DE1219482B - Process for the preparation of 6alpha- or 6beta-aminosteroids of the androstane series - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. α .:

C07c

German class: 12 ο -25/04

Number: 1219 482

File number: A 42617IV b / 12 ο

Filing date: March 15, 1963

Opening day: June 23, 1966

The present invention relates to a process for the preparation of 6-aminoandrostane compounds.

The new compounds prepared according to the invention have the general formula

(A)

NHR

wherein Y is oxygen or a radical of the formula - 0 (CHJ _n O -

denotes in which η is 2 or 3 and the alkylene chain can be substituted by methyl and R denotes a hydrogen atom or an acyl radical. The amino group or the substituted amino group in the 6-position of the steroid molecule can have the «- or / 3-configuration.

The compounds which can be prepared according to the invention are pharmaceutically valuable as endocrine disruptors and cause a favorable shift in the ratio of anabolic to androgenic effects, as is the case with the ratio of levator ani growth to prostate growth in warm-blooded animals is measured. The new compounds prepared according to the invention are also available as intermediates valuable for the synthesis of other hormonal agents.

The process according to the invention is characterized in that, when the NHR group is in the α-position to the steroid structure, a 17-alkylenedioxy-3a, 5a-cycloandrostan-6-one with excess hydroxylamine is heated by methods known per se 6-Oximino-17-alkylenedioxy-3 «, 5oc-cycloandrostane is separated off and reduced in alcoholic solution in the presence of an alkali metal, whereupon the 6a-aminolV-alkylenedioxy-SajSa-cycloandrostane formed is isolated from the reaction mixture and optionally in a manner known per se the 6'-amino group acylated, optionally the amino or the N-acyl compound saponified with aqueous acid on the 17-ketal group to form the oxo group, the oxo compound in the form of its hydrochloride or as the free base, optionally after conversion into the acetic acid salt, isolated and process for the production of 6a or
6 /? - aminosteroids of the androstane series

Applicant:

Abbott Laboratories,

North Chicago, JU. (V. St. A.)

Representative:

Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse and
Dipl.-Chem. Dr. rer. nat. E. Frhr. v. Bad luck man,
Patent Attorneys, Munich 9, Schweigerstr. 2

Named as inventor:

John Soloman Tadanier, Chicago, JH .;

John Wayne Cole,

Deerfield, Jll. (V.St.A.)

Claimed priority:

V. St. v. America March 16, 1962 (180 357)

optionally the amino compound on the 6 "amino group acylated or that if the NHR group is in / 3 position to the steroid structure, in likewise in a manner known per se, a sulfonic acid ester of 3 /? - hydroxy-17-alkylenedioxy-androst-5-ene Treated with ammonia, the 6 ^ -amino-3 ", 5" -cycloandrostane-17-one-ketal obtained isolated and this optionally acylated on the 6 /? - amino group, optionally the amino or the N-acyl compound with aqueous acid on the 17-ketal group to the oxo group saponified, the oxo compound in the form of its hydrochloride or as a free base, if appropriate after conversion into the acetic acid salt, isolated and optionally the amino compound on the 6 /? - amino group acylated.

The process according to the invention is illustrated in more detail by the examples below. For the production protection of the starting materials is not sought in the context of the present invention.

example 1

a) 6-oximino

17-ethylenedioxy-3a, 5'-cycloandrostane

A solution of 4.8 g of 17-ethylenedioxy-3 ", 5" -cycloandrostan-6-one and 5.0 grams of hydroxylamine hydrochloride

