DE2715078A1 - STEROID DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND COMPOSITIONS THEREOF - Google Patents

Description

Steroid derivatives, processes for their preparation and containing them Compositions

The invention relates to anesthetic steroids.

There are many anesthetic steroids known, most of which are 3 ^A -hydroxy-5QC or Δ -compounds of the 17 & - unsubstituted-20-oxo-pregnane and -androstane series, and the best compounds are often an 11-oxo group exhibit. These compounds are often insufficiently soluble in water and it was therefore necessary to formulate them for administration in aqueous solutions of parenterally acceptable, nonionic surfactants, as for example in British Patent 1,317,184 with regard to the important anesthetic 3 <X- Hydroxy-5 <x-pregnan-11,20-dione is described. Anesthetic steroids are also known which have water-solubilizing groups at various points on the steroid structure

7098A1 / 0974

27 Ibu78

/ M.

have, for example in the 2β or 3 / Xr position or the 21-position in a pregnane or the 17ß-position in an androstane; however, the incorporation of the water-solubilizing group often resulted in a decrease in activity or Stability.

A very interesting anesthetic activity has now been found in the group of ^ OC-Hydroxy- ^ OC-, 5ß- or Δ- or A -Pregnans and -androstanes as well as their D-homoanalogues, which have an amino group disubstituted by aliphatic or araliphatic groups, or have a heterocyclic amino group in the 11oc position, in particular in the case of the water-soluble salts of these compounds with acids.

The invention thus relates to steroids of the formula

R ⁸ R ¹⁰

(D

^a R

^ is a group -NR ^a R, in which R ⁸ and R (which can be the same or different) are C _/) _ ₆ -alkyl, C ^^ - alkenyl or cycloalkyl groups (with the proviso that R ^a and R together contain 2 to 7 carbon atoms and that, if R ^a and /

or R represents an alkenyl group which belongs to the nitrogen ο ν,
atom in the group -NR R adjacent carbon atoms or the carbon atoms adjacent thereto is or are saturated), or in which one of the groups R ^a and R is a benzyl group

70984 1 / 097A

or Phenyläthy1gruppe and the other group is a methyl group · or where R ^a and R (together with the nitrogen atom) an azetidino, pyrrolidino, piperidino, hexamethyleneimine or morpholino group, these groups optionally substituted by one or two methyl groups could be;

R ^ is a hydrogen atom or a C ^^ alkyl group;

R is a hydrogen atom or a C 1 -C -alkyl, C ₁ _ (-alkoxy- (which may optionally be substituted by a halogen atom, for example chlorine), benzyloxy, coc-alkanoyloxy or thiocyanato group or a halogen atom means;

R ^ represents a hydrogen atom or a methyl group; R represents a hydrogen atom or a methyl group;

R 'represents a hydrogen atom or (unless R is a group (c) as defined below) a chlorine atom; and

R (a) is a cyano group;

(b) a group -COR, in which R is a methyl group or such a group substituted by a fluorine atom, a C 1-4 alkoxy, hydroxy, C 1-4 alkyl, methoxymethyl, ethoxymethyl, C ₀ is c-alkanoyloxy, benzoyloxy or C _{0 κ} -alkoxycarbonyloxy group; or wherein R · ^{7 is} a C ₁ , alkoxy or cyclopropyl group; or in which R ⁷ signifies the group -NR ^x R ^y , in which R ^x and R ^ (which can be identical or different) represent methyl or ethyl groups; or

(c) represents a vinyl group or

10

together with R represents a Z-substituted methylene group in which the substituent is a methyl or cyano group is;

7 098 A1 / 0974

"*". ■ 27-1 bü78

B represents a hydrogen atom (with the exception of the case that R and R together form a substituted methylene group);

and the broken lines indicate the possible presence of double bonds at the indicated positions;

• 5 4 with the proviso that at least one of the radicals R and R

-z 4 represents a hydrogen atom; and R and R together represent a hydrogen atom when there is a 1,2 double bond; and that the 2-position is saturated if a 4.5-

5 4

Double bond is present; and that R is a hydrogen atom, R represents a hydrogen atom or a methyl group and R ^ represents a hydrogen atom or optionally (if R is a hydrogen atom) is a methyl group when a 5β-hydrogen atom present;

as well as the D-homo-analogs thereof, the R in the 17ass position,

7th
in the illustration and R 'in the 17 position

sen; as well as the acid addition salts thereof.

In the investigations carried out with the compounds according to the invention have been shown to be generally good anesthetics, which tend to be quick Induction of anesthesia when administered intravenously. The water soluble salts are especially important as they are more aqueous Solution can be formulated and in general comparison with known water-soluble anesthetic steroids are superior in terms of their effectiveness and / or the quality of anesthesia and / or are free of side effects such as thrombophlebitis are. The aqueous solutions of the water-soluble salts have also generally proven to be very stable. The compounds according to the invention are useful for the initiation or induction of anesthesia, for example by a Inhalation anesthetic such as ether, halothane, nitrous oxide or trichlorethylene maintains. The compounds can also be used to maintain anesthesia to a sufficient extent be able to perform surgical operations without the help of an

709841 / 097A

" * ~ 27 15Ü78

halation anesthetic allows, with the anesthesia if necessary is maintained by repeated or continuous administration. The compounds can be useful to others Have central nervous system depressive effects, for example they can be suitable as Sedadiva.

away

As indicated above, the R and RC groups can be alkyl groups which are straight or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl or 1,3-dimethylbutyl; or C _x ^ alkenyl groups such as allyl groups. If R or R represent a cycloalkyl group, this can be, for example, a cyclopentyl or cyclohexyl group.

Q V)

If one of the groups R and R represents a C ₇ -C alkenyl group, there is preferably only one double bond, for example as in an allyl group, and the other group preferably represents an alkyl group, for example a methyl group.

away
If -NR R is a heterocyclic group, it is

is preferably a pyrrolidino group.

a b Preferably one of the groups R and R represents a methyl group and the other group is a methyl, ethyl, propyl, isopropyl or butyl group. Compounds in which both R and R represent methyl groups are particularly preferred.

If a 20C (R ^) substituent is present, this is preferred a methyl group.

If R is a methyl group, the 6-position is preferably saturated.

Compounds with a 2 [beta] (R) substituent are particularly important in the 5oc rows; Examples of such substituents are a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy,

709841/0974

27 Ί bÜ78

Acetoxy or thiocyanato group or a chlorine, bromine or fluorine group.

Compounds of the 50C and 5β hydrogen series are generally preferred, as well as compounds in which the tetracyclic steroid

6 1

system is saturated and wherein both R and R 'are hydrogen atoms; Ir preferably also represents a hydrogen atom. If the steroid rings are unsaturated, Δ ¹ compounds are preferred.

A group of compounds according to the invention are compounds

away
fertilize, in which R and R are different from benzyl or phenylethyl groups; R is different from the group -COR, in which R 'is an Ilethyl group substituted by a C _0/1 -alkyl group; and wherein each of the groups R, R and R ^{y represents} hydrogen atoms if a 5 [beta] hydrogen atom is present.

A preferred group of compounds are compounds of the formula II

1 from from

R is a group -NR R in which one of the radicals R and R is a methyl group and the other is a methyl, ethyl, propyl, isopropyl, butyl or allyl group, or in which both R ^a and R are ethyl groups or where R ^a and

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R (together with the nitrogen atom) is a pyrrolidino group form;

R represents a hydrogen atom or a methyl group;

R is a hydrogen atom or a methyl, methoxy, ethoxy, Represents propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom;

R (a) is a cyano group;

(b) a group -COR, in which R ^ is a methyl group or these Group substituted by a methyl, hydroxy or acetoxy group, or R ^ represents a cyclopropyl group; or

(c) represents a vinyl group or

10
together with R forms a Z-ethylidene group; and

R is a hydrogen atom (except when R and R together form an ethylidene group);

with the broken lines indicating that if applicable there is a double bond in the 1,2-position;

3 4 with the proviso that at least one of the radicals R and R

3 4 represents a hydrogen atom; that R and R together

Form hydrogen atom if there is a 1,2 double bond

3 4

lies; and that R is a hydrogen atom and R is hydrogen represents atom or a methyl group, if a 5β-hydrogen atom is available;

O / In

and the D homoanalogues, the R in the 17sß position and R in the 17aoO position;

as well as the acid addition salts thereof.

R preferably represents a cyano group or a -COR group

where R is a methyl group (optionally substituted by a hydroxy, methyl or acetoxy group) or a cyclo-

709841/097 4 _0RIGlNAL INSPECTED

- »-. '27 1SU78

is propyl group. The 1,2-position is preferably saturated.

In the compounds of the formulas I and II, R preferably represents an acetyl or cyano group; R is preferably hydrogen atom, if a 5β-hydrogen atom is present or is a hydrogen atom or an alkoxy group, advantageously one Ethoxy group if there is a 50 ^ hydrogen atom; and

■ 7.
R ^ is preferably a hydrogen atom. R particularly preferably represents an acetyl group, ring D has 5 members

away

and -NR R represents a methylamino group. Particularly preferred are 506 connections.

As mentioned above, the ability is that of the present invention Bases for the formation of water-soluble acid addition salts are of particular importance. Thus, the compounds according to the invention can simply be formulated in the form of their bases in aqueous acidic solution.

Examples of suitable salts are hydrochlorides, hydrobromides, phosphates, sulfates, p-toluenesulfonates, methanesulfonates, citrates, Tartrates, acetates, ascorbates, lactates, maleates, succinates, tricarballylates, Glutarates, aconitates, citraconates, mesaconates, salicylates and glutaconates. The citrate and hydrochloride salts are particularly preferred for use as anesthetics.

When these salts are used as anesthetics, they should be physiological in the dosages at which they are administered be compatible. However, other salts can be used, for example to isolate the product, from a synthetic reaction be suitable.

Preferred connections are:

1.) 11 (X 1, N, N-dimethylamino-3 & 1-hydroxy-5iX / -pregnan-20-one;

2.) 1106-N, N-dimethylamino-2ß-ethoxy-3X-hydroxy-5a-pregnan-20-one;

$.) 11ÖU-N, N-dimethylamino-30Cr-hydroxy-2ß-methyl-5ciC-preEnan-2O-one;

7 09841 / 097Δ

"■ * '" 2 7 1 b ύ 7 8

4.) 11 (VN, N-Dimet hy 1 amino-3 & 1-hydroxy-2 (X _/ -methyl-506-pregnan-20-one;

5.) 11 <X-N, N-dimethylamino-30 (1-hydroxy-5β-pregnan-2O-one;

6.) 1ioo-N, N-dimethylaraino-3X-hydroxy-50 (r-androstane-17β-carbonitrile

7.) IIOC ^ -N-butyl-N-methylamino-3 ^ hydroxy-50G-pregnan-20-one;

8.) 2β-chloro-100-N, N-dimethylaminu-3oC-hydroxy-500-pregnan-20-one;

9 ·) 11 (X ^ -N, N-diraetliylamino-2ß-fluoro-300-hydroxy-5oCrPregnan-20-one;

10.) 110 ^ N, N-dimethylamino-30C-hydroxy-2ß-methoxy-50 (7-pregnaii-20-one;

11.) 2β-Ethoxy-11Cx ^ -N-ethyl-N-methylamino-3iXr-hydroxy-5 ^ -pregnan-20-one;

12.) 11oO-N-ethyl-N-methylamino-3flO-hydroxy-50C-pΓegnan-20-one; 3 ·) 3o ^ -Hydroxy-116 ^ -N-methyl-N-propylamino-5X-pregnan-20-one;

14.) 11iX-N-Ethyl-N-ynethylainino-3iX ^ -hydroxy-2ß-methoxy-5 (X, -pregnan-20-one;

15 ·) 30 <^ Hydroxy-1iOC-N-isopropyl-N-raethylainino-2ß-methoxy-5 <X-pregnan-20-one;

16.) 1iOG-N-allyl-N-methylainino-2ß-ethoxy-3 (? C-hydroxy-5PCrPregnan-20-one;

17.) 2β-Ethoxy-300-hydroxy-11o0-pyrrolidino-5X-pregnan-2O-one;

18.) 110Cr-N, N-dirriethylamino-3C ^> C-hydroxy-2β-propoxy-50C-pregnan-2O-one;

19 «) 116-N, N-dimethylamino-3ijC-ty ⁽ iroxy-2ß-isopropoxy-5 (XrP ^re B ^nan -20-one;

20.) 2β-Acetoxy-11 (X ^ N, N-dimethylamino-3 (^ - hydroxy-5o (rPregnaLn-20-one;

? 21) 2ß-acetoxy-1iOO-N-ethyl-N-methylamino-3-hydroxy-0-P ^re 5oC S ⁿ a ⁿ -20-one;

22.) 2β-acetoxy-3 / Xr-hydroxy-11 <Xr-N-isopropyl-N-ineth.ylamino-50C-pregnan-20-one;

23.) 1100-N-ethyl-N-methylamino-2ß-fluoro-3c <7-hydroxy-5iX-pregnan-20-one;

24.) 2ß-fluoro-3 ^ -hydroxy-11 (X-N-isopropyl-N-methylamino-5cC-pregnan-

20-one;

70SB41 / 0 ^ 7 ^

- 2 ° - .27 I bü78

25 ·) 2β-chloro-11oO-N-ethyl-N-methylamino-3oo-hydroxy-5 (X-pregnan-20-one;

26.) 2β-chloro-3oG-hydroxy-11 (X3-N-isopropyl-N-methylamino-5oC-pregnan-20-one;

27-) 2β-Bromo-110O-N, N-dime-bh.ylamino-3 (> C-h.hydroxy-5CC-pregnane-20-ori;

28.) 11 (X 1, N, N-dimethylamino-30C-hydroxy-2β-thiocyanato-506-pregnan-20-one;

29 ·) 11 () (j-N, N-Diinethylaraino-3iX ^ hydroxy-5: X-pregn-1-en-20-one; 30.) 11 & 0-N, N-dimethylamino-3 * X ^ hydroxy-D-homo-50irpr egnan-20-one;

31 ·) 110O-N, N-diraethylamino-2ß-ethoxy-3iX-hydroxy-D-homo-5iX.-pregnan-20-one;

32.) 11flC _r -N, N-dimethylamino-21,21-ethylene-3OC ~ hydroxy-5OC-pregnan-20-one;

33 ·) 1 '^ öO-N, N-dimethylamino-30C-hydΓoxy-21-methyl-5ίC-pΓegnan-2O-one;

34.) 11 (Xr-N, N-dimethylamino-2β-ethoxy-3! X1-hydroxy-21-methyl-50C-pregnan-20-one;

35.) 21-Acetoxy-110-N, N-dimethylamino-2β-ethoxy-3X-hydroxy-0-pregnan-20-one;

? 36.) 11öC-N _i N-diethylamino-3i G-hydroxy-5ß-pregnan-20-one; 37 ·) 300-Hydroxy-100-N-isopropyl-N-methylamino-5β-pregnan-2O-one; 38.) IIOG-N-ethyl-N-methylamino ^ X-hydroxy- ^ ß-pregnan ^ O-one; 39 ·) 30C _> 21-dihydroxy-116 -N, N-dimethylamino-5β-pregn8n-2O-one;

40.) 21-Acetoxy-11 (Xj-N, N-dimethylamino-3X-hydroxy-5β-pregnan-20-one;

41.) 11oo-N, N-dimethylamino-3X-hydroxy-5β-androstane-17β-carbonitrile

42.) 11c (rN, N-diraethylamino-2ß-ethoxy-3X-hydroxy-5C> C7androstane ^/ 17ßcarbonitrile;

43.) (Z) -1106-N, N-dimethylamino-3C <.- hydroxy-5x-pregn-17 (20) -ene;

7 0 S G A 1 / C 9 7 A

"^" 2 7 Ί b Ü 7 8

-'IC '

44.) Methyl-1 ^ ou-N, N-I) iinethylamino-2ß-ethoxy-3öCrliydroxy-5C (randrostan-17ß-carboxylate;

45.) 11 ^ N, N-dimethylamino-30-hydroxy-5 (X7-pregn-20 (21) -ene;

46.) 2β-Butoxy-1iOc ^ N, N-dimethylainino-3oG-hydroxy-5 (? 0-pregnan-20-one;

47.) 11fi6-N, N-dimethylamino-2ß-ethoxy-306rhydroxy-21-propyl-5 (Xr pregnan-20-one;

and the physiologically acceptable or usable water-soluble ones Salts of these compounds.

When conducting research in the form of their citrate salts in aqueous solutions (sometimes in the presence of sodium and chloride ions) all of the above compounds showed one good effectiveness. Tests on tricarballylate, hydrochloride and phosphate also showed good effectiveness and methanesulfonate of compound No. 1; of acetate, hethanesulfonate, Lactate, phosphate, tartrate, tricarballylate, hydrochlorlds, succinate, citraconate, aconite and mesaconate Compound no. 2; of acetate, hydrochloride, tartrate, lactate, Tricarballylate, phosphate, methanesulfonate and succinate of the Compound No. 5 and the acetate salt of Compound No. 10.

Among the above compounds are compounds 1, 2, 5, 6, 8, 9, 31, 36 to 38, 41 and 42 and their salts particularly preferred.

The compound no. 5 and its physiologically acceptable, in Water soluble salts (especially the hydrochloride and citrate) are particularly preferred. Compound No. 2 and its physiological Compatible, water-soluble salts (especially the hydrochloride and the citrate) is particularly preferred.

The compounds of the invention may be formulated according to conventional pharmaceutical practices as appropriate (including medical and veterinary practice

709841/0974

"^" 27 1bU78

tiken), one or more pharmaceutical carriers or excipients. For anesthetic purposes, the steroids are administered by injection and are thus comprised A feature of the present invention is a composition for parenteral administration comprising one or more compounds contained according to the invention in a parenterally acceptable vehicle.

If the compounds (e.g. the salts) are sufficiently soluble in water, they can be presented in aqueous injection vehicles. The preparation of suitable solutions by dissolving the free bases in aqueous acid is described below. For induction anesthesia or introductory anesthesia, these solutions usually contain 0.1 to 4.0 % (expediently 0.2 to 2 %) w / v. of the active compound, but stronger solutions can also be made with the more soluble salts. Optionally, the free base and the acid necessary for salt formation can be packaged separately in a two-pack form for formulation in use. Alternatively, the steroid salt and aqueous injection vehicle can be packaged separately in a two-pack form.

Although the compounds according to the invention are preferably used as simple aqueous solutions of their salts are formulated, the free bases or salts can also be in an aqueous solution of a parenterally acceptable, nonionic surfactants in the same way (and using the same proportions of the materials) as described in British patent specification 1 5 ^ 7 184 for the 3 (XrHydroxy-5 (X ^ pregnan-11,20-dione, be formulated. The simple aqueous solutions have the advantage that they cause anaphylactic reactions, for example Avoid from surface active agent sensitive patients.

The aqueous solutions can be toned with, for example, sodium chloride can be set.

7098 Λ 1/0974

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The anesthetic solutions of the present invention are generally administered by intravenous injection, although in
In certain cases (e.g. children or animals) it may be preferred to inject intramuscularly.

The simple aqueous solutions of the salts can also be used subcutaneously administered. Hydrochloride salts can be particularly suitable for intramuscular injection.

As is common in the anesthetic field, the amount of steroid used to induce anesthesia depends on the weight of the individual being anesthetized. For intravenous administration generally proves to be the average
Humans use a dosage of 0.1 to 8.0 mg / kg as sufficient to induce anesthesia, with the preferred dose being im
Range from 0.2 to 4.0 mg / kg. The dose depends, of course, to some extent on the physical condition of the
Patient and the extent and duration of the anesthesia desired.

If prolonged anesthesia is desired, repeated doses of the above solutions can be used, such repeated doses generally being of the same order of magnitude as or less than the original dose. Alternatively
continuous administration using solutions containing 0.01 to 0.4 % (preferably 0.02 to 0.2%) w / v. of the active compound, for example in
to an extent of 0.0125-0.2 (e.g. 0.025-0.1) mgAg / min. Continuous administration can also be used to achieve sedation for extended periods of time.

If anesthetic solutions are administered intramuscularly or subcutaneously, higher dosages are generally necessary.

The compounds of the present invention are known by various methods using generally known or customary tech-

709841 / 097Λ

2 7 1 b ü 7 8

niken are made. Appropriate procedures are provided in the described below.

1. Conversion of an unsubstituted or monosubstituted HOCr amine to a disubstituted amine.

This reaction can be carried out by reacting a corresponding compound of the formula I, in which either or both of the groups H ^a and R are hydrogen, with a compound of the formula R ^a X, in which X is an easily displaceable or replaceable group, such as a halide (e.g. Iodide), a hydrocarbon sulfonyloxy group (e.g. toluene-p-sulfonyloxy), hydrocarbon oxysulfonyloxy (e.g. methoxysulfonyloxy), or a dialkoxyphosphonyloxy group (e.g. dimethoxyphosphonyloxy). The reaction is preferably carried out in the presence of a base (for example potassium carbonate or silver oxide) in solution at any suitable temperature from room temperature to the reflux temperature, expediently at room temperature. Excess of the compound R ^a X, e.g. methyl iodide, can be used as the reaction solvent, but there are many other solvents as alternatives such as halogenated hydrocarbon solvents (e.g. methylene chloride), alkanols (e.g. ethanol or methanol) or acetonitrile.

If an N-monosubstituted starting material is used, the reaction can lead to N, N-disubstituted compounds according to the invention, in which R ¹
represent different groups.

lead of the invention, wherein R ^a and R either the same or different

The N-monosubstituted starting materials can be prepared in the same way by reacting a compound of the formula I in which both groups R ^a and R are hydrogen atoms with a compound of the formula R ^a X, as described above.

Compounds in which -NR R is a heterocyclic amino group, can also be produced according to this procedure

7098 ^ 1 / Π97 /.

271SU78

away

den, by using a reagent X-H -R -X, wherein X is as above is defined (e.g. a 2,2'-dihaloethyl ether or a dihaloalkane, such as 1,4-diiodobutane).

If there is a 20-oxo group in the starting material, then these may be protected as the 20-ketal group as described below. Such protection is with the N-substitution reaction not necessary, but a 20-ketal group is often present as a result of earlier stages in the presentation sequence. The isolation of the product of the N-substitution reaction often takes place under acidic conditions, which also serve to produce the desired 20-oxo group to regenerate.

The Hoo amino starting materials required for this reaction can be prepared, for example, by stereoselective reduction of the corresponding 11-oxime. This reduction can by means of an alkali or alkaline earth metal reducing agent in alcohol and / or an amine and / or ammonia, e.g. sodium in n-propanol, optionally in the presence of a suitable solvent, e.g., tetrahydrofuran, at any suitable temperature up to and preferably at reflux.

The 11-oximes themselves can be obtained from the corresponding 11-0xo compounds in which the 20-oxo group (if any) is protected as a ketal group. The 11-oxo compound can for example with hydroxylamine under strongly alkaline conditions in aqueous alcohol (e.g. ethanol), preferably under reflux conditions implemented. If no other oxo groups are present, the reaction can be carried out under acidic conditions (e.g. pH 4), e.g. in buffered pyridine.

