NL8103358A - 3-Hydroxy-11-amino-androstane 17-carboxylic acid derivs. - useful as antiarrhythmic agents with no general anaesthetic properties - Google Patents

Abstract

3alpha-Hydroxy-11alpha-aminoandrostane 17beta-carboxylate esters of formula (I) and their D-homo-17abeta-carboxylate analogues and acid-addn. salts are new. In (I), R1 is 1-8C alkyl or 3-7C cycloalkyl; R2 is H, 1-6C alkoxy or 2-5C alkanoyloxy; R3 is 1-8C alkyl or 3-7C cycloalkyl; with the proviso that R2 must be H when (I) has a 5beta-H atom. Intermediates of formula (I) where at least one of R1 and R3 is H, and their D-homo-17abeta analogues and their salts and amphionic forms are also new. (I) have higher antiarrhythmic activity than the cpds. of BE 853227 and are free of general anaesthetic activity.

Description

* * - 1 - \ 'z' \ 11a-amino-androstanes and methods for preparing and using these compounds.

The invention relates to aminosteroids with antiarrhythmic activity, in particular to certain compounds in the androstane series with a substituted amino group at the 11a position.

The purpose of the antidysrhythmic or antiarrhythmic therapy is to reduce dangerous, abnormal heart rhythms to normal, or to reduce the likelihood of dangerous rhythms developing in risk patients due to hypertension, atheromas, diabetes or heart conditions, such as myocardial disease disorders, ischaemia or an in-market.

It is known that arrhythmias in patients who have had a heart attack and can be treated and protected with other conditions. A number of drugs are available to treat ventricular arrhythmias, but their use is limited by their lack of effectiveness or their toxicity, which give rise to several side effects.

Thus, there is a demand for drugs suitable for use in the treatment of patients with arrhythmias, which are at risk of sudden cardiac death. In addition, there is a demand for such medicaments for administration, for example for long-term protection, to patients at risk of developing arrhythmias, in which case an activity by oral administration is desired.

In the Belgian patent specification 853227 a group of 11a-tert. amino-3a-hydroxysteroids with an anesthetic effect. In addition to the 11a-tert.amino and 3a-hydroxyl groups, compounds with different substituents in other places, including the 178 position, are also possible, with a possible 170 substituent being an alkoxycarbonyl group. Corresponding 11a primaries and secondary aminosteroids are 8103358.

Also described as intermediates for the preparation of the tertiary amino compounds. Any 11a primary or secondary amino-170-alkoxycarbonyl compounds are not specifically described in this Belgian patent specification 853227, nor is a In particular, anesthetic activity for such compounds has been mentioned In addition, no antiarrhythmic activity has been attributed to any of the compounds of the aforementioned Belgian patent, or to any compounds of a similar structure.

It has now been found that a group of 11a-sec.aml-no-3a-hydroxysteroids with a 173-carboxyl ester group has a surprisingly high antiarrhythmic effect; while it generally has no anesthetic effect. The antiarrhythmic. the,.

action of compounds is considerably greater than of similarity. future compounds specifically described in Belgian Patent 853227iS with other 17B groups. Thus, the compounds of the invention can be used as antiarrhythmic drugs,

The invention relates to compounds of formula 1, in which an alkyl group with at most 8 carbon atoms or: a cycloalkyl group with 3 to 7 carbon atoms, a hydrogen atom, an alkoxy group with at most 6 carbon atoms or an alkanoyloxy group with 2 to 5 carbon atoms and R 4 represent an alkyl group with up to 8 carbon atoms or a cyclo-25 alkyl group with 3 to 7 carbon atoms, provided that if the compounds contain a 53 hydrogen atom, Rg represents a hydrogen atom, and the D-homo analogs thereof having a -CO 2 R 2 group, wherein R 2 has the meaning indicated above, in the-17aS position, as well as the acid addition salts thereof.

When R 1 or R 1 represents a cycloalkyl group, it may be, for example, a cycloalkyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

To give ' ·. the substituents R1 or an alkyl group, it may have a straight or branched chain.

If R 1 is an alkyl group, it preferably has 8103358 * «τ 1 * - 3 - 3 to 7 carbon atoms and can, for example, be a propyl, butyl, pentyl, isopentyl, hexyl, isohexyl or neohexyl group to be.

Eg represents an alkoxy group, it may be, for example, a methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy group 5; an example of an alkanoyloxy group is the acetoxy group.

Represents an alkyl group, it may be, for example, a methyl, ethyl, propyl, isopropyl, butyl or isopentyl group.

The total number of carbon atoms in the groups R ^,

Rg and Rj together are preferably between 3 and 10 carbon atoms.

R 1 is preferably an alkyl group having up to 8 carbon atoms, and if compounds having good activity are desired by oral administration, R 1 is preferably a methyl or ethyl group. Ring D is suitably a five-ring.

The compounds preferably contain a 5a hydrogen atom.

Recommended compounds are 5a -androstanes, of which ring D is a five-membered ring, in which: R ^ is an isopentyl, hexyl, iso-hexyl, neohexyl, cyclopentyl or cyclohexyl group, Rg is a hydrogen atom or a methoxy, ethoxy or propoxy group, in particular, without a methoxy or ethoxy group and R 1 represents a methyl or ethyl group, in particular a methyl group.

The compounds of formula 1 can form acid addition salts; physiologically acceptable salts are recommended. Examples of such salts are hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methane sulfonates, eggrates, tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, glutarates and glutaconates. The hydrochlorides are preferred as acid addition salts.

Preferred compounds based on their potent anti-arrhythmic action are, for example: 1. methyl 2f3-ethoxy-3a-hydroxy-11α- (3-methylbutyl-amino) ~ 5a-androstane-17β-carboxylate , 2. methyl 2B-methoxy-3a-hydroxy-11a- (3-methylbutyl-35 amino) -5a-androstane-17B-carboxylate, 8103358 »Λ Τ 'β * 1 - k - 3. methyl 11 α-cyclohexylamino- 2S-ethoxy-3a-hydro2y-5'-androstane-173-caroxylate,

Ij, methyl 11ct- (3,3-dimethylbutylamino) -2S-etho: xy-3a-hydroxy-5a-androstane-176-carboxylate, 5 5.methyl 11a-cyclohexylamino-3cC-hydroxy-26-methoxy-5a- androstane-17 g-carboxylate, 6. methyl 3ct-hydroxy-11 a- (3-methylhutylamino) -5a-androstane-17β-carboxylate, 7. methyl 1ta-cyclohexylamino-3a-hydroxy-5a-androsetane-17B -carboxylate, 8.methyl 11a-cyclopentylamino-3a-hydroxy-5a-androsane-173-carboxylate, 9.methyl 3a-hydroxy-1a - - - methylbutylamino ^ g-propoxy ^ a-androst-173- carboxylate, 10. 10. methyl 2f3-ethoxy-11a-hexylamino-3a-hydroxy-5a-androstane-178-caroxylate, 11. methyl 11a-cyclopentylamino-3α-hydroxy-2β-methoxy-5a-androstane-173 ”Carhoxylate, 12 ethyl 2g-ethoxy-3a-hydroxy-11a (3-methylbutylamino) -5a-androstane-17β-carboxylate, 13.methyl 11α-cycloheptylamino-3a-hydroxy-2g-methoxy-5a-androstane- 17β-carboxylate and 1 ^. methyl 11α-cyclobutylaminO-3a-hydro: xy-2-methoxy-5a-androstane-173-caroxylate 25 and their physiologically acceptable acid addition salts, for example their hydrochlorides.

A highly recommended compound from this group is compound 1 and its physiologically acceptable acid addition salts, such as the hydrochloride. Studies conducted both in vitro and in experimental animals show that this compound has a highly desirable combination of pharmacological properties. Thus, in particular against aconitin-induced arrhythmias in anesthetized rats, this compound exhibits a high degree of activity, both after oral and intra-venous administration. The oral and intravenous therapeutic values 8103358

T 1 J

- 5 - \ are high and a single oral dose of the compound has a long-lasting effect. The compound is very effective in reducing mortality and the occurrence and duration of ventricular bigemini, tachicardia and fibrillation in anesthetized coronary artery rats. The compound was effective against intravenous arrhythmias in an informed dog after intravenous or oral administration.

Other compounds that have the same properties as compound 1 are compounds 2, 5 and J.

10 Allow the compound to be used to treat patients who suffer from heart rhythm disturbances *, whether spontaneously, or as a result of treatment with other medicines, for example cardiac glyeosides, or as a result of myocardial ischaemia or an in-market disease. However, they can also be used for the prophylactic treatment of patients at risk of arrhythmias or sudden death from coronary artery disease.

Thus, the invention further provides compounds of formula 1, as well as their physiologically acceptable acid addition salts, for use in the therapy or to prevent eardial arrhythmias in humans or animals. Furthermore, the invention also provides compounds of formula 1 and their physiologically acceptable acid addition salts and protocols for their use, in the therapy or for the prevention of cardiac arrhythmias in humans or animals.

Yet another aspect of the invention is to provide compounds of formula II, wherein R ^ has the meaning indicated above, provided that if the compounds contain a 5 (3-30 hydrogen atom, R ^ is a hydrogen atom, R ^ is a hydrogen atom or a the predefined group and R ^ represent a hydrogen atom or a predefined group R ^, provided that at least one of the substituents R ^ or R ^ is a hydrogen atom and its D-homo analogues, in which the -CO ^ R ^ group 35 at the 17aB site, as well as its salts and internal ions.

The compounds of formula II can also form acid addition salts. Compounds of formula 2 wherein -COgRj. represents a carboxyl group may also form salts with bases or exist as internal ions.

Examples of acid addition salts are those mentioned above in connection with the compounds of formula 1. The base salts may be inorganic base salts, such as alkali metal salts, for example, sodium, potassium, and 1X-thium salts, alkaline earth metal salts, for example, calcium and magnesium salts, and ammonium salts, or salts with organic bases, for example, amine salts.

Compounds of formula II are useful as intermediates for preparing the compounds of formula III using the methods described below.

The compounds of the invention can be prepared by many different methods, using generally known methods. Suitable methods for this are described below: 1. A substituent on the 11a amino group can be introduced by reacting the corresponding 11a amino compound, ie a compound of formula 2 wherein R 1 represents a hydrogen atom, with a compound of formula R ^ X, wherein X is an easily displaceable atom or displaceable group, such as a halide, for example iodide, a hydrocarbon sulfonyloxy group, for example toluene-p-sulfonyloxy group, a hydrocarbon oxysulfonyloxy group, for example a methoxy-sulfonyloxy group, or a dialkoxyphonyonyloxy group, for example dimethoxyphosphine group , is. When the reaction is carried out with compounds of the formula II in which R ^ also represents a hydrogen atom, such a reaction can lead to esterification to form a compound of the formula I wherein R ^ = R ^. Substituent R 3, if not desired in the final product, can then be replaced by transesterification, for example, as described below under 8. Entering a substituent on the 1-lot amino group is called it is preferably carried out in the presence of a base, for example potassium carbonate or silver oxide, dissolved at a suitable temperature between room temperature and the reflux temperature, for example between +20 and + 100 ° C.

