compound I-ae as a white solid.¹H-NMR(300MHz，DMSO-d₆Relative to TMPpm of S): δ 7.85(bb, 3H), 4.10(m, 2H), 4.03(m, 1H), 3.06(m, 3H), 2.80(m, 1.5H), 2.77(m, 1.5H), 2.80-1.09(m, 18H), 0.82(s, 1.5H), 0.79(s, 1.5H), 0.78(s, 1.5H), 0.74(s, 1.5H).

Example 6

(E)3- (2-Aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione fumarate (I-af)

To a stirred solution of 3- (E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione (II-c, preparation 3, 200mg) in dry THF (0.96mL) was added a 1M solution of tetrabutylammonium fluoride in THF (0.390 mL). After stirring at room temperature for 2h, the solution was concentrated to a small volume and purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 90/10/1). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added and evaporated to dryness. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-af as a white solid (112mg, 88%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.00(m, 4H), 6.40(s, 2H), 4.06(m, 2H), 4.01(m, 1H), 2.97(m, 3H), 2.77(s, 3H), 2.80-1.09(m, 18H), 0.78(s, 3H), 0.73(s, 3H).

Example 7

(Z)3- (2-Aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ag)

The product was prepared in 94% yield from 3- (Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione (II-d, preparation 3, 160mg) and 1M tetrabutylammonium fluoride in THF (0.314mL) as described in example 1. With Et₂Grinding the crude product, filtering the precipitate,this was dissolved in water and lyophilized to give the title compound I-ag.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.40(s, 2H), 4.07(t, 2H), 4.02(m, 1H), 3.02(m, 1H), 2.99(s, 2H), 2.80(s, 3H), 2.70(m, 1H), 2.57(m, 1H), 2.42(m, 1H), 2.29-1.07(m, 15H), 0.84(s, 3H), 0.80(s, 3H).

Example 8

(E, Z)3- (3-N-methylaminopropoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ah)

The product was prepared as described in example 1 starting from 6-aza-6-methyl-7 a-carbaandrostane-3, 7, 17-trione (II-b, preparation 2, 90mg) 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 40mg) in 40% yield. The phases were separated and the aqueous phase was extracted with THF (3 ×). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-ah as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.50(bb, 2H), 4.10-3.95(m, 3H), 2.94(bb, 2H), 2.80(m, 3H), 2.76-2.61(m, 2H), 2.56(s, 3H), 2.46-1.80(m, 8H), 1.78-1.10(m, 11H), 0.83(s, 1.5H), 0.79(s, 1.5H), 0.78(s, 1.5H), 0.73(s, 1.5H).

Example 9

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ai)

The product was prepared in 40% yield as described in example 1 starting from 6-aza-6-methyl-7 a-carba-androstane-3, 7, 17-trione (II-b, preparation 2, 80mg) and 3- (R) -pyrrol-oxyalkylamine dihydrochloride (III-c, preparation 17, 42 mg). In Na₂SO₄Upper trunkThe combined organic extracts were dried, filtered and evaporated to dryness. The crude product was dissolved in water and lyophilized to give the title compound I-ai as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.42(bb, 2H), 4.77(m, 1H), 4.12(m, 0.5H), 4.04(m, 0.5H), 3.30-3.06(m, 4.5H), 2.98(m, 0.5H), 2.80(s, 1.5H), 2.77(s, 1.5H), 2.82-1.10(m, 20H), 0.83(s, 1.5H), 0.79(s, 1.5H), 0.78(s, 1.5H), 0.73(s, 1.5H).

Example 10

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carb-7-thiaandrostane-17-one hydrochloride (I-aj)

The product was prepared in 76% yield as described in example 1 starting from 6-aza-7 a-carba-7-thiaandrostane-3, 17-dione (II-e, preparation 4, 75mg) and 2-aminoethoxyamine dihydrochloride (33 mg). The phases were separated and the aqueous phase was extracted with THF (3 ×). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-aj as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.76(d, 0.5H), 9.72(d, 0.5H), 7.91(bb, 3H), 4.09(m, 2H), 3.85(m, 1H), 3.23(m, 0.5H), 3.04(m, 2H), 2.93(m, 0.5H), 2.85-1.04(m, 18H), 0.85(s, 3H), 0.80(s, 3H).

Example 11

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carbaandrostane-17-one dihydrochloride (I-ak)

To a stirred solution of 6-aza-7 a-carbaandrostane-3, 17-dione (II-f, preparation 5, 75mg) in dioxane (1mL) was added rapidly dropwise a solution of 2-aminoethoxyamine dihydrochloride (33mg) in water (1 mL). After 3h the mixture was lyophilized and Et₂O grindingThe residue was ground for 5h and the precipitate was filtered. The crude product was dissolved in water and lyophilized to give the title compound I-ak as a white solid (89mg, 83%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.87(bb, 0.5H), 9.54(bb, 0.5H), 8.40(bb, 1H), 8.15(bb, 1.5H), 8.06(bb, 1.5H), 4.13(m, 2H), 3.56(m, 0.5H), 3.30-2.94(m, 5H), 2.85(m, 0.5H), 2.73-1.03(m, 18H), 1.10(s, 1.5H), 1.08(s, 1.5H), 0.79(s, 3H).

Example 12

(E, Z)3- (3-N-methylaminopropoxyimino) -6-aza-7 a-carbaandrostane-17-one difumarate (I-al)

The product was prepared in 70% yield as described in example 1 starting from 6-aza-7 a-carbaandrostane-3, 17-dione (II-f, preparation 5, 74mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 6, 39 mg). The crude product was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 85/15/1.5). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂After O the precipitate was filtered to give the title compound I-al as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.00(bb, 6H), 6.46(s, 4H), 3.96(m, 2H), 3.20-2.70(m, 6H), 2.50(s, 3H), 2.50-0.82(m, 20H), 0.94(s, 3H), 0.78(s, 3H).

Example 13

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-7 a-carbaandrostan-17-one dihydrochloride (I-am)

The product was prepared as described in example 1 starting from 6-aza-7 a-carba-androstane-3, 7, 17-trione (II-f, preparation 5, 76mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 39mg) in 90% yield％。¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.77(bb, 1H), 9.33(bb, 2H), 8.27(bb, 1H), 4.79(m, 1H), 3.64-1.00(m, 28H), 1.09(s, 1.5H), 1.08(s, 1.5H), 0.79(s, 3H).

Example 14

(E, Z)3- (2-aminoethoxyimino) -6-aza-6-formyl-7 a-carbaandrostane-17-one hydrochloride (I-an)

Prepared as described in example 1, starting from 6-aza-6-formyl-7 a-carbaandrostane-3, 17-dione (II-g, preparation 6, 80mg) and 2-aminoethoxyamine dihydrochloride (38mg) in 90% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-an as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 8.40-7.40(m, 4H), 4.09(m, 2H), 3.95-0.72(m, 24H), 0.93(s, 1.5H), 0.88(s, 1.5H), 0.75(s, 3H).

Example 15

(E, Z)3- (3-N-methylaminopropoxyimino) -6-aza-6-formyl-7 a-carbaandrostan-17-one hydrochloride (I-ao)

Prepared as described in example 1 starting from 6-aza-6-formyl-7 a-carbaandrostane-3, 17-dione (II-g, preparation 6, 80mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 42mg), in 50% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-ao as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.37(s, 0.5H), 8.34(bb, 2H), 8.32(s, 0.5H), 3.99(t, 2H), 3.80(m, 1H), 3.55(m, 1H), 3.05-2.82(m, 4H), 2.72(t, 1H), 2.52(s, 3H), 2.46-0.98(m, 19H), 0.92(s, 1.5H), 0.87(s, 1.5H), 0.74(s, 3H).

Example 16

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-aza-6-formyl-7 a-carbaandrostane-17-one hydrochloride (I-ap)

Prepared as described in example 1 starting from 6-aza-6-formyl-7 a-carbaandrostane-3, 17-dione (II-g, preparation 6, 100mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 53mg), in 78% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-ap as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.00-8.00(m, 3H), 4.75(m, 1H), 3.95-0.70(m, 28H), 0.92(s, 1.5H), 0.87(s, 1.5H), 0.75(s, 3H).

Example 17

3- (E, Z) - (2-aminoethoxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostane-17-one hydrochloride (I-aq)

Prepared as described in example 1, starting from 6-aza-7 a-carba-7- (Z) -hydroxyiminoandrostane-3, 17-dione (II-h, preparation 7, 100mg) and 2-aminoethoxyamine dihydrochloride (44mg), in 40% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-aq as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.11(bb, 1H), 7.97(bb, 3H), 5.45(bb, 1H), 4.09(m, 2H), 3.43(m, 1H), 3.24(m, 0.5H), 3.04(m, 2H), 2.94(m, 0.5H), 2.52-0.94(m, 18H), 0.83(s, 1.5H), 0.82(s, 1.5H), 0.78(s, 3H).

Example 18

3- (E, Z) - (3-N-methylaminopropoxyimino) -6-aza-7 a-carb-o-7- (Z) -hydroxyimino-androstan-17-one hydrochloride (I-ar)

Prepared as described in example 1 starting from 6-aza-7 a-carba-7- (Z) -hydroxyiminoandrostane-3, 17-dione (II-h, preparation 7, 148mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 79mg), in 60% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-ar as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.90(bb, 1H), 8.66(bb, 2H), 5.22(bb, 1H), 3.98(m, 2H), 3.40(m, 1H), 3.10(m, 0.5H), 2.91(m, 2H), 2.85(m, 0.5H), 2.52(s, 3H), 2.47-0.94(m, 18H), 0.82(s, 1.5H), 0.81(s, 1.5H), 0.78(s, 3H).

Example 19

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyimino-androstan-17-one hydrochloride (I-as)

Prepared as described in example 1 starting from 6-aza-7 a-carba-7- (Z) -hydroxyiminoandrostane-3, 17-dione (II-h, preparation 7, 179mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 94mg) in 60% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.27(bb, 2H), 8.93(bb, 1H), 5.26(bb, 1H), 4.76(bb, 1H), 3.43(m, 1H), 3.06-3.30(m, 4.5H), 2.87(m, 0.5H), 2.45(m, 0.5H), 2.39(m, 1H), 2.26(m, 0.5H), 1.90-2.17(m, 8.5H), 1.82-0.93(m, 10H), 0.83(s, 1.5H), 0.82(s, 1.5H), 0.78(s, 3H).

Example 20

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carb-o-7- (Z) -methoxyimino-androstan-17-one hydrochloride (I-at)

Prepared as described in example 1, starting from 6-aza-7 a-carba-7- (Z) -methoxyiminoandrostane-3, 17-dione (II-i, preparation 8, 65mg) and 2-aminoethoxyamine dihydrochloride (28mg), in 60% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-at as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.87(bb, 3H), 5.31(bb, 0.5H), 5.28(bb, 0.5H), 4.08(m, 2H), 3.57(s, 3H), 3.21(m, 0.5H), 3.02(m, 2H), 2.92(m, 0.5H), 2.50-0.75(m, 18H), 0.82(s, 1.5H), 0.81(s, 1.5H), 0.78(s, 3H).

