FR2485020A1 - 11A-AMINO, 4 OR 5 PREGNANES AND ANDROSTANES - Google Patents

Abstract

STEROID OF FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS AN -NHR GROUP, IN WHICH R IS A HYDROGEN ATOM OR A CC ALKYL GROUP, CC BENZYL OR PHENETHYL CYCLOALKYL OR A CC ALKENYL GROUP HAVING ONE OR TWO DOUBLE BONDS AND IN WHICH THE CARBON ATOM ADJACENT TO NITROGEN OF THE -NHR GROUP IS SATURATED, AND THE DIFFERENT OTHER SUBSTITUTES HAVE THE MISCELLANEOUS MEANINGS SPECIFIED IN THE APPLICATION.

Description

t ;. The present invention relates to steroids

anesthesia s.

  Many steroids are known to possess anesthetic activity, mainly the 3a-hydroxy 5a or A 17a-non-substituted compounds. 20-oxo-pregnans and androstanes, the compounds

  more advantageous frequently having an 11-oxo group.

  These substances are, for the most part, insufficiently

  soluble in water and it was necessary to incorporate them

  for administration purposes to aqueous solutions

  parenterally acceptable nonionic surfactants

  tables, as described, for example, in the patent

  No. 1,317,184 concerning the important anesthetic

  What is 3α-hydroxy-5-pregnane-11,20-dione. We know

  also anesthetic steroids that have

  water solubilizers at various positions of the sterol

  of, for example, in position 25 or 3 "or in position 21 in a pregnane or in 17P position in an androstane, but the introduction of the water-solubilising group has frequently

  entrained a loss of activity or stability.

  The Applicant has now discovered an extremely interesting anesthetic activity in a group of 3α-hydroxy 5β-, 5β- or A4 or A5 pregnanes and androstanes and

  their analogous D-homo having an amino group,

  2.5 tituated by aliphatic or araliphatic radicals, or

  a heterocyclic amino group at position 11, in particular

  bind in the water-soluble salts of these compounds with acids.

  The present invention is therefore more particularly

  especially for stoarids corresponding to the following general structure formula:

R8 R10

R4 _ R7

R4 A.I

HO ---

R5 R6

R6

4-.2 2485020

  in which: R1 represents a group -NRaRD where Ra and Rb (which may be identical or different) represent C1-C6 alkenyl radicals, C6-C6 alkenyl radicals or cycloalkyl groups (with the proviso that R and Rb together contain from 2 to 7 carbon atoms and that when Ra and / or Rb represent an alkenyl group, the carbon atom (s) adjacent to the nitrogen atom in the -NRaRb group is or are saturated), or one of the

  symbols Ra and Rb represents a benzyl or phenolic group

  the other of these symbols representing a group

  thyle, or Ra and Rb (together with the nitrogen atom)

  represent an azetidino, pyrrolidino, piperidine or

  no, hexamethyleneimino or morpholino, which radicals may optionally be substituted by one or two methyl groups; R} represents a hydrogen atom or an alkyl group

C1-C5 alkyl;

  R4 represents a hydrogen atom or a C1-C5 alkyl, C1-C5 alkoxy group (which may optionally be substituted by a halogen atom, for example chlorine), benzyloxy, alkanoyl (C2-Cs) oxy thiocyanato or a halogen atom; R5 represents a hydrogen atom or a methyl group; R6 represents a hydrogen atom or a methyl group; R7 represents a hydrogen atom or (except when R8 is a group (c) as defined below) a chlorine atom; and R8 represents (a) a cyano group; (b) a group -COR9 o

  R9 represents a methyl group or such a substituent group

  killed by a fluorine atom, a C1-C4 alkoxy, hydroxy, C1-C4 alkyl, methoxymethyl, ethoxymethyl,

  alkanoyl (C1-C5) oxy, benzoyloxy, or (C2-C5) alcozy carbonyl -

  oxy, R may also represent a C1-C5 alkoxy group or a cyclopropyl group or a NRXRY group

  in which Rx and Ry (which may be the same or different

  which represent methyl or ethyl radicals; or (c) a vinyl group or together with R10 a Z-substituted methylene group wherein the substituent is a methyl or cyano radical; r), 8e R10 represents a hydrogen atom (except when R8 and R10 together represent a substituted methylene group); the dashed lines indicate the presence

  optional double bonds in the positions

  sented; with the proviso that at least one of R 3 and R 4 represents a hydrogen atom and that R 3 and R 4 together represent a hydrogen atom when a double bond is present at positions 1, 2 and that the position 2 is saturated when a double bond is present in positions 4, 5 and R 3 represents a hydrogen atom, R 4 represents a hydrogen atom or a methyl group and R 5 represents a hydrogen atom or optionally (when R 4 represents a hydrogen atom) a methyl group, when a hydrogen atom is present at the 5p position; and the analogous D-homo compounds of these compounds carrying R8 at position 17a, R10 at position 17aa and R7 at position 17; and

  the acid addition salts of the aforementioned compounds.

  During the tests carried out by the Applicant, it has been found that the compounds in accordance with the invention are generally good anesthetics, usually inducing

  quickly anesthesia after administration by the way -

  intravenous ..The water-soluble salts are especially

  important in the sense that they can be presented under the

  aqueous solutions and, in general, in comparison with

  sound of known water-soluble anesthetic steroids, -. they have superior properties with regard to the power and / or quality of the anesthesia and / or the absence

  side effects, such as thrombophle- titis.

  found that aqueous solutions of hydrosolu-

  in general were very stable. The compounds according to the invention can be used to induce -anesthesia

  which must be maintained, for example, by anesthetic.

  inhalation, such as ether, halothane, nitrous oxide or trichlorethylene. The compounds may also be capable of maintaining anesthesia to a degree sufficient to permit the performance of surgical procedures without the aid of an inhalation anesthetic, where the anesthesia is maintained as required by repeated or continuous administration.

- '2485020

  steroid according to the invention. The compounds may have other depressive activities of interest on

  the central nervous system, for example, we can use them

to sedate.

  As indicated above, the symbols Pa and R may represent C1-C6 alyl groups which may be straight-chained or branched-chain, such as methyl, ethyl, propyl, iso-propyl or butyl radicals. n-butyl, pentyl, iso-pentyl and 1,3-dimethylbutyl,

  or C3-C6 alkenyl groups, such as an allyl group.

  When Ra or represents a cycloalkyl group, this can

  be, for example, a cyclopentyl or cycloheiyl radical.

  Loisque one of the symbols Ra and Rb represents a

  C3-C6 alkenyl group, the latter does not contain, preferably

  only one double bond, as is the case, for example, of one allyl group and the other

  preferably an alkyl radical, for example a methyl radical.

  When -NRaRb represents a hetero, erocyclic group,

  it can be, preferably, a pyrrolidino group.

  Preferably, one of the symbols Ra and Rb represents a methyl group, while the other represents a methyl, ethyl, propyl, isopropyl or butyl group. Particularly preferred compounds are Raet Rb

  represent methyl radicals.

  When a substituent 2a (R3) is present, the latter

  is preferably a methyl radical.

  When R6 represents a methyl group, the position

6 is preferably saturated.

  The compounds of the 5a series which have a

  2p (R 4) are particularly important, examples of such substituents being methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetoxy and the like.

  thiocyanato or the atoms of chlorine, bromine and fluorine.

  Compounds of the 5α and 5β-hydrogeno series are generally preferred, as are the compounds in which

  the tetracyclic steroid system is saturated and in

  R6 and R7 are both hydrogen;

  R5 is also preferably a hydrogen atom.

  When the steroid nuclei are not saturated, it is preferred to

the compounds A '.

  A group of compounds according to the invention is

  formed by the substances in which Ra and Rb represent

  other substituents than benzyl radicals or phle-

  néthyle; R represents another substituent that the group -COR9 o R9 represents a methyl group substituted with a

  C2-C4 alkyl radical and in which R3, R4 and R5

  all have hydrogen atoms when the atom

  hydrogen is present in position 5 ,.

  A preferred group of compounds is that formed by the substances which correspond to the formula R 1 R 10 R 3 R 13 R 43

H0 (IL)

in which:

  R1 represents a group -NRaRb in which!

  symbols Ra and Rb represent a methyl group, the other of these symbols represents a methyl, ethyl, propyl, isopropyl, butyl or allyl group, or in which the two symbols Ra or R represent ethyl groups,

  or in which Raet Rb (together with the nitrogen atom)

  have a pyrrolidino group; R3 represents a hydrogen atom or a methyl group; R4 represents a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom; R8 represents (a) a cyano group; (b) a -COR9 group wherein R9 represents a methyl radical or such a radical substituted by a methyl, hydroxy or acetoxy group, or R represents a cyclopropyl group, or

2485020

  (c) a phenyl group or R8 together with R10 forms a 2-ethylidene group; and -R is a hydrogen atom (except when R 8 and R 1 together represent an ethylidene group); dashed lines indicate the optional presence of a double bond in positions 1, 2; with the condition that at least one of the symbols

  R 3 and R represent a hydrogen atom, that R 3 and R 4 represent

  together they sense a hydrogen atom when a double bond is present in positions 1, 2 and R 3 represents a hydrogen atom and R 4 represents a hydrogen atom or a methyl group when a hydrogen atom is present in position 5p;

  as well as D-homo analogues carrying R8 in posi-

  17a $ and R10 in position 17au; as well as the acid addition salts of the aforementioned compounds. R8 preferably represents a cyano group or a -COR9 group in which R9 represents a methyl group (optionally substituted by a hydroxyl, methyl or acetoxy group) or a cyclopropyl group;

preferably, saturated.

  In the compounds of formulas (I) and (II), R8

had 4

  preferably has an acetyl or cyano group, R

  preferably present a hydrogen atom when a hydrogen atom is present in the 5P position, or R4

  represents a hydrogen atom or an alkoxy group,

  is an ethoxy group, when a hydrogen atom is present in position 5a and R3 is preferably a hydrogen atom. It is particularly advantageous

  that R is an acetyl group, that the ring D has 5 chai

  nQns and that the group -iRaR is a diethylamino group.

  The most advantageous substances are represented by

the compounds 5a.

  As indicated above, the ability of bases according to the invention to form addition salts

  of water-soluble acids is particularly important.

  In this way, comoosés according to the invention, in the form of their bases, can be simply introduced

rf 8: 2485020-

in an aqueous acid solution.

  Examples of suitable salts are: hydrochlorides, hydrobromides, phosphates, sulphates, D-toluenesulfonates, methanesulphonates, citrates, tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, glutarates, aconitates, citraconates, mesaconates, salicylates and glutaconates. We particularly prefer

  citrates- and hydrochlorides for use in anesthesia.

  When salts are used as anesthetics, they must be physiologically acceptable at doses

  o they are administered. Other salts may, however, be used

  for example, for the isolation of the product from its environment

of synthesis.

  Preferred compounds are: 11α-N, N-dimethylamino-3α-hydroxy-5α-pregnane-20-one;

  11α-N, N-dimethylamino-2-ethoxy-33α-hydroxy-5c-pregnane

-one;

  3. 1-N, N-dimethylamino-3cc-hydroxy-2B-methyl-5c-pregnane

-one;

  4. 11 1-N, N-dimethylamino-3cc-hydroxy-2α-methyl-5α-tetanus

  -one; 5. N-N, N-dimethylamino-3α-hydroxy-5-pregnan-20-one;

  6. 11-N, N -dimethylamino-3-c-hydroxy-5α-androstane-17β-

  carbonitrile; 7. 11-N-butyl-N-methylamino-3α-hydroxy-5α-pregnan-20one;

  8. 2β-Chloro-11α-N, N-dimethylamino-3α-hydroxy-5'-pregnan

-one;

  9. 11-N, N-dimethylamino-2β-fluoro-3-hydroxy-5α-pregnane

-one;

  10. 1α-N, N-dimethylamino-3α-hydroxy-23-methoxy-5-pregnanane

-one;

  11. 2-ethoxy-1-ca-N-ethyl-N-methylamino-3ac-hydroxy-5x-pregnan

  -one; 12. 11-N-ethyl-N-methylamino-3α-hydroxy-5x-pregnan-20-one; 13. 3α-hydroxy-1α-N-methyl-N-propylamino-5x-pregnan-20-one;

  14. 11-N-ethyl-N-methylamino-3ac-hydroxy-2-methoxy-5cc-pre-

gnane-20-one;

  3α-hydroxy-1α-N-iso-propyl-N-methylamino-23-methoxy-5 "-

pregnane-20 -one;

  16. 11-C-N-allyl-N-methylamino-2β-e-thoxy-β-hydroxy-5: -

prégrnane-20-one;

  17. 2B-Ethoxy-3cc-hydroxy-11 -pryrolidino-5 "-prygnane-

  -one; 18. 1α-N, N-dimethylamino-3α-hydroxy-2-ylpropyloxy-5-hexregnan-20-one;

  19. 11-N, N-dimethyl-1-eno-3cc-hydroxyl-2B-L-5-pox-5a

pregnan-20-one;

  20. 2-acetoxy-1 1, N, N, N-dimethylamino-3-hydroxy-5 "-

pregnan-20-one;

  21. 23-Actox: y-1 1xc-N-ethanyl-T-methyl-n-3-c-hydroxy

a-pregnan-20-one;

  22. 2β-acetoxy-3α-hydroxy-11-α-N-iso-propyl-N-methyl-

Anino-5a-pregnan-20-one;

  23. 1 1 α-N-ethyl-N-methylaino-23-fluoro-3α-hydroxy

cc-pregnan-20-one;

  24. 2-Fluoro-3α-hydroxy-1α-N-iso-propyl-N-1-methyl-

amino-5a-pregnan-20-one;

  25. 2-chloro-11α-ethyl-N-methylamino-3α-hydroxy-

5ac-pregnane-20-one;

  26. 2 8-Chloro-3-hydroxy-1-N-i-n-propyl-T-methyl

amino-5a-pregnan-20-one;

  27. 2'2-bromo-1H-α-N, -dimethylamino-3c-hydroxy-5c-

pregnan-20-one;

  28. 11-N, -dimethylamino-3c-hydroxy-2-thiocyanato

a-pregnan-20-one;

  29. 11α-N, N-dimethylamino-3α-hydroxy-5x-pregn-1-ene

-one;

  30. 11C-N, N-dimethylamino-3α-hydroxy-D-homo-5α

pregnan-20-one;

  31. 11-N, N-dimethylamino-2-ethoxy-3-hydroxy-D-

5c-homo-pregna-ne-20-one;

  32. 11-W, N-dimethylamino-21,21-4thylene-3-y'ldroxy-

a-pregnan ane-20-one;

  33 to 1 Ic-N, N-dimethylamino-3-hydroxy-21-methyl-5α

pregnan-20-one;

  34. 11α-N, N-dimethylamino-2β-ethoxy-3-hydroxy-21-

  'AT. methyl-5m-pre-20-one; - '

  35. 21-Acetoxy-1-W, N-dimethylamino-2-ethoxy-3c-

  5c-hydroxy-pregnan-20-one; 36α-N, N-dithylamino-3α-hydroxy-5g-pregnan-20-one;

  37. 3α-hydroxyl-1-s-propyl-N-methylamino-55-pregnan

-one;

  38. 1α-N-ethyl-N-methylamino-3α-hydroxy-5-pregnan-20-

  one; 39. 3α, 21-dihydroxy-11α-N, N-dimethylamino-55-pregnan-20-one;

  40. 21-acetoxy-1-N, N-dimethylamino-3α-hydroxy-5-pregnan

-one;

  41. 11α-N, N -dimethylamino-53α-hydroxy-51-androstane-17β-

carbonitrile;

  42. 11x-N, N-dimethylamino-20-ethoxy-3α-hydroxy-5α-andro-stannic acid

17-carbonitrile;

  43. (2) -1α-N, N-dimethylamino-3α-hydroxy-5α-preEn-17 (20) -

ene;

  44. 11α-Dimethylamino-2-ethoxy-3α-hydroxy-5α-androstane

  44., 11-N, methyl 17 P-carboxylate; 45. 11 N, N-dimethylamino-3-hydroxy-5a-pregn-20 (21) -ene;

  46. 2p-Butoxy-1α-N, N-dimethylamino-3α-hydroxy-5α-pregnan

-one;

  47. 1-ccN, N-dimethylamino-21-ethoxy-3α-hydroxy-21-propyl-5-

  pregnan-20-one; as well as physiologically acceptable water-soluble salts

aforementioned compounds.

  All the above-mentioned compounds showed a

  good activity during tests, in the form of their

  trates, in aqueous solutions (sometimes in the presence of sodium and chloride ions). There has also been evidence of

  good activity during tests carried out with tricar-

  ballylate, the hydrochloride, the phosphate and the methanesulphonate of compound No. 1; acetate, methanesulfonate, lactate, phosphate, tartrate, tricarballylate, hydrochloride, succinate, citraconate, aconitate and mecaconate of compound No. 2; acetate, hydrochloride, tartrate, lactate, tricarballylate, phosphate, methanesulfonate

  and the succinate of Compound No. 5; and the acetate of compound No. 10.

  Of the above-mentioned compounds, Compounds Nos. 1, 2, 6, 8, 9, 31, 36-38, 41 and 42 and their salts are all

particularly advantageous.

- Z485020

  The compound Ho 5 and its physiologically acceptable water-soluble salts (in particular the hydrochloride and the citrate) are particularly preferred. Compound No. 2 and its physiologically acceptable water-soluble salts (in particular hydrochloride and citrate) are the most promising.

  Convenient compounds can be conveniently incorporated into

  my invention to pharmaceutical compositions (both human and veterinary) by implementation of recipes

  generally known pharmaceutical products, using one or more

  any excipients or pharmaceutical vehicles. For purposes

  anesthetics, steroids can be administered by injection

  tion and, therefore, one of the characteristics of the pre-

  This invention resides in compositions suitable for

  parenteral administration, including one or more

  poses according to the invention in a parenteral vehicle-

acceptable.

  When the compounds (eg salts) are sufficiently soluble in water they can be

  aqueous vehicles for injection. The preparation of

  By placing the free bases in solution in an aqueous acid, the following is described hereinafter. For the induction of anesthesia, these solutions usually contain from 0.1 to 4.0% w / v, conveniently 0.2 to 2% w / v, of the active compound, but it is quite obvious

  that more concentrated solutions can be

  of the most soluble salts. If desired, the free base and the acid necessary for forming the salt can be packaged separately in a two-component package for the production of the composition when the latter is needed. The steroid salt and the aqueous injection vehicle can be further packaged separately in a

two-component packaging.

  Although it is preferred to present the compounds

  To the invention, in the form of simple aqueous solutions of their salts, the free bases or salts may also be incorporated into an aqueous composition of a parenterally acceptable nonionic surfactant,

  same way and using the same proportions of

  than those described in British Patent Specification No. 2485020

  No. 1317184 concerning 3α-hydroxy-5α-pregnane-11,20-dione.

  Simple aqueous solutions have the advantage, for example, of avoiding the appearance of anaphylactic shock in subjects

  sensitive to surfactants. We can adjust the tone of the

  aqueous solutions, for example, with sodium chloride. The anesthetic solutions according to the invention are generally administered by intravenous injection, although in some cases (for example in children or

  animals), intramuscular injection may be preferred.

  Aqueous solutions can also be administered

  simple salts subcutaneously. Hydrochlorides

  come particularly well to intramuscular injection. As is common in the case of anesthetics,

  the amount of sterode used to induce the anesthesia de-

  hangs from the weight of the individual to anesthetize. During the administration

intravenous treatment to the average man, we have

  that a dose of 0.1 to 8.0 mg / kg was generally satisfactory.

  fraction to induce anesthesia, the preferred dose ranging from -0.2 to 4.0 mg / kg. The dose in question may naturally vary to a certain extent, depending on the physical state of the

  patient and the desired degree and period of anesthesia.

  If it is desirable to maintain anesthesia

  long-term, repeated doses of the aforementioned solutions may be used, such repeated doses being generally of the same order of magnitude or less than the original dose. Continuous administration can also be performed using solutions containing 0.01 to 0.4% w / v, preferably 0.02 to 0.2% w / v, of the active compound at the rate of, for example, 0.0125 to 0.2 (e.g., 0.025 to 0.1) mg / kg / min. One can also practice a continuous administration to produce

  sedation for prolonged periods of time.

  When administering anesthetic solutions

  by the intramuscular or subcutaneous route, it is clearly

  that higher doses are usually needed.

  The compounds according to the invention can be prepared according to several different processes, by the use of

technical skills

  generally known techniques. Appropriate methods are

described below.

ç. r -

-2485020

  1. Conversion of an unsubstituted or mono-substituted 11-amine

  substituted in a disubstituted amine.

  This reaction can be carried out by reacting a corresponding compound of the formula (I) in which one or both of the symbols Ra and Rb represent hydrogen atoms.

  gene, on a compound of the formula RaX in which X represents

  a readily displaceable group, such as a halogen

  Nure (e.g. iodide), hydrocarbylsulfoxyloxy (e.g., toluene-p-sulfonyloxy), hydrocarbyloxysulfonyloxy

  (eg methoxysulfonyl) or a dialkoxysulfonyl group

  oxy (for example, dimethoxyphosphonyloxy). The reaction is

  preferably in the presence of a base (e.g.

  potassium bonate or silver oxide), in solution, at any suitable temperature varying from room temperature

  at reflux temperature, conveniently at ambient temperature.

  you. Excess of the RaX compound, eg, methyl iodide, can be used as a solvent for the reaction, but

  There are many other solvents, such as hydro-

  halogenated carbon (eg methylene chloride),

  alkanols (eg ethanol or methanol) or acetonitrile

Trile.

  When using a N-mono starting material

  substituted, the reaction can produce N, N-disubstituted

  according to the invention in which Ra and Rb represent

  try identical or different substituents.

  N-monosubstituted starting materials can be prepared in a similar manner by reacting a compound of formula I wherein Ra and Rb are both hydrogen atoms, on a compound of the formula RaX such that

described above.

  Compounds in which -NRaRb represents a heterocyclic amino group may also be prepared

  by carrying out this process, by using a reaction

  tif of the formula X-Ra-Rb-X in which X has the meanings

  above-mentioned cations (for example, a 2,2'-dihaloethyl ether

  or a dihaloalkane, such as 1,4-diiodobutane).

  When a 20-oxo group is present in the starting material, the latter may be protected in the manner described

  below, in the form of a 20-ketal group. Such a pro-

  is not necessary during the N-subsystem reaction.