609 580/440

3 4

in 200 ml of pyridine was obtained on a steam cloandrostane for 3 hours. that warms up from the bathroom. After cooling, the mixture of crystallization medium in the form of a white gel was diluted with 1.21 of water and extracted with ether. farewell, which turned into a fine The ether extract was washed with water and distributed white solid body. After dried over magnesium sulfate. The solvent 5 drying the product melted at 193 to 197 ° C. was evaporated and the residue from aqueous The product was crystallized by its infrared absorption ethanol, crystals being identified by 6-oximino diagram and by elemental analysis. ^ -äthylendioxy-Sa.Sa-cycloandrostane was obtained- The latter agreed with the empirical formula. The crystals were filtered off, matched with aqueous C ₂₃ H ₃₅ O ₃ N,
Washed ethanol and dried, with 4.18 g io

this new intermediate product, F. 182 to 186 ⁰ C, example 2

were obtained. Part of this product was _a ) 6 «-amino-

recrystallized, with an analysis sample, F. 186 "_,," ",,,,.,

to 187 ° C. The with this analysis- S ^ -cycloandrostan-H-on-hydrochlond

The analytical values obtained in samples corresponded to 2.8 g of the free prepared according to Example 1, b)

the calculated values for 6-oximino-17-ethylene amine were in a mixture of 1.5 ml of ice

dioxy-3a, 5a-cycloandrostane with the empirical for- acetic acid and 15 ml of water and dissolved by adding

mel C ₂₁ H ₃₁ O ₃ N. 2 ml of concentrated hydrochloric acid have a

b) 6 ″ -amino installation initiated, which occurs after cooling for 2 hours

n-äthylendioxy-Sa ^ -cycloandrostan ^{20 had} largely ended.

The product was on a smter glass filter

A solution of 4.1 g of o-oximino - ^ - äthylendioxy- collected and mixed with a few drops of ice water

Wash 3 <x, 5oc-cycloandrostane in 400 ml of anhydrous ethanol. Recrystallization from water gave white

was boiled under reflux, while crystals of 6 "-amino-3", 5 "-cycloandrostan-17-one-

of 90 minutes 36 g of metallic sodium por- 35 hydrochloride with a [«■] f = + 128 ° (1%

were added in portions. It was further solution in methanol).
Boiled under reflux for 60 minutes, the warm

Reaction mixture with 200 ml of anhydrous ethanol. .

diluted and filtered through a sintered glass filter. The ^b ) acetic acid salt of

The filtrate was made by adding ice and 21 cold 30 6 "-amino-3a, 5" -cycloandrostan-17-one
Cooled water and then extracted with ether.

The ether extract was washed with water and 6 "-amino-3a;, 5a-cycloandrostan-17-one hydrochloride

then dried over magnesium sulfate. The ether of Example 2, a) [1.53 g] was charged with 100 ml of 5% ^er ig

was evaporated and left behind 4.33 g of a viscous, sodium hydroxide solution and 200 ml of ether, shaken,

light yellow oil. This oil was dissolved in 80 ml of ether, 35 The aqueous phase was separated and filled with 200 ml

2.5 ml of glacial acetic acid were added to this solution, and the ether was extracted. The ether solutions became the

resulting solution stirred until it became homogeneous. Washed three times with 100 ml of water each time,

This solution was then combined with water to make 200 ml and dried over magnesium sulfate. then

diluted and extracted twice with 200 ml of ether each time. the ethereal solution was concentrated to 40 ml and

The ether solutions were added sequentially twice ₄₀ 1.2 ml of glacial acetic acid. The crystallization

Washed with 150 ml of water each time and this washing medium was left to stand for several hours and

add water to the original aqueous extract - the crystalline acetic acid salt (1.0 g) by filtration

joined. The aqueous solution thus obtained, which is collected on a sintered glass filter. Recrystallize

containing acetic acid salt of the amine, 200 ml from a methanol-ether solution yielded 758 mg of the

5% strength sodium hydroxide solution added to ^it with ₄₅ acetic acid salt of oa-amino-Soc ^ Ä-cycloandro-

Ether extracted. The ethereal solution was with stan-17-on with [α]! ³ = + 124 ° (1% iie solution in

Washed water, dried over magnesium sulfate (methanol),
and the ether evaporated, with 2.83 g of 6a-amino-

17-ethylenedioxy-3 ", 5" -cycloandrostane remained _{c) 6} ". Amino-3"_> 5flW ^ cloandrostaii-17-one
identified by the infrared spectrum and identified by 50

Conversion into other derivatives was characterized. j) _{as the} acetic acid salt of Example 2, b) (505 mg)

was with a mixture of 200 ml of ether and

c) OEA acetamido 100 ml of 5 ° / oig ^he shaken sodium carbonate solution.

