BE564226A - - Google Patents

Description

       

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   The present invention relates to improvements to organic compounds, in particular to the preparation of
 EMI1.1
 21-alkylated derivatives of 17 p-hydroxy-17c "pi'egn-20-ynes9 which are of value because of their progestational properties or as intermediates in the preparation of compounds having useful progestational properties.



   An aim of the present invention is to provide pharmaceutical and veterinary preparations of novel derivatives.
 EMI1.2
 21-alkylated 17-hydroxyl7 n -pregn-20-ynest

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 According to the present invention. we precure: derivatives
 EMI2.1
 21-alkylated 17 # -hydroxY-17-prregn-20-ynes having the general formula:
 EMI2.2
 wherein R is a confident alkyl group of 1 to 8 carbon atoms.



   The new compounds can be 21-alkya derivatives
 EMI2.3
 17 -hydroxy-17 0 -pregn-4-en-p-yn..3.one and 17 -hydroxy-6-methyl-17 lX -pregn-hèn-0-yn-3..onee ..



   The present invention provides the following new compounds:
 EMI2.4
 3j $, 17 -dihydroxy21-methyl-l7at-pregn-5.èn-0-yne, 3, 17 dihydrocy.21.-éthyl-17 c -pregn.5-en.0.-yne 6 @ 21.-Dimethyl-17 c -pregn-O.yne-3 5,17 / 2 '-triol, 5c, 17 & -dihydroxy-6, 21-d1mêthYl-17D: -pregn20..yn-3-one, the 21-ethyl-b J -methyl-17-0 -pregn-20-yne-3 p a5 (,, 17 -triol, 5 cc, 17 f> .dihydrocy-21-ethyl-6 -methyl-17 (- prregn-20-yn-3-one and, 6,21-dimethyl-17 aC -pregn-5.èn-2..yne-3 tl7 -diol which are useful as intermediates in the preparation of compounds having properties. useful progestational drugs.



   The present invention also provides the following novel compounds
 EMI2.5
 17 -hydroxy-21-methyl-17Ct -pregn..t-en-2 (ï-yn-3-ine, 9, 17j $ -hydroxy-xl-ethyl7-17 # -pregn4-en-20- yn-3-one,

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 EMI3.1
 6 0, 21-dimethyl.-17 -.hydroxy-l'J c -pregn..lèn-.Uyn-.3..one, 21-ethyl-17 -hydroxy-6 c (-methyl-17 o '-Pregn-4-en-20-yn-3-one which are valuable because of their progestational properties.



  The last two are especially remarkable in this respect; they were found to be about 9 and about 12 times more effective than ethisterone when administered orally in the Glauberg test. They therefore find application in the treatment of symptoms arising from the syndrome known as premenstrual tension. They can also be used to counteract the overestrinization occurring in patients with persistent menorrhagia and to ensure the establishment of normal progestational effects in the uteri of women with secondary amenorrhea.



   According to the present invention, there is further provided a process for preparing 21-alkyl derivatives of 17 ss -hydroxy-.
 EMI3.2
 17 0 (-pregn-20-ynes having the general formula
 EMI3.3
 
 EMI3.4
 starting from 17 j) -hydroxy-17 (-pregn-0-ynes having the general formula:
 EMI3.5
 

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 This process comprising protecting the 17 ss -hydroxyl group from the 17 ss -hydroxy-17oC -pregn-20-yne by converting it to an ether, alkylating the ethynyl group at the 21 'position, and regenerating the 17-hydroxyl group. 'to give the 21-alkyl derivative (I).



   The protection of. 17-hydroxyl group in compounds of the general formula (II) may conveniently be carried out by condensation with vinyl ethers, such as, for example, isopropyl vinyl ether or 2,3-dihydropyran. 2,3 - Dihydropyran is the preferred reagent because it is commercially available.



   Condensation of the compounds of the general formula (II) with 2,3-dihydropyran to give the tetrahydropyranyl ethers & of the general formula
 EMI4.1
 t can conveniently be accomplished by mixing the compound of formula II with an excess of 2,3-dihydropyran, preferably in an organic solvent, such as chloroform or tetrahydrofuran, and in the presence of a catalytic amount of an acidic reagent, such as, for example, hydrochloric acid or phosphorus oxychloride. Purification of the tetrahydropyranyl ether resulting from the general formula (III) is generally not necessary and the raw material can be used directly for the next phase of the process.

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   A 21-alkylation of the tetrahydropyranyl ether of the general formula (III) can be carried out by converting the compound (III) into a metal derivative at C21 and condensing the latter with, for example, a halide or an alkyl sulfate. to give the 21-alkyl tetrahydropyranyl ether of the formula
 EMI5.1
 general: 0-0 0 ", I4e ¯¯¯ c = Cl, 11 1 IV), {The lithium, sodium, and potassium derivatives of compound III are very suitable in this regard. Their formation is easily accomplished by adding compound III to a solution of the metal amide in liquid ammonia.

   Thus, for example, the compound 111 can be dissolved in a solvent, such as ether, and the solution can be added to lithium, sodium or potassium amide in ammonia. liquid, and then a conversion to the metal derivative takes place. An alkyl halide, such as, for example, ethyl bromide or ethyl iodide, is then added to the solution, and the 21-alkyl (IV) tetrahydropyranyl ether is obtained.
Regeneration of the 17 ss -hydroxyl group from compound (IV) to give the desired 21-alkyl derivative of a substituted 17 ss hydroxy-17 Ó -pregn-20-yne can be accomplished by methods well known to those skilled in the art. this domain This is how, for example,

   that a 17 ss -hydroxyl regeneration can be accomplished by treating the 21-alkyl tetrahydropyranyl ether with an acidic reagent, such as, for example, hydrochloric acid, toluene-p-sulfonic acid or oxalic acid,

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 in a solvent, such as ethanel, either at room temperature or under reflux conditions, depending on the nature of the substituents in 21-alkyl tetrahydropyranyl ether.



