BE889639A - 11-ALPHA-AMINO-ANDROSTANES, THEIR PREPARATION AND COMPOSITIONS CONTAINING THE SAME - Google Patents

Description

       

    <EMI ID = 1.1>

  
and compositions containing it <EMI ID = 2.1> having an amino group substituted in the lice position.

  
The goal of anti-dysrhythmic therapy is to reduce dangerous abnormal heart rhythms to normal, or reduce the likelihood of developing dangerous rhythms in patients at risk

  
due to hypertension, atheromas, diabetes or

  
  <EMI ID = 3.1>

  
or infarction.

  
It is known that dysrhythmias can be treated and prevented in patients who have suffered a heart attack - or who suffer from other heart diseases. There are many drugs for the treatment of ventricular dysrhythmias, but their application is limited by their lack of efficacy or by their toxicity which gives rise to various side effects.

  
Therefore, there is a demand for drugs suitable for use in treatment

  
of patients with dysrhythmias and therefore at risk of sudden cardiac death. In addition, there is a demand for such drugs to be administered,

  
  <EMI ID = 4.1>

  
patients at risk of developing dysrhythmias, in which case activity after oral administration is desirable.

  
  <EMI ID = 5.1>

  
  <EMI ID = 6.1>

  
the possibility is provided that the compounds are provided. various substituents in other positions, including <EMI ID = 7.1>

  
  <EMI ID = 8.1>

  
specific in Belgian patent n [deg.] 853 &#65533; 227 of any

  
  <EMI ID = 9.1>

  
any of the compounds described in the specification of the aforementioned Belgian patent, or, in fact, to any compound of comparable structure.

  
The Applicant has now discovered that the

  
  <EMI ID = 10.1>

  
The anti-dysrhythmic activity of the compounds is significantly higher than that of the analogous compounds specifically described in the specification of the

  
  <EMI ID = 11.1>

  
The compounds in question are therefore of potential interest for use as anti-dysrhythmic drugs.

  
The present invention therefore more particularly relates to compounds which correspond to the following general structural formula:

  

  <EMI ID = 12.1>


  
  <EMI ID = 13.1>

  
a C3-C7 cycloalkyl group;

  
represents a hydrogen atom, an alkoxy group

  
  <EMI ID = 14.1>

  
C3-C7 cycloalkyl;

  
(provided that when the compounds contain a

  
  <EMI ID = 15.1> <EMI ID = 16.1>

  
  <EMI ID = 17.1>

  
as also the acid addition salts of these substances.

  
  <EMI ID = 18.1>

  
it can be, for example, a cyclopropyl group, cyclo-

  
  <EMI ID = 19.1>

  
  <EMI ID = 20.1>

  
alkyl group, the latter may be straight chain or branched chain.

  
  <EMI ID = 21.1>

  
preferably has 3 to 7 carbon atoms and may be, for example, a propyl, butyl, pentyl, isopentyl, hexyl, isohexyl or neobexyl radical. When R represents an alkoxy group, it can be, for example,

  
  <EMI ID = 22.1>

  
an alkyl group, this can be, for example, a methyl, ethyl, propyl, isopropyl, butyl or isopentyl radical.

  
The total number of carbon atoms in the

  
  <EMI ID = 23.1>

  
from 3 to 10.

  
  <EMI ID = 24.1>

  
in Ci -08 and when it is desired to obtain compounds which have good activity by administration by

  
  <EMI ID = 25.1>

  
methyl or ethyl radical.

  
The nucleus D comprises. conveniently 5 links.

  
The compounds preferably have a hydrogen atom in position 5a.

  
  <EMI ID = 26.1>

  
having a 5-membered ring D in which: R represents an isopentyl, hexyl, isohexyl, neohexyl, cyclopentyl or cyclohexyl group; R <2> represents a hydrogen atom or a methoxy, ethoxy or propoxy group, in particular

  
  <EMI ID = 27.1>

  
methyl or ethyl, in particular a methyl group.

  
  <EMI ID = 28.1>

  
acid addition salts; physiologically acceptable salts are preferred. As examples of salts of this kind, mention may be made of hydrochlorides, hydrobromides, phosphates, sulphates, p-toluenesulphonates, methanesulphonates, citrates, tartrates,

  
  <EMI ID = 29.1>

  
succinates, tricarballylates, glutarates and glutaconates. The hydrochlorides are the preferred acid addition salts.

  
  <EMI ID = 30.1>

  
on the basis of their high anti-dysrhythmic activity, the following substances may be mentioned:

  
  <EMI ID = 31.1>

  
17 de -methylcarboxylate, <EMI ID = 32.1>

  
6. 3a-hydroxy-11a- (3-methylbutylamino) -5a-androstane- ,.

  
Methyl 17p-carboxylate,

  
  <EMI ID = 33.1>

  
and their physiologically acceptable acid addition salts, for example their hydrochlorides.

  
A particularly preferred substance belonging to this group is compound 1 and its physiologically acceptable acid addition salts, such as its hydrochloride. In vitro and animal examinations <EMI ID = 34.1>

  
The compound more specifically manifested against aconitine induced dysrhythmias in rats of high activity levels after administration both by

  
  <EMI ID = 35.1>

  
both oral and intravenous

  
and a single oral dose of the compound gave an extended duration of action. The compound was extremely effective in reducing mortality and the incidence and duration of ventricular bigemina. tachycardia. and fibrillation in anesthetized rats with ligated coronary artery. Administered intravenously or orally, the compound was effective against dysrhythmias after infarction in the conscious dog.

  
Other compounds having properties similar to those of compound 1 are compounds 2, 5 and 7.

  
The compounds can be used for the treatment of patients suffering from cardiac arrhythmias, whether they appear spontaneously or as a result of treatment with other drugs, for example cardiac glycosides, or whether they are the consequence of myocardial infarction or ischemia. They can also be used for prophylactic treatment

  
patients at risk for heart rhythm disturbances or sudden coronary death.

  
The present invention therefore also has

  
  <EMI ID = 36.1>

  
addition of physiologically acceptable acids to use

  
  <EMI ID = 37.1>

  
in a human or an animal. The present invention also relates to compounds of formula (I) and their physiologically acceptable acid addition salts in association with instructions for their use in

  
  <EMI ID = 38.1>

  
in a human or an animal.

  
The present invention also has the characteristic of compounds of the general formula which follows:

  

  <EMI ID = 39.1>
 

  
  <EMI ID = 40.1>

  
ment indicated (: as long as the compounds

  
  <EMI ID = 41.1>

  
  <EMI ID = 42.1>

  
  <EMI ID = 43.1> amphionics.

  
The compounds of formula (II) can generate acid addition salts. Compounds of the formula

  
  <EMI ID = 44.1>

  
As examples of acid addition salts, mention may be made of those indicated above with regard to the compounds.

  
  <EMI ID = 45.1>

  
salts with inorganic bases, such as alkali metal salts, for example sodium, potassium and lithium salts, alkaline earth metal salts. for example calcium and magnesium salts and ammonium salts, or salts with organic bases, for example amine salts.

  
The compounds of formula (II) are suitable as intermediates for the preparation of the compounds of formula CI) by implementing the methods described hereinafter.