17-ethylenedioxy-3 <x, 5 «-cycloandrostane ψ? aqueous phase was separated and with 200 ml

55 ether extracted. The ethereal solutions were

One made from 1.6 g of 6 "-amino-17-ethylenedioxy-3", 5 "-cy- three times in sequence with 100 ml of water each time

cloandrostan from Example 1, b), 36 ml of pyridine and wash, combined and over anhydrous magnesium

12 ml of acetic anhydride prepared solution was sulfate dried. The ether was evaporated and

left to stand overnight at room temperature. the residue crystallizes as pentane, with 390 mg

The solution was then poured into 400 ml of water. 60 6 "-amino-3", 5 "-cylloandrostan-17-one, F. 67 bis.

and the precipitated white solid on a 70 ° C was obtained. Recrystallize from pentane

Sintered glass filter filtered off. This material was produced in an analytical specimen, m.p. 70 to 72 ° C. The

200 ml of chloroform taken up, the chloroform analysis corresponded to the empirical formula C ₁₉ H ₂₉ ON. solution washed twice with 100 ml of water each time and

dried over magnesium sulfate. The chloroform 65 φ 6 "-Acetamido-3a, 5" -cycloandrostan-17-one
was evaporated and the residue from a

Ether-pentane solution crystallized and recrystallized A solution of 285 mg ßix-Aanno-S / x ^ ix-cyclo-

siert, with 6 "-Acetamido-17-äthylendioxy-3öi, 5a-cy androstan-17-one in 6 ml of pyridine, 2 ml of vinegar

5 6

acid anhydride added. This solution became Example 5

Let stand for 16 hours at room temperature and add 6 «-propionamido-

then diluted with water and extracted with ether. 17-ethylenedioxy-L, 5 _Ä -cycloandrostane
The Atherextrakt was successively with small

Amounts of water, dilute hydrochloric acid, 5 The procedure of Example 1, e) was repeated, except that 14 ml of pro was washed. The ethereal solution was dried over magnesium anhydride instead of 5 ml of acetic anhydride and concentrated, using 331 mg. It was obtained oa-Propionamido-n-äthyrohen oa-Acetamido-Sa ^ a-cyloandrostan-IV-one obtained dioxy-Sa.Sa-cycloandrostane, which were obtained by th. Recrystallization of this material from io its infrared absorption spectrum and the elemen-acetone - ether yielded large crystals, m.p. 90 to 95 ° C. taranalysis was identified. The latter corresponded to the after drying in vacuo, the solvent-empirical formula C ₂₄ H ₃₇ O ₃ N.
free, pure, oa-acetamido-Sa ^ a-cycloandrostan-17-one, m.p. 117 to 134 ° C, obtained, [«] f = + 164 °

(1% rg ^e solution in chloroform). The infrared spectrum 15 examples
corresponded to the functional groups present

and the elemental _{analysis of the empirical formula a} ) 6 / S-amino-17-ethylenedioxy-3Ä, 5a-cycloandrostane
C ₂₁ H ₃₁ O ₂ N.

e) Alternatively, oa-Acetamido-Sa ^ oc-cyloandro- A mixture of 15 g of 3 /? - p-toluenesulfonoxy-17-ethy-

stan-17-one by hydrolysis of ooc-acetamido-20 lendioxyandrost-5-en, which is described in Bull. Soc. Chim. France,

17-ethylenedioxy-3a, 5a-cycloandrostane of Example 1, 1960 p. 268, and 60 ml of liquid

c) according to the example 6 below, c) ammonia was in a pressure vessel for 15 hours

described method produced. The resulting heated to 100 ⁰ C. Then the mixture was

Product was crystallized from ether-acetone and cooled and excess ammonia evaporated

provided 6 "-acetamido-3", 5 "-cycloandrostan-17-one, 25 left. The residue was washed with 300 ml of ether

that in all respects with that obtained by acetylating and 200 ml of 5% aqueous sodium hydroxide

6α-amino-3 ", 5" -cycloandrostan-17-one obtained Pro- shaken. The aqueous phase was separated off and

product was identical. extracted with 200 ml of ether. The ether solutions

were washed separately with water, combined,

Example 3 ³ ° ^u ^ ^er anhydrous magnesium sulfate and dried

the solvent evaporated, leaving 9.4 g of an oil

6 "-p-nitrobenzamido- remained.