* r

  tion, but a 20-ketal group is often present by following

  the implementation of the previous stages of the operation

  of preparation. Isolation of the product from the reaction of N-

  substitution frequently involves the presence of acidic conditions which also serve to regenerate the desired 20-oxo-group. The starting materials of the 11a-amino type necessary for carrying out this reaction may, for example, be

  prepare by stereo- selectively reducing the corresponding 11-oxime

  ponding. This reduction can be carried out using a reducing agent of the alkali metal or alkaline earth metal type in an alcohol and / or an amine and / or ammonia, for example sodium in n-propanol, if desired, in the presence of a suitable solvent, for example, tetrahydrofuran, at any suitable temperature up to and,

  preferably, the reflux temperature.

  The 11-oximes can themselves be prepared from the corresponding 11-oxo compounds in which the 20-oxo group (if present) is protected, for example, as a ketal group. The 11-oxo compound may, for example, be preacted on hydroxylamine, under strongly alkaline conditions, in an aqueous alcohol (eg ethanol), preferably at room temperature.

  reflux. When other oxo groups are absent, we can

  read the reaction under acidic conditions (pH about 4), for example, in buffered pyridine; the severe conditions used to carry out the reduction of 11-oxime make it necessary or desirable the introduction of certain

  optional substituents after the formation of the 11-a-group

  amino, which may be mentioned as examples the radicals 173-cyano and alkoxycarbonyl, 21-alkanoyloxy and -halo, 2-halo,

  -alkanoyloxy and -thiocyanato, and 16a-chloro. During the introduction

  some of these substitutes (by

  hereinafter, for example, by carrying out acylation or esterification reactions) it may be desirable to protect the 1-amino group,

  for this purpose, methods of protecting amine

  for example, an acylation (for example with trifluoroacetic acid or formic acid or a reactive derivative thereof) or by silylation.

2485.020

  2. An appropriate sterile 11x-acylamino can be reduced

  that is to say in which one of the symbols Ra and Rb possesses

  of the aforementioned meanings and the other represents a group, acyl), for example, using aluminum hydride aluainiun in an ether-type solvent (for example tetrahydrouran or dimethoxyethane) to any appropriate temperature up to the reflux temperature. The starting material may have a 20-ketal group which is then to be converted to a 20-oxo group or a 3a-esterified hydroxy group which is then converted to a 3-hydroxy group during the reaction.

implementation of the reaction.

  The starting materials of the type can be prepared

  acylamino by acylation of a compound of the type 11i-amino monosub-

  (or a derivative of the 20-ketal or 20-hydroxy type thereof

  ci), for example, with the appropriate carboxylic acid (or a reactive derivative thereof, for example, an acid halide, an ester or an anhydride), if desired, in the presence of a acids (for example, pyridine). The 3x-hydroxy group and any other hydroxy group present will be acylated during this reaction and, if desired,

  can be regenerated by treatment with a base before

  yield to the reduction; if a 20-hydroxy group is present, the acylamino intermediate can be further oxidized and

  ketalized to form the desired protected 20-oxo group.

  If the 11a-acylamino compound has a 3-oxo group

  this can then be reduced to form the group

3x-hydroxy desired.

  3. Opening of a desired 2a, 3a-epoxy.

  This reaction can be used to prepare saturated ring A 5a-2psubstituted compounds and it is preferred to prepare the 23-halo, alkoxy, alkanoyloxy and thiocyanato compounds. This method of general preparation of the compounds of the type 2P by this route is described in the British patent

  No. 1,376,892. Thus, in general, the reaction includes the treatment of

  corresponding 2a, 3a-epoxide by a compound of the formula

  ER, under acidic conditions (if necessary in the presence of a

  additional acidic catalyst, for example, sulfuric acid,

  perchloric acid or boron trifluoride) or with a

  which generates the anion (R4) (o R4 possesses the

  mentioned above, other than hydrogen) and then treating 1i5. O2485020 (when the initial product has a 3a-hydroxy group

  deprotonated) produced by a source of protons (eg

  aqueous ammonium chloride), so as to generate the 3-hydroxy group. Examples of reagents of the HR type include alcohols, carboxylic acids, thiocyanic acid and hydrogen halides (F

  can be used in the form of an HF-urea complex,

  demented in the absence of a solvent); examples of reactions

  which generate anions (R4) - include alkyl-metals, such as lithium dimethylcuprate, -the

  alkali metal or ammonium salts of the acids of the

  HR4 mule and alkali metal alkoxides. The reaction is preferably carried out under anhydrous conditions in a suitable solvent (for example a hydrocarbon or an ether) at any suitable temperature ranging from

  up to the reflux temperature. The compounds of the type 28-

  halo and thiocyanato can also be prepared in

aqueous media.

  The starting materials necessary for the realization

  of this reaction may, for example, be prepared

  by first introducing the 11-amino-substituted group

  (for example, by carrying out the process described in the above-mentioned reaction 1), using a Type 36 starting material, then forming a salt (for example with toluene-p-sulfonic acid) and epoxidizing then

  the compound of type A2 with a peracid and regenerating

  nally the free base. A2 compounds can be prepared by formation of 3-methanesulfonate and removal

  subsequent methanesulfonic acid.

  4. A corresponding substituted 11-amino or 11-amino compound (or a -cetal of such a compound) can be alkylated with a suitable mono- or dicarbonyl compound in the presence of a reducing agent. For example,

  with compounds of the 11a-amino type, the use of

  mono-carbonyls, such as formaldehyde or acetal-

  dehyde, can provide the 11α-dimethyl or -diethylamines, while a dicarbonyl compound can provide the compound in which -NRaRb represents a heterocyclic amino group (for example, glutardialdehyde can be used for

  form a piperidino group). When using a subset

  lb t-. Starting from 11-N-mono-substituted, a mono-carbonyl compound should be used. The reducing agents that can be used are those generally known for reducing

  for example, formic acid (for example,

  What is the appropriate temperature up to 100-120 ° C., for example, from ambient temperature to 100 ° C. and using the carbonyl compound as a solvent for carrying out the reaction, in the presence or absence of water),

  an alkali metal borohydride or a cyanooborohydride of

  alkali metal cyanoborohydride (e.g., sodium cyanoborohydride or borohydride, using an alcohol, such as ethanol, as a solvent, suitably at room temperature), pentacarbonyl iron or a hydrogen carbonate; alkali metal x-carbonylate (e.g., Fe (CO) 5-or 1.Fe (CO) 4) M represents sodium or potassium, at any temperature

  appropriate up to the reflux temperature, in use

  an ether, such as tetrahydrofuran or an alcohol or an aqueous alcohol, as a 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 solvent for carrying out the reaction, conveniently at room temperature), or an amalgam aluminum in the presence of water (conveniently at room temperature and in the presence of a solvent ether, such

than tetrahydrofuran).

  The metal catalyst may, for example, be a noble metal catalyst; such as platinum, platinum oxide, palladium or rhodium. The catalyst may be supported, for example, by charcoal or kieselguhr. It is also possible to use a homogeneous catalyst, such as trisphenylphosphine-rhodium chloride. If we

  If desired, the intermediate imino compound can be isolated.

  Similar 11-amino-N-mono-substituted starting materials can be prepared by reacting the corresponding amino compound on a

  ketone or an appropriate aldehyde, in the presence of a reducing agent

  as described above. Thus, for example, the use of formaldehyde, acetaldehyde or acetone, can generate 1 lx-N-methyl-, N-ethyl or IN-iso-propyl amines respectively Obtaining a compound of the type 11a-N-mono- or N, N-disubstituted depends, in part, on the proportion of ketone

or aldehyde used.

  5. The saturated N-ring unsubstituted 5-steroids 2 according to the present invention can be prepared from suitable 3-oxo compounds by sterically specific reduction, for example by the method of Bro'nme and Kirk (J. Chem., Soc., 1969, 1653) or according to the method described in British Patent No. 1,409,239. This latter method preferably uses a preformed helium-based catalyst reduction system. For example, a reduction system can be prepared from an acid of iridium or a salt thereof (for example chloriridic acid), a trivalent phosphorus compound, such as an ester phosphorous acid (for example trimethyl phosphite), water and an organic reaction medium (for example an alcohol, such as isopropanol). The reduction system is then neutralized (for example to a pH

  from 6 to 8.5) with an organic base, such as a secondary amine

  dary or tertiary (eg triethylamine) and

  then gives way to the reaction with steroids.

  If the catalyst is preformed by refluxing, for example, for 16 to 72 hours, the reduction can be carried out, for example, within 2 to 3 hours at the reflux temperature; longer times may be needed at room temperature

  6. Reduction of a compound of the 3-oxo type 53.

  The 3α-hydroxy 5β-steroids can be prepared by hydride reduction of the corresponding 3-oxo compound.

  (in which a 20-oxo group, if present, is

  protected with), for example with sodium borohydride, using an alkanol (for example, ethanol) or pyridine,

as a solvent.

  7. Inversion of derivatives of 3P-hydroxy compounds

correspondents.

  This preparation process is suitable for obtaining compounds which are unsubstituted in the 3-position and which do not have a 5,6-double bond. The starting material may be a corresponding compound having a readily displaceable 3 P group, such as a hydrocarbyl sultoinyloxy group (eg, p-toluenesulfonyloxy or mesyloxy) and the group may be displaced by hydrolysis, for example under acidic conditions) in order to generate the desired 3-hydroxy compounds. Preparation processes

4 J

  of compounds by this route are described in the patent

British No. 1,372,175.

  8. Reduction of the corresponding compound A16.

  Compounds in which R 8 represents a group (a) or (b) as defined above, may be prepared by hydrogenating the corresponding compound A 16, in the presence of a hydrogenation catalyst (for example, a palladium catalyst). ), in a suitable solvent (for example, an alcohol, an ester or an ether). The reaction can conveniently be carried out at or near room temperature.

  ambient temperature and at atmospheric pressure, in pre-

  Tertiary base, for example, triethylamine (except when a readily displaceable substituent (eg bromine) is in the 2p position and / or d: an acid, for example

example acetic acid.

  9. Hydrochlorination of the corresponding compound A6.

  Compounds of the 16-chloro type can be prepared by reacting the corresponding compound A16 with hydrochloric acid in an inert solvent (for example an ether) at a temperature of, for example, 15 to 40 ° C, in the manner of

  generally described in British Patent No. 1,380,248.

  10. Dehydration of a corresponding 178-carbamoyl compound or oxime of a corresponding 17P-formyl compound. The 17P-cyano compounds can be prepared by desiccating the appropriate oxime, for example, with

  acetic anhydride under reflux. The 3a-hydroxy group is gen-

  Esterified during the implementation of this reaction and must be regenerated by esterifications. The starting material of the oxime type necessary for carrying out this reaction can be prepared from the compound. Corresponding 17-formyl (with NH2OH) itself prepared by splitting at

  periodate of the corresponding 20,21-dihydroxy-pregnane.

  The corresponding 17P- (unsubstituted carbamoyl) compound can also be dehydrated, for example, using an ethyl polyphosphate ester, in the manner described in US Pat.

  described in British Patent No. 1,580,246.

  Esterification of a corresponding 170-carboxylic acid

laying. - -

  The 17P-alkoxycarbonyl compounds can be prepared

  by reaction of the corresponding 17 P-carboxylic acid or a reactive derivative thereof (e.g. an acid halide or an anhydride or a salt) with the appropriate alcohol or alkyl halide. preferably, this reaction at temperatures of -20 to 110 C, in the manner

  described, for example, in British Patent No. 1,380,246.

  The 17B-carboxylic acid can be conveniently formed by oxidizing the corresponding 17P-acetylated compound, using,

  for example, NaOBr in an aqueous inert solvent (e.g.

  ple, dioxane). The acids are conveniently obtained in the form of their triethylammonium salts by neutralization and addition of triethylamine, followed by extraction into a triethylammonium salt.

  appropriate solvent (eg, chloroform). We can trans-

  to form these salts into their alkali metal salts by treatment with an alkali metal alkoxide (for example, the methylate

of lithium).

  12. Reaction of the corresponding 173-carboxylic acid

on an amine.

  The compounds of the 17p- (carbamoyl) type can be prepared

  substituted) by reacting the corresponding 17 P-carboxylic acid

  or a reactive derivative thereof (for example an acid halide or an ester) to an amine of the formula

  NRRXRy in which Rx and RY have the meanings

  cited. Here again, the reaction is preferably carried out in

  presence of an acid-binding agent, generally

  described in British Patent No. 1,380,246.

  13. Acyloxylation of an unsubstituted compound in position

21 correspondent.

  The 21-alkanoyloxy and benzoyloxy compounds can be prepared by treating the unsubstituted compound in solution.

  Corresponding 21 (in which the 3 "-hydroxy group is optionally

  protected) with the appropriate lead tetraacylate, preferably

  ference, in the presence of a Lewis acid (for example, the

  boron trifluoride) in a hydrocarbon / alcohol solvent.

  The reaction in question is described in general terms in

British Patent No. 1,317,185.

  14. Displacement of an iodine atom at position 21 by a

fluorine atom.

  The 21-fluorides can be prepared from

  corresponding 21-iodine poses by treatment with a source of fluoride ions (for example, an alkali metal fluoride or silver fluoride), as generally described in the patent

No. 1,430,932.

  15. Deacylation of a compound of the 21-acyloxy type corresponding to

laying.

  The 21-hydroxy compounds can be prepared by hydrolyzing a corresponding 21-acyloxy compound.

  (for example, a 21-acetoxy compound), under

  in the manner generally described in the patent

British Patent No. 1,377,608.

  16. EEth, eradication of a 21-hydroxy compound

or 21-halo corresponding.

  The 21-alkoxy compounds can be prepared by etherifying a corresponding compound having a 21-hydroxy group or a displaceable substituent at the 21-position (e.g., a 21-halo compound, such as a 21-bromo compound ), with, for example, a suitable alkali metal, diazoalkane or alkali metal alcoholate, these processes being also generally described in the British patent

  No. 1,377,608. It is desirable to protect the group

  hydroxy during the implementation of these reactions.

  17. Acyloxylation of a substituted compound at the corresponding 21-position.

  The 21-alkanoyl compounds can be prepared

  oxy and benzoyloxy by reacting a corresponding compound having a readily displaceable substituent at position 21 (for example, a bromine, chlorine or iodine atom or a

  hydrocarbylsulfonyloxy group) on a salt of the carboxylic acid

  appropriate. This reaction is usually described in

British Patent No. 1,317,185.

  18. Acylation of the corresponding 21-alcohol.

  Compounds of the type 21 can also be prepared.

  alkanoyloxy and benzoyloxy by acylating the corresponding 21-alcohol

  this reaction is also generally described in British Pat. No. 1,317,185. The esters can be prepared

21 2485020

  of the 21-carbonate type in a similar manner using, for example, the appropriate alkyl chloroformate 19. Dehydrohalogenation of a corresponding 2P-halo compound. A1-5a compounds can be prepared by

  dehydrohalogenation of a corresponding 2-halo compound

  (preferably a 2-p-bromo compound) using

  for example, a Lewis base containing nitrogen, for example, dimethylformamide or dimethylacetamide. The starting material may comprise a protected 3-hydroxy group and the reaction is advantageously carried out in the presence of an alkali metal or alkaline earth metal halide or carbonate (for example, a mixture of calcium carbonate and lithium bromide) at a temperature of 80170 C. This reaction is described generally in

British Patent No. 1,380,248.

  For example, a 17P group can be introduced

  vinyl by partial hydrogenation of a compound of type 17 (-

  Suitable ethynyl compounds The 17P-ethynyl compounds required for this operation can themselves be prepared from a

  17 P-acetyl steroid by first forming the corresponding 20-hydrazone

  pondanite, by iodizing the hydrazone (for example, with iodine and triethylamine) and then dehydroiodising the iodide (for example, with ethanolic potassium hydroxide) o

  Compounds 17 (-ethylenic)

  by treating a suitable 21-m-thanesulfonyloxy-20-oxo steroid with toluene-p-sulphonylhydrazide and then

a base.

  21. A 17 P-vinyl group may also be introduced by treating a suitable 20, 21-epoxide with an alkali metal selenocyanate (eg, potassium), for example, in an alcoholic solvent. The epoxides of the generally described in the British patent

No. 1,377,608.

  22. A Z-ethylidene or Z-cyano-

  methylene by carrying out a Wittig reaction, by reacting a 17-oxo-steroid on, for example, an appropriate organo-ophosphorus reagent, such as (i) a methylene phosphorane

  substituted or unsubstituted (for example, triphenyl ethylidene

  phosphorane), which can be conveniently 'repaired' using a base (eg sodium hydride) in a

  solvent (such as dimethylsulfoxide or tetrahydro-

  úuranne) and a substituted or unsubstituted methylphosphonium salt

  substituted (for example, an ethyltriphenylphosphonyl

  phonium, para. bromide or chloride), or (i) a substituted methyl diakylphosphonate (e.g.

  diethyl cyanomethylphosphonate).

  23. Compounds in which Ra is methyl or cyclopropyl to a methyl group substituted with a C1-C4 alkyl radical may be prepared by reacting 17-carboxylic acid or, more preferably, a salt (e.g. of lithium or triethylamine), on the appropriate alkyl lithium (eg, using 2-4 moles of alkyl lithium per mole of the carboxylic acid or its salt). Examples of suitable solvents for carrying out the invention include ethers and hydrocarbons (for example diethyl ether and hexane); the reaction is conveniently carried out at room temperature and this is followed by protonation (e.g.

addition of water). -

  24. Decetalization of a corresponding 20-ketal As mentioned above, it is frequently necessary or desirable to protect a 20-oxo group during the preparation of the pregnanes according to the invention, for example, by ketalization. . The 20-oxo group can then

  to be regenerated as a final step in the preparation.

  The ketal is preferably the corresponding 20,20-ethylene dioxy compound and the 20-oxo group can be regenerated,

  for example, by hydrolysis, in the presence of an acid (e.g.

  hydrochloric acid, sulfuric acid or acetic acid), or by an exchange reaction with a ketone, by

  for example, acetone, in the presence of an acid catalyst, for example

  P-toluene sulfonic acid, at a varying temperature

* from 0 to 100 C.

  2-5. Deprotection of a corresponding compound possessing

a protected 3c-hydroxy group.

  This process is frequently a last necessary step in the preparation of the compliant compounds

-. 2485020

  according to the invention, in that the 3c-hydroxy group is

  either deliberately protected or brought to the esterified state

  by inversion of a 3P-hydroxy compound (for example, in

  both the 3P-alcohol with diethyl azodicarboxylate, in the presence of an acid, such as formic acid or acid

  benzoic acid and a phosphine, such as triphenylphosphine).

  The group present at position 3a in the starting materials used for carrying out this reaction may thus be an ester group, for example an alkanoyloxy group, and such esters may be hydrolysed to generate the

  desired 3a-hydroxy compounds under basic conditions.

  moderate acids. Slightly basic conditions are generally most convenient (using, for example, an alkali metal bicarbonate in aqueous methanol,

  any appropriate temperature up to the time

  reflux temperature). Mineral acids can also be used.

  diluted metals (for example, perchlorous acid in methanol

  aqueous). Strong bases can also be used (eg

  ple, the alkali metal hydroxides), if one realizes

briefly the reaction.

  The starting material used for the implementation

  of this reaction can also be a 3a-hydroxyprotect

  ge, such as 3a-ether (e.g., ether 3a-tetrahydro-

  pyrannyl) or a compound of the type III-nitro-oxyo Such groups

  protective ether can be removed by treatment with

  an aqueous ade and such nitro-oxy groups may be

  reduced by, for example, zinc and

of acetic acid.

26. Salt formation.

  The compounds according to the invention are advantageously used in the form of a salt and, consequently, the formation of a salt by reacting the base with an acid

is particularly important.

  A generally convenient method of forming the salts is to mix appropriate amounts of the

  free base and acid in a mixture of water and a sol-

  from the base (for example, an alcohol, such as ethanol), to remove the solvent (for example, by evaporation) and to

  then dissolve, if desired, the residue in water.

* - 2485020

  In some cases, solid salts can be formed by treating the free base with an acid (eg, citric acid, hydrochloric acid) in an anhydrous solvent, such as diethyl ether. In most cases, it is possible to form an aqueous solution of the salt by simply mixing the free base with an aqueous acid. If desired, one or more steroid bases may be used

and one: several acids.

  During these preparations, it is not necessary to use

  - cessation of the equivalent quantities of the base and acia. When the acid is a weak acid, it is sometimes

  desirable to use an excess of this acid. During the pre-

  Parotian of aqueous solutions, one notes, in some cases, that one can use an excess of the base, implying that the free base is dissolved to a certain extent in;

the salt solution.

  If desired, the pHi of the salt solution can

  to be subsequently adjusted by addition of a base, for example.

  sodium hydroxide and / or disodium hydrogenated citrate.

  The processes described above for preparing the comosms according to the invention can be used as

  ultimate stage of a series of preparatory reactions.

  Ation.:. The same general methods can be used to

  Introduction of the desired groups or unsaturation to -

  during an intermediate stage of the tiered training of -

  desired compound and it must be understood that these methods gen - -

  can be combined in many different ways at: - during the implementation of such stepwise processes

  as it will be clear from the examples

  Following, for example, the 11a-aminosubstituted group can be formed either before or after the reduction of a

  gro1: eg 3-oxo or double bond in position 16, 17. and-

  before or after the introduction of a substitute

  in positions 16, 17. or 21 or the formation of a double bond in positions 1,2. The rest of the reactions during the implementation of the multi-step processes must of course

  be: chosen so that the reaction conditions used

  do not affect groups of the molecule that are

in the final product.

-

  Other structural features that must

  present in the compounds according to the invention can

  may be introduced by the following processes.

  Processes are generally suitable for introducing

  substitution of 2a and 2P substituents are described

  in British Patent No. 1,380,248.

  A4-steroids can be obtained by implementation

  processes described in British Patent No. 1,372,175.

  Compounds having a group can be prepared

  alkyl or 21-substituted alkyl or a cycloalkyl group

  propyl at position 20 para. implementation of the general methods

  described in British Patent No. 1,372,175.

  Compounds having a group can be prepared

  alkyl or 21-substituted alkyl or a cycloalkyl group

  propylated at position 20 by carrying out the general processes

  described in British Patent No. 1,436,324.

  Compounds having a 6β-methyl group can be prepared by hydrogenating a 6-methyl-3-oxo-4,6-diene followed by reduction of the 6β-methyl-3-oxo compound formed, for example , using chloriridic acid in the compounds of the series 5, in the manner

described above.

  D-homo, A5 and A1,5 compounds can be prepared

  choosing starting materials from the appropriate structure

asked.

  The following examples illustrate the present invention. In these examples: the temperatures are in degrees Celcius; the melting points were determined on a Kofler bench and are indicated in uncorrected values; rotational powers were determined at room temperature on chloroform solutions (about 1% w / v), unless otherwise specified;

  Thin layer chromatography (TLC) prepa-

  ration and column chromatography (CC) were carried out

  on silica; the chlorodic acid reagent was prepared by refluxing a mixture of chlorodic acid (50 mg),

  isopropanol (94 ml), water (6 ml) and

  (24 ml) for 24 hours and adjusting the pH to 7 by

  the addition of triethylamine immediately before use.