  
The compounds according to the invention can be prepared by implementing a certain number of different methods, using techniques which are known as a whole. Appropriate preparation methods are described below.

  
1. We can introduce a substituent on the function

  
  <EMI ID = 46.1>

  
laying, that is to say a compound of formula (II) in <EMI ID = 47.1>

  
  <EMI ID = 48.1>

  
group or an easily movable atom such as an atony

  
  <EMI ID = 49.1>

  
hydrocarbyloxysulfonyloxy group (for example methoxysulfonyloxy) or a dialkoxyphosphonyloxy group (for

  
  <EMI ID = 50.1>

  
  <EMI ID = 51.1>

  
also represents a hydrogen atom such a reaction can lead to esterification to generate

  
  <EMI ID = 52.1>

  
  <EMI ID = 53.1>

  
(e.g. potassium carbonate or silver oxide)

  
in solution, at any suitable temperature which varies from room temperature to

  
  <EMI ID = 54.1>

  
deny the reaction in a suitable reaction solvent. As suitable solvents, there may be mentioned ethers
(e.g. dioxane), substituted amides (e.g.

  
  <EMI ID = 55.1>

  
tallow oxides (e.g. tallow dimethyl oxide), alkanols (e.g. ethanol or methanol) or acetonitrile.

  
When X represents a chlorine atom or a bromine atom, the reaction can be facilitated by the addition of iodide, such as sodium iodide.

  
The compounds of formula (II) in which R represents a hydrogen atom can be prepared by reduction of the corresponding 11-oxime. Such a reduction can be carried out using an alkali metal or an alkaline earth metal in an alcohol and / or an amine and / or ammonia, for example sodium in n-propanol, if in the presence of CI-, a suitable solvent :,

  
  <EMI ID = 56.1>

  
reflux and "preferences, to the latter.

  
The 11-oximes can themselves be prepared from the corresponding 11-oxo type compounds.

  
The compound of the 11-oxo type can, for example, be

  
  <EMI ID = 57.1>

  
The reaction can also be carried out under conditions

  
  <EMI ID = 58.1>

  
buffered pyridine.

  
The harsh conditions used to effect reduction of 11-oxime make it necessary or desirable that certain substituents, for example the 17p-alkoxycarbonyl substituent and a 2p-alkanoyloxy substituent when necessary, be introduced.

  
  <EMI ID = 59.1>

  
  <EMI ID = 60.1>

  
the description of British patent n [deg.] 1,376,892. So,

  
  <EMI ID = 61.1>

  
  <EMI ID = 62.1>

  
under acidic conditions (if necessary in the presence of an additional acid catalyst, for example sulfuric acid, perchloric acid or etherate of

  
  <EMI ID = 63.1>

  
  <EMI ID = 64.1>

  
treatment of the product with a source of protons (for example aqueous ammonium chloride) so as to form

  
  <EMI ID = 65.1>

  
mention may be made of alcohols and carboxylic acids.

  
  <EMI ID = 66.1>

  
appropriate up to reflux.

  
The reaction can be carried out in a medium

  
  <EMI ID = 67.1>

  
(for example by the above-mentioned reaction 1 method)

  
  <EMI ID = 68.1>

  
  <EMI ID = 69.1>

  
This reaction can also be used to pre-

  
  <EMI ID = 70.1>

  
be protected, for example in the form of the trichlorethoxycarbonyl derivative. The trichlorethoxycarbonyl group can subsequently be removed by hydrolysis with an alkali or, preferably, by reduction with zinc and acetic acid.

  
  <EMI ID = 71.1>

  
corresponding, i.e. a compound of the formula

  
  <EMI ID = 72.1>

  
with a monocarbonyl compound used to introduce the

  
  <EMI ID = 73.1>

  
  <EMI ID = 74.1> duction of a cycloalkyl group, as also of an alkyl group. The reducing agents which can be used are those generally well known for carrying out mine reduction, examples being formic acid (for example at an appropriate temperature

  
  <EMI ID = 75.1>

  
temperature that fluctuates from room temperature to

  
  <EMI ID = 76.1>

  
reaction, in the presence or absence of water), an alkali metal borohydride or cyanoborohydride
(e.g. sodium borohydride or cyanoboro-

  
  <EMI ID = 77.1>

  
  <EMI ID = 78.1>

  
hydrogenated alkali metal nylate (e.g. Fe (CO) 5 or

  
  <EMI ID = 79.1>

  
at any suitable temperature up to reflux temperature, using an ether, such as

  
  <EMI ID = 80.1>

  
as 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 reaction solvent, conveniently at room temperature), or a

  
  <EMI ID = 81.1>

  
room temperature and in the presence of an ether type solvent, such as tetrahydrofuran).

  
The metal catalyst can, for example, be a catalyst based on a noble metal, such as platinum, platinum oxide, palladium or rhodium. The catalyst can be supported, for example, on charcoal or kieselguhr. It is also possible to use a homogeneous catalyst, such as tristriphenylphosphine rhodium chloride. If desired, the imino Intermediate compound can be isolated.

  
  <EMI ID = 82.1> <EMI ID = 83.1>

  
or N-cyclohexyl-amines respectively. It should be understood that the conditions must be chosen so as to give the predominantly desired N-monosubstituted compound and to minimize the production of the compound.

  
  <EMI ID = 84.1>

  
  <EMI ID = 85.1>

  
both represent hydrogen atoms is preferably carried out under alkaline conditions.

  
4. Reduction of a corresponding 3-oxo type compound.

  
Unsubstituted 2p steroids according to the invention can be prepared from compounds of the 3-oxp type.

  
  <EMI ID = 86.1>

  
  <EMI ID = 87.1>

  
and Kirk (J. Chem. Soc. C, 1969, 1653) or by implementing the method described in the specification of the patent

  
  <EMI ID = 88.1>

  
a trivalent phosphorus compound, such as an ester of phosphorous acid (for example trimethyl phosphite), water and an organic reaction medium (for

  
  <EMI ID = 89.1>

  
then the reduction system (for example to a pH of 6 to 8.5) with an organic base, such as a secondary or tertiary amine (for example triethyl- '

  
  <EMI ID = 90.1>

  
catalytic system is preformed by reflux heating,

  
  <EMI ID = 91.1>

  
res, the reduction can be carried out for example within 2 to 3 hours at reflux; longer periods may be required at room temperature.

  
  <EMI ID = 92.1>

  
to the hydride of the corresponding 3-oxo type compound, for example, using sodium borohydride using an alcohol (for example ethanol) or pyridine, as solvent.

  
  <EMI ID = 93.1>

  
N-mono substituted compound.

  
The compounds of formula (I) can be prepared from the corresponding lla-tert.-amino type compounds by replacing one of the groups with a hydrogen atom, for example by dealkylation using, for example, nitrite sodium, this operation being followed by a catalytic hydrogenolysis.

  
Thus, more particularly, one can prepare

  
  <EMI ID = 94.1>

  
protected) corresponding having a substituent R 'in

  
more of the protecting group, which can be, for example,

  
an acyl group, such as a trichlorethoxycarbonyl radical, a trifluoroacetyl radical or a formyl radical, or a silyl radical, for example a trimethylsilyl group.