The severe conditions used to reduce the 11-oxime make it necessary or desirable to introduce certain of the possible substituents after the formation of the 11oi-amino group, Examples of such groups are 17β-cyano and -alkoxycarbonyl, 21-alkanoyloxy and -halogen, 2β-halogen, -alkanoyloxy.

70984 1/097 I *

"^ ⁶ " 27 I b ü 7 β

and thiocyanato and loo ^ chlorine. When introducing certain of these substituents (according to the methods described below, e.g. by acylation or esterification reactions) it may be desirable to protect the 110G amino group. Usual amine protection methods can be used, e.g. acylation, (e.g. with trifluoroacetic acid or formic acid or a reactive Derivative thereof) or by silylation.

2. A corresponding 110C-ACyI amino steroid (i.e. wherein one of the

away
Groups R and R is as defined above and the other

represents an acyl group) can be reduced, for example with lithium aluminum hydride in an ethereal solvent (e.g. tetrahydrofuran or dimethoxyethane) at any suitable Temperature to reflux. The starting material can have a 20-ketal group which is subsequently converted into a 20-oxo group or a 3oC-esterified hydroxy group that should be converted to a 3oO "hydroxy group in the course of the reaction will.

The acylamino starting materials can be prepared by acylating an appropriate 1100 monosubstituted amino compound (or a 20-ketal or 20-hydroxy derivative thereof) for example with the suitable carboxylic acid (or a reactive derivative thereof, e.g. an acid halide, ester or anhydride), optionally in the presence an acid binding agent (e.g. pyridine). The 3 <X hydroxy group and any others present Hydroxy group is acylated in this reaction and can optionally be regenerated by treatment with a base before the reduction will; if a 20-hydroxy group is present, the acylamino intermediate can first be oxidized and ketalized with formation of the corresponding protected 20-oxo group. Knows the 11-acylamino compound has a 3-oxo group, this can then reduced to form the desired 3i> C-hydroxy group will.

41/0974

3. Opening of a corresponding 2 (X, 3oo epoxy.

This reaction can lead to the production of Hing Α-saturated 2ß-substituted 500 compounds are used and represents the preferred way to prepare the 2ß-halogen, alkoxy, alkanoyloxy and thiocyanato compounds. The general method for making 2 [beta] compounds in this way is described in British Patent 1,376,892. Thus, the reaction generally involves treatment of the corresponding 2 &, 3o6 epoxide with a compound HR under acidic conditions (if necessary in the presence of an added acid catalyst, e.g. sulfuric acid, perchloric acid or boron trifluoride) or one Compound giving the anion (R) ~ (wherein R is as defined above and is different from H) and then (if the starting product is a deprotonated 306-hydroxy group treatment of the product with a source of protons (e.g. aqueous ammonium chloride) to form the 3oO-

Hydroxyl group. Examples of HR reagents are alcohols, carboxylic acids, Thiocyanic acid and hydrogen halide (HF can be used in the form of the HF-urea complex, expediently in its absence a solvent); Examples of reagents that produce anions (R) ~ are metal alkyls such as lithium dimethyl cuprate, Alkali metal or ammonium salts of HR acids and alkali metal alkoxides. The reaction is preferably carried out under anhydrous conditions in a suitable solvent (e.g. a Hydrocarbon or an ether) at any suitable temperature up to reflux. The 2β-halogen and thiocyanato compounds can also be produced in an aqueous medium.

The starting materials required for this reaction can be prepared, for example, by first having the introduces desired HOt-substituted araino group (e.g. after

p the method of the above reaction 1) using an A - starting material, whereupon a salt (e.g. with toluene-p-sulfone-

acid) and then the Δ -compound with a per-

709841/0 9 74

27 ibü78

ρ acid is epoxidized and finally the free base is regenerated. Δ connections can by forming the 3-methanesulfonate and subsequent Elimination of methanesulfonic acid can be produced.

4. A corresponding Hofc-amino or 11o (rmonosubstituted-amino compound (or a 20-ketal thereof) can be reductively alkylated with a suitable mono- or dicarbonyl compound in the presence of a reducing agent. For example, in the case of 11OCr-amino compounds, monocarbony compounds can be used such as formaldehyde or acetaldehyde, lead to 11o (r dimethyl or diethylamines, whereas a dicarbonyl compound can lead to a compound in which -NR ^a R is a heterocyclic amino group (e.g. glutaraldehyde can be used to form a piperidino group) 11 (XN-monosubstituted starting material, one should use a monocarbonyl compound. The reactants used can be those which are generally customary for the reduction of imines, examples are formic acid (e.g. at any suitable temperature up to 100 to 120 ⁰ C, e.g. from room temperature up to 100 ⁰ C, and use of the Carbonylverbi in the presence or absence of water), an alkali metal borohydride or cyanoborohydride (e.g. sodium borohydride or cyanoborohydride, using an alcohol such as ethanol, as a solvent, suitably at room temperature), iron pentacarbonyl or an alkali metal hydrogen iron carbonylate _{(e.g. Fe (CO) 5 or MHFe} (CO) ^, where M is sodium or potassium, at any suitable temperature up to reflux using an ether such as tetrahydrofuran or an alcohol or aqueous alcohol as the solvent), hydrogen in the presence of a metal catalyst (using an alcohol such as ethanol, an ether, for example dioxane or an ester, for example ethyl acetate, as the reaction solvent, expediently at room temperature), or aluminum amalgam in the presence of water (expediently at room temperature and in the presence of an ether solvent such as tetrahydrofuran).

7 0 9 8 4 _1/0 9 1 1 ^, NSpECTED

The metal catalyst can, for example, be a noble metal catalyst, such as platinum, platinum oxide, palladium or rhodium. Of the The catalyst can be on a carrier, e.g. on carbon or activated carbon or kieselguhr. A homogeneous catalyst, like Tristriphenylphosphine rhodium chloride can also be used. The imino intermediate compound can optionally be isolated will.

HoCrN monosubstituted amino starting materials can be used in are prepared in the same way by reacting the corresponding 1100-amino compound with a corresponding aldehyde or ketone in the presence of a reducing agent as described above. For example, the use of formaldehyde, Acetaldehyde or acetone to the 1 loO-N-methyl-, -N-ethyl or -N-Isopropylamines lead. Whether you have a Ho ^ -N-mono- or -Ν, Ν-disubstituted compound, depends in part on the proportion or the amount of the ketone or aldehyde used.

5. In ring A saturated 2β-ubstituted 50C-steroids according to of the invention can be made from corresponding ^ -oxo compounds can be produced by stereospecific reduction, e.g. according to the method of Browne and Kirk (J. Chem. Soc. C, 1969 * 1653) or according to the method of British patent specification 1 4-09 239 » The latter method preferably uses a preformed iridium catalyst reduction system. For example can be a reducing system of an iridic acid or a salt (e.g. chloriridic acid), a trivalent phosphorus compound, such as a phosphorous acid ester (e.g. trimethyl phosphite), water and an organic reaction medium (e.g. an alcohol, such as Isopropanol). The reduction system is then neutralized (e.g. to a pH value of 6 to 8.5) by means of an organic base such as a secondary or tertiary amine (e.g. triethylamine) and reacted with the steroid. If the catalyst system is formed in advance by refluxing for example for 16 to 72 hours, the reduction can be carried out be complete, for example, in 2 to 3 hours under reflux;

709841/0974

ORIGINAL INSPECTED

-. 27 ί b U 7 8

longer times may be necessary at room temperature.

6. Reduction of a corresponding 3-oxo-5β compound.

3PC-Hydroxy-5ß-steroids can be obtained by hydride reduction of the corresponding 3-oxo compound (in which a 20-oxo group, if present, is optionally protected) for example by means of sodium borohydride using an alcohol (e.g. ethanol) or of Pyridine can be produced as a solvent.

7. Inversion of derivatives of the corresponding 3β-hydroxy compounds

This preparative procedure is for making compounds suitable, which are unsubstituted in the 3ß-position and have no 5,6 double bond. The starting material can be a be a corresponding compound which has an easily displaceable or replaceable 3β group, such as a hydrocarbon sulfonyloxy group (e.g. p-toluenesulfonyloxy or mesyloxy), and the 3β group can be replaced by hydrolysis (e.g. under acidic conditions) to form the desired 30C-hydroxy compounds. Procedures for making & connections on this Routes are described in British Patent 1,372,175.

8. Reduction of the corresponding ^ compound.

Compounds in which R is a group (a) or (b) as above represents defined, can by hydrogenating the corresponding Δ -compound in the presence of a hydrogenation catalyst (e.g. a palladium catalyst) in a suitable solvent (e.g. an alcohol, ether or ester). The reaction can expediently at or about room temperature and at atmospheric pressure in the presence of a tertiary base, e.g. triethylamine (except if there is an easily replaceable substituent, e.g. bromine, in the 2ß-position) and / or an acid such as acetic acid.

70934 1/097 4

27 Ί 5078

16 9 · Hydrochlorination of the corresponding A compound.

1600-chlorine compounds can be prepared by reacting the corresponding

A compound with hydrogen chloride in an anhydrous solvent (for example an ether) at a temperature of, for example, 15-40 ⁰ C, as generally described in British patent 1,380,243.

10. Dehydration of a corresponding 17β-carbamoyl compound or the oxime of a corresponding 17β-iOrmyl compound

17β-cyano compounds can be prepared by refluxing the corresponding oxime, for example with acetic anhydride. The 30C-hydroxy group is generally esterified in this reaction and must be regenerated by ester saponification. The oxime starting material for this reaction can be prepared from the corresponding 17β-formyl compound (with NH ₂ -OH), which is itself prepared by periodate cleavage of the corresponding 20,21-dihydroxypregnane.

Alternatively, the corresponding 17β- (unsubstituted carbamoyl) compound be dehydrated, e.g. using polyphosphate ethyl ester, as in British Patent 1,380 described.

11. Esterification of a corresponding 17β-carboxylic acid.

17ß-Alkoxycarbonylverbindungen can by reacting the corresponding 17β-carboxylic acid or a reactive derivative thereof (e.g. an acid halide or anhydride or a salt) with the appropriate alcohol or alkyl halide.

This reaction is preferably carried out at temperatures from -20 ⁰ C

e.g. i 709841/0974

to 110 ⁰ C through, as for example in the British patent

271bU78

document 1 380 246.

The 17ß-carboxylic acid can expediently by oxidation of the corresponding 17ß-acetyl compound can be formed, for example NaOBr in an aqueous inert solvent (e.g. Dioxane) is used. The acids are expediently obtained in the form of their triethylammonium salts by neutralizing and adding Triethylamine followed by extraction into a suitable solvent (e.g. chloroform). These salts can be converted into their alkali metal salts by treatment with an alkali metal alkoxide (e.g. lithium methoxide).

12. Reaction of the corresponding 17β-carboxylic acid with an amine.

17ß- (substituted garbamoyl) compounds can be prepared by reacting the corresponding 17ß-carboxylic acid or a reactive derivative thereof (e.g. an acid halide or ester) with an amine HNR ^X R ^, where E ^x and R ^ are as defined above, getting produced. The reaction is carried out again, preferably in the presence of an acid-binding agent, as generally indicated in British Patent 1,380,246.

13 · Acyloxylation of a corresponding 21-unsubstituted compound.

21-alkanoyloxy and benzoyloxy compounds can be treated by treating the corresponding 21-unsubstituted compound (in which the 3oC-hydroxy group is optionally protected) with the corresponding Lead tetraacylate, preferably in the presence of a Lewis acid (e.g. boron trifluoride) in a hydrocarbon / alcohol solvent getting produced. This implementation is described generally in British Patent 1,317,185.

14. Replacement of a 21-iodine atom with fluoride.

21-fluorides can be obtained from the corresponding 21-iodine compounds

7.0 9841/09 * 74

ORIGINAL INSPtCTlZD

271bU78

prepared by treatment with a source of fluoride ions (e.g. an alkali metal or silver fluoride), as in general in British Patent 1,430,932.

15 · Deacylation of a corresponding 21-acyloxy compound.

21-Hydroxy compounds can be obtained by hydrolysis of a corresponding 21-acyloxy compound (e.g. a 21-acetoxy compound) under basic conditions as generally in the British patent 1,377,608.

16. Etherification of a corresponding 21-hydroxy or 21-halogen compound.

21-alkoxy compounds can be etherified by a corresponding Compound with a 21-hydroxy group or a replaceable substituent in the 21-position (e.g. a 21-halogen, such as a 21-bromo compound) with a suitable alkanol, diazoalkane or alkali metal alkoxide are prepared; these methods are generally described in British Patent 1,377,608 described. The 3C0-hydroxy group becomes desirable in this reaction protected.

17 · Acyloxylation of a corresponding 21-substituted compound.

21-Alkanoyloxy- and -benzoyloxyverbindungen can by reaction a corresponding compound with an easily replaceable substituent in the 21-position (e.g. a bromine, chlorine or Iodine atom or a hydrocarbon sulfonyloxy group) with a salt of the appropriate carboxylic acid. This implementation is generally described in British Patent 1,317 described.

709841 / 097Ä

27-1 bü78

18. Acylation of the corresponding 21-alcohol.

21-Alkanoyloxy and benzoyloxy compounds can also be prepared by acylating the corresponding 21-alcohol as also described in British Patent 1,317,185. 21-carbonate can be prepared from the corresponding Alkylchlorameisensäureester example, in the same way using.

19. Dehydrohalogenation of a corresponding 2β-halogen compound.

A -5o (rCompounds can be prepared by dehydrohalogenating a corresponding 2β-halogen compound (preferably a 2β-bromine compound) using, for example, a nitrogen-containing one Lewis base, e.g., dimethylformamide or dimethylacetamide. The starting material can be a protected one Have 3oG-hydroxy group and the reaction becomes appropriate in the presence of an alkali metal or alkaline earth metal carbonate or halide (e.g. a mixture of calcium carbonate and lithium bromide) at a temperature of 80-170 ° C. This reaction is described generally in British Patent 1,380,248.

20. A 17ß-vinyl group can, for example, by partial Hydrogenation of a corresponding 17β-A * thynyl compound are introduced.

The 17β-A * thiny! Compounds required for this manufacture can themselves be prepared from a 17β-acetyisteroid by first adding the corresponding 20-hydrazone forms, the hydrazone codes (e.g. with iodine and triethylamine) and then the iodide (e.g. with ethanolic potassium hydroxide) dehydrated.

70 9841/0974

- «5 - 27 1 bü78

The 17ß-ethynyl compounds can also, by treating a suitable 21-methanesulfonyloxy-20-oxosteroids with toluene-psulfonylhydrazide and then made a base.

21. A 17ß-vinyl group can also be obtained by treating an appropriate 20,21-epoxide with an alkali metal (e.g. potassium) selenocyanate, for example in an alcoholic solvent, to be introduced. The epoxies can be prepared as generally described in British Patent 1,377,608.

22. A Z-Ä'thyliden- or Z-cyanomethylene group can by means of a Wittig reaction are introduced by reacting a 17-oxosteroid with, for example, a suitable one

Organophosphorus reagent, such as (i) a substituted or unsubstituted one Methylenephosphorane (e.g. ethylidene triphenylphosphorane), which is conveniently prepared in situ using a base (e.g. sodium hydride) in a solvent (e.g. Dimethyl sulfoxide or tetrahydrofuran) and a substituted one or unsubstituted methylphosphonium salt (e.g. a Ethyl triphenylphosphonium halide, e.g. bromide or chloride), or (ii) a substituted methyl dialkyl phosphonate (e.g. diethyl cyano-diethyl phosphonate).

23 · Compounds in which R is a methyl or cyclopropyl group or a methyl group substituted by a C 1-4 alkyl group represents, can by reaction of the 17ß-carboxylic acid or preferably a salt (e.g. a lithium or triethylamine salt) with the corresponding lithium alkyl (e.g. using 2 to 4 moles of the lithium alkyl per mole of the carboxylic acid or the salt). Examples of suitable reaction solvents include ither and hydrocarbons (e.g. Diethyl ether and hexane); the reaction is expediently carried out at room temperature, followed by protonation (e.g. by adding of water).

709841/0974

- ae - 27 1bü78

24. Decetalization of a corresponding 20-ketal.

As indicated above, it is often 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 be regenerated as a final step in the manufacturing process. The ketal is preferably the corresponding 20,20-ethylenedioxy compound and the 20-oxo group can, for example, by hydrolysis in the presence of an acid (e.g. hydrochloric acid, sulfuric acid or acetic acid) or by exchange reaction with a ketone, e.g. acetone, in the presence of an acid catalyst, e.g. p- Toluenesulfonic acid, at a temperature of 0 to 100 ⁰ C, are regenerated.

25 · Removal of the protective group of a corresponding compound with a protected 3 ^, - hydroxy group.

This procedure is often a necessary final stage in the preparation of the compounds according to the invention, since the 5oc ^ hydroxy group is often either intentionally protected or in the esterified state by inversion from a 3ß-hydroxy compound (for example by treating the 3ß-alcohol with Dietary azodicarboxylate in the presence of an acid such as formic acid or benzoic acid and a phosphine such as triphenylphosphine) is formed. Those in the 3uO position in the starting materials The group present in this reaction may be such an ester group as an alkanoyloxy group and such esters can form the desired 3o (r-hydroxy compounds under hydrolyzed in mild acidic or basic conditions. Weakly basic conditions are generally most convenient (using, for example, an alkali metal bicarbonate in aqueous methanol at any suitable temperature until reflux). Dilute mineral acids (e.g. perchloric acid in aqueous methanol) can also be used. Strength Bases (e.g. alkali metal hydroxides) can be used if the reaction is carried out briefly or quickly.

709841/0974

- ^ - 27 1 bU78 • 36

Alternatively, the starting material used for this reaction can be a protected 3P0-hydroxy compound such as a 3 (Kr ether (e.g. 300-tetrahydropyranyl ether) or a JOC-nitrooxy compound. Such ether protecting groups can be obtained by treatment with an aqueous acid and such nitrooxy groups by reduction using for example zinc and acetic acid are split off.

26. Salt formation.

The compounds according to the invention are often used in the form of a salt and thus the salt formation by reaction of the Base with an acid particularly interesting.

A generally convenient method of forming the salts is by mixing appropriate amounts of the free base and acid in a mixture of water and a solvent for the base (e.g. an alcohol such as ethanol), removing the solvent (e.g. by evaporation) and then if necessary Dissolve the residue in water.

In some cases, solid salts can be prepared by treating the free base with an acid (e.g. citric acid, HCl) in an anhydrous Solvents such as diethyl ether can be prepared. In most cases it is possible to use an aqueous solution of the salt by simply mixing the free base with an aqueous acid. Optionally, one or more Steroid bases and / or one or more acids can be used.

In these preparations, the base and the acid do not necessarily have to be be used in equivalent amounts. If the acid is a weak acid, it is sometimes an excess of the acid is beneficial. In the production of aqueous solutions, for example, it has been shown in some cases that that an excess of the base can be used, which implies that the free base to some extent in the

709341/097 A

- * »'- 2 7-1 b U 7 β

Solution of the salt is dissolved.

If necessary, the pH of the salt solution can then be increased Addition of a base, e.g. sodium hydroxide and / or disodium hydrogen citrate, can be set.

The methods given above for the preparation of the compounds according to the invention can be used as the last main step in the Manufacturing sequence can be used. The same general methods can be used to incorporate the desired groups or unsaturations be used in an intermediate step in the stepwise formation of the desired compound and it can be seen that these general methods can be combined in various ways in such multi-step processes as this can be seen from the examples below. For example, the desired 11 (Xr-substituted amino group can either before or after the reduction of a 5-oxo group or 16,17 double bond are formed and either before or after the introduction of a possible substituent in the 16,1? ß- or 21 positions or the formation of a double bond in the 1,2 position. The sequence of reactions in multi-step processes should be chosen so that the reaction conditions used does not affect the groups in the molecule that are desired in the final product.

Other structural features included in the compounds of the invention can be introduced by the following methods.

Methods which are generally suitable for introducing substituents in the 206 and 3 [beta] positions are described in the British patent 1 380 248.

Δ -steroids can be according to the British patent 1 372 175 methods described can be obtained.

709041/0974

271SÜ76 • 3 * · "

Compounds having an alkyl group or substituted alkyl group in the 21-position or a cyclopropyl group in the 20-position can according to the general methods described in the British patent 1 4-36 324- described methods.

Compounds with a 6β-methyl group can be hydrogenated a corresponding 6-methyl-3-oxo-4,6-diene followed by one Reduction of the 6β-methyl-3-oxo compound formed, e.g., using chloriridic acid in the 50O series as above described.

The D-homo- and Δ -compounds as well as Δ, 5β-compounds can by choosing the starting materials with suitable structure.

The following examples serve to illustrate the invention. The temperatures are given in C.

Melting points were determined on a Kofier bench and are not corrected. Optical rotations were determined on solutions in chloroform (approximately 1 % w / v) at room temperature, unless otherwise stated.

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

The chloriridic acid reagent was made by refluxing a mixture of 50 mg of chloridic acid, 94 ml of isopropanol, 6 ml of water and 8 ml of trimethyl phosphite for 24 hours and adjusting the pH adjusted to 7 by adding triethylamine immediately before use.

Methylene chloride was distilled and dried.

Solutions were either azeotroped or using mag-

709841/0974

- 30 -

2 V ι b ü 7 β

Dried nesium or sodium sulfate.

In the following examples and preparations, reagents and solvents that occur frequently have been abbreviated for simplicity: ethyl acetate = EA; Petroleum ether (bp 60-80 ⁰ C) = PE; Acetonitrile = AN; Chloroform = CH; Methylene chloride = DM; Diethyl ether = DE; Dimethyl sulfoxide = DMSO; Pyridine = PY; THF = tetrahydrofuran; Water = W; Benzene = B; Toluene-4-sulfonic acid = PTSA; Methyl acetate = MA; Ethanol = ET; Denatured alcohol (industrial methylated spirits) = IMS; Propan-1-ol = PE; 1,2-dichloroethane = TLC; Dioxane = D; Petroleum ether (bp 40-60 ⁰ C) = PT; Dimethylformamide = DMF; Acetone = AC; Methanol = ME; and barely any temperature = ET.

In the manufacturing processes and examples, 98-100% formic acid and formaldehyde were used as an aqueous solution of 37- ^ 0 % w / v. used.