   The method of the invention can be applied to 17 fi; hydroxy-17 Ó -pregn-20-ynes (1) containing a series of substituents and unsaturated bonds in the molecule, as will be understood by those skilled in the art. Such substituents may include, for example, exe, hydroxyl groups (in addition to the C17 hydroxyl group). phenolic-hydroxyl and methyl.

   By way of example:, methods for providing these unsaturated bonds and additional substituents are as follows: (i) isolated unsaturated bonds, for example at 9,11; they do not in general interfere with the process of the invention; (ii) methyl groups, such as, for example, C2, C7, C16; they do not in general interfere with the process of the invention;

   (iii) hydroxyl groups, such as, for example, C5, C6, and C11 and phenolic-hydroxyl groups; groups are conveniently protected by conversion to tetrahydropyranyl ethers concurrently with the conversion of the 17 ss -hydroxyl group (see formula II) to tetrahydropyranyl rether (see formula III) and then regenerated. Thus, for example, 6 ss -methyl-17 Ó - pregn-20-yne-3 ss, 5Ó, 17ss -triol (V) can be converted to tritetrahydropyranyl ethers (VI and VII)
 EMI6.1
 

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 EMI7.1
 namely: the ether (VI: Ro 9 R.

   H), which can be further 21-alkylated, for example by the action of ethyl iodide on its lithium derivative to give the tetrahydropyranyl ether 21-
 EMI7.2
 alkylated; ether (VI; R - alkyl; Re m nose), which gives, on treatment with dilute oxalic acid, the desired 2l-alkyl-17-pregn-20-yne-3,5 Ó, 17 -triol ; and ether VII R-alkyl).



  (iiii) oxo groups
 EMI7.3
 Oxo groups can conveniently be protected, for example. by formation of ketal or enol ether, and then regenerated Thus, for example, 17-hydroxy-6 (-methyl-17c (- prégn-4-en-20-yn-3-one (VIII) can be converted to the ethylenic ketal (IX and X).
 EMI7.4
 
 EMI7.5
 namely the ketal (IX: R a R = H) which can then be condensed with 2,3-dihydropyran to give ether ketal tetrahydro-
 EMI7.6
 pyranylic; the ketal (IX: R - H; RI a ¯ [j) which is then alkylated to give the 21-alkylated derivative; ketal (IX: R = alkyl;

   Ru "Jt. J) which, by treatment with dilute ethanpli-1 oxalic acid, leads to the regeneration of the 17 ss -hydroxyl group and
 EMI7.7
 the 3-oxo group to give the desired 21-alkyl-17 ahydroxy-6 C6 -methyl-17 .pregn -.- en-0-yn-3 one; and the ketal X (R a alkyl).



  The invention therefore also provides a process for the preparation of 21-alkyl derivatives of 17 r, -hydroxy-17c <: - pregn-20-ynes having the general formula 1 above, in which

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 R is an alkyl group containing 1 to 8 carbon atoms, which process comprises converting a 17 -hydroxy-17 o (-prregn-
 EMI8.1
 20-yn-3-one to a 3,3..ethylenedioxy derivative, condensation of the riveted 3,3-ethylenedioxy with 2,3-dihydropyran to give a 17 ss -tetrahydropyranyl ether of the 3,3-ethylenedioxy derivative, the alkylation of this ether to give a 21-alkyl derivative,

   and treating this 21-alkylated derivative with dilute ethanolic oxalic acid to regenerate the 17 ss -hydroxyl group and the
 EMI8.2
 3-oxo group and give the desired 21-alkyl-17-hydroxy-17 0 \ -prregn-20-yn-3-one.



   Pharmaceutical preparations of some of the new
 EMI8.3
 calves 1-alkyl-17 -hydroxy-17 0 -pregn-o-Ynes (I), and in particular particular pharmaceutical preparations of 6 0 (1-dimethyl-17.-hydroxy-17 G -pregn-4-en- 20-yn-3-one and 21-ethyl-17 -hydroxy-6 çl -methyl-17 et -prêgn-4-en-20-yn-3'-one. Can take the form of tablets, tablets, capsules, tablets for sublingual absorption, elixirs, injections and suppositories.



  These materials can be associated with solid or liquid supports. The compositions may comprise the steroid mixed with compatible solid diluents and / or tablets forming aids, such as, for example, lactose, starch or magnesium stearate.



   Methods of carrying out the invention are described below by way of example.



   EXAMPLE 1
 EMI8.4
 17 vâroxv-1-méthvl-1 -préKn -.- en-20-yn-3-one having the formula:
 EMI8.5
 

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 in which R - CH
3 Process (a)
 EMI9.1
 A solution of 3 /, 17 -dihydroxy-17 Q-prregn-5- en-20-yne (10 g) in tetrahydrofuran (85 ml) was mixed with 2,3-dihydropyran (25 ml) then with 1 Phosphorus oxychloride (0.2 ml).

   After 2.5 hours the mixture was poured into water (2 L) and the solids obtained were collected and crystallized from aqueous acetone with a trace.
 EMI9.2
 of pyridine. -3 al7 bis.-tetrahydropyranyl ether of 3 0.17 fJ. -dikydroxy.l7 c '-pregn-5-en-20-yne had a point of 21.

   fusion of l3 --17tC 'a - of -120 (c, 0.61 in chloro-
Formal D
The above compound (4.1 g) in dry ether (165 ml) was added dropwise over a period of one hour to a stirred solution of ferric snow (0.2 g) and lithium (0, 45 gr) in liquid ammonia (110 ml) maintained at a temperature between -35 ° C and -40 ° C. After stirring for a period of two and a half hours, a solution of methyl iodide (11 ml) was added in dry ether (50 ml) over a period of 30 minutes, and stirring was then continued for 3 hours. Ammonium choride (5 g) was added to the mixture, and the ammonia was allowed to evaporate.