Example 21

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino-6-aza-7 a-carb-7- (Z) -methoxyimino-androstan-17-one hydrochloride (I-au)

Prepared as described in example 1 starting from 6-aza-7 a-carba-7- (Z) -methoxyiminoandrostane-3, 17-dione (II-i, preparation 8, 61mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 31mg) in 70% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-au as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.72(bb, 2H), 5.31(bb, 1H), 4.75(m, 1H), 3.58(s, 3H), 3.50-0.90(m, 26H), 0.82(s, 1.5H), 0.81(s, 1.5H), 0.78(s, 3H).

Example 22

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-carbaandrostane-7, 17-dione hydrochloride (I-av)

As described in example 1, the reaction mixture was purified from 7 a-aza-7 a-homoandrostane-3, 7, 17-trione (II-j, preparation 9,96mg) and 2-aminoethoxyamine dihydrochloride (47mg) were prepared in 65% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-av as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.97(bb, 3H), 6.99(bb, 1H), 4.08(m, 2H), 3.58(m, 1H), 3.10-1.75(m, 3H), 2.50-1.00(m, 18H), 1.05(s, 1.5H), 1.04(s, 1.5H), 0.78(s, 3H).

Example 23

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-aza-7 a-carbaandrostane-7, 17-dione hydrochloride (I-aw)

Prepared as described in example 1 starting from 7 a-aza-7 a-carbaandrostane-3, 7, 17-trione (II-j, preparation 9, 58mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 32mg), in 70% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-aw as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.50(bb, 2H), 6.98(bb, 1H), 3.97(m, 2H), 3.59(m, 1H), 2.88(m, 3H), 2.52(s, 1.5H), 2.51(s, 1.5H), 2.50-0.95(m, 20H), 1.05(s, 1.5H), 1.04(s, 1.5H), 0.78(s, 3H).

Example 24

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ax)

Prepared as described in example 1 starting from 7 a-aza-7 a-carbaandrostane-3, 7, 17-trione (II-j, preparation 9, 95mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 32mg), in 75% yield. With Et₂The crude product was triturated and the precipitate was filtered to give the title compound I-ax as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.04(bb, 2H), 6.99(bb, 1H), 4.74(bb, 1H), 3.58(bb, 1H), 3.07-3.28(m, 3H), 2.88(m, 2H), 2.46-1.31(m, 18H), 1.09(m, 2H), 1.05(s, 1.5H), 1.04(s, 1.5H), 0.78(s, 3H).

Example 25

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-homoandrostane-17-one difumarate (I-ay)

Prepared as described in example 1, starting from 7 a-aza-7 a-carbaandrostane-3, 17-dione (II-k, preparation 10, 44mg) and 2-aminoethoxyamine dihydrochloride (21mg), in 71% yield. After 1.5h the mixture was lyophilized and the residue 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. Et was added₂O, followed by filtration of the precipitate to give the title compound I-ay as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.45(s, 4H), 4.07(t, 2H), 3.00(m, 2H), 2.92(m, 1H), 2.78(bb, 2H), 2.70(t, 1H), 2.41(m, 1H), 2.28-1.20(m, 10H), 0.94(m, 2H), 0.93(s, 1.5H), 1.04(s, 1.5H), 0.78(s, 3H).

Example 26

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-aza-7 a-carbaandrostan-17-one difumarate (I-az)

Prepared as described in example 1 starting from 7 a-aza-7 a-carbaandrostane-3, 17-dione (II-k, preparation 10, 63mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 37mg), in 60% yield. After 1.5h the mixture was lyophilized and the residue was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 85/15/1.5). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂O, followed by filtration of the precipitate to give the title compound I-az as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.49(bb, 1H), 8.39(bb, 2H), 6.61(s, 4H), 3.96(t, 2H), 3.47(bb, 1H), 3.11(bb, 2H), 2.92(bb, 2H), 2.89(bb, 1H), 2.55(s, 3H), 2.34(bb, 1H), 2.23-1.30(m, 18H), 0.96(s, 1.5H), 0.95(s, 1.5H), 0.81(s, 3H).

Example 27

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-carbaandrostane-17-one difumarate (I-ba)

Prepared as described in example 1 starting from 7 a-aza-7 a-carbaandrostane-3, 17-dione (II-k, preparation 10, 93mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 53mg), in 82% yield. After 2h the mixture was lyophilized and the residue was purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 83/17/1.7). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂O, followed by filtration of the precipitate to give the title compound I-ba as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.45(s, 4H), 4.72(bb, 1H), 3.25(m, 3H), 3.11(m, 1H), 2.87(m, 3H), 2.44(m, 1H), 2.30-0.99(m, 20H), 0.94(s, 3H), 0.79(s, 3H).

Example 28

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-formyl-7 a-carbaandrostane-17-one hydrochloride (I-bb)

7 a-aza-7 a-formyl-7 a-homoandrostane-3, 17-dione (II-l, preparation 11, 50mg) and 2-aminoethoxy as described in example 1Amine dihydrochloride (23mg) was prepared as the starting material in 75% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bb as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.12(s, 1H), 7.86(bb, 3H), 4.11(t, 1H), 4.06(t, 2H), 3.46(bb, 1H), 3.18(t, 1H), 3.03(m, 0.5H), 3.02(t, 2H), 2.91(m, 0.5H), 2.35(m, 1H), 2.72-1.12(m, 17H), 0.90(s, 3H), 0.78(s, 3H).

Example 29

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-aza-7 a-formyl-7 a-carbaandrostane-17-one hydrochloride (I-bc)

Prepared as described in example 1 starting from 7 a-aza-7 a-formyl-7 a-carbaandrostane-3, 17-dione (II-l, preparation 11, 66mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 35mg), in 63% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bc as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.54(bb, 2H), 8.12(s, 1H), 4.11(t, 1H), 3.95(t, 2H), 3.46(m, 1H), 3.17(t, 1H), 2.95(bb, 0.5H), 2.88(t, 2H), 2.81(bb, 0.5H), 2.51(s, 3H), 2.35(m, 1H), 2.20-1.05(m, 20H), 0.89(s, 3H), 0.78(s, 3H).

Example 30

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-aza-7 a-formyl-7 a-carbaandrostane-17-one hydrochloride (I-bd)

Prepared as described in example 1 starting from 7 a-aza-7 a-formyl-7 a-carbaandrostane-3, 17-dione (II-l, preparation 11, 64mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 34mg) in 65% yield. With Et₂O grinding the crude product and filtering the precipitate to obtainI-bd as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.96(bb, 2H), 8.12(s, 1H), 4.73(m, 1H), 4.11(m, 1H), 3.50-3.05(m, 6H), 2.97(m, 0.5H), 2.83(m, 0.5H), 2.40-1.05(m, 20H), 0.89(s, 3H), 0.78(s, 3H).

Example 31

(E, Z)3- (2-aminoethoxyimino) -7-oxa-7 a-carbaandrostane-6, 17-dione hydrochloride (I-be)

Starting from 7-oxa-7 a-carbaandrostane-3, 6, 17-trione (II-m, preparation 12, 88mg) and 2-aminoethoxyamine dihydrochloride (41mg), as described in example 1

Line preparation, 66% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-be as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.78(bb, 3H), 4.29(t, 1H), 4.13-3.69(m, 3H), 3.28-3.18(m, 1H), 3.04(m, 2H), 2.97(m, 0.5H), 2.75-2.24(m, 2.5H), 2.21-1.06(m, 14H), 0.87(s, 3H), 0.81(s, 3H).

Example 32

(E, Z) -3- (3-N-methylaminopropoxyimino) -7-oxa-7 a-carbaandrostane-6, 17-dione hydrochloride (I-bf)

Prepared as described in example 1 starting from 7-oxa-7 a-carbaandrostane-3, 6, 17-trione (II-m, preparation 12, 130mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 72mg), 74% yield. With Et₂O grinding the crude product and filtering the precipitate to obtain I-bf as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 8.53(bb, 3H), 4.32(m, 1H), 4.09-3.94(m, 3H), 3.29-3.19(m, 1H), 2.91(m, 2H), 2.86(m, 0.5H), 2.68-2.57(m, 1H),2.53(s，3H)2.46-2.24(m，8.5H)，2.19-1.05(m，15H)，0.86(s，3H)，0.81(s，3H)。

example 33

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7-oxa-7 a-carbaandrostane-6, 17-dione hydrochloride (I-bg)

Prepared as described in example 1 starting from 7-oxa-7 a-carbaandrostane-3, 6, 17-trione (II-m, preparation 12, 87mg) and 3- (R) -pyrrolidinoalkyloxyamine dihydrochloride (III-c, preparation 17, 48mg), 55% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bg as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.20(bb, 1H), 9.12(bb, 1H)4.76(bb, 1H), 4.43-4.21(m, 1H), 4.13-3.97(m, 1H), 3.28(m, 4H), 3.20(bb, 0.5H)2.69-2.23(m, 3H), 2.20-1.08(m, 16H), 0.87(s, 3H), 0.81(s, 3H).

Example 34

(E, Z)3- (2-aminoethoxyimino) -6-oxa-7 a-carbaandrostane-7, 17-dione fumarate (I-bh)

Prepared as described in example 1, starting from 6-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-n, preparation 12, 60mg) and 2-aminoethoxyamine dihydrochloride (28mg), in 56% yield. After 20h, the crude product (SiO) was purified by flash chromatography₂，CH₂Cl₂/MeOH/26％NH₄OH 93/7/0.7). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂O, followed by filtration of the precipitate to give the title compound I-bh as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 6.42(s, 2H), 4.59(m, 1H), 4.06(t, 2H), 3.39(m, 0.5H), 2.98(t, 2H), 2.92(bb, 0.5H), 2.41(m, 2H), 2.31(bb, 1H), 2.22-1.03(m, 15H))，0.93(s，1.5H)0.91(s，1.5H)，0.80(s，3H)。

Example 35

(E, Z)3- (2-aminoethoxyimino) -7 a-oxa-7 a-carbaandrostane-7, 17-dione hydrochloride (I-bi)

Prepared as described in example 1, starting from 7 a-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-o, preparation 13, 80mg) and 2-aminoethoxyamine dihydrochloride (37mg), in 58% yield. With Et₂O triturate the crude product and filter the precipitate to give I-bi as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.66(bb, 3H), 4.72(t, 1H), 4.06(t, 2H), 3.14(m, 1H), 3.02(m, 2H), 2.99(m, 0.5H), 2.42(m, 0.5H), 2.30-1.12(m, 17H), 1.06(s, 1.5H)1.05(s, 1.5H), 0.79(s, 3H).

Example 36

(E, Z)3- (3-N-methylaminopropoxyimino) -7 a-oxa-7 a-carbaandrostane-7, 17-dione hydrochloride (I-bj)

Prepared as described in example 1 starting from 7 a-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-o, preparation 13, 75mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, preparation 16, 41mg), 71% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bj as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.70(m, 1H), 3.97(t, 2H), 3.13(m, 1H), 2.98-2.84(m, 3H), 2.54(s, 3H), 2.44(m, 1H), 2.28-1.09(m, 18H), 1.06(s, 1.5H)1.05(s, 1.5H), 0.78(s, 3H).