The reaction is suitably carried out in a suitable solvent for the reaction. Examples of suitable solvents are ethers, for example dioxane, substituted amides, for example Η, Ν-dimethylformamide or Η, ϊϊ-dimethylacetamide, sulfoxides, for example dimethyl sulfoxide, alcohols, for example ethanol and methanol »or acetonitrile.

If X represents a chlorine or bromine atom, the course of the reaction can be facilitated by adding an iodide such as sodium iodide.

Compounds of formula 2 in which R 1 represents a hydrogen atom can be prepared by reduction of the corresponding 11-oxime. Such a reduction can be carried out with an alkali or alkaline earth metal in an alcohol and / or an amine and / or ammonia, eg sodium in n-propanol, if desired in the presence of a suitable solvent, for example tetrahydrofuran, with any suitable temperature to, preferably the reflux temperature.

The 11-oximes themselves can be obtained again from the corresponding 11-oxo compounds. An 11-oxo compound can be obtained, for example, by reaction with hydroxylamine under strongly alkaline conditions in an aqueous alcohol, for example ethanol, preferably at the reflux temperature.

The reaction can also be carried out under acidic conditions, approximately pH, for example, in buffered pyridine.

The stringent conditions used in the reduction of the 11-oxime make it necessary or desirable that certain substituents, if desired, for example, a 17-alkoxycarbonyl or a 23-alkanoyloxy substituent upon formation of the 1 1a-amino group will be introduced.

35 8103358

ff V

r '* - 8 - 2, Opening of a similar epoxy 2a, 3a.

This reaction can be used to prepare 2--substituted 5a compounds. The general method of preparing 20 compounds by this route is described in Applicant's British Patent No. 1376892. Thus, generally, this reaction includes treating the corresponding 2a, 3cx epoxy with an Hb compound under acidic conditions, optionally in the presence of an added acid catalyst, for example sulfuric acid, perchloric acid or boron trifluoride etherate, or a compound containing the (R2) anion wherein R2 has a meaning as defined above, but is not hydrogen, and then, if the initially obtained product contains a deprotonated 3a-hydroxyl group, treatment of the product with a proton source, for example, aqueous ammonium chloride, to form the 3a-hydroxyl group. Examples of HR reagents are alcohols and carboxylic acids. Examples of reagents which form (Rp anions are the alkalim etal or ammonium salts of HRg acids and alkali with alkaline oxides. The reaction is preferably carried out under anhydrous conditions at any suitable temperature up to the reflux temperature.

The reaction can be conducted in a suitable solvent medium, for example, a hydrocarbon, halogenated hydrocarbon or ether, or, if the reagent is a compound HRg, an excess of the reagent can be used as the reaction solvent.

The starting materials required for this reaction can be prepared, for example, by first entering the desired 11a-amino group, for example, by the method of the above reaction 1, using a 2.

30 Λ starting material, then to form a salt, for example 2 with toluene-β-sulfonic acid, and then epoxidize the Δ compound with a peracid and finally regenerate the free base. Δ. compounds can be prepared by formation of the 3-methanesulfonate and then removal of methanesulfonic acid.

6103358 - 9 -, ί ί k

This reaction can also be used to "prepare the intermediates of formula 2, but if the epoxidation is carried out in the presence of a primary or secondary 11a amino group, the amino group can also be" protected, "for example, as a trichloroethoxycarbonyl derivative. The trichloroethoxycarbonyl group. can then be removed by hydrolysis with an alkali, or "preferably by reduction with zinc and acetic acid.

JO 3. A corresponding Πα-amino compound, that is, a compound of formula 2, which represents a hydrogen atom, can be alkylated reductively with a mono-carbonyl compound which serves to introduce the substituent, in the presence of a reducing agent, the term 15 "alkylated" is used to indicate the introduction of both a cycloalkyl and an alkyl group. The reducing agents to be used are generally known for reducing imines, examples of which are formic acid, for example at any suitable temperature up to 100- 120 ° C, for example from room temperature to 100 ° C, and using the carbonyl compound as a reaction solvent, in the presence or absence of water, an alkali metal hydride or cyanoborohydride, for example, sodium sulfide or cyanoborohydride, using an alcohol such as ethanol, as solvent, suitable at room temperature, iron pentacarbonyl or an alkali metal Hydrogen iron carbonylate, for example Fe (CO) ^ or MHFe (CO) ^, where M is sodium or potassium at any suitable temperature up to the reflux temperature, using an ether such as tetrahydrofuran or an alcohol or an aqueous alcohol solvent, hydrogen in the presence of a metal catalyst, using an alcohol, for example ethanol, an ether, for example dioxane, or an ester, for example ethyl acetate, as a reaction solvent, suitable at room temperature, or aluminum amalgam in the presence of water, suitable at room temperature and in the presence of an ether as a solvent, such as tetrahydrofuran.

8103358 v £ τ * s ν -10-

The metal catalyst can be, for example, a noble metal catalyst such as platinum, platinum oxide, palladium or rhodium. The catalyst may be supported, such as charcoal or kieselguhr, for example. A homogeneous catalyst, such as tristriphenylphosphine rhodium chloride, may also be employed. If desired, the intermediate intermediate may be separated.

For example, the use of formaldehyde, acetaldehyde, 3-methylbutanol or cyclohexanone can lead to the formation of 11 α-Ν-methyl, H-ethyl, H-iso-pentyl or ΪΓ-cyclohexylamines, respectively. It will be appreciated that the conditions will have to be chosen so that the desired H-monosubstituted compound is predominantly obtained and the formation of the corresponding N, N-disubstituted-15 compound is minimized. Reductive alkylation of compounds of formula 2 wherein R 1 and R 1. both hydrogen atoms are preferably carried out under basic conditions.

20 Reduction of a corresponding 3-oxo compound.

20-unsubstituted steroids of the invention can be obtained by stereospecific reduction of suitable 3-oxo compounds. 5a-compounds are preferably obtained by the method of Browne and Kirk (J. Chem. Soc. C, 1969 25 1653) or of the Applicant's British patent specification 1, 09239. The latter method preferably uses a preformed iridium catalyst reduction system. For example, a reduction system can be prepared from an iridic acid or salt, for example, chloriridic acid, a trivalent phosphorus compound, such as an ester of phosphoric acid, for example, trimethyl phosphite, water, and an organic reaction medium, for example, an alcohol, such as: isopropanol. The reduction system is then neutralized with an organic base, such as a secondary or tertiary amine, for example, triethylamine, for example, to a pH of 6 to 8.5, and reacted with the steroid 8103358-11. If the cat alysat or system is pre-formed by reflux heating, e.g., for 16 to 2 hours, then the reduction can be completed, for 2 to 3 hours under reflux, 5 longer times may be required. room temperature.

53 steroids can be obtained by hydride reduction of the corresponding 3-oxo compound predisposed with sodium horohydride using an alcohol, predominantly ethanol, or pyridine as a solvent.

5. Conversion of a 1-W-disubstituted 11 I-amine to a 1-mono-substituted compound.

Compounds of formula 1 can be derived from corresponding 11-tert. amino compounds are prepared by replacing one of the groups with a hydrogen atom, predisposed by deaikylation using predominant sodium nitrite, followed by catalytic hydrogenolysis.

Thus, in particular, the compounds can be prepared by linking a corresponding 11a (protected amino) compound with a substituent except the protecting group, which includes, for example, an alkyl group, such as a trichloroethoxycarbonyl group, trifluoroacetyl group, or a formyl or silyl group , for example, a trimethylsilyl group, may be to cleave off the protecting group. An alkyl group can be removed by hydrolysis, for example with acid or alkali. The trichloroethoxy-earbonyl group can also be removed by reduction with, for example, zinc and acetic acid. It is also possible to remove an arylmethyl protecting group, such as a benzyl group, by catalytic hydrogenation, to form the unprotected 11a-amino compound. A silyl group can be expanded, for example, by solvolysis, with water, optionally containing an acid or base, or an alcohol, or by treatment with an ionic fluoride, such as tetrabutyl ammonium fluoride.

This method can also be used to prepare compounds of formula 2 in which R 1 represents a hydrogen atom, by cleaving off a corresponding 1 1a (protected amino compound) to the protecting group, Tan 8103358 • fc * * 1-12. to form a free 11a amino group.

5 6. Esterification of a corresponding 173-carboxylic acid.

Compounds of formula 1 can be prepared by reacting the corresponding compound of formula 2, wherein R 1 represents a hydrogen atom or a reactive derivative thereof, for example an acid halide or anhydride or salt, with a suitable alcohol or alkyl or cycloalkyl halide . The reaction is preferably carried out at a temperature between -20 and + 110 ° C, as described, for example, in applicant's British patent 13802½. If an alcohol is used in the esterification reaction, a coupling agent can be used, for example a carbodiimide, such as dicyclohexylcarbodiimide, preferably in the presence of a catalyst, such as dimethyl aminopyridine.

It is also possible to carry out the esterification with a diazoalkane, such as diazamethane.

Compounds of formula 2 wherein R 1. a hydrogen atom can conveniently be obtained by oxidation of the corresponding 173-acetyl compound, for example, a pregnan-20-one, using, for example, NaOBr in an aqueous, inert solvent medium, for example, aqueous dioxane.

Compounds of formula II in which R1 represents a hydrogen atom can also be obtained from their corresponding esters with other 173-ester groups than the previously defined R1 group, for example by hydrolysis under acidic or basic conditions. Examples of suitable acids for such hydrolysis are mineral acids, such as hydrogen chloride, while examples of suitable bases are alkali metal hydroxides and carbonates, such as sodium and potassium hydroxide and carbonates.

35 It is possible to apply 8103358 k Λ -13- r *! the reagents, for example, alkyl halides, are required to protect the 11a-amino group, for example, as a trichloroethoxycarbonyl derivative.

5 7 · Reduction of a corresponding Δ ^ connection.

This reduction can be carried out by hydrogenation in the presence of a catalyst, for example a palladium catalyst, in a suitable solvent, for example an alcohol, ether or ester. The reaction may conveniently proceed at or in turn of room temperature and atmospheric pressure, in the presence of a tertiary base, for example triethylamine and / or an acid, for example acetic acid.

The starting materials can be prepared by reacting the corresponding 17-oxo compound with aqueous hydrogen cyanide to form the 17-eyanhydrin which can be dehydrated to 16 the Δ-176-cyano compound. This gives the Δ -176-carboxylic acid on hydrolysis and the corresponding λ ^ -173 ester on alkylation.