   The product isolated with ether was triturated with methanol to give a
 EMI9.3
 material having a melting point of z20 - 15 C. This material (400 mgr) in ethanol, (50 ml) was treated with toluene-p-sulfonic acid (150 mgr) and the mixture was heated for 30 minutes in a boiling water bath. Concentration followed by the addition of water gave a solid which was purified with medium.
 EMI9.4
 aqueous thanol. 3%, 17 -hydroxy-21-methyl-17 <y-prregn-5-en.



    20-yne formed plaques with a melting point of 177 to 179 ° C, [Ó] 20 of -124 (ci 1 in chloroform).



   D.

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   The preceding compound (1.2 g) was dissolved in a mixture of toluene (100 ml) and cyclohexanone (40 ml) and the solution was distilled until 30 ml of distillate was collected. Aluminum isopropoxide (5g) in toluene (20ml) was added and the mixture was heated under reflux for 1 hour. After washing with dilute sulfuric acid, the solvents were removed by steam distillation and the product was isolated with ether. The benzene solution was filtered through a short column of alumina.

   A purification starting from a mixture of equal parts of acetone and he-
 EMI10.1
 xane gave 17 fb Ahydroxy2lretkyl-1.7 C -pregn-Y-en-20-yn-3-one in microneedles, melting point Z50 151-0
22 [Ó] D of 11 (c, 0.53 in ethanol).



  Method (b)
 EMI10.2
 A solution of 17-hydroxy-17 .pregn..l --- n-20.yn 3-one (r) in a mixture of benzene (110 ml) and ethenic glycol (6 ml) was distilled to what the distillate is
 EMI10.3
 more cloudy. Then, toluene-p-sulfonic acid (0.1 g) was added and the mixture was heated under reflux for 4 hours. The product which separated on cooling was crystallized with aqueous pyridine to give 3,3-ethylene-.
 EMI10.4
 dioxy-17 -hydroxy l'7 0 (-pregn-5-en-20gyne in soft plaques, melting point 236 "- 259-Ct [<3 (] 25 of - 690 (c, 0.75 in pyridine).



   The previous compound (3.8 gr) in tetrahydrofuran
 EMI10.5
 (200ml) was treated with 2,3-dihydro-pyran (10ml) followed by phosphorus oxychloride (0.08ml). After 2.5 hours the mixture was poured into a dilute aqueous solution of sodium bicarbonate, in which the solids were purified in aqueous acetone containing a trace of pyridine. Ether 17 fi ...
 EMI10.6
 3,3-ethylenedioxy-17 hydroxy tetrahydropyranyl 1? <Y-

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   pregnant-5-en-20-yne had a melting point of 170 - 174 C and a
22 [Ó] 22 of -92 (c, 0.77 in pyridine).



  D
The preceding compound (4 g) in dry tetrahydrofuran (100 ml) was added dropwise over a period of one hour to a stirred solution of ferric nitrate (0.2 g) and lithium (1.55 g) in liquid ammonia (400 ml) maintained at a temperature between -35 and -40 ° C. After stirring for 2 and a quarter hours, a solution of methyl iodide (11 ml) in dry ether (50 ml) over a period of 30 minutes and stirring was then continued over a further period of 2 hours 45 minutes. Ammonium chloride (5 g) was added to the mixture and the ammonia allowed to evaporate.

   The product isolated with ether was triturated with ethanol to give material with a melting point of 145-146 C, which was purified with aqueous acetone containing a trace of pyridine.



  17 ss-3,3-ethylenedioxy-17ss-hydroxy-21-methyl-17 Ó -pregn-5-en-20-yne tetrahydropyranyl ether formed needles
22 with a melting point of 148-149 C and a [Ó] .. of -84 (c, 0.99 in pyridine). D
The preceding compound (200 mgn) in ethanol (20 ml) was treated with 25% aqueous oxalic acid (10 ml) and the mixture was heated under reflux for 45 minutes. Dilution with an equal volume of water (30 ml) gave a small amount of crystalline material which was removed by filtration.



  Further addition of water to the filtrate gave plates with a melting point of 100-104 C, which were purified with acetone / hexane. The 17 ss-hydroxy-21-methyl-17 Ó prégn-4-en-20-yn-3-one separated into prismatic needles, with a melting point of 151 to 152 c, not lowered on a mixture with a specimen prepared by method (a) above.

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  EXAMPLE 2
 EMI12.1
 % 1-Ethyl = i? li -hydroxy-17 Qt -pré; n-4.-en-20 '"" il1-3-one (formula XI) (R - Czars) Process (a)
A solution of 3ss ether, 17 ss -bis-tetrahydro-
 EMI12.2
 . 3p, 17 I -dihydroxy17 Ot -pregn - $ - en-20-yne pyranyl (6 gr) (prepared as described in method a of Example 1) in dry ether (100 mL) was added dropwise drop over a period of one hour to a stirred solution of ferric nitrate (0.3 gr) and lithium (1.1 gr) in liquid ammonia (200 ml) maintained at a temperature between -35 and -40 C.



  After stirring for two and a half hours, a solution of ethyl iodide (21 ml) in dry ether (100 ml) was added over a period of 30 minutes, and stirring was then continued over a period of 30 minutes. period of 3 extra hours. Ammonium chloride was added to the mixture, and the ammonia was allowed to evaporate. The product, isolated with ether, was dissolved in ethanol (60 ml) and heated under reflux for 30 minutes with toluene-p-sulfonic acid (0.6 g). The product was isolated with ether and crystallized with acetone / hexane,
 EMI12.3
 and then the 917 P -dihydroxy-21-ethyl-17 0 (-pregn-5-en-20 '<yne separated: in fine needles with a melting point of 78 -
2280 C and a [cc] ... of -107 (c, 0.4 in pyridine).