Example 37

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-7 a-oxa-7 a-carbaandrostane-7, 17-dione hydrochloride (I-bk)

Prepared as described in example 1 starting from 7-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-o, preparation 13, 95mg) and 3- (R) -pyrrolidinoalkoxyamine dihydrochloride (III-c, preparation 17, 58mg), in 69% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bk as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.89(bb, 2H), 4.71(m, 2H), 3.41-3.05(m, 5H), 2.93(m, 1H), 2.43(m, 1H), 2.30-1.09(m, 18H), 1.06(s, 1.5H)1.05(s, 1.5H), 0.78(s, 3H).

Example 38

(E, Z)3- (2-aminoethoxyimino) -6-oxa-5 beta-androstane-7, 17-dione hydrochloride (I-bl)

Prepared as described in example 1, starting from 6-oxa-5 β -androstane-3, 7, 17-trione (II-p, preparation 14, 360mg) and 2-aminoethoxyamine dihydrochloride (176mg) in 30% yield. With Et₂The crude product was triturated and the precipitate was filtered to give I-bl as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.88(bb, 3H), 4.41(bb, 1H), 4.11(m, 2H), 3.16(m, 0.5H), 3.05(m, 2H), 2.76(m, 1H), 2.70(m, 0.5H), 2.61-1.93(m, 5H), 1.74-1.08(m, 10H), 1.02(s, 3H), 0.82(s, 3H).

Example 39

(E)3- (2-Aminoethoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione fumarate (I-bm)

Preparation of 3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-7 a-carba-androstane-7, 17-dione (II-q, preparation 18, 720mg) with 1M tetrabutylammonium fluoride at room temperatureA mixture of THF (1.49mL) solution was stirred for 2 h. The solution was concentrated to small volume and purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 86/14/1.4). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added and evaporated to dryness. With Et₂The crude product was triturated and the precipitate filtered to give the title compound I-bm (340mg, 57%) as a white solid.¹H-NMR(300MHz，D₂O, ppm relative to TMS): δ 7.37(bb, 1H), 6.66(s, 2H), 4.25(m, 2H), 3.76(m, 1H), 3.30(m, 2H), 3.01(m, 1H), 2.69-1.10(m, 18H), 0.97(s, 3H), 0.92(s, 3H).

Example 40

(Z)3- (2-aminoethoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione fumarate (I-bn)

A mixture of 3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-7 a-carba-androstane-7, 17-dione (II-r, preparation 18, 688mg) and 1M tetrabutylammonium fluoride in THF (1.5mL) was stirred at room temperature for 2H. The solution was concentrated to small volume and purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 86/14/1.4). To the concentrated fractions a stoichiometric amount of fumaric acid in MeOH was added and evaporated to dryness. With Et₂The crude product was triturated and the precipitate filtered to give the title compound I-bn (320mg, 56%) as a white solid.¹H-NMR(300MHz，D₂O, ppm relative to TMS): δ 7.38(bb, 1H), 6.56(s, 2H), 4.26(m, 2H), 3.75(m, 1H), 3.32(m, 3H), 2.66-1.16(m, 18H), 0.97(s, 3H), 0.92(s, 3H).

EXAMPLE 41

(E, Z)3- (2-aminoethoxyimino) -B-homoandrostane-17-one hydrochloride (I-bo)

As described in example 1Prepared from B-homoandrostane-3, 17-dione (50mg, H.J.Ringold, J.Am.chem.Soc.1960, 961) and 2-aminoethoxyamine dihydrochloride (25 mg). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. The crude product was triturated with EtOAc and the precipitate was filtered to give the title compound I-bo as a white solid (57mg, 87%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.40(s, 2H), 4.06(m, 2H), 3.04(m, 2H), 2.88(m, 0.5H), 2.81(m, 0.5H), 2.44-0.80(m, 23H), 0.90(s, 3H), 0.77(s, 3H).

Example 42

(E, Z) -3- [3- (R) -pyrrolidinyl ] oxyimino-B-homoandrostane-17-one hydrochloride (I-bp)

Prepared as described in example 1 starting from B-plus-carboandrostane-3, 17-dione (50mg, H.J.Ringold, J.Am.chem.Soc.1960, 961) and 3- (R) -pyrrolidinoalkylamine dihydrochloride (III-c, preparation 17, 58 mg). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. With Et₂The crude product was triturated and the precipitate filtered to give the title compound I-bp as a white solid (96mg, 69%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.02(bb, 2H), 4.71(m, 12H), 3.40-3.05(m, 4H), 2.81(m, 0.5H), 2.75(m, 0.5H), 2.45-0.82(m, 25), 0.91(s, 3H), 0.78(s, 3H).

Example 43

(E, Z) -3- (3-N-methylaminopropoxyimino) -6-oxa-7 a-carbaandrostane-7, 17-dione fumarate (I-bq)

6-oxa-7 a-homoandrostane-3, 7, 17-trione (II-n) as described in example 1Preparation example 12, 210mg) and 3-N-methylaminopropoxyamine dihydrochloride (III-b, 117mg) were prepared as starting materials in 49% yield. After 20h, the crude product (SiO) was purified by flash chromatography₂，CH₂Cl₂/MeOH/26％NH₄OH 90/10/0.1). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂O, followed by filtration of the precipitate to give the title compound I-bq as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.42(s, 2H), 4.58(m, 1H), 3.98(m, 2H), 3.23(m, 0.5H), 2.89-1.0(m, 22.5H), 2.47(s, 3H), 0.92(s, 1.5H), 0.91(s, 1.5H), 0.79(s, 3H).

Example 44

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-oxa-7 a-carbaandrostane-7, 17-dione fumarate (I-br)

Prepared as described in example 1 starting from 6-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-n, preparation 12, 210mg) and 3(R) -pyrrolidinoalkyloxyamine dihydrochloride (III-c, 117mg) in 51% yield. After 2h, the crude product (SiO) was purified by flash chromatography₂，CH₂Cl₂/MeOH/26％NH₄OH 90/10/0.1). To the concentrated fractions was added a stoichiometric amount of fumaric acid in MeOH. Et was added₂O, followed by filtration of the precipitate to give the title compound I-br as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.44(s, 2H), 4.74(m, 1H), 4.62(dd, 0.5H), 4.54(dd, 0.5H), 3.40-1.00(m, 25H), 0.92(s, 1.5H), 0.91(s, 1.5H), 0.79(s, 3H).

Example 45

(E, Z) -3- (2-aminoethoxyimino) -6-oxa-7 a-carbaandrostane-17-one hydrochloride (I-bs)

According to the examples1, starting from 6-oxa-7 a-homoandrostane-3, 17-dione (II-s, preparation 19, 35mg) and 2-aminoethoxyamine dihydrochloride (17 mg). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. The crude product was triturated with EtOAc and the precipitate filtered to give the title compound I-bs as a white solid (43mg, 94%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.87(bb, 3H), 4.08(m, 2H), 3.78-3.40(m, 3H), 3.18(m, 0.5H), 3.04(m, 2H), 2.94(dd, 0.5H), 2.50-1.75(m, 18H), 0.90(s, 1.5H), 0.90(s, 1.5H), 0.79(s, 3H).

Example 46

(E, Z) -3- (2-aminoethoxyimino) -7 a-oxa-7 a-carbaandrostane-17-one hydrochloride (I-bt)

Prepared as described in example 1 starting from 7 a-oxa-7 a-carbaandrostane-3, 17-dione (II-t, preparation 20, 85mg) and 2-aminoethoxyamine dihydrochloride (41 mg). In Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. The crude product was triturated with EtOAc and the precipitate was filtered to give the title compound I-bt as a white solid (80mg, 72%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.83(bb, 3H), 4.07(m, 2H), 3.65-3.35(m, 3H), 3.02(m, 2H), 2.46-1.01(m, 18H), 0.95(s, 1.5H), 0.94(s, 1.5H), 0.79(s, 3H).

Example 47

(E, Z)3- (2-aminoethoxyimino) -6-azaandrostane-7, 17-dione hydrochloride (I-bu)

Prepared as described in example 1, starting from 6-azaandrostane-3, 7, 17-trione (II-u, preparation 21, 147mg) and 3- (2-aminoethoxyamine dihydrochloride (72mg) in Na₂SO₄The combined organic extracts were dried, filtered and evaporated to dryness. The crude product was triturated with EtOAc and the precipitate was filtered to give the title compound I-bu as a white solid (141mg, 73%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.88(bb, 3H), 7.46(s, 0.5H), 7.37(s, 0.5H), 4.09(m, 3H), 3.17(m, 0.5H), 3.04(m, 3.5H), 2.40-1.00(m, 16H), 0.90(s, 3H), 0.82(s, 3H).

Example 48

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-azaandrostane-7, 17-dione fumarate (I-bv)

Prepared as described in example 1 starting from 6-azaandrostane-3, 7, 17-trione (II-u, preparation 21, 55mg) and 3(R) -pyrrol-oxyalkylamine dihydrochloride (III-c, 32mg) in 58% yield. After 2h, 2M NaOH and CH were added₂Cl₂(3X) extract the aqueous phase. The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. The residue was dissolved in MeOH and a stoichiometric amount of fumaric acid in MeOH was added. EtOAc was added, after which the precipitate was filtered to give the title compound I-bv as a white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.46(s, 0.5H), 7.33(s, 0.5H), 6.42(s, 2H), 4.72(m, 1H), 3.30-2.95(m, 6H), 2.40-1.00(m, 18H), 0.89(s, 3H), 0.81(s, 3H).

Preparation example 1

6-aza-7 a-carba-androstane-3, 7, 17-trione (II-a)

Adding the mixture into a stirring device 3, 3: 17, 17-bis (ethylenedioxy) androstan-6-one (4.5g) in THF (92mL) was added rapidly dropwise hydroxylamine hydrochloride (2.4g), Na₂HPO₄·12H₂H of O (12.33g)₂O (44.5mL) solution. After 24h the mixture was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, over Na₂SO₄Dried, filtered and evaporated to dryness to give 3, 3: 17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane (4.65g, 100%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 10.37(s, 1H), 3.92-3.67(m, 8H), 3.15(bb, 1H), 2.16(m, 1H), 1.95-1.07(m, 17H), 0.94(s, 1H), 0.74(s, 3H), 0.64(s, 3H).

Stirring at 0 ℃ 3, 3: tosyl chloride (10.15g) was added to a solution of 17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane (7.2g) in pyridine (115 mL). After 24h at room temperature the solution was heated to 40 ℃ and held for 48 h. After cooling to room temperature, water (5.5ml) was added. After 48h, 5% NaHCO was used₃The aqueous solution was quenched to pH 8. The solution was evaporated, water (180mL) was added and CH was used₂Cl₂The aqueous phase was extracted (3X 80 mL). The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. Purification of the crude product by flash chromatography (SiO)₂hexane/Et₂O90/10) to yield 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostan-7-one (6.56g, 91%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.03(bb, 1H), 3.93-3.69(m, 8H), 3.47-3.37(m, 1H), 2.32(m, 1H), 1.98-1.10(m, 17H), 0.76(s, 3H), 0.72(s, 3H).