3 ", 5" -cycloandrostan-17-one This crude product was in a mixture of

30 ml of methanol and 3 ml of glacial acetic acid dissolved and the

A mixture of 231 mg of the acetic acid salt 35 solution with 300 ml of ether and 200 ml of water is

from Example 2, b), 330 mg of p-nitrobenzoyl chloride, 5 ml shakes. The aqueous layer was separated and

Benzene, 5 ml of water and extracted 15 ml of 5 ° / _o aqueous with 200 ml of ether. The ether solutions

Sodium hydroxide was used for 90 minutes at room- were sequentially three times with 100 ml of water each time

temperature stirred. Then the mixture was washed and the wash waters to the original

Ig 30 ml of 5% aqueous sodium hydroxide and 40 ^is added to the aqueous extract.

45 ml of benzene added. The organic layer The aqueous solution thus obtained, which the water was separated, washed with water, contained over a soluble mixture of acetic acid salts, was dried with magnesium sulfate and the solvent was evaporated off 300 ml of ether and 200 ml of 5% aqueous sodium. Recrystallize the residue from hydroxide shaken. The aqueous phase was separated from an ethanol-water mixture yielded 214 mg of 6 "-p-45 and the ether solution with water ge-nitrobenzamido-3a, 5" -cycloandrostan-17-one, which was washed and dried over magnesium sulfate. The 164 to 166 ⁰ C melted and a \ tx \ f - + 101 ° ether was evaporated and left 6.9 g of a (1% solution in chloroform). The crystalline residue found. Recrystallization of these analytical values corresponded to the empirical material from pentane yielded a first crystallization formula C ₂₆ H ₃₂ O ₄ N ₂ . 50 of 2.4 g of 6jS-amino-17-ethylenedioxy-3a, 5 «-cycloandro-

stan, F. 100 to 110 ⁰ C. Further recrystallization of the

Example 4 Product from pentane also provided the pure amine

a melting point of 108 to 110 ⁰ C and one

6a-p-Nitrobenzamido- [a-jf = + 18 ° (l ^o / _o solution in chloroform). the

17-ethylenedioxy-3 ", 5" -cycloandrostane 55 Analysis results corresponded to the empirical formula C ₂₁ H ₃₃ O ₂ N.

6a-amino ₄ 17-ethylenedioxy-3a, 5 «-cycloandrostane The mother liquor of the above crystallization was further-

according to Example l, b) was processed at room temperature, with another 6 ^ -amino-17-äthylendioxy-

a mixture of 5% aqueous sodium 3 «, 5a-cycloandrostane after removal of the isomers

hydroxide, benzene and excess nitrobenzoyl 60 3a- and 3/3-amino-17-ethylenedioxyandrost-5-ene, the

chloride stirred. The benzene solution was separated when by-products were obtained

washed with water, over anhydrous magne- The 3/3-amine was in the form of its acetic acid salt

sium sulfate dried and. the solvent is separated off by crystallization from methanol. That

steamed. The residue was extracted from ethanol-water and the acetic acid salt of the 3'-amine.

recrystallized and gave pure 6a-p-nitrobenzation 65 separated from ether-pentane. The isomers

amido-17-ethylenedioxy-3a, 5a-cycloandrostane. The EIe-3-amino compounds are different from that

mental analysis corresponded to the empirical formula 6 / S-amine due to its low optical rotation and

C ₂₈ H ₃₆ O ₅ N ₂ . their nuclear magnetic resonance spectra.