  Methylene chloride (dichloromethane) was redistilled

  meethane) and dried; the solutions were dried, either by azeotropic distillation or by the use of magnesium sulphate or

sodium.

  Similarly, in the examples and preparations that

  following, the name of the reagents and

  frequently used, for reasons of simplicity

  city. Thus, ethyl acetate = EA; petroleum ether (B.E.

  -80 C) = PE; acetonitrile =., T; chloroform = CH; dichloro-

  methane = DM; diethyl ether = DE; dimethyl sulfoxide = OD 50; pyridine = PY; THF = tetrahydrofuran, water = 1f, benzene = B; toluene-4-sulfonic acid - PTSA; methyl acetate = .A; ethanol = AND; denatured alcohol with methanol = INS; propan-1-ol = PR; 1,2-dichloroethane = DC; dioxane = D; petroleum ether (bp 40-60 C) = PT; dimethylformamide = DPL; acetone = AC;

  methanol = E; and room temperature = RT.

  In the preparations and examples, 98-100% formic acid was used and formaldehyde was used.

  in the form of a 37-40% w / v aqueous solution.

  In the preparations the following starting materials were used: 20,20-ethylenedioxy-3α-hydroxy-5β-pregnan-11-one (1) 3xhydroxy-2β-methoxy-5α-pregnan-11,10-dione ( II) 2β-Butoxy-3α-hydroxy-5xepregnane-1,1,10-dione (III) 20-ethylenedioxy-2-,3a-epoxy-5cc-pregnan-11one (IV) 3-hydroxy-20,20-ethylenedioxy-5a -Pregnan-11-one oxime (V) 20,20-ethylenedioxyl-5α-pregn-2-en-11-one (VI) 2β-ethoxy-3α-hydroxy-5α-pregnane-11,10-dione (VII), 20-ethylenedioxy 3α-hydroxy-2α-methyl-5-pregnane-11-one (VIII), 20-ethylenedioxy-3α-hydroxy-3β-methyl-5α-pregnan-11-one (IX) 6-methylpregna-4,6-diene-5 11,20-trione (X) 35.3-hydroxy-21-methyl-5-hexane-11,20-dione (XI) 21,21-ethylene-3α-hydroxy-5-pregnane-1-1,20-dione (XII) 3α-hydroxy-21-methoxy-5α-pregnan-11,20-dione (XIII) 2'-ethoxy-3α-hydroxy-5α-pregnan-11,20-dione (XIV) 3α-hydroxy-D-homo-5O-pregnan 11,20-dione (XV) 2-thoxy-3x-hydroxy-D-homo-5-pregnan-11H-20,20-dione (XVI) -c - - Z2485020 208,21- epoxy-3α-hydroxy-5-pregnan-11-one (XYvII) -pregna-2,16-diene-11,20-dione (XVIII) 3α-hydroxy5α-androstane-11,17-dione (XIX) 3a, 20. 21-trihydroxy-5a-pregnan-11-one (XX) 20,20-ethylenedioxy-3α-hydroxy-5, -pregnane-11-one (XXI) 3α, 20,21-trihydroxy-53-pregnan-11- one (XII) Preparation 1 (Z) - 1α-Amino-5c-pregn-17 (20) -ene-3α-ol (XLI)

  A solution of (Z) -3α-hydroxy-5c-

  Pregn-17 (20) -ene-11-one oxime (9.6.58 g) in RP (200 ml) under a nitrogen atmosphere while adding sodium (9.6 g) in portions. After all the sodium had been reacted, about 90 ml of PR was distilled off and the residue was poured into water, ice was added and the crystalline solid (9.19 g) was collected. ) by filtration. A fraction of the product (6.17 g) was crystallized from ET-W to give the title compound (3.6 g), mp 118-125, -α-D + 5.4 Preparation 2 6-Methyl-5α-pregnane-3,11,20-trione (XXIII) Product X (1.7 g) was hydrogenated in EA (100 ml) at atmospheric pressure using charcoal bearing 10 g. % of palladium (Pd-c) (500 mg) serving as a catalyst. The catalyst was separated

  by filtration and the filtrate was evaporated. There crystallizes

  The residue in an AC-PE mixture gave the title compound (720 μg), mp 174-176, m.p.

Za_7D + 1060.

  Preparation 3 -3-hydroxy-63-methyl-5α-butanane-11,20-dione The product XXIII (600 mg) was refluxed

  with chloro-licidic acid reagent (35 ml), pen-

  for a total duration of 8.5 hours. We diluted the mixture

  Reaction with water and extracted with EA.

  Evaporation of the extract afforded a foam which was purified by preparative thin layer chromatography in EA-PE (1: 1) to give the title compound (440). mg) in the form

a foam, -7o + 88 '.

Preparing.

  21-N, N-dimethylaminomethyl-2-ethoxy] -3-hydroxy-5-c-pregnane

  11 20-dione. (YIV) Compound XIV (10.0 g) was dissolved in dry acetonitrile (50 ml) and N, N-dimethyl (m-ethylene) anonium chloride (5.0 g) was added. The mixture was heated under reflux for 2 hours, cooled and partitioned between 2N hydrochloric acid and EA and the acid extract was basified with NaOH solution for 1 hour. extract with CH (2 x). The extract was dried (Na2SO4) and evaporated to give the

  compound indicated in the title (10,7 g) in the form

of a foam.

  Preperation 5 2 -Sethoxy-3 "-hydroxy-21-methylene-5-uramen-1-1,20-dione (70TV) The product XXiV (10.5 g) was dissolved in ME (105 ml) and iodomethane (10.5 ml) was added The mixture was kept at -20 for 20 hours and then evaporated under reduced pressure The residue was dissolved in DM (200 ml) and vigorously stirred the resulting solution

  with a 5% solution of NaHCO3 (100 ml) for 1.5 hours.

  The layers were separated and the organic phase was dried (Na 2 SO 4).

  and evaporated to give a foam. The chroma-

  columnography using EA-PE mixture (1: 1).

  yielded the title compound (3.48 g),

M.p. 181-184, A7D ± 112 ".

  Preparation 6 2.-Ethoxyl-3-hydroxy-21-methyl-5-pregnane-1,1,20-dione The compound = V (3.37 g) was hydrogenated at atmospheric pressure and at 230 ° C. EA (150 ml) on charcoal

  of wood supporting 5% of palladium. We have. separate the catalyst

  by filtration and the filtrate was evaporated to give the title compound as a

  foam (3.27 g), m.p. 147-149, - / a-D + '92 0.

  Preparation 7 3α-hydroxy-5-pregn-20-en-11-one Compound XVI (330 mg) was treated in a mixture of WI, E- (1:10, 11 ml) with potassium selenocyanate and heated the solution at 60 C for 20 hours. The solution was filtered through kieselguhr and evaporated.

29Z485020

  filtrate to dryness under reduced pressure. The residue was dissolved in DMI and purified by column chromatography eluting with EA-PE (1: 1) to give a foam which was crystallized from a mixture. DE-PE to give the title compound as a pale yellow solid (80 mg),

Mp 1.37.5-139.5.

  PREPARATION 8 (Z -3ac-hydroux-5-pregn-17 (20) -en-1-one Sodium hydride (% dispersion in oil, 1.0 g) was washed with from the EP and it was heated

  in dry DMSO at 70-80 until the obtent-ion of one. solutions

  Green. The solution was cooled to room temperature

  and then treated with ethyl iodide.

  triphenylphosphonium (13.3 g) in DMISO (50 ml) Compound XIX (2.0 g) was added in distilled D, 30O (40 ml)

  in one go and heated the mixture to 40-60.

  After 6 hours, the reaction mixture was poured into water and extracted into ED. Evaporation of the washed and dried extract afforded an oil which was purified by column chromatography using EA-PE (1: 1) and crystallization from EA-PE mixture. to obtain the title compound (824 mg),

L 70o +, 29.0Q.

Preparation 9-

  -oximino-5a-irégna-2.16-diene-11-one. (XXVI) A mixture of compound XVIII (60 g) of hydroxeylammonium chloride (21 g) and pyridine was allowed to stand

  anhydrous (240 ml) at room temperature until the next day

  before diluting with ice and water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum at 80 (62 g). Crystallization from EA afforded the compound

  indicated in the title, mp 168-182e.

Lr._7D. +137.

  Preparation a-androst-2-ene-11, 17-dione (XXVII) A solution of compound XXVI (60 g) was treated

  in anhydrous pyridine (250 ml) with 225 ml of a solution of

  prepared from phosphorus oxychloride (55 ml) in anhydrous pyridine (250 ml) while maintaining the reaction temperature above 5 at room temperature.

  during the addition of the reagent. We then added the

  The reaction mixture was treated with concentrated HCl (3550 ml) in water (3 L). The mixture in question was stirred

  60 hours before collecting the precipitate by filtration.

  tion. The precipitate was washed with water, dissolved in hot ISI and treated with 2N HCl (50 ml) at room temperature. After 1 hour, the

  reactive mixture with water and collected the

  filtered, washed with water and

  it was dried (38.4 g). Crystallization in MIE has

  put to obtain the compound indicated in the title ,. Mp 188-192,

"-7D + 207.

Premaration 11

  1 1? -Mino-2e-ethoxy-3? -Hydroxy-2? -Mathyl-5? -Reno-20-

one (LXII)

  2α-Ethoxy-20,20-ethylenedioxy was dissolved

  3α-hydroxy-21-methyl-5α-pregnan-11-one oxime (2.8 g) in RP (150 ml) and the solution was refluxed. We have

  Na (12.6 g) was added and the heating continued.

  flow until the dissolution of all sodium. We have

  PR was distilled off with simultaneous addition of water.

  The mixture thus obtained was extracted with EA (2x) and the washed organic layer was re-extracted with HCl 2. The acid extract was basified to pH 11 with a solution. to 40% NaOH, extracted with EA (2x), dried (Na2SO4) and evaporated to give the title compound as d a foam

(1.94 g).

Preparation 12

  21-bromo- 11 I-N. N-dimethylamino-2B-éthox_-3o-hydroxy-5S-Pre-

  gnane-20-one (XXVIII) A solution of hydrochloride of

  1-N, N-dimethylamino-2-ethoxy-3-hydroxy-5 "-prennin-2O-

  in dry ME (50 ml), dropwise, with a solution of

  bromine (0.1 ml) in ME (5 ml) at 0 under stirring.

  tion. Each subsequent drop of the reagent solution was added when the color due to the previous additions had disappeared. Once the addition is complete, we have added a

-1 = 2485020

  10% solution of K2CO3 (150 ml) and the mixture was stirred for 15 minutes. The precipitate was filtered off

  and was washed with water and dried. Purification

  Thin layer chromatography preparation in EA-PE (1: 1) afforded the title compound.

in the title.

  Preparation 13 11, 11 N-dimethylamino-2-ethoxy-3-hydroxy-5-hexandrostane

178-lithium carboxylate (LXXV.

  Bromine (4.3 ml) was added to a stirred solution.

  NaOH (12.1 g) in water (90 ml) at a temperature ranging from 5 to 00. Dioxane (42 ml) was added and

  this mixture was added to a stirred solution of 11-N, N ---

  dimethylamino-2β-e-thoxy-4α-hydroxy-5α-pregnan-20-one (10.0 g) in dioxane (316 ml) and water (90 ml) at 8. The mixture was stirred at a temperature of from 10 to 3.5 hours. A solution of sodium sulfite heptahydrate (4.66 g) in water (20 ml) was added

  and the mixture was boiled for 15 minutes.

  The solution was filtered hot and the filtrate was extracted.

  cooled with chloroform. The chlorobut extract was washed

  formed with water and the aqueous fractions were acidified

  reunited with concentrated HCl until a pH of 3 is obtained.

  Triethylamine (50 ml) was added and the solution was extracted with chloroform. The extract was dried (MgSO4) and evaporated to dryness to give the

  crude triethylammonium salt which has been dissolved in

  thanol (20 ml) and treated with a solution of

  lithium (20.4 mmol) in methanol (35.7 ml). We have

  solution to dryness and the residue crystallized from a mixture of IE (36 mL), PT (36 mL), and ED (354 mL) to give the title compound (7, 03 g),

Mp 300, E + 9.1.

Preparation 14

  3β, 21-dihydrox-1α-N, -α-dimethylamino-2-ethoxy-5-rernan

  -one (YXX) A solution of C-XIX (2.8 g) in E (100 ml) was treated at room temperature with 10% K 2 CO 3 solution (15 ml) for 15 minutes. We diluted the mixture

32 2485020

  with water to 700 ml and the oily precipitate was extracted into DE (.3x). The extracts were washed with

  the water. they were dried (NIa2SO4) and evaporated until

  while obtaining a foam (2.5 g). A sample of product (300 mg) was purified by preparative thin layer chromatography in EA-PE (1: 1) to give the title compound (160 mg), under

foam shape, / La7D + 650.

  PREPARATION 15-N, N-dimethylaminomethyl-2-ethoxy-5α-prenegane-3. 290 (21-triol

1 O 1)

  A solution of the compound EX (2.2 g) was treated

  in 1M (50 ml) with sodium borohydride (230 mg) 0.

  After 10 minutes, the mixture was diluted with a solution

  10% K2CO (80 ml) and water up to 300 ml. We have-

  The mixture is extracted with DE (x3) and the extracts are washed with water, dried ('4a2SO4) and evaporated until a foam is obtained. it was purified by column chromatography eluting with DM-AC (1: 1) to give the title compound (700 mg), as a foam, 7D. Preparation-16,20-ethylenedioxM-3c-hydroxy-2-methyl-5-pregnane-1-one A stirred suspension of dried cuprous iodide (19.6 g) was cooled in dry xylene (.350 ml), under a nitrogen atmosphere, to -10 and 1.9 M methyl lithium in ED (108 ml) was added until redissolution of the precipitate

  yellow, so as to obtain a colorless solution

  simply clear. A solution of compound IV (12.9 g) in xylene (430 ml) was added dropwise at a temperature ranging from -10 to -50. After the addition, the mixture was stirred overnight at room temperature and

  then poured into a 25% solution of NH4Cl (1200 ml).

  The mixture was extracted with DE and washed with 25% MCl 2 solution and water. Evaporation of the DE - left an oily solid which was shown by thin layer chromatography to be a 2: 1 mixture.

  of the starting material and the compound indicated in the title.

  This solid was recycled using the same amounts of reagent, the same temperatures and the same durations. The resulting solid was crystallized from EA-PE to give the title compound (7.22 g),

M.p. 167-168, / - a7D + 68.1.

Preparation 17

  20. 20-Ethylenedioxy-23-ethoxy-3α-hydroxy-5x-pregnan-11-

  one (XXXII) A solution of compound VII (8.2 g) in benzene (300 ml) and ethylene glycol (40 ml) was treated

  with PTSA (200 mg) at reflux temperature, using

  with a water trap from Dean and Stark, under vigorous

  tation. After 6 hours, solid NaHCO3 (500 mg) was added to the cooled mixture. A saturated aqueous solution of NaHCO3 (100 ml) and water (50 ml) was added and the organic phase was washed with water (3x), dried (Na2SO4) and

CD 24

  evaporated to a foam which was purified by column chromatography eluting with EAPE (1: 2) to give 6 g of product which was crystallized 500 mg in a MA-PE mixture to give the title compound (210 mg) mp 124-127 ° C, +530 Preparations 18-26 Table 1 summarizes the preparation of the 20-ketals

  by carrying out the following method.

  A solution of the appropriate 20-ketone was worn

  in benzene and ethylene glycol under reflux using

  with a water trap from Dean and Stark, in the presence of PTSA,

  during the period of time indicated.

  The cooled mixture was then treated by one of the following methods: A. The mixture was treated with solid NaHCO.sub.5 and diluted (i) with a mixture of diethylether and water or (ii) some water. The organic phase was separated, it was

washed, dried and evaporated.

  B. The mixture was diluted with aqueous NaHCO 3 and extracted with (i) ethyl acetate or (ii) dichloromethane. The extract was washed, dried

and we evaporated it.

  C. The mixture was poured into aqueous NaHCO 3 solution, the layers were separated, and the aqueous layer was extracted with benzene. We've washed out the organic extracts

  combined, dried and evaporated.

  The obtained material was purified by one of these methods by chromatography (column or thin layer) and / or crystallization. Pre-ation 27α, 20-ethylenedioxy-5α-crégn-2-en-11-one 1-oxime (YXXTII) A solution of compound VI (5 g) was treated in

  ethanol (150 ml) with a mixture of hydrochloride

  hydroxylamine (10 g) and a 50% solution of NaOH (40 ml) at a pH of 11. The mixture was refluxed for 3 days, diluted with water and the precipitate formed was filtered off. was washed with water and dried. The residue (5.5 g) was recrystallized from MA-PE (2 x)

  to obtain the product (2.2 g). We have more

  sized a portion of the product (200 mg) to give the title compound (150 mg), mp 174-179 ° C,

- 4_7D + 144a.

* Preregistration 28

  20-Ethylenedioxy-2e-ethoxy-3α-hydroxy-5α-pregnan-11-

  One 11-oxime (XxxIV) A solution of compound XXXII (5 g) in ethanol (200 ml) was treated with a mixture of hydroxylamine hydrochloride (15 g) and a 40% solution of NaOH (60 ml) at reflux temperature for 18 hours at a pH of about 11. The mixture was diluted with water

  up to 2 liters and the precipitate formed was filtered off

  it was washed with water and dried under

  empty so as to obtain 4.5 g of product which has been crystallized

  read a sample (500 mg) in a MA-PE mixture of fe on

  to obtain the title compound (150 mg), m.p.

  with softening 170 C- / -c_7D + 83.3.

  Preparation 29,20-ethylenedi-y-3 -Hv roxy-51-regnan- 11 -one-11oxime

(^ XXXV)

  A solution of compound XXI (11 g) in ethanol (150 ml) was treated with a mixture of hydroxylamine hydrochloride (15 g) and 50% NaOH (50 ml). reflux for 24 hours at a pH of 11, then diluted to 2 liters with water.

3 J55 -

  precipitate formed (11 g) by filtration, washed with water and dried. A fraction of the product (500 mg) was purified by preparative thin layer chromatography and crystallized from a DEPE mixture to give the title compound (100 mg), m.p.

228 c, L-7D + 100. -

  Preparations 30-46 Table 2 summarizes the preparation of 11-oximes

according to the following method.

  A solution of the corresponding 11-ketone was

  in refluxing ethanol with a mixture of hydroxylamine hydrochloride and aqueous NaOH at a pH of 11 or higher for the indicated period of time. The cooled mixture was diluted with water and the precipitate was filtered off, washed and dried. The material obtained was purified by chromatography (chromatography on

  column or thin layer chromatography) and / or crystal

  lisation. Preaction 47 11-Amino-2-ethoxy-3α-hydroxy-D-homo-5α-pregnan-20-one

(LXIV)

  -. Sodium (8 g) was added in fractions to a

  solution at reflux of 23-ethoxy-20,20-ethylenedioxy-3a

  hydroxy-D-homo-5a-pregnan-11-one 11-oxime (4.0 g) in RP (200 ml). Refluxing was continued for 4 hours, then IIE (10 ml) was added. Solvent alcohols were distilled off while adding water. The cooled aqueous suspension was extracted with EA (3x) and the combined extracts were washed with saturated brine (2x), dried and evaporated to a foam. The latter was dissolved in EA and extracted with HC! 2N (3 x). The combined aqueous extracts were alkalinized with a solution

  ammonia (d: 0.88) and extracted with EA.

  The combined EA extracts were washed with saturated brine.

  dissolved, dried and evaporated to give the title compound as a foam (2.43 g),

--L 7D + 400. -

6- <-62485020

  Preparation 3.20B, 21-Trihydroxy-5-pre-11-one 11-oxime (eX-Vi) A 50% solution of KOH (32 ml) was added to a solution of dihydrochloride. hydroxylamine (16 g) in water (32 ml) with cooling and the mixture was added

  thus obtained to a solution of XXII (8 g) in ethanol-

  (256 mi). The reaction mixture was refluxed for 4 days, a little ethanol was distilled off and the mixture was poured into ice-cold 2N HCl. The steroid was extracted with ethyl acetate and crystallized from ethyl acetate to give the title compound (6.7 g), mp 226. -229, - + 82 0 (c 0.7 D); Preparation 49 20,20-ethylenedioxy-5a-pregn-2-en-11-amine (XXXVII) A solution of the compound XXXIII (1 85 g) in RP (250 ml) at reflux temperature with Na (20 g) added over 1.5 h After the sodium had been consumed, ME (20 ml) was added. and the mixture was diluted to 2 liters with water The mixture was extracted with DE and the extract washed with water, dried

  (Na2SO4) and evaporated to give the title compound

  in the title as an oil (2 g).

  Prep. 50 11α-amino-20,20-ethylenedioxy-2-ethox. -5-orégnane'-5ol

(XXXVIII)

  A solution of the compound XX] IV (4 g) was treated in

  PR (500 ml), at reflux, with Na (40 g), in space -

  of one hour. Once all the dissolved sodium has been added, methanol (20 ml) is added. The constant subaddition of water was then distilled until all of the PR was removed. The product was extracted into DE (2x) and the extract was washed with water (2x), dried (Na2SO4) and evaporated to leave a foam. (3.7 g)

  that was purified by column colomatography using -

  eluting with methanol to give the title compound as a foam (2.5 g),

_7 + 13.7.

  Preparation 1α-amino-20,20-ethylenedioxv-5-organane-3α-ol (XXXIX) A solution of Compound XXV- (2 g) in PR (250 ml) was refluxed with sodium (20 g), in the space of one hour. Once all the sodium dissolved, methanol was added. The PR was distilled off during the careful addition of water. The residue was extracted with DE and the extract was washed with water, dried (Na 2 SO 4) and evaporated to leave

  a solid which has been purified by chromatogra-

  column, eluted with ME and crystallized from MA, to give the title compound

  (220 mg), 153-155 ° C, -α-D +5 (c 0.65).

  Preparations 52-63 Table 3 summarizes the preparation of 11-amines

  by carrying out the following method.

  A solution of the corresponding 11-oxime was treated

  in refluxing RA with sodium. Once the total

  When sodium is reacted, PR is removed by

  distillation and simultaneously replaced with water.

  The residual mixture was treated by one of the following methods: A. The mixture (i) was extracted with DE or (ii)

  of EA and the extract was washed, dried and evaporated.

  B. The precipitate formed was filtered off,

it was washed and dried.