The following known starting materials were used in the manufacturing process used:

20,20-ethylenedioxy-3ot- ^Q ydroxy-5 <ft * -pregnan-11-one (I)

3 / XrHydroxy-2ß-methoxy-500-pregnane-11,20-dione (II)

2ß-butoxy-3öO-hydroxy-5ö0rpregnan-11,20-dione (III)

20, 2O-ethylenedioxy-20C * 3iVepoxy-5X-pregnan-11-one (IV)

3ß-Hydroxy-2O, 2O-ethylenedioxy-50C-P ^re S ^nail - ' ^l ' ¹ - ^on - ^ox i ^m (V)

20,20-ethylenedioxy-5Xrpregn-2-en-11-one (VI)

2ß-Ethoxy-30Crnydroxy-5cC-pregnan-11,20-dione (VII)

20, 2O-ethylenedioxy-30 (rhydroxy-2.X-methyl-5 ^ P ^re 6 ^nan - ¹¹ ~ ^one (VIII)

2O, 2O-ethylenedioxy-30Crliydroxy-3ß-methyl-50O-pregnan-11-one (IX)

6-methylpregna-4-, 6-diene-3,11,20-trione (X)

30 & -hydroxy-21-methyl-5G < _r pregnan-11,20-dione (XI)

21,21 -ethylene- 306-hydroxy-5c <7Pregnane-11,20-dione (XII)

300-hydroxy-21-methoxy-50 (rpregnan-11,20-dione (XIII)

2ß-ethoxy-30 <rhydroxy-5 & -p: regnan-11,20-dione (XIV)

3C> C-Hydroxy-D-homo-5 <.> RPregnan-1'J, 20-dione (XV)

2ß-ethoxy-3; Xrhydroxy-D-homo-5 <X-pregnan-11,20-dione (XVI)

20β, 21-epoxy-3X-hydroxy-5, XrPregnan-11-one (XVII)

709841 /.097A

ORIGiNAL INSPECTED

27

5 <& - Pregna-2,16-diene-11,20-dione (XVIII)

3oC-Hydroxy-5oo-androstane-11,17-dione (XIX)

30C, 20β, 21-trihydroxy-5CC-pregnan-11-one '(XX)

20,20-ethylenedioxy-3 (Xrhydroxy-5ß-pregnan-11-one (XXI)

20β, 21-trihydroxy-5β-pregnan-11-one (XXII)

Production 1 (Z) -11PG-Araino-50l-pregn-17 (2O) -en-3 -öl (XLI)

A solution of 9.638 g of (Z) -3 <Xr-hydroxy-5OC-pregn-17 (20) -en-11-one oxime in 200 ml of PR was refluxed under Np, while 9.6 g of Na were added in portions became. When all of the Na had reacted, about 90 ml of PR were distilled and then the residue was poured into water; Ice was added and the crystalline solid (9 »19 g) was collected by filtration. A portion of 6.17 g was crystallized from ET-W, 3.6 g of the title compound having a melting point of 118-125 ° ^ / _D + 5.4 °.

Manufacturing 2

6β-methyl-5ftC-pregnane-3,11,20-trione (XXIII)

1.7 g of X in 100 ml of EA were hydrogenated at atmospheric pressure using 500 mg of 10% palladium on carbon (Pd-C) as a catalyst. The catalyst was filtered off and the filtrate was evaporated. Crystallization of the residue from AC-PE gave 720 mg of the title compound with a melting point of 174-176 °, / ScZ-q + 106 °.

Preparation 3 3gC-Hydroxy-6ß-methyl-5 / XrPregnan-11,20-dione

600 mg of XXIII were refluxed with 35 ml of chloridic acid reagent heated for a total of 8.5 hours. The reaction mixture was diluted with water and extracted with EA. By Evaporation of the extract gave a foam which was purified by preparative thin layer chromatography in EA-PE (1: 1) to give 440 mg of the title compound as a foam.

709841/097 ^ ORJGINAL INSPECTED

■ 27 ΐ ^ ü '/ a 'tfj.

+ 88 °.

Manufacturing 4

21-N, N-dimethylaminomethyl-2ß-ethoxy-3 ^ hydroxy-5: X ^ pregnan-11,20- dione (XXIV)

10.0 g of XIV were dissolved in 50 ml of dry AN and 5.0 g of N, N-dimethyl (methylene) ammonium chloride were added. The mixture was refluxed for 2 hours, cooled and between 2 η-hydrochloric acid and EA divided and the acidified The extract was made basic with NaOH solution and extracted 2 χ CH. The extract was dried over NapSO ^ and evaporated, 10.7 6 of the title compound were obtained as a foam.

Manufacturing 5

2ß-A'thoxy-30C-hydroxy-21-methylene-5X-pregnane-11,20-dione (XXV)

10.5 g XXIV was dissolved in 105 ml ME and 10.5 ml iodomethane was added. The mixture was ^{kept at 20 °} C. for 20 hours and then evaporated under reduced pressure. The residue was dissolved in 200 ml of DM and stirred vigorously with 100 ml of a 5% NaHCO ^ solution for 1 1/2 hours. The layers were separated and the organic phase was _{dried over Na 2} SO 4 and evaporated to form a foam. Column chromatography using EA-PE (1: 1) gave 3.48 g of the title compound of F = 181-184 °, fitf ^ + 112 °.

Preparation 6 2β-Ethoxy-3 ^ hydroxy-21-methyl-5 _: Xr Pregnane-11,20-dione

3.37 g XXV were hydrogenated at atmospheric pressure and 23 ° in 150 ml EA over 5 % Pd-C. The catalyst was filtered off and the filtrate was evaporated, whereby 3.27 g of the title compound were obtained as a foam with a melting point of 147-149 °, / pi / ^ + 92 °.

Preparation 7 3 ^ (rHydroxy-50u-pre ( ^ n-2O-en-11 -one

09841/0974 originally inspected

5078

330 mg XVII in 11 ml W-ME (1:10) were treated with potassium selenocyanate and the solution was ^{heated to 60 °} C. for 20 hours. The solution was filtered through kieselguhr and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in DM and purified by column chromatography eluting with EA-PE (1: 1) to give a foam which was crystallized from DE-PE to give 80 mg of the title compound as a pale yellow solid from F = 137.5-139.5 °

Manufacturing 8

1.0 g of sodium hydride (80 % dispersion in oil) was washed with PE and heated to 70-80 ° C. with dry DMSO until a green solution was obtained. The solution was cooled to room temperature and then 13.3 g of ethyltriphenylphosphonium iodide in 50 ml of DMSO were added. 2.0 g of XIX in 40 ml of distilled DMSO were added all at once and the mixture was warmed to 40-60 °. After 6 hours the reaction mixture was poured into water and extracted into DE. Evaporation of the washed and dried extract gave an oil, which was purified by column chromatography using EA-PE (1: 1) and crystallization from EA-PE to give 824 mg of the title compound; 3Q ^ + 29.0 °.

Manufacturing 9

20-0ximino-5fl-rpregna-2,16-dien-11-one (XXVI)

A mixture of 60 g XVIII, 21 g hydroxylammonium chloride and 240 ml anhydrous PY was left to stand at room temperature overnight, after which it was diluted with ice and water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo (62 g). Crystallization from EA gave the title compound with a melting point of 168-182 °, / ö £ 7 _D + 137 °.

ORIGINAL INSPECTED 7 0 9 8 A1 / 0974

"**" .. 27 ι bü7a

Manufacturing IQ

506-androst-2-en-11,17-dione (XXVII)

A solution of 60 g of XXVI in 250 ml of anhydrous PY was mixed with 225 ml of a solution prepared from 55 ml of phosphorus oxychloride in 250 ml of anhydrous PY, the reaction temperature being kept at <^ 5 ° while the reagent was added. The reaction mixture was then added to a solution of 550 ml of concentrated HCl in 3 l of water. This mixture was stirred for 60 hours, after which the precipitate was filtered off. The precipitate was washed with water, dissolved in hot IMS and dissolved with 50 ml of 2N HCl at room temperature. After 1 hour the reaction mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water and dried (38.4 g). Crystallization from ME gave the title compound with a melting point of 188-192 °, / 0 ^ _D + 207 °.

Preparation 11 11 (XrAmino-2ß-ethoxy-3 (Xrhydroxy-21-methyl-5XrPregnan-20-one (LXII)

2.8 g of 2β-ethoxy-20,20-ethylenedioxy-3'rhydroxy-21-methyl-5 (X-pregnan-11-one oxime were dissolved in 150 ml of PR and heated to reflux. 12.6 g of Na were added was added and refluxed until all Na was dissolved. The PR was removed by distillation while adding water. The resulting mixture was extracted twice with EA and the washed organic layer was re-extracted with 2N HCl acidic extract was basified to pH 11 with 40% NaOH solution, extracted twice with EA, dried over NapSO ^, and evaporated to give 1.94 g of the title compound as a foam.

Manufacturing 12

21 -Bromo-iiiX ^ NiN-dimethylamino ^ ß-ethoxy ^ flc-hydroxy- 5PC-P ¹¹⁶ EP ¹³¹¹ - 20-one (XXVIII)

709841/0974

ORIGINAL INSPECTED

27 1 bu78

A solution of 450 mg 11 | £ -N, N-dimethylamino-2ß-ethoxy-3 <X-hydroxy-50G-pregnan-20-one hydrochloride in 50 ml of dry ME was added dropwise with a solution of 0.1 ml of bromine in 5 nil of ME added at 0 C with charging. The individual drops of the reagent solution were added after the color of the previous additions had disappeared. After the addition was complete, 150 ml 10% KpCO ^ solution was added and the mixture was left for 15 minutes touched. The precipitate was filtered off, washed with water and dried. By purification by preparative thin layer chromatography in EA-PE (1: 1), 230 mg of the title compound were obtained.

Manufacturing 13

, N-dimethylamino-2ß-ethoxy-3öG-hydroxy-50 (7 androstane-17ß carboxylic acid lithium salt (LXXV)

4.3 ml of bromine were added to a stirred solution of 12.1 g of NaOH in 90 ml of v / water at -5 to 0 °. 42 ml of D was added and the mixture was added to a stirred solution of 10.0 g of 11o6-N, N-dimethylamino-2ß-ethoxy-3 ^ -hydroxy-506-pregnan-20-one in 316 ml of D and 90 ml of V / ater joined at 8 °. The mixture was stirred at 5 to 10 ° for 3.5 hours. A solution of 4.66 g of sodium sulfite heptahydrate in 20 ml of water was added and the mixture was boiled for 15 minutes. The solution was filtered hot and the cooled filtrate was extracted with CH. The CH extract was washed with water and the combined aqueous fractions were acidified to pH 3 with concentrated HCl. 50 ml of triethylamine were added and the solution was extracted with CH. The extract was over MgSO ^. dried and evaporated to dryness, giving the crude triethylammonium salt which was dissolved in 20 ml of ME and treated with a solution of 20.4 mmol of lithium methoxide in 35 * 7 ml of ME. The resulting solution was evaporated to dryness and the residue was crystallized from a mixture of 36 ml ME, 36 ml PT and 354 ml DE, giving 7> O3 g of the title compound, F => 300 °, ^ c7 _D +9, 1 °.

7 0 9 8 A ^{1/0 9 7 A RlGINAL}

- 27 I b

Manufacturing 14

(XXX)

A solution of 2.8 g XXIX in 100 ml ME was treated at room temperature with 15 ml of a 10% K-CO ^ solution for 15 minutes. The mixture was diluted to 700 ml with water and the oily precipitate was extracted three times in DE. The extracts were washed with water, dried over Na ^ SO ^ and evaporated to give 2.5 g of a foam. A 300 mg sample was purified by preparative TLC in EA-PE (1: 1), 160 mg of the title compound being obtained as a foam; ß> Q- ^ + 65 °.

Manufacture 15

11 (X ^ N, N-dimethylamino-2ß-ethoxy-5XrPregnan-3f> C 20ß, 21 -triol (XXXI)

A solution of 2.2 g XXX in 50 ml ME was treated with 230 mg sodium borohydride. After 10 minutes the mixture was diluted to 300 ml with 80 ml of a 10% KpCO ^ solution and with water. The mixture was extracted three times with DE and the extracts were washed with water, over Na ₂ SO ^, dried and evaporated to a foam which was purified by column chromatography eluting with DM-AC (1: 1) to give 700 mg of the Title compound was obtained in the form of a foam; {βζΐ-κ -5 ° ·

Manufacturing 16

20,20-ethylenedioxy-5-hydroxy-2β-methyl-5 <X-pregnan-11-one

A stirred solution of 19 »6 g of dried cuprous iodide in 350 ml of dry xylene under nitrogen was cooled to -10 ° and 108 ml of 1 m-methyllithium was added until the original yellow precipitate was redissolved to form an almost clear one colorless solution. A solution of 12.9 g of IV in 430 ml of xylene was added dropwise at -10 to -5 °. After the addition, the mixture was stirred overnight at room temperature and then poured into 1200 ml of a 25% NH ^ Cl solution. The mixture was extracted with DE and the extract was washed with 25% NH ^ Cl-Lö-

709841/0974

ORIGINAL INSPECTED

2 7 Ί b ü 7 β

solution and water washed. Evaporation of the DE left an oily solid which was found to be a 2: 1 mixture of the starting material and the title compound in thin-layer chromatography. This contaminant was recycled using the same amounts of reagents, temperatures and reaction times. The resulting solid was crystallized from EA-PE to give 7.22 g of the title compound; F = 167-168 °, β <7 ^ + 68.1 °.

Manufacturing 17

20,20-ethylenedioxy-2ß-ethoxy-3 (Q-hydroxy-5 (& - pregnan-11-one (XXXII)

A solution of 8.2 g of VII in 300 ml of B and 40 ml of ethylene glycol was treated with 200 mg of PTSA under reflux in a Dean-Stark water trap with vigorous stirring. After 6 hours, 500 mg of solid NaHCO _{5 were added} to the cooled mixture. 100 ml of an aqueous saturated NaHCO ^ solution and 50 ml of water were added and the organic phase was washed three times with water, dried over Na ^ SO ^ and evaporated to a foam which was determined by column chromatography, eluting with EA-PE (1: 2 ) was purified to give 6 g of product. 500 mg thereof was crystallized from MA-PE to give 210 mg of the title compound; F = 124-127 °, ßf ^ + 53 °.

Manufactures 18-26

In Table 1, the preparation of 20-ketals is as follows Way summarized.

A solution of the corresponding 20-ketone in B and ethylene glycol was refluxed under a Dean-Stark trap in the presence of PTSA for the time indicated.

The cooled mixture was then worked up using one of the following methods:

A - Solid NaHCO3 was added to the mixture, and (i)

709841 / 097A.

ORIGINAL INSPECTED

ü 7 β

DE water or (ii) diluted water. The organic phase was separated off, washed, dried and evaporated.

B - The mixture was diluted with aqueous NaHC (X solution and extracted with (i) EA or (ii) DM. The extract was washed, dried and evaporated.

C - The mixture was poured into aqueous NaHCO, solution containing the
Layers were separated and the aqueous layer was extracted with B. The combined organic extracts were washed, dried and evaporated.

The material obtained by either of these procedures was by chromatography (column or thin-layer chromatography) and / or crystallization purified.

709841/0974

ORIGINAL

Her Baseline Weight Vol. Ethylene PTSA Tabel 1 system Crystal the end F. Zx7 _D Aufar stel material (S) B. glycol (mg) Lisa- prey ( ⁰ C) processing lung Verb. Or (ml) (ml) Reak solution solution (S) method Manuf. 6th ions Chromatography sensational No. Time Type middle 18th II 7th 150 40 300 (Hours.) EA-PE DE 5.1 15O- + 52 ° A (i) 155 19th III 5.4 180 20th 200 24 - EA-PE PE-DE 3 126- + 42 ° A (ii) 150 20th 5 5.18 50 2.5 70 18th CC - DE-PT 2.64 112- + 50.8 ° B (i) CD 5.8 EA-PE 115 to 21 6th 50 1.5 50 72 CC - 5.58 + 48 ° B (i) OO 22nd XII 5.19 110 5 56 EA-PE ME 0.697 180- + 51.5 ° B (ii) 18th - 181 O 25th XI 1.5 110 5 .56 120 cc _ ME 1.28 126- + 47.9 ° B (ii) to 127 -J 24 XIII 6.21 55 2.5 15th 5 cc EA-PE ME-PY 1.04 188- + 56 ° B (ii) 189 25th XV 1.95 275 27.5 275 5 _ EA-PE EA-PE 2.22 156- + 5.6 ° C. 157 26th XVI 100 10 100 72 cc DE-PE 1.62 140-
1444— + 8.4 ° C.
ho 17th TLC

CC = column chromatography TLC = thin layer chromatography

OP

- - 2 / ι-u / S 'it-

Manufacturing 27

20,20-ethyl end ioxy-5fl6-pregn-2-en-11-one-11-oxime (XXXIII)

A solution of 5 g VI in 150 ml ET was mixed with of 10 g of hydroxylamine hydrochloride and 40 ml of a 50% NaOH solution from pH 11 added. The mixture was refluxed for 3 days, diluted with water and the precipitate was removed filtered off, washed with water and dried. The residue (5 »5 g) was crystallized from 2 χ MA-PE, 2.2 g of des Product received. A 200 mg portion was further crystallized to give 150 mg of the title compound; F = 174-179 °,

Manufacturing 28

2O, 2O-ethylenedioxy-2ß-ethoxy-3X / -hydroxy-50c-pregnan-11-one-1 ^/ 1-oxime (XXXIV)

A solution of 5 g XXXII in 200 ml ET was treated with a mixture of 15 g hydroxylamine hydrochloride and 60 ml 40 % NaOH solution under reflux at a pH of about 11 for 18 hours. The mixture was diluted to 2 liters with water and the precipitate was filtered off, washed with water and dried in vacuo to give 4.5 g of product, of which a 500 mg sample was crystallized from MA-PE, giving 150 mg the title compound received; F = softening> 170 ° C, / X / _D + 83.3 °.

Manufacturing 29

20,20-ethylendioxy-336-hydroxy-5ß-pregnan-11-one-11-oxime (XXXV)

A solution of 11 g XXI in 15Ο ml ET was treated with a mixture of 15 g hydroxylamine hydrochloride in 50 ml 50 % NaOH. The mixture was refluxed at pH 11 for 24 hours and then diluted to 2 liters with water. The precipitate (11 g) was filtered off, washed with water and dried. A 500 mg portion was purified by preparative thin layer chromatography and crystallized from DE-PE to give 100 mg of the title compound; F = 224.-228 ⁰ C / OJ ^ + 100 °.

709841/0974

ORIGINAL INSPECTED

-M-

• so-

Manufactures $ 0 to 46

Table 2 shows the preparations of 11-oximes according to the compiled in the following way of working.

A solution of the corresponding 11-ketone in ET was made with a Mixture of hydroxylamine hydrochloride and aqueous NaOH at pH - ^ 11 heated under reflux for the specified time. The cooled mixture was diluted with water and the precipitate was filtered off, washed and dried. The received Material was purified by column or thin layer chromatography and / or crystallization.

7098 Λ 1/097 A

CO ^ N, I. a) sys φ
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OJ LfN I. V " O 4- OO 4 " oo LfN v OJ OJ v- LfN I. LfN CO «D OJ KN OJ V " I. I. I. QS I. LfN OJ (N τ- CU -P OJ OJ OJ OJ OJ vD O O V V " I. v ~ Ι U) EH «Dta QN KN ro KN KN ro 9 V LfN O V OJ OJ OJ KN KN OJ 4th U) -R ιΠ ON V CN OJ OJ OJ v ~ (Q (D kV KN CN ro O vD ro CN O I. .a VD VD ro OJ ω ON OJ (Q «I! O O O KN OJ O 4th <A I. rH V- O KN rH
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V TA vD KN LfN OJ OJ OJ OJ OJ OJ CN ro M. O KN KN O ^ W. KN KN KN KN KN 4th VD ro O OJ 6th KN KN KN 4th 4- KN VD 4th 4th

709ΒΛ1 / Π97Λ

ORIGINAL

2 7 I b U 7 β

1 IMS was used as the solvent; a further 15 »35 g of hydroxylamine hydrochloride and aqueous NaOH were added 41 hours added.

2 Work-up by dividing between EA and water. The crude product was treated with the same amounts of reagent during treated at the same time.

3 The crude product was treated with a solution of 2.79 g of NaOH in

9 ml of water and then with 1.25 g of hydroxylamine hydrochloride treated under reflux for 89 hours.

Preparation 47 11 /) (7-Amino-2ß-ethoxy-3iXrhydroxy-D-homo-50 (3-pregnan-20-one (LXIV)

8 g of Na were added in portions to a refluxed solution of 4.0 g of 2β-ethoxy-2O, 2O-ethylenedioxy-30 <7-hydroxy-D-homo-50 <rpregnan-11-one-11-oxime added in 200 ml PR. It got more

Refluxed for 4 hours and then 10 ml of ME were added. The alcohol solvents were removed by distillation while adding water. The cooled aqueous suspension was extracted three times with EA and the combined extracts were washed with saturated brine twice, dried and evaporated to a foam. This was dissolved in EA and extracted three times with 2N HCl. The combined aqueous extracts were basified with ammonia solution (0.88) and extracted with EA. The combined EA extracts were washed with saturated brine, dried and evaporated to give 2.43 g of the title compound as a foam. / p ^ - ^ + 40 °.

Manufacturing 48

3ος 20ß, 21-trihydroxy-5ß-pregnan-11-one-11-oxime (XXXVI)

32 ml of 50 % KOH solution was added to a solution of 16 g of hydroxylamine hydrochloride in 32 ml of water with cooling and the resulting mixture was added to a solution of 8 g of XXII in 256 ml of ET. The reaction mixture was taking four days

7098 £ 1/097

W6PECTED

. · 2V.I bü '/ β

Heated to reflux, some ET was distilled off and the mixture was poured into ice-mixed 2N HCl. The steroid was extracted with EA and crystallized from EA to give 6.7% of the title compound; F = 226-229 °, 3Q ^ + 82 ° (J 0.7 D).

Preparation 49 20,20-ethylenedioxy-5gG-prep; n-2-en-11ft> amine (XXXVII)

A solution of 1.85 g XXXIII in 250 ml PR was refluxed treated with 20 g of Na which was added over 1.5 hours. After the Na had been consumed, 20 ml of ME were added and the mixture was diluted to 2 l with water. The mixture was extracted with DE and the extract was washed over with water NapSO ^, dried and evaporated, leaving 2 g of the title compound received as oil.

Preparation 50 11 ^ 6-Amino-20,20-äthylendioxy-2ß-ethoxy-5iy-preKnan-3 ^ ol (XXXVIII)

A solution of 4 g XXXIV in 500 ml PR was one hour with 40 g Treated under reflux. After all the Na had dissolved, 20 ml ME was added. The mixture was then taken under constant addition of water distilled until all of the PR was removed. The product was extracted twice in DE and the Extracts were washed twice with water, dried over NapSO ^ and evaporated to give 3.7 g of a foam which was purified by column chromatography eluting with ME, 2.5 6 of the title compound were obtained as a foam;

+ 13.7 °.
Manufacture 5 ^

1iQG-amino-20,20-ethylenedioxy-5ß-pregnan-3 ^/ v: -ol (XXXIX)

A solution of 2 g XXXV in 250 ml PR was refluxed during 20 g of Na are added for 1 hour. After all of the Na had dissolved, ME was added. The PR was made by distilling removed, carefully adding water. The residue

• 7 "09841/0974

ORIGINAL INSPECTED

2 V 1 b Ü 7 β

was extracted with DE and the extract washed with water, over NapSO. dried and evaporated to give a solid which was purified by column chromatography eluting with ME and crystallized from MA to give 220 mg of the title compound; F = 153-155 ° C, 3Q ^ + 5 ° (c 0.65).