Under reflux, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostan-7-one (2.42g) and pTSA. H₂A solution of O (5.67g) in acetone (190mL) and water (19mL) was stirred for 2 h. 5% NaHCO was added₃The aqueous solution neutralized the solution and the acetone was evaporated. By CH₂Cl₂The aqueous phase was extracted (3X 50 mL). The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. With EtOAc/Et₂The O40/60 mixture triturated the residue and the precipitate was filtered to give the title compound II-a as a white solid (1.50g, 95%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.23(bb, 1H), 3.86-3.73(m, 1H), 2.64-1.04(m, 19H), 0.92(s, 3H), 0.80(s, 3H).

Preparation example 2

6-aza-6-methyl-7 a-carbaandrostane-3, 7, 17-trione (II-b)

In N₂(40mL), the mixture was stirred at a rate of 3, 3: to a THF solution of 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostan-7-one (preparation 1, 1.00g) was added NaH (60% dispersed in 490mg mineral oil). MeI (1.064mL) was added after 1 h. Stirred at room temperature for 1.5H, after which H was added₂The mixture was quenched with O (30mL) and the aqueous phase was extracted with EtOAc (3 ×). The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness to give 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-6-methyl-7 a-homoandrostan-7-one (1.00g, 97%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 3.95-3.70(m, 9H), 2.76(s, 3H), 2.50(m, 1H), 2.14-2.00(m, 2H), 1.94-1.08(m, 15H), 1.04-0.92(m, 1H), 0.79(s, 3H), 0.75(s, 3H).

According to the procedure for the preparation of 6-aza-7 a-carba-androstane-3, 7, 17-trione (preparation example 1) described above, a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-6-methyl-7 a-carbaandrostane-7-one 6-aza-6-methyl-7 a-carbaandrostane-3, 7, 17-trione (II-b) was prepared in 85% yield. By H₂The combined organic extracts were washed with O over Na₂SO₄Dried and evaporated to dryness to give the title compound II-b.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.32(m, 1H), 3.04-2.93(m, 1H), 2.76(m, 1H), 2.73(s, 3H), 2.46-1.05(m, 17H), 0.83(s, 3H), 0.79(s, 3H).

Preparation example 3

3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carba-androstane-7, 17-dione (II-c) and

3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) -aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione (II-d)

CH at 0 ℃₂Cl₂In (35mL) in N₂(E, Z)3- (2-aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione hydrochloride (I-ae) (430mg, 35/65 ratio) and Et₃To a stirred solution of N (301. mu.L) was added 9-fluorenylmethoxycarbonylchloride (301 mg). After stirring overnight at room temperature, water was added and CH was used₂Cl₂The mixture is extracted. With 5% NaHCO₃Washing the organic phase over Na₂SO₄Dried and evaporated to dryness. Purification of the residue by flash chromatography (SiO)₂(ii) a n-hexane/EtOAc 70/30) to yield 3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione (II-c, 205mg, 33%) and 3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carbaandrostane-7, 17-dione (II-d, 168mg, 27%). II-c:¹H-NMR(300MHz，DMSO-d₆ppm relative to TMS): δ 7.87(bb, 2H), 7.67(bb, 2H), 7.45-7.26(m, 5H), 4.31-4.15(m, 3H), 4.02-3.80(m, 3H), 3.27-3.16(m, 2H), 2.75(s, 3H), 2.72-2.52(m, 2H), 2.46-1.78(m, 7H), 1.68-0.98(m, 12H), 0.74(s, 3H), 0.66(s, 3H). II-d:¹H-NMR(300MHz，DMSO-d₆ppm relative to TMS): δ 7.88(bb, 2H), 7.66(bb, 2H), 7.45-7.27(m, 5H), 4.34-4.15(m, 3H), 4.02-3.78(m, 3H), 3.21(m, 2H), 2.92(m, 1H), 2.75(s, 3H), 2.76-2..35(m, 3H), 2.82-1.00(m, 17H), 0.78(s, 3H), 0.77(s, 3H).

Preparation example 4

6-aza-7 a-carba-7-thiaandrostane-3, 17-dione (II-e)

To a stirred solution of 6-aza-7 a-homoandrostane-3, 7, 17-trione (II-a, preparation 1, 52mg) in toluene (2mL) was added Lawesson's reagent (40mg), and the mixture was stirred at room temperature for 3 hours. Adding SiO₂And the mixture was evaporated to dryness. The residue was purified by flash chromatography (hexane/acetone 65/35) to give the title compound II-e (48mg, 88%).¹H-NMR(300MHz，DMSO-d₆Relative to each otherPpm in TMS): δ 9.72(bb, 1H), 4.13(m, 1H), 2.91-2.70(m, 3H), 2.46-2.30(m, 2H), 2.22(m, 1H), 2.13-1.89(m, 4H), 1.80-1.08(m, 9H), 0.93(s, 3H), 0.81(s, 3H).

Preparation example 5

6-aza-7 a-carbaandrostane-3, 17-dione (II-f)

At room temperature, N₂(35mL) over 5 minutes to a stirred 3, 3: a solution of 17, 17-bis (ethylenedioxy) -6-aza-7 a-plus-androstan-7-one (1.175g) in THF was added portionwise LiAlH₄(0.607mg), the mixture was stirred under reflux for 1 h. The suspension was cooled with an ice bath, after which H was carefully added₂O (0.6mL) and 4N NaOH (0.6mL) were quenched. The mixture was filtered through a pad of Celite and the filter cake was washed with THF (3X 10 mL). The filtrate was washed with brine over Na₂SO₄Dried, evaporated to dryness and the residue purified by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 92/8/0.8) to yield 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostane (880mg, 77%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 3.87-3.07(m, 8H), 2.84(m, 1H), 2.64-2.51(m, 2H), 1.91-0.99(m, 19H), 0.76(s, 3H), 0.75(s, 3H), 0.67(m, 1H).

According to the procedure for the preparation of 6-aza-7 a-homoandrostane-3, 7, 17-trione described above (preparation example 1), a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostane-3, 17-dione was prepared with a yield of 95%. By H₂The combined organic extracts were washed with O over Na₂SO₄Dried and evaporated to dryness to give the title compounds II-f.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 2.94-2.76(m, 2H), 2.63(m, 1H), 2.46-2.21(m, 3H), 2.14-1.89(m, 5H), 1.82-1.02(m, 11H), 0.97(s, 3H), 0.84(m, 1H), 0.79(s, 3H).

Preparation example 6

6-aza-6-formyl-7 a-carbaandrostane-3, 17-dione (II-g)

Formic acid in CHCl at 0 deg.C₃(3.9mL) of a 1M solution was added dropwise to DCC (403mg) in CHCl₃In solution. The mixture was stirred for another 5min before adding it to an ice-cold solution of 6-aza-7 a-homoandrostane-3, 17-dione (II-f, preparation 5, 300mg) in pyridine (2.9 mL). The mixture was then stirred for 1h under ice bath. The solvent was evaporated, then EtOAc was added to give a precipitate, which was removed by filtration and washed with EtOAc. The combined organic extracts were evaporated to dryness and the residue (SiO) was purified by flash chromatography₂Hexane/acetone 1/1) to give the title compound II-g (250mg, 76%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 8.29(s, 1H), 3.81-3.72(m, 2H), 3.29(m, 1H), 2.93(m, 1H), 2.47-0.97(m, 18H), 0.97(s, 3H), 0.76(s, 3H).

Preparation example 7

6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostane-3, 17-dione (II-h)

According to the procedure for the preparation of 6-aza-7 a-carba-7-thiaandrostane-3, 17-dione (preparation 4) described above, a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostane (preparation 5, 567mg) preparation of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carba-7-thiaandrostane in 62% yield. Purification of the crude product by flash chromatography (SiO)₂hexane/EtOAc 40/60).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 9.55(bb, 1H), 3.92-3.65(m, 9H), 2.80-2.58(m, 2H), 1.99-0.98(m, 17H), 0.77(s, 3H), 0.73(s, 3H).

Adding the mixture into a stirring device 3, 3: to a solution of 17, 17-bis (ethylenedioxy) -6-aza-7 a-carba-7-thiaandrostane (600mg) in pyridine (30mL) was added hydroxylamine hydrochloride (789 mg). After 48h at 60 ℃ the solution was cooled and treated with 5% NaHCO₃The aqueous solution was quenched to pH 8. The solution was evaporated, then water (180mL) was added, followed by CH₂Cl₂The aqueous phase was extracted (3X 80 mL). The combined organics were washed with brineExtract of plant of the genus Na₂SO₄Dried and evaporated to dryness. Purification of the crude product by flash chromatography (SiO)₂，CH₂Cl₂isopropanol/MeOH 94/3/3) to give 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostane (510mg, 85%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.70(s, 1H), 4.90(bb, 1H), 3.94-3.68(m, 8H), 2.12-1.07(m, 19H), 0.86(bb, 1H), 0.75(s, 3H), 0.70(s, 3H).

According to the procedure for the preparation of 6-aza-7 a-carba-androstane-3, 7, 17-trione (preparation example 1) described above, a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carba-7- (2) -hydroxyiminoandrostane (461mg) 6-aza-7 a-carba-7- (Z) -hydroxyiminoandrostane-3, 17-dione was prepared with a 95% yield. Purification of the crude product by flash chromatography (SiO)₂，CH₂Cl₂/iPrOH 95/5) to give the title compound II-h (369 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.83(s, 1H), 5.14(bb, 1H), 3.67(m, 1H), 2.70(m, 1H), 2.48-1.90(m, 9H), 1.81-1.02(m, 9H), 0.91(s, 3H), 0.73(s, 3H).

Preparation example 8

6-aza-7 a-carb 7- (Z) -methoxyiminoandrostane-3, 17-dione (II-i)

Adding the mixture into a stirring device 3, 3: methoxyamine hydrochloride (380mg) was added to a solution of 17, 17-bis (ethylenedioxy) -6-aza-7 a-carba-7-thiaandrostane (preparation example 6) (240mg) in pyridine (6.5 mL). After 48h at 60 ℃ in a sealed autoclave, the solution was cooled and treated with 5% NaHCO₃The aqueous solution was quenched to pH 8. The solution was evaporated, then water (180mL) was added, followed by CH₂Cl₂The aqueous phase was extracted (3X 80 mL). The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. Purification of the crude product by flash chromatography (SiO)₂Acetone/hexane 50/50) to yield 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carb-7- (Z) -methoxyiminoandrostane(210mg，85％)。¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.90(bb, 1H), 3.96-3.65(m, 8H), 3.57(s, 3H), 2.12-1.10(m, 19H), 0.94-0.80(m, 1H), 0.75(s, 3H), 0.70(s, 3H).

According to the procedure for the preparation of 6-aza-7 a-carba-androstane-3, 7, 17-trione (preparation example 1) described above, a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -6-aza-7 a-carba-7- (Z) -methoxyiminoandrostane (210mg) 6-aza-7 a-carba-7- (Z) -methoxyiminoandrostane-3, 17-dione was prepared with a 95% yield. Purification of the crude product by flash chromatography (SiO)₂hexane/EtOAc 5/95) to yield the title compound II-i (176 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 5.32(bb, 1H), 3.69(m, 1H), 3.57(s, 3H), 2.73(m, 1H), 2.47-1.90(m, 8H), 1.81-0.99(m, 10H), 0.90(s, 3H), 0.79(s, 3H).