  The material obtained by crystallization was purified

  tion. Preparation 64 (Z) -1-amino-2B-ethoxy-5ca-pregn-17 (20-en-53-ol (LXV)

  A reflux solution was treated (under atmospheric

  Nitrogen) of (Z) -2P-ethoxy-γ-hydroxy-5m-pre-gn-17 (20) -ene-11-

  one 11-oxime (450 mg) in PR (15 ml) with Na fragments (450 mg). When there was no more trace of lia, the mixture was added to chilled water to obtain

  a simple precipitate that has been collected by filtration.

  The solid was dissolved in EA, dried (Nia 2 SO 4) and evaporated to a broth

  it was partitioned between 2N hydrochloric acid and DE.

  The insoluble material which had separated by filtration was collected and partitioned between EA and 2NaOH solution. The organic phase was isolated, washed with water, dried (Na2SO4) and evaporated to obtain a broth which was crystallized from PE to obtain the title compound (110 mg),

Mp 65-700 / -7D + 10.

  Prenaration 65 IIc-dimethylamino-53-pregnane-203. SI21-triol (LIII) Compound XXXVI (5.75 g) was dissolved in RP (500 ml) and sodium (6 g) added fractions, under

  nitrogen atmosphere. The excess of PR was distilled off

  under vacuum and EA (11) was added to the reaction mixture.

  cooled. The solution was washed with water (4 ×), dried (MgSO 4) and evaporated. The crude amine was dissolved in HCHO (60 mL) and HCOOH (1.2 mL). The solution was heated to 100 for 6 minutes and poured onto ice, basified with 50% solution.

  of NaOH and the steroid was extracted with EAO.

  under the gum thus obtained in ME (80 ml) and a 25% aqueous solution of NaOH (20 ml) was added. We have left

  place the solution at room temperature for 45 minutes and then acidified with HC1O1. The solution was washed with EA and basified with 50% NaOH. Extraction with EA gave a material which was triturated with pentane and crystallized from a mixture of methyl acetate-pentane to give the compound

  indicated in the title (1.8 g), 124-128.

  Preparation 66 11'-Amino-3α-hydroxy-D-homo-5α-fluan-20-one (LXIII)

  20,20-Ethylenedioxy-3α-hydroxy-D-

  homo-5α-pregnan-1,1-one-11-oxime (1.87 g) in RP (200 ml) with Na (10 g) and treated as described in Preparation 47. The crystallization from EA-PE gave the title compound (-128 mg),

M.p. 154-157, mp + 36.1.

  PREPARATION 67 1α-amino-5-hydroxy-5α-pregnan-20-one (MIV) To a solution (under a nitrogen atmosphere) of compound V (7.0 g) in refluxing PR (700 ml), added small fragments of metallic Na (14 g). Once all

I, - 2485020

  of the sodium consumed, the reaction mixture was evaporated

  than about 200 ml and added cold water. The

  refrigeration until the next day made it possible to obtain

  which was collected by filtration and then partitioned between HC12N and DE. The aqueous phase was basified with 2N NaOH solution and extracted with DE. We have

  washed the organic extract with water and evaporated

  only to a small volume. The crystalline material which had separated by filtration was collected and crystallized from ED to give the title compound,

PoFo 150-152, 7D + 58.30.

  Preparation 68 11-N-Ethylamino-3α-hydroxy-55-regulan-20-one Compound XXXIX (1 g) was dissolved in ethanol (30 ml) and K2CO3 (1 g) and magnesium were added. ethyl iodide (3 ml) was added (3 ml). The reaction mixture was stirred under reflux for 2.5 hours and then evaporated to dryness. The residue was redissolved in ethanol (10 mL) and 2N HCl (10 mL) at room temperature and after 15 minutes it was basified with aqueous KOH. The steroid was extracted with EA and purified by thick layer chromatography of preparation, using EA-MIE (3: 1) -1 as eluent, to collect the indicated compound. in the title

  (210 mg) as a broth - 7D + 43.

  Preparation 69 11a-N-Butylmino-31-hydroxy-5-orange-20-one (LXVI)

  A solution of 11α-amino-20,20-ethylene-

  dioxy-5cc-pregnan-3α-ol (XL) (1.5 g) in 1-iodobutane (20 ml), at 80, with K 2 CO 3 (3 g) and stirred for 3 hours. The mixture was partitioned between ED and water and the organic layer was extracted with HC1N. The extract was basified with 4N NaOH solution and the oily deposit was extracted into DE. The extract was washed with water, dried (Na2SO4) and evaporated to leave a foam (1.5 g). A fraction of the product (500 mg) was purified by preparative thin layer chromatography in acetone to give the title compound (350 mg), as

an oil, - x7D + 60 '.

40.2485020

  Preparation 70-D-Hydroxy-1-yl-N-oro-vinylamino-5α-orane-20-one (IZ; I) A solution of the compound XL (1 g) in 1-iodopropane ( 10 ml) was refluxed with KC (3) for 40 minutes and the mixture was then treated as described in Preparation 69. Chromatography on column using methanol and removal of the solvent from the subsequent fractions were carried out. allowed to get a residue that

  it was crystallized in PE so as to collect the

  stated in the title (450.mg), m.p. 138-141, L-a7D +320.

  Preparation 71 11 N -ethylamino-3c-hydroxy-5a-pregnan-20-one (LXVIII)

  A solution of the compound XL (4 g) was stirred in

  ethyl iodide with Ag20 (12 g) at room temperature for 2 hours. Ag20 was removed by filtration and the filtrate was treated as described in US Pat.

  preparation 69. Column chromatography and chroma-

  Thin film mapping has made it possible to obtain the compound

indicated in the title (400 mg).

  Preparation 72 11x-aaino-2-oxy-hydrox-5-rgnan-20-one A solution of the compound X = VTIII (750 mg) in ethanol (10 ml) was treated with bromide. allyl (2 ml) and K 2 COO (1 g) at 80 for 3 hours. After filtration, the reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and brine (adjusted to a pH of about 9 by the addition of 2N Na 2 CO 3). The aqueous layer was extracted with additional EA and the combined extracts were washed with brine, washed (Na 2 SO 4) and evaporated. Thin layer chromatography of the preparation gave the compound indicated in FIG.

  title in the form of a gum (107 mg) .-

  Preoaration 73 11a-ethylamino-50-pregn-2-en-20-one (XLII)

  The compound OXVII (1 g) was mixed with acetal-

  dehydrogen (0.4 ml) in ethanol (20 ml) at 21 and sodium cyanoborohydride (400 mg) was added. After 15 minutes,

  the clear solution was basified with NaHCO 3 solution.

  Brine was added and the mixture was extracted with EA

  (3x). The combined organic solutions were washed with brine

Z485020

  (3x) and then shaken with 2N HCl. Excess of 40% aqueous NaOH was added and the layers were separated. The organic solution was washed

  with brine (2 x) and evaporated to dryness.

  The oil thus obtained was chromatographed in EA-TE to give the title compound.

  in the form of a crystalline solid (774 mg). We have

  crystallized a sample in an ET-W mixture and the

  duit thus obtained had a P.F. of 105-1Q8 -_7D +

89.60.

  Preparation 11c-N-cyclohexylamino-25-ethoxy-3-hydroxy-5a-pregnane-20one Compound XDXVIII (0.5 g) was mixed with

  cyclohexanone (2 ml) in ethanol (20 ml) at room temperature

  Ambient and NaBH 4 CN (250 mg) and acetic acid (0.1 ml) were added. After 20 hours, the mixture was treated as described in Preparation 73 and purified by thin layer chromatography to give the title compound (268 mg) under

  the shape of a foam -a_7D + 26.6.

  Preparation 75 1-s-N-benzylamino-23-ethoxy-3a-hydrox: (-5-pregnan-20-one Compound XXXVIII (0.5 g) was mixed with

  benzaldehyde (1 ml) in ethanol (10 ml), at room temperature

  Ambient and NaBH3CN (250 mg) and acetic acid (0.1 ml) were added. After 1 hour, the mixture was treated as described in Preparation 73 and

  it was purified by column chromatography and

  thin layer graphing to obtain the title compound (205 mg) as a foam,

L-7D + 34.1.

  Preparation 116 116-Isopropylamino-5m-Orn-2-en-20-one (XLIII) Compound X8-XII (200 mg) was mixed with AC

  (0.2 mL) in ET (5 mL) containing NaBH3CIN (200 mg).

  After 31 hours, the mixture was treated in the manner described above.

  written in Preparation 73 and purified by chroma-

  column chromatography in EA-PE mixture, followed by recrystallization from ET-W to give the title compound (55 mg),

4 2 2485020

  M.p. 99-101 + 80.60 (c 0.52).

  Preparation 77 3-hydroxy-N-soprroamino-5'-o-nano-20-one Compound XGXIX (920 mg) was dissolved in ethanol (40 ml) and added to NaBHb-C (450 rag). AC (40 ml) was added, then acetic acid (0.2 ml) was added and the reaction mixture was kept at room temperature for 17 hours. We divided

  the two-part reaction mixture for extraction.

  (a) The solution was partitioned between EA and Na 2 CO 3 solution and the organic layer was suitably washed with water, dried (H 2 SO 4) and evaporated to dryness . The residue was dissolved in methanol (10 ml) and 2N HCl (10 ml) was added. The mixture was allowed to stand at room temperature for minutes and then basified with a solution.

  of Na2CO3 and the steroid was extracted with EA.

  (b) The second portion of the reaction mixture was partitioned between EA and Na2CO3 solution as described in (a) above and the organic layer was then shaken with 2T HCl and let stand

  during 30 minutes. The reaction mixture was then alkalinized

  with NaHCOO and extracted with EA. The combined EA extracts were washed with water,

  dried (MgSO4) and evaporated.

  The products obtained in (a) and (b) were combined and subjected to thick plate chromatography using EA as the solvent and the steroid was eluted with EA-ME, so that obtain the indicated compound

  in the title (590 mg), -c-7D + 38 0.

-Preoaration 78

  (Z) -11m-N-Ethylamino-Sm-or 8gn-17 (20) -N-Sm-ol.

  NaBH3CN (398 mg) was added to a solution of compound XLI (1.027 g) in ethanol (30 ml) and

  After dissolution was complete, acetaldehyde (9 ml) was added.

  After 35 minutes, the solution was diluted with 2N HCl and water and washed with EA, basified with 2N NaOH and the precipitated material extracted with water. EA. The washed organic extract was evaporated under vacuum to collect an oil. Purification by preparative thin-layer chromatography (IME-EA 1: 1) yielded

  an oil which crystallized by trituration with a little NA.

  Recrystallization from W-AN afforded the title compound (287 mg), mp 106-109.

/ - 7D-19.9o.

  PREPARATION 79 (Z) -11-Isooropylamino-5cc-pre-g (7) (20) -N-35-ol A solution of XLI compound (422 mg) in IMS (6 ml) containing of AC (1 ml) per NaBH3CN and the mixture thus obtained was treated as described in Preparation 78. Purification by TLC (ET-CH 1: 1) afforded the compound indicated in the title (180 mg), under the

form of a broth.

Preparation 80 '

  23-Ethoxy-20,20-ethylenedioxy-11-α- (4-methyl-2-ylamino) -

  cc-pregnane-3α-ol isomers A (L) and B (LI) - Compound 7, zVIII (1.06 g) was refluxed with 4-methylpentan-2-one (2 ml) in PR (40 ml), under a nitrogen atmosphere, for 20 hours. Refluxing was continued under nitrogen and sodium (4 g) was added over 3 hours. We added water

  (about 50 ml) and the PR was evaporated under reduced pressure.

  The aqueous residue was extracted with EA. The combined extracts were washed with brine, dried (Na2SO4) and evaporated to a gum. This product was purified by preparative thin layer chromatography by developing with a mixture of ME-EA (1: 9) to separate the isomers of the title compound to obtain the isomer A (333 mg) ( gum) and isomer B (322 mg)

3 (eraser).

  Preparation 81 11-N-th-N-Eth-N-methylamino-5-pregn-2-en-20-one (XLVI) The compound XLII (658 mg) was heated at 100 for 1 minute with formic acid (0.32 mp) in an aqueous solution of HCHO (37% solution, 2.5 mm). The mixture was cooled to 21 and an excess of an aqueous Na 2 CO 3 solution was added. The mixture was extracted with EA and the combined organic layers were washed with saturated brine, dried and evaporated to dryness.

- 2485020

  / filtered the residual gum through silica gel in a

  EA-PE mixture (1: 9). Evaporation of the eluate resulted in

  denote the title compound (477 mg), -7D + 111.

  Prep. 82 N-isoprop-N-methyl-5-pregn-2-en-20-one (XLVII) The reaction of XLIII (8.38 mg) on a 37% aqueous solution of HCHO (3, 3 ml) containing formic acid (0.43 ml)

  carried out in a manner similar to that described in the

  81 and the recrystallization of the product thus obtained in an ET-W mixture, made it possible to obtain the compound indicated in

  title (643 mg), m.p. 88-99, L - d + 115 .-

  Preparation 83 11-N, TN-dimethylamino-5a-pregn-2-en-20-one (XLV) Twenty-six (32.2 g) was heated to 95-10 in 32 ml of a solution. 37% aqueous HCHO and formic acid (4 ml) for 6 minutes. We quickly cooled the mixture

  and partitioned between EA and 2N Na2CO5 solution.

  The aqueous layer was extracted with EA and the combined organic solutions were washed with brine prior to evaporation to obtain a solid which was dissolved in EA and filtered through silica gel. The eluate was evaporated and the residue was recrystallized from methanol

  to obtain the title compound (4.0 g), m.p.

126, LSa7D + 110.

  Preparation 84 11 N-N, N-dimethylamino-5α-pregnan-3α, 20β-triol (LiI) was dissolved. 11-amino-5-peganane-5-, 20P, 21-triol (950 mg) in methanol (20 ml) and methyl iodide (10 ml) and stirred at room temperature with K2CO3 (3 g) for 4 hours. The treatment done in the way

  described in Preparation 69 and the purification by chroma-

  Thin film chromatography in -AC and crystallization in DE afforded the title compound (160 ml), m.p. 121125, _E _7D - 167 Preparation 85

  11 e-N. -diméthvlamino-28-ethoxy-20,20-éthvlènedioxy-

cc-regnane-3a-ol (LXI)

  Compound XXrVIII (5.0 g) was dissolved in a mixture of

  40% aqueous solution of HCHO (60 ml) and 98-100% formic acid (2.1 ml) were added and the resulting solution was heated on the steam bath for 15 minutes. The solution was cooled, diluted with water (190 ml) and saturated aqueous NlaHCO 3 solution (25 ml) and the pH was brought to 11 by the addition of NaOH (0, 0). 3 g) in solution in water (30 ml). The resulting brecipitate was collected by filtration, washed with water and dried to give the title compound of Example 1.

(5.41 g), 73 ° + 57.5, mp 700.

  Preparation 86 11cc-dimethylanmino-30-hydroxy-5S-prenyl-20-one (LVII) A mixture of compound XLIV (0.5 g) of a 37% solution of HCHO (3 ml) was maintained and 98% formic acid (0.3 ml) at 100 for 3 minutes before pouring

  in an aqueous solution of NaHCO3. We collected the pre-

  obtained by filtration and partitioned between EA and 2N HCl. The acid phase was basified with 2N NaOH solution, extracted with EA, washed with

  water and evaporated to a broth.

  Column chromatography (EA-PZ 1: 2) and crystallization

  in EA-PE gave the title compound (300mg). 5a-pregnan-20-one (LXIX) Compound XLV (1.9 g) and PTSA (170 g) were dissolved in DC (150 ml) and m-chloroperbenzoic acid (1.24 g) . After stirring the mixture at 20 for 15 hours,

  the organic solution was successively washed with a solution of

  diluted aqueous solution of Na2S205, a solution of NaHCO3 and water. Each law re-extracted the organic layer with DC. The combined organic layers were dried (MgSO4) and evaporated. The residue was filtered through silica gel in 1: 3 EA-PE and the eluate evaporated to give crystals which on recrystallization from PE gave the title compound. the title. (0.51 g), mp 154-157, L-7D + 80, soo o Preparation 88 2a, 2a-eoxy-11H-N-ethyl-1-t-methylamino-5-butan-20-one. XLVI compound (6.0 g) and PTSA

  (3.21 g) in DC (300 ml) and m-acid was added.

  chloroperbenzoic acid (4.4 g) to the solution thus obtained.

Z485020

  After 1 hour, the mixture was treated as described in Preparation 87 (except that DPI was used instead

  from DC). The purification carried out by co-chromatography

  using an EA-PE mixture resulted in

  stated in the title (4.49 g), + 79-, 50. Preparation 2, 3: Cpoxoy-11-MH-N-Methylamino-5-hexan-90-one Compound XLVUI (300 mg) and PTSA (154 mg) were dissolved in DC (30 ml). ) and m-chloroperbenzoric acid (210 mg) was added. After 30 minutes, we added

  an additional amount of oxidant (60 mg). After 30 minutes

  In addition, the reaction mixture was treated as described in Preparation 87. Purification by preparative thin layer chromatography (EA-PE) and recrystallization from W'-ET allowed the compound to be obtained. indicated in the title (114 mg), PF 114-116,

L 7Dt 84.5.

  PREPARATION 90 2m, 3-epoxy-5.x-androstane-11,17-dione (XLVII) A mixture of compound Y-VII (37.2 g), m-chloroperbenzoic acid (30 g ) and CH (600 ml) for 0.5 hours at room temperature, before partitioning between CH and saturated aqueous NaHCO 3 solution. The organic layer was isolated and washed with water. 'water,

  it was dried and evaporated to a small volume.

  The addition of PE, followed by refrigeration until the next day

  resulted in a crystalline substance (27.5 g).

  crystallisation in an EA-PE mixture gave the

  compound reported in the title m.p. 166'-167 - a7_D + 1260.

Preparation 91 - -

  A solution of XLVIII (5.0 g) in absolute ethanol (250 ml) was treated with 8 drops of fuming H 2 SO 4 (28 mL). at room temperature. After 45 minutes, the reaction mixture was treated with aqueous NaHCO 3 solution and evaporated to a small volume. We added

  the water to the mixture, which was then refrigerated

  tomorrow. The precipitate was collected by filtration, washed with water and dried. Recrystallization from a mixture of water and ethanol gave compound II.

  reported in the title (2.1 g), mp 164-167, L 7D-114.

_Preparation 92

  (Z) -23-ethoxy-5α-hydroxyl-5α-pregn-17 (20) -ene-11-one

  A mixture of XLIX compound (1.742 g) was stirred.

  of ethyltriphenylphosphonium iodide (627 g)

  sodium (360 ram) and dried tretahydrofuran on

  dium (100 ml) and refluxed under a nitrogen atmosphere. After 4.5 hours, the reaction mixture was partitioned between EA and water. The organic phase was isolated, washed with water, dried (Na2SO4) and

  evaporated to give an oil (4.0 g). The chroma-

  columnography (EA-PE 1: 2), followed by chromatogra-

  Thin layer separation (EA-PE, 1: 1 2x) and crystallization from EA-PE afforded the title compound (110 mg), m.p. 172-178 o,

7cC "7D + -25.

  Preparation 93 11-amino-2G-ethoxy-3.2-h: y-hydroxy-5-organane-20-one- (LIX) Compound XXVIII (10 g) was suspended in water (38 ml) and treated the suspension with concentrated HCl (12 ml). The insoluble material was filtered off and washed with a small fraction of water. This material was resuspended in water (50 ml) and treated with 2N NaOH to pH 9. The mixture was stirred at 0 for 10 minutes and then collected the solid by filtration to then wash it with water to obtain the indicated compound

  in the title P.F. 160-164, [-a_7D + 79.2.

  Preoaration 94 11-amino-35-hydrox-5-pregnan-20-one (LX) XXXIX (2g) was dissolved in PIE (20 ml) and 2N HCl (20 ml) was added. The reaction mixture was kept at room temperature for 15 minutes, basified with ice-cold NaH4 solution and the white solid was collected by filtration.-Crystallization from a mixture of methanol and water resulted in

  title compound (1.13 g), mp 128-130.

: * 48 2485020

Preparation 95

  23-Ethoxy-4α-hydroxy-11- (4-methyl-2-ylamino) -5-c-vinylamine

  -one isomer A Compound L (3.30 mg) was dissolved in IM (20 ml) and 211 hydrochloric acid (0.5 ml) was added. After 210 min, the mixture was quenched with 2N Na2CO3 solution and evaporated to a small volume. The residue was distributed between EA and brine. The aqueous layer was extracted with additional EA and the combined organic solutions were washed with brine (2x), dried (Na2SO4) and evaporated to dryness (310 mg). The product was purified by preparative thin layer chromatograph developing with EA containing 5% Me and EA to give the title compound as a white foam,

- -7D 1. -

Preparation 96

  2α-thoxy-3m-hyroxy-1α- (L-methyl-2-ylamino) -5 .-.

-one isomer B

  The LI compound (322 mg) was treated in the manner described above.

  prepared in Preparation 95 to obtain the title compound (170 mag) as a foam, r_7D + 2.1

(c 0, .35).

Preparation 97

  11-N-dimethylamino-3α-hydroxy-5α-androstane-173-carbalde

  Hyde oxime (LV) A solution of compound LII (250 mg) in D (15 ml) and water (3 ml) was treated with periodic acid (1 g) for 30 minutes. An aqueous solution of NaOH (2N, 10ml) and water (200ml) were added and the oily precipitate was extracted with DE. The extract was washed with water, dried (Na2SO4) and evaporated to give

  1 cc-N, N-dimethylamino-3-hydrox-y-5'-andro-stan-17-carbal-

  dehyde in the form of a foam (185 mg).

  The aldehyde was dissolved in Et 2 (50 ml) and a mixture of Nl (20H.HCl (300 mg) and a solution of NaOH (211, 5 ml) was added at a pH of 11. minutes, the mixture was diluted with water and the precipitate was extracted with D. The mixture was washed with water, dried (Na 2 SO 4) and

  it has been evapoored so as to obtain a foam which has been crushed

**. 49 2485020

  sized in PE-DE mixture to give the title compound (130mng) mp 107.5-110 ° C

7dD 7+ 40.

  Preparation 98 11.a. N, T-dimethylamino-238-thoxy-3-hydroxy-5-hydroxy-5-butanediol-173-carboxidoidal (LVI) was treated with the compound i2Xi (650 mg) from way

  described in Preparation 97 and the

  in a hexane-DE mixture in order to obtain the

  As stated in the title (.380 mg) PF 99-102, -cc_ D + 120. PREPARATION 99 11-Dimethylaminomethyl-3-hydroxy-53-andro-stear 17-carbaraldehyde (LIV) Compound LIII (1) 3 g) in D (65 ml) and periodic acid (1.3 g) was added in water (6.5 ml). The reaction mixture was kept at room temperature for 15 minutes, poured into a solution

  * Aqueous NTaTiO3 and the steroid was extracted with EA.