Manufactures 52 to 63

Table 3 gives a summary of the production of 11 & amines according to the following working method:

A solution of the appropriate 11-oxime in PR was refluxed mixed with sodium. After all of the sodium had reacted, the PR was distilled and replaced with water at the same time.

The remaining mixture was prepared by one of the following methods worked up:

A - The mixture was extracted with (i) DE or (ii) EA and the extract was washed, dried and evaporated.

B - The precipitate formed was filtered off, washed and dried.

The obtained material was purified by crystallization.

709841/097,

Tabel

Her-
place Baseline
material Weight
(S) Vol.
PR Weight
sodium Crystallization
solution solution the end
prey ( ⁰ O) + 37 ° Work-up
method lung Manuf.
No. 2.8 (ml) (ε) middle (ε) + 8.5 ° B. 52 33 6th 500 30th DE 2.1 143-145 + 20 ° A (i) 53 32 3.6 800 60 (1) 2 - - A (i) 54 31 3.2 500 40 MA-PE 2.5 156-158 - A ('ii) 55 ² 46 0.9 500 35 - 0.950 - + 7 ° A (ii) * - *
OD 56 43 1 130 8th DE-PE 0.4 100-102 + 9.8 ° A (ii) 30th
E-- 57 37 1.16 120 10 EA-PE 0.412 156-157 + 13.4 ° A (U) ^. 58 38 0.945 100 10 EA-PE 0.750 144-146 -9.7 ° B. r> 59 39 1.85 100 9.45 ME 0.389 188-189 + 6.9 ° A (U) CO 60 36 3.5 110 9.3 EA-PE 1.08 + 4.7 ° A (U) r- 61 35 3.87 420 34 EA-PE 2.6 155-157 + 5 ° A (U) 62 34 10 450 26.53 DE-PE 2.31 116-118 A (U) 63 ² 30th 1200 100 DE 6th 175-177

1) purified by column chromatography eluting with ME.

2) ME added before adding water.

27. ί ν υ 7 8

Preparation of 64- (Z) -11fc-ATnino-2ß-ethoxy-5'XrPreffn-17 (20) -en-50l-ol (LXV)

A reflux and nitrogen solution of 450 mg of (Z) -2β-ethoxy-30 ^ hydroxy-5 (> H? Regn-17 (20) -en-11-one-11-oxime 450 mg of sodium pieces were added to 15 ml of PR. When there were no more traces of sodium in the mixture, it was added to chilled water, whereby a fine precipitate was formed obtained by filtration.

The solid was dissolved in EA, dried over NapSO ^, and evaporated to a foam which was partitioned between 2N HCl and DE. The insoluble material that separated out was collected by filtration and partitioned between EA and 2N NaOH solution. The organic phase was isolated, washed with water, dried over Na — SO 4 and evaporated to give a foam which was crystallized from PE to give 110 mg of the title compound; F = 65-70 °, βj ^ + 10 °.

Production 65 11t>G-Dimethylamino-5ß-prep; nan-3o <U20ß, 21-triol (LIII)

5.75 g of XXXVI were dissolved in 500 ml of PR and 6 g of Na were added in portions under nitrogen. Excess PR was removed in vacuo and 11 EA was added to the cooled reaction mixture. The solution was washed four times with water, over MgSO ^. dried and evaporated. The crude amine was dissolved in 60 ml of HCHO and 1.2 ml of HCOOH. The solution was heated to 100 ° for 6 minutes and poured onto ice, made basic with 50% NaOH solution and the steroid was extracted with EA. The resulting gummy product was redissolved in 80 ml of ME and 20 ml of 25 % aqueous NaOH was added. The solution was left to stand for 45 minutes at room temperature and then acidified with HCl. The solution was washed with EA and made basic with 50% NaOH solution. Extraction with EA gave a material which was triturated with pentane and crystallized from MA-pentane to give 1.8 g of the title compound

709841/0974

INSPECTED

-48- 27 ι b υ 7 β

received; F = 124-128 °.

Manufacturing 66

1106-AmJnO- ^ (Xr hydroxy-D-homo-5o ^ pregnan-20-one

1.87 g of 20,20-ethylenedioxy-3öd-hydroxy-D-homo-5 ^ -pregnan-11-one-11-oxime in 200 ml of PR were treated with 10 g of Na and worked up as described in Preparation 47. By crystallizing from EA-PE one received 128 mg of the title compound with a melting point of 154-157 °,

Manufacture 67 11o6-amino-3ß-hydroxy-5oa-pregnan-20-one (XLIV)

To a solution of 7.0 g of V under nitrogen in 700 ml of PR, which was kept under reflux, 14 g of Na metal were added in small pieces. After all the Na metal was consumed, the reaction mixture was evaporated to about 200 ml and cold water was added. Cooling overnight gave a precipitate which was collected by filtration and then partitioned between 2N HCl and DE. The aqueous phase was made basic with 2N NaOH solution and extracted with DE. The organic extract was washed with water and evaporated to a small volume. The crystalline material that separated was collected by filtration and crystallized from DE to give the title compound; F = 150-152 °, 3 <7τ \ + 58.3 °.

Preparation 68 11p6-N-ethylamino-30 ^ -hydroxy-5ß-pregnan-2O-one

1 g XXXIX was dissolved in 30 ml ET and 1 g K ₂ CO ₃ and 3 ml ethyl iodide were added. The reaction mixture was stirred under reflux for 2.5 hours and then evaporated to dryness. The residue was redissolved in 10 ml of ET and 10 ml of 2N HGl at room temperature and, after 15 minutes, made basic with aqueous KOH. The steroid was extracted with EA and purified by preparative thick layer chromatography under

709841/0974

ORIGINAL INSPECTED

- · »- 27 1büVB 'it-

Use of EA-ME (3: "I) as eluant, 201 mg of the title compound being obtained as a foam; / J) QQ + 4-3 °.

Manufacture 69 11f) GN-Butylamino-50G-hydro; xy-5x-pregnan-2O-one (LXVII)

A solution of 1.5 g 11iX7Amino-2O, 2O-ethylenedioxy-50 (7-pregnan-30G-Ol (XL) in 20 ml of 1-iodobutane were added at 80 ⁰ C with 3 g of K ₂ GO ₅ and stirred for 3 hours The mixture was partitioned between DE and water and the organic layer was extracted with 2N HGl. The extract was basified with 4N NaOH solution and the oily deposit was extracted into DE. The extract was washed over with water Na ^ SO ^ dried and evaporated to give 1.5 g of a foam, a portion of 500 mg was purified by preparative thin layer chromatography in AC to give 350 mg of the title compound as an oil; / Ö <7 _D + 60 °.

Manufacture 70 3o (rHydroxy-11 <XN-propylamino-5C <rPregnan-20-one (LXVI)

A solution of 1 g of XL in 10 ml of 1-iodopropane was stirred under reflux with 3 g of KpCO ^ for AO minutes and the mixture was worked up as in Preparation 69. Column chromatography using ME and removal of the solvent from the later fractions left a residue which was crystallized from PE to give 4-50 mg of the title compound with a melting point of 138-141 °, ^ / _D + 32 °.

Preparation 71 11 | XrN-ethylamino-3o <> - hydroxy-5X.-pregnan-20-one (LXVIII)

A solution of 4 g of XL in ethyl iodide was _{stirred with 12 g of Ag 2} O for 2 hours at room temperature. Ag ₂ O was removed by filtration and the filtrate was worked up as in Preparation 69. Column chromatography and thin layer chromatography gave 400 mg of the title compound.

709841/0974 ORiGlNAL INSPECTED

- 5β - 2 7 ι b U 7 8 • »" J.

Manufacturing 72

A solution of 750 mg XXXVIII in 10 ml ET was _{treated with 2 ml allyl bromide and 1 g K 2} CO ₅ for 3 hours at 80 °. The reaction mixture, after filtration, was evaporated to dryness and the residue was partitioned between EA and brine (adjusted to pH about 9 by the addition of 2N Na. The aqueous layer was extracted with more EA and the combined extracts were blended with Washed brine, _{dried over Na 2} SO 4 and evaporated .. By preparative thin layer chromatography 107 mg of the title compound were obtained as a gummy product.

Manufacturing 73

2-en-20-one (XLII)

1 g of XXXVII was mixed with 0.4 ml of acetaldehyde in 20 ml of ET at 21 ° and 400 mg of sodium cyanoborohydride were added. After 15 minutes the clear solution became alkaline with NaHCO ^ solution made. Brine was added and the mixture was extracted three times with EA. The combined organic solutions were washed three times with saline and then with

2 N HCl shaken. Excess 40% aqueous NaOH solution was added and the layers were separated. The organic solution was washed with 2 brine and evaporated to dryness. The resulting oil was chromatographed in EA-PE to give 774 mg of the title compound as a crystalline solid. A sample was recrystallized from ET water and showed a melting point of 105-108 °, β <2 ^ 89.6 °.

Manufacturing 74

1iQ ^ rN-Cyclohexylamino-2ß-ethoxy-336-hydroxy- ^ 3 (> pregnan-20-one

0.5 g of XXXVIII were mixed with 2 ml of cyclohexane in 20 ml of ET at room temperature mixed and 250 mg NaBH ^ CN and 0.1 ml acetic acid were added. After 20 hours the mixture was

709RA ^- ! / Π97Λ

ORIGINAL INSPECTED

27.1 bO '/ β

Position 73 worked up and purified by thin layer chromatography to give 268 mg of the title compound as a foam; £ EQ-q + 26.6 °.

Preparation 75 ^/ 11fio-N-Benzylamino-2ß-ethoxy-3yrhydroxy - ^ (X.-pregnan-20-one

0.5 g XXXVIII was mixed with 1 ml benzaldehyde in 10 ml ET at room temperature and 250 mg NaBH ₅ CB and 0.1 ml acetic acid were added. After 1 hour the mixture was worked up as in Preparation 72 and purified by column and thin layer chromatography to give 205 mg of the title compound as a foam; / XZn + 34.1 °.

Preparation 76 110 <7-Isopropylainino-5 {Xrpregn-2-en-20-one (XLIII)

200 mg XXXVII were mixed with 0.2 ml AG in 5 ml ET containing 200 mg NaBH _$ .CN.

After 3 1/2 hours the mixture was worked up as in Preparation 73 and purified by column chromatography in EA-PE followed by recrystallization from ET water to give 55 mg of the title compound; F = 99-101 °, £ oQ + 80.6 ° (c 0.52).

Manufacturing 77 3D6-Hydroxy-N-isopropyl amino - 5β-pr e gnan-20-one

920 mg XXXIX were dissolved in 40 ml ET and added to 450 mg NaBH ₅ CN. 4 ml of AC was added, followed by 0.2 ml of acetic acid and the reaction mixture was kept at room temperature for 17 hours. The reaction mixture was divided into 2 parts for extraction.

(a) The solution was _{partitioned between EA and Na 2} COv solution and the organic layer was washed well with water, dried over MgSO ^, and evaporated to dryness. The return

709841/0974

2 7 Ί b u 7 a

Stand was dissolved in 10 ml ME and 10 ml 2N HCl were added added. The mixture was left at room temperature for 30 minutes left to stand and then basic with Na-CO, solution made and the steroid was extracted with EA.

(b) The second part of the reaction mixture was partitioned between EA and Na ^ CO ^ solution as in (a) above and the organic The layer was then shaken with 2N HCl and allowed to stand for 30 minutes. The reaction mixture was then made basic with NaHCO 3 and extracted with EA. The combined EA extracts were washed with water, dried over MgSO ^ and evaporated.

(a) and (b) were combined and subjected to thick plate chromatography using EA as a solvent, and the steroid was eluted with EA-ME to give 590 mg of the title compound; / pQ- ^ + 38 °.

Manufacturing 78

(Z) -110G-N-ethylamino-5 <Xrprep: n-17 (20) -en-30irTo l

398 mg NaBH ^ CN were added to a solution of 1.027 g XLI in 30 ml ET and after complete dissolution, 9 ml acetaldehyde were 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 was extracted into EA. The washed organic extract was evaporated in vacuo to give an oil. Purification by preparative thin layer chromatography (ME-EA 1: 1) gave an oil which crystallized on trituration with a little AN. Recrystallization from water-AN gave 287 mg of the title _{compound of P - 106-109 °, ^ / D} -19.9 °.

Manufacturing 79

(Z) -1iO (r-Isopropylamino-5 ^ -pregn-17 (20) -en-3o <rol

A solution of 422 mg XLI in 6 ml IMS containing 1 ml AC,

709841/0974

ORfGlNAL INSPECTED

27 15ü78

was treated with NaBH, CN and the resulting mixture became worked up as described in preparation 78. By cleaning thin layer chromatography (ET-CH 1: 1) gave 180 mg of the title compound as a foam.

Manufacturing 80

2ß-ethoxy-20,20-ethylenedioxy-110 <^ (4-methylpent-2-ylamino) -5oC- pregnan-5c <r-ol isomeres A (L) & B (LI)

1.06 g of XXXVIII were refluxed with 2 ml of 4-methylpentan-2-one in 40 ml of PR under nitrogen for 20 hours. The reflux under nitrogen was maintained and 4 g of Na was added over 3 hours. About 50 ml of water was added and the PR was evaporated under reduced pressure. The aqueous residue was extracted with EA. The combined extracts were washed with brine, dried over NapSO ^ and closed a gummy product evaporated. This was done through preparative Thin-layer chromatography, developed in ME-EA (1: 9) purified to give isomers of the title compound, namely 333 mg of isomer A (rubbery) and 322 mg of isomer B (rubbery).

Preparation 81 110C-N-Ethyl-N-Methylamino-5 (XTPregn-2-en-2O-one (XLVI)

658 mg XLII, 5 minutes at 100 ⁰ C with 0.32 ml of formic acid in 2.5 ml of a 37% aqueous HCHO solution heated. The mixture was cooled to 21 ° and excess aqueous NapCO ^ solution was added. The mixture was extracted with EA and the combined organic layers were washed with saturated saline, dried and evaporated to dryness. The remaining gummy product was filtered through silica gel in EA-PE (1: 9). Evaporation of the eluate gave 477 mg of the title compound; ß ^ Jj, + 111 °.

709841/0974

27.1 bü78

Preparation 82 • 11.9 (rN-Isopropyl-N-inethylainino-3 (X-prep; n-2-en-20-one (XLVII)

By reacting 838 mg of XLIII with 3.3 ml of 37% aqueous HCHO containing 0.43 ml of formic acid in the same way as Described in preparation 81 and recrystallization from ET water gave 643 mg of the title compound with a melting point of 88-99 °,

Preparation 83 1i06-N, N-Dimethylamino-5 (Xrpregn-2-en-20-one (XLV)

8.2 g of XXXVII were heated in 32 ml of 37% strength aqueous HCHO solution and 4 ml of formic acid to 95 ° to 110 ° for 6 minutes. The mixture was rapidly cooled and partitioned between EA and 2N NapCO * solution. The aqueous layer was extracted with EA and the combined organic solutions were washed with brine and then evaporated to leave a solid which was dissolved in EA and filtered through silica gel. The eluate was evaporated and the residue was crystallized from ME to give 4.0 g of the title compound; F = 123-126 °, / OJ ^ + 110 °.

Preparation 84 11 (XJ-N, N-dimethylamino-5 (X7pregnan-3o ^ 20ß, 21-triol (LII)

950 mg of 1i0 & -Amino-50Crpregnan-3o (; 2Oß, 21-triol were dissolved in 20 ml of ME and 10 ml of methyl iodide and stirred at room temperature for 4 hours with 3 g of KJCO ^ . Work-up as in preparation 69 and purification by means of thin-layer chromatography in AC and crystallization from DE gave 160 mg of the title compound with a melting point of 121-125 °, M ^ -16.7 °.

Manufacture 85

1i0O-N, N-dimethylamino-2ß-ethoxy-2O, 2O-ethylenedioxy-506-pregnan- 3 (XrQl (LXI) _____

7098Λ 1 / 097Λ ORIGINAL INSPECTED

- ■ 2 7.1 b ü 7 β - CV.

5.0 g of XXXVIII was dissolved in a mixture of 60 ml of 40% aqueous HCHO and 2.1 ml of 98-100 % formic acid and the resulting solution was heated on the steam bath for 15 minutes. The solution was cooled, diluted with 190 ml of water and 25 ml of saturated aqueous NaHCOv and the pH was brought to 11 by adding 0.3 g of NaOH dissolved in 30 ml of water. The resulting precipitate was collected by filtration, washed with water and dried to obtain 5.41 g of the title compound. / y? ^ + 57.5 °, F 70 °.

Manufacturing 86

11ß6-dimethylamino-3ß-hydroxy-5o6-pregnan-20-one (LVII)

A mixture of 0.5 g XLIV, 3 ml 37% HCHO solution and 0.3 ml 98 % formic acid was kept at 100 ° for 3 minutes and then poured into aqueous NaHCO, solution. The resulting precipitate was collected by filtration and partitioned between EA and 2N HCl. The acidic phase was basified with 2N NaOH solution, extracted with EA, washed with water and evaporated to a foam. Column chromatography (EA-PE 1: 2) and crystallization from EA-PE gave 300 mg of the title compound with a melting point of 119-121 °, / ptf ^ + 68.0 °.

Manufacturing 87

11 (XN, N-dimethylamino-2o ( _J 3QTr epoxy-5 (y-pregnan-20-one (LXIX)

1.9 g XLV and 1.0 g PTSA were dissolved in 150 ml DC and 1.24 g m-chloroperbenzoic acid was added. After stirring the mixture at 20 ° for 15 hours, the organic solution was washed successively with aqueous Na-SpOr solution, NaHCO 3 solution and water. Each time the organic layer was back extracted with TLC. The combined organic solutions were dried over MgSO ^ and evaporated. The residue was filtered through silica gel in EA-PE (1: 3) and the eluate was evaporated to give crystals which, upon recrystallization from PE, gave 0.51 g of the title compound; F = 154-157 °, / OC7-Q + 80 °.

7098UZO ₉ Vi ^miQ ' ^N ^

Manufacture 88

6.0 g XLVI and 3.21 g PTSA were dissolved in $ 00 ml DC and 4.4 g m-chloroperbenzoic acid was added. After 1 hour the mixture was worked up as in Preparation 87 (but using DM instead of TLC). Purification by column chromatography using EA-PE gave 4.49 g of the title compound; foj ^ + 79.5 °.

Manufacture 89

2CX «3 (Xt epoxy-1" V-N -isopropyl-N-methylamino-5i'K, -pregnan-20-one

300 mg XLVII and 154 mg PTSA were dissolved in 30 ml DC and 210 mg m-chloroperbenzoic acid were added. After 30 minutes, 60 mg of additional oxidizing agent were added. After a further 30 minutes, the mixture was worked up as in Preparation 87. Purification by preparative thin layer chromatography (EA-PE) and recrystallization from water-ET gave 114 rag of the title _{compound with a melting point of} 114-116 °, / α / Ώ + 84.5 °.

Manufacture 90

2 06 30G-Ep oxy-5 (Xr androstane-11,17-dione (XLVIII)

A mixture of 37.2 g XXVII, 30 g m-chloroperbenzoic acid and 600 ml CH was left to stand for 0.5 hours at room temperature, after which it was partitioned between CH and saturated aqueous NaHCO ₃ , solution. The organic phase was isolated and washed with water, dried and evaporated to a small volume. Addition of PE and subsequent freezing overnight gave 27.5 g of crystalline material. Recrystallization from EA-PE gave the title compound with a melting point of 166-167 °, + 126 °.

Manufacture 91

2ß-ethoxy-3QC-hydroxy-506-androstane-11,17-dione (XLIX)

709841/0974. ^

ORIGINAL INSPECTED

- vT- 27 ibuva • cc.

A solution of 5.0 g XLVIII in 250 ml absolute ET was with 8 drops of smoking HpSOy, added at room temperature. To The reaction mixture was treated with aqueous NaHCO ^ for 45 minutes and evaporated to a small volume. V / ater was added to the mixture, which was then cooled overnight became. The precipitate was collected by filtration, washed with water and dried. By recrystallization from water-ET 2.1 g of the title compound with a melting point of 164-167 °> were obtained

Manufacture 92

A mixture of 1.742 g of XLIX, 6.27 g of triphenylphosphonium iodide, 360 mg of sodium hydride and 100 ml of tetrahydrofuran dried over Na was stirred and refluxed under nitrogen. After 4.5 hours the reaction mixture was partitioned between EA and V / water. The organic phase was isolated, washed with water _{, dried over Na 2} SO 4 and evaporated to give 4.0 g of an oil. Column chromatography (EA-PE 1: 2) and subsequent preparative thin-layer chromatography (EA-PE 1: 1 χ 2) and crystallization from EA PE gave 110 mg of the title compound with a melting point of 172-178 °, ^ x / _D + 25 ° .

Manufacture 93 11 (X> Amino-2ß-ethoxy-30 <5-hydroxy-5 & -pregnan-2O-one (LIX)

10 g of XXXVIII were suspended in 38 ml of water, and 12 ml of concentrated HCl were added. The insoluble material was removed by filtration and washed with a small amount of water / water. The material was resuspended in 50 ml of water and brought to pH 9 with 2N NaOH. The mixture was stirred at 0 for 10 minutes and then the solid was collected by filtration and washed with water to give the title compound; F = 160-164 °, J5 ^ _D + 79.2 °.

709841/0974

Preparation 94 1KXr-Amino-300-hy-droxy- ^ ß-pregnan-20-one (LX)

2 g of XXXIX was dissolved in 20 ml of ME and 20 ml of 2N HCl was added. The reaction mixture was left for 15 minutes at room temperature held, basified with iced NaOH solution and the white solid collected by filtration. By crystallizing 1.13 g of the title compound with a melting point of 128-130 ° were obtained from ME-W.

Manufacture 95

2β-Ethoxy-36-hydroxy-1i £> G- ( ^/ <-methylpent-2-ylamino) -5iX7pregnan- 20-one isomer A

330 mg of L were dissolved in 20 ml of ME and 0.5 ml of 2N HCl were added added. After 15 minutes at 21 °, the mixture was

^ neutralized and evaporated to a small volume. The residue was divided between EA and salt solution. The aqueous layer was extracted and extracted with additional EA and the combined organic solutions were washed twice with brine, dried over NaoSO ^ and evaporated to dryness (3 ^"1 O mg). It was purified by preparative thin layer chromatography developed in 5% ME in EA and EA purified to give the title compound as a white foam. / Η7τ \ - 1 ° ·

Manufacture 96

2ß-Ethoxy-3ß6-hydroxy-11 tXj • (4-methylpent-2-ylamino) -506-pregnan- 20-one isomer B

322 mg of LI were treated as described in Preparation 95, 170 mg of the title compound being obtained as a white foam5 + 2.1 ° (c 0.36).

Manufacture 97

^ OO- hydroxy- 5X-androstane-17ß-carbaldehyde-

oxime (LV)

709HA1 / 097Λ -—

ORIGINAL INSPECTED

u7Ö

A solution of 250 mg LII in 15 ml D and 3 ml water was mixed with

I g of periodic acid are added over a period of 30 minutes. 10 ml aqueous 2N NaOH solution and 200 ml of water were added and the oily precipitate was extracted into DE. The extract was washed with water, dried over NaoSO ^ and evaporated, 185 mg 110G-N, N-dimethylamino-3 (Xrhydroxy-5iXTandrostane-17β-carbaldehyde received as foam.