  
An acyl group can be removed by hydrolysis, for example with an acid or an alkali. You can also remove the

  
  <EMI ID = 95.1>

  
for example, zinc and acetic acid. Furthermore, it is also possible to remove a protective group of the arylmethyl type, such as a benzyl radical, by catalytic hydrogenation, so as to generate the compound of the unprotected 11a-amino type. A silyl group can be removed, for example by solvolysis, with water (optionally containing an acid or a base) or with an alcohol, or by treatment with an ionic fluoride, such as

  
  <EMI ID = 96.1>

  
This process can also be used to

  
  <EMI ID = 97.1>

  
represents a hydrogen atom by deprotection of a

  
  <EMI ID = 98.1>

  
laying.

  
  <EMI ID = 99.1>

  
gene or a reactive derivative of such a compound (e.g.

  
  <EMI ID = 100.1>

  
suitable alcohol or suitable alkyl or cycloalkyl halide. This reaction is preferably carried out

  
  <EMI ID = 101.1>

  
as described, for example, in the specification of British Patent No. [deg.] 1,380,246.

  
When an alcohol is used to carry out the esterification reaction, it is

  
  <EMI ID = 102.1>

  
in the presence of a catalyst, such as 4-dimethylamino-pyridine.

  
Esterification can also be performed by

  
  <EMI ID = 103.1>

  
hydrogen, by oxidizing the corresponding 17p-acetylated compound, that is to say a pregnane-20-one, using, for example, NaOBr in an aqueous inert solvent medium (for example aqueous dioxane).

  
Compounds of the

  
  <EMI ID = 104.1>

  
  <EMI ID = 105.1>

  
under acidic or basic conditions. As examples of acids suitable for the implementation of such hydrolyses, mention may be made of mineral acids, such as the acid

  
  <EMI ID = 106.1>

  
there may be mentioned alkali metal carbonates and hydroxides, such as sodium or potassium carbonates and hydroxides.

  
When using some of the above reagents

  
  <EMI ID = 107.1>

  
The reduction can be carried out by hydrogenation in the presence of a catalyst (for example a palladium catalyst) in a suitable solvent (for example a

  
  <EMI ID = 108.1>

  
the reaction at ambient temperature or approximately at ambient temperature and at atmospheric pressure,

  
  <EMI ID = 109.1>

  
The starting materials can be prepared by reacting the corresponding 17-oxo compound with acid

  
  <EMI ID = 110.1>

  
8. The compounds of the formula can also be prepared

  
  <EMI ID = 111.1>

  
tion of a corresponding compound comprising a group

  
  <EMI ID = 112.1>

  
  <EMI ID = 113.1>

  
basic, at any temperature which varies from room temperature to reflux temperature, conveniently at a temperature which fluctuates from 50 to 100 [deg.] C, so as to generate a compound of formula (I) having a group 17p -est different from the starting material; normally an excess of alcohol is used. As examples of suitable acid catalysts, mention may be made of

  
mineral acids, for example sulfuric and hydrochloric acids and as examples of suitable basic catalysts, mention may be made of alkali metal carbonates and hydroxides, for example sodium or potassium carbonates or hydroxides.

  
i <EMI ID = 114.1>

  
wish.

  
  <EMI ID = 115.1>

  
  <EMI ID = 116.1>

  
the protected 3a-hydroxyl compound thus obtained as described in 10 below.

  
  <EMI ID = 117.1>

  
Compounds can be formed corresponding to the compounds of formula (I) but containing groups

  
  <EMI ID = 118.1>

  
An ester group (for example alkanoyloxy) can be hydrolyzed so as to obtain the desired 3a-hydroxylated compound, under moderately acidic or basic conditions. Weakly basic conditions are generally the most convenient (using, for example, an alkali metal bicarbonate in aqueous methanol, at any suitable temperature up to reflux temperature). It is also possible to use dilute mineral acids (for example perchloric acid in

  
aqueous methanol).

  
We can remove a protective ether group

  
(for example a tetrahydropyrannyl ether group)

  
by treatment with an aqueous acid and a protective nitro-oxy group by reduction; for example by using zinc and acetic acid

  
  <EMI ID = 119.1>

  
reaction of the free base with a suitable acid.

  
The methods indicated above can be used to prepare the compounds according to the invention as the last main step in the continuation of the preparation operations. The same general methods can be used for the introduction of the desired groups to the

  
  <EMI ID = 120.1>

  
can combine these general processes in different ways during such multi-step processes, as well

  
  <EMI ID = 121.1>

  
The sequence of reactions in these multi-step processes must obviously be chosen so that

  
  <EMI ID = 122.1>

  
  <EMI ID = 123.1>

  
keep in the final product.

  
  <EMI ID = 124.1>

  
can be prepared by essentially similar methods, using appropriate starting materials of the desired structure.

  
Unless otherwise specified, the processes indicated above for the preparation of compounds of formula (I) also apply to the preparation of compounds of formula (II). Salts of the compounds of formula (II) with bases can be prepared by the reaction of the free acid on an appropriate base. For example, the alkali metal salts can be prepared by reaction with a 2-ethylhexanoate, a bicarbonate,

  
an alkali metal carbonate or hydroxide.

  
  <EMI ID = 125.1>

  
and their physiologically acceptable acid addition salts in any manner which is suitable for their administration and, therefore, the scope of the present invention also extends to compositions

  
  <EMI ID = 126.1> bles, suitable for use in human medicine or veterinary medicine. These compositions can be presented in a conventional manner as a mixture with one or more excipients or pharmaceutical vehicles.

  
  <EMI ID = 127.1>

  
addition of physiologically acceptable acids may,

  
  <EMI ID = 128.1>

  
  <EMI ID = 129.1>

  
oral may be in unit dose form and may contain conventional excipients, such as

  
  <EMI ID = 130.1>

  
for example lactose, sugar, corn starch, calcium phosphate or sorbitol; lubricants,

  
  <EMI ID = 131.1>

  
polyethylene glycol or silica; disintegrating agents, for example sodium starch glycolate or potato starch; or wetting agents

  
  <EMI ID = 132.1>

  
tablets can be coated according to good methods. known to those skilled in the art. Other liquid preparations for oral administration may be in the form of, for example, aqueous or oily elixirs, syrups, emulsions, solutions or suspensions, or they may be presented as '' a dry product intended to be added with water or any other suitable vehicle before use.

  
Such liquid preparations may contain additional additives, such as suspending agents, for example sorbitol syrup, methyl-

  
  <EMI ID = 133.1>

  
hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifiers, for example lecithin,

  
  <EMI ID = 134.1>

  
non-aqueous vehicles (which may include edible oils), for example almond oil, coconut oil. fractionated, oily esters, propylene glycol or ethyl alcohol and preservatives, for example

  
  <EMI ID = 135.1>

  
be in the form of suppositories, for example, containing bases for conventional suppositories, such as cocoa butter or. other glycerides.