  D
The preceding compound (1 g) was dissolved in a mixture of toluene (80 ml) and cyclohexanone (32 ml) and the solution was distilled until the distillate was no longer cloudy.



  Aluminum isopropylate (4 g) in toluene (16 ml) was added and the mixture was heated under reflux for 20 minutes. The product was isolated in the usual manner and its solution in benzene was subjected to chromatography on alumina. 21-ethyl-17 -hydroxy-17 Ó -prregn-4-en-20-yn-3-one se

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 crystallized from acetone / hexane in plates with a melting point of 118 - 12U C and a [Ó] 23 of + 12 (c, 0.74 in
D ethanol).



  Method (b)
17 ss-3,3-ethylenedio- tetrahydropyranyl ether
 EMI13.1
 xy-17 -hydroxy-170 '-pregn-5-en-20-yne, prepared as described in process (b) of example 1, was ethylated by a process similar to the methylation process described in process (b ) of Example 1, to give 17 ss -tetrahydropyranyl ether
 EMI13.2
 of 2l-ethyl-.3, .3-ethylenedioxy-17 p -hydroxy 1? Lk '-pregn-5-en-20-yne which crystallized in acetone containing a trace of pyridine, in needles with a melting point of 120 - 121 C and
21 ..... a [Ó] of -105 (c, 1.01 in pyridine).



   The preceding compound (2g) in ethanol (200ml) was heated under reflux with 2% aqueous oxalic acid (100ml) for 55 minutes. The product was isolated with ether and its solution in benzene was filtered through a
 EMI13.3
 column of lumina. 1-Ethyl-17 -hydroxy-17- -Pregn-4-en-20-yn-3-one crystallized from acetone / hexane in plates of melting point 118 - 119 C, not lowered. , when mixed with a specimen prepared by method (a) above.



   EXAMPLE 3
 EMI13.4
 2L-n-Propyl.-17 -hYdroXY-17çX -présn-Y-en-20-Vn-3-one (. Formula XI) (R = normal propyl) Method (a)
A solution of 3 ss, 17 ss -bis-tetrahydropyra- ether
 EMI13.5
 3 / $, 17 -dihydroxy-17 <X -prregn-5-en-20-yne (8 gr) (prepared as described in method a of Example 1) in dry ether (200 ml) ) was added dropwise over a period of one hour to a stirred solution of ferric nitrate (0.2g) and lithium (1.5g) in liquid ammonia (300ml)

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 maintained at a temperature between -35 and -40 ° C. After stirring for 2.5 hours, a solution of normal propyl iodide (13.5 ml) in dry ether (100 ml) was added to a period of 30 minutes and stirring was then continued for a further 3 hours.

   Ammonium chloride was added to the mixture and the ammonia allowed to evaporate. The product, isolated with ether, was dissolved in ethanol (80 ml) and heated under reflux for 30 minutes with toluene-p-sulfonic acid (0.8 g). The product was isolated with ether and crystallized from ethe / petroleum ether, and then the
 EMI14.1
 3 A 17 Normal P -dihydroxy-21-propyl-17 ± y -pregn-5-en-20-yne separated into fine needles with a melting point of 70 - 71 C and a --- of 110 (c, 1.002 in chloroform).



   D
The preceding compound (1.2 g) was dissolved in a mixture of toluene (100 ml) and cyclohexanone (40 ml) and the solution was distilled until the distillate was no longer cloudy. Aluminum isopropylate (5 g) in toluene (20 ml) was added and the mixture was heated under reflux for 20 minutes. The product was isolated in the usual manner and its solution in benzene was subjected to chromatography.
 EMI14.2
 on alumina.

   21-n-propyl 17 J -hydroxy-17-prregn-4-en-20-yn-3-one crystallized from acetone / hexane in long prisms with a melting point of 84-86 C. (b)
The 17 ss-3,3-ethylene-dioxy-17 -hydroxy-17 Ó -pregn-5-en-20-yne tetrahydropyranyl ether, prepared as described in process (b) of Example 1 was n-propylated by a process similar to the methylation process described in process (b) of Example 1, to give 17 ss -tetrahydropyranyl ether
 EMI14.3
 3,3-ethylenedioxy-17fi -hydroxy-21-n-propyl-17Q ('-pregn-5-en-20-yne which crystallized with acetone containing a trace

 <Desc / Clms Page number 15>

 of pyridine, in needles with a melting point of 104Ó - 106 C and
25 of a [Ó] D of 134 (c, 1.07 in chloroform).



   The protecting groups present in the preceding compound were removed with aqueous ethanolic oxalic acid under the conditions described in process (b) of Example.
 EMI15.1
 ple 2, to give 17 () -hydroxy-21-n-propyl-17CC -pregn-4- en-20-yn-3-one which crystallized from acetone / hexane in
 EMI15.2
 dense prisms with a melting point of 860-870e and a 10] - 27
D of +8 (c, 0.72 in chloroform).



     EXAMPLE 4
 EMI15.3
 21-n-Eutyl-17 -hydroxy-17o (. -Présn-h-en-2Ù-Yn-3-one (formula XI) (R = normal butyl)
Ether 17 ss -etrahydropyranyl 3,3-ethylene-
 EMI15.4
 dioxy-17 & -hydroxy-17o (-pregn-5..en-0-yne, prepared as described in process (b) of Example 1 was n-butylated and the crude product was treated with acid aqueous ethanolic oxalic
 EMI15.5
 hot.