The aldehyde was dissolved in 50 ml of ET and a mixture of

300 mg of NH ₂ OH-HCl and 5 ml of 2 N NaOH solution were added to pH

II added. After 15 minutes the mixture was diluted with v / ater and the precipitate was extracted into DE. The extract was washed with water, dried over NapSO ^ and evaporated, a foam was obtained which was crystallized from PE-DE to give 130 mg of the title compound; P = 107.5-110 °,

Manufacture 98

11i6-N, N-dimethylamino-2ß-ethoxy-3oc-hydroxy-5i>& - androstane-17ß carbaldehyde oxime (LVI)

650 mg of XXXI were treated as described in Preparation 97 and crystallized from hexane-DE to give 380 mg of the title compound; F - 99-102 °, / p $ ^ + 12 °.

Production 99 1106-Dimethylamino-3: X-hydroxy-5ß-androstane-17ß-carbaldehyde (LIV)

1.3 g of LIII was dissolved in 65 ml of D and 1.3 g of periodic acid in 6.5 ml of water was added. The reaction mixture was kept at room temperature for 15 minutes, poured into aqueous NaHCO 3 and the steroid was extracted with EA. A 300 mg portion of the steroid was subjected to preparative thick plate chromatography using EA-PT 1: 3. Eluting with ME gave 150 mg of the title compound as a foam; ßQ-. + 24 ° (c 0.5).

709841/0974

- * ° - 27 11 / ύ 7 β '69 -

Preparation 100 3 (X ^ acetoxy-11X-di: Tiethylamino - 5ß-androstane-17ß-carbonitrile (LXXII)

4 ml of 50 % aqueous KOH were added to a solution of 2 g of NHpOH.HCl in 4 ml of water with cooling. This solution was then added to 860 mg LIV in 32 ml ET and the mixture was kept at room temperature for 10 minutes. By diluting with water and extracting with EA, 890 mg of the 17B-oxime were obtained.

This material was dissolved in 20 ml of acetic anhydride and refluxed for 15 minutes. After diluting with iced aqueous NallCO ^ solution, the mixture was a further 30 minutes touched. The steroid was extracted with EA and preparative thin layer chromatography using EA-PT 1: 3 subjected as a solvent. Eluting with ME and crystallizing from EA-ME gave 560 mg of the title compound from P - 148-152 °.

Manufacturing 101

(LXX)

A solution of 1.30 g LV in 20 ml acetic anhydride was refluxed for 1 hour. The mixture was poured into 300 ml of iced, saturated NaHCO ^ solution and the precipitate was extracted into DE. The extract was washed with water, dried over Na ^ SO ^ and evaporated, leaving a foam which was purified by preparative thin layer chromatography in EA-PE (1: 5) and crystallized from DE to give 300 mg of the title compound of F-167 -171 ⁰ C, / pC / y. + 53 ° received.

Manufacturing 102

30 (r-Acetoxy-11iX-N, N-dimethylamino-2ß-ethoxy-5X-androstane-17ß carbonitrile (LXXI)

500 mg LVI were treated as described in Preparation 101 and by preparative thin layer chromatography in AC-PE

709841/0974

ORIGINAL INSPECTED

- £ <i- 27 I b υ 7 β • 70

purified to give 380 mg of the title compound; 3 (J ^ + 57 °

Manufacture 103 11 '> ^ - N, N-Dimethylamino - ^ - pregnan-3,20-dione (LVIIl)

A cold solution of 181 mg LVII in 10 ml AC was added dropwise with 0.25 ml Jones reagent (prepared from 66.7 ε CrO ^ in water and 53.3 ml concentrated HpSO ^, diluted with water to 250 ml). The reaction mixture was partitioned between EA and aqueous NaHCOv solution, the organic phase was isolated, washed with water, dried over NapSO ^ and evaporated to 170 mg of a solid. Crystallization from DE-PE gave 158 mg of the title compound with a melting point of 146-152 °, / ÖLZ-q + 62.5 °.

Manufacture 104 17,17-ethylenedioxy-2ß-ethoxy-3Xrhydroxy-5iX7-androstan-11-one (LXXVI)

A mixture of 8.0 g of XLIX, 160 mg of PTSA, 13 ml of ethylene glycol, 8.3 ml of triethyl orthoformic acid ester and 80 ml of CH was kept at room temperature overnight, after which it was partitioned between CH and saturated NaIIC O ^ solution. The organic phase was isolated, washed with water and dried over NapSO ^. Evaporation of this solution gave a foam which was purified by preparative thin layer chromatography (AC-PE) and crystallization from EA-PE to give 60 mg of the title compound; F = 142-145 °; W ^ + 18.2 °.

Manufacturing 105

17,17-ethylenedioxy-2ß-ethoxy-3DC-hydroxy-5C ⁾ 0-androstane-11-one-17- oxime (LXXVII)

A mixture of 8.2 g LXXVI, 15 g NH ₂ OH-HCl, 90 ml 44% aqueous NaOH and 500 ml ET was stirred and refluxed for 24 hours, after which it was evaporated to about half volume. Addition of water and cooling overnight gave a precipitate which was collected by filtration, washed with water and dried (6.4 g). By crystallizing from EA-PE

70984 1/097 4 ^,

- 62 - 2Vi buV8

the title compound was obtained from P «136-140 °

Manufacture 106

11OC-Amino-2ß-ethoxy- ^ X, -hydroxy- ^ x-androstan-17-one (LXXVIII)

5.7 g of LXXVII in 400 ml of PR under reflux were mixed with 7.5 g of sodium metal in small pieces under Np. The reaction mixture was evaporated to a small volume and partitioned between EA and W. The organic base was washed with water, dried over NapSO ^, and evaporated to a foam. The foam was split between 2N HCl and PE. The acidic layer was basified with 2N NaOH and extracted with EA. The EA phase was washed with water, dried over Na-SO ^ and evaporated to a foam. Crystallization from DE gave 2.43 g of the title compound with a melting point of 144-148 °, β> Q ^ + 61.5 °,

Preparation 107 1iQ6-Dimethylamino-2ß-ethoxy-3 (Mr-hydroxy-5X-aiidrostan-17-one (LXXIX)

A solution of 2.2 g LXXVIII, 1.2 ml HCO ₂ H and 12 ml HCHO was kept at about 100 ° for 3 minutes and then poured into a saturated NaHCO ^ solution. Vigorous stirring gave a precipitate which was collected by filtration, washed with water and dried. Column chromatography (EA-PE) and subsequent preparative thin-layer chromatography (EA-PE) as well as crystallization from ET water gave the title compound with a melting point of 65-68 °; / 5Q ^ + 41.7 °.

Production of 108 HpC aminoti go genin

2.0 g of 11-oxotigogenin-ii-oxime in 140 ml of PR were given under Rückf.erw. and 10 g of Na was added. After the Na had reacted, the PR was distilled off and the volume was increased by adding water held. The aqueous liquids were extracted with EA and the extract was washed with water, over NapSO ^. dried and evaporates. The solid residue was crystallized from EA-PE

709Β * 1/0974 0RK3 / NAL

-ο- 2 / ibüva

siert, whereby 450 mg of the title compound were obtained; F * 180 D.

182 °; / M _x . -72.5 °.

Preparation 109 3ß, 26-Diacetoxy-110 ^ -N, N-dimethylamino-5, y-furost-20 (22) -en (LXXX)

2.0 g of H&C dimethylaminotigogenin in 6 ml of acetic acid and. 3 nil PY were heated on a steam bath for 30 minutes. The mixture was evaporated to give a solid. This was dissolved in 10 ml of octanoic acid and 1 ml of acetic anhydride and the mixture was distilled under N ~ until the internal temperature reached 240 °. This temperature was maintained for 2 hours after which the mixture was cooled and extracted into EA. The extracts were washed with dilute NaHCO ^ solution and water and evaporated to give a gummy product. This was dissolved in 20 ml of ME, treated with 2.0 g of KOH and heated on a steam bath for 2 hours. The product was precipitated by adding warm water and isolated by filtration. It was dissolved in 6 ml acetic anhydride and 3 ml PY and heated on a steam bath for 30 minutes. The crude product was isolated by evaporation and then purified by column chromatography and crystallization from DE to give 500 mg of the title compound; F »131-134 °; / bg ^ + 4.2 °.

Preparation 110 3β-Acetoxy-1i06-N, N-dimethylamino-5oo-pregn-16-en-20-one (LXXXI) 2.0 g LXXX in 21 ml acetic acid were cooled to 10 ° in a water bath and mixed with 800 mg CrO ^ added to 7 ml of water. The reaction mixture was stirred for 30 minutes and poured into B and water. The B liquids were separated and the aqueous liquids were extracted with B. The combined B extracts were washed with dilute NaHCO ^ solution and water, filtered and evaporated, giving 1.9 6 crude 3ß-acetoxy-11 & -N, N-dimethylamino-16ß- (5-acetoxy-4-pentanoyloxy) -5ot-pregnan-20-one received as a foam.

709841/0974 or / γ, µλ.

ORK3 / NAL INSPECTED

- 64 - 2V) -υ /

1.9 g of the foam in 5 ml of acetic acid containing a trace of PY was refluxed for 30 minutes. The mixture was allowed to cool and evaporated to give an oil. This was dissolved in EA, washed with 5% NaHCO 3 solution and water. The EA fluids were via NapSO. dried and evaporated to form a foam. This was purified by preparative thin layer chromatography to give 250 mg of the title compound, 3Q ^ + 9.3 °.

Manufacture 111

, N-dimethylamino-3ß-hydroxy-5 ^ -pregn-16-en-20-one (LXXXII)

6.0 g of LXXXI in 100 ml of D were mixed with 2.0 g of KOH in 20 ml of water and stirred for 72 hours at room temperature. The solution was concentrated by evaporation, diluted with water and extracted with EA. The extracts were washed with water, over NapSOy, dried and evaporated to form a foam. This was purified by column chromatography and crystallization from EA to give 466 mg of the title compound; F = 135-140 °; / og ^ + 12.9 °.

Manufacturing 112

11O6-N, N dimethylamino-30C-hydroxy-5 (X: -pregn-16-en-20-one (LXXXIII)

900 mg of LXXXII in 35 ml of THF were _{mixed with 0.27 ml of HCO 2} H and 1.96 g of triphenylphosphine and stirred for 15 minutes at room temperature. 865 mg of hydroxyl azodicarboxylate in 8 ml of THF were slowly added to the reaction mixture and the solution was stirred at room temperature for 6 hours. The reaction mixture was concentrated by evaporation and the residue was dissolved in EA and washed with NaHCO, solution and water. The EA liquids were dried over Na ^ SO ^ and evaporated to form a solid. This was purified by column chromatography to give the crude 3 (XrFormate. This was dissolved in 10 ml of ME, _{treated with 12 drops of 60% HClO 4} and stirred for 3 hours at room temperature. The reaction mixture was concentrated by evaporation, with 10 ml of 5% NallCOv solution and 20 ml water

7 0 9 R A1 / Π974

ORIGINAL INSPECTED

27

ser diluted and extracted with EA. The EA extracts were washed with water, over Na ₂ SO. dried and evaporated to form a foam. This was purified by preparative thin layer chromatography to give 500 mg of the title compound as a foam; S (JQ + 16 °.

Manufacturing 113 HQG- ^ N-dimethylaminotigogenin

1.1 g of HDC aminotigogenin in 25 ml of HCHO and 0.25 ml of HCO ₂ H were heated to about 100 ° for 15 minutes. The solution was allowed to cool, diluted with 50 ml of saturated NaHCO ^ and 150 ml of water. The precipitated product was isolated by filtration and crystallized from ME water, giving 256 mg of the title compound of F - 103-105 °, / & 7 _D -78 , 1 ° received.

Manufacturing

110C-aminopregn-4-ene-3,20-dione (LXXXIV)

60 ml of 40 % aqueous NaOH and then 15 g of NH ₂ OH-HCl were added to a suspension of 5 »0 g of 3.3 _i 20,20-bisäthylenedioxypregn-5-en-11-one in 200 ml of ET. The mixture was refluxed for a total of 107 hours, then cooled and diluted with 2 liters of water while stirring. The precipitate (5.01 g) was collected, washed with 2 liters of water and dried in vacuo at 60 ° over Pp ^ 5. The PMR spectrum (CDCl _5. ) Indicated that the material contained 3,3,20,20-bis-ethylenedioxypregn-5-en-11-one-11-oxime.

4.5 g of Na were stirred in portions over 30 minutes refluxed solution of 4.50 g of oxime in 225 ml of PR added. The mixture was refluxed for 2 hours warmed and 10 ml ME was carefully added. The alcohol solvents were then removed by distillation, 225 ml of water was added to maintain volume. The resulting aqueous suspension was cooled and extracted with EA and the extract was washed with saturated saline, dried and evaporated to a solid. This one was

709841/0974

WSPECTH)

2Vi buy β

divided between 2 n-HCl and EA. The aqueous portion was washed with EA, then covered with EA, basified with ammonia solution (0.88) and the layers separated. The aqueous layer was extracted with more EA and the combined extracts were washed with saturated brine, dried and evaporated to a solid. This was crystallized from EA-PE to give 1.12 g of the title compound; F - 146-148 °, / Öcjy + 180 °.

Manufacturing

11 (X-dimethylaminopreg!; N-4-en-5,20-dione (LXXXV)

0.29 ml of HCO ₂ H was added to a suspension of 1.00 g of LXXXIV in 8 ml of HCHO and the mixture was heated to about 100 ° over 15 minutes after which it was cooled and partitioned between 5% aqueous NaHCO and EA. The organic extract was washed with saturated saline, dried and evaporated. The residue was crystallized from AN to give 0.67 g of the title compound; F »159-162 °, / yj ^ + 174 °.

example 1 1iOC-N, N-dimethylamino-2ß-ethoxy-3Q6-hydroxy-5o (> - pregnan-20-one

A solution of 500 mg XXXVIII in 5 ml. Methyl iodide was stirred with 1.5 6 KpCO for 2 hours. The mixture was partitioned between DE and water and the organic phase was extracted with 2N HCl. The combined extracts were washed with DE and made basic with 6N NaOH. The oily precipitate was extracted into DE and the extract was washed with water, _{dried over Na 2} SO ^ and evaporated to give a foam which was purified by preparative thin layer chromatography in AC-PE (1: $) and crystallization from PE-DE to give 180 mg of the title compound; F = 139-143 ° C, / Ö <J ^ + 84 °.

Example 2

C-N, N-dimethylamino-2ß-ethoxy-3c> C-hydroxy-5c <-prep; nan-20-one

709841 / Π974

ORK3INAL INSPECTED

2 7 I MJ 7 8

10 g XXXVIII were in a mixture of 120 ml HCHO solution and 4.3 ml of formic acid were stirred at room temperature for 6 1/2 hours.

40 ml DM were added and the mixture was then brought to pH 11 with NaOH solution. The organic phase was separated off, washed with water and washed first with a solution of 4.0 ml of concentrated HpSO ^ in 70 ml of water and then with water. The acidic extracts were combined and adjusted to pH 11 with NaOH solution and extracted again with DM. The organic extracts were washed with water and evaporated under reduced pressure to a solid which was purified by filtering through silica gel in DM-MA (9: 1) and crystallizing from AC water to give 6.43 g of the title compound; 3 (7- ^ + 84.1 °, F = 123-131 °.

Example 3 11 ^ Mmethylaroino-3 <y-h; ydroxy-5ß-pregnan-20-one

500 mg of XXXIX were partially dissolved in 10 ml of HCHO and 0.2 ml of formic acid dissolved and the reaction mixture was heated to about 100 ° under nitrogen for 5 minutes. The reaction mixture was in NaHCO ^ solution poured and the steroid was extracted into EA and the extract washed with water. The organic layer was extracted with 2N HCl and the extract was made with NaOH solution Made basic and extracted with EA. Removal of the solvent from the extract left a foam, which in a small amount of CH is dissolved and placed in a column of silica was filled in PT. Eluting with EA-PT (1: 1) and removing the solvent from the eluate gave 370 mg the title compound as a white foam, / Öi / ^ + 83 ° (C, 1.5)

Example 4

11 (Xr-dimethylamino-3p (-hydroxy -!? Ss-preKnan-20-one

2.8 g XXXIX were dissolved in 30 ml methyl iodide and 3 g K ₂ COv was

7 0 9 8 4 1/0374 _{0R | G (NAL | NSpECTED}

- 68 - 2 V i;, υ 7 a

the added. The reaction mixture was 1? Stirred for hours, the methyl iodide was evaporated and the solid residue was partitioned between EA and water. The organic layer was washed with water, over MgSO. dried and evaporated. The residue was dissolved in a small volume of CH and placed in a column of 60 g of basic alumina in PT. The column was washed with EA and the eluate evaporated to form a foam. The foam was dissolved in 20 ml of ME, 5 nil of 2N HCl were added and the solution was left to stand for 15 minutes at room temperature and poured into iced NaHCOv solution. The solid was filtered off, purified by preparative thin layer chromatography using AC-PT (1: 3) as the solvent. Eluting with EA gave 800 mg of the title compound, / k7 _d + 85 °.

Example 5 HtX-dimethylamino-30i-hydroxy-5β-preRnan-20-one

200 mg XXXIX were stirred at room temperature with 4 ml HCHO and 0.08 ml formic acid for 23 hours. The solution was in 20 ml of 2N HCl poured and kept at room temperature for 15 minutes. By Dilute with aqueous NaHCO ^ solution and extract with EA one the title compound in the same way by thin layer chromatography and gas phase chromatography as for the product des Example 3

Examples 6-23

Table 4 gives a summary of the production of the the following compounds from the corresponding iioc-amino-20-ketal at:

6. 11oo-N, N-dimethylamino-3ofc-hydroxy-5 (X ^ pregnan-20-one

7. 1100-N, N-dimethylamino-30Qrhydroxy-6β-methyl-5oc-pregnan-20-one

8. 11oc ^ N, N-dimethylamino-21,21-ethylene-3cc-hydroxy-5oc-pregnan-20-one

709841/0974 0RK3INAL (NSPECTED

27IMJV8

10. 11oc-N, N-dimethylamino-30'-hydroxy-21-methoxy-5 (X-pregnan-20-one

11. 11 (Xr-N, N-dimethylamino-3ö (.- hydroxy- 2 <X-methyl-50C-pregnan-2O-one

12. 11oc-N, N-diraethylaraino-3oC-hydroxy-3ß-niethyl-5oC-pregnan-20-one 13 · 3oi-hydroxy-10 <> morpholino-5β-pregnan-20-one

14. 11Cc-N, N-dimethylorairio-3 ^ -hydiOxy-2ß-methoxy-5X-pregnan-20-one

15 x 11 (X-N, N-Dipropyl amino-3 ^ Cr-hydroxy-5i? C-pregnan-20-one

16. 3 & -hydroxy-11 <X.-morpholino-5i ⁾ (rpregnan-20-one

17 · 110Cr-N, N-dimethylamino-3iXr-hydroxy-2ß-methyl-5vX? -Pregnan-20-one

18. 2β-Butoxy-11 (X-N, N-dimethylamino-30C-hydroxy-5x-pregnan-2O-one

19 · 2β-Ethoxy-30-hydroxy-110Crmorpholino-5X-pregnan-20-one

20. 2β-Ethoxy-3X-hydroxy-1iC "i-pyrrolidino-5i \ -pregnan-20-one

21. 110Cr-Azetidino-2ß-ethoxy-3OC-hydroxy-5tv-pregnan-20-one

22. 11oc-N, N-diallylamino-2β-ethoxy-3c <rhydroxy-5C ^| Grpregnan-20-on

23. 11 (X-N, N-diethylamino-306-hydroxy-50C-pregnan-20-one. The following manufacturing processes are used:

A. The 11 ^ area was diluted with formic acid in aqueous HCHO
about 100% heated and the mixture was cooled and partitioned between EA and 5% aqueous NaHCO ^ solution. Of the
EA extract was extracted with 2N HCl and the aqueous
Extract was made basic with 40% NaOH solution, extracted again with EA, washed with water, dried and evaporated.

709841/0974

-9O- ■ 2 7 1 b O 7 β • Vf.

B. The 11 (X-Ainin was at room temperature (unless otherwise stated) stirred with an alkyl halide and KpCO ^. The reaction mixture was then worked up using one of the following methods:

(i) KJSO ₇ , filtered off and the alkyl halide removed under reduced pressure. The mixture was partitioned between EA and water and the organic phase was extracted with 2N HCl. The aqueous layer was made basic with aqueous NaOH solution and extracted with EA. The EA layer was washed, dried and evaporated.

(ii) The mixture was partitioned between (a) DE or (b) CH and water and the organic phase was extracted with 2N HCl. The acidic phase became basic with aqueous NaOH solution made and extracted again with DE. The extracts were washed, dried and evaporated.

(iii) As described in Preparation 72.

(iv) The mixture was diluted with DE and water and the organic layer was washed with water, dried and evaporates.

The material obtained by either of these procedures was subjected to column chromatography and / or preparative thin layer chromatography and / or crystallization purified.