Preparation example 9

7 a-aza-7 a-carbaandrostane-3, 7, 17-trione (II-j)

H at atmospheric pressure₂The ratio of 3, 3: a mixture of 17, 17-bis (ethylenedioxy) androst-5-en-7-one (5.99g) and 10% Pd/C (0.599g) in dioxane (186mL) was stirred for 7 h. The mixture was filtered through Celite and the filtrate was evaporated to dryness. Purification of the crude product by flash chromatography (SiO)₂hexane/EtOAc 75/25). With hexane/Et₂The product was triturated with O1/1 and the precipitate was filtered to give 3, 3: 17, 17-bis (ethylenedioxy) androstan-7-one (4.06g, 67%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 3.94-3.74(m, 8H), 2.47(m, 1H), 2.40(m, 1H), 2.20(m, 1H), 1.94-1.02(m, 17H), 1.13(s, 3H), 0.82(s, 3H).

According to the above 3, 3: preparation of 17, 17-bis (ethylenedioxy) -6(E) -hydroxyiminoandrostane (preparation 1) from 3, 3: 17, 17-bis (ethylenedioxy) androstan-7-one (2.20g) produced 3, 3: 17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 10.17(s, 1H), 3.88-3.71(m, 8H), 2.89(bb, 1H), 2.23-2.05(m, 2H), 1.89-0.97(m, 16H), 0.90(s, 3H), 0.80(m, 1H), 0.77(s, 3H).

According to the procedure for the preparation of 6-aza-7 a-homoandrostane-3, 7, 17-trione described above (preparation example 1), a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane (1.1g) 7(E) -hydroxyiminoandrostane-3, 17-dione was prepared in 59% yield. Purification of the crude product by flash chromatography (SiO)₂，CH₂Cl₂Acetone/hexanes 20/20/60) to give 7(E) -hydroxyiminoandrostane-3, 17-dione (508 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 10.37(s, 1H), 3.00(bb, 1H), 2.57-2.30(m, 5H), 2.15-1.88(m, 4H), 1.74-0.89(m, 10H), 1.13(s, 3H), 0.82(s, 3H).

According to the above 3, 3: preparation of 17, 17-bis (ethylenedioxy) -6-aza-7 a-homoandrostan-7-one (preparation example 1) 7 a-aza-7 a-homoandrostane-3, 7, 17-trione was prepared from 7(E) -hydroxyiminoandrostane-3, 17-dione (490mg) in 79% yield.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.00(bb, 1H), 3.62(bb, 1H), 2.95-2.82(m, 1H), 2.54-2.24(m, 2H), 2.27-1.30(m, 14H), 1.15(s, 3H), 1.11(m, 2H), 0.79(s, 3H).

Preparation example 10

7 a-aza-7 a-carbaandrostane-3, 17-dione (II-k)

According to the above 3, 3: preparation of 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostane (preparation example 1) from 3, 3: 17, 17-bis (ethylenedioxy) -7(E) -hydroxyiminoandrostane (preparation 9, 640mg) 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-carbaandrostan-7-one in 91% yield. With 9/1 hexane/Et₂O triturating the crude product to yield 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-carbaandrostan-7-one (583 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 6.74(bb, 1H), 3.88-3.71(m, 8H), 3.30(m, 1H), 2.75-2.65(m, 1H), 1.99-1.10(m, 17H), 0.96(m, 1H), 0.92(s, 3H), 0.75(s, 3H).

According to the above 3, 3: preparation of 17, 17-bis (ethylenedioxy) -6-aza-7 a-carbaandrostane (preparation example 5) from 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-carbaandrostan-7-one (296mg) preparation of 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-carbaandrostane with a yield of 44%. The crude product was purified by flash chromatography to give 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-carbaandrostane (125 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 3.90-3.60(m, 8H), 2.74-2.57(m, 2H), 2.25(m, 1H), 1.93-1.08(m, 19H), 0.85(m, 1H), 0.80(s, 3H), 0.75(s, 3H).

According to the procedure for the preparation of 6-aza-7 a-homoandrostane-3, 17-dione (preparation example 5) described above, a mixture of 3, 3: 17, 17-bis (ethylenedioxy) -7 a-aza-7 a-homoandrostane (395mg) 7 a-aza-7 a-homoandrostane-3, 17-dione was prepared in 42% yield. Purification of the crude product by flash chromatography (SiO)₂，CH₂Cl₂/MeOH/26％NH₄OH 93/7/0.7) to give the title compound II-k (128 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 2.80-2.60(m, 2H), 2.45-2.24(m, 3H), 2.15-1.16(m, 16H), 1.15-0.93(m, 2H), 1.05(s, 3H), 0.79(s, 3H).

Preparation example 11

7 a-aza-7 a-formyl-7 a-carbaandrostane-3, 17-dione (II-l)

7 a-aza-7 a-formyl-7 a-homoandrostane-3, 17-dione was obtained in quantitative yield from 7 a-aza-7 a-homoandrostane-3, 17-dione (II-k, preparation 1055mg) according to the procedure for preparation of 6-aza-6-formyl-7 a-homoandrostane-3, 17-dione (preparation 6) above. Purification of the crude product by flash chromatography (SiO)₂Hexane/acetone 60/40) to give the title compound II-l (60 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 8.13(s, 1H), 4.15(m, 1H), 3.52-3.39(m, 1H), 3.18(m, 1H), 2.47-1.08(m, 19H), 0.91(s, 3H), 0.89(s, 3H).

Preparation example 12

7-oxa-7 a-homoandrostane-3, 6, 17-trione (II-m) and

6-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-n)

DMAP (94mg) and Ac were added to a stirred solution of 6 alpha-hydroxyandrostane-3, 17-dione (4.90g) in pyridine (10mL) at 0 deg.C₂O (4.55 mL). After stirring overnight at room temperature the solution was evaporated. The residue was treated with water and extracted with EtOAc (2 ×). The combined organic extracts were washed with brine, over Na₂SO₄Dried, filtered and evaporated to dryness to give 6 α -acetoxyandrostane-3, 17-dione (5.57g, 100%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.66(m, 1H), 2.47-2.33(m, 2H), 2.30-2.01(m, 4H), 2.00(s, 3H), 1.98-1.08(m, 12H), 1.05(s, 3H), 1.00(m, 1H), 0.84(m, 1H), 0.80(s, 3H).

At 0 ℃ and N₂Add NaBH portionwise to a stirred solution of 6 α -acetoxyandrostane-3, 17-dione (5.57g) in MeOH (188mL) over 15min₄(615 mg). After stirring at room temperature for 1.5H, H was added carefully₂The mixture was quenched with O (200 mL). MeOH was evaporated and the concentrated solution was extracted with EtOAc. The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. Purification of the mixture by flash chromatography (SiO)₂cyclohexane/Et₂O/acetone 60/20/20) to give 6 α -acetoxyandrostane-3 β,17 β -diol and 6 α -acetoxyandrostane-3 α,17 β -diol (mixture of 90/10, 5.30g, 95%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.55(m, 1H), 4.49(bb, 1H), 4.43(bb, 1H), 3.41(m, 1H), 3.28(m, 1H), 1.97(s, 3H), 1.88-0.82(m, 19H), 0.79(s, 3H), 0.64(m, 1H), 0.61(s, 3H)。

To a stirred solution of 6 α -acetoxyandrostane-3 β,17 β -diol and 6 α -acetoxyandrostane-3 α,17 β -diol (90/10 mixture, 5.30g) in DMF (120mL) at 0 deg.C was added imidazole (4.53g) and tert-butyldimethylchlorosilane (5.02 g). After stirring overnight at room temperature, H was added₂The mixture was quenched with O (150 mL). Evaporation of DMF and Et₂O extracting the concentrated solution. The combined organic extracts were washed with brine, over Na₂SO₄Dried and evaporated to dryness. Purification of the mixture by flash chromatography (SiO)₂cyclohexane/Et₂O95/5) to give 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -6 α -acetoxyandrostane and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) -6 α -acetoxyandrostane (mixture of 90/10, 7.58g, 87%).¹H-NMR(300MHz，DMSO-d₆Acetone-d₆Ppm relative to TMS): δ 4.60(m, 1H), 3.59(m, 1H), 3.55(m, 1H), 1.95(s, 3H), 1.93-0.88(m, 20H), 0.85(m, 20H), 0.68(s, 3H), 0.68(m, 1H), 0.03-0.00(m, 12H).

To a stirred solution of 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -6 α -acetoxyandrostane and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) -6 α -acetoxyandrostane (a mixture of 90/10, 7.58g) in MeOH/dioxane 1/4(100mL) was added K₂CO₃(896 mg). Stirring at 40 ℃ for 72H, after which H is added₂And O quenching the mixture. The organic solvent was evaporated and the concentrated solution was extracted with EtOAc. The combined organic extracts were washed with brine, over Na₂SO₄Dried over sodium chloride and evaporated to dryness to give 3 β,17 β -bis (dimethyl tert-butylsilyloxy) androstan-6 α -ol and 3 α,17 β -bis (dimethyl tert-butylsilyloxy) androstan-6 α -ol (90/10 mixture, 6.30g, 85%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.30(bb, 1H), 3.55(bb, 1H), 3.47(m, 1H), 2.05(bb, 1H), 1.92-1.73(m, 2H), 1.68-0.87(m, 17H), 0.84(s, 18H), 0.72(s, 3H), 0.62(s, 3H), 0.56(m, 1H), 0.02(s, 3H)H)，0.01(s，6H)，0.01(s，3H)。

In N₂Down to CH of 3 beta, 17 beta-bis (dimethyl tert-butylsilyloxy) androstan-6 alpha-ol and 3 alpha, 17 beta-bis (dimethyl tert-butylsilyloxy) androstan-6 alpha-ol (mixture of 90/10, 6.30g)₂Cl₂(60mL) solution NMNO (4.07g), TPAP (0.412g) andmolecular sieve (3.50 g). The mixture was stirred for 2h, after which SiO was added₂. Purification of the mixture by flash chromatography (SiO)₂n-Hexane/Et₂O50/50) to give 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -androstan-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) androstan-6-one (mixture of 90/10, 6.30g, 100%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 3.68(m, 1H), 3.67-3.57(m, 1H), 2.38-2.30(m, 1H), 2.20-2.12(m, 1H), 1.99-1.05(m, 18H), 0.90(s, 9H), 0.88(s, 9H), 0.75(s, 3H), 0.74(s, 3H), 0.07-0.03(s, 12H).