   There was obtained al-n-butyl-17 P -hydroxy-17 c <-pregn-i-en-20-yn-3-one which crystallized from ether / light petroleum, in prisms of a point. of fusion of 80 - 81 C and a
21 [Ó] of + 2 (c, 1 in ethanol). d EXAMPLE 5
 EMI15.6
 21-Methyl-19-nor-17 o <'-prena-1 ,,,, 3.5 (1U) -triene-ü-vne-3.17 -diol.
 EMI15.7
 where R = CH3

 <Desc / Clms Page number 16>

 
 EMI16.1
 Or treated 19-.lor-17 0 (-prégna-1, 3,5; (1Q) -trien-20-yne-3,17 ss -diol (2gr) in dry tetrahydrofuran (17ml) and 2, 3-Dihydropyran (5ml) with phosphorus oxychloride (0.04ml). After 2.5 hours at room temperature the mixture was treated with excess of very dilute aqueous sodium bicarbonate and the product was isolated with ether.

   On being crystallized with aqueous acetone containing a trace of pyri-
 EMI16.2
 dine, 1-nar-7.7 qr '3.17 fi -bis-tetrahydropyranyl ether. Pregna-1,3,5 (10) -trien-20-yne-3,17 p -diol formed needles with a melting point of 155-157 C
The preceding compound (1 g) in dry ether (30 ml) was added over a period of 30 minutes to a stirred solution of ferric nitrate (0.05 g) and lithium (0.2 g) in water. Liquid ammonia (50 ml) maintained at a temperature below the boiling point. The mixture was stirred for 9½ hours, methyl iodide (3 mL) in ether (10 mL) was added over a period of 30 minutes and stirring continued for another 3 hours. Ammonium chloride was added and the ammonia allowed to evaporate.

   The product, isolated with ether, was heated under reflux for 30 minutes with toluene-p-sulonic acid (100 mgr) in ethanol (12 ml). Chromatography of the product gave the
 EMI16.3
 21-methyl-19-nor-17 -prea-1,3,5 (10) -tr3.ene-0-yne-3,17 J .. diol which crystallized (as a monohydrate) in par- both aqueous methanol, in plaques with a melting point of 110 ° C and a [Ó] 23 of +30 (c, 0.37 in chloroform).



   D.



   EXAMPLE 6
 EMI16.4
 21-Ethyl-19-nor-17 - ré a-1 10 ..tri.èn-20.- ne- 1 -diol (formula XII) (R - C2H5)
The above compound was prepared by the procedure described in Example 5, ethyl iodide being employed instead.

 <Desc / Clms Page number 17>

 of methyl iodide in the alkylation phase. When it was crystallized with methanol. aqueous, the compound separated as a monohydrate, in prisms with a melting point of
23
 EMI17.1
 80 C and a [c {! ' of -1 (c, O, hS in chloroform).



  D EXAMPLE 7 21-n-Propvl-19-nor-17 ce - ré a-1 lü -triene-n- ne- 1 - diol (formula XII) R = normal propyl)
The above compound was prepared by the procedure described in Example 5, with normal propyl iodide being used instead of methyl iodide in the alkylation phase. On being purified with ether / hexane, the compound formed needles
21 with a melting point of 107-108 C and a [Ó] of -5 (c, 0.33 in chloroform). '
EXAMPLE 8
 EMI17.2
 21-n-Butyl-19-nor-17 c <. -prena-1, 3. 5 (10) -triene-0-ynē, 3 17i -diol, (formula XII) (R = normal butyl)
The above compound was prepared by the procedure described in Example 5, butyl nomal iodide being employed instead of methyl iodide in the alkylation phase.

   The compound crystallized from ether / hexane in needles of a dot
22
 EMI17.3
 of 98 * e and a [µ .. of-3 (c, 0.32 in chloroform).



   EXAMPLE 9
 EMI17.4
 6, nil., 1-dimethyl l'7 -h, ydroxy-17 '-pren-1-en-aU-yn-3-one
 EMI17.5
 (XIII)

 <Desc / Clms Page number 18>

 in which R - CH
3 '
 EMI18.1
 A suspension of 6 P -methyl-17 p (-pregn-20-yne..3, 5c, 17 -triol (1.2 g) in dry ether (10 ml) and 2,3-dihydropyran ( 2 ml) was treated with phosphorus oxychloride (5 drops) After 1 hour, the homogeneous solution was washed with dilute aqueous sodium bicarbonate and water and dried, and the solvent was removed under reduced pressure. The residue (2.25 g) consisted of a clear gum and was used without further purification for the next phase of the process.



   The above product (10 g) in dry ether (150 ml) was added dropwise over a period of 45 minutes to a stirred solution of ferric nitrate (0.4 g) and lithium (2.4 g). ) in liquid ammonia, maintained at a temperature between -30 and -40 0. After stirring for a further 2 ½ hours, a solution of methyl diodide (21 ml) in dry ether ( 100 ml) over a period of 30 minutes, and stirring was then continued for 3 hours. Ammonium chloride (20 g) was added to the mixture, and the ammonia was allowed to evaporate. The product was isolated with ether and obtained as a gum.

   9.2g of product was heated under reflux for 1 hour with oxalic acid dihydrate (10g) in methanol (100ml) and water (10ml). The crystalline product obtained on concentration of the solution under reduced pressure was purified with ethanol: aqueous for
 EMI18.2
 give 6% 21-dimethyl-17 c -pren-20-yne-3. ,, 5 cl, 17/3 - tol in needles with a melting point of 219 to 221 C decompo-
21 sition and a [Ó] of -63 (c, 0.88 in chloroform).



   A solution of the above triol (3.4 g) in pyridine (35 ml) was added to a solution of chromic anhydride (3 g) in pyridine (30 ml) and the mixture was allowed to stand for a period of time. night. The product, isolated with benzene, was crystallized with acetone / hexane to give 5 Ó, 17 -

 <Desc / Clms Page number 19>

 
 EMI19.1
 dihydroxy-6, 21-dimethyl-17q -pregn-2U-yn-3-one in needles
25 with a melting point of 248-250 G decomposition, and a [Ó] D of -45 (c, 0.82 in chloroform).