  A fraction of the steroid (300 mg) was subjected to a chromatin

  thick plate graph of preparation using

  EA-PT mixture 1: 3). Elution with I has resulted in

  Add the title compound as a foam (150mg), 7az-, + 24 (c 0.5). Preparation 100-acetoxy-11-dimethyl-aminomethyl-58androstane-173-carbonitrile (LXXi On A 50% aqueous solution of KOH (4 ml) was added to a solution of 1NI20H.-Cl (2 g) in water (4 ml) under cooling, and this solution was then added to the LIV compound. (860 mg) in ET (32 ml) and the mixture was maintained at room temperature for 10 minutes Dilution with water and extraction with EA gave 17p oxime (890 mg) This material was dissolved in acetic anhydride (20 ml) and brought to room temperature.

  at reflux for 15 minutes. After dilution with a solution

  An aqueous solution of NI-aHC03, the mixture was stirred for additional minutes. The steroid was extracted with EA and subjected to thin layer chromatography.

  preparation using EA-PT (1: 3) mixture as the sol-

  efore. Elut-oen with Mne and crystallization in an EA-ME mixture made it possible to obtain the compound in-i-ul

title (560 rg) m.p. 148-152.

  EXAMPLE 101 3x-Acetoxy-1α-dimethylamino-5β-androstane-173s-acrylonitrile (L: t) A solution of compound LV (1.30 g) 1 in acetic anhydride (20 ml) was added. ) at reflux for 1 hour. The mixture was poured into ice-cold saturated NaHCO 3 solution (500 mL) and the precipitate was extracted with DE. The extract was washed with water. it was dried (Na 2 SO 4) and evaporated to leave a foam which was purified by thin-layer chromatography of preparation in EA-PE (1: 5) and crystallized the product in ED to give the title compound (300 mg), mp 167-171 ° C,

/ - -7D + 53

  Preparation 102 - x-ac etoxy-. 1-N, N-dimethylamino-2,8-ethoxy-5-yandro-stane 173-carbonitrile (LXI) The compound LVI (500 mg) was treated in the manner

  described in Preparation 101 and purified by

  thin-layer matography of preparation in an AC-PE mixture so as to obtain the compound indicated in the title

(380 mg),), a7D + 57.

  PREPARATION 103 1α-N, N-dimethylamino-5-n-gran-3. 20-dione (LVIII) We treated a cold solution of comoose LVI

  (181 mg) in DC (10 ml), dropwise, by reaction with

  Jones tif (0.25 ml) prepared from CrO (66.7 g) in

  water and concentrated H2S04 (53.3 ml) diluted to 250 ml-

  with water). The reaction mixture was partitioned between EA and aqueous NaHCO 3 solution, the organic phase was isolated, washed with water, dried (Na 2 SO 4) and evaporated. until a solid (170 mg) is obtained. Crystallization in a DE-PE mixture allowed

  to obtain the title compound (158 mg) m.p.

146-152, e_7D + 62.5.

Pr-oaration 104

  17; 17-othylenedioxy-2-thox-5-hydroxy-5-audrostane

11-one (LXXVI)

-. '' ' 5I AT2485020

  A mixture of XLIX (8.0 g) PTSA (160 mg), ethylene glycol (13 ml), triethyl orthoformate (8.3 ml) and CH (80 ml) was maintained at room temperature. the ambient temperature

  overnight, before distributing it between CH 2 and saturated NaHCO 3 solution. The organic phase was isolated,

  it was washed with water and dried (Na2Sq4).

  poration of this solution resulted in a broth

  Thin layer chromatography was purified from preparative

  (AC-PE) and crystallization in an EA-PE mixture, in order to

  to obtain the title compound (60 mg), m.p.

o, 7D + 18.2 ..

Preparation 105

  17.17-thylenedioxy-28-ethoxy-3-hydroxy-5α-androstane-1-one

  Oxime (LXXVII) A mixture of LXXVI (8.2 g), NH20H.HCl (15 g), NaOH (90 ml), NaOH (44 ml) and 500 ml) and refluxed for 24 hours before being evaporated to about half the

  original volume. The addition of water followed by refrigeration

  overnight, gave a precipitate which was collected by filtration, washed with water and dried (6.4 g). Crystallization from a mixture of EA-PE gave the title compound PoF. 136-140,

LZ.-7D + 41,10-

  Preparation 11-Amino-2-ethoxy-3α-hydroxy-5α-androstan-17-one (LXXVIII) LXXVIII was treated in refluxing PR (400 ml) with small pieces of Na metal (7%). 5: g), under a nitrogen atmosphere. The reaction mixture was evaporated to a small volume and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (Na 2 SO 4) and evaporated to give

  a foam. This scum was distributed between 2N HCl and PE.

  It has been alkalinized. acid layer with 2N NaOH and extracted with EA. The EA was washed with water, dried (Na 2 SO 4) and evaporated to foam. Crystallization with DE afforded the title compound (2.43 g), PoFo 144-148,

+ 6150

52-

: 2485020

  Preparation 107, 1 - [] Dimethylamino-2-ethoxy-3 "-hydroxy-5a-andlostanenone

(LXXIX) -

  A solution of LXXVIII (2.2 g), HCOO2H (1.2 ml) and HCHO (12 ml) was maintained at about 100 ° C.

  for 3 minutes before pouring into a saturated solution

  NaHC03. The vigorous stirring gave a precipitate which was collected by filtration, washed with water and dried. Thin layer chromatography (EA-PE), followed by preparative thin layer chromatography (EA-PE)

  crystallization in an ET-Wi mixture resulted in

  denote the title compound, mp 65'68, / r-7D +

41.7. '

  Preparation 108 1 1x-aminotigogenin - 11oxotigogenin-11-oxime (2.0 g) was heated

  in refluxing RA (140 ml) and Na (10 g) was added.

  After the Na reaction, the PR was distilled off and the volume was maintained by the addition of water. The aqueous liquors were extracted with EA and the extract was washed with

  water, dried (Na2SO4) and evaporated. We shouted.

  the solid residue in an EA-PE mixture so as to obtain

  hold the title compound (450 mg), mp 180-182,

- 72.5.

  Preparation 109 33, 26-Diacetoxy-11a-N, N-dimethylamino-5ac-furost-20 (22) -ene

(LXXX)

  11e-dimethylaminotigogenin (2, 6g) in acetic anhydride (6 ml) and pyridine (3 ml) were heated in the steam bath for 30 minutes. The mixture was evaporated to give a solid. This solid was dissolved in octanoic acid (10 ml) and acetic anhydride (1 ml) and the mixture was distilled under a nitrogen atmosphere until the internal temperature had reached 240. This temperature was maintained for 2 hours, then the mixture was allowed to cool and extracted with EA. The extracts were washed with dilute NaHCO 3 solution and water and evaporated to give a gum. This gum was dissolved in MIE (20 ml), treated with KOH (2.0 g) and

  heated solution to the steam bath for 2 hours.

2485020T

  The product was precipitated by the addition of hot water and gold. isolated by filtration. This product was dissolved in acetic anhydride (6 ml) and pyridine (3 ml) and heated in a steam bath for 30 minutes. The crude product was isolated by evaporation and then

  purified by column chromatography and crystallized

  ED in order to obtain the compound indicated in

  the title (500 mg), P. ?. 131-134, LD + 4.2.

  Preparation 110 38-Acetoxy-1 X N N -dimethylamino-5-ene-6-ene-20-one LXXX (2.0 g) was cooled in acetic acid (21 ml) until the reaction was complete. to 10 in a water bath and treated with CrO3 (800 mg) in water

  (7 mil) The reaction mixture was stirred for 30 minutes.

  and poured it into benzene and water. We separated

  The benzene liquors were removed and the aqueous liquors were extracted with benzene. The combined benzene extracts were washed with a dilute solution of NaHCO 3 and water,

  they were filtered and evaporated to give 3P-acetoxy-

  11α-N, N-dimethylamino-16β- (5-acetoxy-4-pentanoyloxy) -5c-pre-

  crude gnane-20-one (1.9 g), in the form of a foam.

  The foam (1.9 g) in acetic acid (5 ml) containing a trace of pyridine under reflux was heated for 30 minutes. The mixture was allowed to cool and evaporated to give an oil. This oil was dissolved in EA, washed with 5% NaHCO 3 solution and water. The liquors were dried with EA (Na2SO4) and evaporated to a foam. We have purified

  this foam by thin layer chromatography of

  in order to obtain the title compound.

  (250 mg), r.7D + 9% * Preparation 111 11, N, N-dimethylamino-3,3-hydroxy-5-cnnn-1-1-e-20-one

(LXXII)

  Compound L! XXXI (6.0 g) in D (100 ml) was treated with KOH (2.0 g) in water (20 ml) and

  stirred at room temperature for 72 hours.

  The solution was concentrated by evaporation, diluted with water and extracted with EA. We washed them

: 485020

  extracted with water, dried (NTa2SO4) and evaporated to a foam. This foam was purified by column chromatography and crystallization from EA to give the title compound (466 mg), m.p. 135-140, F 7D + 12.9. Preparation 112 -! -NOT. N-Dimethylamino-3? -Hydroxv-5-urea-6-en-20-one Compound T! CXII (900 mg) in THF (35 ml) was treated with THF (THF) (35 ml). with HCO 2 H (0.27 ml) and triphenylphosphine (1.96 g) and stirred at room temperature for 15 minutes. AzodicarDoxylate was slowly added

  of diethyl (865 mg) in SEF (8 ml) to the reaction mixture

  and the solution was stirred at room temperature

  6 hours. The reaction mixture was concentrated by

  The residue was dissolved in EA and the solution was washed with NaHCO 3 solution and water. We have

  dried the liquors with EA (Na2SO4) and evaporated

  than getting a solid. This product was purified by column chromatography to obtain the crude 3-formate. This compound was dissolved in ME (10 ml), the solution was treated with 60% HClO4 (12 drops) and

  stirred at room temperature for 3 hours.

  The reaction mixture was concentrated by evaporation, diluted with 5% NaHCO 3 solution (10 ml) and water (20 ml) and extracted with EA 2. extracted with EA with water, dried (Na2SO4) and evaporated to a foam. This product was purified by preparative thin layer chromatography to obtain the title compound as the title compound.

  form of a foam (300 mg), - D + 160.

  Preparation 113 1 N-Dimethylaminotigo genin 11aaminotigogenin (1.1 g) was heated in HCHO (25 ml) and HCO2H (0.25 ml) until about 15 minutes. The solution was allowed to cool, diluted with saturated NaHCO 3 solution (70 ml) and water (150 ml). The crude precipitated product was isolated

  by filtration and crystallized from a mixture.

  in order to obtain the title compound (256 mg),

- '55; 2485020

Pff 10.3-105, 7D 7800.

FIP. 10 0.305O, PcC7D - 78.1o.

  Pre-ation 114 C-aminooret-4-en-3-yl-20-dione (LXXXIV) A 40% aqueous solution of NaOH (60 ml) was added and then NH2OH-HO1 (15 g) suspension of 3.5; 20,20-bisethylenedioxypregn-5-ene-11-one (5 g) in ET (200 ml). The mixture was refluxed for a total of 107 hours, then cooled and diluted with water (2 liters) with stirring. The precipitate was collected (5.01 g), we washed it with water

  (2 liters) and vacuum dried at 600 on P2O5.

  The proton magnetic resonance spectrum (CDC13) of the

  product showed that the material contained 3.3; 20,20-

  bisethylenedioxypregn-5-en-11-one 11-oxime.

  Na (4.5 g) was added in fractions, in the

  30 minutes, to a solution heated to reflux and

  oxime (4.50 g) in RP (225 ml). We heated

  the mixture was refluxed for 2 hours and then added

  carefully 10 ml of ME. The alcoholic solvents were then distilled off while adding

  water (225 ml) to maintain the volume. On-chilled

  the aqueous suspension thus obtained and extracted with EA and the extract was washed with saturated brine,

  it was dried and evaporated to a solid.

  This product was partitioned between 2N HCl and EA. The aqueous portion was washed with EA, then overlaid with EA, alkalized with ammonia solution (0.88) and the layers separated. The aqueous layer was extracted with an additional fraction of EA, and the combined extracts were washed with saturated brine,

  dried and evaporated to a solid. We shouted

  this product in an EA-PE mixture so as to collect

  read the title compound (1.12 g), mp. 146-1480, -7D + 1800, Preparation 115 1α-Dimethylaminoirer-4-ene-3. 20-dione (LX'DV) H 2 O 2 H (0.29 ml) was added to a suspension of LXXI.V (1.00 g) in HCHO (8 ml) and the mixture was warmed to room temperature. at about 100 for 15 minutes, then cooled and partitioned between an aqueous solution of NaHCO.sub.4 and EA. The oraniye extract was washed with saturated brine, dried and evaporated. The residue was crystallized from 1% to give the title compound (0.67 g), m.p. 159-1627, m.p.

L-D + 174.

-: 1XEXMIPLE 1

  11.1 N, N-dimethylamino-23-ethoxy, -3-hydroxyl-5c-urngnan-2-one A solution of MDMVIII (500mg) in methyl iodide (5mL) was stirred with K CO (1.5 g) 2 3 for 2 hours. The mixture was distributed between DE and

  water, and the organic phase was extracted with HCI-2N.

  The combined extracts were washed with DE and basified with 6N NaOH. The oily precipitate was extracted into DE and the extract was washed with water, dried (Na 2 SO 4) and evaporated to give a foam which was purified by preparative thin layer chromatography in a mixture AC-PE (1: 3) and crystallization in a mixture PE-DE, so as to obtain the compound indicated in the title

  (180mg), m.p. 139-143oC, L-7D + 84.

EXAMPLE 2

  11-N, N-dimethylamino-28-ethoxy-3. -Hdrdoxy-5α-orane-20-one The compound = V03ZIII (10 g) was stirred in a mixture of a solution of HCHO (120 ml) and formic acid (4.3 ml),

  at room temperature for 6.5 hours.

  DM (40 ml) was added to the mixture which was then adjusted to pH 11 with NIaOH solution. The organic phase was separated, washed with water and extracted with H 2 SO 4 solution (4.0 ml) in water (70 ml) and then extracted with water. with water. The acid extracts were combined and adjusted to pH 11 with NaOH solution.

  and they were re-extracted with DM. The organic extracts were washed

  with water and evaporated under reduced pressure to obtain a solid which was purified by filtration through silica gel in a DM-A mixture (9: 1) and crystallization from a mixture ACW, to give the title compound (6.43 g), -7D + 84.1, P.F.

123-131.

57 2485020

EXE2MPLE 3

  11-dimethy-1-yl-yl-hydroxy-5-yl) -pron-20-one Partially dissolved = 2IX (500 mg) in HCHO (10 ml) and formic acid (0.2 mi) and the reaction mixture was heated to about 1000 under a nitrogen atmosphere for 5 minutes. The reaction mixture was poured into a solution of NalICO and extracted.

  steroid by EA and the extract was washed with water.

  The organic layer was dried with 2N HCl and alkali -

  The solution was extracted with NaOH solution and extracted with EA. Removal of the solvent from the extract afforded a foam which was dissolved in a small amount of CH to add the resulting solution to a silica column in PE. The luton with EA-PT (1: 1) and removal of the solvent from the eluate gave the title compound as the title compound.

  white foam (370 mg), -7D + 83 (C, 1.5).

EXEMPLE 4

  1 cc-dimethylamino-3-hydroxy-5-organane-20-one. XXiXIX compound (2.8 g) was dissolved in

  methyl iodide (30 ml) and K2CO3 (3 g) was added.

  The reaction mixture was stirred for 17 hours. The methyl iodide was evaporated and the solid residue was partitioned between EA and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was dissolved in a small volume of CH and the solution was introduced into a column of basic alumina (60 g) in PT. The column was washed with EA and the eluate evaporated to give a scum. This scum was dissolved in IE (20 mL), 2N HCl (5 mL) was added and allowed to dry.

  rest the solution at room temperature for 15

  and then poured into an ice-cold solution of NaHCO3. The solid was filtered off and purified

  by thin layer chromatography of preparation using

  AC-PT mixture (1: 3) as solvent Elution with EA gave the title compound

(800mg), --7D + 85.

24s5o2o

EI =) THE 5

  I1-dimethylamino-3c-h] ydroxy-53-orane gnane-20-one

  XXXIX (200mg) was stirred at room temperature.

  at room temperature, with HCHO (4 ml) and formic acid (0.08 ml), for 23 hours. The solution was poured into 2N HCl (20 mL) and kept at room temperature for an additional 15 minutes. Dilution with the aqueous NaHCO3 solution and extraction with EA afforded the title compound, similar to the product of Example 3 by chromatography.

  thin layer and gas chromatography.

EXF2.'LES 6-23

  Table 4 summarizes the preparation of the following compounds from the corresponding 11α-amino-20-ketal: 11 c-N, N-dimethylamino-3α-hydroxy-5-pregnan-20-one

  7. 1ol-N, N-dimethylamino-3α-hydroxy-6-methyl-5α-pregnane

-one

  8. 11α-N, N-dimethyl-21,21-ethylene-3α-hydroxy-5-

préggnane-20-one

  9. 11C-N, N-dimethylamino-3X-hydroxy-21-methyl-5x-pre. gnane-

-one

  10. lcc-N, N-dimethylamino-3-hydroxy-21-methoxy-5a-pregnane

-one

  i1. 11-N, N-dimethylamino-3α-dihydroxy-2α-methyl-5-pregnanate

20-one

  12. 1C1-N, N-dimethylamino-3c-hydroxy-3-methyl-5-pregnane

  -one 13. 3x-hydroxy-1-morpholino-5α-pregnan-20-one

  I 4. 11C-N, N-dimethylamino-3N-hydroxy-2'-methoxy-5a

  pregnan-20-one 15. 1-N, N-dipropylamino-3α-hydroxy-5x-pregnan-20-one 16. 3α-hydroeryl-11α-morpholino-5-pregnan-20-one

  17. 11c-N1, N-dimethylamino-35c-hydroxy-2-methyl-5a-pregnane

-one

  18. 2-Butoxy-1-NN-dimethylamino-3c-hydroxy-5a-pregnane

  -one 19. 2pP-ethoxy-3a-hydroxy-1-yl-morpholino-5-ac-pregnan-20-one 20. 2-methoxy-3α-hydroxy-pyrrolidino-5-pregnan-20-one 21. * I-2-azetidino-3-ethoxy 3α-hydroxy-5-pregynan-20-one 21α-azSet-d-ino-2-Sethox-γ-3mhydiromy-5a-pregnan-20-one * d-

  22. 11-N, N-diallylamino-2β-ethoxy-3α-hydroxy-5-pregnan-20-

one

  23. 11-N, N-diethylamino-3m-hydroxy-5cc-pregnan-20-one.

  The following preparation methods were used: A. The llamine was heated to about 1000 with formic acid in an aqueous HCHO solution. The mixture was cooled and partitioned between EA and 5% aqueous NaHCO 3. The extract was extracted with EA 2N HCl and the aqueous extract was basified. with a 40% NaOH solution, it was re-extracted with

  EA, washed with water, dried and evaporated.

  B. The 11-amine was stirred at room temperature (unless otherwise specified) with an alkyl halide and K 2 CO 3. The mixture was then treated by one of the following methods: (i) K 2 CO 3 was filtered off and the alkyl halide was removed under reduced pressure. The mixture was partitioned between EA and HCl. water and the organic phase was extracted with 2N1 HCl. The aqueous layer was basified with an aqueous NaOH solution and extracted with

  from the EA. The layer was washed with EA, dried and evaporated.

  (ii) - The mixture is distributed between (a) DE or (b) -

  CH 2 and water and the organic phase was extracted with 1N HCl. The acidic phase was basified with aqueous NaOH and reextracted with ED. The extracts were washed,

they were dried and evaporated.

  (iii) As described in Preparation 72.

  (iv) The mixture was diluted with DE and water and

  washed the organic layer with water, dried it and evaporated

porated.

  The material obtained by purifying one of these methods has been purified by column chromatography and / or

  Thin layer chromatography-preparation and / or crystallization

tion.

E. M54PLE 24

  11α-diethylamino-3α-hydroxy-58-preynane-20-one The compound was dissolved. X'XI (0.5 g) in ET (25 ml) and acetaldehyde (5 ml) and NaBH3CN (250 mg) was added. The reaction mixture was kept at room temperature for 15 minutes and then acidified with dichloromethane. 2485020 l1HC1 2N. After another 15 minutes, the solution was basified with KOH and extracted with EA. Crystallization in an IE-ir mixture made it possible to obtain

  title compound (354 mg), m.p. 123-125 0-

L-7D + 36.

EXAMPLE 25

  L-di (amino) amino) -benzyl-5-ene-20-one.

  Compound XXEIX (50 mg) was dissolved in ET (2.5 ml) and alketaldehyde (0.25 ml) and NaBH4 (25 mg) were added. The reaction mixture was kept at room temperature for 30 minutes and then

  treated in the manner described in Example 24, in order to obtain

  the compound indicated in the title which has been shown to be

  identical to the product obtained in Example 24, according to the chroma-

gas phase graphography.

FEXETLE 26

  23-Ethoxv, -3 "-hydroxy-11-pioeridino-5α-oregnan-20-one Compound XCXVII (0.5 g) was mixed with a 25% aqueous solution of glutaric dialdehyde (2 ml) in ET (10 ml) at room temperature and NaBHE3CN (250 mag) and acetic acid (0.1 ml) were added After 6 hours, the mixture was treated as described in Preparation 73 and purified by column chromatography and thin layer chromatography to give the title data (211 mg) as the

  foam form, L-a-7D + 35.2.

EXAMPLE 27

  3a-hydroxv = -1-piperidino-58-pregnan-20-one Compound XXXIX (1 g) was mixed with NaBH3CN

  (500 mg) and a 25% aqueous solution of gluteal dialdehyde

  (5 ml) in ET. (10 ml) at room temperature

  and acetic acid (0.2 ml) was added. After 3-o'clock

  The mixture was partitioned between EA and aHCO3- solution. The organic solution was washed with 2N HCl and the organic extracts were washed with water, basified using 50% NaOH solution, extracted with EA, washed with water, dried (MIgSO4) and evaporated to give a foam., This material was purified by preparative thin layer chromatography eluting with

  MSe containing about 1% water and the solution was evaporated.

  The product was then dissolved in DE, filtered and evaporated to give the title compound.

  in the title (318 mg), -J7D + 58.5.

EXEIPLE 28

  11a-dimethylamino-2-ethoxy-3m-yl-5-hydroxy-5-butanone-20-enne (a) LIX compound (200mg) was heated to about

  100 with HCHO (4 ml) and formic acid (0.08 ml)

  10 minutes. The reaction mixture was poured into a

  NaHCO3 solution and the steroid was extracted using EAA.