Table 4

2715U78

At-
sp. Baseline
material Weight
(S) Alkyl
funds lot Reak
ions the end
prey Chroma
togra Iristalli-
sation solution E. - F.
( ⁰ C) + 79 ° method Her
alternate
No. 2 40ml /
0.8ml Time (ε) phie solvent DE-PE V ^v / +57.4 A. 6th 63 0.6 HCHO /
HCO ₂ H 12ml /
0.24ml 10 min. 1.51 CC
EA EA-PE EA-PE 123-124 + 125.5 ° A. -J
O 7th 60 0.54 HCHO /
HCO ₂ H 11ml /
0.21ml 10 min. 0.33 CC
EA EA-PE AC-W 122-123 + 68.9 ° A; -O
co 8th 57 0.6 HCHO /
HCO ₂ H 12ml /
0.24ml 10 min. 0.38 CC
EA - DE-PE - + 80.5 ° A. 1/09 9 58 0.7 HCHO /
HCO ₂ H 14ml /
0.28ml 10 min. 0.33 CC EA
TLC EA-P - + 87.9 ° A. ~ J
* - 10 59 1.7 HCHO /
HCO ₂ H 10ml /
4.5g 10 min. 0.3 CC
EA - + 82.5 ° B (i) 11 62 2.1 MeI /
K ₀ CO, 38ml /
6.3g 7 hours 0.83 CC
ME 133-136 + 53 ° B (i) 12th 61 1.5 MeI /
f \ ^ *. V / \ J - / 9ml
0.9g 4 hours 0.63 CC
ME I6I-171. j + 87.3 ° B (i) 13th 51 1.5 (ClC ₂ H ^) ₂ O 20ml /
3g Buckf1.
4 hours 0.23 CC
EA-PT
j EA B (ϋ) (ε 14th 54 MeI /
K ₂ Co ₃ 3 hours. 0.8 CC
EA 154-157

Table 4 (continued)

At-
sp. Starting Ma- Alkyly-
material resources Weight
(δ) CH ₅ CH ₂ CH ₂ I. lot Reak
ions
Time the end
prey
(ε) Chroma
togra-
phie Kristalli
location solution
solvent P.
(° c) +62.5 ⁽ method 15 · Her
put,
• No. 1 K ₀ CO, 10ml
3g / Back
flow
40 min. 0.25 CC ME
TLC AC-PI ME-W
: 80-85 + 60 ° 16
CD
Ό 63 1 MeI /
K ₂ CO ₅ 4ml / 140 ^he
0.6g 2 hours 0.45 TLC - - + 100 ° ⁵ B (UKa) V> 17
\ 63 1.5 MeI /
K ₂ CO ₅ 80ml / 5 hours
Y 0.6 CC AC-DM
TLC AC-PI DE-PE
: 121-123 + 58 ° B (U) (b) CD
-J 52 3 20ml / 5 hours
5g j 0.61 CC CH!
TLC AC-PE} - + ^{£ 29.8} t- 53 0.5 3ml / 140 °
0.3g 2 hours 0.13 TLC EA j
i - (3) Ώ f £ £ \ f ** \ 20th
(2) 50 0.5 Br (CH ₂ ) ₅ Br / 4ml / . 0.13 CC EA-PE *
TLC EA-PE - + 32 °
(c 0.6: B (iii) 21
(2) 50 · 0.5 CH ₂ = CHCH ₂ Br /
K ₂ CO ₅ 4ml /
1g /
0.2f j. 0.17
ι TLC EA-FE
<
l - + 30 ° B (iii) 22nd
(2) 50 0.75 EtI /
K ₂ CO ₅ f return
18 hours
I. 0.25 TLC EA-PE
i
'! - + 47 ° ; B (iii)
i 23
I. 50 0.7 t return
17 1/2
ζ ¹ hour 0.4
k- TLC EA-PE
■ I - B (iii) 63 2ml / 80 °
1g! 3 hours. B (iv) 4ml / i 3 days
0.7g! at RT
I 6 hours
on the back

2 7 1 ^ υ 7 8

1) 30 ml of DM was used as a solvent.

2) 10 ml of ET was used as a solvent.

3) The ^ values (CDCl ₃ ) include: 6.14 (s, 3 [beta] -H), 6.2-6.4 (M, 2 [beta] -H and -OCjI ₂ CH ₅ ), 7.0 (triplets and Doublets, JH and 3 Hz, 11β-H), 7.2-7.7 (M, -

-CH ₂ -N-CH ₂ -), 7.90 (S, 21-CH ₃ ), 8.85 (1 ', J 7Hz, -OCH ₂ CJi ₃ ),' 8.99 (S, 10-CH ₃ ) and 9.37 (S, 13-CH ₃ ).

Example 24 11oi-diethylamino-3Ä-rhydrox; 7-5ß-preKnan-20-one

0.5 g XXXIX was dissolved in 25 ml ET and 5 ml acetaldehyde and 250 mg NaBH ₃ CN were added. The reaction was kept at room temperature for 15 minutes and then acidified with 2N HCl. After an additional 15 minutes the solution was basified with KOH and extracted with EA. Crystallization from ME water gave 354 mg of the title compound with a melting point of 123-125 °, + 36 °.

Example 25 11fo-diethylamino-3 $ r-hydroxy-5ß-pregnan-20-one

50 mg XXXIX were dissolved in 2.5 ml ET and 0.25 ml acetaldehyde and 25 mg NaBH ^ were added. The reaction was kept at room temperature for 30 minutes and then as in Example worked up to give the title compound which, by gas chromatography, is identical to the product of Bei-

709841/0974 ordinal inspected

- s »- 2 ν ι ;, υ 7 8 • 'J.

game 24 proved.

Example 26

2β-Ethoxy-3fc-hydroxy-11 a ^ piperidino-5 {xrpregnan-20-one

0.5 6 XXXVIII were mixed with 2 ml of 25% aqueous glutaraldehyde solution at room temperature in 10 ml of ET and 250 mg of NaBH ^ CN and 0.1 ml of acetic acid were added. After 6 hours the mixture was worked up as in Preparation 73 and purified by column chromatography and thin-layer chromatography to give 211 mg of the title compound as a foam; ZK / _D + 35.2 °.

Example 27 50C-Hydroxy-1iQC-piperidino-5β-pregnan-2O-one

1 g of XXXIX was mixed with 500 mg of NaBIUCN and 5 ml of 25% aqueous solution of glutaraldehyde in 10 ml of ET at room temperature and 0.2 ml of acetic acid was added. After 3 hours the mixture was partitioned between EA and NaHCO ^ solution. The organic solution was washed with 2N HCl and the combined acidic extracts were washed with EA, basified using 50% NaOH solution, extracted with EA, washed with water, over MgSO 4, dried and evaporated to give a foam .

This material was purified by preparative thin layer chromatography, eluting with ME containing approximately 1 % water, and the solution was evaporated. The product was then dissolved in DE, filtered and evaporated to give 318 mg of the tit el compound; βζ7 ^ + 58.5 °

Example 28

11flO-Dimethylamino-2β-ethoxy-306-hydroxy-5X-pregnan-20-one

(a) 200 mg of LIX were mixed with 4 ml of HCHO and 0.08 ml of formic acid heated to about 100 ° for 10 minutes. The reaction mixture was then poured into NaHCO, solution and the steroid

709841/0974 ORK ₃₁ NAL inspected

- ■ P5- 2 7 1 b U 7 8

was extracted with EA. By preparative thin layer chromatography using AC-PT (3: 7) and crystallization from DE-PT gave 50 mg of the title compound with a melting point of 140-14-3 °.

(b) 250 mg of LIX was dissolved in 25 ml of EA and 0.5 ml of 37% aqueous HCHO. 250 mg of 10 % palladium on carbon 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 over MgSO ^ and evaporated to dryness. Preparative thin-layer chromatography using CH-MA-ME (49: 49: 2), followed by crystallization from AC water, gave 100 mg of the title compound with a melting point of 129-134 °.

(c) 100 mg LIX was dissolved in 10 ml EA and 0.2 ml HCHO. 50 mg Tris (triphenylphosphine) chloro rhodium was added and the solution was hydrogenated for 17 hours. Then it was with water washed and the organic layer was dried over MgSO ^. dried and evaporated to dryness. By thick plate chromatography using MA-PT-ME (33: 65: 2) as a solvent, 30 mg of the title compound were obtained, which can be identified by thin layer chromatogram and gas phase chromatography proved identical to the product of part (a).

Example 29 11i96-N, N-Dimethylamino-3iX-hydroxy-5ß-pregnan-20-one (LXXIII)

(a) 50 rag of LX were at room temperature with 1 ml of HCHO and 0.02 ml Formic acid was stirred for 23 hours to give the title compound, which was identified by thin-layer chromatography as proved to be the same as the product of Example 3.

(b) 50 mg of LX was dissolved in 10 ml of EA and 100 ml of paraformaldehyde and 50 mg of 10 % platinum on carbon was added. The reaction mixture was stirred under hydrogen for 17 hours to give the title compound which was found to be identical to the product of Example 3 by thin layer chromatography.

709841/0974

(c) 100 mg of LX was dissolved in 10 ml of EA and 1 ml of HCHO and 100 mg of 10 % Pd / C was added. The reaction mixture was hydrogenated for 17 hours and the catalyst was removed by filtration through kieselguhr. The solution was washed with water, dried over MgSO 4, and evaporated to dryness to give 110 mg of the title compound which was identical to the product of Example 3 by thin layer chromatogram and PMR spectrum.

(d) A solution of 20 ml HCHO in EA (prepared by heating paraformaldehyde to 200 ° and blowing the HOHO gas into the EA for 5 minutes) became 100 mg LX and 100 mg 10 % Pd / C in 5 ml EA joined. The reaction mixture was stirred with hydrogen for 30 minutes, giving the title compound, which was found to be identical to the product of Example 3 by thin-layer chromatogram.

Example 30

11 (XrN, N-dimethylamino-2β-ethoxy-3Äj-hydroxy-21-methyl-50 <rpregnan- 20-one

1.00 g of LXII was heated to about 100 ° for 10 minutes in a mixture of 20 ml of HCHO solution and 0.4 ml of formic acid. The cooled reaction mixture was diluted with 50 ml of 5% NaHCO, solution and extracted with EA. The organic extracts were extracted with 2N HCl, basified to pH 11 with 40% NaOH solution and extracted again with DM. The extract was dried with Na SO 4 and evaporated to give a foam, which was purified by column chromatography using EA as an eluent to give 828 mg of the title compound as a foam; ßxj ^ + 72 °.

Example 31 11 & 6-Dimethylamino-3o <r-hydroxy-D-homo-5Q6-pregnan-20-one

A suspension of 656 mg LXIII in 5 ml HCHO was 0.21 mg Treated formic acid and then the mixture was 5 Mi

poor. The kül

09841/0974

grooves heated to about 100 °. The cooled solution was between

ORIGINAL INSPECTED

-Ψ7- 27I5U78

EA and 2 n-NapCCU split. The organic portion was with saturated brine, dried and evaporated to give a foam of 704 mg. This was done by preparative Purify thin layer chromatography (ME) and crystallize from ME to give the title compound; F = 116-118 °,

Example 32

11lXr-Dimethylamino-2ß-ethoxy-3fX, -hydroxy-D-homo- ^ OC-preKnan-20-one

0.29 ml of formic acid was added to a suspension of 1 g of LXIV in HCHO. The mixture was heated on the steam bath for 20 minutes, cooled, and partitioned between EA and 5% aqueous NaHCO 3. The organic extract was washed with saturated saline, dried and evaporated to a foam. This was purified by preparative thin layer chromatography (ME) and crystallization from AN and gave 469 mg of the title compound with a melting point of 132.5-133.5 °, / β / _D + 46.8 °.

Example 33 (Z) -1KXr-Dimethylamino-2β-ethoxy-5y7-pregn-17 (20) -en-3X-ol

A mixture of 1.8 g of LXV, 12 ml of HCHO and 1.2 ml of formic acid was heated to 100 ° for 5 minutes and then poured into aqueous NaHCCK solution. The precipitated solid was collected by filtration, washed with water and dissolved in EA. Evaporation gave a foam which was filtered through a plug of silica in EA-PE 1: 1. Recrystallization from ME-W then gave the title compound with a melting point of 63-78 °, 3Q ^ -2 °.

Example 34- (Z) -11 & 7-Dimethylamino-5 & ^ reKn-17 (20) -en-3% -ol

A suspension of 550 mg XLI in 4 ml HCHO was mixed with 0.3 ml formic acid and the mixture was stirred until the steroid dissolved. The solution was on for 10 minutes

709841/0 9 74- ofwg / nal inspected

-? β- 27 1 b Ü 7 θ

heated to about 100 ° and diluted with excess NaOH solution. The precipitated material was extracted in EA, the extract was washed with water and then 2N HCl. The acidic extract was washed with EA, basified with NaOH and extracted again with EA. Evaporation of the washed organic extract gave crystalline material which was purified by preparative thin layer chromatography (5% ME-CH) and crystallization from ME-water to give 309 mg of the title compound; F = 59-61 °, βj ^ -8.1 °.

Example 35 (Z) -11gl-Diethylamino-5fc-pregn-17 (20) -en-5C <: - ol

A solution of 608 mg XLI in 20 ml ET was mixed with 0.1 ml acetic acid and 231 mg NaBH ^ CN. The mixture was kept at room temperature for 27 minutes and then 3 ml of acetaldehyde was added. After a further 15 minutes, the mixture was worked up as in Example 24 and purified by preparative thin layer chromatography (EA) and crystallization from AN water, whereby 333 mg of the title compound were obtained; F - 89-90 °, m ^ -38.1 °.

Example 36

(Z) -110Cr-piperidino-5iXrPrep; n-17 (2O) -en-30C-ol

A solution of 795 mg XLI in 10 ml IMS was treated with 395 mg NaBH ₅ CN, 2 ml 25% aqueous glutaraldehyde and 0.1 ml acetic acid. The mixture was kept at room temperature for one hour and then worked up as in Example 24. Purification by preparative thin layer chromatography using 10 % ME-EA gave 410 mg of the title compound as a foam; / ptf ^ -15.3 °.

Example 37

110l ^ -Dimethylamino-5 ^ j-pregn-20-en- 3 <% - ol

650 mg of 100-amino-5oG-pregn-20-en-3C (rol in 15 ml of methyl iodide were

709IH 1/097 4 _0BK3INAL , NSPECTEO

- J79 - 27 1 bÜVÖ

6 hours with KpCO, stirred. 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. The acidic extract was washed with EA, basified with concentrated ammonia solution, and extracted with EA. The organic extract was washed with water, dried over MgSO ^ and evaporated to form a foam. This was determined by preparative thin layer chromatography (EA-PE 1: 1 ) to give 270 mg of one of the title compound as a crystalline solid, F = 151-133 °.

Example 38-46

Table 5 gives a summary of the production of 11 / 5C-N, N-disubstituted amines from the corresponding 11 (L-N-monosubstituted Amines in the following way:

The amine was dissolved in HCHO solution containing formic acid and the mixture was heated to about 100.degree.

The mixture was then worked up using one of the following methods:

A. The mixture was partitioned between EA and aqueous NaHCO ^ and the EA extract was washed with brine, dried and evaporated.

B. The mixture was diluted with water and extracted into EA. The aqueous layer was made basic with NaOH, with EA extracted and evaporated. The original EA washes were washed with NaOH and water and evaporated. The residues were combined.

7 fl 9 R A 1/0 9 7 4 ORJGINAL INSPECTED

C. The mixture was mil; NaOH neutralized and extracted with EA. The washed extract was evaporated.

D. The mixture was diluted with saturated NaHCO ^ solution and the precipitate was recovered.

The material of one of these procedures was analyzed by column chromatography or preparative thin layer chromatography and / or crystallization.

The following connections were established:

^{38.1 /} iAC-N-Cyclohexyl-N-methylamino-2ß-ethoxy-3OC-hydroxy-5Xr pregnan-20-one

39. 2ß-Ethoxy-3Orhydroxy-110 (^ (N-methyl-N-4-methylpent-2-ylamino) -50C-pregnan-2O-one, Isomer A

40.2ß-Ethoxy-3 (Xrhydroxy-110Cr (N-methyl-N-4-methylpent-2-ylamino) -50 £ rpregnan-20-one, Isomer B

41. 11 (X-N-Benzyl-N-methylamino-2ß-ethoxy-30C-hydroxy-5L% -pregnan-20-one

42. 1106-N-Allyl-N-methylamino-2ß-ethoxy-3X-hydroxy-5OC-pregnan-20-one

43. (Z) -11ö0-N-Ethyl-N-methylamino-5X-pregn-17 (20) -en-30C-ol 4A. (Z) -1-16-N-Isopropyl-N-methylaniino-50O-pregn-17 (20) -en-3oC-ol

45. 11 & yN-ethyl-N-methylamino-30G-hydroxy-5β-pregnan-20-one

46.3 (Fe-Hydroxy-10G-N -isopropyl-N-methylamino-5β-pregnan-2O-one

709841/0974

Table 5

At-
sp. Baseline
material Weight
CF?) HCHO
(ml) HCO ₂ H
(ml) Reak
ions
Time
(Min.) the end
prey
(mg) Chromato
graphics Kristallisa-j F
solution I / O _r \
medium j ^CC;
I. DE - 63-70 + 34.4 ° method 38 Manuf
ment no. 1 3.8 0.49 5 819 CC EA-PE ET-W AN-W - + 51.5 ° A. 39 74 0.67 2.5 0.32 5 624 CC EA-PE - ET-W AN-W - + 84.0 °
(c 0.44) A. 40 95 0.27 1 0.13 5 187 CC EA-PE - - - + 57.5 °
(c 0.33) A. -J
σ 41 96 0.47 1.9 0.25 5 100 TLC EA-PE - - + 60.0 ° A. co
co
* "· 42 75 0.26 1 0.12 5 170 TLC EA-PE 104-107 -2 ° A. - * 43 72 0.22 4th 0.3 12th 137 TLC ME-EA 128-130 ± °° B. σ
OK 44 78 0.42 4th 0.3 10 313 - - + 81 ° C. * ~ 45 79 0.60 15th 0.15 10 328 TLC EA-PT - + 79 ° D. 46 68 0.4 10 0.1 5 270 TLC EA-ME D. 77

CD 'Ct

- 82 -

2 7-11, u 7 β

Example 47

3o6-Hydroxy-1,100-N-diethyl-N-propylaTTiino-3 (Vrprep; iian-20-one

A solution of 380 mg of LXVI in 10 ml of methyl iodide was _{stirred with 1 g of K 2} CO for 4 hours. The mixture was diluted with DE and water and the organic phase was extracted into 2N HGl. The extract was made basic with 6N NaOH and the oily precipitate was extracted into DE. The extracts were washed with water, over Na ₂ SO ^. dried and evaporated, leaving a foam which was purified by preparative thin layer chromatography. By crystallization from PE to give 210 mg of the title compound F - 149-152 ⁰ C, §Q ^ + 90 °.

Example 48

^1/1 (XRN-butyl-N-methylamino-3QGrhydroxy-3C <rPreEnan-20-one

A solution of 1 g of LXVII in 40 ml of methyl iodide was stirred with 3 g of KpCO 2 for 3 hours. Working up as in Example 47 and purifying by preparative thin layer chromatography in AC-PE (1: 3) gave 680 mg of the title compound; 3 ^ + 83 °.

Example 49

11 ^ 6-N-Ethyl-N-methylamino-3PG-hydroxy-3oC-prep; nan-20-on

A solution of 370 mg LXVIII in 2 ml methyl iodide and 40 ml DM was stirred with 1 g KpCO3 for 3 hours. DE and water were added and the organic phase was washed with water, _{dried over Na 2} SO ^ and evaporated to give a foam which was purified by preparative thin layer chromatography in AC-PE (1: 3), 350 mg of the Title compound was obtained in the form of a foam; Stf-r, + 83.7 °.

Example 50

1106-N, N-dimethylamino-2β-ethoxy-30 <^ hydroxy-5X-pre% nan-2O-one

560 mg of LXIX were mixed with 0.5 ml of boron trifluoride etherate in 25 ml of ET Stirred for 4 days at 20 °. The mixture was concentrated by evaporation

7f) 9fU1 / 097A ORIGINAL INSPECTED

- ** " 2 ν ι b ü 7 a • ft.

centered and divided between EA and 2N Na ^ CO ^ solution. The aqueous layer was extracted with more EA and the combined organic solutions were washed with saturated brine, dried over MgSO 4 and evaporated to leave an oil. The oil was purified by preparative thin layer chromatography and recrystallization from PE to give 46 mg of the title compound; F = 131-137.5 °, ßÜ ^ + 83.3 °.

Example 51

1iQ (, - N, N-DiinethylaTnino-2ß-ethoxy-3Q (r hydroxy-5X-pregnan-20-one

2 ml of 60% aqueous perchloric acid was added to a stirred solution of 1 g LXIX in 100 ml ET added at 20 °. After 2 hours, NapCO ^ solution was added to bring the mixture up to pH 9 and most of the ET has evaporated. The residue was partitioned between EA and water. The watery Layer was extracted with more EA and the combined organic solutions were washed with saturated brine, dried over NapSO ^ and evaporated to a gummy product. This gummy product was purified by preparative thin layer chromatography and recrystallization from ET-W, whereby 504 mg of the title compound were obtained; F = 119-123 °, + 83 °.

Examples 32-70

Table 6 contains a compilation of the preparation of 2β-substituted 11oi-disubstituted amines from the corresponding 206, 3O ^ epoxy according to the following procedure:

The 20C, 3C? * - epoxide was (if necessary) treated with the appropriate alcohol or the acid in the presence of a catalyst at room temperature (or 100 ⁰ C in the case of 2ß-acetoxy) during the specified time. The mixture was diluted with aqueous Na ^ CO ^ solution (or aqueous NaOH in the case of 2ß-fluorine compounds) and worked up using one of the following methods:

7OQ 8 4 1/097 /. ORIGINAL INSPECTED

A. The mixture was extracted with EA and the extract was washed with brine, dried and evaporated.

B. The solid that separated was collected by filtration
recovered, washed and dried.

C. The alcohol was evaporated and the aqueous residue extracted as under A above.

The material from one of these procedures was further analyzed by column chromatography and / or preparative thin layer chromatography and / or crystallization.

The following 2β-substituted derivatives of 3 # j-hydroxy-ii £> t-N, N-di.-methylamino-5Ai-pregnan-20-one were produced (the numbers of the examples are given in brackets):

2β-fluorine (66), -chlorine (61), -bromine (65),
-Thiocyanato (64), -Acetoxy (69), -propoxy (54),
-Benzyloxy (59), -Chlorethoxy (60), and -Isopropoxy (52)

and from 1iAG-N-jithyl-N-methylamino-3i> 6-hydrox7-5iX-pregnan-20-one:

2ß-fluoro (68), -chlorine (62), -methoxy (55), -ethoxy (53) and -acetoxy (70)

and 3P6-Hydroxy-110C-N-isopropyl-N-methyl-5 <% - pregnan-20-one:

2β-fluoro (67), -chlorine (63), -methoxy (56), -ethoxy (57) and -acetoxy (58).

HClO ^ was used as a 60% aqueous solution.

7 09 R 41/097

2 7 I b ü 7 β

At-
sp. Baseline
material Weight,
(mg); Acid or alcohol Propan-2-ol (ml) 50 Table 6 H ₂ SO ₄ 0.12 Reak
ions the end
prey Chromato
graphics EA-PE Crystal
Lisa- j? - β <7τ) up-
working + 82 °
(CO, 6) A. Manuf.
No. · 750 VoI ET 15th 30th HClO ₄ 1 Time (mg) EA-PE tionslö- ^w
communication
tel - management
method + 82 ° A. 52 87 500 50 30th HClO ₄ 1.5 4 hours 145 cc:
TLC EA-PE - - - + 73.8 ° C. 53 88 750 PR 100 3 catalyst HClO ₄ 1 3 1/4
Hours. 236 _ TLC EA-PE - - + 80.5 ° C ' 54 87 500 ME 5 ■ · Vol (ml) HClO ₄ 0.66 1 H. 452 TLC EA-PE - - + 79 ° C * 55 88 300 ME 10 HClO ₄ 0.5 37 min. 349 TLC EA-PE - - + 75 ° C. O
co '56 89 400 ET 2.4 - - 25 min. 233 TLC EA-PE - - + 78.5 ° A. co 57 89 ■ 300 acetic acid 4th HClO ₄ 0.8 "1 H. 178 TLC EA - - + 67 ° A ¹ 58 89 424 Benzyl alcohol 2.5 HClO ₄ 0.8 3 hours. 173 TLC EA - - ₊ 63 ° A. ο 59 87 388 2-chloroethanol - - - 45 min. 141 TLC - 135- + 86.8 ° B. (O 60 87 300 conc. HCl 10 - - 40 min. 202 TLC EA-PE - 149 + 61.2 ° B. * - 61 87 500 "conc. HCl 6.2 - - 15 minutes. 101 - EA-PE PE 127-
129 + 73.5 °
(CO, 56) B. 62 88 300 'conc. HCl - - 37 min. 362 TLC EA - 183-
185 + 88.5 ° A. 63 89 500 HSCN in.DE ⁵ - - 30 min. 127 TLC EA-PE Pentane 139-
142 + 90.5 ° A. 64 87 ² 1500 47% aq.
HBr - - 45 min. 279 CC CC, TLC
EA-PE PE - + 69.5 ° B. 65 87 500 HF * ■ 15th 267 CC EA-PE 66 87 19 hours 276 -

2 7 J ', J78

Table 6 (continued)

Manuf.wt. No. (mg)

When- starting ma- acid or alcohol catalyst reac- Aus Chromato- Kristal- F sp. material loot graphics lisa- o _c

Vol Cl) TOlCl) ^time <"«>srngsm?;.

tel

working method

500 HF 500 HF

6.2 ■ 6.2

Std. 182 TLC EA-PE
Std. 148 TLC EA-PE

500. Acetic acid 500 acetic acid

1 1/2 263 CC EA-PE Hours. 2 3/4 333 TLC EA-PE Hours.