To stirred CH of 3 beta, 17 beta-bis (dimethyl tert-butylsilyloxy) androstan-6-one and 3 alpha, 17 beta-bis (dimethyl tert-butylsilyloxy) androstan-6-one (mixture 90/10, 660mg) at 0 ℃ over 15min₂Cl₂To the solution (10mL) was added 3-chloroperbenzoic acid (. about.70%, 1.20g) in portions. After stirring at room temperature for 72h, 5% K was carefully added₂CO₃The mixture was quenched with aqueous solution (200 mL). With Na₂SO₃The organic layer was washed with brine and Na₂SO₄Dried and evaporated to dryness. Purification of the mixture by flash chromatography (SiO)₂cyclohexane/EtOAc 13/1) to yield 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one (90/10 mixture, 101mg, 14%).¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): delta 4.21-4.09(m, 1)H) 3.93(m, 1H), 3.69-3.57(m, 1H), 3,64(m, 1H), 3,10(m, 1H), 2.02-1.02(m, 17H), 0.89(s, 9H), 0.88(s, 9H), 0.86(s, 3H), 0.77(s, 3H), 0.06(s, 6H), 0.04(s, 3H), 0.03(s, 3H), 3 β,17 β -bis (dimethyl-tert-butylsilanyloxy) -6-oxa-7 a-haloandrostan-7-one and a mixture of 3 α,17 β -bis (dimethyl-tert-butylsilanyloxy) -6-oxa-7 a-haloandrostan-7-one (90/10, 203mg, 28%) (M.R.R.¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): δ 4.48(m, 1H), 3.72-3.60(m, 1H), 3, 65(m, 1H), 2.64-2.53(m, 1H), 2.34-2.25(m, 1H), 2.602-1.00(m, 17H), 0.90(s, 3H), 0.89(s, 9H), 0.88(s, 9H), 0.76(s, 3H), 0.07(s, 6H), 0.04(s, 3H), 0.03(s, 3H).

To a stirred solution of 3 β,17 β -bis (dimethyl tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one and 3 α,17 β -bis (dimethyl tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one (mixture of 90/10, 680mg) in THF (15mL) was added a 1M solution of TBAF in THF (7.40 mL). After 48h, 5% Na is added₂HPO₄The mixture was quenched with aqueous solution and CH₂Cl₂And (4) extracting. By H₂The combined organic extracts were washed with O over Na₂SO₄Dried and evaporated to dryness. Purification of the residue by flash chromatography (SiO)₂，CH₂Cl₂Acetone 80/20) to yield 3 β,17 β -dihydroxy-7-oxa-7 a-homoandrostan-6-one and 3 α,17 β -dihydroxy-7-oxa-7 a-homoandrostan-6-one (90/10 mixture, 390mg, 98%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.56(bb, 1H), 4.52(bb, 1H), 4.14(m, 1H), 3.83(bb, 1H), 3.46-3.36(m, 1H), 3.31(m, 1H), 3.03(m, 1H), 1.93-0.87(m, 17H), 0.74(s, 3H), 0.63(s, 3H).

Following the procedure described above for the preparation of 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -androstan-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) -androstan-6-one (mixture of 90/10, preparation 12), 3 β,17 β -dihydroxy-7-oxa-7 a-carbAndrostan-6-one and 3 α,17 β -dihydroxy-7-oxa-7 a-homoandrostan-6-one (90/10 mix, 390mg) 7-oxa-7 a-homoandrostane-3, 6, 17-trione was prepared in 84% yield. Purification of the crude product by flash chromatography (SiO)₂Hexane/acetone 80/20) to give 7-oxa-7 a-homoandrostane-3, 6, 17-trione (II-m, 330 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.31(bb, 1H), 4.05(bb, 1H), 3.60(m, 1H), 2.84(bb, 1H), 2.47-1.10(m, 16H), 0.94(s, 3H), 0.82(s, 3H).

Following the procedure described above for the preparation of 3 β,17 β -dihydroxy-7-oxa-7 a-homoandrostan-6-one and 3 β 1,17 β -dihydroxy-7-oxa-7 a-homoandrostan-6-one (mixture of 90/10, preparation 12), 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostan-7-one and 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -6-oxa-7 a-homoandrostan-7-one (mixture of 90/10, 1.32g) were prepared as 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostan-7-one and 3 β 0, 17 beta-dihydroxy-6-oxa-7 a-homoandrostan-7-one (mixture of 90/10) in 96% yield. Purification of the crude product by flash chromatography (SiO)₂Hexane/acetone 60/40) to give 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostan-7-one and 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostan-7-one (mixture of 90/10, 740 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.72(bb, 1H), 4.51(bb, 1H), 4.43(m, 1H), 3.46-3.36(m, 1H), 3.32(m, 1H), 2.16(m, 1H), 2.13(m, 1H), 1.96-0.81(m, 17H), 0.76(s, 3H), 0.62(s, 3H).

6-oxa-7 a-homoandrostane-3, 7, 17-trione was prepared from 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostane-7-one and 3 β,17 β -dihydroxy-6-oxa-7 a-homoandrostane-7-one (620 mg of mixture 90/10 mg) in 70% yield following the procedure described above for the preparation of 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) androstane-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) androstane-6-one (mixture 90/10, preparation 12). Purification of the crude product by flash chromatography (SiO)₂hexane/acetone/CH₂Cl₂50/25/25) to give the title compound II-n (440 mg).¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): δ 4.81(m, 1H), 2.87-2.67(m, 2H), 2.57-2.40(m, 4H), 2.33-2.22(m, 1H), 2.17-1.21(m, 12H), 01.15(s, 3H), 0.92(s, 3H).

Preparation example 13

7 a-oxa-7 a-carbaandrostane-3, 7, 17-trione (II-o)

According to the above 3, 3: preparation of 17, 17-bis (ethylenedioxy) androstan-7-one (preparation example 9) 3 β,17 β -dihydroxyandrostan-7-one was prepared from 3 β,17 β -dihydroxyandrost-5-en-7-one (700mg) with a yield of 96%. Purification of the crude product by flash chromatography (SiO)₂hexane/acetone/CH₂Cl₂10/10/10) to give 3 beta, 17 beta-dihydroxyandrostan-7-one (670 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.53(bb, 1H), 4.44(bb, 1H), 3.47-3.27(m, 2H), 2.45-2.31(m, 2H), 2.05-1.91(m, 1H), 1.89-0.78(m, 17H), 0.99(s, 3H), 0.59(s, 3H).

3 β,17 β -dihydroxy-7 a-oxa-7 a-homoandrostan-7-one was prepared from 3 β,17 β -dihydroxyandrostan-7-one (730mg) in 86% yield following the procedure described above for the preparation of 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) -7-oxa-7 a-homoandrostan-6-one (mixture of 90/10, preparation 12). Purification of the crude product by flash chromatography (SiO)₂hexane/acetone/CH₂Cl₂40/30/30) to give 3 beta, 17 beta-dihydroxy-7 a-oxa-7 a-homoandrostan-7-one (660 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.55(bb, 2H), 4.40(bb, 1H), 3.54-3.43(m, 1H), 3.32(m, 1H), 2.99(m, 1H), 1.93-0.94(m, 18H), 0.91(s, 3H), 0.61(s, 3H).

3 beta, 17 beta-bis (dimethyl-tert-butylsilyloxy) androstan-6-one and 3 alpha as described abovePreparation of 17 β -bis (dimethyl tert-butylsilyloxy) androstan-6-one (mixture of 90/10, preparation 12) 7 a-oxa-7 a-homoandrostan-3, 7, 17-trione was prepared from 3 β,17 β -dihydroxy-7 a-oxa-7 a-homoandrostan-7-one (300mg) in 81% yield. Purification of the crude product by flash chromatography (SiO)₂hexane/acetone/CH₂Cl₂50/25/25) to give the title compound II-o (240 mg).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.73(m, 1H), 3.16(m, 1H), 2.47-2.27(m, 3H), 2.13(m, 1H), 2.08-1.33(m, 13H), 1.22(m, 1H), 1.16(s, 3H), 0.80(s, 3H).

Preparation example 14

6-oxa-5 beta-androstane-3, 7, 17-trione (II-p)

To a stirred t-BuOH (385mL) solution of 3 β -hydroxyandrosta-5-ene-7, 17-dione and 0.25M K at 60 ℃ with vigorous stirring₂CO₃To an aqueous solution (97.5mL) was added 0.37M NaIO₄Aqueous solution (63.4mL) and 0.05M KMnO₄Aqueous solution (7.3 mL). After 15 minutes, 0.05M KMnO was added₄Aqueous solution (5mL), then 0.37M NaIO was added dropwise over 0.5h₄Aqueous solution (253.6 mL). After 5 minutes 0.05M KMnO was added₄Aqueous solution (3 mL). After 1.5h at 60 ℃ the suspension was cooled with an ice bath, after which 10% NaHSO was carefully added₃The aqueous solution is quenched. NaCl (100g) was added to the concentrated aqueous solution, followed by CH₂Cl₂And (4) extracting. By H₂The combined organic extracts were washed with O over Na₂SO₄Dried and evaporated to dryness to give 3 β -hydroxy-5, 17-dioxo-5, 7-seco-B-norandrosta-7-carboxylic acid (4.16g, 78%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 12.17(bb, 1H), 4.65(bb, 1H), 4.17(bb, 1H), 3.05(bb, 1H), 2.44-2.13(m, 3H), 2.13-1.18(m, 10H), 0.90(s, 3H), 0.76(s, 3H).

Formation of 3 β -hydroxy-5, 17-dioxo-5, 7-seco-B-norandrosta-7-carboxylic acid (200mg) in toluene (2.9mL) and MeOH (4mL) at 0 deg.CTo the stirred solution of (3), a 2M (trimethylsilyl) diazomethane solution in hexane (0.412mL) was added dropwise. SiO was added after 2h₂And purifying the mixture (SiO) by flash chromatography₂，CH₂Cl₂MeOH 90/10) to give 3 β -hydroxy-5, 17-dioxo-5, 7-seco-B-nor-androsta-7-carboxylic acid methyl ester (180mg, 88%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.66(bb, 1H), 4.19(bb, 1H), 3.43(s, 3H), 2.98(m, 1H), 2.43-2.24(m, 3H), 2.11-1.95(m, 2H), 1.91-1.19(m, 11H), 0.87(s, 3H), 0.77(s, 3H).

At 0 ℃ and N₂Next, NaBH was added portionwise to a solution of 3 β -hydroxy-5, 17-dioxo-5, 7-seco-B-norandrosta-7-carboxylic acid methyl ester (900mg) in THF (9mL) over 15min₄(306 mg). After stirring at room temperature for 1.5h, the mixture was quenched by careful addition of 1N HCl to acidic pH and CH₂Cl₂Extraction of/tBuOH 9/1. In Na₂SO₄The combined organic extracts were dried and evaporated to dryness to give 3 β,17 β -dihydroxy-6-oxa-5 β -androstan-7-one (800g, 94%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.61(bb, 1H), 4.49(bb, 1H), 4.24(bb, 1H), 3.57(bb, 1H), 3.45(m, 1H), 2.42(m, 1H), 2.08-1.11(m, 14H), 1.04(m, 1H), 0.97-0.85(m, 1H), 0.93(s, 3H), 0.64(s, 3H).