  
The compounds of formula (I) and their physiologically acceptable acid addition salts can also be introduced into suitable compositions

  
  <EMI ID = 136.1>

  
unit doses in ampoules or in containers that contain multiple doses with a preservative

  
  <EMI ID = 137.1>

  
shapes like suspensions, solutions or

  
  <EMI ID = 138.1>

  
contain composition agents, such as suspending, stabilizing and / or dispersing agents. The active ingredient can also be present in the torso of a powder which is added to an appropriate vehicle, for example sterile pyrogen-free water, before use.

  
When the compositions are in the form of unit doses, each unit preferably contains at least 5 mg, more advantageously at least

  
10 mg of the active ingredient and it advantageously contains from 25 to 500 mg. The daily dose, as used for the treatment of adult humans, preferably ranges from 25 to 2500 mg, preferably

  
from 50 to 1000 mg, depending on the mode and frequency of administration. Compounds can be given as

  
  <EMI ID = 139.1>

  
The compounds of formula (I) and their physiologically acceptable acid addition salts can be administered in combination with other therapeutic agents.

  
The following examples illustrate the present invention.

  
The melting points in capillaries have been determined and these melting points are given in corrected values. Rotational powers were determined at room temperature on 1% solutions in chloroform.

  
The preparation thin layer chromatography and the column chromatography were carried out on silica.

  
The term "petroleum" refers to petroleum ether with a boiling point of 60 to 80 [deg.] C.

  
The solutions were dried using anhydrous sodium sulfate.

  
The IR spectra were determined in bromororm and they relate to the stretching frequency of the carbonyl group of the 17p-carboxylic acid ester group.

  
Reagents based on chloriridic acid were prepared by refluxing a mixture of chloriridic acid (50 mg), isopropanol (94 ml), water (6 ml) and

  
  <EMI ID = 140.1>

  
the pH of the mixture at 7 by the addition of -trlethylamine, adjusted before use.

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

  
The following abbreviations have been used in the tables:

  
  <EMI ID = 141.1>

  
Intermediate 1

  
  <EMI ID = 142.1>

  
A solution of 20,20-ethylenedioxy-5a-pregn-2-ene-11-one-11-oxime (9.36 g) in propane-1-ol (215 ml) was heated to reflux temperature and sodium (8 g) was introduced over 2 hours.

  
When all the sodium had been consumed, the propane-1-ol was distilled off. The residue was extracted with ether (x 3) and these extracts were extracted with a 2M HCl solution (x 3). The extracts thus obtained were washed with ether and brought to a

  
  <EMI ID = 143.1>

  
mixture with ether (x 2) and the extracts were washed

  
with water, they were dried and evaporated so as to leave a solid (8.77 g) which was crystallized from a mixture of ethyl acetate and petroleum so as to obtain the compound indicated in the title (6.15 g) in two harvests. We recrystallized a fraction of the product

  
  <EMI ID = 144.1>

  
20-one

  
We treated a solution of 1: intermediate 1
(0.331 g) in pyridine (3 ml) with chloroformate

  
  <EMI ID = 145.1>

  
the reaction mixture with water (30 ml) and it was extracted with ether (x 3). The combined ethereal extracts were washed with water (x 3) 9, dried and evaporated to give an oil. Purification by chro-

  
  <EMI ID = 146.1>

  
1: 3 ethyl acetate and petroleum gave the compound

  
  <EMI ID = 147.1>

  
  <EMI ID = 148.1> Intermediate 3

  
  <EMI ID = 149.1>

  
pyridine (20 ml). After 16 hours, no complete reaction was obtained. An additional amount has been added.

  
  <EMI ID = 150.1>

  
and, after 30 minutes, the reaction mixture was diluted with water (30 ml). The mixture was extracted with 1 '

  
  <EMI ID = 151.1>

  
(x 4) and water (x 2) and they were dried. Evaporation

  
  <EMI ID = 152.1>

  
purified by column chromatography on silica eluted using a mixture of ethyl acetate and petroleum (1: 3), so as to obtain a solid (2.5 g).

  
A fraction of the product was crystallized from a mixture of ether and petroleum so as to obtain the indicated compound

  
  <EMI ID = 153.1>

  
Bromine (0.61 ml) was added to a solution of sodium hydroxide (1.44 g) in water (10.8 ml),

  
  <EMI ID = 154.1>

  
(5.4 ml) and the mixture thus obtained was introduced into

  
  <EMI ID = 155.1>

  
dioxane (25.5 ml) and water (8.1 ml) at 10 [deg.] C. After

  
4 hours at 10 ° C., sodium sulfite (0.45 g) was added and the mixture was stirred for 0.25 hours. The reaction mixture was filtered and the filtrate was brought to a pH of 2

  
  <EMI ID = 156.1>

  
suspension with chloroform (x 3). The extract was washed with water, dried and evaporated to leave <EMI ID = 157.1>

  
thin layer chromatography of preparation in a

  
  <EMI ID = 158.1>

  
By repeating the procedure used with respect to 1 [deg.] Intermediate 4, the indicated compound was prepared

  
  <EMI ID = 159.1>

  
at 0 [deg.] C. The mixture was stirred for 2 hours, then the solid was filtered off. The filtrate was diluted with water (50 ml) and extracted with ethyl acetate (x 2). The extract was washed with brine (x 2)

  
  <EMI ID = 160.1>

  
obtaining an oil (1.586 g) which was purified by column chromatography, eluting with a mixture of ethyl acetate and petroleum (1: 2) so as to obtain

  
  <EMI ID = 161.1>

  
Intermediaries 7 to <1> 1

  
Table 1 summarizes the preparation of 170-esters

  
  <EMI ID = 162.1>

  
intermediate 6.

  
Intermediate 7 is 3a-hydroxy-11a- (2,2,2-

  
  <EMI ID = 163.1>

  
methyl.

  
Intermediaries 8 to 10 are esters of

  
  <EMI ID = 164.1>

  
ethyl.

  

  <EMI ID = 165.1>


  

  <EMI ID = 166.1>
 

  
  <EMI ID = 167.1>

  
for 1.5 hours. We filtered the mixture and diluted

  
  <EMI ID = 168.1>

  
  <EMI ID = 169.1>

  
  <EMI ID = 170.1>

  
  <EMI ID = 171.1>

  
washing liquids with dichloromethane and the combined extracts were washed with water, dried and evaporated to give a foam (11.531 g). Part of this product was purified by thin layer chromatography of preparation in a mixture of EtOAc / petroleum (1: 3) so as to obtain the compound indicated in

  
  <EMI ID = 172.1>

  
By repeating the operating mode implemented

  
  <EMI ID = 173.1>

  
  <EMI ID = 174.1>

  
+160) from the intermediary <1> 1 (620 mg) in use <EMI ID = 175.1>

  
A solution of intermediate 5 was stirred
(2.2 g) in ether (20 ml) with cyclohexanol

  
  <EMI ID = 176.1>

  
ques reunites and they were evaporated so as to leave a foam which was purified by chromatography

  
  <EMI ID = 177.1> methyl carboxylate

  
Cyclohexanone (0.3 ml) and

  
  <EMI ID = 178.1>

  
let the mixture sit for 24 hours. We added

  
  <EMI ID = 179.1>

  
with ether (x3). The extract was washed with 3 [deg.] Water,

  
it was dried and evaporated so as to leave a foam which was purified by column chromatography and by thin layer chromatography of preparation, so as to obtain the compound indicated in the title (80 mg)

  
  <EMI ID = 180.1>

  
Intermediate 18

  
  <EMI ID = 181.1>

  
ice bath, during the addition of 2,2,2-trichlorethyl chloroformate (36 ml). When the addition was complete, water was carefully added and when no further reaction occurred, the mixture was washed with 2M HCl solution (x 2)

  
and water., The solution was dried and evaporated so as to leave an oil (24.6 g) which was treated with ether so as to obtain the indicated compound in the title (14.1 g), in the form of a solid.