8. Compounds of formula 1 may also be obtained by transesterification, ie by reaction of a corresponding compound with a 170-ester group other than the desired R 1 group with an alcohol of formula R 1 OH in the presence of an acidic or basic catalyst at any temperature between room temperature and reflux temperature, suitably between 50 and 100 ° C, whereby a compound of formula 1 with another 173-ester group is obtained from the starting material, normally an excess of alcohol is used. Examples of suitable acidic catalysts are mineral acids, for example sulfuric acid and hydrogen chloride, while examples of suitable basic catalysts are alkali metal hydroxides and carbonates, for example sodium and potassium hydroxide and carbonates.

35 9 · Conversion of a corresponding 30-bydroxy compound- 8103358 * c t% l -Tick bond.

Compounds of formula 1 can be prepared from corresponding 3g-hydroxy compounds by introducing an easily replaceable 33 group, such as a hydrocarbon sulfonyl-5 oxy group, for example a p-toluene sulfonyloxy group or mesyloxy group, the 36 group by hydrolysis, for example under acidic conditions, is replaced to form the desired 3a-hydroxy group.

It is also possible to treat the 33 alcohol in the presence of an acid, such as formic acid or benzoic acid and a phosphine, such as triphenylphosphine, with diethyl azodiarboxylate and the resulting 3a-protected hydroxyl compound as described below under 10. , split off the protecting group.

10. Cleavage of a protecting group from a corresponding compound with a protected 3a-hydroxyl group.

Compounds corresponding to the compounds of formula 1 but containing protected, eg esterified or etherified, 3α-hydroxy groups can be formed if a 3α-hydroxyl group is deliberately protected or esterification or etherification of a 3a-hydroxyl group under the same conditions -hes if a reaction takes place elsewhere in the molecule.

An ester, for example alkanoyloxy group, can be hydrolyzed under mild acidic or basic conditions to the desired 3a-hydroxy compound. Weak basic conditions are generally most suitable using, for example, an alkali metal dicarbonate in. aqueous methanol and at any suitable temperature up to the reflux temperature. Dilute mineral acids, for example perchloric acid in aqueous methanol, can also be used.

An ether, for example tetrahydropyranyl ether, protecting group can be removed by treatment with an aqueous acid and a nitro-oxy protecting group by reduction, for example using zinc and acetic acid.

35 8103358

V

, V.

2-15 12. Acid addition salts can be prepared by reacting a free base with an appropriate acid,

The above-described methods of preparing the compounds of the invention can be used as the final major step of preperative synthesis. The same general methods can be used to introduce the desired groups at an intermediate step in the stepwise formation of the desired compound. It will be appreciated that these general methods can be combined in many multistep methods in many different ways, as will be apparent from the following examples. The order of the reactions in these multi-step processes will, of course, be chosen so that the reaction conditions employed do not affect groups in the molecule that are desired in the desired final product.

The D-homo analogs of the compounds of the invention having a -CO 2 R 1 group in the 17αβ position can be prepared by substantially similar methods, using suitable starting materials of the required structure.

Unless otherwise stated, the methods described above for preparing compounds of formula 1 are also used to prepare the compounds of formula 2. Bas ez out and of the compounds of formula 2 can be obtained by reaction of the free acid with a suitable base. For example, alkali metal salts can be obtained by reaction with an alkali metal hydroxide, alkali metal carbonate, alkali metal dicarbonate or 2-ethylhexanoate.

The compounds of formula 1 and their physiologically acceptable acid addition salts can be processed for administration in any suitable manner and the invention therefore also relates to a method of preparing pharmaceutical preparations comprising at least one or more compounds of formula 1 and / or their physiologically acceptable salts thereof, suitable for use in human or veterinary medicine. Such formulations can be used 8103358

+ V

I V 1 -16- are presented in a manner which is optionally mixed with one or more pharmaceutical carriers or excipients.

For example, the compounds of the invention of the formula I and their physiologically acceptable acid addition salts may be presented in a form suitable for absorption by the gastrointestinal tract. Tablets and capsules for oral administration may be presented in unit dosage form and may be conventional excipients such as binders, eg syrups, acacia, gelatin, sorbitol, tragacanth, mucilage or starch or polyvinylpyrolidone, fillers, for example lactose, sugar, corn starch, calcium phosphate or sorbitol, lubricants, e.g. magnesium stearate, talc, poly-si. "Ethylene glycol or calcium oxide, disintegrants, for example potato starch or sodium starch glycolate or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated by known methods. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented in the form of a dry product for processing with water or other suitable vehicle before use. Such liquid preparations may include conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, glucose sugar syrup, gelatin, hydroxyethyl cellulose, carboxy methyl cellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia, non-edible carriers oils may be included, / e.g. contain almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol and preservatives, e.g. methyl or propyl p-hydroxybenzoates or sorbic acid. The compounds and their salts can also be processed into suppositories containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

The compounds of formula 1 and their physiological 8103358

• * I

Acceptable acid addition salts and may also be processed for injection purposes and may be presented in unit dosage forms in ampoules or in multiple dose containers with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain processing agents such as suspending agents, stabilizing agents and / or dispersing agents. It is also possible that the active ingredient is present in powder form for use with a suitable carrier, for example sterile, pyrogen-free water.

If the compositions contain dosage units, each unit will preferably contain at least 5 mg, especially at least 10 mg of the active ingredient, especially an amount between 25 and 500 mg. The daily dose, as used to treat adult humans, will preferably be between 25 and 2500 mg, preferably between 50 and 1000 mg, depending on the mode and frequency of administration. The compounds can also be administered in separate doses, for example 1 to 4 times a day.

The compounds of the formula I of the invention and their physiologically acceptable acid addition salts may, if desired, be administered together with other drugs.

The following applies to the following examples:

Melting points were determined in capillaries and corrected. The optical rotational powers were determined from 1% solutions in chloroform and at room temperature.

Preperative thin layer chromatography and column chromatography were performed on silica.

Petrol refers to petroleum ether with a boiling point 30 between 60 and 80 ° C.

The solutions were dried using anhydrous sodium sulfate.

The I.E. spectra were determined in bromoform and indicate the earbonyl stretch frequency of the 17? -Carboxylic acid ester group 35.

8103358

# V

* τ * -18-

The chloriridic acid reagent was prepared by boiling a mixture of 50 mg of chloriridic acid, 9 ml of isopropanol, 6 ml of water and triphenylphosphite under reflux for 2 hours and immediately adjusting the pK to 7 by adding triethylamine.

It. Jones reagent was prepared from 26.8 g of chromium trioxide and 23.0 ml of concentrated sulfuric acid, diluted to 100 ml with water.

The following abbreviations were used in the tables: A = acetonitrile, Ch = chloroform, M = methanol, I = isopropanol, Am = 0.88 ammonia, E = ethanol, D = diethyl ether, Ea = ethyl acetate and Pe = petroleum ether.

Intermediate 1: 11a-Amino-5a-pregn-2-an-20-one.

A solution of 9, 36 g of 20,20-ethylene-dioxy-5a-pregn-2-en-11-one 11-oxime in 215 ml of propanol-1 was refluxed and 8 g of sodium was added for 2 hours.

Once the entire amount of sodium was consumed, the propanol-1 was distilled off. The residue was extracted three times with ether and these extracts were extracted three times with a 2M hydrochloric acid solution. Then the extracts were washed with ether and their pH adjusted to 9 · 25 with ammonia. The mixture was extracted twice with ether and the extracts were washed with water, dried and evaporated to give 8.77 g of a solid product which crystallized from a mixture of ethyl acetate and petroleum ether. Thus, 6.15 g of the title compound are obtained in two fractions. Part of this was recrystallized from a mixture of ethyl acetate and petroleum ether, mp 127-129 ° C / a / D + 121 °,

Intermediate 2: 35 11a- (2,2,2-Trichloroethoxycarbonylamino) -5a-pregn-2-en-20-one.

8103358

I · I

-19-

A solution of 0.331 g of intermediate 1 in 3 ml of pyridine was treated with 0.3 in 2,2,2-trichloroethyl chloroformate and this mixture was stirred at room temperature. After 30 minutes, the reaction mixture was diluted with 30 ml of water and extracted 3 times with ether. Then the combined ether extracts were washed 3 times with water, dried and evaporated to give an oil. Purification by preparative thin-layer chromatography in a mixture of ethyl acetate and petroleum ether (1: 3) gave the title compound 10 as a foam (0.397 g), / a / D + 56 °.

Intermediate 3: 2g-Ethoxy-11α- (2,2,2-trichloroethoxycarhonylamino) -3α- (2,2,2-trichloroethoxycarhonyloxy) -5a-pregnan-20-one.

1 ml of 2,2,2-trichloroethyl chloroformate was added to a stirred solution of 2 g of 11a-amino-2-ethoxy-3a-hydroxy-5a-pregnane-20-one in 20 ml of pyridine. After 16 hours, the reaction was not yet completely completed. An additional 1 ml of 2,2,2-trichloroethyl chloroformate was then added and the mixture was diluted after 30 minutes with 30 ml of water. The mixture was extracted 2 times with ether, washed the extracts U times with 2M hydrochloric acid and 2 times with water and dried. Evaporation of the solution left a yellow foam, which was purified by column chromatography over silica gel and eluting with a mixture of ethyl acetate and petroleum ether (1: 3) to give 2.5 g of solid product. A portion of this was crystallized from a mixture of ether and petroleum ether to give the title compound, m.p. 1-1-1-1.9 ° C, α / β + k8 ° *.

30

Intermediate fr; Π q- (2,2,2-trichloroethoxycarbonylamino) -5a-androst-2-en-178-carboxylic acid.

0.61 ml of bromine was added to a solution of 35 µg of sodium hydroxide in 10.8 ml of water, keeping the temperature at -10 ° C for one hour. Then ml of dioxane was added and the resulting mixture was added to a stirred solution of 1.7 g of intermediate 2 in 25.5 ml of dioxane and 3.1 ml of water at a temperature of 10 ° C. After 10 hours 50 ° C, 5 g of sodium sulfite was added and the mixture was stirred for 15 minutes. The reaction mixture was then filtered and the pH of the filtrate adjusted to 2 with concentrated hydrochloric acid. The resulting suspension was extracted 3 times with chloroform, the resulting extract was washed with water, dried and evaporated, yielding 1.3 of a foam, which was purified by preparative thin layer chromatography in a mixture of chloroform and methanol (9 l) to give 1.08 g of the title compound, / a / + 2k °.

Intermediate 5'2g-Ethoxy-3a-hydroxy-11a (2,2,2-trichloroethoxycarbonylamino) -5a-ahdrostane-17B-carboxylic acid.

According to the method used for intermediate k, the title compound (680 mg; / a / + + 13 °) was prepared from 2.5 g of intermediate 3 using 0.6 ml of bromine and a solution of 1 .75 g of sodium hydroxide in 13 ml of water.