  TLC preparation-using AC-PT (3: 7) and crystallization from DE-PT gave the title compound.

(50mg), mp 14o-143.

  (b) LIX compound (250 mg) was dissolved in EA (25 ml) and a 37% aqueous solution of HCHO (0.5 ml). Charcoal bearing 10% palladium (250 mg) was added and the solution was hydrogenated for 17 hours. The catalyst was filtered off through kieselguhr and the solution was washed with water, dried (14 gSO4) and evaporated to dryness. Thin-layer chromatography preparation using CH-XA-ME (49: 49: 2), followed by crystallization in an AC-W mixture, allowed

  to obtain the title compound (100 mg), m.p.

129-134.

  (c) LIX compound (100mg) was dissolved in EA

  (10 ml) and HCHO (0.2 ml). Tris (triphenyl-

  phosphonate) chloro-rhodium (50 mg) and the solution was hydrogenated for 17 hours. It was then washed with water and the organic layer was dried (MgSO 4) and evaporated to

  dryness. Chromatography on thick plates using

  a mixture of iMA-PT-, (33: 65: 2) as solvent allowed to obtain

  The title compound (30 mg), as indicated by thin layer chromatography and gas chromatography, is identical to the product of part (a). b2 2485020

EX EM_-T THE 29

  1i1 ir: -N. T-Diethylamino-3-hydroxyl-5-enznan-20-ona (LoIl) (a) Compound LX (50 mg) was stirred at room temperature with HOHO (1 mL) and brine. formic acid (0:02 ml) for 23 hours to give the title product as indicated by thin layer chromatography.

  that it was identical to the product of Example 3.

  (b) Compound LX (50 mg) was dissolved in EA (10 ml) and paraformaldehyde (100 mg) and charcoal bearing 10% platinum (50 mg) was added. We have

  stirred the reaction mixture for 17 hours, under atmospheric

  of hydrogen, so as to obtain the title compound whose thin layer chromatography revealed that

  was identical to the product obtained in Example 3.

  (c) Compound LX (100 mg) was dissolved in EA (10 ml) and HOCHO (1 ml) and charcoal bearing 10% palladium (100 mg) was added. the reaction mixture for 17 hours and the catalyst was filtered off through kieselgubr. The solution was washed with water, dried (MgSO 4) and

* it was evaporated to dryness in order to obtain the

  reported in the title (110 mg) including thin-layer chromatography and magnetic resonance spectroscopy

  protonic revealed that it resembles the product of lexem-

ple 3.

  (d) A solution of HCHO in EA (20 ml, prepared by heating 200% paraformaldehyde and bubbling the gaseous HCHO in EA for minutes) was added to LX compound (100 mg) and charcoal

  supporting 10% palladium (100 mg) in EA (5 ml).

  The reaction mixture was stirred with hydrogen for minutes to give the title compound which thin layer chromatography revealed to be

  identical to the product of Example 3.

35.LEE1PL 30-

  11 -N. iT-dinethvilmino-28-ethoxy-3-hydroxy-21-methyl-5cc

prgngane-20-one-

  The ZIEI compound (1.00 g) was heated for minutes to about 100 ° in a mixture of a solution of HCHO0 (20 ml) and formic acid (0.4 ml). The reaction mixture was diluted with 5% NaHCO 3 solution (50 ml) and extracted with EA. The organic extracts were extracted with 2N HCl, alkalinized to pH of 11 with 40% NaOH and reextracted with DM. The extract was dried (Na SO 4) 24 'and evaporated to give a foam which was purified by column chromatography using EA as the eluent to give the title compound. indicated in the title as a foam (828 mg). L, - 7D +

72.

EXAMPLE 31

  11-Dimethylamino-3x-hydrox-D-homo-5a-Dre, gnane-20-one A suspension of LXIII (656 mg) in HCHO (5 ml) was treated with formic acid (O, 21 mg) and the mixture was heated to about 100 for 5 minutes. We have

  distributed the cooled solution between EA and 2N Na2CO3.

  The organic fraction was washed with brine, saturated, dried and evaporated to give a foam (704 mg). This compound was purified by preparative thin layer chromatography (MIE) and crystallized from

  to obtain the compound indicated in the title m.p.

118, L7: D + 41.5.

EXAMPLE 32

  11 "-methylamino-2-ethoxy-3α-hydroxy-D-homo-5o-pregnan-20-

  Formic acid (0.29 ml) was added. to one

  suspension of LXIV compound (1 g) in-HCHO-O. We heated

  the mixture in a steam bath for 20 minutes, it was

  cooled and partitioned between 1EA and a 5% aqueous solution of NaHCO 3 -. The organic extract was washed with saturated brine, dried and evaporated to a foam. This product was purified by thin layer chromatography (Ti) and by crystallization in ANI to

  obtain the title compound (469 mg), m.p.

132.5-133.5, - o_7D + 46.80.

  EXAMPLE 33 (Z) -11cc-dimethylamino-23-ethoxy-5-oxo-17-enen (20) -ene-oeol A mixture of LXV (1.8 g), HCHO (12 g) ml) and formic acid (1.2 ml) at about 1000 for 5 minutes before pouring into a solution

6 * 4 {2485020

  aqueous NaHCO3. The solid precipitate formed was collected by filtration, washed with water and dissolved in EA. Evaporation yielded a foam which was filtered through a silica pad in a 1: 1 EA-PE mixture. Recrystallization in an i-W mixture allowed

  to obtain the title compound, m.p. 63-78o, -

L7s ^ / D - 2.

EXE MPLE 34

  (Z) -1-t-dimethylamino-5-pregn-17 (20) -ene-3 "-ol A suspension of compound XLI (550 mg) in HC-HO (4 ml) was treated in formic acid (0.3 ml) and

  stirred the mixture until the steroid was dissolved ..

  The solution was heated to about 100 for 10 minutes.

  It was cooled and diluted with an excess of NaOFH solution. The precipitated material was extracted with EA, the extract was washed with water and then with 2N HCl. The acid extract was washed with EA,

  alkalized with NaOH and reextracted with EA.

  Evaporation of the washed organic extract gave a crystalline material which was purified by layer chromatography

  preparation of 5% óE-CH and by crystallization in one

  SE-W mixture so as to obtain the compound indicated in

  title (309 mg), mp 59-61, -D-8.1.

EXEIPLE 35

  (7) -1α-diethylamino-5α-nren-17 (20) -ene-3x-ol A solution of compound XLI (608 mg) in ET (20 ml) was treated with acetic acid ( 0.1 ml) and NaBH-3CN (231 mg). The mixture was kept at room temperature for 27 minutes and then acetaldehyde (3 ml) was added. After another 15 minutes, the mixture was treated as described in Example 24 and purified by preparative thin layer chromatography (EA) and crystallization from ANWX to give the title compound. in the title

  (333 mg), m.p. 89-90, L - D -38.1.

EXEMPLE -36 -

  (Z) -Di-ridino-5α-amino-17 (20) -en-5α-ol A solution of compound XLI (725 mg) in 1IS (10 ml) was treated with NaBF. CN (395mg), a 25% aqueous solution of glutaric dialdehyde (2ml) and

: 485020

  acetic acid (0.1 ml). The mixture was kept at room temperature for 1 hour and then treated as described in Example 24. Purification by thin layer chromatography preparation using 10% IE-EA mixture allowed obtain the compound indicated in the title, under the

  foam (410 mg), _7D - 15.30.

EXEIPLE 37

  1-Dimethylamino-5-ac-crégn-20-ene-35-ol 11-Amino-5-cis-20-en-3a-ol (650 mg) was stirred in methyl iodide (15 ml) with K2CO3. , for 6 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was partitioned between EA and water. The organic layer was washed with water and then extracted with dilute HCl. We extracted the extract

  acid with EA, it was alkalized with a concentrated solution

  ammonia and extracted with EA. The organic extract was washed with water, dried (MgSO4) and evaporated to give a foam. This foam was purified by preparative thin layer chromatography (EA-PZ 1: 1), to give the title compound as a crystalline solid (270 mg), mp 131-133 ° C.

FEXIEPLE 38-46

  Table 5 summarizes the preparation of N-N-disubstituted 11-amines from N-monosubstituted 11-amines according to the following method:

  The amine was dissolved in a solution of HCHO con-

  Formic acid was added and the mixture was heated to about 0 ° C. The mixture was then treated according to one of the following methods: A. The mixture was partitioned between EA and aqueous NaHCO 3 solution and washed the extract with EA with brine,

it was dried and evaporated.

  B. The mixture was diluted with water and extracted with EA. The aqueous layer was basified with NaOH, extracted with EA and evaporated. The original EA wash liquors were washed with NaOH and water and evaporated. We gathered

residues.

- 66

Z485020

  C. The mixture was neutralized with lTaOI- and

  extracted by the EA. The washed extract was evaporated.

  D. The mixture was diluted with saturated solution

  of ITaHC03 and the precipitate was collected.

  The obtained material was purified by one of these methods by column chromatography or by thin layer chromatography preparation and / or by

cry stallization.

  The following compounds were prepared:

  38 o 11-C-N-cyclohexyl-N-methylamino-2β-e-thoxy-3c-hydroxy

a-prégnanr.e-20-one

  23-Ethoxy-3? -Hydroxy-1? -1- (N? -Methyl) -1-4-metylpfen

  2-ylamino) -5a-pregnan-20-one, isomer A

  40. 2-Ethyloxy-3α-hydroxy-11α- (N-methyl-N-4-methylpentane)

  2-ylamino) -5a-pregnan-20-one, isomer B

  41. 11α-N-benzyl-N-methylamino-2-ethoxy-β-hydroxy

a-pregnan-20-one

  42. 11 o-N-allyl-N-methylamino-2β-ethoxy-3α-hydroxó-

c-pregnan-20-one

  45. (Z) -Cl-N-ethyl-N-methylamino-5? -Pregn-17 (20) -ene-

3cc-ol

  44. (Z) - 1α-N-isopropyl-N-methylamino-5α-pregn-17 (20) -

ene-3 "ol

  45. 11a-N-ethyl-N-methylamino-3cc-hydroxy-5f8-pregna8ae-

20-one

  46. 3α-Hydroxy-11α-N-iso-propyl-IN-methylamino-55-precursor

  EXAMPLE 47 3α-Hydroxy-1α-methyl-2-propylamino-5α-pregnane-20-one A solution of LXVI compound (380 mg) in methyl iodide (10 ml) was stirred with hexane-20-one. K2CO3 (1 g) for 4 hours. The mixture was diluted with DE and with

  water, and the organic phase was extracted with 2N HCl.

  The extract was basified with 6N NaOH and the oily precipitate was extracted with DE. The extracts were washed with water, dried (Na2SO4) and evaporated to leave a foam which was purified by preparative thin-layer chromatography and crystallization from DE, to give the title compound (210 mg), mp 149-152 ° C, -g-7D + 90

* 67 248.5020

EXAMPLE 48

  1α-N-Butyl-11-methylamino-3-hydroxy-5α-pregelane-20-one ODn stirred a solution of the compound LXVII (1g) in methyl iodide (40ml) with K2CO3 (3-g) for 3 hours. The treatment carried out as described in Example 47 and the purification by chromatography in co. Thin preparation prepared in a mixture of AC-PE (1: 3) afforded the title compound (680 mg), a /, D + 83 0.

EXAMPLE 49

  11m-N-ethyl-N-methylamino-3c-hydroxyl-5α-pregnan-20-one A solution of LXVIII (370mg) in methyl iodide (2ml) and D-4 was stirred. (40 ml) - with K2CO3 (1 g), for 3 hours. DE and water -15 were added, and the organic phase was washed with water, dried (Na2SO4) and evaporated to give a foam which was

  it was purified by thin layer chromatography of prepa-

  in a mixture of AC-PE (1: 3), so as to obtain the

  title compound (350 mg), in the form of a -

foam, _ / -7D +83.7. -

  EXELwLE 50 11 -N. N-Dimethylamino-28-ethox-3-hydroxy-5α-pregnane-20one LXIX (560 mg) was stirred with boron trifluoride etherate (0.5 ml) in TE ( 25 ml) at 20 for 4 days. We concentrated the mixture

  by evaporation and partitioned between EA and a solution.

  2N Na2CO3. The aqueous layer was extracted by

  additional amount of EA and the organic solutions were washed

  These were pooled with saturated brine, dried (IgSO4) and evaporated to give an oil. This oil was purified by preparative thin-layer chromatography and recrystallization from PE to give the title compound (46 mg), mp 1351-137.5,

LcC 7D + 83.3.

EXAMPLE 51

  11 -NV. N-dimethylamino-23-ethoxy-3α-hydroxy-5-precan-20-one A 60% aqueous solution of perchloric acid (2 ml) was added to a stirred solution of LXIX ( 1 g) in ET (100 ml) at 200. After 2 hours a solution of Ia2CO3 was added so as to raise the pHI of the mixture to 9 and -2CO b8

Z 2485020

  hunted most of the ET by evaporation. The residue was partitioned between EA and water. The aqueous layer was extracted with additional EA and the combined organic solutions were washed with saturated brine, dried (INa 2 SO 4) and evaporated to dryness.

  - hold an eraser This cream was purified by chromatography.

  thin layer of preparation and recrystallisa-

  in an ET-W mixture so as to obtain the compound

  reported in the title (504 mg), m.p. 119-123, / -a 7D + 83.

E IPF LE 52-70

  Table 6 summarizes the preparation of 2P-substituted

  11-amines disubstituted from the corresponding 2,3-epoxide corresponding

  According to the following process: The 2 × 3a-epoxide was treated with the appropriate alcohol or acid, in the presence of a catalyst (when necessary) at room temperature. (or at 100 C

  in the case of 20-acetoxy compounds) during the period of -

  indicated time. The mixture was diluted with an aqueous solution of Na2CO3 (or an aqueous solution of NaOIS in the case of the 2p-fluoro compounds) and treated according to one of the following methods: A. The mixture was extracted with the EA and we washed

  the extract with brine, then dried and evaporated.

  B. The solid that precipitated by

  filtration, washed and dried.

  C. The alcohol was evaporated and the residue was extracted

  aqueous as described in A above.

  The obtained material was purified by one of these methods by column chromatography and / or preparative thin layer chromatography and / or by

crystallization. -

  The 25-substituted derivatives were thus prepared

  3a-hydroxy-11X-1, -N, N-dimethylamino-5a-pregnane-20-

  one (the numbers of the examples are given in parentheses) - 23-fluoro (66), - chloro (61), bromo (65), - thiocyanato (64), -acetoxy- (69), propoxy (54),

  benzyloxy (59) -chloroethoxy (60), and iso-

  propoxy (52); 1 x-N-thyl-1-metaylamino-3α-hydroxy-5α-pregnane-20one:

2485O20

  fluoro (63), chloro (62), methoxy (55) ethoxy (53) and acetoxy (50);

  and 3α-hydroxy-1α-n-iso-propyl-methyl-5c-pregnane

-one: -

  23-fluoro (67), -chloro (63), -methoxy (56),

ethoxy (57) and acetoxy (58).

  HC104 was used as a 60 t aqueous solution.

EXEM! PLE 71

  10.?1.-N. N-Dimethylamino-3α-hydoxy-5 "-androstane-173-carbonitrile A solution of compound LXX (500 mg) in IE (150 ml) was treated with saturated NaHCO 3 solution (20 ml) at room temperature. reflux for 24 hours.

  mixture with water up to 1 liter and separated the

  The precipitate formed by filtration was washed with water and dried. The solid (340 mg) was purified by preparative thin layer chromatography in EA-PE (1: 2) and crystallization from DE-PE to give the title compound (170). mg), mp 183-186 ° C,

L, 7D + 47.5;

EXAMPLE 72

  11 a-N. ' N-dimethvlamino-23-aesthoxy-t -b-bromo-5a-androstane

  17. Carbonitrile A solution of compound IXXI (320 mg) in 1. (80 ml) at reflux temperature was treated with saturated NaHCO3 solution (8 ml). After 5 hours, the mixture was diluted to 600 ml with water and the precipitate was extracted with DE. The extracts were washed with water,

  they were dried (Na2SO4) and evaporated to the

  retention of a foam (300 mg) which was purified by preparative thin layer chromatography in a mixture of AC-PE (1; 3), to obtain the compound indicated in FIG.

  titre (250 mg), in the form of a foam | -a_ D + 46.

EXAMPLE 7-3

  11-dimethylamino-3? -Hydroxv-5% -androstane-17-carbonitrile CHCO3 (1 g) in water (20 ml) was added to a solution of compound LXXII (500 mg) in EMI (50 ml) and the mixture was refluxed under nitrogen for 2 hours. Dilution with water and extraction with EA provided a crude product which was crystallized from a DE-PE mixture and a MI-V mixture, to obtain the compound indicated in FIG. title (170 mg), P .. 137-139o / -x7D + 67

ZE'EMPLE 74

  21-aceto: y-11-T1, N-dit 2,4 Tl-mino-q-hyro, 5G - =. Leaded tetraacetate (1.0 g) was added to a solution of IXXIi (0: 5 g) in benzene (18 ml) and H (1.15 ml). The solution was cooled to 10 and boron trifluoride etherate (2.85 ml) was added thereto; The reaction mixture was stirred at 100 for 5 hours and then poured into an aqueous solution of NaIO3. n We have

  extracted the steroid with DE and subjected to a chromato-

  thin-layer graphing of preparation in EA-PT 2: 1 mixture. Elution with EA, followed by crystallization in DE, gave the compound indicated in FIG.

titre (100 mg), mp 150-152.

E.EX: 1PLE 75

  3c. 21-dihydroxy-11-dimethylamino-5-o-organ-20-one Compound LXXIV (500 mg) was dissolved in Me (20 ml) and an aqueous solution of kMC03 (5 ml) was added. ,%). The solution was refluxed under a nitrogen atmosphere for 2 hours and then poured into

  water and the steroid was extracted with EA. The weather

  Thin-film preparation prepared using a 1: 2 ACPT mixture as the solvent and eluting with AC afforded the title compound as a white foam (310). mg), / ú --- D + 470 '

FXEMPLE 76

  1-dimethylamino-3α-hydroxy-5m-pt 8rane-20-one

  The compound LVIII (110 mg) was treated with a solution of

  refluxing of the chloriridic acid reagent (3 ml) for 1 hour, before partitioning between EA and aqueous NaHCO 3 solution. The organic phase was isolated, washed with water and evaporated to a foam. Crystallization from PE gave the compound.

  titre (78 mg), PF. 119-122, L-α7D + 76.00.

EXAMPLE 77

  11α-dimethylaminopoly-5-hydroxy-5-enan-20-one to a mixture of the compound LVII (362 mg) of acid

  formic acid (0.11 ml), triphenylphosphine (787 mg) and tetra-

  hydrofuran (15 ml), a solution of azodicarboxylic acid was added

  diethylate (348 mg) in tetrahydrofuran (3 ml).

  The solution was allowed to stand overnight at room temperature.

  at room temperature, before distributing it between ethyl acetate and aqueous NaHCO 3 solution. The organic phase was isolated, washed with water, dried (Na 2 SO 4)

  and evaporated to obtain a scum. The chroma-

  columnography (eluting with DM)

  Permitted to obtain a foam that has been dissolved in E--

  (10 ml) and treated with 10 drops of perchloric acid.

  After 0.5 hours, the reaction mixture was treated as described in Example 76. Crystallization from PE allowed

  to obtain the title compound (106 mg), m.p.

119-123, cc 7 D + 76.70.

EXAMPLE 78

  1-Dimethylamino-21-ethoxy-3-hydroxyl-pregnane-20-one XLV (100 mg) was stirred with PTSA

  (61 mg) in DC (10 ml) and ET (5 ml) for 5 minutes.

  2-Chloroperbenzoic acid (75 mg) was added and, after 24 hours at 20, thin layer chromatography was allowed

  to note the formation of the compound indicated in the title.

EX = EPLE 79

  1α-N, N-dimethylamino-28-ethoxy-3-hydroxyl-sa-propan-20-one Compound XI (3.0 g) was dissolved in DM (20 ml)

  and the solution was extracted with a sulfuric acid solution

  Concentrate (18 ml) in water (25 ml) and then with water (15 ml). The combined aqueous extracts were kept at room temperature for 10 minutes and then

  brought to a pH of 11 by the addition of a solution of NaOH.

  The precipitate was extracted with DM and the extracts were washed with water. The dried solution (MgSO 4) was subjected to column chromatography eluting with dim-MA (9: 1). The eluate was evaporated to give a foam which was crystallized from AC-W (4: 1) to give the title compound (1.66 g) -xD. + 74 0 mp 135-14 oX:

E-X.MLE 80

  i1 cc-W \ fN. 2-dimethylamino-2-yloxy-3α, -hydroxy-5α-androstane-173-

  Methyl carboxylate Iodomethane (8.4 ml) was added to a solution of compound LTV (3.5 g) in dimethylformamide (30 ml) and triethylamine (25 ml). After stirring for 20 hours, the mixture was poured into 5% NaHCO 3 solution (50 ml) and extracted with CH 2. The combined extracts were dried (MgSO4) and evaporated. The residue was purified by column chromatography using 1: 4 EA-PE as eluent, to give the title compound.

  title in the form of a foam (965 my), D + 35.

EX = IPLE 81 -

  1. N N -dimethylamino-25-ethoxy-5-hydroxyl-21-uropyr-5-yl

  Pregnan-20-one Butyl lithium in hexane (8.6 ml, 1.7 M) was added to a suspension of LXXV (2.0 g) in DE (12 ml), under an atmosphere of nitrogen, while cooling with an ice bath and water. The mixture was stirred vigorously for 31 hours and then diluted with water (25 ml). The mixture was extracted with EA and the combined extracts were washed with 0.1N NaOH. The dried extract (IgSO4) was evaporated to obtain a foam which was purified

  by thin layer chromatography of preparation on aluminum

  mine, using an EA-PE 1; 2 mixture as eluent,

  to obtain the title compound (146 mg), under

  the shape of a foam, / - ', 7D + 75 -

EXE?, PLE 82

  C1-diethylamino-3α-hydroxy-5α-pregn-1-en-20-one

  2.-Bromo-11-N, N-dimethylamino was stirred.

  3-hlydroxy-5-pregnan-20-one (2.76 g) with dihydropyran

  (7 ml) and PTSA (1.30 g) in benzene (150 ml) at 21 ° C.