Claims (1)

h) 6β Acetamido According to the in the previous examples 17-ethylenedioxy-3 _a , 5 "-cycloandrostane wrote the ^ aminosteroids of the Examples 6, a) and d) m the following compounds are converted to a solution of 1.03 go / I-amino-IV-ethylene-:
dioxy-3 «, 5a-cyloandrostane from Example 6, a) in 25 ml 5 8 ml of acetic anhydride were added to pyridine. o / Sp-Nitrobenzarnido-n-ethylenedioxy-This solution was left to stand for 24 hours at room temperature and then shaken with 250 ml.
Water and 250 ml of ether. The ether solution was o ^ -propionamido-Sa.Sa-cycloandrostan-n-one; worked up by the method of Example l, c) io o / S-p-nitrobenzamido-Sa ^ a-cycloandrostan- and the resulting o ^ -acetamido-IV-ethylenedioxy-17-one.
3 ", 5" -cycloandrostane from benzene — Skellysolve B (Trade name for a mixture of hexanane) recrystallized in the compounds that can be prepared according to the invention in a ratio of 1: 1, with 1.05 g of pure being characterized by an extremely favorable ratio of material with a melting point of 158 to 160 ⁰ C 15 of the anabolic to androgenic effect, were received afterwards. The infrared absorption diagram indicated by the ratio of weight gain corresponded to the functional groups of the levator ani (LA) present for weight gain and the analytical values of the empirical formula ventral prostate (VP). The increase in weight of the C ₂₃ H ₃₅ O ₃ N. LA under the action of an anabolically active . . _n . ., “, 20 compound is a desirable one to gain weight c) o / J-Acetamido ^^ - cycloandrostan-lT-one of _{the γρ Μη§6§6η an undesirable} effect. Ge A solution of 504 mg oß-Acetamido-n-Ethylen- heimlich results in anabolically active compounds dioxy-3a, 5 «-cycloandrostane in 50 ml of ether, an increase in the weight of both muscles in one un- at room temperature with 1.0 ml of concentrated chlorine-favorable ratio. The LA / VP ratio of stirred hydrochloric acid. After 15 minutes, 25 compounds according to the invention are in the following 200 ml of water and 150 ml of ether added. The experiments described in the extract correspond to the ratio tion and evaporation of the ethereal solution after the LA / VP with a known, anabolically effective The procedure of Example 7 resulted in 446 mg of crude product. Juxtaposed connection: Rapid crystallization from ether yielded 340 mg. The experiments were carried out with groups of five each 6j5-acetamido-3 ", 5" -cycloandrostan-17-one, which was carried out in 30 rats. The animals were for experimental 140 to 141 ° C melted and a [oc] f = + 79 ° (1% start 21 days old. A comparison group received Solution in chloroform). The substance was not given any anabolic agent. One by its infrared absorption diagram and the group of test animals received oral by 7 days analytical values that correspond to those given for the empirical formula of 5 mg / kg daily 6 ^ -acetylamino-17-ethy- C ₂₁ H ₃₁ O ₂ N calculated corresponding, further character- 35 lendioxy-3 «, 5a-androstane from examples (connection terized. dung a). Another group of laboratory animals jwoa-t / t i j λ η were the same quantities of the d) o ^ -Amino-Sa ^ -cycloandrostan-U-on _{nameQ)> Oxym} etholone «from Parke-Davis and A mixture of 2 g of 6jS-amino-17-ethylenedioxy-Syntex known 17/3-hydroxy-17 «-methyl- 3 ", 5" -cycloandrostane in 40 ml of ether was treated with 40 2- (hydroxymethylene) -5a-androstan-3-one for 7 days 0.8 ml of concentrated hydrochloric acid was stirred. administered orally. On the 8th day, all animals White crystals of the ent- autopsies were formed on standing. speaking hydrochloric acid salt. This was done in the group that received compound A. obtained by decanting the supernatant, the LA showed compared to the untreated severed. Recrystallization of the product from 45 comparison group a weight increase of 37% Water led to pure white