PL172502B1 - Method of obtaining novel 6-hydroxymethyl-substituted derivatives of 3-keto-4,6-pregnadiene - Google Patents

Abstract

METHOD OF MAKING NEW 6-HYDROXYRAETHYL SUBSTITUTED 3-KETO- DERIVATIVES? -4,6-PREGNADIENE PATTERN 1, PATTERN 1 PL

Description

The subject of the invention is a process for the preparation of new 6-hydroxymethyl substituted 3-keto-A-4,6-pregnadiene derivatives with therapeutic effect.

In particular, the invention relates to a process for the preparation of 3-keto-6-hydroxymethyl-A-4,6-pregnadiene derivatives of formula 1,

Formula 1 wherein R3 is hydroxy, acetoxy or alkyl, R5 is oxyalkyl and hydroxyalkyl, and R4 is 2 hydrogen atoms, keto, methylene or hydroxy.

The 16-position may also be substituted with a methyl, ethyl, or methylene group or be bonded to a carbon-carbon double bond to carbon 17 or carbon 15.

These pregnans may be substituted at the 17α position with a hydroxyl or alkyl group, and at the 17β position with an oxoalkyl or hydroxyalkyl chain, linear or branched.

There are many publications on steroid compounds, the following of which are the closest prior art.

AND). Steroids publication, Vol. 23, No. 4, April 1974, San Francisco, pp. 585-602 relates to the pregnancy promoting and anti-estrogenic effects of certain new 11 β-substituted steroids, especially 1 -β-chloro-19-norprogerterun. The compound may be optionally substituted at the 6-position. For example, it may be substituted with chloro, formyl, fluoro, methyl.

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B). The publication WO-A-85/01504 (Theramex S.A.) relates to a new method for the preparation of 17a-hydroxy-19-norprogesterone derivatives of the formula:

wherein R is a hydrogen atom or an acyl group of an organic saturated or unsaturated aliphatic or cycloaliphatic carboxylic acid. The method consists in treating 3-alkoxy-19-norpregna-3,5,17 (20) -triene with a formylating reagent to obtain the corresponding 6-formylated derivative, reducing it to the 6-hydroxymethylated derivative, dehydrating it by acid treatment to the derivative methylene, isomerization of the latter to the 6-methylpregna-4,6,17 (20) -triene derivative, and then reacting it with a bis-hydroxylating reagent to form the corresponding 17a-hydroxy-19-norprogesterone, which can be acylated by functional action saturated or unsaturated carboxylic acid derivative. The compounds obtained in this process find use in therapy as progestogens or antiandrogens.

C). The subject of the publication W <O - ^ - ^t ^ <0/12027, (Theramex SA.) Are 17α and, if necessary, 21-alkyl derivatives of 6-methyl-19-norpregna-4,6-diene with the general formula:

wherein R 'and R, the same or different, represent a hydrogen atom or a straight or branched chain alkyl radical with 1 to 3 carbon atoms and R 1 is a straight or branched lower alkyl radical with 1-6 carbon atoms. This invention also relates to a process for the preparation of the compounds of general formula (I) and their use as active ingredient of medicaments.

This method consists in etherification of 17α-Ri-3,20-diketo-19-norpregna-4-ene in an acidic environment in order to obtain 17a-R1-3-alkoxy-19-norpregna-3,5-diene, formylation of the obtained enol ether to the corresponding methylated 6-hydroxy derivative, dehydrating it with an acid to give a methylene derivative, and isomerizing the latter to the 17- and, if desired, 6-methyl-19-norpregna-4,6-diene 21-alkylate.

D). WO-A-90/15067, (Theramex S.A.) relates to 3-keto-6-methylestra-4,6-dienes, optionally substituted at the 17-position with an oxoalkyl substituent of the general formula:

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where A is hydrogen or a lower oxoalkyl radical and B is a hydrogen atom, or A is a free or esterified hydroxyl group and B is a lower alkyl or a lower alkynyl radical, or A and B together form an oxygen atom of the keto group. The invention also relates to a process for the preparation of compounds of general formula (I). These compounds are valuable in the synthesis enabling the preparation of pharmacologically active 6-methyl-19-nanoregna-4,6-dienes.

The method consists in subjecting 3-ketoestra-4-ene to etherification in an acidic environment to form 3-alkoxyestra-3,5-diene, formylating it to 3-alkoxy-6-formylester-3,5-diene, reducing it to 3-alkoxy- 6-hydroxymethylated estra-3,5-diene, dehydrating it in an acid medium to form 3-keto-6-methylene estra-4-ene and its isomerization to 3-keto-6-methylestra-4,6-diene.