Intermediate 6:

Methyl 2g-ethoxy-3ct-hydroxy-11a- (2,2,2-trichloroethoxycarbonyl-25 amino) -5a-androstane-17g carboxylate.

1.15 g of potassium carbonate and 0.8 ml of methyl iodide were added at 0 ° C to a solution of 1.¼ g of intermediate 5 in 25 ml of dimethylformamide. The mixture was then stirred for 2 hours, after which the solid product obtained was filtered off. The filtrate was diluted with 50 ml of water and extracted 2 times with ethyl acetate. The extract obtained was washed 2 times with a solution of sodium chloride and water and dried. Evaporation yielded 1.586 g of an oil which was purified by column chromatography and eluting with a mixture of ethyl acetate and petroleum ether (1: 2) to give 1.211 g of the title oil. compound, / cc + 1T, 5 °.

The intermediates 7-Π.

In Table A, the preparation of IJ esters using the general method described for intermediate 6 is included.

Intermediate 7 is methyl 3a-hydroxy-11a (2,2,2-trichloroethoxycarbonylamino) -56-androstane-173-carboxylate.

Intermediates 8-10 are esters of 23-ethoxy-10 3a-hydroxy-11a (2,2,2-trichloroethoxycarbonylamino) -5a-androstane-173-carboxylic acid.

Intermediate 11 is ethyl 1 1a- (2,2,2-trichloroetho-an xycarbonylamino) -5a-androst-2-I-173-carboxylate.

15 8103358

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Intermediate 12:

Methyl 1lg- (2,2,2-trichloroethoxycarbonylamino) -5ct-androst-2-ones-

V

17B carboxylate.

A solution of 1.06k g of intermediate 5 was stirred in 2U ml of dimethyl or formamide at 0 ° C with 0.893 g of K 2 CO 2 and 0.6 ml of methyl iodide for 1.5 hours. The mixture was then filtered, the filtrate was diluted with 50 ml of water and extracted 3 times with ethyl acetate. The extract was washed with a solution of sodium chloride in water and water, dried and evaporated, yielding 0.798 g of a foam, which was purified by preparative thin layer chromatography using a mixture of ethyl acetate and petroleum ether (1: 3), whereby 0.621 g of the title compound are obtained as a foam, a / + + 26.5 °.

15

Intermediate 13:

Methyl 2a, 3a-epozy-11a- (2,2,2-trichloroethoxycarbonylamino) -5'-androstane-17B-caroxylate.

A solution of 12.372 g of intermediate product 12 in 200 ml of dichloromethane was treated with 6.56 g of m-chloroperoxyhenzoic acid. After 1 hour, the reaction mixture was washed with a NaHSOg solution, a HaHCO3 solution and water. The aqueous washings were then extracted with dichloromethane and the combined extract was washed with water, dried and evaporated, yielding 11.531 g of a foam. A portion of this was purified by thin layer chromatography in a mixture of ethyl acetate and petroleum ether (1: 3) to give the title compound / a / + 21 °.

30 Intermediate product 1:

Ethyl 2a, 3a-epoxy-nct- (2,2,2-trichloroethoxycarhonylaminoMandrosane-17-8-carboxylate.

According to the method used for intermediate 13, 5hh mg / a / + 16 ° of the title compound 35 was obtained from 620 mg of intermediate 11, using 319 mg of m-chloro-8103358 -2k-, 1 * peroxybenzoic acid. . Purification was by preparative thin layer chromatography using a mixture of chloroform and methanol (19:11.

5 Intermediate 15:

Cyclohexyl 2g-ethoxy-3a-hydroxy-11a (2,2,2-trichloroethoxycarbonyllamino) -5a-androstane-17g carboxylate.

A solution of 2.2 g of intermediate 5 in 20 ml of ether was stirred. with 2.1 ml of cyclohexanol, 0.907 g of dicyclo-10-hexylcarbodiimide and 0.056 g of k-dimethylamino pyridine for 18 hours. 100 ml of ether were then added and the mixture was filtered. The filtrate was washed 2 times with 2M hydrochloric acid, a HaHCO 2 solution and a sodium chloride solution, dried and evaporated to give 2.902 g of a foam.

15

Intermediate 16:

Methyl 11q-amino-2a, 3a-epoxy-5a-androstane-17g carboxylate.

570 mg of toluene-1-sulfonic acid were added to a solution of 1.0 g of methyl 11a-amino-5a-androst-2-en-17g-carboxy-20 in 25 ml of 1,2-dichloroethane. After 30 minutes, 810 mg of m-chloroperoxybenzoic acid was added and the mixture was left to stand for an additional 2 hours. The mixture was then washed with a NaHSO 2 solution, a 5% HaHCO 2 solution and water. The aqueous phases were extracted with dichloromethane and the combined organic phases 25 'dried and evaporated to leave a foam which was purified by preparative thin layer chromatography in a mixture of methanol and 0.88 MH 2 (50: 1) to give: 369 mg of the title compound as a foam / α / τ. + ^ U °, obtained 1722 cm-1.

30

Intermediate 17:

Methyl 11a-cyclohexylamino-2a, 3a-epoxy-5a-androstane-17g earboxylate.

0.3 ml of cyclohexanone and 330 mg of sodium-35 cyanoborohydride were added to a solution of 300 mg of the intermediate 8107358-a-25-product in 8 ml of ethanol and left to stand for 2 hours. A 5% NaHCO 2 solution was then added and the resulting mixture extracted 3 times with ether. Then the extract was solidified with water, dried and evaporated to leave a foam, which was purified purely by column chromatography and preparative thin layer chromatography to give 80 mg of the title compound in the form of a foam / α / ^ -2 °.

10 Intermediate 18; 11a- (2,2,2-trichloroethoxycarbonylamino) -3α- (2,2,2-trichloroethoxy-carbonyl} -5a-nregnane-20-one.

A solution of 19.5 g of 11a-amino-3a-hydroxy-5a-pregnan-20-one in 250 ml of dichloromethane and 26.5 ml of pyridine was cooled while adding 36 ml of 2,2,2-trichloroethyl chloroformate in an ice bath. After the addition, rwater was added cautiously and if no further reaction occurred, the mixture was solid 2 times with 2 M hydrochloric acid and more. The solution was dried and evaporated, leaving 2 g, 6 g of an oil, which was treated with ether, giving 1 h, 1 g of the title compound as a solid product.

Intermediate 19 ".

3a-Hydroxy-11a- (2,2,2-trichloroethoxycarbonylamino) -5a-androstane-1TB-carboxylic acid.

According to the method used to prepare intermediate U, the title compound is prepared from 15.5 g of intermediate 18 using 3.85 ml of bromine 30 and a solution of 11 g of sodium hydroxide in 85 ml of water. Purification was effected by column chromatography and eluting with equal parts of ethyl acetate and petroleum ether to obtain 73 g of the title compound. A portion of this crystallized from a mixture of ether and petroleum ether, melting point: 100 ° C (dec.) / A / + 19 °.

8103358

* V

I 't -26- TUs sproduct20:

Methyl 3a-hydro: iiy-11a- (2'-2,2-trichloroethoxycyccarbonylamino) -5α-androstane-173-cahboxylate.

A solution of kg of intermediate 5 19 was stirred in 80 ml of dimethylformamide with 3.7 g of K2CO3 ^ C, followed by adding 2.6 ml of methyl iodide and stirring the resulting mixture for 2 hours. Then 300 ml of water were added and the mixture was extracted 3 times with ether. It extracts. was washed with water, dried and evaporated to leave a foam, which was purified by column chromatography and eluting with a mixture of ethyl acetate and petroleum ether (1: 2) and crystallized from ether to yield 2.5 g of the in the title obtained said compound; melting point: 167-170 ° C,

/ a / D + 25V

15

Intermediate 21:

Methyl 3a-hydroxy-2g-methoxy-T 1a- (2,2,2-trichloroethoaycarbonyl-amino) -5a-androstane-17g earboxylate.

11.3 ml of boron trifluoride diethyl etherate were added to a solution of 5 * 266 g of the intermediate 13 in 60 ml of methanol and this mixture was stirred at room temperature for 1 hour. This mixture was then diluted with a 5% HaHCO 2 solution and extracted 3 times with ethyl acetate. The extract obtained was washed with water, dried and evaporated to give a foam 2-5. 193 Mg of these were purified by preparative thin layer chromatography using equal parts of ethyl acetate and petroleum ether to obtain 1½ mg of the title compound as a foam, α / π + 23 °, v

4 "U IHQiX

1722 cm, 30

Intermediate 22:11 - (2,2,2-trichloroethoxycarbonylamino) -3a-.beta.-2-trichloro-ethoxy arb onyloxy) -5g-pregnan-20-one.

39 µl pyridine and 53 ml 2,2,2-trichloro-35 ethyl chloroformate were added to an ice-cooled solution of 8103358% -27-26.54 g 11 a-amino-3a-hydroxy-50-pregnane-2O- on in 350 ml dichloromethane. After 2 hours, 400 ml of water were added, the organic phase was separated and evaporated, leaving a "brown oil which crystallized out by" treating with a mixture of ether and petroleum ether. There was thus obtained 47.86 g. M.p .: q q of the title compound, 174-176 C, α / ^ + 60. Intermediate 23: 3a-Hydroxy-11a- (2,2,2-trichloroethoxycarbonylamino) -5B-androstane-10 17β-carboxylic acid.

According to the method used to prepare Example 4, 12.5 ml of bromine and a solution of 35 µl of 1 g of sodium hydroxide in 270 ml of water were used to convert 47 g of the intermediate 22 into the corresponding 178-carboxylic acid, which was then was taken up in dioxane. A 2M solution of sodium hydroxide was added to adjust the pH to 11 and the mixture was stirred for 3 hours. The pH of the mixture was then adjusted to 2 with concentrated hydrochloric acid and diluted with water. The precipitate was extracted 2 times with chloroform 20 and the extract was washed with water, dried and evaporated to leave an oil which crystallized from a mixture of ether and petroleum ether, yielding 22.5 g of the title compound, mp 250-251 ° C / a / ^ + 34 °.

25

The intermediates 24-28.

Table B summarizes the preparation of 2β-substituted compounds from the corresponding 2a, 3a epoxide using the general method described for intermediate 21.

Intermediate 24 is ethyl 20-butoxy-3a-hydroxy-11a (2,2,2-trichloroethoxycarbonylamino 1 -5a-androstane-1J-beta-carboxylate).

Intermediates 25-28 are 2g alkoxy analogs of intermediate 21.

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8103358 i -

, * I

-29- *

Intermediate 29: 11a- (2,2,2-Trichloro-oxioxycarbonylamino) -36- (2-2-2-tricliloroetho-xyearbonyloxy) -5-pregan-20-one.