crystals of 6 /? - amino and the VP such of 2% · the ratio of Sa ^ a ^ cycloandrqstan-iy-on hydrochloride, which in 262 weight gains LA / VP was therefore 18. melted to 264 ° C with decomposition and a "In the case of the known compound, the weight [oi \ ² o - + 81 ° (1% solution in methanol) showed. increase in LA compared to untreated A mixture of 2 g of this hydrochloride, 50 ml 50 equal group 52% ^and the weight gain of the Methanol, 250 ml ether and 200 ml 5% aqueous VP 199%. The ratio of weight gains Sodium carbonate was shaken and then the LA / VP was therefore 0.26. Layers separated. The organic layer gave results similar to Compound A washed with water, over magnesium sulfate with o / ^ amino-n-ethylenedioxy-SoCjSa-cycloandrostane dries and concentrated to a volume of 15 ml. 55 from Example 6, a) achieved when this rat After adding 1 ml of glacial acetic acid and cooling, the borrowed doses of 3 mg / kg in vegetable oil were subcutaneous acetic acid salt of ö ^ -amino-SöCjSa-cycloandrostan- was administered. 17-one obtained, which ^{melted at 125 to 126 0} C and from these results it can be seen that the [a] f = + 72 ° (1% solution in methanol). bonds according to the invention a desirable The free base o-ßAmino-SajSoc-cycloandrostan- 60 stimulating effect on muscle growth, at At the same time, 17-one became almost negligibly less androgenic by shaking the above acetic acid Salt with cold 5% aqueous sodium hy- effect, from which their superior therapeutic droxyd and ether received. This connection was resulting in table effect,
as in previous examples worked up and melted after recrystallization from pentane at 100 to 101 ° C 65 claim:
and showed [«]? = + 112 ° (1% solution in chloro- ' shape). The analytical values corresponded to those for processes for the preparation of 60c- or 6ß-ami- calculated the empirical formula C ₁₈ H ₂₉ NO. nosteroids of the androstane series of the'general formula NHR wherein R is a hydrogen atom or an acyl group and Y is an oxygen atom or a residue of formula - O (CH ₂ ) "O - means in which η = 1 or 3 and the alkylene chain can be substituted by methyl, or its hydrochloride, characterized in that, if the NHR group is in the position to the steroid structure, a 17 is made according to methods known per se -Alkylenedioxy-3 ″, 5 ″ -cycloandrostan-6-one heated with excess hydroxylamine, the δ-oximino-lT-alkylenedioxy-Sa ^ a-cycloandrostane obtained is separated off and reduced in alcoholic solution in the presence of an alkali metal, whereupon one 10 the resulting 6 "-amino-17-alkylenedioxy-3", 5a-cycloandrostane isolated from the reaction mixture and, if appropriate, acylated on the 6'-amino group in a manner known per se, if appropriate the amino or the N-acyl compound with aqueous acid on the 17-ketal group to the oxo group saponified, the oxo compound in the form of its hydrochloride or as a free base, if appropriate after conversion into the acetic acid salt, isolated and optionally the amino compound on the 6 "-amino group acylated or that if the NHR group is in ^ -position to the steroid structure is, by methods also known per se, a sulfonic acid ester of 3 /? - Hydroxy-17-alkylenedioxy-androst-5-ene treated with ammonia, the o / J-amino-SajSa-cycloandrostane-17-one-ketal obtained isolated and this optionally acylated on the 6/3 amino group, optionally the amino or the N-acyl compound with aqueous acid on the 17-ketal group to the oxo group saponified, the oxo compound in the form of its hydrochloride or as a free base, if necessary after Conversion into the acetic acid salt, isolated and optionally the amino compound on the 6 ^ amino group acylated. Considered publications:
U.S. Patent Nos. 3,000,910, 3,009,925;
Chem. Soc., 1957, p. 906 ff. A priority document was displayed when the registration was announced 609 580/440 6.66 © Bundesdruckerei Berlin