The resulting compounds have or do not have an oxoalkyl substituent at the 17-position.

E). The description of FR-A-2271883 (J. M. Gastaud) relates to 6-methyl-17a-hydroxy19-norpregna-4,6-dieno-3,20-dione derivatives with the general formula:

wherein R is a hydrogen atom, an aliphatic alkyl of 1-8 carbon atoms, a tetrahydropyranyl group, an acyl group derived from a saturated or unsaturated aliphatic carboxylic acid with at least 12 carbon atoms, and a method of their preparation.

This method consists in subjecting the 17a-acetoxy-3,20-diketo-19-norpregna-3,5-diene to acidic methylation to obtain the 3-methoxy-17a-acetoxy-20keto-19-norpregna-3,5- derivative. a diene, formylating it with Vilsmeier reagent (POCI3), dimethylformamide) to obtain 6-formyl-3-methoxy-17α-acetoxy-20-keto-19-norpregna-3,5-diene, reducing it to the corresponding 6-hydroxymethylated derivative, dehydrating it in acidic medium to 6-methylene-17a-acetoxy-20-keto-19-norpregna-4-ene, and isomerization of the obtained compound to 3,20-diketo-6-methyl-17a-acetoxy-19-norpregna -4,6-diene followed by hydrolysis to 3,20-diketo-6-methyl-17α-hydroxy-19-norpregna-4,6-diene. This compound can be esterified or etherified.

F). WO-A-85/00609 (Research Triangle Institute) relates, on page 9, to a compound of formula (G): 17α-ethynyl-6-methyl-19-norprogestrone.

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The process according to the invention relates in particular to the preparation of the following new compounds:

- 3,20-diketo-6-hydroxymethyl-17a-hydroxy-19-norpregna-4,6-diene or its acetate

- 3,20-diketo-6-hydroxymethyl-17a-methyl-19-norpregna-4,6-diene

The compounds according to the invention exhibit interesting pharmacological properties, in particular strong progestogenic properties. Therefore, they are used as progestogenic drugs for the treatment of menopausal symptoms, such as hot flushes, skin lesions, and circulation problems. They are used in the form of pharmaceuticals intended for parenteral, oral, rectal, transmucosal or transdermal administration. They will therefore be in the form of injection solutions or suspensions in ampoules, auto-syringes or multi-dose bottles; in the form of plain and film-coated tablets, capsules, pills, wafer powders, powders, suppositories or rectal capsules, solutions or suspensions in a polar solvent for transdermal use; creams, gels or ointments and suppositories.

In therapeutic applications, these compounds are administered in a dose of 20 to 50 mg, preferably 5 to 25 mg, per unit dose. The daily dosage is 5 to 200 mg per day depending on the therapeutic indication and the route of administration.

According to the invention, the method for producing the compound of Formula 1 is that an alkyl ketal

Formula 2 wherein R2 is lower alkyl, R3, R4 and R5 are as defined above, treated with a formylating agent of the Vilsmeier-Haack type and the resulting 6-formylated derivative of Formula 3,

Formula 3 wherein R2, R3, R4, R5 is as defined above, is reduced by the action of a mixed alkali metal hydride, and then the obtained hydroxymethyl derivative of Formula 4,

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formula 4 wherein R ', R3, R4, R5 are as defined above, treated with a quinone dehydrating agent in an inert water-miscible solvent, and after decomposing the excess reagent, the hydroxymethyl derivative of formula 1 is obtained.

In the process according to the invention, the quinone dehydrating agent is preferably dibromodicyanobenzoquinone, chloranil, dichloronaphthoquinone or dichlorodicyanobenzoquinone.

The invention is illustrated in more detail by the following example:

Example. Preparation of 17a-acetoxy-6-hydroxymethyl-3,20-diket-19-norpregna-4,6-diene (A) and 17a-hydroxy-6-hydroxymethyl-3,20-diketo-19-norpregna-4,6-diene ( B)

Step 1: Preparation of 17a-acetoxy-3-ethoxy-6-formyl-20-keto-19-norpregna-3,5-diene

A formylating reagent of the Vilsmeier-Haack type was prepared by dropping into 224 ml of dimethylformamide at 2 ° C under nitrogen atmosphere and 25.2 ml of freshly distilled POCl3, and the mixture was stirred for 5 minutes. The thus obtained reagent was added dropwise over 10 to 15 minutes to a solution of 56 g of 17α-acetoxy-3-ethoxy-20-keto-19-norpregna-3,5-diene in 448 ml of dimethylformamide.