To stirred NaBrO₃(664mg) of H₂Adding RuO into O (9mL) solution₂Dihydrate (24mg) and EtOAc (18 mL). After 10min 3 β,17 β -dihydroxy-6-oxa-5 β -androstan-7-one (450mg) was added. After stirring at room temperature for 15 minutes, the mixture was quenched by careful addition of i-PrOH and extracted with EtOAc. In Na₂SO₄The combined organic extracts were dried and evaporated to dryness. With hexane/Et₂The crude product was triturated with O1/1 and the precipitate was filtered to give the title compound II-p (360mg, 80%).¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): δ 4.61(bb, 1H), 2.98-2.87(m, 1H), 2.83-2.73(m, 2H), 2.64-2.18(m, 5H), 1.94-1.46(m, 8H), 1.32-1.18(m, 1H), 1.25(s,3H)， 0.92(s，3H)。

preparation example 15

2-N-methylaminoethoxyamine dihydrochloride (III-a)

To a suspension of potassium hydroxide (19.7g) in DMSO (200mL) was added, under vigorous stirring, benzyl ketoxime (20.2 g). A DMSO (40mL) solution of N-methyl-2-chloroethylamine hydrochloride (5.2g) was added dropwise. After 2.5 hours at room temperature the reaction was poured into ice/water (400mL), acidified to pH 2.5 with 37% HCl, and Et₂And O washing. The aqueous layer was treated with powdered KOH to pH 10 and Et₂Extracting for 3 times with O; the combined organic layers were washed with water over Na₂SO₄Dry above and evaporate the solvent to dryness. Purification by flash chromatography (SiO)₂，CHCl₃MeOH: AcOH from 9: 1: 0.1 to 7: 3: 0.3) to give benzophenone O- (2-N-methylaminoethyl) oxime (4.65g, 62%) as a viscous oil.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 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. Reaction cooled and Et₂And (4) extracting. The aqueous layer was evaporated to dryness to afford the title compound III-a (1.78g, 80%) as a hygroscopic white solid.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 10.5(5H, bb), 4.26(2H, t), 3.22(2H, t), 2.55(3H, s).

Preparation example 16

3-N-methylaminopropoxyamine dihydrochloride (III-b)

Benzophenone O- (3-N-methylaminopropyl) oxime was prepared from benzophenone oxime and N-methyl-3-chloropropylamine hydrochloride in 62% yield according to the procedure for preparing benzophenone O- (2-N-methylaminoethyl) oxime (preparation example 15) described above.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 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 in 80% yield from benzophenone O- (3-N-methylaminopropyl) oxime following the procedure described for the preparation of 2-N-methylaminoethoxyamine dihydrochloride (III-a, preparation 15).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 11.08(3H, bb), 9.10(2H, bb), 4.10(2H, t), 2.91(2H, m), 2.50(3H, s), 1.96(2H, m).

Preparation example 17

3(R) -Pyrrolidinoalkoxyamine dihydrochloride (III-c)

To a solution of (S) -3-hydroxypyrrolidine hydrochloride (15.0g) and triethylamine (37.3mL) in MeOH (150mL) at 0 deg.C was added di-tert-butyl dicarbonate (29.2 g). After stirring at room temperature for 3h, the solvent was evaporated. By CH₂Cl₂The residue was diluted, washed with water and the organic phase was evaporated to dryness to obtain N-tert-butoxycarbonyl- (S) -pyrrolidinol (21.4g, 95% yield), which was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 4.87(1H, d), 4.19(1H, m), 3.30-3.00(4H, m), 1.90-1.60(2H, m), 1.37(9H, s).

To CH of N-tert-butoxycarbonyl- (S) -pyrrolidinol (10.0g) and triethylamine (8.2mL) at 0 deg.C₂Cl₂To the solution (150mL) was added methanesulfonyl chloride (4.34 mL). After stirring at room temperature for 3h, the reaction mixture was poured into ice/water and diluted with CH₂Cl₂And (4) extracting. With 5% NaHCO₃The organic phase was washed with aqueous solution, water, brine, dried and evaporated to dryness to give an oil which solidified after standing overnight in a refrigerator. With Et₂The solid was triturated to give N-tert-butoxycarbonyl- (S) -3-pyrrolidinylmethanesulfonate as a pale yellow solid (13.0g, 92%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 5.23(1H, m), 3.60-3.10(4H, m), 3.23(3H, s), 2.11(2H, m), 1.39(9H, s).

To a suspension of KOH powder (4.86g) in DMSO (250mL) was added benzyl ketoxime (7.86g) with vigorous stirring. After stirring at room temperature for 30min, a DMSO (70mL) solution of N-tert-butoxycarbonyl- (S) -3-pyrrolidinylmethanesulfonate (10g) was added. After 18h at room temperature, the reaction was poured into ice water (900mL) and Et₂And (4) extracting. The combined organic layers were washed with water, brine, dried and the solvent was evaporated. To give benzophenone O- [ (R) -3-pyrrolidinyl) as a white solid]Oxime (13.0g, 96%) was used in the next step without purification.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): Δ 7.50-7.20(10H, m), 4.84(1H, m), 3.50-3.00(4H, m), 2.01(2H, m), 1.38(9H, s).

Reacting benzophenone O- [ (R) -3-pyrrolidinyl)]The oxime (13.0g) was suspended in 6N HCl (250mL) and the mixture was refluxed for 2 h. After cooling with Et₂And (4) performing extraction reaction. Evaporation of the aqueous layer gave a crude brown solid which was treated with 0.34g of activated carbon in absolute EtOH (255mL) at reflux for 2 h. The solid obtained by evaporation was recrystallized from 96% EtOH (40mL) to give the title compound III-c as a milky white solid (2.98g, 72%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 11.22(3H, bb), 9.74(1H, bb), 9.54(1H, bb), 4.98(1H, m), 3.60-3.00(4H, m), 2.40-2.00(2H, m).

Preparation example 18

3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-7 a-carba-androstane-7, 17-dione (II-q) and

3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) -aminoethoxyimino) -6-aza-7 a-carbaandrostane-7, 17-dione (II-r)

According to the preparation procedure of the above-mentioned 3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-6-methyl-7 a-carba-androstane-7, 17-dione (II-c) and 3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) -aminoethoxyimino) -6-aza-6-methyl-7 a-carba-androstane-7, 17-dione (II-d, preparation example 3), from (E, Z)3- (2-aminoethoxyimino) -6-aza-one7 a-Carcinostane-7, 17-dione hydrochloride (I-aa, example 1, 1.24g) A mixture of the title compounds was prepared. Purification of the crude product by flash chromatography (SiO)₂cyclohexane/iPrOH/CH₂Cl₂50/5/45) to give 3(Z) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-7 a-carba-androstane-7, 17-dione (II-r, 820mg, 46%) and 3(E) - [2- (9H-fluoren-9-ylmethyl carbonyl) aminoethoxyimino) -6-aza-7 a-carba-androstane-7, 17-dione (II-q, 830mg, 47%). II-r:¹H-NMR(300MHz，DMSO-d₆ppm relative to TMS): δ 7.88(m, 2H), 7.77(m, 2H), 7.40(m, 2H), 7.37(bb, 1H), 7.31(m, 2H), 7.17(bb, 2H), 4.10(m, 3H), 3.93(t, 2H), 3.35(m, 1H), 3.22(m, 2H), 3.06(m, 1H), 2.50-0.70(m, 18H), 0.78(s, 3H), 0.76(s, 3H). II-q:¹H-NMR(300MHz，DMSO-d₆ppm relative to TMS): δ 7.88(m, 2H), 7.67(m, 2H), 7.40(m, 2H), 7.34(bb, 1H), 7.31(m, 2H), 7.17(bb, 1H), 4.25(m, 3H), 3.93(t, 2H), 3.39(m, 1H), 3.21(m, 3H), 2.85(m, 1H), 2.50-0.80(m, 18H), 0.79(s, 3H), 0.75(s, 3H).

Preparation example 19

6-oxa-7 a-carbaandrostane-3, 17-dione (II-s)

N at 0 deg.C₂Under the pressure of (14mL), the reaction solution was stirred in a column of LiAlH₄(165mg) to a stirred suspension in THF was added dropwise 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) -6-oxa-7 a-carb-androstan-7-one (preparation 12, 240mg) and BF₃·Et₂O (1.96mL) in THF (14mL), after 45 minutes the mixture was refluxed for 1 h. The suspension was cooled with an ice bath, after which THF/H was added carefully₂O1/1 solution, followed by additional 2N HCl for quenching. With Et₂O (3X) extraction of the mixture, followed by CH₂Cl₂And (4) extracting. With 5% NaHCO₃The combined organic extracts were washed with aqueous solution over Na₂SO₄Dried, filtered and evaporated to dryness. Purification of the residue by flash chromatography (SiO)₂cyclohexane/CH₂Cl₂/acetone 1/1/1)6-oxa-7 a-homoandrostane-3 β,17 β -diol (50mg, 25%) was obtained.¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.51(d, 1H), 4.30(d, 1H), 3.70-3.20(m, 5H), 1.87-0.60(m, 19H), 0.76(s, 3H), 0.62(s, 3H).

6-oxa-7 a-homoandrostane-3, 17-dione was prepared from 6-oxa-7 a-homoandrostane-3, 17-diol according to the procedure described above for the preparation of 3 β,17 β -bis (dimethyl-tert-butylsilyloxy) androstane-6-one and 3 α,17 β -bis (dimethyl-tert-butylsilyloxy) androstane-6-one (preparation example 12). The mixture was stirred for 2h, after which SiO was added₂. Purification of the mixture by flash chromatography (SiO)₂Cyclohexane/acetone 85/15) to give 6-oxa-7 a-homoandrostane-3, 17-dione (35%).¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): δ 3.90-3.50(m, 3H), 2.06-0.90(m, 19H), 1.11(s, 3H), 0.88(s, 3H).

Preparation example 20

7 a-oxa-7 a-carbaandrostane-3, 17-dione (II-t)

7 a-oxa-7 a-homoandrostane-3 β,17 β -diol was prepared from 7 a-oxa-7 a-homoandrostane-3, 7, 17-trione (preparation example 13) according to the procedure described above for the preparation of 6-oxa-7 a-homoandrostane-3 β,17 β -diol (preparation example 19). The mixture was stirred for 2h, after which SiO was added₂. Purification by flash chromatography (SiO)₂cyclohexane/acetone/CH₂Cl₂1/1/1) to give 7 a-oxa-7 a-homoandrostane-3, 17-diol (65%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 4.45(d, 1H), 4.41(d, 1H), 3.57-3.01(m, 5H), 1.90-0.75(m, 19H), 0.79(s, 3H), 0.60(s, 3H).

7 a-oxa-7 a-homoandrostane-3, 17-dione was prepared from 7 a-oxa-7 a-homoandrostane-3, 17-diol according to the procedure for the preparation of 6-oxa-7 a-homoandrostane-3, 17-dione (preparation example 19) described above. The mixture was stirred for 2h, after which SiO was added₂. Purifying the mixture by flash chromatography(SiO₂cyclohexane/acetone/CH₂Cl₂70/15/15) to yield the title compound II-t (85%).¹H-NMR (300MHz, acetone-d)₆Ppm relative to TMS): δ 3.75-3.50(m, 3H), 2.15-1.15(m, 19H), 1.18(s, 3H), 0.87(s, 3H).

Preparation example 21

6-azaandrostane-3, 7, 17-trione (II-u)

3 β -hydroxy-6-azaandrostane-7, 17-dione (Heterocycles, 38(1994)5, 1053-dione) was prepared from 3 β - (tert-butyldimethylsilyloxy) -6-azaandrostane-7, 17-dione according to the procedure described above for the preparation of 3 β,17 β -dihydroxy-7-oxa-7 a-homoandrostane-6-one and 3 α,17 β -dihydroxy-7-oxa-7 a-homoandrostane-6-one (preparation 12). The mixture was stirred for 2h, after which SiO was added₂. Purification of the mixture by flash chromatography (SiO)₂，EtOAc/EtOH/CH₂Cl₂50/10/40) to give 3 beta-hydroxy-6-azaandrostane-7, 17-dione (83%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.25(s, 1H), 446(d, 1H), 3.39(m, 1H), 2.91(dd, 1H), 2.40-0.90(m, 17H), 0.80(s, 3H), 0.78(s, 3H).