12 ml of pyridine and 0 ml of 2,2,2-trichloro-5-ethylchloroformate were added to a cooled, stirred solution of 2b g of 11a-amino-3E3-hydroxy-5a-pregnan-20-one in 300 ml of dichloromethane . After 2 hours, 300 ml of water was added, the organic phase was separated and the solvent was removed by diluting, leaving an oil which was eluted by column chromatography and eluting with mixtures of ethyl acetate and petroleum ether (1: ¼) and (1: 2). was purified to give 27.27 g of the title compound, / cc / ^ + Uo °,

Intermediate 30: 15 3 S-Hydroxy-Π a- (2,2,2-trichloroethoxycarbonylamino) -5a-androstane-17β-carboxylic acid.

According to the method used for the preparation of intermediate b, 18.17 g of the title compound (melting point: 212-220 ° C / a / ^ + 16 °) was prepared from 27 g of intermediate 29 under using 7.2 ml bromine and a solution of 20 g NaOH in 155 Bil water. The product evaporates a mixture of ether and petroleum ether crystallized.

Intermediate 31:25 Methyl 38-hydroxy-11a- (2,2'-2-trichloroethoxycarbonyl-amino) -5a-androstane-17β-carbokylate.

16 g of potassium carbonate and 11.2 ml of methyl iodide were added to a stirred solution of 17.8 g of intermediate 30 in 325 ml of dimethylformamide at 0 ° C. After 1 hour and 30 minutes, the mixture was diluted with 1 .5 L of water and the precipitate was extracted 2 times with ethyl acetate. The extract was washed 2 times with sodium chloride solution, dried and evaporated to leave an oil which, on evaporation from ether, gave 15.5 g of the title compound / a / 35 + 15 °.

8103358 * Λ. * -30- • ι

Intermediate 32:

Methyl 11a-amino-3g-hydroxy-5o-androstane-17g carboxylate.

36 g of zinc powder were added to a stirred solution of 15 g of intermediate 31 'in IfOO 1n glacial acetic acid. The mixture was then stirred for 20 hours, the zinc filtered off and filtered with water.

The volume of the filtrate was reduced under reduced pressure and the resulting residue was adjusted to 10 with 0.88 M solution. The oil was extracted 2 times with ethyl acetate and the extract was washed 2 times with a solution of sodium chloride, dried and evaporated, yielding 7.93 g of an oil. A sample of mg00 mg of this was purified by preliminary thin layer chromatography to give the title compound as a foam, α / D + 29 °.

Intermediate 33:

Methyl 11a-cyclohexylamine-3g - hydroxy-5a-androstane-17β-carboxylate.

20.5 g of sodium cyanorium hydride and 12 ml of cyclohexanone were added to a stirred solution of 7.5 g of intermediate 32 in 100 ml of ethanol. After 60 hours, the mixture was diluted with 100 ml of a 5% NaHCO 2 solution and the resulting precipitate was extracted 2 times with ether. The extract was shaken 2 times with 2 M HCl and the aqueous phase was washed with ether, its pH adjusted to 9 with a 0.88 NH 2 solution and extracted 2 times with ether. The extract was washed twice with water, dried and evaporated to give a foam which was purified by column chromatography over cilica and eluting with a mixture of chloroform and methanol (19: 1).

Thus, 1 +, 1 + 11 g of the title compound, which was crystallized from petroleum ether, mp: 82-81 + ° C / a / D -1 °.

35 Intermediate product 3k: 8103358 i -31- * *

Methyl 11 α-cyelohexylamino-3-oxo-5a-androstane-17B-caroxylate.

Jones reagent was added dropwise to a stirred solution of 300 mg of methyl 11a-cyelohexylamino-3S-hydro: xy-5a-androstane-1 76-carboxylate in 10 ml of acetone until the reagent-5 color no longer changed. Then 200 ml of water were added and the pH of the mixture was adjusted to 10 with a 0.88 HH 2 solution. Then 5 ° ml of ether was added and the mixture was filtered. The aqueous phase was separated, extracted with 50 ml. ether and the organic phase was washed with water, dried and evaporated to leave 289 mg of an oil which was crystallized from petroleum ether to give the title compound, m.p .: 93-9 ° C, / a / ^ -12 °.

Intermediate 35 '3a-Hydroxy-11-hydroxy imino-5a-androstane-178-carboxylic acid.

U g of hydroxylamine hydrochloride was added to 16 ml of a water-cooled, 50% solution of sodium hydroxide. This mixture was then added to a solution of 1.5 g of 3a-hydroxy-11-oxo-5a-androstane-173-carboxylic acid in 70 ml of ethanol. This mixture was then heated under reflux for 2 hours, cooled, and adjusted to pH 1 with concentrated hydrochloric acid. 800 ml of water were then added, the precipitate (13k2 g) was filtered off, washed 2 times with 300 ml portions of water and dried. Crystallization from ethyl acetate gave 1 g of the title compound, melting point: 250-253 ° C (fontl.), Α / ρ + 12k ° (EtOH C = 1%).

Intermediate 36:30 11a-Cyclohexylamino-2g-ethoxy-3a-hydroxy-5a-pregnan-20-one,

A solution of 2 g of 1la-amino-2S-etho-xy-3a-hydroxy-5a-pregnan-20-one 20-ethylene acetal in 20 ml of ethanol was stirred with 1.5 ml of cyclohexanone and 2.015 g of sodium cyanoborohydride for 6 hours. Then h-0 ml of a 5% 35% NaCO 3 solution was added and the mixture was extracted 2 times with ether.

8103358 -32- t t. s

The extracts were washed 2 times with water, dried and evaporated, leaving a foam which was dissolved in 50 ml of a 2 M HCl solution and 50 ml of ethanol. 100 ml of water were added thereto and the mixture was washed twice with ether. The washing liquid was extracted with a 2M ICI solution and the pH of the combined acid fraction was adjusted to a basic value with a 2M NaOH solution. The mixture was then extracted x 2 times with ether, washed the extract 2 times with water, dried and evaporated to leave a foam which was purified by chromatography and eluting with a mixture of chloroform and methanol (9: 1). Thus, 1,235 g of the title compound were obtained, .alpha. V 1695 cm.

Intermediate 37:15 Methyl 2B-acetoxy-3a-hydroxy-11a (2,2,2-trichloroethoxycarbonyl-amino) -5ct-androstane-17B carboxylate.

20.5 g of the intermediate 513 in 100 ml of glacial acetic acid was heated for 3.25 hours. on a steam bath. The reaction mixture was then allowed to cool, evaporated and diluted with 0.88 M 2 solution to pH 9.0. It was then extracted 3 times with ethyl acetate. The extracts were washed once with water, dried and evaporated, yielding 23.8 g of foam. A small sample of this was purified by preparative thin layer chromatography in a mixture of equal parts of ethyl acetate and petroleum ether and crystallized from ether to give 220 mg of the title compound, mp: 200-201 ° C, / a / D + 26.1 °.

Intermediate 38: 2g-Ethoxy-3a-hydroxy-11a (3-methylbutylamino) -5a-pregnan-20-one.

20 g of 11a-amino-2g-ethoxy-3a-hydroxy-5a-pregnan-20-one 20-ethylene acetal were stirred in 200 ml of ethanol with 25 g of K 2 CO 2, 1 g KaJ and 50 ml 1-broam-3 methyl butane and then heated this mixture under reflux for 2 hours. The excess K 2 CO 2 was then removed by filtration and washed with ethanol.

8103358 -33- 'i 4

The filtrate and washings were acidified to PI 2 with 2 Jd-HCl, washed with ether and the ether wash liquor was again washed with M-HCl and 3 times with water. The water layers were adjusted to pH 10 with 2 M-NaOH and the resulting suspension was extracted 2 times with ether. The ether layers were combined, washed 2 times with water, dried and evaporated to leave 18.96 g of a foam, which was purified by column chromatography and eluting with a mixture of chloroform and methanol (19: 1) and crystallizing from acetonitrile. . This gave 9.211 g of the title compound, mp: 110.5-112 ° C / ct / D + 56 °.

Between product 39 *

Methyl 11a-amino-5 '-androst-2-en-17g carboxylate.

1.2 g of zinc were added to a stirred solution of 1.2 g of the intermediate 12 in 10 ml of glacial acetic acid and this mixture was stirred for 20 hours. The mixture was then filtered and the zinc washed with acetic acid and water. The filtrate was concentrated and the residue was diluted with 15 ml of water and adjusted to pH 9 and extracted 3 times with ether. Then the extract was washed with water, dried and evaporated to give 793 mg of a foam, which was purified by preparative thin layer chromatography in a mixture of methanol and 0.88 Ni (50: 1) to give 449 mg of the title compound verbinding a / + + 57 °.

Intermediate 40;

Methyl 11a-cyclohexylamino-5a-ancLrost-2-en-17g carboxylate.

4.3 ml of cyclohexanone and 4.3 g of sodium 30-borohydrohydride were added to a stirred solution of 4.329 g of the intermediate 39. in 58 ml of ethanol. After 21 hours, an incomplete reduction of the imine intermediate was demonstrated by thin layer chromatography. 0.5 g of sodium borohydride were added and the mixture was allowed to stand for an additional 30 minutes. Then a 5% NaCO 2 solution was added and the mixture was extracted 3 times with ether. The extract was washed with water, dried and evaporated to give an oil. A portion of this was purified by preparative thin layer chromatography using a mixture of chloroform and methanol (19i) to yield 157mg of the title compound.

Voorheelden part A.

10 Example I.

Methyl 11a-amino-r2g-ethoxy-3a-hydroxy-5a-androstane-17B-carboxylate.

Meh added 2 tk g zinc powder to a stirred solution of 1.1 g of intermediate 6 in 25 ml glacial acetic acid and stirred this mixture for 6 hours. Then it was filtered, zinc and washed with water. The aqueous filtrate was washed 2 times with ether and then brought to pH 10 with a 2 M -ITAOH solution. Then the mixture was extracted 2 times with ether, the extract washed 2 times with water, dried and evaporated to give 58 mg of an oil which was purified by preparative thin layer chromatography using methanol to give 180 mg of the title compound.

JJ H13fX

Example II.

Methyl 11a-amino-3a-hydroxy-5a-androstane-17B-caroxylate.

A solution of 2.0 g of intermediate 20 in 25 ml of glacial acetic acid was stirred with 2.5 g of zinc for hours. The zinc was then filtered off. and wash it with 50 ml of water and 50 ml of ether. The pH of the filtrate and washings was then adjusted to 10 with 0.88 HH solution and extracted with ether for one hour. The extract was washed with water, dried and evaporated, yielding 1.65 g of a solid product.

A portion of this was crystallized from ether to give the title compound, m.p .: 113-116 ° C, 8103358 * -35- / a / D + 38 °.

Example III.

Methyl 11a-amino-3a-hydroxy-2g-methoxy-5a-androstane-17g - carbon: xy-5 late.