- +72.1 ^υ Β

- + 79 ° A (CO, 43)

EA-PE 156- + 81 ° B 158.5 Cd, 6)

- + 82 ° β

1 After preparative thin-layer chromatography, further purified by dissolving in EA and extract in HCl. The extract was basified with NaOH and again extracted with EA, washed, dried and evaporated.

2, dissolved in 10 ml TLC

3 Prepared by extracting one obtained from 3.0 g of KSCN and 4.6 g of phosphoric acid Mixture.

4 Preformed complex of 5 g urea and HF

- 27 ibü78

Example 71 11 /) C-N, N-Diinethylamino-5;> C-hydroxy-3fXrandrostane-17β-carbonitrile

A solution of 500 mg LXX in 150 ml ME was treated with 20 ml saturated NaHCOν solution under reflux for 24 hours. The mixture was diluted to 1 liter with water and the precipitate was filtered off, washed with water and dried. The solid (34-0 mg) was purified by preparative thin layer chromatography in EA-PE (1: 2) and crystallization from DE-PE, whereby 17O mg of the title compound were obtained. F = 183-186 °, ßd ^ + 47.5 °.

Example 72

11 (^ N, N-dimethylamino-2ß-ethoxy-3x-hydroxy-5iXrandrostan-17ß carbonitrile

A solution of 320 mg of LXXI in 80 ml of ME was treated under reflux with 8 ml of saturated NaHCO, solution. After 5 hours the mixture was diluted to 600 ml with water and the precipitate was extracted into DE. The extracts were washed with water, dried over NapSO ^ and evaporated to 300 mg of a foam, which was purified by preparative thin layer chromatography in AC-PE (1: 3) to give 250 mg of the title compound as a foam; IÖQ-q + 4-6 °.

Example 73 11 (X, -Dimethylamino-30C-hydroxy-5β-androstane-17β-carbonitrile

1 g of KHCO7 in 20 ml of water was added to a solution of 500 mg of LXXII in 53 ml of ME and the mixture was refluxed under nitrogen for 2 hours. Dilution with water and extraction with EA gave a crude product which was crystallized from DE-PE and ME-water to give 17O mg of the title compound. F = 137-139 °, / ßj ^ + 67 °.

ORJGINAL INSPECTED 9841/0974

- .88 -

2Vli, U7e

Example 7 ^

21-Acetoxy-11ft ^ -N, N-dimethylamino-30C - hydroxy-5ß-prep; nan-20-on (LXXIV)

1.0 g of lead tetraacetate was added to a solution of 0.5 β LXXIII added in 18 ml of benzene and 1.15 ml of ME. The solution was on Cooled 10 ° and 2.85 ml of boron trifluoride etherate were added. The reaction mixture was stirred at 10 ° for 5 hours and then poured into aqueous NaHCO ^ solution. The steroid was made extracted in DE and subjected to preparative thin layer chromatography in 2: 1 EA-PT. EA and then rait by eluting Crystallization from DE gave 100 mg of the title compound with a P = 150-152 °.

Example 75

5flC21-dihydroxy-1iQ6-dimethylamino-5ß-prep; nan-20-one

500 mg of LXXIV was dissolved in 20 ml of ME and 5 ml of 20% aqueous KHCO was added. The solution was refluxed under nitrogen for 2 hours and then poured into water and the steroid extracted with EA. Preparative thin layer chromatography using AG-PT 1: 2 as solvent and eluting with AC gave 310 mg of the title compound as a white foam / θ ^ τ \ + 4-7 °

Example 76

11fX, -Dimethylamino-3C <, -hydroxy-5 (Xb-pregnan-20-one

110 mg LVIII was treated with a refluxing solution of 3 ml chloridic acid reagent for one hour, after which it was partitioned between EA and aqueous NaHCO, solution. The organic phase was isolated, washed with water and evaporated to a foam. Crystallization from PE gave 78 mg of the title compound with a melting point of 119-122 °, ßf ^ + 76.0 °.

ORIGINAL INSPECTED 709841/0974

27 Ί bO7β

example 77 11QC-DiTnethylami'no-3o <-hydroxy- ^ p6-prep; nan-20-on

A solution of 48 mg diethyl azodicarboxylate in 3 ml tetrahydrofuran was added to a hybrid of 362 mg LVII, 0.11 ml formic acid, 787 mg triphenylphosphine and 15 ml tetrahydrofuran. The reaction mixture was left to stand overnight at room temperature, after which it was partitioned between EA and aqueous NaHCO ^ solution. The organic phase was isolated, washed with water, dried over Na ^ SCL and evaporated to give a foam. Column chromatography (eluting with DM) gave a foam which was dissolved in 10 ml ME and treated with 10 drops of perchloric acid. After 0.5 hours, the reaction mixture was worked up as in Example 76. Crystallization from PE gave 106 mg of the title compound with a melting point of 119-123 °, M ^ + 76.7 °.

Example 78

100 mg XLV were mixed with 61 mg PTSA in 10 ml DC and 5 ml ET for 5 minutes touched. 75 mg of m-chloroperbenzoic acid were added and after 24 hours at 20 ° C., the thin-layer chromatogram showed the formation of the title compound.

Example 79

1iQ6-N, N-dimethylamino-2ß-ethoxy-3.V-hydroxy-5X-pregnan-20-one

3.0 g of LXI were dissolved in 20 ml of DM and the solution was mixed with a solution of 1.8 ml of concentrated HpSO ^, in 25 ml of V / water and then extracted with 15 ml of water. The united aqueous extracts were kept at room temperature for 10 minutes and then adjusted to pH by adding NaOH solution 11 brought. The precipitate was extracted into DM and the extracts were washed with water. The dried over MgSO ^ The solution was subjected to column chromatography eluting with DM-MA (9: 1 ^. The eluate was evaporated, whereby a

709841/0974 ORIGINAL INSPECTED

-vsr- 2 V-IIIe78 • 53.

Foam which crystallized from AC water (4: 1) to give 1.66 g of the title compound; & j \ + 74 °, F = 135-143 °.

Example 80

Methyl IIOC- ^ N-dimethylamino ^ ß-ethoxy ^ OC- hydroxy- 5c> 6-andro stan-17ß-carboxylate

8.4 ml of iodomethane were added to a solution of 3.5 g of LXXV in 30 ml of dimethylformamide and 25 ml of triethylamine. After stirring for 20 hours, the mixture was poured into 50 ml of 5% NaHCO, solution and extracted with CH. The combined extracts were dried over MgSO ^, and evaporated. The residue was chromatographed on the column using EA-PE 1: 4 as the eluent to give 965 mg of the title compound as a foam; & Q ^ + 35 °.

Example 81

1iOG-N, on 20-N-Dimethylamino-2ß-ethoxy-30 ^{<<-hydroxy-21-propyl-5iK.-pregnan}

8.6 ml (1.7 mol) of butyllithium in hexane were added to a suspension of 2.0 g of LXXV in 12 ml of DE under nitrogen and cooling in ice-water. The mixture was stirred vigorously for 31 hours at 20 ° and then diluted with 25 ml of water. The mixture was extracted with EA and the combined extracts were washed with 0.1 N NaOH. The extract, dried over MgSO ^ was evaporated to give a foam which was purified by preparative thin layer chromatography on alumina using 1: 2 EA-PE as the eluent to give 146 mg of the title compound as a foam; ßQ ¹ ^ + 75 °

Example 82 11 () C-Dimethylamino-3C '(-hydroxy-5c <-pregn-1-en-20-one

2.76 g of 2β-bromo-11CXr-N, N-dimethylamino-3CC-hydroxy-5! Xrpregnan-20-one were added with 7 ml of dihydropyran and 1.30 g of PTSA in 15O ml of B. Stirred at 21 °. After 1 hour, the clear solution with excess

7 OP - AW Π q 7 Λ _0RiGmL

27 1 S078

siger 2 N-Na-CO ^ -solution and brine and washed over Na-SO ^, dried. The B was evaporated to an oil, which was then dissolved in 75 ml of DMF and mixed with 7.5 g of CaCO, and 10 g of LiBr for 19 hours was heated to 105-115. The mixture was diluted with ME and insoluble solids were filtered off. The residue was washed with more ME and the combined ME solutions were diluted to approximately 300 ml.

This solution was adjusted to pH 1 with 2N HCl and after one hour at 21 °, 2N Na-CO, solution was added to raise the pH of the mixture to 9.0 and the ME became evaporated at reduced pressure. The residue was extracted twice with EA and the combined extracts were washed with brine, dried over NapSO ^ i and evaporated to an oil. Residual DMF was evaporated using an oil pump, leaving a gummy product. This was dissolved in 1: 1 EA-PE and filtered through 30 g of silica gel to give the crude product. This was purified by preparative thin layer chromatography (EA-PE) to give 611 mg of the title compound; / Ö (7j) +1.5

Examples 83-157 Preparation of the salts

In Table 7 are the properties and the manufacturing methods of aqueous solutions of salts according to the invention according to one of the following methods:

A. The 10C-amine was added to a solution of the acid in water and the mixture was stirred or shaken until a clear solution was obtained. The solution was made with water brought to the specified weight, filtered through a membrane and the pH was determined.

B. As described under A above, but before processing the solution was filtered with water and drop-

709841/0974

ORIGINAL INSPECTED

2 7 1 b Ü 7 β

wise with 0.1 M NaOH solution was added until the originally formed precipitate no longer dissolved on stirring.

C. A solution of the "iipC-amine in ET was mixed with a solution of the Treated 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 that remained undissolved was collected on a weighed funnel and the weight of the dissolved free base was calculated. The solution was brought to the indicated weight with water and its pH was measured.

D. The £ 110 amine was added to a solution of the acid in water and the mixture was stirred or shaken. If the free base remained undissolved, additional acid was added and the mixture was agitated again. The solution was made up with water and any material that remained undissolved was collected on a weighed funnel and the weight of dissolved free base was calculated and the pH of the Solution measured.

E. The 11OC amine was added to a solution of the acid in water and the mixture was stirred or shaken. The solution was brought to the indicated weight with water. The undissolved material was collected on a weighed funnel and the weight of the dissolved free base was calculated and the pH of the solution was measured.

The solid citric acid was used in the form of its monohydrate.

709841/0974 _0RK3 | _NA l INSPECTED

6th salt - ^ o - 120.5 Molar
activity of
acid
solution 2715078 Weight
the
Lo
sung
(G) pH 6th Citrate Table 7 120 0.1 24 6.5 6th Il 120 0.1 acid 12th 5.6 6th Hydro
chloride Method solved
de 11oc-amine
(mg) 120 0.1 5.4 ml 12th 4.85 6th phosphate B. 120 0.1 3.34 ml 10 5.7 Free
sp. base
Ex.
No. 6th Mesylate C. 120 0.1 3.4 ml 10 5.5 83 7th Tricarb
allylate B. 100 0.1 3.4 ml 12th 6.05 84 8th Citrate B. 102 - 5.4 ml 10 5.0 85 9 It B. 101 - 2.5 ml 10 5.7 86 10 It B. 105 - 54 mg 10 5.8 87 11 It B. 101 - 55 mg IO 3.7 88 12th dd A. 102 - 56 mg 10 3.7 89 12th Il A. 84 - 55 mg 10.06 3.7 90 14th acetate A. 100 0.5 57 mg 10 4.4 91 14th Citrate A. 100 0.1 57 mg 10 4.8 92 15th acetate A. 100 0.5 1.59 ml 10 3.9 93 16 Citrate E. 100 0.1 2.6 ml 10 3.5 94 17th Citrate B. 550 0.1 1.5 ml 16.5 5.0 95 18th It B. 100 0.1 2.5 ml 55 5.1 96 19th Il B. 16 0.1 4.5 ml 10 4.0 97 20th Il C. 52 - 9.0 ml 5 2.45 98 21 dd B. 45 - 2.5 ml 5 3.26 99 23 It B. 150 - 48. mg 5 3.58 100 24 Il D. 100 0.1 24.5 mg 15th 5.5 101 26th Il E. 41 - 25.5 mg 10 4.5 102 27 dd E. 100 - 5.5 ml 5 5.4 103 30th Il B. 100 - 54 mg ; 12th 5.0 104 51 dd B. 94 - 25.5 mg 10 3.7 105 52 Il E. 100 - ■ 104.2 mg 10 3.8 106 Il D. - 50 mg 10 3.7 107 A. 60 mg 108 E. 50 mg 109 A. 110 111

709841/0974

ORiGlNAL

free
base
Ex.
No. salt - 94 -
* "0? 96 27-1 bO7 8th pH 37 Citrate Table 7 100 (Continuation) 3.1 34 Il 103 Molar acid
did that
Acid-
solution Weight
the
Lo
sung
(B) • 3.65 at
sp. 35 Il Method solved
de "1iouAmin
(rag) 102 121.6 mg ; 20th 29 3.45 112 36 Il D * 78 62 mg 10 21 3.0 113 33 η A. 17th 74 mg 10, 8 3.16 114 38 Il D. 25th 114 mg 10, 2.85 115 39 • ι D. 41 63 mg 7, 2.65 116 40 Il A. A3 22 mg 5 2.8 117 42 It E. 87 44 mg 5 2.9 118 43 • I. D. 99 44 mg 5 7 3.75 119 44 Il D. 100 48 mg 5 28 3.1 120 45 η D. 100 51 mg 8th, 3.75 121 46 It a: 100 105 mg 10, 3.75 122 47 ti D. 101 55.9 mg 10 4.9 123 48 It A - 125 54 mg 10 , 1 3.6 124 49 Il A. 48 0.1 2.6 ml 10 , 5 6.0 125 52 It B. 50 0.1 '2.5 ml 10, 3.65 126 53 Il B. 48 0.1 3.2 ml 12, 3.6 127 54 Il B. 50 25 mg 5 3.0 128 55 Il E. 43 25 mg 5 3.75 129 56 It A. 48 50 mg 5 3.5 130 57 Il D. 41 26 mg 5 3.45 131 58 Il A. 47 26 mg 5 3.5 132 61 It E. 50 24 mg 5 2.97 133 62 Il E. 33 24 mg 5 3.18 134 63 It E. 43 53 mg 5 2.8 135 64 It E. 21 38.5 mg ; 5 2.82 136 65 Il E. 49 50 mg 5 2.55 137 66 Il D. 45 50 mg 5 3.58 138 67 Il D. 50 48 mg 5 2.95 139 68 Il D. 27 mg 5 3.6 140 E. 52 mg 5 141 D. - 27 mg 5 142 A.

1/097 /.

- 99 -

271b.Ü7 8

Table 7 (continued)

Bei-free sp. base

Ex.

No.

Salt Metho- Dissolved Molaride HouAmin did that (rag) acid solution

Acid weight * of the solution (6)

PH

143
144
145
146
147
148
149
150
151
152

153
154

155 183

156 186

157 188

69 70 71 72 73 74

75 80 81 82

59 60

Citrate E.

Il Il It Il Il Il Il Il Il Il Il It It It It

E B B A A A B B D E E A A E

49 49 100 100 100 100

100 100

60 24 47 46

25 80 86

25.5 mg mg mg mg mg mg mg mg mg mg mg mg mg mg mg

.5

10 10 10 10 10 10

8.9

3.52

3.6

5.4

5.05

3.6

3.7

3.7

4.5

3.7

2.6

3.6

3.5 3.0 3.60 3.5

Since undissolved material remained after the second addition of acid, ET was added dropwise until it was completely dissolved and the resulting solution was reduced to dryness in vacuo. The residue was dried and in Dissolved in water.

7098A1 / 0974

27 i sυ7β

Example 158-171

Preparation of salts of 11p (.- N, N-dimethylamino-2ß-ethoxy-5c <r pregnan-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 was achieved. The solution was then either:

(A) 0.1 M NaOH was added dropwise until the originally formed precipitate just dissolved, brought to the specified weight with water, through a membrane filtered and the pH was determined; or

(b) brought to the specified weight with water, filtered through a membrane and the pH determined.

salt Metho
de A. Tabel 8th acid Weight
the
Lo
sung
Ck) pH
value Citrate A. B. 12.4ml 50 4.4 At-
sp. acetate B. A. solved
11tX-amine
(mg) Molar
activity of
acidic
Solution 0.75ml 5 4.0 158 Lactate A. B. 500 O., 1 1.5ml 10 4.2 159 Mesylate A. B. 50 0.5 2.5ml 10 4-, O5 160 phosphate A. B. 101 0.5 0.5ml 10 5.6 161 (+) - tartrate A. B. 100 0.1 57.5mg 10 4.5 162 Tricarbally
lat A 100 0.525 46 mg 10 4.9 165 Hydrochloric
rid 101 - 2.5ml 10 5.55 164 sulfate 101 - 2.5ml 10 5.5 165 Citraconate 101 0.1 56mg 10 5.8 166 Mesaconate 100 0.05 52mg 8.1 5.02 167 Aconitate 100 - 55mg 8.1 5.58 168 Succinate 81 - 58mg 10 5.7 169 Salicylate 81 - 27.6mg 8.1 4.48 170 100 - 171 81 -

709 8 A1 / 0974

27.1 SQ78

Examples 172-180

Preparation of salts of 110 (.- N, N-dimethylamino-33 £ -hydroxy-5ß 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 was obtained. The solution was brought to the specified weight with water, filtered through a membrane and the pH was determined.

salt Table 9 50 Molar
activity of
acidic
solution acid Weight
the
Lo
sung
(*) pH
value Citrate 50 0.1 4.0 ml 12th 3.2 At-
sp. Hydrochloride solved
11 -Amin
(mg) 0.1 1.4 ml 5.06 2.9 172 acetate 120 0.5 0.55 ml 5 4.5 173 Succinate 50 - 16.3 mg 5 4.5 174 Mesylate 50 0.1 1.4 ml 5 3.85 175 phosphate 50 0.52 0.4 ml 5 2.5 176 50 - 24.4 mg 5 4.15 177 50 0.5 0.14 ml 5 4.1 178 Tricarballylate 50 - 20.7 mg 5 3.65 179 Lactate 180 (+) - tartrate 11 (XrN, N-dimethylamino-2ß-ethoxy-3 ^< ^ -liydroxy-5X-pregnan-20-one- Example 181 hydrochloride salt

A solution of 10.5 g of 10'c-N, N-dimethylamino-2ß-ethoxy-30thydroxy_50 ^ _ppegnan-2O-one in 80 ml of dry DE was stirred, a stream of HCl being passed through. The precipitated solid became

709841/0974

27 15Ü78

recovered by filtration under a nitrogen atmosphere and washed well with dry DE and dried to give 11 »5 B of the title compound; F = 200 ⁰ C (decomposition) + 35 ° (ME).

Example 182

110 ^ -N, N-dimethylamino-2ß-ethoxy-3 <Xl-hydroxy-5 ^ rpregnan-20-one citrate salt

A solution of 1 g of 11f> 0-N, N-Diinethylamino-2ß-ethoxy-50C-hydroxy-5 (Xbrpregnan-20-one in 20 ml of DE was added to a stirred solution of 1.05 g of citric acid monohydrate in 60 ml of DE. It made up A precipitate immediately appeared, which was collected by filtration under nitrogen pressure, to give the title compound obtained containing 1 mol of citric acid in excess.

The filtrate was evaporated to half its volume and the precipitate recovered by filtration, further title compound containing 1 mol of citric acid in excess. The X values (D ₂ O) include 9.35 (s, 18-H), 8.87 (s, 19-H), 8.84- (t, J 7Hz, -OCH ₂ CH ₃ ), 7 , 78 (s', 21-H), 7.67 (triplet of doublet, J 12 and 5 Hz, 11β-H), 7.02 and 7.24 (ABq, J 16Hz, -CH ₂ - of citric acid) , 6.97 and 7.09 (2 singlets, 11 * - ⁺ NH (CH,) ₂ ), 6.2-6.6 (m, -OCH ₂ CH ₃ , 2 ^ -H and 1β-H) and 6.05 (m, 3 [beta] -H).

Example 183

21-Acetoxy-110OrN, N-dimethylamino-2ß-ethoxy-30 (rliydroxy-5i / fc-P ^re S ^na n- 20-one (XXIX)

A solution of 200 mg XXVIII in 10 ml AC was at room temperature stirred with 200 mg of anhydrous potassium acetate for 4 hours. the Mixture was diluted to 100 ml with water and the precipitate was extracted into DE. The extract was washed with water, dried over NapSO ^ and evaporated to 180 mg of a foam, by preparative thin layer chromatography in EA-PE (1: 1)

7098 / .1 / 097 / »

_ 99 -

27 15Ü78

was purified to give 114 mg of the title compound as a foam; β <2 ^ + 90.5 °.

example

11QC-dimethylamino-50C-hydroxy-5β-pregnan-2O-one

44 mg of 11 (X-amino-5β-pregnane-3 (Xi20β-diol in 1 ml of 37% aqueous HCHO and 0.01 ml of HGO ₂ H were heated on the steam bath for 5 minutes. The cooled solution was diluted with NaHCO 4 solution and extracted with EA. Evaporation of the washed organic extract, dried over MgSO ^, gave a gummy product which was purified by preparative thin layer chromatography in AC-PE (2: 3) to give 11C <r-dimethylamino-5β-pregnan-3X- 20β-diol received.

0.24 ml of Jones reagent was added to the latter compound (40 mg) in 4 ml of AC at 0 °. After 15 minutes the mixture became poured into iced NaHCO, solution and extracted with EA. The washed and dried over MgSO ^ extract was evaporated, to give a solid which was obtained by filtering through silica gel in AC-PE (1:10) and crystallizing from ME water was purified, giving 10 mg of 11 (X-dimethylamino-5β-pregnane-3,20-dione received.

A solution of 250 mg of the last-mentioned compound in 17 ml of ET was _{stirred for 15 minutes with 125 mg of NaBH 7} at room temperature. Excess NaBH ^ was decomposed by adding a little acetic acid and the mixture was then diluted with NaHCO, solution and extracted with EA. Evaporation of the washed and MgSO ^ dried extract gave a foam which was purified by preparative thin layer chromatography using AC-PE (1: 5) to give the title compound; 3Q- ^ + 66.2 °.