6-azaandrostane-3, 7, 17-trione was prepared from 3 β -hydroxy-6-azaandrostane-7, 17-dione according to the procedure described above for the preparation of 3 β,17 β -bis (dimethyl-t-butylsilyloxy) androstane-6-one and 3 α,17 β -bis (dimethyl-t-butylsilyloxy) androstane-6-one (preparation example 12). The mixture was stirred for 35 minutes, after which time SiO was added₂And evaporated to dryness. Purification of the mixture by flash chromatography (SiO)₂Acetone/toluene 1/1) to give 6-azaandrostane-3, 7, 17-trione (75%).¹H-NMR(300MHz，DMSO-d₆Ppm relative to TMS): δ 7.34(s, 1H), 3.31(dd, 1H), 2.57-1.07(m, 17H), 0.99(s, 3H), 0.83(s, 3H).

Biological research and results

Compound pair of the present invention to Na⁺，K⁺ATPases exhibit avidity and inhibit their enzymatic activity. To test the inhibitory effect on activity, Na was purified according to Jorghensen (Jorghensen p., BBA, 1974, 356, 36) and Erdmann (Erdmann e.et al., arzneim. forsh., 1984, 34, 1314)⁺，K⁺ATPase, and measuring the inhibition in the presence and absence of the test compound, expressing it as³²Hydrolysis of P-ATP% (Mall F.et al, biochem. Pharmacol., 1984, 33, 47; see Table 1). S.DeMunari et al, J.Med.chem.2003, 46(17), 3644-.

TABLE 1 dog kidney Na⁺，K⁺Inhibition of ATPase

The ability of these compounds to reduce blood pressure was tested using animal models with genetic arterial hypertension, in particular Milan rats (MHS) with spontaneous hypertension, and rats with hypertension caused by slow instillation of ouabain according to Ferrari P. et al J.pharm.Exp.Ther.1998, 285, 83-94 (Bianchi G., Ferrari P., Barber B.the Milan hyper tension strain. in Handbook of hypertension, Vol.4: Experimental and genetic models of hypertension, Ed.W.dejong-Elsevier Science Publishers B.V., 1984: 328-349).

When the compounds were tested for their antihypertensive activity in the above model, the procedure used was as follows: systolic Blood Pressure (SBP) and Heart Rate (HR) were measured by indirect tail-cap method.

To test the compounds in the MHS model, one month old hypertensive rats (MHS) were divided into two groups of at least 7 animals each, one group receiving the compounds and the other, blank group receiving only vehicle. The compound suspended in Methocel 0.5% (w/v) was administered orally for 5 weeks. SBP and HR were measured once a week at 6 hours post-treatment.

Compared with the compound 22b ((EZ)3- (2-aminoethoxyimino) androstane-6, 17-dione hydrochloride) reported in J.Med.Chem.2003, 46(17), 3644-3654 by S.De Munari et al, the compound of the present invention has higher efficacy and curative effect. At the end of the 5-week treatment period, the activity of reference compound 22b and some of the novel compounds in lowering blood pressure in MHS rats with spontaneous hypertension is shown in the table below, expressed as the reduction in systolic blood pressure (expressed as both reduction in mmHg and in percentage) and the change in heart rate (heart beats/min) relative to the vehicle-only blank group.

Systolic blood pressure drop in spontaneously hypertensive rats (MHS)

Example n DEG	RATS	DOSE^＊ μg/kg/os	SBP -mmHg	SBP -％	HR heartbeat/min.	HR ％
							Compound I-aa	8	10	12.3+/-1.1	7.1	-7.5	-2.1
Compound I-aa	8	1	10.0+/-2.1	6.0	-12.4	-3.6
							Compound I-aa	8	0.1	11.3+/-1.5	6.5	-16.3	-4.8
Compound I-aa	8	0.01	8.8+/-1.6	5.2	-7.5	-4.8
							Compound I-aa	8	0.001	1.0+/-1.1	0.0	-17.5	-5.0
Compound I-ac	8	10	7.2+/-0.7	4.2	0.0	0.0
							Compound 22b	7	100	10.7+/-7.5	6.6	-7.2	-2.0
Compound 22b	7	10	3.6+/-4.8	2.2	-15.8	-4.3

^＊In Methocel 0.5% w/v

As further demonstrated by the blood pressure lowering effect in ouabain sensitive hypertensive rats, compounds suspended in Methocel 0.5% (w/v) were orally administered daily at a dose of 10 μ g/kg/day for 4 weeks. SBP and HR were measured once a week at 6 hours post-treatment.

Systolic blood pressure drop in ouabain-sensitive hypertensive rats (OS rats)

Example n DEG	RATS	SBP mmHg	SBP -mmHg	SBP -％	HR heartbeat/min.
						Compound I-aa	8	153.0	17.0	10.0	385
Compound I-ap	8	154.0	15.0	9.4	387
						OS rat	8	170.0	-	-	368
Blank space	8	150.0	-	-	376

Furthermore, as shown by Cerri et al (Cerri a.et al, j.med.chem.2000, 43, 2332) after slow intravenous drip in anesthetized guinea pigs, the compounds of the present invention have the property of increasing the force of muscle contraction and are of low toxicity compared to standard cardiotonic steroids, such as digoxin. Compared to compound 22b ((EZ)3- (2-aminoethoxyimino) androstane-6, 17-dione hydrochloride) reported in j.med.chem.2003, 46(17), 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 compounds I-ba and I-bk in the above assay is shown in Table 2 below. The effect on the force of muscle contraction is shown as: maximum increase in contractile force (E)_maxAt + dP/dT_maxMeasured), dose inducing the maximum muscle contraction increasing Effect (ED)_max) Affecting the efficacy of muscle contraction (ED)₈₀Make + dP/dT_maxDose increased by 80%); toxicity, expressed as the ratio between lethal dose and efficacy affecting muscle contraction (calculated in dead animals); maximum dose instilled in surviving animals; time to effect muscular contraction force, tables thereofShown as relative to ED measured at 20 minutes after the end of instillation_maxIn other words, a reduced value of the effect.

TABLE 2 muscle contraction and lethal dose in anesthetized guinea pigs

As reported in Table 2, compounds I-ba and I-bk showed a higher safety ratio in terms of the effect of increasing the muscular contraction force than digoxin and compound 22 b. In fact, no lethal dose/ED was determined since no animals died₈₀And (4) the ratio. In addition, I-ba and I-bk had a longer duration of action as indicated by the persistent effect on the force of muscle contraction after cessation of instillation. Since the maximum increase in contractile force was higher for I-ba and I-bk than for digoxin and Compound 22b, the highest dose of these two compounds was not tested.

Claims

1. A compound having the general formula (I):

wherein:

a is a divalent group selected from:CH₂CH₂CH₂CH(OR³)CH₂CH₂CH₂CH(OR³)CH₂C(＝X)CH₂CH₂CH₂C(＝X)CH₂BCH₂CH₂CH₂BCH₂BCH₂BC(＝X)CH₂C(＝X)BCH₂BC(＝X)whereinThe symbol represents an alpha or beta single bond linking the a group to the androstane skeleton at position 5 or 8;

b is oxygen or NR⁴；

R³Is H or C₁-C₆An alkyl group;

x is oxygen, sulfur or NOR⁵；

R⁴Is H, C₁-C₆Alkyl, or when A isBCH₂CH₂CH₂BCH₂OrBCH₂When R is⁴And also formyl;

R⁵is H or C₁-C₆An alkyl group;

R¹absent, bond at position 17 of androstane skeletonIs a double bond;

R²is DNR⁶R⁷Or group

Wherein the group D or Z is attached to an oxygen atom;

d is C₂-C₆A linear or branched alkylene group;

R⁶and R⁷Identical or different is H, C₁-C₆An alkyl group;

R⁸is H, C₁-C₆Straight or branched chain alkyl, optionally substituted with one or more hydroxy, methoxy, ethoxy;

z is a single bond;

y is CH₂；

n is 1;

m is 1.

2. The compound of claim 1, wherein A is selected fromCH₂CH₂CH₂BCH₂CH₂BC(＝X)CH₂AndC(＝X)BCH₂

3. the compound of claim 1 or 2, selected from the group consisting of:

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostan-17-one dihydrochloride;

3- (E, Z) - (3-N-methylaminopropoxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostan-17-one hydrochloride;

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-7 a-carb-7- (Z) -hydroxyiminoandrostan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-aza-7 a-carb-7- (Z) -methoxyimino androstan-17-one hydrochloride;

3- (E, Z) - [3- (R) -pyrrolidinyl ] oxyimino) -6-aza-7 a-carb-7- (Z) -methoxyimino androstan-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -7 a-aza-7 a-homoandrostan-17-one difumarate;

(E, Z)3- (2-aminoethoxyimino) -6-oxa-7 a-homoandrostane-7, 17-dione fumarate;

(E, Z)3- (2-aminoethoxyimino) -B-homoandrostane-17-one hydrochloride;

(E, Z) -3- (2-aminoethoxyimino) -6-oxa-7 a-homoandrostane-17-one hydrochloride;

(E, Z)3- (2-aminoethoxyimino) -6-azaandrostane-7, 17-dione hydrochloride;

(E, Z)3- [3- (R) -pyrrolidinyl ] oxyimino-6-azaandrostane-7, 17-dione fumarate;

(E)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostane-7, 17-dione fumarate; and

(Z)3- (2-aminoethoxyimino) -6-aza-7 a-homoandrostane-7, 17-dione fumarate.

4. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (II)

Wherein the symbols A andhas the same meaning as defined in claim 1, and wherein R¹In the absence of the presence of the agent,

with a compound of the general formula (III),

R²ONH₂ (III)

wherein R is²Has the same meaning as defined in claim 1,

the reaction is carried out in a polar solvent at a temperature of from 0 ℃ to reflux temperature.

5. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of cardiovascular diseases.

6. Use according to claim 5, wherein the cardiovascular disease is heart failure and/or hypertension.

7. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of a disease caused by the hypertensive effects of endogenous ouabain.

8. The use according to claim 7, wherein the disease caused by the hypertensive effects of endogenous ouabain comprises exacerbation of renal failure in autosomal dominant polycystic kidney disease, preeclamptic hypertension and exacerbation of proteinuria and renal failure in patients with adducin polymorphisms.

9. A pharmaceutical composition comprising one or more compounds according to claim 1 or 3 in association with an excipient and/or a pharmacologically acceptable diluent.

10. A process for the preparation of a pharmaceutical composition according to claim 9, which process comprises mixing one or more compounds according to any one of claims 1 to 3 with suitable excipients, stabilizers and/or pharmaceutically acceptable diluents.

11. Use of a compound of any one of claims 1-3 for the manufacture of a medicament for treating a mammal having a cardiovascular disorder.

12. Use of a compound according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of a mammal suffering from a disease caused by the hypertensive effects of endogenous ouabain.