Kt9 g of zinc powder was added to a stirred solution of 4.87 g of intermediate 21 in glacial acetic acid and stirred for one hour. The zinc was then filtered off and washed with water. The pH of. the filtrate and the 10 washings were adjusted to 10 with 0.88% H 2 solution and extracted 3 times with ether. The extract was then washed with water, dried and evaporated to leave a solid product which was crystallized from ethyl acetate. There was thus obtained 1.716 g of the title compound, melting point: 117 DEG-180 DEG C./alpha. + 53 DEG.

Examples XV-XVI.

Table C summarizes the preparation of 11a-amino compounds from the corresponding 11a (2,2,2-trichloroethoxylcarbonylamino) -20 compounds according to the general method described in Examples I-III.

Purification was by preparative thin layer chromatography (pj, column chromatography (c) or crystallization (X).

The compounds prepared were: IV. ethyl 11 ct-amino-22-ethoxy-3a-hydroxy-50i-androsane-176-carboxylate, V 3-methylbutyl 11a-amino-2B-ethoxy-3a-hydroxy-5a-androstane-17g carboxylate, 30 VI propyl 11a-amino-2g-ethoxy-3a-hydroxy-5ct-androstane-17g-earboxylate, VII ethyl 11a-amino-2g-butoxy-3a-hydroxy-5a-androsane-172-carboxylate, VIII methyl 11a-andno-2B-hutaxy-3a-hydroxy-5a-androsane-17g-carboxylate, 8103358 a * 1. vt -36- IX methyl 11 a-amino-3a-hydroxy-2B-pentyloxy-5a androstane -17B-caroxylate, X-methyl 11a-amino-26-hexyloxy-3a-hydroxy-5a-anhydrous-17L-carboxylate, 5XI cyclohexyl 11a-amino-2g-ethoxy-3a-hydroxy-5a-androstane-173 caroxylate, XII methyl 11a-amino-3a-hydroxy-2B-propoxy-5a-androsane-17β-carboxylate, XIII methyl 11a-amino-3a-hydroxy-5S-androstane-173 ~ 10 caroxylate, XIV methyl 2g- acetoxy-11a-amino-3a-hydroxy-5a-anhydrous-17S carboxylate.

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Example XV

2B-Ethoxy-3a-hydroxy-1Ί a- (3-methylbutylamine) -5a-andr on-173-tartaric acid.

A solution of 50 mg of the product of Example B1 in 10 ml of dioxane with 1.5 ml of concentrated hydrochloric acid and 5 ml of water was heated at 100 ° C for 5 days, then the pi of the cooled mixture was adjusted with a 50% aqueous solution of sodium hydroxide at 11 and extracted 3 times with ether. The extract was washed with water, dried and evaporated to leave the title compound as a solid product, α / π + 5%, v 1635 cm @ 1550 cm h max 20 Mg of this product were dissolved in 1 ml of methanol and this solution was heated with reflux for 1 hour with 1 drop of concentrated sulfuric acid. Thin layer chromatography of the reaction mixture showed that methyl 2-ethoxy-3a-hydroxy-11α- (3-methylbutylamino) -5a-androstane-17-3-carboxylate had been formed.

Example XVI

Methyl 11a-amino-3a-hydroxy-5d-androstane-173-arboxylate.

1 g of sodium was added to the refluxing solution of 0.3 g of intermediate 35 in 20 ml of propanol-1. As soon as all the sodium was consumed, 10 ml of water was added. The mixture was then evaporated and the residue was dissolved in 20 ml of 2 M-HCl. The solution was then evaporated to dryness and an azeotrope with benzene was distilled 3 times. The resulting oil was then dissolved in 30 ml of methanol and the resulting solution was heated under reflux for 3 hours with 0.5 ml of concentrated sulfuric acid. The cooled mixture was then applied with a 0.88 HH 2 solution. a basic pH and. diluted with .100 ml of water. The precipitate was extracted twice with ether and the extract was washed with water, dried and evaporated to leave a foam which was dissolved in 50 ml of ether. The solution was extracted 2 times with a 35 2 M-HCl solution and water. Thereafter, the pH of the water was extracted to 10 with a 0.88 NK 2 solution and the precipitate was extracted 3 times with ether. The extract was then washed with water, dried and evaporated to leave 226 mg of the title compound as a foam, / a / ^ + 35 ° 5

Example 2 mi-B-Ethoxy-3a-hydroxy-11a (3-methylbutylamino) -5a-androstane-178-carboxylic acid.

0.8 ml of bromine at 0 ° C was added to a solution of 1.2k g of sodium hydroxide in 16 ml of water. Then 6 ml of dioxane were added and this mixture was added at 10 ° C to a solution of 1.1k g of intermediate 38 in 50 ml of dioxane and 16 ml of water. After 6 hours a further 10 g of sodium metabisulfite were added and the mixture was stirred for 30 minutes. A concentrated HCl solution was then added to adjust the pH to 1 and the mixture evaporated to dryness. The solid product was extracted with ether and ethyl acetate and the resulting solutions were evaporated to leave 1.31 g of the title compound as a solid product.

20

Examples XVIII-XXVI

Table D summarizes the preparation of the hydrochloride salts of the 11a amines.

A solution of hydrochloric acid 25 in water was added to the base or a suspension of the base in any additional water and the mixture was stirred or shaken until a clear solution was obtained or no base dissolved.

This mixture was made up to the appropriate weight or volume with water and filtered and any undissolved base was collected, dried and weighed to determine the concentrations of the solution. The pH was also measured.

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Examples-Part B.

Example I

Methyl 2B-ethoxyl-3a-hydroxyl-11α - (3-methylbutylamino) -5a-androstane-17B-carboxylate.

2.51¼ g of potassium carbonate, 107 mg of sodium iodide and 6 ml of 1-tromo-3-methylbutane were added to a stirred solution of 2 g of the product of Example A I in 30 ml of ethanol and this mixture was boiled for 2¼ hours. under reflux.

The reaction mixture was then cooled, acidified with a 2M HCl solution and solidified with ether. The ethereal solid liquid was extracted with an M-HCl solution. and 2 times with vater. The pH of the total evaporation phase was then adjusted to 10 with a 2 M-NaOH solution and extracted 2 times with ether. The extract was evaporated 2 times with water, dried and evaporated, leaving an oil which was purified by crystallization from acetonitrile. There was thus obtained 91¼ mg of the title compound, melting point: 122-12¼ ° C / a + 22 ° C.

Example II

Methyl 3a-hydroxy-26-methoxy-1 lot— (3-methylbutylamino) -5a-andros-t-17β-carboxylate.

9 * 5 ^ ml 1-broam-3-methylbutane, 2.9¼ g potassium carbonate and 0.111 g sodium iodide were added to a stirred solution of 2.8 g of the product of Example A III in 25 1/4 ml ethanol and boiled mixture under reflux for 22 hours. The cooled mixture was then diluted with water and extracted 3 times with ethyl acetate. Then, the extracted, evaporated with water, dried and evaporated, yielding a foam which is purified by preparative thin layer chromatography using a mixture of chloroform and methanol (19: 1). Thus, 1.2¼ g of the title compound, / a / + 22 °, v 172¼ cm 2, were obtained.

JJ IflcLX

Examples III-X

35 In Table E, the preparation of 11a-alkylaminoverbin is 8103358 ..........-........ ^ - ·· .- ': -; ': · .. -; .-., ·· »·. ..... .. · .. -: ..> - „. .....

j ► «fc> -42- from the corresponding 11-amines described using the general method of examples I and II. Work-up was carried out as described in example I (i) or in pre-prepared II (il).

Purification was carried out by preparative thin layer chromatography (P) s column chromatography (c) or crystallization (x).

In Examples III-VII and IX the halo-alkane was r-bromo-3-methylbutane, in Example VIII it was iodine-10 propane and in Example X it was 1-iodo-3-methylbutane.

The compounds prepared are: III ethyl 23-ethoxy-3a-hydroxy-11a- (3-methylbutylamino) -5a-androstane-1TS carboxylate, IV. methyl 2g-butoxy-3a-hydroxy-11a- (3-methylbutyl-15 amino) -5a-androstane-173-carboxylate, V methyl 3a-hydroxy-11 a— (3-methylbutylamino) -2β-pentyloxy-5a-androstane -1T3-carboxylate, VI methyl 26-hexyloxy-3a-hydroxy-11a- (3-methylbutylamino) -5a-androstan-176-carboxylate, 20 VII methyl 3a-hydroxy-11a- (3-methylbutylamino) -5a- androstane-17 {5-carboxylate, VIII methyl 26-ethoxy-3a-hydroxy-11a-propylamino-5a-androstane-17β-carboxylate, IX methyl 3a-hydroxy-2g-propoxy-11a- (3-methylbutyl-25 amino) -5a-androstane-17β-carboxylate, X λ methyl 3a-hydroxy-11a- (3-methylbutylamino) -5 (3-androstane-17β-carboxylate.

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Example XI

Methyl 11 α-cyclohexylamino-3a-hyayoxy-2g-methoxy-5a-androstane-173-carboxylate ♦

A suspension of 1.512 g of the mixture was stirred. product 5 of example A III in 15 ml ethanol and 1.5 ml eyelohexanone for 2 hours with 1.5 g sodium cyanoborohydride. A 5% NaHCO 2 solution and then water were then added. The mixture was extracted 2 times with ether, washed the extract with water, dried and evaporated to leave a foam which was 10 <3-002 * column chromatography using a mixture of chloroform and methanol (19:11). was purified and crystallized from acetonitrile. There was thus obtained 1.069 g of the title compound, melting point: 1 ^ 3-1 ^ 5 ° C / a / ^ + 9.5 °.

15

Example XII

Methyl 11a-cyclohexylamino-3a-hydroxy-5a-androstane-1Tβ-carboxylate.

2 g of sodium cyanoborohydride were added to a mixture of 2 g of the product of Example A II and 2.5 ml of eyelohexanone in 30 ml of ethanol. This mixture was then kept at 21 DEG C. for 5 hours. Then a 5% NaHCO 2 solution and water were added and the mixture was extracted 2 times with ether. The extract was then washed with water, dried and evaporated to leave a foam which was subjected to column chromatography and preparative layer chromatography using a mixture of. chloroform and methanol (9: 1) were purified. There were thus obtained 0.763 g of the title compound in the form of a foam, a / + +6, V 1720 cm.

JJ JflaJC

3 °

Examples XIII-XXV

Table F summarizes the preparation of 11a-alkylamino compounds from the corresponding 11a-amines using the general method of Examples XI and XII.

The aldehydes-8103358-U5-f ketones used in Examples XIII-XXV are: cyclohexanone (examples XIII, XV, XX, and XXII), cyelopentanone (examples XVI and XVII), 3,3-dimethylbutyraldehyde (example XTV), hexaldehyde (example XVIII), t-methyl-pentanal (example XIX), 3-methylbutanal (example XXI), cyclobeptanone (example XXIII), cyclobutanone (example XXIV) and acetone (example XXV).