   A solution of the previous ketone (1.5 g) in ethanol (45 ml) containing concentrated hydrochloric acid (4 drops) was refluxed for 1 hour. The product obtained on the addition of water was purified with methanol
 EMI19.2
 aqueous. 6,21-dimethyl-17 fb -hydroxy.17 1l -pregn..l..èn..20 yn-3-one formed plaques with a melting point of 99-102 C
 EMI19.3
 [Found: C = z; H = 9.6; C23H32028 H2O asks for C = 77.1; H = 9.6% Melting point 88-92 C after drying for 6 hours at 0.1 mm and 80 C (weight loss: Found: 5.1.
 EMI19.4
 CH OH 0. Requires 5.05%)] 'of a [D of + 10 (c, 1.03 in chloroform), max 241 m, log ll-, 16 (in alcohol) .



   EXAMPLE 10
 EMI19.5
 21-Ethyl-17 -hydroxy-60f -methyl-11 0 (- re n- -èn-20- n- -one '(formula XII) (R = ethyl)
 EMI19.6
 To a suspension of 6.-Methyl-17 0 -pregn-20-yne- 3 fi y 5 (x, 17 / -triol (10 g) in dry ether (550 ml) containing 2,3 -dihydropyran (16 ml), phosphorus oxychloride (0.5 ml) was added. After 3 hours at room temperature, the homogeneous solution was washed with dilute aqueous potassium bicarbonate and with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

   The residue (17 g) which was a clear gum, placed in dry ether (20U ml) and tetrahydrofuran (5U ml) was added dropwise over a period of 45 minutes to an amide suspension of lithium (from 3.6 g of lithium) in liquid ammonia (600 ml) containing ferric nitrate -U, 6 g). After stirring for a further period of two and a half hours at -30 to -40. A solution of ethyl iodide (30 ml) in dry ether (150 ml) was added over half an hour, and the mixture was stirred for another 3 hours at the same temperature.

   We added

 <Desc / Clms Page number 20>

 ammonium chloride (20 gr) and the ammonia allowed to evaporate Water and ether were added to the residue, the organic layer was separated, washed with dilute sulfuric acid, aqueous potassium bicarbonate diluted with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. the residue (16.6g) in methanol (150ml) and water (15ml) was refluxed with oxalic acid (15g) for 1 hour. The resulting solution was concentrated under d pressure. picked, diluted with water and extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure.

   Crystallization of the residual gum with aqueous methanol gave 21-ethyl-.
 EMI20.1
 6 -methYl-17Y -pregn-U-yne-3,, 5 ce, 17 -triol in the form of needles with a melting point of 168 - 170 C or 1100 -
 EMI20.2
 11200 (dimorphic forms), and a {¯ 20 of 166.2 (c, 0.72
D ... in chloroform).



   A solution of the above triol (6.7 g) in pvri-dine (70 ml) was added to a solution of cromic anhydride (6 g) in pyridine (60 ml). The mixture was stirred for 2 hours at room temperature and allowed to stand overnight at the same temperature. The product was isolated with benzene and crystallized with aqueous methanol to give 5 Ó
 EMI20.3
 17 di.hydroxyl-ethyl-6 -methyl-17 ty -pregn-0-yn-3 one in the form of needles with a melting point of 225 - 227 C and a
18. ,, ..



   [Ó] of -44.5 (ce 0.892 in chloroform).



   .! A solution of the above ketone (1.5 g) in ethanol (45 ml) containing concentrated hydrochloric acid (4 drops) was refluxed for 1 hour. Concentration of the solution under reduced pressure followed by dilution with water gave a gum which was extracted into ether. The extract was washed with dilute aqueous sodium bicarbonate and with water, dried over anhydrous sodium sulfate and

 <Desc / Clms Page number 21>

 evaporated to dryness under reduced pressure.

   Crystallization of the residual gum with aqueous methanol gave the
 EMI21.1
 1 - ethyl-17 -hydroxy-6 -methyl-17-prregn-4-en-20-yn-3-one in the form of lamellae with a melting point of 74 - .76 0 [Hole vé: 0 " 77.7; H = 9.95; 21II.3l. 2.H20 demands C = 77s35; H at 9.75%; melting point: 70 to 73 C after drying for 7 hours
 EMI21.2
 at 0.1 mm and 55 ° C. (weight loss: Found: 4.95. 24H3402.



  H2O requires 4.85%), [#] D 22 of +17.2 (c, 1.02 in chloro-
 EMI21.3
 shape), #max 241 m, log # 4.18 (in alcohol).



  EXAMPLE 11 1-n-Pro 1-1 -hydroxy-6 .meth 1-1 Ot - re n- -èn-0- n-. one Ether 3 / $ 5, Ó, 17 -tri (tetrahydropyranyl) of
 EMI21.4
 6-methyl-17 Ci (... prreg-0-yne. 3, 0 (, 17 Il; -triol (10 gr) was prepared as in Example 10. A solution of the crude product in dry ether ( 150 ml) and tetrahydrofuran (50 ml) was added over half an hour to a suspension of lithium amide (from 3.6 g of lithium) in liquid ammonia (600 ml), containing ferric nitrate ( 6.6 g), and the mixture was stirred for another two hours at -30 to -40 C. A solution of normal propyl iodide (30 ml) in dry ether (150 ml) was added over a period of time. half an hour,

   and the reaction mixture was stirred for another 3 hours at the same temperature. The crude product, isolated with ether, was refluxed for 1 hour in methanol (150 ml) and water (15 ml) containing oxalic acid (15 g). Concentration of the solution under reduced pressure, followed by dilution with water, gave a gum which was extracted into ether. The ethereal solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

   The gummy product crystallized from aqueous methanol to give
 EMI21.5
 21-n-propyl-6 -methyl-17-prregn-20-yne-3 / e5 5 cX, 17/3 -triol in the form of needles with a melting point of 177 - 179 U or

 <Desc / Clms Page number 22>

 
 EMI22.1
 of 9Z - 94 'C (dimorphic fornia) and a rock] of -46 ,,., 9' (ee.