  After 1 hour, the clear solution was washed with an excess of

  2N Na2CO3 solution, a brine to finally

  Dry (Na2SOA). The benzene was then evaporated off.

  in order to obtain an oil which was then dissolved in Dn. (75 ml) and heated to 105 ° -115 ° with CaCO 2 (7.5 g) and LiBr (10 g) for 19 hours. The mixture was diluted with E and the insoluble solids were separated.

  by filtration. The residue was washed with an additional amount of

  In addition, the combined methanolic solutions were diluted to a volume of about 0.00 ml. The pH of this solution was recalibrated to 1 with 2N HCl and, after 1 hour at 210, a solution of 2N Na2CO3 was added to raise the pH of the mixture to 9.0 and the iE was evaporated. reduced pressure. The residue was extracted twice with EA and the combined extracts were washed with

  brine, then dried (Na2SO4) and evaporated to obtain

  nir an oil. Residual DMFL was removed using an oil pump to leave a gum. This gum was dissolved in a 1: 1 EA-PE mixture and the solution was filtered through silica gel (30 g), so that

  get the raw product. This product was purified by chromatography

  Thin layer preparation (EA-PE), to give the title compound (611 mg), Z-L_7D

+ 1.50.

EXAMPLE 83-157

  Salt Preparation Table 7 summarizes the properties and preparation of aqueous solutions of salts according to the invention by one of the following methods: A. 11-amine is added to a solution of the acid

  in water and the mixture was shaken or shaken until

  than obtaining a clear solution. The weight of the solution was brought to the indicated value with water, filtered through a membrane and

determined the pH.

  B. Process identical to that described in A above,

  except that before adding water, the solution was filtered

  tion and was treated drop by drop by a solution

  0.1 N NaOH, until the initial precipitate is

  If formed, it is not redissolvated much more by agitation. C. A 1-amine solution was treated in

  ET with a solution of the acid in water.

  The mixture was evaporated in vacuo and dried to constant weight. The residue was dissolved in a little water and any material which remained then remained undissolved in a weighed funnel and the weight of dissolved free base was calculated. The solids were brought to the indicated value with water, and the temperature was increased.

its pH.

  The 1α-amine was added to a solution of the acid and the mixture was stirred or strained. As the subsistence of undissolved free base,

  additional acid has been added and

  veal stirred the mixture. The solution was filled with water and then all the material was collected.

  then remained in the undissolved state in -n. eno-

  weighed and the weight of the dissolved free phase was calculated and the pH of solution E was measured. The 11-amine was added to a solution of the acid.

  in water and the mixture was shaken or shaken.

  The weight of the solution has been brought to the

  with water. The material was collected smsi-

  both in the undissolved state in a weighed funnel and the weight of the dissolved free base was calculated

  and the pH of the solution was measured.

  Solid citric acid was used under the heading

of its monohydrate.

EM PLES 1-58-171

  Preparation of salts of 1 x-oren-20-one (Table 8) The amine was added to a solution of the acid in water and the mixture was stirred or shaken until a clear solution. The solution was then treated as follows: (A) dropwise with 0.1M NaOH until the initially formed precipitate was redissolved just to the weight indicated with I 'ean,

  it has been filtered through a membrane and in 9E has

  finished the pH; or (B) the weight was brought to the indicated value with e-au, filtered through a membrane and

* the pH was determined.

EXAMPLES 172-180

  Preparation of 1α, 11c-N, N-dimethylamino-3'-hydroxy-salts

  58-pregnan-20-one (Table 9) The amine was added to a solution of the acid in water and the mixture was stirred or shaken. until a clear solution is obtained. The weight of this solution was brought to the indicated value with water, filtered through

  a membrane and determined the pH.

To * EXAMPLE 181

  11a-N, N-dimethylamino-26-thoxy-3α-hydroxyhydrochloride

a-pregnan-20-one

  A solution of 11-N, N-dimethylamino-

  2β-Ethoxy-3α-hydroxy-5α-pregnan-20-one (10.5 g) in DE

  (80 ml), while passing a current of HCl

  through it. The precipitated solid was collected by filtration.

  under the pressure of a nitrogen atmosphere and was washed thoroughly with DE and dried,

  to obtain the title compound (11.5 g), m.p.

  Dec. 200 C, Z a-7D + 35 - (ME) EXAMPLE 182

  11-N, N-dimethylamino-28-ethoxy-53-hydroxyl-5c-citrate

pregnan-20-one

  A solution of 11a-N, N-dimethylamino was added.

  28-ethoxy-3α-hydroxv-5α-pregnan-20-one (1 g) in DE (20 ml) to a stirred solution of citric acid monohydrate (1.05 g) in DE (60 ml); A precipitate formed immediately which was collected by filtration under nitrogen pressure so as to obtain the compound indicated in the title

  containing 1 mole of citric acid in excess.

  The filtrate was evaporated to half of its

  volume of origin and the precipitate was collected by filtration.

  in order to obtain an additional amount of

  title product containing 1 mole of citric acid

  than in excess. Values 6 (D20) encompass 9.35 (s, 18-H), 8.87 (s, 19-H), 8, 84 (t, J 7Hz, -OCH 2 CH 3), 7.78 (s, 21-H) ), (doublet triplet, J 12 and 5 Hz, 11P-H), 7.02 and 7.24 (qAB, J 16 Hz, -CH 2 - citric acid), 6.97 and 7.09 (2 singlet, 11- + NH (CH3) 2), 6.2-6.6 (m, -OCH2CH3, 2a-H and

1o-H) and 6.05 (m, 3P-H).

: -: 765

-76 to 2485020

EXAMPLE 183

  21-acetoxy-11 "-N, N-dimethylamino-23 - methoxy-3c-hydroxy-5-

  pregnane-20-one (XXIX) A solution of compound XXVIII (200 mg) in AC (10 ml) was stirred at room temperature with anhydrous potassium acetate (200 mg), for 4 hours. The mixture was diluted with water to 100 ml and the precipitate was extracted with DE. The extract was washed with water, dried (Na2SO4) and evaporated to give a foam (180 mg) which was purified by chromatography. in a thin layer of EA * PE preparation (1: 1), to give the title compound (414 mg),

  in the form of a foam, --ó_7D ± 90.5.

  EXAMPLE 184 -15 11-Dimethylamino-3-hydroxy-53-pregnan-20-one 11cc-amino-5-pregnan-3a, 20P-diol (4 / mg) was heated in a 37% aqueous solution of HCHO (1 ml) and HCO2H (0.01 ml) in a steam bath for 5 minutes. The cooled solution was diluted with NaHCO 3 solution and extracted with EA. Evaporation of the washed and dried organic excess (MgSO 4) yielded an eraser which

  was purified by thin layer chromatography of

  in a mixture of AC-PE (2: 5), so as to obtain the

  11-dimethylamino-5β-pregnane-3α, 20α-diol.

  The latter compound (40mg) was treated in AC (4ml) at 0 with Jones reagent (0.24ml). After minutes, the mixture was poured into ice-cold NaHCO 3 solution and extracted with EA. The washed and dried extract (MgSO 4) was evaporated to give a solid which was purified by filtration through silica gel in a mixture of AC-PE (1:10) and crystallization from a mixture. ME-W, so as to obtain 11-dimethylamino-5B-pregnane-3,20-

dione (10 mg).

  A solution of this last compound (250 mg) in ET (17 ml) was stirred at room temperature for 15 minutes with NaBH4 (125 mg). Excess NaBH4 was decomposed by the addition of a little acetic acid and the mixture was then diluted with NaHCO3 solution.

  to finally extract it from the EA. The evaporation of the former

  washed and dried (MgSO4) line gave a foam that

  it was purified by thin layer chromatography of

  paration using an AC-PE mixture (1: 5), so that

  obtain the title compound a-7 + 66.20.

EXENIPLE 185

  1. N, N-dimethylamino-28-ethoxy, -3α-hydroxy-5α-pregnan-20-one Triethylarmmonium salt of LXXV (500 mg) was dissolved in dry THF (5 ml). Methyl lithium (7.2 ml, 1.7 M solution in ED) was added and the mixture was stirred.

  mixture at 20, under a nitrogen atmosphere, for 28 hours.

  Water (25 μl) was added and the mixture was extracted with EA (3x). The combined extracts were dried (MgSO 4) and evaporated to give the title compound (372 mg), which was chromatographed to reveal that it was

  similar to the product obtained in Example 1.

EXAMPLE 186

  (Z) -17-cyanomethylen-11-dimethylamino-23-etthoxy-5a-androstane

3x-ol

  To a mixture of NaH (500 mg), cyanomethyl phospha-

  of diethyl (4 ml) and dry THF (16 ml) was added

  solution of compound LXXIX (1.2 g) in dry THF (12 ml).

  The reaction mixture was stirred overnight at room temperature before being partitioned between EA and water. The organic phase was washed with water, it was

  dried (Na2SO4) and evaporated to an oil.

  Purification by column chromatography (EA-PE) and crystallization in a ME-W "mixture, made it possible to obtain the

  title compound (83.3 mg), mp 128-146, - / D-

  , 8, whose nuclear magnetic resonance spectrum has

  revealed that it contained the corresponding E isomer.

EXAMPLE 187

  1α-dimethylamino-3m-hydrox-5m-pregnan-20-one LWdXIII compound (100 mg) was hydrogenated in EA (10 ml) containing a few drops of acetic acid at atmospheric pressure. using charcoal bearing 5% palladium as catalyst. After 24 hours,

  the catalysts were separated by filtration through diatomaceous earth

  and the filtrate was evaporated to give the title compound (70 mg), which showed thin layer chromatography, gas liquid chromatography, and proton magnetic resonance spectrum.

78- 2485O2O

  was similar to the product of Example 6.

EXIPLE 188

  1α-dimethylamino-3h-ydroxpyr-eg-4-en-20-one A solution of NaEH4 (117 mg) in water (5 ml) was added to a stirred solution of Lj-XXXV compound ( 500 mg) in THF (20 ml). The solution was stirred for about 5 hours at about +21 and then glacial acetic acid was added dropwise until effervescence ceased. The solution was partitioned between water and EA and the organic extract was washed with saturated brine and then dried. Evaporation made it possible to obtain the

  1-Dimethylamino-preS> 4-ene-3,20-diol (510 mg).

  A solution of diethyl azodicarboxylate (3548 mg) in dry tetrahydrofuran (2 ml) was added dropwise over a period of 5 minutes to a stirred solution of the above-mentioned thiol (361 mg) in dry THF. (12 ml) containing triphenylphosphine (787 mg) and chloroacetic acid (283 mg). The solution was stirred at about +21 for 1 hour and then partitioned between a solution

  A 5% aqueous solution of NaHCO 3 and EAO. The organic extract was washed.

  with saturated brine, dried and evaporated to give a solid (1.58 g). This solid was purified by preparative thin layer chromatography (WA-PE) of

  to obtain 3cc-chloroacetoxy-11-dimethylamino-pregnane

4-ene-20; -ol.

  A solution of the above-mentioned compound (438 mg) in AC (10 ml) was cooled to 0-5 with stirring and added dropwise over a period of about 3 minutes. Jones reagent (0.3 ml). After a further 20 minutes at 0 to 5, the mixture was partitioned between 25% aqueous NaHCO 3 and EA. The organic extract was washed with saturated brine, dried and evaporated to give a foam. This product was purified by preparative thin layer chromatography (EA-PE) to obtain 3-chloroacetoxy-1-dimethylaminopregn-4-ene-20-one. A solution of this compound (469 mg) was added to ME (15 ml) at reflux and NaHCO3 solution (181 mg) in water (2.5 ml) was added. The mixture was refluxed for 30 minutes, then cooled and partitioned between water and EA0. The organic extract was washed with saturated brine (100 ml),

  it was dried and evaporated to obtain a liquid.

  This liquid was purified by thin layer chromatography.

  of preparation (EA-PE) so as to obtain a liquid (123 mg). The proton magnetic resonance spectrum revealed that the material contained the title compound and

  11α-dimethylamino-3β-hydroxy-pregnanone.

  The aforementioned epimer mixture was mixed (121 mg) with similarly obtained material (158 mg).

  and we have resubmitted everything to purificatioi by chromatogra-

  Thin film (EA-PE). The most polar band was elected

  with CA and evaporated to give the title compound as a foam (123 mg),

-TO + 1700 '

-15-S-D + 1700. EXPLE 189 - -

  1H-dimethylamino-2H-t-oxo-21-fluoro-3-hydroxyl-5-fluoran-20-one and its citrate. A mixture of XXVrIII (4.9 g), sodium iodide (5 g) and AC (300 ml) was brought to the dish for 30 minutes before being evaporated to a small volume and dried. divide it between DE and water. The organic phase was washed with water, dried and evaporated to a scum. This product was dissolved in AxT (550 mI) and the solution thus obtained was treated with silver fluoride (3 g) in water (15 ml) at 45 for 24 hours. We split the mixture

  reactior-nel between DE and a solution of potassium carbonate

  sium. The organic phase was washed with water, dried

  It was evaporated to obtain a foaming layer. Purification by preparative thin layer chromatography (EA-PE) 1: 1) gave the title compound as the title compound.

  foam (240mg), 7D + 69.8.

  This free base (85 mg) was stirred with a solution of citric acid (82 mg) in water (8 ml). The weight of the solution was brought to 8.5 g with water and separated.

  residue which is insoluble by filtration so as to obtain a solution

  a concentration of 8.2 mg / ml and a pH of 2.9.

  The above compound and sn salt are com-

  according to the preferred invention. Thus, a further preferred group of compounds according to the invention is that formed by the substances corresponding to formulas (i) and (II) in

  which R 9 represents the fluoromethyl group.

2485020

EXEPLES A - F

  Compositions based on 11i-N.N-dimethylamino-22-et.oxv-3c-

hvdro: sxv-5ox-pregnane-20-one

  A. Unicute dose injection, 5 mg / m -

  dp / v steroid 0.50 citric acid 0.26 sodium chloride 0.80 sodium hydroxide up to pH 4.5 water for injections up to 100.00 The citric acid was dissolved in: most of water and the steroid was added under stirring and under a nitrogen atmosphere. Once the steroid entered

  solution, sodium chloride was added and dissolved.

  O5 then adjusted the pH with a solution of sodium hydroxide

  dium and the volume of the composition was completed. We have

  The solution was filtered through a membrane and placed in clean glass ampoules under a nitrogen atmosphere. Sealed containers were sterilized.

using moist heat.

  B. Unicute dose injection 5 mg / ml% pl

steroid O, 50-

  hydrochloric acid (pure) 0.11 sodium chloride 0.62 disodium hydrogen citrate 0.3 2 sodium hydroxide up to pH 4.5 Water for injections up to 100.00 The steroid was added to a solution diluted

  hydrochloric acid and caused its dissolution by

  under a nitrogen atmosphere. Hydrogen disodium citrate and sodium chloride were added and dissolved, the pH was adjusted with sodium hydroxide solution and

  completed the volume of the composition. The solution has been clarified

  filtration through a membrane and introduced

  in glass ampoules under a nitrogen atmosphere. We have

  sealed containers with moist heat.

81 - - 24S5020

  C. Solution for intravenous infusion due to D / v steroid 0.050 citric acid 0.026 sodium chloride 0.89 sodium hydroxide to pH 4.5 water for injections up to 100.00 Citric acid was dissolved in most of the water and the steroid was added with stirring and

  under a nitrogen atmosphere. Once the steroid has been

  sodium chloride was added and dissolved. The pH was adjusted with sodium hydroxide solution and

  completed the volume of the composition. The solution has been clarified

  filtering through a membrane and was introduced

  pickled in clean glass bottles, under atmosphere

  nitrogen. The bottles were closed with rubber plugs

  kept in place by aluminum sealing rings

  and sterilization of the bottles with the aid of

of moist heat.

  D. Solution for intravenous infusion do p / v, steroid 0.050 hydrochloric acid (pure) 0.011 disodium hydrogen citrate 0.032 sodium chloride 0.87 sodium hydroxide to pH 4.5 water for injections up to 100.00 Added the steroid to a dilute solution of hydrochloric acid and dissolved by shaking under

  nitrogen atmosphere. Hydrogen citrate was added and dissolved

  With disodium disodium and sodium chloride, the pH was adjusted with sodium hydroxide solution and the volume of the composition was completed. The solution was clarified by filtration through a membrane and introduced into

  clean glass bottles under a nitrogen atmosphere.

  The bottles were closed with rubber stoppers held in place by aluminum sealing rings

  and the bottles were sterilized with moist heat.

82 '-2485020

  E. Multiple dose injection $ D / v steroid 1.00 citric acid 0, .52 sodium chloride 0.50 benzyl alcohol 1.00 p / v sodium hydroxide to pH 4.5 water for injections up to 100.00 Benzyl alcohol was dissolved in most of the water and the citric acid was added and dissolved. The steroid was added and dissolved by stirring

  under a nitrogen atmosphere. Then the chlorine was dissolved

  sodium chloride and the pH was adjusted with a solution of

  of sodium hydroxide. We have completed the volume of the com-

  position and sterilized by filtration through a membrane. The solution was then aseptically introduced under nitrogen into sterile glass vials and closed with sterile rubber stoppers held in place by rings.

aluminum sealing.

  F. Steroid multiple dose injection, 100 hydrochloric acid (pure) 0.22 disodium hydrogen citrate 0.65 sodium chloride 0.15 benzyl alcohol 1.00 p / v sodium hydroxide to pH 4.5 water for injections up to 100.00 The benzyl alcohol was dissolved in a solution

  diluted with hydrochloric acid and the

  roade with agitation and under a nitrogen atmosphere. Hydrogen disodium citrate and sodium chloride were added and dissolved. The pH was adjusted with a hydroxide solution

  sodium, the volume of the solution was

  This is done by filtration through a membrane.

  The solution was asceptically introduced into sterile glass vials under a nitrogen atmosphere and the flasks were closed with sterile rubber stoppers,

  held in place by aluminum sealing rings.

8.3 - 2485020

  Similar compositions can also be prepared.

  res in which 11a-N, N-dimethylamino-

  3x-hydroxy-5β-pregnan-20-one with 11α-N, N-dimethylamino-2-one

  ethoxy-3a-hydroxy-5a-pregnan-20-onr.e. - Many compounds that have been subjected to reactions

  have received numbers to avoid the repetition of their names.

  The following index is given for easy identification

  the compounds that correspond to these numbers.

o, elduraxa * -

lExXXq

- AIXXXI

IIIXXIX

"- IIXNX

AIXXX '

IIXX lIXXi [xixx xIxIAN AxI

AIXX'I

AiXX '

IIIXXI

IIXXI xx. ' x'i

-. XIX1

  MAY IIIAXi 'IIAXU IAX't -' A! I IIIX IAI Ai:; i.9odCoD cg V8 08 - T16 Z9 - I8 ú9 ú9 9L I ú1

69 ú9

8ç 8Z LZ Li * ZSI ç: o Ndla AIA

IIII-X

II.I IA I

IIIAIX

IIAXXX

IIIXX

IIIX] C

IXAX AXIXX illIxx "xx * xixxx

IIIAXXX

  IIAXX IAXX exxx AXX AiXX IIIXX: IXX2t "Xx Xo CGtO OZOS8 't79 1i1 ILO you ET1 ZOI Lt -01 zot ú18 IL 0y ZOL TT ç9 ú6 ú01: o0'dz

TABILEAU 1

- r- - - --- - -

  Prep. Ethyl-PTSA Du- Chromatogra- Sol- Ren- P.F. f7D Pro-

  part Bene (mg) with Cécédé - (ml) glycol ype System of comp. or (mi) react- (g)

prep. No (g) talli-

  sation 18 II 6 150 40 300 24 DE 5.1 150-153 +52 A (i) 19 III 7 180 20 200 18 CC EA-PE PE-DE 3 126-130 + 42o A (ii) 3 5.4 50 2.5 70o 72 CC EA-PE DE-PT 2.64 112-113 +30.8, B (i) 21.6 3.18 30 1.5 30 18 3.58. +480 B (i) 22 XII 3.8 110 5 36 120 CC EA-PE ME 0.607 180-181 +51.3 B (ii) 23 XI 3, 19 110 5 36 5 CC EA-PE ME 1.28 126 -127 + 47.9O B (ii) 24 XIII 1.5 55 2.5 15 3 ME-PY 1.04 188-189 +56 B (ii)

  XV 6.21 275 27.5 275 72 CC EA-PE EA-PE 222 156-157 +3.60 C

  26 XVI 1.95 100 10 100 17 TL EA-PE DE-PE 1.62 140-141 +84.4 C

______ .., ___.__ I

o M u N Co u r IC

e6L-9L4.

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f6 I. -

? 4? -

961. -

91. E '

61. Z-

  6ZZ-L6L 161- OZ O6 /. 51Z? 91.? 17 ??

16ZZ7-

6 ?? z-

17 'O I.

ú

Z17'01

  88'0 9 'S6lo t7910 L910 j (6'ú: ú -l "',: -td-vIa As zi6-V. L 1bM (% 1.) H6-V 1tcIV; rdcisa HId" -V ei1a 1L sai-va id-VE I-TZs

1I-, T,

M-_19

14-15th

H 'DISL

  a-va I 'qi s'-VM'OD e17 Az / 917 el. 81. L9 ZL e8 8; 8L zz 8t7 91. 17? G. f Z '! 7 çz7' g 9'5 * 9z49 Q? L '

* 17 '?

   'Ot 0L 01O' 0L oz, 1g- QZ Where Q Q * o Q Of OOZ 09L Z q 1 14 "L4fo

9ZIOL,

$ 9 L L e 4 ZZI? 9Z'ú

? ' 1 L

  ! 21. Z9'l g'g ss' I.9 9'6 xx]. 9? L 9Z 1I 17th úZ O? oe XI III A 1.

  ------. * -, ----. t-6 * - -g-- "--g-f- ê.ne.annu ,.

    ## EQU1 ## ## EQU0000 ## ## EQU1 ## ## EQU1 ## EE "_7. [* A * -a or SQG Gwqu: 0.; sS GoncE ajF _01XE'A op aaqFq.I lq" of <o CI + r oj QN cY Q Qi -D Coo0e + o 1 ''17 + o. 06+ o0! '. 7+

0 LOGF

08 16+

  o6 '67Q + o 176+ o90 L + OLLLl L .. oO6 +

o QG'6-

  ú177 t '? 17 oq LQ 9, 17u' CI Zú Where Q 02 Q 1-m- .. i. -, 1. 1., i - i, 0 ,,. ",., 1.I s.1. -, M riv la ri ay 1

  IMS was used as the solvent; an additional amount has been added

  The treatment was then partitioned between ethyl acetate and water. The gross product was reprocessed by the same quantities

  of reagent for the same duration.

  The crude product was reprocessed with a solution of NaOH (2.79 g) in water (9 ml) and then hydroxylamine hydrochloride (1.25 g) at room temperature.

  reflux temperature, for 89 hours.