Purification was by preparative thin layer chromatography (P), column chromatography (c) or crystallization (X).

The following compounds were also prepared: XIII ethyl 11a-cyclohexylamino-2g-ethoxy-3a-hydro: xy-5a-androstane-1β-carbacylate, XTV methyl 11a (3,3-dimethylbutylamino) -23-ethoxy-3a-hydroxy -5a-androstane-17β-carboxylate, 15 XV methyl 11 a-cyelohexylamino-23-ethoxy-3a-hydroxy-5a-androstane-173-carbaxylate, XVI methyl 11 a-cyclopentylamino-3a-hydroxy-5 "-an-dry -173-carboxylate, XVII methyl 11 a-cyclopentylamino-3a-hydroxy-2f3-methoxy-5a-androstane-17 B-carboxylate, XVIII methyl 2f3-ethoxy-1a-hexylamino-3a-hydroxy-5a-androstane -17β-carboxylate, XIX methyl 26-ethoxy-3o-hydroxy-11 a- (U-methylpenyl-amino-5a-androstane-17β-carboxylate, 25 XX methyl 11 α-cyclohexylamino-3a-hydroxy-53-andros - tane-17β-carboxylate, XXI methyl 2j3-acetoxy-3 ot-hydroxy-11o- (3-methylbutyl-amino) -5o-androstane-17β-carboxylate, XXII methyl 2B-acetoxy-1a-cyclohexylamino- 3o-hydro- 30 xy-5 <x-androstane-173-earboxylate, XXIII methyl 11a-cycloheptylamino-3a-hydroxy-26-methoxy-5 a-androstane-17 '' carbox ylate, XXIV methyl 11 o -cyclohutylamino-3cuhydroxy-23-methoxy-5α-androst-1J β-carboxylate, 35 XXV methyl 2 & -ethoxy-3o-hydroxy-11 ct- (1-methylethyl-8103358 -ίΐ 'aV.: ·' - 'ί · ί ..- · ν: .Γ. · - ^ - ·· Λτ *> -: ---.-- 1: .. Λ-. · - - -V - · -. '· -, · .-. , - ·, -.- .... .1 .... 1 .. - <.. · n ι.: - _____; · :; [K y * 1 -w-amino] -5a-androstane-1Tg-carboxyzZlate.

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Notes bi.i 'table F.

1) An additional work-up step was applied as follows:

The product obtained after evaporation of the ether extract 5 was dissolved in 2 M-HCl, water and ethanol and the sen.

solution was intuitive. with ether. The ethereal wash liquor was extracted with M-HCl and water and the pH of the total aqueous phase was adjusted to 10 with 0.88 NH 2 solution and extracted with ether. The extract was then washed, dried and evaporated to give a residue which was purified.

2) After 18 hours, 0.05 g of sodium borohydride was added.

3) After 22 hours 0.01 g of sodium horium hydride was added.

1+) Only part of the product was purified.

5) After 1 + 5 hours, 0.15 g of sodium borohydride was added.

Example XXVI

Propyl 2g-ethoxy-3a-hydroxy-11a- (3-methylbutylamino) -5a-androstane-178-carboxylate.

A solution of 0.9 g of the product of Example B1 was heated in 20 ml of propanol-1. for 2b hours with 25 ml of concentrated sulfuric acid at 100 ° C. The pH of the cooled mixture was then adjusted to 9 with a 5% NaHCO 2 solution and extracted 2 times with ether. The extract was washed with water, dried and evaporated to leave an oil which was purified by preparative thin layer chromatography using a mixture of chloroform and methanol (9 + 1). There was thus obtained 0.612 g of the title compound as an oil, α / + + 22 °, v 1720 cm @ -1.

D max

Example XXVII

Cyclohexyl 2g-ethoxy-3a-hydroxy-11a- (3-methylbutylamino) -5a-andros- 8103358 - - ¢ - - «· - · -. . f | .ΧΛ ^^ - a ·. ^., ^ .- · »· .11» ·. * - -. t ~ '"ΊΤιιΐΚΐ ΜΙΓι · - ·! * * *

II

-k9-tane-178-caroxylate.

A solution of kf26 g of the product of Example B1 was stirred in 30 ml of cyclohexanol for 8 hours with 2 ml of concentrated sulfuric acid at 110 ° C. The mixture was then brought to a basic pH with a 0.88 l solution and extracted twice with ether. The extract was then washed with water, dried and evaporated to leave an oil which was purified by column chromatography and eluting with a mixture of ethyl acetate and methanol (3: 1) and chloroform and methanol (19: 1). . There was thus obtained 857 mg of the title compound, / a / _. + 11 °, v 1713 cm.

JJ 3HSX

Example XXVIII

Methyl 11a-cyclohexylamino-2B-ethoxy-3a-hydroxy-5a-androstane-15 17β-carboxylate.

0.5 ml of bromine at 0 ° C was added to a stirred solution of 1.2 g of sodium hydroxide in 8 ml of water.

Then ¾ ml of dioxane was added and this mixture was added again at a temperature of 10 ° C to a solution of 0.58 g of intermediate 36 in 25 ml of dioxane and 8 ml of water. The mixture was then stirred at room temperature for 3 hours. Then 2 g of sodium metabisulfite were added and after ten minutes the mixture was diluted with 100 ml of water. The solvents were removed by evaporation to leave a solid product, which was dissolved in 30 ml of methanol, and this solution was heated under reflux for 5 hours with 1 ml of concentrated sulfuric acid. The pH of the mixture was then adjusted to 10 with a 0.88 HH 2 solution and diluted with 150 ml of water. The resulting precipitate was extracted 3 times with ether, washed with 100 ml of water, dried and evaporated, leaving an oil which was purified by column chromatography and eluting with a mixture of chloroform and methanol (9: 1). . An oil thus remained, from which 0.235 g of the title compound was obtained by crystallization from acetonitrile. Melting point and mixed melting- 8103358 -50-, ¥> point: 110-112 ° C, / ct / yy + 13 °.

Example XXIX

Methyl 2g-ethoxy-3ot-hyclroxy-11α- (3-methylbutylamino) -5a-andros-5-tane-17B-carboxylate.

2 ml of methanol and 100 mg of dicyclohexylcarhodilmide were added to a stirred mixture of 221 mg of the product of Example A XVII in 20 ml of ether, whereby a solution was obtained. 10 mg of U-dimethylaminopyridine was added thereto and the mixture was stirred for 72 hours. The mixture was then filtered and the filtrate was evaporated to leave a foam. This foam was purified by column chromatography on silica and eluting with a mixture of chloroform and methanol (19: 1) to give 130 mg of the title compound 15 which was crystallized from acetonitrile, mp: 123-125 ° C / a / ^ + 18 °.

Example XXX

Methyl 2g-ethoxy-3a-hydroxy-11a (3-methylbutylamino) -5a-andros-20-tane-17 g-carboxylate.

10 drops of concentrated sulfuric acid were added to a solution of 75 mg of the product of Example B III in 3 ml of methanol and this mixture was heated to reflux and further heated for 6 hours. The pH of the cooled mixture was then adjusted to 10 with 0.88 HCl solution, diluted with 50 ml of water and extracted 3 times with ether. The extract was washed with water, dried and evaporated to leave 70 mg of an oil which was crystallized from acetonitrile. There was thus obtained 30 1 * 0 mg of the title compound having a melting point and mixed melting point of 123-125 ° C / a / ^ + 21 °.

Example XXXI

Methyl 2g-ethoxy-3ot-hydroxy-11ct - (3-methylbutylamyl) -5a-andros-35-tane-17g-carboxylate.

8103358 «* '-51-

A solution of. diazamethane in ether to a solution of 550 mg of the product of Example A XVII in 20 ml ether and 20 ml tetrahydrofuran. After 30 minutes 2 drops of glacial acetic acid were added and the pH of the mixture was adjusted to 10 with a 0.88 KH 2 solution and diluted with 100 ml of water. The organic phase was then washed with water and the combined aqueous phases were extracted with ether. The total organic phase was washed with water, dried and evaporated to give an oil, which was purified by column hydro-1Q matography and eluting with a mixture of chloroform and methanol (19 l). The product obtained was crystallized from acetonitrile to obtain 57 mg of the title compound, m.p. 123-125 ° / o + 21 °.

15

Example XXXII

Methyl 2g-ethoxy-3'-hydroxy-11a- (3-methylbutylamino) -5o-androsane-178-carboxylate.

1 ml of concentrated sulfuric acid was added to 2Q, a solution of 500 mg of the product of Example A XVII in 20 ml of methanol, and this mixture was refluxed for 6 hours. The pH of the cooled mixture was then adjusted to 10 with a 0.88 HH 2 solution and diluted with 150 ml of water. The resulting precipitate was extracted 3 times with 2 ^ ether and the resulting extract was washed with water, dried and evaporated to leave an oil which crystallized from acetonitrile. There was thus obtained 2.5 mg of the title compound with a melting point of 123-125 ° C / a / D + 23 °.

30

Example XXXIII

Methyl 11a-cyclohexylamino-3a-hydroxy-2B-methoxy-5 '-androstane-17B-ethoxylate.

0.2 ml of boron trifluoride diethyl etherate 35 was added to a suspension of 35 mg of intermediate 17 in 5 ml of 8103358 -52-4 methanol. This mixture was then stirred for 1 hour and + 5 minutes, diluted with 5% NaKCO 2 solution and extracted 3 times with ether. The extract was washed with water, dried and evaporated to leave a foam, which was purified by preparative thin layer chromatography in a mixture of chloroform and methanol (9: 0). This gave a foam, from which crystallization from acetone. nitrile 56 mg of the title compound, melting point 141-1 J + 3 ° C / a / + 10 °, were obtained.

10

Example XXXIY

Methyl 11a-cyclohexylamino-3a-hydroxy-5a-androstane-17g-carboxylicate.

V70 mg of diethylazotricarboxylate was added to a mixture of 790 mg of triphenylphosphine, 0.11 ml of formic acid and 132 mg of intermediate 32 in 10 ml of dry tetrahydrofuran. The mixture was then allowed to stand for 20 hours, brought to a basic pH with a 5% HaHCO2 solution and extracted 3 times with ethyl acetate. The extract was then washed with water, dried and evaporated to leave a solid product which was purified by preparative thin layer chromatography in a mixture of chloroform and methanol (19: 1). The resulting oil was dissolved in ethyl acetate and this solution was extracted 3 times with a 2 M HCl solution and 3 times with water. The pH of the extract was then adjusted to 10 with 0.88 HH 2 solution and the resulting precipitate was extracted 1 time with ethyl acetate. This extract was dried and evaporated to leave a foam, which was purified by preparative thin layer chromatography in a mixture of chloroform 30 and methanol (9 · 1). In this way, 67 mg of the title compound, aα / ° + U °, were obtained.