  
Intermediate 19

  
  <EMI ID = 182.1>

  
By repeating the procedure used for intermediate 4, the title compound was prepared from intermediate 18 (15.5 g)

  
  <EMI ID = 183.1>

  
in water (85 ml). We carried out the purification

  
  <EMI ID = 184.1>

  
with an EtOAc / petroleum mixture (1: 1), so as to obtain the compound indicated in the title (4.73 g). A fraction of the product was crystallized from a mixture of ether and petroleum, the substance having a melting point with

  
  <EMI ID = 185.1>

  
and the mixture was stirred for 2 hours. We added <EMI ID = 186.1>

  
ether (x 3). The extract was washed with water, dried and evaporated so as to leave a foam which was purified by chromatography on a colossus, eluting with a mixture of EtOAc and petroleum (1: 2) and crystallized from ether so

  
obtaining the compound indicated in the title (2.45 g),

  
  <EMI ID = 187.1>

  
mix at room temperature for 1 hour. The mixture was diluted with 5% NaHCO solution, and extracted with ethyl acetate (x 3). We have

  
  <EMI ID = 188.1>

  
so as to leave a foam. A fraction of the product (193 mg) was purified by preparation thin layer chromatography using a mixture of

  
  <EMI ID = 189.1>

  
Pyridine (39 ml) and

  
  <EMI ID = 190.1>

  
  <EMI ID = 191.1>

  
organic and evaporated so as to leave a brown oil which crystallized by trituration with a

  
  <EMI ID = 192.1> compound indicated in the title (47.86 g), P.F. 174-176 [deg.] C,

  
  <EMI ID = 193.1>

  
By repeating the procedure used

  
  <EMI ID = 194.1>

  
a solution of sodium hydroxide (35.1 g) in water

  
  <EMI ID = 195.1>

  
the corresponding 170-carboxylic acid which we then have

  
  <EMI ID = 196.1>

  
2M to obtain a pH of 11 and the mixture was stirred for 3 hours. The pH of the mixture was brought to 2 using a concentrated HCl solution and diluted with water. The precipitate was extracted with chloroform (x 2) and the extract was washed with water, dried and evaporated

  
  <EMI ID = 197.1>

  
Intermediaries 24 to 28

  
Table 2 summarizes the preparation of the compounds

  
  <EMI ID = 198.1>

  
  <EMI ID = 199.1>

  
intermediate 21.

  
  <EMI ID = 200.1> analogs of intermediary 21.
  <EMI ID = 201.1>
  <EMI ID = 202.1>
 Intermediate 29

  
  <EMI ID = 203.1> pregnane-20-one (24 g) in dichloromethane (300 ml).

  
After 2 hours, water (300 ml) was added and the organic phase was separated and the solvent was removed by evaporation so as to leave an oil which was purified by column chromatography in the process

  
  <EMI ID = 204.1>

  
The repetition of the process used with respect to intermediate 4 made it possible to prepare the indicated compound

  
  <EMI ID = 205.1>

  
from intermediate 29 (27 g) using

  
  <EMI ID = 206.1>

  
  <EMI ID = 207.1>

  
mixture of ether and petroleum.

  
  <EMI ID = 208.1>

  
  <EMI ID = 209.1>

  
of intermediate 30 (17.8 g) in dimethylformamide

  
  <EMI ID = 210.1>

  
  <EMI ID = 211.1>

  
ethyl acetate (x2). The extract was washed with brine (x2), dried and evaporated to leave an oil which, by evaporation from ether, gave the title compound ( 15.45 g),

  
  <EMI ID = 212.1> <EMI ID = 213.1>

  
methyl

  
Zinc powder (36 g) was added to a

  
  <EMI ID = 214.1>

  
glacial acetic acid (400 ml). The mixture was stirred for 20 hours and the zinc was filtered off and washed with water. The filtrate was reduced in mass in vacuo and the pH of the residue was brought to 10 with a solution of

  
  <EMI ID = 215.1>

  
  <EMI ID = 216.1>

  
oil (7.93 g). We purified a product sample
(400 mg) by thin layer chromatography of preparation so as to obtain the compound indicated in the title under

  
  <EMI ID = 217.1>

  
methyl

  
  <EMI ID = 218.1>

  
and cyclohexanone (12 ml) to a stirred solution of

  
  <EMI ID = 219.1>

  
After 60 hours, the mixture was diluted with a solution

  
  <EMI ID = 220.1>

  
thus obtained with ether (x2). The extract was shaken with 2M HCl (x2) and the aqueous phase was washed with ether, the pH was brought to 9 with a solution of

  
  <EMI ID = 221.1>

  
  <EMI ID = 222.1>

  
until a foam is obtained which has been purified by chromatography on a silica column while eluting

  
  <EMI ID = 223.1>

  
methyl <EMI ID = 224.1>

  
no longer discharged. We added water (200 if) and

  
  <EMI ID = 225.1>

  
  <EMI ID = 226.1>

  
  <EMI ID = 227.1>

  
ether (50 ml) and the organic phase was washed with

  
  <EMI ID = 228.1>

  
sister oil (289 mg) which crystallized in petroleum

  
  <EMI ID = 229.1>

  
  <EMI ID = 230.1>

  
  <EMI ID = 231.1>

  
  <EMI ID = 232.1>

  
  <EMI ID = 233.1>

  
  <EMI ID = 234.1>

  
at a pH of 1- using a concentrated HCl solution.

  
Water (800 ml) was added and the precipitate was collected
(1.42 g) by filtration, it was washed with water (2 x 300 ml)

  
  <EMI ID = 235.1>

  
ethyl gave the title compound (1 g),

  
  <EMI ID = 236.1>

  
in ethanol (20 ml) with cyclohexanone (1.5 ml) and sodium cyanoborohydride (2015 g) for 6 hours.