  0.82 in chloroform). D
A solution of the above triol (700 mgr) in pyridine (10 ml) was added to a solution of chromic anhydride (0.8 g) in pyridine (10 ml) and the mixture was stirred for 1 hour. and a half at room temperature. After standing overnight at the same temperature, the product was isolated from solution with benzene. Evaporation of the benzene extract left a crystalline residue (melting point 185194 C) which, on purification with aqueous methanol,
 EMI22.2
 gave 6..methyl-I-n-propyl3-oxo-171-pregn-0-yne-5r; 17 lamellar diol with a melting point of 176 - 178 C and a
22
 EMI22.3
 fc <T- of 10y7 (c, 0.78 in chloroform).

   Ge product was in. methanol (25 ml) containing dissolved / concentrated hydrochloric acid (2 drops) and the solution was refluxed for 1 hour. Concentration under reduced pressure, followed by dilution with water, give A gum was born which was subjected to chromatography on aluminum in solution in benzene. Elution with benzene gave a gummy fraction which, after crystallization with
 EMI22.4
 aqueous methanol, gave 1-.n-propyl-17 -hydroxy-6 -methyl-17 Q -pregn-t-en-0-yn-3..one as needles having a
14 melting point of 107-109 C, a [Ó] 14 of -22.3 (and 0.81 in. ', D
 EMI22.5
 du- chloroform), Amax 240 me 10.660.



   Preparations of some of the above steroid derivatives. Crits / may take the form of tablets for buccal or sublingual administration, capsules, injections, elixirs and other suitable pharmaceutical forms. The following examples illustrate certain typical formulas which, however, can be modified to an appreciable degree. Thus, with a compound for which the preferred base dose is 0.5 mg, although much larger (eg, at least 2.5 mg) or smaller doses could be expected, the following types of preparation

 <Desc / Clms Page number 23>

 rations can be used to illustrate typical formulas.



   EXAMPLE 12
Tablets
 EMI23.1
 21-Ethyl-17 -hydroxy-6 .methyl-17 c - Pregn-4-en-20-yn-3-one '0.5 mgr Lactose 83 mgr Magnesium stearate 1 mgr Starch from mats (in the form of a paste 10%) a sufficient quantity Dried corn starch sufficient quantity to give 97 mgr.



   The first two ingredients are mixed and reduced to grains with the starch paste, drying at 50 C then being provided, The resulting granules are passed through a 20 mesh sieve and the lubricant (aluminum stearate) is added, together with a sufficient quantity of dried starch to give the required weight. Tablets each weighing 97 mgr are compressed from this mixture.



   EXAMPLE 13
Capsules
 EMI23.2
 1-Ethyl-17 -hydroxy-6 ex -methyl- "17 ex -pregn-4-en-20-yn-3-one 0.5 mgr Lactose sufficient quantity
0.5 mg of the finely subdivided steroid is triturated with: lactose to give a volume of powder that just fills a two piece hard gelatin capsule.



   EXAMPLE 14
Parenteral solution in de. oil
 EMI23.3
 1-Ethyl-17) -hydroxy-6 [X -methyl- 17 Ci. -Pregn -% - èn-20-yn-3-one 0.5 mgr Benzyl alcohol 0.05 ml Ethyl oleate (or suitable oil ) sufficient quantity to give
1 ml.

 <Desc / Clms Page number 24>

 



   The ethyl oleate is sterilized by heating at 160 ° C. for 1 hour and allowed to cool. Benzyl alcohol is added with aseptic precautions. The steroid is dissolved in the hot mixture at about 50 ° C. and the resulting solution is clarified by passing it through a previously sterilized No. 2 sintered glass filter. The filtrate is distributed in suitable containers which are finally subjected to dry heat of 100 ° C. for one hour.



   EXAMPLE 15
 EMI24.1
 6.2l-Dimethv1-17or -pren-5-en-20-vne 3 I .17 -diol
Purified acetylene was bubbled through a CO2 acetone trap and two wash bottles containing concentrated H2SO4 through dry ether (100 ml) into a 1 liter flask fitted with a stirrer with Hg, for 30 minutes.

   A solution of potassium (2 g) in tertiary amyl alcohol (30 ml) (dried by standing over calcium sulfate and distillation over potassium) and 6-methyldéhydroepiandrosterone acetate (2 g) in dry ether (100 ml) and dry benzene (10 ml) were added dropwise over a period of 30 minutes, and stirring was continued for 5 hours with the acetylene continuing to bubble.
The reaction mixture was acidified with a saturated solution of ammonium chloride containing a small amount of hydrochloric acid, and the product was isolated with ether.

   We
 EMI24.2
 obtained crude 6-methyl-17-prreg-5-en-20-yne-3t, 17 f -diol? as a solid with a melting point of 190 - 194 c. Purification with a small volume of methanol gave plaques with a melting point of 203 - 207 C.



   The above diol in dry tetrahydrofuran (10ml) and 2,3-dihydropyran (3ml) was treated with phosphorus oxychloride (0.02ml). The mixture was stored overnight at room temperature and then poured into water.

 <Desc / Clms Page number 25>

 (300 ml) containing a little dissolved sodium bicarbonate. The HUI le thus obtained was isolated with ether and recrystallized from acetone containing a trace of pyridine.