709BA1 / 097Λ ORIGINAL INSPECTED

2 7 1 b U 7 θ

Example 185

, N Dimethylümino-gß-ethoxy- ^ X-hydroxy-5 '"X-prep; nan-20-one

500 mg of LXXV triethylammonium salt were dissolved in 5 nil of THF. 7.2 ml of methyl lithium (1.7 M solution in DE) were added and the mixture was stirred under nitrogen at 20 ° for 28 hours. 25 ml of water was added and the mixture was made three times extracted with EA. The combined extracts were dried over MgSO ^ and evaporated to give 372 mg of the title compound which was identified by chromatography to be the same as the product of example 1 proved.

Example 186
(Z) -17-cyanomethylene-11 (Xrdimethylamino-2ß-ethoxy-5 (X-androstan-

A solution of 1.2 g of LXXIX in 12 ml of dry THF was added to a mixture of 500 mg of NaH, 4 ml of diethyl cyanomethylphosphonate and 16 ml of dry THF. The reaction mixture was stirred at room temperature overnight after which it was partitioned between EA and water. The organic phase was washed with water, dried over Na ^ SO ^ and evaporated to an oil. Purification by column chromatography (EA-PE) and crystallization from ME water gave 833 mg of the title compound with a melting point of 128-146 °, S (J ^ -10.8 °, the NMR spectrum showing that it was the corresponding Contained Ε isomers.

Example 187

1iOUDimethylamino-3o ^ • hydroxy-5 (XrPregnan-20-one

100 mg of LXXXIII in 10 ml of EA containing a few drops of acetic acid was hydrogenated at atmospheric pressure using 5% Pd-C as a catalyst. After 24 hours the catalyst was filtered off through kieselguhr and the filtrate was evaporated to give 70 mg of the title compound which was found to be the same as the product of Example 6 by PMR spectrum, gas chromatography and thin layer chromatography.

709841/0974 _{0RK3lNAL WSP} ECTS)

- - »el- 27 Ibü78

Example 188 11 (X, -Dimethylamino-5iXrhydroxypregn-4-en-20-one

A solution of 117 mg NaBH ^ in 5 ml water was stirred into one Solution of 500 mg LXXXV in 20 ml THF added. The solution was stirred for 5 1/4 hours at about +21 and then was Glacial acetic acid was added dropwise until there was no more effervescence. The solution was partitioned between water and EA and the organic The extract was washed with saturated saline and dried. Evaporation gave 510 mg of HDC-dimethylaminopregn-4-en-3β, 20 ^ -diol.

A solution of 348 mg of dietary azodicarboxylate in 2 ml of dry THF was added over about 5 minutes to a stirred solution of 361 mg of the above diol in 12 ml of dry THF which was 787 mg Triphenylphosphine and 283 mg of chloroacetic acid contained, added dropwise. The solution was stirred for one hour at about 21 ° and then partitioned between 5% aqueous NaHCO 3 and EA. The organic extract was washed with saturated saline, dried and evaporated to give 1.58 g of a solid received. This was purified by preparative thin layer chromatography (EA-PE), 306-chloroacetoxy-11;) C-dimethylamino-pregn-4-en-20f-ol received.

A solution of 438 mg of the above compound in 10 ml of AC was cooled to 0 to 5 ° with stirring, and 0.3 ml of Jones reagent was added dropwise over about 3 minutes. After a further 20 minutes at 0-5 °, the mixture was partitioned between 2 1/2% aqueous NaHCO 3 and EA. The organic extract was washed with saturated saline, dried and evaporated to form a foam. This was purified by preparative thin layer chromatography (EA-PE), giving 3l ε-chloroacetoxy-1KX7-dimethylaminopregn-4-en-20-one.

A solution of 469 mg of this compound in 15 ml of ME was used for Heated to reflux and a solution of 181 mg NaHCO * in 2.5 ml

709841/0974 ORJGINAL INSPECTED

- -we - 2 7 I b Ü 7 β

Water was added. The mixture was refluxed for 30 minutes heated and then cooled and divided between water and EA. The organic extract was saturated with 100 ml Brine, dried and evaporated to obtain a liquid. This was determined by preparative thin layer chromatography (EA-PE) to obtain 123 mg of a liquid. The PMR spectrum showed that the material the title compound and 11 (XrDimethylamino-3ß-hydroxypregn-4-en-20-one contained.

The above epimeric mixture (121 mg) was 158 mg in material obtained in the same way and subjected to a further thin-layer chromatography purification (EA-PE). the Band of the more polar product was eluted with AC and evaporated,

whereby 123 mg of the title compound were obtained as a foam; IR] - * + 170 °.

Examples A-F

Formulations of 11 / Xr-N, N-dimethylamino-2ß-ethoxy-5, X _r hydroxy- 50tr-pregnan-20-one

A. Single dose injection 5 mg / ml

% W / v

Steroid 0.50

Citric acid 0.26

Sodium chloride 0.80

Sodium hydroxide to pH 4.5

Water for injection to 100.00

The citric acid was dissolved in most of the water and the steroid was stirred under a nitrogen blanket added. After the steroid had dissolved, the sodium chloride was added and dissolved. Then the pH was adjusted with sodium hydroxide solution stopped and the product was brought to volume. The solution was clarified by membrane filtration and filled into clean glass ampoules under nitrogen. The locked

° ⁴ *

- 27.1 bü78

These containers were sterilized with moist heat.

B. Single dose injection 5 mg / ml

% W / v

Steroid 0.50

Hydrochloric acid (pure) 0.11

Sodium chloride 0.62

Disodium hydrogen citrate 0.32

Sodium hydroxide to pH 4.5

Water for injection to 100.00

The steroid became a dilute solution of hydrochloric acid added and dissolved by stirring under a nitrogen blanket. Disodium hydrogen citrate and sodium chloride were added and dissolved, the pH was adjusted with sodium hydroxide solution and the product was brought to volume. the Solution was clarified by membrane filtration and filled into glass ampoules under nitrogen. The closed containers were sterilized by moist heat.

C. Solution for intravenous infusion

% W / v

Steroid 0.050

Citric acid 0.026

Sodium chloride 0.89

Sodium hydroxide to pH 4.5

Water for injection to 100.00

The citric acid was dissolved in most of the water and the steroid was added with stirring under a nitrogen blanket. After the steroid dissolved, the sodium chloride was added and dissolved. The pH was adjusted with sodium hydroxide solution stopped and the product was brought to volume. The solution was clarified by membrane filtration and turned into pure Glass bottles filled under nitrogen. The bottles were closed with rubber stoppers, which were closed by aluminum sealing rings.

■ 7098'.1 / 0971 0RK3INAL INSPECTCD

2? I b Ü 7 β

have been kept and sterilized in moist heat.

D. Solution for intravenous infusion

% W / v

Steroid 0.050

Hydrochloric acid (pure) 0.011

Dinatriura Hydrogen Citrate 0.032

Sodium chloride 0.87

Sodium hydroxide to pH 4.5

Water for injection to 100.00

The steroid became a dilute solution of hydrochloric acid added and dissolved by stirring under a nitrogen blanket. The disodium hydrogen citrate and sodium chloride were used added and dissolved, the pH was adjusted with sodium hydroxide solution and it was made up to volume. The solution was clarified by membrane filtration and filled into pure glass bottles under nitrogen. The bottles were through Rubber stoppers closed, held in place with aluminum locking rings have been and have been sterilized by moist heat.

E. Multi-dose injection

% W / v

Steroid 1.00

Citric acid 0.52

Sodium chloride 0.50

Benzyl alcohol 1.00 vol / v

Sodium hydroxide to pH 4.5

Water for injection to 100.00

The benzyl alcohol was dissolved in most of the water and the citric acid was added and dissolved. The steroid was made added and dissolved with stirring under a nitrogen blanket. The sodium chloride was dissolved and the pH was adjusted with sodium hydroxide solution adjusted. The product was based on volume brought and sterilized by membrane filtration. The solution

709841/0974 ORIGINAL INSPECTED

- *> 5 - 2715Ü78

was aseptically filled into sterile glass vials under nitrogen, which were closed with sterile rubber stoppers or stoppers held in place by aluminum locking rings.

F. Multi-dose injection

% W / v

Steroid 1.00

Hydrochloric acid (pure) 0.22

Disodium hydrogen citrate 0.65

Sodium chloride 0.15

Benzyl alcohol 1.00 vol / vol sodium hydroxide to pH 4.5

Water for injection to 100.00

The benzyl alcohol was dissolved in a dilute solution of hydrochloric acid and then the steroid was dissolved with stirring under a nitrogen blanket. The disodium hydrogen citrate and sodium chloride were added. The pH was adjusted with sodium hydroxide solution and the product became brought to volume and sterilized by membrane filtration. The solution was aseptically placed under nitrogen in sterile glass vials filled and the vials were closed with sterile rubber stoppers or stoppers secured by aluminum sealing rings was held.

Similar formulations were also made in which the 11ft> -N, N-dimethylamino-2ß-ethoxy-30O-hydroxy-5J <? - pregnan-20-one by , N-dimethylamino-3 (Xrhydroxy-5ß-pregnan-20-one was replaced.

709841/0974

- U06 -

■ 27.16078

Example 189

11a-Dimethylamino-2ß-ethoxy-21-fluoro-3oc-hydroxy-5a-pregnan- 20-one and its citrate salt

A mixture of 4.9 g XXVIII, 5 g sodium iodide and 300 ml AC was refluxed for 50 minutes, to a low volume evaporated and divided between I) E and water. The organic phase was washed with water, dried and closed evaporated in a foam. This foam was dissolved in 350 ml of AN and with a solution of 3 g of silver fluoride in 15 ml of water treated at 45 ° for 24 hours. The reaction mixture was partitioned between D and E and potassium carbonate solution. the organic phase was washed with water, dried and evaporated to a foam. By purification by preparative thin layer chromatography (EA-PE 1: 1), 240 mg of the title compound were obtained as a foam; [a] -n = + 69.8 °.

85 mg of the above free base was stirred with a solution of 82 mg of citric acid in 8 ml of water. The solution was brought to 8.5 g with water, an insoluble residue was filtered off, and a solution having a concentration was obtained of 8.2 mg / ml of pH 2.9.

The above compound and its salt are preferred compounds according to the invention. Thus, a further preferred group of compounds comprises those of the formula I or II,

where R is a Fluorine thy! group.

709841/0974

- 107 -

The following is an overview of the examples above compounds used with Roman numerals and the corresponding preparation examples are listed:

Connection no. Manufact. No Connection no. Manufact. No XXIII 2 LV 97 XXIV 4th LVI 98 XXV 5 LVII 86 XXVI .9 LVIII 103 XXVII 10 LIX 93 XXVIII 12th LX 94. XXIX 183 * LXI 85 XXX 14th LXII 11 XXXI 15th LXIII 66 XXXII 17th LXIV 47 XXXIII 27 LXV 64 XXXIV 28 LXVI 70 XXXV 29 LXVII 69 XXXVI 48 LXVIII 71 XXXVII 49 .. LXIX 87 XXXVIII 50 LXX 101 XXXIX 51 LXXI 102 XL 63 69 LXXII 100 XLI 1 LXXIII 29 * XLII 73 LXXIV 74 * XLIII 76 LXXV 13th XLIV 67 LXXVI 104 XLV 83 LXXVII 105 XLVI 81 LXXVIII 106 XLVII 82 LXXIX 107 XLVIII 90 LXXX 109 XLIX 91 LXXXI 110 L. 80 LXXXII 111 LI 80 LXXXIII 112 LII 84 LXXXIV 114 LIII 65 LXXXV 115 LIV 99

* No. of the example
709841/0974

Claims (1)

Claims away
R and R, which can be identical or different, are C / | _c-alkyl, C _x , - alkenyl or cycloalkyl groups, with the proviso that R and R together have 2 to 7 carbon atoms a b contain and that, if R and / or R is an alkenyl group, the carbon atom or the carbon atoms in post Ability to the nitrogen atom in the group -NR R unsaturated ο b is or are; or in which one of the radicals R and R is a benzyl or PhenyläthyIgruppe, the other group a b is a methyl group; or wherein R and R, together with the Nitrogen atom, an azetidino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group, where the Groups can optionally be substituted by one or two methyl groups; R ^ a hydrogen atom or a C ,. , Denotes -alkyl group; 709 8 A1 / 0974 ORIGINAL INSPECTED ". 271SU78 R is a hydrogen atom or a C ^ c which may optionally be substituted by a halogen atom, benzyloxy, Cpc-alkanoyloxy or thiocyanato group or represents a halogen atom; Ir is a hydrogen atom or a methyl group; R is a hydrogen atom or a methyl group; TJ Q R 'is a hydrogen atom or, with the exception if R is a group (c) as defined below, a chlorine atom means; and R (a) is a cyano group; ή Q (b) a group -COR, in which R is a methyl group or such a group substituted by a fluorine atom, a C ^ _.- alkoxy, hydroxy, C ^ .- alkyl, methoxymethyl, ethoxymethyl, C ₀ n- Alkanoyloxy, benzoyloxy or C ₀ c alkoxycarbonyloxy group; or where R ^{y is} a C _x , _r -alkoxy- q '"> * _{x Ύ} or cyclopropyl group; or in which R ^{y is} the group -NR R ^J , in which R ^x and R · ^, which can be identical or different, are methyl or ethyl groups; or 10 (c) a vinyl group or together with R a Z sub- represents a substituted methylene group in which the substituent is a methyl or cyano group; 10 R R is a hydrogen atom, with the exception of the case that R 10
and R together form a substituted methylene group, means; the broken lines indicate that double bonds may be present are in the specified positions; with the proviso that at least one of the radicals R ^ and R is a hydrogen atom; and R * and R together are a hydrogen represent atom when there is a 1,2 double bond; and that the 2-position is saturated when a 4,5 double _ Il there is a bond; and that R ^ is a hydrogen atom, R is Hydrogen atom or a methyl group and R a hydrogen Il atom or optionally, if R is a hydrogen atom, mean a methyl group if a 5ß-hydrogen atom is in front of 70 9841/0974 ORIGINAL INSPECTEP 2 7 1 b Ü 7 β lies; as well as the D-homo-analogs thereof, the R in the 17ass position, 1O 7 Have R in the wheel position and R ^r in the 17 position; as well as the acid addition salts thereof.
2. Compounds according to claim 1, wherein R ^a and R differ- borrowed from benzyl or phenethyl groups; R differ- 9 9 borrowed from the group -COR ^, wherein R is a methyl group substituted by a C _o _ ^ alkyl group; and in what X £ l ^ R, R and R each have V / water: 5 [beta] -hydrogen atom. X IL 5 R, R and "Rr each represent hydrogen atoms, if a 3. Compounds according to claim 2 with a 5 <^ - or 5ß-hydrogen atom. 4. Compounds according to claim 2 or J>, wherein the tetracyclic steroid system sat)
Mean hydrogen atoms. see steroid system is saturated and R, R and R 'respectively 7th 5 · Compounds according to any one of claims 2 to 4, wherein R ^ a Is hydrogen atom or a methyl group. 6. Compounds according to any one of claims 2 to 5, wherein the ring D is a 5-membered ring. 7 · Compounds according to any one of claims 2 to 6 with a 5o6 hydrogen atom. 8. Compounds according to any one of claims 2 to 7 »wherein R (a) a cyano group or (b) a group -COr "in which R- 'is a methyl group or this group substituted by a hydroxy, methyl or acetoxy group, or wherein R ^{7 is} a cyclopropyl group. 9 · "\ f compounds according to claim 8, wherein R is an acetyl group 7 0 9 Π U 1 / Π q 7 A 27-1 bO78 • ν. 10. Compounds according to claim 8, wherein R is a cyano group. 11 50C compounds according to one of the preceding claims, wherein R is a hydrogen atom or a methyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or is a chlorine, bromine or fluorine atom. H. 12. Compounds according to claim 11, wherein R is a hydrogen atom or an ethoxy group. 13. Compounds according to any one of claims 2 to 12, wherein R ^a and R are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 1,3-dimethylbutyl, allyl, Are cyclopentyl or cyclohexyl groups, or wherein -NR R represents a pyrrolidino group. 14. Compounds according to claim 13 »wherein one of the radicals R ^a and R represents a methyl group and the other represents a methyl, ethyl, propyl, isopropyl, butyl or allyl group. away 15. Compounds according to claim 13, wherein both radicals R and R Are methyl groups. 16. Compounds according to claim 1 of the formula (II) wherein 7Ό9841 / 0974 2 7 1 b U 7 θ ο * R is a group -NR ^a R, in which one of the radicals R ^a and R is a methyl group, and the other group is a methyl, ethyl, propyl, isopropyl, butyl or allyl group, or in which both radicals R and R represent ethyl groups away
len, or where R and R together with the nitrogen atom form a pyrrolidino group; R ^ represents a hydrogen atom or a methyl group; R is a hydrogen atom or a methyl, methoxy, ethoxy, Represents propoxy, isopropoxy, butoxy, acetoxy or thiocyanato group or a fluorine, chlorine or bromine atom, R (a) is a cyano group; Q Q (b) a group -COR ⁷ , wherein R ^{7 is} a methyl group or this group substituted by a methyl, hydroxy or q
Is acetoxy group, or R is a cyclopropyl group; or (c) is a vinyl group, or together with R forms a Z-ethylidene group; and 10
R. is hydrogen, with the exception of the case that R and R together form an ethylidene group; the broken line indicates that a The double bond is in the 1,2-position; with the proviso that at least one of the groups R- ^ and R represents a hydrogen atom; that R ^y and R together form a hydrogen atom when there is a 1,2 double bond; and that R ^ is a hydrogen atom and R is a hydrogen atom or a methyl group when a 5 [beta] hydrogen atom is present; as well as the D-homoanalogues, the R in the 17ass position and 10
Wear R in the 17aoC position; and the acid addition salts thereof. 17 · Compounds according to claim 16, wherein R is a dimethylamino z 4 group, R ^ a hydrogen atom, R a hydrogen atom or is an alkoxy group, R is an acetyl or cyano group and 709841 / 0S7A 271SÜ78 the ring D has 5 members. 18. Compounds according to claim 2 in the form of their hydrochloride, Hydrobromide, phosphate, sulfate, p-toluenesulfonate, nethanesulf onate, citrate, tartrate «, acetate, ascorbate, lactate, Maleate, succinate, tricarballylate, glutarate or gluconate salts. 19. Compounds according to any one of claims 1 to 17 in the form their aconite, citraconate, mesaconate or salicylate salts. 20. Compounds according to claim 2 in the form of their citrate or hydrochloride salts. 21. 11 (X ^ N, N-dimethylamino-2ß-ethoxy-3oCrhydroxy-50 ^ pregnan-2O-one according to claim 2 and its physiologically useful acid addition salts. 22. 11oC-N, N-dimethylamino-30 (rhydroxy-5ß-pregrian-20-one according to claim 2 and its physiologically useful acid addition salts. 23. A pharmaceutical composition containing one or more compounds according to any one of the preceding claims together with one or more pharmaceutical carriers or excipients or with customary auxiliaries and carriers. 24. The composition of claim 23 in the form of a solution of Compound or compounds in a parenterally acceptable vehicle. 25. The composition of claim 24 in the form of a simple aqueous acidic solution of the compound or compounds. 709841/0974 27 ISÜ78 26. The composition of any one of claims 23-25, wherein the compound is a compound of claim 2. 27. The composition of claim 25, wherein the compound is a compound according to any one of claims 21 or 22. 28. Process for the preparation of a compound according to claim 1, characterized in that: (a) a corresponding steroid in which either one or O V) both of the groups R and R represent or represent a hydrogen atom with a compound of the formula R ^a X or, in the preparation of a compound in which R is a heterocyclic amino group, a compound of the formula away
XR -R -X, where X is an easily replaceable substituent, implements; (b) a corresponding HOCrAcyl amino steroid is reduced; (c) saturated Α-in the production of ring 2ß-substituted 5 ⁰ ^ steroids the epoxide ring of a corresponding 20C opens 3 "rEpoxids; (d) a corresponding HOC-amino- or 1i0c ~ roonosubstituier- ■ fcies Aminosteroid reductively alkylated; (e) in the production of 5β-steroids or ring A-saturated 2β-unsubstituted 5Ct-steroids the corresponding one 3-oxosteroid reduced; (f) in the production of 3ß-unsubstituted compounds, which do not contain a 5,6 double bond, an inversion of the 3-hydroxy group of a derivative of a corresponding 3β-hydroxy compound carries out; (g) in the preparation of compounds wherein R is a group (a) or (b) as defined in claim 1, the corresponding Δ connection reduced; (h) for the production of 16oC chlorine compounds the corresponding Δ compound hydrochlorinated; 709841/0974 ~ 271SÜ78 (i) in the production of 17β-cyano compounds the corresponding one 17β-carbamoyl compound or the oxime of the corresponding 17β-iOrmyl compound dehydrated; (j) in the preparation of 17β-alkoxycarbonyl compounds esterifies the corresponding 17β-carboxylic acid; (k) in the preparation of 17β- (substituted carbamoyl) compounds the corresponding 17β-carboxylic acid is reacted with an amine; (1) in the manufacture of 21-alkanoyloxy or 21-benzoyloxy compounds acyloxylates the corresponding 21-unsubstituted compound; (m) the iodine atom in the production of 21-fluorine compounds of the corresponding 21-iodine compound replaced by fluoride ; (n) in the preparation of 21-hydroxy compounds a corresponding 21-acyloxy compound is deacylated; (o) in the production of 21-azoxy compounds a corresponding Etherified compound with a 21-hydroxy group or a replaceable 21-substituent; (p) in the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds acyloxylated a corresponding compound with an easily replaceable 21-substituent; (q) in the preparation of 21-alkanoyloxy or 21-benzoyloxy compounds acylated the corresponding 21-alcohol; (r) in the production of Δ-50C connections a corresponding one 2β-halogen compound dehydrohalogenated; (s) in the production of 20-oxo compounds a corresponding one Decetalized 20-ketal; (t) splitting off the protective group from a corresponding compound with a protected 30C-hydroxy group; (u) when preparing a salt, treating the corresponding free base with an acid; 709841/0974 -O16- (ν) in the production of 17β-vinyl compounds the corresponding 17β-ethynyl compound partially hydrogenated; (w) in the production of 17 [beta] -viny compounds, the corresponding one 20,21-epoxy treated with an alkali metal selenocyanate; (x) in the preparation of 17- (Z) -ethylidene or 17- (Z) -cyanomethylene compounds reacting the corresponding 17-oxosteroid with an organophosphorus reagent; or (y) in the preparation of compounds in which R ^{y is} a methyl or cyclopropyl group or a methyl group substituted by a C 1 -C 4 -alkyl group, a 17β-carboxylic acid or a salt thereof is reacted with the corresponding lithium alkyl. 29. The method according to claim 28, characterized in that one a connection according to claim 2 according to any one of parts (a) to (x) according to claim 28 produces. 7098A1 / 0974