  
  <EMI ID = 237.1> <EMI ID = 238.1>

  
  <EMI ID = 239.1>

  
  <EMI ID = 240.1>

  
  <EMI ID = 241.1>

  
evaporated so as to leave a foam which remains

  
  <EMI ID = 242.1>

  
Intermediate 13 (20.5 g) was heated in 1 [deg.] Glacial acetic acid (100 ml) in a steam bath

  
  <EMI ID = 243.1>

  
  <EMI ID = 244.1>

  
then diluted with a solution of NE 3 0.88 to a

  
  <EMI ID = 245.1>

  
  <EMI ID = 246.1>

  
they were dried and evaporated until a

  
  <EMI ID = 247.1>

  
produced by thin layer chromatography of preparation

  
  <EMI ID = 248.1> <EMI ID = 249.1>

  
mix at reflux for 24 hours. We separated the excess

  
  <EMI ID = 250.1>

  
acidified the filtrate and the washing liquors with

  
  <EMI ID = 251.1>

  
and the ethereal wash liquor was in turn washed with gel 14 and water (x3). We brought the diapers

  
  <EMI ID = 252.1>

  
sion thus obtained with ether (x2). We gathered the

  
  <EMI ID = 253.1>

  
dried and evaporated so as to obtain a foam (18.96 g) which was purified by column chromatography:

  
  <EMI ID = 254.1>

  
EXAMPLES - Section A

Example 1

  
  <EMI ID = 255.1>

  
methyl

  
Zinc powder (2.4 g) was added to a

  
  <EMI ID = 256.1>

  
glacial acetic acid (25 ml) and the mixture was stirred for 6 hours. The zinc was removed by filtration and washed with water. The aqueous filtrate was washed with ether (x2) and brought to pH 10 with a solution

  
  <EMI ID = 257.1>

  
and the extract was washed with water (x2), dried and

  
  <EMI ID = 258.1>

  
which has been purified by thin layer chromatography

  
preparation using methanol, so as to obtain

  
  <EMI ID = 259.1>

Example 2

  
  <EMI ID = 260.1>

  
methyl A solution of intermediate 20 was stirred
(2.4 g) in glacial acetic acid (25 ml) with zinc (2.5 g) for 4 hours. We separated the zinc by

  
  <EMI ID = 261.1>

  
(50 ni). The pH of the filtrate and the liquors of

  
  <EMI ID = 262.1>

  
  <EMI ID = 263.1>

  
water, dried and evaporated to leave a solid (1.65 g). We crystallized a fraction

  
  <EMI ID = 264.1>

  
  <EMI ID = 265.1>

  
methyl carboxylate

  
Zinc powder (4.9 g) was added to a stirred solution of intermediate 21 (4.874 g) in glacial acetic acid (15 ml) and the mixture was stirred for 1 hour. The zinc was separated by filtration and

  
  <EMI ID = 266.1>

  
  <EMI ID = 267.1>

  
they were extracted with ether (x3). The extract was washed with water, dried and evaporated so as to leave a solid which was crystallized from ethyl acetate, so as to obtain the compound Indicated in the

  
  <EMI ID = 268.1>

  
  <EMI ID = 269.1>

  
Table 3 summarizes the preparation of compounds

  
  <EMI ID = 270.1>

  
work of the general process described in Examples 1-3.

  
The purification was carried out by preparation thin layer chromatography (P), column chromatography (C) or crystallization (X).

  
The compounds prepared were as follows:

  
  <EMI ID = 271.1>

  
methyl carboxylate.

  

  <EMI ID = 272.1>


  

  <EMI ID = 273.1>


  

  <EMI ID = 274.1>
 

  
  <EMI ID = 275.1>

  
during 5 days. The pH of the cooled mixture was brought to 11

  
  <EMI ID = 276.1>

  
  <EMI ID = 277.1>

  
A sample (20 mg) of this product has been dissolved

  
  <EMI ID = 278.1>

  
  <EMI ID = 279.1>

  
for 4 hours. Thin layer chromatography of

  
  <EMI ID = 280.1>

  
methyl late.

Example 16.

  
  <EMI ID = 281.1>

  
methyl

  
Qn added sodium (1 g) to a solution

  
  <EMI ID = 282.1>

  
  <EMI ID = 283.1>

  
added 1 [deg.] water (10 ml). The mixture was evaporated and the residue was dissolved in 2M HCl (20 ml). We evaporated

  
  <EMI ID = 284.1>

  
  <EMI ID = 285.1>

  
resulting oil in methanol (30 ml) and heated

  
  <EMI ID = 286.1>

  
during 3 hours. The cooled mixture was brought to pH

  
  <EMI ID = 287.1>

  
diluted with water (100 ml). The precipitate was extracted with ether (x2) and there was. washed the extract with water,

  
  <EMI ID = 288.1>

  
foam which was dissolved in ether (50 ml). We have <EMI ID = 289.1>

  
dried and evaporated so as to leave the compound indicated in the title (226 mg) in the form of a foam,

  
  <EMI ID = 290.1>

  
  <EMI ID = 291.1>

  
  <EMI ID = 292.1>

  
  <EMI ID = 293.1>

  
  <EMI ID = 294.1>

  
evaporate the mixture until dry. We leached the solid

  
  <EMI ID = 295.1>

  
solutions so as to leave the indicated compound

  
  <EMI ID = 296.1>

  
Examples 18-26

  
  <EMI ID = 297.1>

  
  <EMI ID = 298.1>

  
A hydrochloric acid solution was added

  
  <EMI ID = 299.1>

  
in any additional water and the mixture was stirred

  
  <EMI ID = 300.1>

  
or until it no longer dissolves base. The mixture was brought to the appropriate volume or weight with water and filtered and any undissolved base was collected, dried and weighed to determine the concentration of

  
the solution. The pH was measured.

  

  <EMI ID = 301.1>


  

  <EMI ID = 302.1>
 

  
  <EMI ID = 303.1>

  
at reflux for 24 hours., The reaction solution was cooled and acidified with HCl solution

  
  <EMI ID = 304.1>

  
ethereal washing with a solution of [deg.] HCl M and water (x2).

  
  <EMI ID = 305.1>

  
  <EMI ID = 306.1>

  
1-bromo-3-methylbutane (9.54 ml) was added,

  
  <EMI ID = 307.1>

  
mix at reflux for 22 hours. We diluted the mixture

  
  <EMI ID = 308.1>

  
of ethyl (x3). The extract was washed with water, dried and evaporated until a foam was obtained which was purified by thin layer chromatography. of preparation

  
  <EMI ID = 309.1>

  
  <EMI ID = 310.1>

  
Table 5 summarizes the preparation of the compounds

  
  <EMI ID = 311.1>

  
dantes, using the general procedure described in examples 1 and 2. The treatment was otherwise identical to that described in example 1 (I) or in example 2
(II). "

  
Purification was carried out by chromatography

  
  <EMI ID = 312.1>

  
on column (C) or crystallization (X)

  
In Examples 3-7 and 9, the haloalkane was

  
  <EMI ID = 313.1>

  
  <EMI ID = 314.1>

  
methylbutane.

  
The compounds prepared were as follows:

  
  <EMI ID = 315.1>

  
170 methyl carboxylate.