Example XXXV

Methyl 11a-cyclohexylamino-3a-hydroxy-5a-androstane-17β-carboxy-35 late.

8103358 -------. 1., ... ^. ..T .- ». ^ .. ^ 1 ^. - «I - ^ --...« - «» -. -------- -.- - ______ * * -53-

The pH of 16 ml of chloro-iridic acid reagent with triethylamine was adjusted to 7 and 860 mg of intermediate 3¼ were dissolved therein. This solution was then refluxed for 27 hours, cooled, and "adjusted to a pH> 0.88 with a 0.88 5 M 2 solution. Then 30 ml of water was added and the mixture was extracted 3 times with ethyl acetate. .

The extract was then washed with water, dried and evaporated to leave a foam, which was purified by preparative thin layer chromatography in a mixture of chloroform and methanol (5: 1). There was thus obtained 2 8 mg of the title compound, α / + + 6 °.

Examples XXXVI-LXII

Table G summarizes the preparation of the hydrochlorides.

A solution of hydrogen chloride in water was added to the base or a suspension thereof in any added water, and this mixture was stirred or shaken until a clear solution was obtained or no base dissolved anymore.

This mixture was then adjusted to the appropriate weight or volume with water and filtered, collected any undissolved base, if any, dried, and weighed to determine the concentrations of the solutions. The pH was also measured.

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Table H contains the preparation of salts of methyl 2 & ethoxy-3a-hydro: xy-11α- (3-methylbutylamino) -5c-androst-1 7 (3-carboxylate).

The appropriate acid was added to a suspension of 50 mg of a free base in 4 ml of water and the resulting mixture was stirred or shaken until a clear solution was obtained. This solution was made up to 5 ml with water to obtain a 1% solution whose pH-10 was measured.

Table H

example

no. acid_ full, or wt. pH

LXIII citric acid hydrate 22.7 mg 3.65 LXIV. maleic acid 12.5 mg 4.55 LXV ascorbic acid 37 »98 mg 4.10 LXVI sulfuric acid (0.1 M) 0.54 ml 2.90 LXVII glutaric acid 14.2 mg 4.70 20

Example A

Tablet - moist granulated mg / tablet methyl 11'-cyclohexylamino-3o (-hydroxy-2-2-methoxy-5o -androstane 17'-carboxylate.

hydrochloride 27 »0 lactose 93.0 corn starch 50» 0 polyvinyl pyrrolidone 2.0 sodium starch glycolate 6.0 magnesium stearate 2.0_ weight of the tablet 180.0 mg

The steroid and corn starch were sieved through a 40 mesh screen. The corn starch and the starch were then mixed in a suitable mixer. A 5-10% w / v aqueous solution was prepared from polyvinylpyrrolidone, after which this solution was added to the mixed powder and mixed until a granular product was obtained.

Then the granular product was passed through a No. 12 screen. The granules were then dried at 50 ° C in an oven or in a liquid bed at 50 ° C. The dry granules were sieved through a 16 mesh sieve and taken up by mixing into the sodium starch glyeolate and magnesium stearate previously sieved through a 60 mesh sieve. Finally, the mixture was pressed into tablets in a suitable automatic tabletting machine.

Example B

Tablet - direct compression mg / tablet methyl 1-cyclohexylamino-3 = hydroxy-2-methoxyandrostane-17 / S-carboxylate. hydrochloride 27 »0 microcrystalline cellulose 135 s0 20 sodium starch glycolate 6.0 magnesium stearate 2.0 170.0 mg

The steroid and the microcrystalline cellulose were screened through a mesh mesh. The sodium starch glycolate and magnesium stearate were also screened through a 60 mesh screen. The powders were then mixed together in a suitable% mixer until a homogeneous product was obtained. This product was pressed into tablets in a suitable automatic tabletting machine.

The tablets, prepared according to Example A or B, can be coated with a thin polymer coating by conventional methods. A pigment may be included in the coating layer.

'35 8103358 f% r- ►

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Example C

Hard gelatin capsule '' mg / capsule methyl 2g-ethoxy-3a-hydroxy-11a- (3-methylbutylaminoJ-5a-androstane-5 ITB-caroxylate hydrochloride 90 lactose, anhydrous A1.0 sodium starch glycolate h, 0 magnesium stearate 1.0 capsule filler weight 200, 0 mg 10

The steroid was screened and mixed with the screened excipients in a suitable mixer using a gradual dilution method. The mixture was then introduced into automatic gelatin capsules of suitable dimensions using an automatic machine.

Example D

Tablet - moist granulated mg / tablet methyl 2B-ethoxy-3a-hydroxy-11a-20 (3-methylbutylamino) -5ct-androstane- 176-carboxy late hydrochloride 108.00 corn starch 138.00 pölyvinylpyrrolidone 2.5 sodium starch glycolate 7 »5 25 magnesium stearate 2.0 weight of the tablet 258.00

The manufacturing method is the same as that described in Example A.

The tablets can be coated with a thin polymer coating by conventional methods. This layer can contain a pigment.

Example E

35 Intravenous injections 8103358 • * -59- before 'Λ

Components: methyl 11α-cyclohexylanrino-3a-hydroxy-2g-with Loxy-5a-androstane-173-carhoxylate hydrochloride or methyl 2g-ethoxy-3a-hydroxy-11a- (3-methylbutylamino} -5a-androstane-1 TB-carhoxylate hydrochloride 5 ( equivalent to 1 to 10 mg free base) sodium chloride sufficient for water isotonicity for injection purposes up to 1 ml

The steroid and sodium chloride were dissolved in some water. If necessary, the pH was adjusted with a sodium hydroxide or hydrochloride solution. Water was made up to the desired volume and stirred until a homogeneous mixture was obtained. The resulting solution was filtered and the filtrate collected in clean glass vials sealed by melting. The solution can be sterilized using an autoclave, filtration or preparation under aseptic conditions.

20 8103358

Claims (12)

1. Compounds of formula 1, wherein an alkyl group with at most 8 carbon atoms or an eycloalkyl group with 3 to 7 carbon atoms represents R 1 a hydrogen atom, an alkoxy group with at most 6 carbon atoms or an alkanoyl-5 oxy group with 2 t / m represents 5 carbon atoms and R 1 represents an alkyl group of at most 8 carbon atoms or an eycloalkyl group of 3 to 7 carbon atoms, provided that if the compounds contain Heix 5f 3 hydrogen atom, R 1 represents a hydrogen atom and the D homo analogs thereof with a -CC ^ R ^ group, wherein R ^ IQ has a meaning as indicated above, or the 17a | 3 position; ·. as well as its acid addition salts. 2. Compounds according to claim 1, in which R 1 is an isopentyl, hexyl, isohexyl, neohexyl, cyclopentyl or cyclohexyl group, R 1 a hydrogen atom or an ethoxy, ethoxy or propoxy group and R 1 a methyl or ethyl group, with a 50 hydrogen atom, wherein ring D is a 5-ring. 3 ·. Compounds according to any one of the preceding claims in the form of physiologically acceptable acid addition salts. k. Compounds according to claim 3 in the form of 2Q hydrochlorides, hydrobromides, phosphates, sulfates, p-toluene sulfonates, methanesulfonates, citrates, tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, glutarates and glutaconates. 5. Methyl 2-3-ethoxy-3a-hydraxy-11a- (3-methylbutyl-2-amino) -5a-androstane-178-carboxylate, and its physiologically acceptable acid addition salts. 6. Methyl 2 & -methoxy-3a-hydroxy-11a (3-methylbutylamino) - α-androstane-17g carboxylate, as well as their physiologically acceptable acid addition salts. 20 7 Methyl 1 l-cyclohexlamino-Sa-hydroxy-g-methoxy-lpa-androst-170-carboxylate, and its physiologically acceptable acid addition salts. 8. Methyl 11a-cyclohexylamino-3a-hydroxy-5a-andros-8103358 Z> -61-ir * ^ j * tane-17β-cartoxylate as well as its physiologically acceptable acid addition salts. Compounds according to claims 5-8 in the form of their hydrochlorides. Method for preparing a pharmaceutical preparation, characterized in that at least 1 compound of formula 1 as defined in claim 1 and / or a physiologically acceptable addition salt thereof, optionally with one or more pharmaceutical carriers and / or excipients, in a dosage form suitable for such an application. A process for preparing a steroid, characterized in that a compound of formula 1. as defined in claim 1 is prepared by leaving (A) a corresponding 11a-amino compound or a corresponding 11a-amino-1T5-carboxylic acid reacting with a compound of formula R ^ X, wherein R ^ has a meaning as defined in claim 1. and X is an easily displaceable atom or group, (B) {if a 23-substituted 5a compound is desired) to react a corresponding 2ct, 3a epoxide under acid conditions with a compound of formula HR ^ or with a compound which forms the (R 2) anion, wherein Rg has a meaning as defined in claim 1, but is not hydrogen, and then, if the starting product contains a deprotonated 30 hydroxyl group, the product obtained with a proton source, (0 reacting a corresponding 11a-amino compound with a monocarbonyl compound in the presence of a reducing agent to introduce the R 1 group, 30 (D) (if a 23-unsubstituted compound is desired) a corresponding 3-oxo compound (E) convert a corresponding N,] J-disubstituted 11a-amino compound into an ï-mono-substituted compound,,, (F) to esterify a corresponding 173-carboxylic acid, 8103358-6-26 ν »'* v ^ ν' (G) to reduce a corresponding Δ-compound, (iï) a corresponding compound with a different ester group than the desired one.» group R ^ (as defined in claim 1) with an alcohol of formula R, OH, wherein R_ has a meaning as defined in claim 1, ester flier, (I) converting a corresponding 33-bydroxy compound, or (J) a corresponding compound having a protected 3a-hydroxyl group cleaving the protecting group and, if necessary, forming an acid addition salt thereof. 12. Compounds of formula 2, wherein R ^ has a meaning as defined in claim 1, provided that if the compounds contain a 5 / - hydrogen atom, R ^ represents a hydrogen atom, R ^ represents a hydrogen atom or an R ^ group as defined. in claim 1 and R 1 represents a hydrogen atom or an R 1 substituent as defined in claim 1, provided that at least one of the substituents R 1 or R 1 represents a hydrogen atom and its D-homo analogs with a -CO 2 R 2 group at the 17a3 position and form salts and internal ions thereof. Method for the protection of humans or animals suffering from or susceptible to cardiac arrhythmias, characterized in that an effective amount of one or more compounds according to claims 1-9 is administered thereto. 1U. Compounds according to claims 1-9 for use in the treatment or prevention of cardiac arrhythmias in human or animal patients. 15 · Method as described in the description and / or examples. 30 ^ 3358. COjRj • 'ΚιΗΝ' '^ ννΙ ^ \ HO''1 H COeRi R ^ HN' / HO Glaxo Group limited, London, Great Britain 81 03 358