. o, * v,

TABLE 3

  Prep. Material Volat Weight Solvent Part.p. Mode Starting Flow / PR Starting PR Crystalline Sodium Process (ml) (g) tallisa- (g) Prep. Weight No. (g)

  52 33 2.8 500 30 FROM 2.1 143-145 +37 B

  53 32 6 800 60 (1) 2 - + 8; 5 A (i) 54 31, .3.6 500 40 MA-PE 2.5 156-158 + 20 A (i) (2) 46 3.2 500 35 - 0.950 - - A (ii) 56 43 0.9 130 8 DE-PE 0.4 100-102 - A (ii) 57 37 i 120 10 EA-PE 0.412 156-157 + 7 A (ii) 58 38 1.16 100 10 EA-PE 0.750 144-146 + 9.8 A (ii)

  59 39 0.945 100 9.45 ME 0, .389 188-189 +1.3.40 B

  36 1.85 110 9 .3 EA-PE 1.08 143-144 - 9.7 A (ii) 61 35 3.5 420 34 EA-PE 2, 6 155-157 + 6.9 A (ii) 62.34.3.87 450 26.53 DE-PE 2.31 116-118 + 4.7 A (ii) 63 (2) 30 10 1200 100 FROM 6 175-177 +. 5 A (ii)

- _ - _ - .. __ *

  (1) Purified by column chromatography

  (2) Methanol added before adding water.

  eluting with methanol nMo VI C> * 4. Co Co i 4.

TABLE 4

_- - W -_ .. -! - -.

  Ex. Alkylating agent material Time Rende- Chromato- Solvent PoF.Lt ID Starting method of mont graphie of (OC)

-_. _-. _ _ _ _ reac- (g) cris-

Prep. 'Quantity Quantity talli-

  6 63 2 HCH0 / 40 ml / 10 min 1.51 CC EA-PE 123-124 + 790 A IIC02H 0.8 ml EA 7 60 0.6 HCH0 / 12 rpm / 10 min 0.33 cc EA-PE 122 125.4 ± 57.4% H₂O₂H 0.24 ml, 0.55 IHCIO / 11 ml / ml, m.p. 38 CC HC02H 0.21 ml A EA +125.50 A oo 9 58 0.6 HCHO / 12 ml / 10 min 0.33 CC EA HC02H 0.24 ml TLC EA-PE - - + 68.9 A 59 0 7 HCH / 14 ml / 10 min. 0 .3 CC - - + 80.5 A HCO2H 0.28 ml EA -, - - - - - - -. +. 1.7 MeIl 10 m / 7 I. 0.83 CC DE-PS 133-136 * 87.90 B (i) K2CO3 4.5 g ME N 12 61 2.1 Me /. 38 ml / 4 h 0.63 cc EA-PE 161-171 + 82.50 B (i) o K2CO3 6.3 g ME

- --- 2 3 M-

* TABLE 4 (cont.) Ex. Alkylating agent material Time Rende-Chromato Solvent P.F. D Method of Oven JovntPF Process of Maintaining (O C)

reac- (g) cris-

Prep. Weight Quantity t-ion talli-

  13 51 1.5 (ClC2H4) 20/9 ml / Reflect 0.23 CC AC-W 191-B194 + 53 B (i) K2CO3 O 9 g 4 h EA-PT EA

- - - - ,, t -. - -. - -_-_ _ - - -

  14 54/15 MeI / 20 ml / 3 h 0.8 CC DE-EP 154-157 + 87, .3 B (ii) (a) K2 C3.3 g EA

  6. ___ __ _ ,,. _ _,. ,,, __! ........... ______ _____

  6.3 1 CH3CH2CH2I / 10 ml reSOx 0.25 CC ME ME-W 80-85 + 62.5 B (ii) (a) K2CO3 3 g 40 min TLC AC-PE 16 63 1 (CiCiHz,) 20/4 ml / 140 0.45 TLC - - + 60 B (ii) (b) K2C03 Q0.6 g 2h 17 52 1.5 MeI / 80 mi / 5 h 0.6 CC AC-DM DEPE 121-123 +100 B (ii ) (a) K 2 CO 3 4 g TLC AC-PE 18 53 '3 MeI / 20 ml / 5 h. 0.61 CC CH 2 K 2 CO 3 5 g TLC AC-PE - + 58 B (ii) (a - .. ..-. 9 - a9-. 9. -a - -r-wo "O Ln CN c> TABLE 4 (continued) E. Material of Duration RndeChromato- Solvent PF, a7 Process of Departure of D

reaction (g) .cris-

Prep. Weight quantity talli-

  19% 0.5 (C 2 H 4) 20o / 3 ml 1400 0.13 TLC EA _ + 29.80 B (iii)

K2C03 0.3g 2 hrs.

, .. _ __ __._ _ -, -. I

  50 0.5 (CH2) 41/4 mi ref2ux 0.13 CC EA-PE B (iii) (2) K2C0 1.g 18 h TLC EA-PE (3) 21 50 0.5 Br (CH2) ) 3Br / 4ml / r2ux 0.17 TCL EA-PE + 320B (iii) (2) K (2C0 i / NaI 1g / 172h (c 0.6) 0.2g 2250 0 75 CH2-CHCH Br / 2 ml / 800 0.25 TLC EA-PE + 300 B (iii) (2) CO 1 g 3 h

_. 3 _, _ _

  23 63 O07 EtI / 4 mi, 3 bus 0.4 TLC EA-PE + - 470 B (iv) K2003 0.7 g RT; 6 hau re_ ',. ## STR2 ## (30 ml) used as an ET solvent (10 ml) as solvent values (CDCl 3) include 6.14 (s, 3 P-H), OCH 2 CH 3), 7.0 (triplets of doublets, JH 7.2-7.7 (MI, -CH2-N-CHu2-), 7.90 (S, 21-CH3), -OCH2 CH53), 8.99 ts, 10-CH3) and 9 , 37 (s,

2485020

  6.2-6.4 (Mi, 2p-H and and 2 Hz, 1 p-H), 8.85 (t, J 7 Hz,

13-CH3).

(1) (3) (3)

TABLE 5

  Ex. Material of HCHO HC02 H Time Rende- Chromato- Solvent of P.F.-7D Process

  starting point (ml) (ml of crystalline

  Prep reaction (mg). Weighting No. (g) (Inn)

  38 74 1 3.8 0.49 5 819 CC EA-PE AND-W 63-70 + 354.4 A

-i ii, i-i-,

- .., ..... _...... -

  359 95 0.67 2.5 0.32 5 624 CC EA-PE + 51.50 A

-64C E-P - - + -5-,

_ ..,.,. __. _ _ .. I_

  410 96 0.27 1 0.1.3 5 187 CC EA-PE - - + 84.0 A

. ___________._____ (c0.44)

_ - .. - -., -

0.47 1.9 0.25

TLC EA-PE

OF

+ 57.5

(c 0.335) A

  42 72 0.26 1 0.12 5 170 TLC EA-PE - - + 60.0 A

- _ _ the F'_,. _. -. - - -i_

  43 78 0.22 4 0, .3 12 137 TLC ME-EA AN-W 104-107 - 2 B

  44 79 0.42 4 0.3 10 313 ET-W AN- 128-130 0

_ _ _ __-. ,, _ _ _ r _

  68 0.60 15 0.15 10 328 TLC EA-PT + 81 D

__.__. -1. _. - -_-- + 7-0 D-

  46 77 0.4. 0.15 270 TLC EA-ME. _79 _ _ _ _ _ _ - _ - O N Co Q O,

TAB3LEAU 6

e --_

  -_.___ -. a.e - q4 '... p ....., .. n. _.

  Ex. Acid Material or Catalyst Rende Chromato- Solvent PF. 7

  starting alcohol from graph of c 6 d

_ _ ------. ---- _ reac- (mg) cris-

Prep. Weight Vol. Flight. talli-

  No. (ming) (ml) (ml) sation 52 87 750 propanediol 0.12 4 h 143 CC EA-PE - +820 A 2-ol.TLC (c6) 5.3 88 500 AND 50 IClO4 1.3 h 236 TLC EA-PE +820 A 54 87 750 PR, 100 HiClO4 1 h 452 TLC EA-PE _ - +73.8 C 88 500 ME 50 HClO4 1 37 min 349 TLC EA-PE - - +80, 5 C 56 89 300 ME 30 IlClO 4 0, 66 25 min 233 TLC EA-PE 3 _ _ 79 C

  _ __..._, __._ ___C__. __.__......; "---....... T '- I ......................

  ........................_, .. DTD: 57 89 400 ET.30 11Cl0 O, 1 hr 178 TLC EA-PE - .. +750 C 58 89 300 acid 3 - 3 h '173 TLC EA-PE + 78t350 A

acetic

that alcohol

benzyl

lic

HC2.04

0.8 mn I

TLC EA

o N rQ o! - TABLE 6 (site) _

  Ex. Acidic Material or Catalyst Duration Rende-Chromato- Solvent P.F. Pro-

  alcoholic alcohol

  -_ -__ -__ - -o. _ Reaction (mg) cris-

Prep Weight Vol. Flight. talli-

  No. (mg) (ml) 87.388 2-chloro-HClO4 0.8 40 min 202 TLC.EA - +6.30 A

roétha-

  No. 61 87 300 HCl 2.4 15 min 101 PE 135-086.8 B conc.

__ - -. -. _ _. -__

  62 88 500 HCl 4 - 37 min 362 TLC RA-PE _ +61,20 B conc. 63 89: 300 HCl 2, 5 - - 30 min 127 TLC EA-PE pentane 127-. + 7.3, .50 B13 cbnc. 129 (cO, 56) 64 87 2500 HSCN _ _ _ 45 min 279 CC EA. PE 183-- +88.50 A ..in 185

- -_ - _ - _. - _. -_ - - '

  87 1500 HBr aq 10 - - 15 267 CC EA-PE EA-PE 139- + 90.5 A

47% 142.

  66. 87,500 HF 6.2 - - 19 hrs 176 CC, TLC -: +69.50 B EA-PE

- - -8 - - -. _ - -

  67 89 500 IIFGv 6 * .2 _ - 19 h 182 TLC EA-PE - +72.10 B

- - -

  After TLC the product was further purified by dissolution in EA and extraction with HCl. The extract was basified with NaOH and

  it was reextracted with EA, washed, dried and evaporated.

  The product was dissolved in DE (10 ml).

  This product was prepared by extracting a mixture obtained from KSCN (3.0 g) and phosphoric acid (4.6 g),

  Preformed complex of urea (5 g) and H-IF.

91, * co Ln N / O

  Ex. Acid Material or Catalyst Rende-Chromato-Solvent Time P.F.

  alcohol ment ment ment from - - this

- - - - - _ _ _ (mg) cris-

Prep. Weight Vol, Vol. talli-

  No. (mg) .a. 68 88 500 HF @ 6.2 - 5 hrs 148 TLC EA-PE _ _ -79O A. . ______________________________________ (cO, _43) 69 87 500 acid 10 _- h 263 CC EA-PE EA-PE 156- +81 aceti- 158.5 (28.6) B 88 500 acid 5 _ _ 24 h.3.33 TLC EA-PE - +823 BO

acetic

- than _ _ _ _ _ _ __ _

TABLE 7

  Ex. EBase Sel Pro-lc-amine Acid Iolarity Free pH weight dissolved dissolved from the

Ex. (Mg) solution solution

Acid number (g)

  I ____ _ _ __ _ _ _ ___ __ ____ _ ____ _ _ _ _ _ _ _ _ _ _ _ _ _ ___ _ _ _ _ _ _ _ _ _

  8.3 6 citrate B 120.5 0.1 3.4 ml 24 6.5 84 6 "C 120 0.1 3.34 ml 12 3.6 6 chlorhy-B 120 0.1.3.4 ml 12 4.85 drate 86 6 phos- B 120 0.1 3.4 ml 5, 7 phate 87 6 mesyl-B 120 0.1 3.4 ml 10.3, .3 late 88 6 tricar- B 120 0.1 2, 3 ml 12 6.05

ballyl-

  ate 89 7 citrate B 100 - 54 mg 10 5.0 8 "A 102 - 55 mg 10 3.7 91 9 t A 101 - 56 mg 10.3.8 92 10 A 10.3 - 55 mg 10 3.7 93 11 It A 101 - 57 mg 10 3.7 94 12 A 102 - 57 mg 10.06 3.7 12 acetate E 84 0.5 1.59 ml 10 4.4 N 96 14 citrate B 100 0.1 2.6 ml 10 4.8 97 14 acetate B 100 0.5 1.5 ml 3, 9 98 citrate B 100. 0.1 2.5 ml 3.5 TABLE 7 'continued)

  -._ r * _, __ * -t- ,! - -_- _. - e- -

  ELs. Base Salt Pro-1-Amine Molarite Acid Weight free pII cI- dissolved from the

1 edéo de (rng) solution I solution

  Acid No. ##. ## STR2 ## (g) citrate ! I! you! V! CBBDEEBBEDAD * AD * ADD 10.3 0, 1 0.1 0.1 0.1 4.5 ml 9.0 ml 2.5 ml 48 mg 24l, 5 mg, 5 mg 3.3 ml 54 mg 23.5 mg 104 , 2 mg mg mg mg 121.6 mg 62 mg 74 mg 114Z mg 16.5 1.3: 10, 29, 21 3, 0, i 4.0 2.45 3.26 3.58 3.3 4.5 3 , l 3,0 3,7 3,8 3,7 3,1 3,65 3,45 3,0, 3 N 4> o O i TABEALiUite TEx. Base Salt Pro- 11 -amine Molarity Acid Weight pH! free.cape dissolved from the

ex * (mg) solution solution

  Acid number (g) 0.1 O, 0.1 0.1 0.1 m 6.3 mg 22 mg 44 mg 44 mg 48 mg 51 mg mg, 9 mg 54 mg 2.6 ml 2.5 ml 53.2 ml mg 25. mg mg 26 mg: 26 mg 24 mg 24 mg 5.3 mg 38.5 mg 7.8. - 8.7, 28, 1 12.5 5., -, 5. 3, s 16 2.85 2.65 2.8 2.9 3.75 3 y 1 3.75 4.9 3.6 6 , 0 3.65 3.6 3.0 3.75

3, 5 ',,:

3.45

3.5 ....

  2,97 3,18: "o ul C> 1.32 3.53 / 47 4S9 5.5 citrate It tlt tt tt tt It ti tt tt tt tt tt tt tt tt tt tttt AEDDDADAABBBEADAEEEEE o101 -48 4.3 l48 I o

table 7

  Ez. Sol Sol Pro-11 oc-nine Molarity. Acid Free pH weight dissolved dissolved from the

ex, (mg) solution solution

  Acid No. ___ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ (g) 1 63 citrate If Tt t '' '' '' '' '' '' '' '' '' 4.3 mg mg 48 mg 27 mg 52 mg 27 mg 5 mg 24 mg 61 mg 54 mg 61 mg 51 mg 56 mgC mg 56 mg 58 mg 2-3 dgI 24 meE I10 2.8 2.82 2.55 3.58 2.95 3.6 3.52 3.6, 4, 05 3.6 3.7 3.7 4.5 3.7 2.6 3.6 3.5 1.37 O o o o o. TABLE 7 (cont'd) * as matter-remained in undissolved state after one second

  addition of acid, ET was added dropwise until

  The solution was evaporated to dryness under reduced pressure. The residue was dried and

dissolved in water ..

  u1 O rNo n 3) Ma o Ex. Base Pro-11a-Amine Salt Molarity Acid Free pH weight dissolved from the

ex. (mg) solution solution

  Acid number 25 - 26 mg 3.0 156 186 "A 80 - 42 mg 8 3.60 157 188" E 86 - 52 mg 8.9 3.5.

TABLE 8

  Ex. Pro-11-amine salt Molarity Acid Weight pH dissolved from the

de (mg) solution solution

  _ _ .. ___.'_, _ ,,,, 1________! - (g)

-....... - .. - - -, -,. 158 citrate A 500 0.1 12.4k ml 50 4.4 159 acetate B 50 0.5 0.75 ml 5 4.0O

  lactate A 101 0.5 1.5 ml 4.2 161 mesylate A 100 0.1 2.5 ml 4.05 162 phosphate A 100 0.525 0.5 ml 5.6 5.6 163 (+) - tartrate A 101 37.5 mg 4, 5 164 tricarbally A 101 - 46 mg 4.9 LH hydrochloride A 101 0.1 2.5 ml 3.55 166 sulfate 100 0.05 2.5 ml 10 3 3 167 citraconate A 100 - 36 mg 10 3.8 168 mésaçonate B 81 - 52 mg 8.13.02 169 aconitate B 81 - 35 mg 8.1 3.38 succinate B 100 - 58 mg 10 3.7 171 salicylate B 81 - 27.6 mg 8,1 4,48. ,, u_ _L _ ,,, ..., _. - ..- .. ,,., ._ .. ,, __ ,,, r o .. ar \ M Co co Q, Q 0>

TABLE 9

- -a- X -

  Ex, Salt '11a-amine Molarity Acid Weight pH dissolved from the

(mg) solution solution

(g)

- --- -_AT __,

  citrate hydrochloride acetate succinate mesylate phosphate tricarballylate lactate (+) - tartrate 120. 50. 0.1 0.1 0.5 0.1 0.52 0.5. 4.0 ml i, 4 ml 0.55 ml 16.3 mg 1.4 ml 0.4 ml 24.4 mg 0.14 ml, 7 mg, 06 ml:, 5., - 3.2 2 , 4.5 4.5 3.85 2.5 4.15 34.1 3.65 -. o raz C: t i

- 104 -: 2485020

  The following will be the results of tests highlighting

  the anesthetic activity of the compounds according to the invention.

  Intravenous mouse assays: Steroid salt solutions according to the invention were prepared as indicated in the examples and diluted in 0.9% physiological saline so as to have a volume of 10 ml / kg. per dose. Compositions containing the two bases tested (compounds of Examples 1 and 3) were prepared by dissolving them in a minimum of acetone and adding a determined volume of Cremophor.

  RH40 (polyoxyethylated fully hydrogenated castor oil having

  about 40 ethylene oxide units per molecule of beaver oil).

  Acetone is removed by passing nitrogen through the metal

  mix and dilute the mixture with distilled water so that

  obtain a final product containing 20% Cremophor RH40. The components

  have been prepared in such a way that the dose envisaged corresponds to a volume equivalent to 10 ml / kg of body weight. Dilutions were made for this purpose with a 20% solution of Cremophor RH40,

  in distilled water and the volume maintained at 10 ml / kg per dose.

  A series of doubling doses were injected into groups

  3-5 albino male mice of the Charles River strain (Hare-

  field) weighing 15 to 30 g., and the lowest dose at which

  all the mice sleep and the lowest dose at which

  some mice die have been determined.

  The compositions were injected into the tail vein in 30 seconds. The time between the end of the injection and the loss of the animal's righting reflex was determined (induction time). Animals that lost their righting reflex were kept at a controlled temperature of 350C when

  are anesthetized and, like animals that have not lost their

  correction, at 240C when they wake up. All animals

  Dose with a dose is kept for 24 hours. and mortality

  tee is determined. The tails are examined for any

sign of thrombophlebitis.

  For all steroids listed below

  induction of anesthesia was immediate at the indicated doses.

  No signs of thrombophlebitis were observed.

  Lowest Dose Compound Lowest Dose If any, to which all mice sleep mice die (mg / kg) mg / kg)

84 12.5 50

93 6.25 50

3t 13 25

97 6,125 25

1 1.56 12.5

158 13 25

3.13 12.5.

162 3.13 25

6.25 25

168 3.13 12.5

129 6.25 25

133. 12.5 50

* .120 6 25 25

103 6.25 25.

128 6.25 25

144 6.25 25

6.25 50

3.13 25

139 6.25 25

152 3.13 25

138 6.25 25.

1ti 3,13. 12.5

89 12.5 50

12.5 50

91 12.5 506

At 3 "- 3.13 12.5

172. - 1.56 -25

179 1.56 12.5

173 3.13 12.5

106 6.25 25

123 3.13 25

124 6.25 25

149 6.25 50

148 3.13 25

- 106 - 248502-0

  Lowest Dose Compound Lowest Dose Example n All of which at which some eep mice sleep mice die (mg / kg) (mgkg) (mg / kg)

147 6.25 25

6.25 50

146 6.25 25

12.5 50

113 12.5 25

112 12.5 50

6.25 25

164 6.25 25

189 3.13 12.5

-107

Claims (3)

A steroid of the formula wherein R 1 aa R is a group -NHR, wherein R is a hydrogen atom or a C 1 -C 6 alkyl, cycloalkyl group C3-C6 benzyl or phenethyl or. a C3-C6 alkenyl group having one or two double bonds and wherein the carbon atom adjacent to the nitrogen of the -NHR group is saturated; R is a hydrogen atom or a C 1 -C 3 alkyl group; R is a hydrogen atom or a C 1 -C 5 alkyl, C 1 -C 5 alkoxy group (which may be optionally substituted with a carbon atom); halogen) benzyloxy, C2-C5 alkanoyloxy or thiocyanato or a halogen atom; is a hydrogen atom or a methyl group R is a hydrogen atom or a methyl group; R is a hydrogen atom or a methyl group;   7 is a hydrogen atom or (except when R is a group (c) as defined below) a chlorine atom; and 8 99   R is (a) a cyano group, (b) a group -COR wherein R is a methyl group or such a group substituted with a fluorine atom or a C1-C4 alkoxy, hydroxy, C1-C4 alkyl group, methoxymethyl, ethoxymethyl, C2-C5 alkanoyloxy, benzoyloxy, or (C2-C5) alkoxy   carbonyloxy; or wherein R is C 1 -C 5 alkoxy or cyclopro-   pyle; or wherein R9 is -NRXRY o Rx and RY (which may be the same or different) are methyl or ethyl; or (c) a   vinyl group or with R a methylene group substituted by a methyl group   thyl or cyano in Z configuration R is a hydrogen atom except when R and R10 together represent a substituted methylene group; 108 2485020 108 -,   the dashed lines indicate the possible presence   a double bond in the positions shown; - 3 4   provided that at least one of R and R is an atom. 3 4   hydrogen; R and R together represent a hydrogen atom when a double bond 1, 2 is present; and that a 1, 2 double bond is not present when a 4, 5 double bond is present; and that R is an atom 4 5   of hydrogen, R a hydrogen atom or a methyl group and R5 an atom   of hydrogen or possibly (when R is a hydrogen atom) a group of   methyl-when a hydrogen atom is present in 5-JS_   as well as the D-homo analogs of compounds carrying the R group at the   at 17a, R1 at position 17a and R at position 17; and the ketals of compounds having a 20-keto group; and addition salts with acids; but excluding compounds of formula R9 H N CO   2x, HO wherein R is a methyl group, a substituted methyl group   by hydroxy or C 2 -C alkanoyloxy and their 20-ketals. 2 5