  

  <EMI ID = 316.1>


  

  <EMI ID = 317.1>


  

  <EMI ID = 318.1>
 

Example 11

  
  <EMI ID = 319.1>

  
A suspension of the product from Example A3 was stirred
(1.512 g) in ethanol (15 ml) and cyclohexanone
(1.5 ml) with sodium cyanoborohydride (1.5 g) for

  
  <EMI ID = 320.1>

  
then water. The mixture was extracted with ether (x2)

  
and the extract was washed with water, dried and evaporated,

  
so as to leave a foam which was purified by column chromatography using a mixture of chloroform and methanol (19: 1) and crystallized from acetonitrile so as to obtain the compound

  
  <EMI ID = 321.1>

  
methyl late

  
Sodium cyanoborohydride (2 g) was added to a

  
  <EMI ID = 322.1>

  
  <EMI ID = 323.1>

  
at 21 [deg.] C for 5 hours. 5% NaHCO3 solution and water were added and the mixture was extracted with ether
(x2). The extract was washed with water, dried and evaporated so as to obtain a foam which was purified by column chromatography and by

  
  <EMI ID = 324.1>

  
  <EMI ID = 325.1> <EMI ID = 326.1>

  
Examples 13-25

  
  <EMI ID = 327.1>

  
  <EMI ID = 328.1>

  
by implementing the general method described in the examples
11 and 12.

  
The aldehydes / ketones used in the examples
13-25 were as follows: cyclohexanone (Examples 13, <EMI ID = 329.1>

  
(example 18); 4-methylpentanal (Example 19); 3-methylbutanal (Example 21); cycloheptanone (Example 23);

  
  <EMI ID = 330.1>

  
The purification was carried out by preparation thin layer chromatography (P), column chromatography (C) or crystallization (X).

  
The following compounds were prepared:

  
  <EMI ID = 331.1>
  <EMI ID = 332.1>
  <EMI ID = 333.1>
 Notes for Table 6

  
1 Additional treatment was used, as follows:

  
  <EMI ID = 334.1>

  
the pH of the total aqueous phase was brought to 10 with

  
  <EMI ID = 335.1>

  
ether. The extract was then washed, dried and evaporated to give a residue which was subjected to purification.

  
2 Sodium borohydride (0.05 g) was added after

  
18 hours.

  
3 Sodium borohydride (0.01 g) was added after

  
22 hours.

  
  <EMI ID = 336.1>

  
5 Sodium borohydride (0.15 g) was added after

  
45 hours.

Example 26

  
  <EMI ID = 337.1>

  
A solution of the product of the example was heated

  
  <EMI ID = 338.1>

  
1 [deg.] Concentrated sulfuric acid (4 ml) for 24 hours.

  
The pH of the cooled mixture was brought to 9 with a solution

  
  <EMI ID = 339.1>

  
  <EMI ID = 340.1>

  
leaving an oil which has been purified by thin layer chromatography of preparation using a mixture of chloroform and methanol (9: 1). so as to obtain the compound indicated in the title (0.612 g)

  
  <EMI ID = 341.1>

  
A solution of the product of example B1 was stirred

  
  <EMI ID = 342.1>

  
concentrated sulfuric acid (2 si) for 18 hours.

  
  <EMI ID = 343.1>

  
Bromine (0.44 ml) was added to a stirred solution of sodium hydroxide (1.24 g) in water (8 ml)

  
  <EMI ID = 344.1>

  
3 hours. Sodium metabisulfite (2 g) was added and after 10 minutes the mixture was diluted to 20 ° -au

  
  <EMI ID = 345.1>

  
so as to leave a solid which was dissolved in methanol (30 ml) and the solution was heated to

  
  <EMI ID = 346.1>

  
  <EMI ID = 347.1>

  
  <EMI ID = 348.1>

  
extract the precipitate with ether (x3) and the extract was washed

  
  <EMI ID = 349.1>

  
leave an oil which has been purified by column chromatography, eluting

  
  <EMI ID = 350.1>

  
collecting an oil which has been crystallized from acetonitrile, so as to obtain the indicated compound

  
  <EMI ID = 351.1>

  
  <EMI ID = 352.1>

  
pyridine (10 mg) and the mixture was stirred for 72 hours.

  
The mixture was filtered and the filtrate was evaporated so

  
to get a foam. This product was purified by chroma-

  
  <EMI ID = 353.1>

  
  <EMI ID = 354.1>

  
  <EMI ID = 355.1>

  
  <EMI ID = 356.1>

  
  <EMI ID = 357.1>

  
washed the extract with water, dried and evaporated so as to collect an oil (70 mg) which 3. $ on 3 crystallized

  
  <EMI ID = 358.1>

  
  <EMI ID = 359.1>

  
  <EMI ID = 360.1>

  
A solution of diazomethane in ether was added to a solution of the product of Example A17 (550 mg) in ether (20 ml) and tetrahydrofuran (20 ml).

  
  <EMI ID = 361.1>

  
(2 drops) and the pH of the mixture was brought to 10 with a <EMI ID = 362.1>

  
The organic phase was washed with water and the total aqueous phase was extracted with ether. The total organic phase was washed with water, dried and evaporated

  
so as to obtain an oil which has been purified by column chromatography, proceeding to the elution

  
  <EMI ID = 363.1>

  
crystallized the product from acetonitrile so as to collect the compound indicated in the title (57 mg),

  
  <EMI ID = 364.1>

  
  <EMI ID = 365.1>

  
solution of the product of Example A17 (500 mg) in methanol (20 ml) and the mixture was heated to reflux

  
  <EMI ID = 366.1>

  
  <EMI ID = 367.1>

  
  <EMI ID = 368.1>

  
(x3) and the extract was washed with water, dried and evaporated so as to leave an oil which crystallized in acetonitrile so as to give the title compound (245 mg ), PF 123-125 [deg.] C,

  
  <EMI ID = 369.1>

  
boron (0.2 ml) to a suspension of 2-intermediate 17
(354 mg) in methanol (5 ml). The mixture was stirred for 1.75 hours, diluted with 5% NaHCO solution, and extracted with ether (x3). We washed

  
  <EMI ID = 370.1>

  
leave a foam which has been purified by thin layer chromatography of preparation in a

  
  <EMI ID = 371.1>

  
a foam which crystallized from acetonitrile, so as to collect the compound indicated in the title

  
  <EMI ID = 372.1>

  
  <EMI ID = 373.1>

  
formic acid (0.11 ml) and intermediate 32 (432 mg) in dry tetrahydrofuran (10 ml). The mixture was allowed to stand for 20 hours, brought to an alacaline pH

  
  <EMI ID = 374.1>

  
ethyl acetate (x3). We washed the extract with water,

  
  <EMI ID = 375.1>

  
a solid which has been partially purified by thin layer chromatography of preparation in a mixture

  
  <EMI ID = 376.1>

  
This oil was dissolved in ethyl acetate and the solution was extracted with 2M HCl solution (x3)

  
  <EMI ID = 377.1>

  
with ethyl acetate (x4). The extract was dried and evaporated to leave a foam which was purified by thin layer chromatography

  
  <EMI ID = 378.1>

  
so as to obtain the compound indicated in the title

  
  <EMI ID = 379.1>

  
We brought the reagent of the chloriridic acid type
(16 ml) at pH 7 with triethylamine and intermediate 34 (860 mg) was dissolved therein. The solution was heated to reflux for 27 hours, cooled

  
  <EMI ID = 380.1>

  
0.88. Water (30 µl) was added and the

  
  <EMI ID = 381.1>

  
extracted with water, it was dried and evaporated so as to <EMI ID = 382.1>

  
thin film writing of preparation in a mixture

  
  <EMI ID = 383.1>

  
  <EMI ID = 384.1>

  
Examples 36-62

  
Table 7 summarizes the preparation of hydrochlorides.