   Bis-tetrahydro ether
 EMI25.1
 6-methyl-17 0 pyranyl (-pregn-5 ... en-20-yne-3, 17 f.> -diol was obtained in the form of fine needles with a melting point of 20
 EMI25.2
 of 178 * - 180 ° This is of a [of -122e20 (c, 0.450 in chloroform).
 EMI25.3
 6-Methyl-17 LX bis-tetrahydropyranyl ether - Pregn-5-en - .. O-yne-3.17 fi-diol (700 mgr) in dry ether (40 ml) was added.

   to a stirred suspension of lithium amide prepared starting from lithium (400 mgr) in liquid ammonia (75 ml) (with an addition of 50 mgr of ferric nitrate) at -35 to - 40 c After stirring for 2.5 hours, methyl iodide (2.5 ml) in ether (15 ml) was added over a period of 25 minutes and then stirring was continued for another 3 hours. . The excess lithium amide was decomposed with ammonium chloride and the ammonia was allowed to evaporate overnight. The product was isolated with ether. Crystallization with aqueous acetone containing a trace of pyridine gave the hydrate of bis- ether.
 EMI25.4
 6,21-dimethyl-17 oc'-pre gn - en-20-yne- tetrahydropyranyl.



  3, 17 -diol in the form of needles with a melting point of
24
 EMI25.5
 160 -161 G and a [1 of -117 (c, Q, 282 in chloroform). ..



  6,21-dimethyl-17 pt-prregn-5..en-0-yne-, 17 / -diol bis-tettahydropyranyl ether dissolved in ethanol (100 ml) was boiled. with a hot solution of oxalic acid dihydrate (1.4 g) in water (50 ml), and boiling was continued for 1 hour. A dilution for. removing cloudiness and long standing gave 6,2i-dimethyl-
 EMI25.6
 17 I, -.pregn-5¯èn-0-yne-3/3, 17 /!) -Diol in the form of needles

 <Desc / Clms Page number 26>

 
22 with a melting point of 164 or 111 to 112 C and a [Ó]
D of -102.6 (ce 0.604 in chloroform).



   EXAMPLE 16
 EMI26.1
 Pharmaceutical preparations from 6, y .21-dimethyl-17 P - hydrox.y-17 '-pré, gn-1-en-0-yn-3-one Preparations of 6 0 (, 1-dimethyl.- The -hydroxy-17-prregn-1-en-0yn-3one, the preferred base dose of which is 5 mg, can take the form of tablets, capsules, powders or other pharmaceutical forms suitable for oral administration. specialists in this field appreciate
 EMI26.2
 Note that the following is given only by way of illustration and that variants can be provided without departing from the scope of the invention.



   Tablets
 EMI26.3
 6 q, 21-Dimethyl-17 / ") -hydroxy-17 pregn-4-en-20-yn-3-one 5 mgr La% ose 81.4 mgr Magnesium stearate 0.972 mgr Corn starch up to 97, 2 mgr
The first two ingredients are mixed and granulated with a 10% starch paste, followed by drying at 50 C.



  The resulting granules are processed through a 20 mesh screen and the lubricant (magnesium stearate is added, along with a sufficient quantity of dried starch to produce the required weight. Tablets each weighing 97.2 mg. are compressed from this mixture.



   Capsules
 EMI26.4
 6 D (, 21-Dimethyl-17 -hydroxp-17 Y. - pregn -% - en-2-yn-3-one 5 mgr Lactose a sufficient quantity
5 mg of the finely divided steroid hormone is triturated with lactose to produce a volume of powder which

 <Desc / Clms Page number 27>

 just fill / a two piece hard gelatin capsule.



    CLAIMS
1. Process for the preparation of 21-alkylated derivatives of 17 ss-hydroxy-17 Ó -pregn-20-ynes of the general formula:
 EMI27.1
 wherein R is an alkyl group containing from 1 to 8 carbon atoms, from 17 ss -hydroxy-17 Ó -pregn-20-ynes, which: protection of the 17/3 - hydroxyl group comprises / of 17 ss - hydroxy-17 Ó -pregn-20-yne by converting it to an ether, alkylation at the C21 position, of the ethynyl group, and regeneration of the 17 ss-hydroxyl group, to give the 21-alkyl derivative.


    

Claims (1)

2. A process according to claim 1 in which the protection of the 17 ss -hydroxyl group is carried out by condensing. tion with vinyl ether, 3. A process according to claim 2, wherein the vinyl ether is 2,3-dihydropybane. 4. A process according to claim 3, wherein 17 ss-hydroxy-17 Ó -pregn-20-yne is condensed with 2,3-di-hydropyran to give a tetrahydropyranyl ether, this is converted to a derivative. metallic C21, and this derivative is condensed with an alkyl sulfate halide to give a 21-alkyl tetrahydropyranyl ether. 5. A process according to claim 4, wherein the tetrahydropyranyl ether is added to a solution of an alkali metal amide in liquid ammonia to form the C21 metal derivative. <Desc / Clms Page number 28> 6.A process according to claim 4, wherein regeneration of the 17 ss -hydroxyl group is carried out by treating 21-alkyl tetrahydropyranyl ether with an acid reagent. 7. A process according to claim 6, wherein the acidic reagent is hydrochloric acid, toluene p-sulfonic acid or oxalic acid. 8. Process for preparing 21-alkylated derivatives of 17-hydroxy-17-prregn-20-ynes having the general formula: EMI28.1 (where R is an alkyl group containing 1 to 8 carbon atoms, which consists of converting a 17 -hydroxy-17 Ó- pregn-20-yn-3-one into a 3,3-ethylenedioxy derivative, condensing this with 2,3-dihydropyran to give a 17 s-tetrahydropyranyl ether of the 3,3-ethylenedioxy derivative, alkylating this ether to give a 21-alkyl derivative, and treating this derivative with acid Dilute ethanolic oxalic acid to regenerate the 17-hydroxyl group and the 3-oxo group and to provide the desired 21-alkyl-17 ss -hydroxy-17 c-prregn-20-yn-3-one. 9. Preparation processes and products obtained by virtue of these processes, as described above.