  
A solution of hydrochloric acid in water was added to the base or to a suspension of the base

  
  <EMI ID = 385.1>

  
mixing until a clear solution is obtained

  
  <EMI ID = 386.1>

  
mix to appropriate volume or weight with water and filter and collect any undissolved base, dry and weighed to determine the concentrations of the solution. The pH was measured.

  

  <EMI ID = 387.1>


  

  <EMI ID = 388.1>
 

  

  <EMI ID = 389.1>


  

  <EMI ID = 390.1>
 

  
Examples 65-67

  
Table 8 summarizes the preparation, salts of

  
  <EMI ID = 391.1>

  
The appropriate acid was added to a suspension of the free base (50 mg) in water (4 ml) and stirred

  
  <EMI ID = 392.1>

  
  <EMI ID = 393.1>

  
  <EMI ID = 394.1>

  
  <EMI ID = 395.1>

  
TABLE 8

  

  <EMI ID = 396.1>


  
The following examples illustrate pharmaceutical compositions of compounds according to the invention. EXAMPLE A

  
  <EMI ID = 397.1>

  

  <EMI ID = 398.1>


  
We pass the steroid and corn starch

  
through a 40 mesh screen. The corn starch is mixed with the steroid in a suitable mixer. A 5-10% w / v aqueous solution of the polyvinylpyrrolidone is prepared.

  
This solution is added to the powder during mixing

  
  <EMI ID = 399.1>

  
  <EMI ID = 400.1>

  
  <EMI ID = 401.1>

  
  <EMI ID = 402.1>

  
  <EMI ID = 403.1>

  
sodium and magnesium stearate previously passed

  
through a 60 mesh screen We compress in a machine

  
  <EMI ID = 404.1>

  
suitable lessons.

EXAMPLE B

  
  <EMI ID = 405.1>

  

  <EMI ID = 406.1>


  
The steroid and microcrystalline cellulose are passed through a 40 mesh screen. The sodium starch glycolate and the magnesium stearate are screened through a 60 mesh screen. The powders are mixed in a suitable mixer until homogeneous. The product is compressed in an automatic tablet press using appropriate punches.

  
The tablets produced in accordance with Example A or Example B can be coated with a thin layer of polymer applied using techniques

  
  <EMI ID = 407.1>

  
coating.

EXAMPLE C

  
  <EMI ID = 408.1>

  
  <EMI ID = 409.1>

  
methyl carboxylate, hydrochloride 54.0
  <EMI ID = 410.1>
  <EMI ID = 411.1>

  
a technique of gradual dilution with sieved excipients, in a suitable mixer. The mixture is then introduced into hard gelatin capsule shells

  
of the appropriate size using an automatic machine.

EXENPLE_D

  
Tablet - granulated at 1 {wet

  

  <EMI ID = 412.1>


  
The manufacturing process is the same as that described in 1- [deg.] Example A.

  
The tablets can be coated with a thin polymer layer applied by the usual techniques. The coating may contain a pigment.

EXAMPLE E

  
Intravenous infections

  
Ingredients:

  
  <EMI ID = 413.1>

  
methyl carboxylate, hydrochloride (equivalent to

  
1 to 10 mg of free base),

  
Sodium chloride in sufficient quantity to

  
  <EMI ID = 414.1>

  
Water for injections up to 1 ml The steroid and sodium chloride are dissolved in a small amount of water. If necessary, the pH is adjusted with a sodium hydroxide solution or a hydrochloric acid solution. It is brought to volume with water and stirred until homogeneous. The solution is filtered into clean glass vials and sealed by fusion. The solution can be sterilized by autoclaving or filtration or by preparation under aseptic conditions.

CLAIMS

  
1. Compounds corresponding to the general formula as follows:

  

  <EMI ID = 415.1>


  
(in which :

  
.

  
  <EMI ID = 416.1>

  
C3-C7 cycloalkyl,

  
  <EMI ID = 417.1>

  
  <EMI ID = 418.1>

  
  <EMI ID = 419.1>

  
  <EMI ID = 420.1>

  
  <EMI ID = 421.1>

  
with the condition that when the compounds contain

  
  <EMI ID = 422.1>

  
as well as: D-homo analogs of these compounds

  
  <EMI ID = 423.1>

  
  <EMI ID = 424.1>

  
the acid addition salts of the compounds in question.


    

Claims (1)

2. Compounds according to claim 1, <EMI ID = 425.1> R represents an isopentyl, hexyl, isohexyl group,  <EMI ID = 426.1>  <EMI ID = 427.1>  <EMI ID = 428.1> a hydrogen atom 5a and in that the nucleus D contains 5 links. 3. Compounds according to any one of claims 1 and 2, characterized in that they appear in the form of physiologically acceptable acid addition salts. 4. Compounds according to claim 3, characterized in that they are in the form of hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, tartrates, acetates, ascorbates, lactates, maleates,  <EMI ID = 429.1> 9. Compounds according to any one of claims 5 to 8, characterized in that they are in the form of their hydrochlorides. 10. Pharmaceutical compositions, characterized in that they comprise at least one compound of formula (I) according to claim 1, or one of its physiologically acceptable acid addition salts, as a mixture with one or more pharmaceutical vehicles or excipients.  <EMI ID = 430.1> formula (I) as defined in claim 1, characterized in that: (A) reacting a compound of the 11a-amino type corresponding to <EMI ID = 431.1> corresponding, on a compound of the formula R <1> X in which R has the meanings indicated in claim 1 and X represents an easily displaceable group or atom, <EMI ID = 432.1>  <EMI ID = 433.1>  <EMI ID = 434.1>  <EMI ID = 435.1> claim 1, other than hydrogen, and then,  <EMI ID = 436.1> deprotonated hydroxyl, the product obtained is treated with a proton source, <EMI ID = 437.1> laying, in the presence of a reducing agent, on a monocarbonyl compound used to introduce the group R \ (D) (when it is desired to obtain a 20-unsubstituted compound) a compound of the corresponding 3-oxo type is reduced, <EMI ID = 438.1> corresponding disubstituted into an N-monosubstituted compound,  <EMI ID = 439.1> (H) a corresponding compound is transesterified having  <EMI ID = 440.1> (as defined in claim 1) with a  <EMI ID = 441.1> or (J) a corresponding compound having a  <EMI ID = 442.1> followed, when necessary, by the formation of acid addition salts. 12. Composed of the following general formula:  <EMI ID = 443.1>   <EMI ID = 444.1>  <EMI ID = 445.1>  <EMI ID = 446.1>  <EMI ID = 447.1> as well as the D-homo analogs of these compounds comprising  <EMI ID = 448.1> salts and their amphionic forms. 13. Method of prophylaxis applied to a human being or an animal suffering from or likely to suffer from cardiac dysrhythmias, characterized in that one  <EMI ID = 449.1> effective amount of one or more of the compounds according to any of claims 1 to 9.  <EMI ID = 450.1> as claims 1 to 9 for therapy or pro-  <EMI ID = 451.1> or in an animal.