The reaction mixture was kept under stirring for 10 minutes, then hydrolyzed by the dropwise addition of a solution of 112 grams of potassium acetate in 224 ml of water, taking care that the temperature did not exceed 30 ° C. The solution, initially colored red, turns yellow as crystallization begins. After stirring for 30 minutes, 840 ml of ice-cold water were added. In this way, 57.6 g of crude 17a-acetoxy-3-ethoxy-6-formyl-20-keto-19-no-p> regna-3,5-diene was isolated. After crystallization from ethanol, 24.8 g of pure product were obtained. The analytical data is as follows:

IR: 170cm'1, CO at 1650 and 1615, δ-3.5

UV: λ max 220 and 320 nm

Step 2: Preparation of 17a-acetoxy-3-ethoxy-6-hydroxymethyl-20-diketo-19-norpregna-3,5 diene

Under nitrogen atmosphere at room temperature to a solution of 24 g of 17a-acetoxy-3-ethoxy6-formyl-20-keto-19-norpregna-3,5-diene in 72 ml of ethanol and 60 ml of dimethylformamide was added in portions of 1000 mg of sodium borohydride in 20 ml ethanol. The mixture was stirred for 2 hours. Thus, 22 g of 17α-acetoxy-3-ethoxy-6-hydroxymethyl-20-keto-19norregna-3,5-diene were obtained. The analytical data is as follows:

IR: 1700 cm ' ¹ (CO in 20)

1660 cm ' ¹ (CO in 3)

1620, 1595 cm ⁴ , C = C

UV: λ max 240 nm

Step 3: Preparation of 17a-acetoxy-6-hydroxymethyl-3,20-diketo-19-norpregna-4,6-diene (A) and 17a-hydroxy-6-hydiOxymethyl-3,20-diketo-19-norpregna-4,6 -dienu (B)

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20 g of 17a-acetoxy-3-doubxy-6-hydroxymethyl-20-keto-19-norpregna-3,5-diere, 200 ml of acetone (20 vol.), 40 ml of water (2) are introduced into the flask 21 with a magnetic stirrer under nitrogen. vol.) and 18.2 g (0.93 parts) of 2,3-dichlpro-5,6-dicyano-p-benzoquinone.

The progress of the reaction is followed by thin layer chromatography. The reaction is complete after 45 minutes. It precipitates into 11 of water. The resulting precipitate is filtered off. The mother liquors are extracted with twice 500 ml of dichloromethane.

The organic phases are washed with water until the pH is neutral. 7.8 g of a chestnut-colored oil are obtained with a yield of 41.9%.

Purification is carried out on a silica gel column, isolating 5.5 g of the first product (A) and 1.2 g of the second product (B) in order.

Product A is recrystallized from methanol to give 3 g of 17α-acetoxy-6-hydroxymethyl-3,20-dik, 3, t, 19-norpregna-4,6-diene.

Tt. 202.4 ° C

NMR:

H4 s 6.37 pp ^m 1 proton H7 s 6.01 pp ^m 1 proton 6-hydroxymethyl s 4.34 ppm 2 protons HC21 s 2.10 pp ^m 3 protons acetate s 2.07 ppm 3 protons H-O s 1.63 pp ^m 1 proton HC18 s 0.73 pp ^m 3 protons

Product B is also recrystallized from methanol to give 0.3 g of 17 [alpha] -hydroxy-6-hydroxymethyl [alpha] -3,20-dicotoxo-19-pregna-4,6-diere.

Melting point (Metler): 251 ° C

NMR:

: H4 s 6.38 pp ^m 1 proton H7 s 6.01 pp ^m 1 proton 6-hydroxymethyl s 4.33 pp ^m 2 protons HC21 s 2.3 ppm 3 protons H-O 6 s 1.63 ppm 1 proton H-C18 s 0.81 pp ^m 3 protons

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Claims (1)

Patent claim A method for the preparation of new 6-hydroxymethyl substituted 3-keto-A- derivatives in which R3 is a hydroxyl, acetoxy or alkyl group, R5 is an oxyalkyl or hydroxyalkyl chain, and R4 is 2 hydrogen atoms, a keto group, a methylene group or a hydroxyl group, characterized by that the alkyl ketal of the general formula II, formula 2 in which R2 is a lower alkyl group, R3, R4 and R5 are as defined above, is treated with a formylating agent of the Vilsmeier-Haack type and the 6-formylated obtained in which R2, R3, R4 , Rs is as defined above, is reduced by the action of a mixed alkali metal hydride, and then the obtained hydroxymethyl derivative of Formula 4 is Formula 4 wherein R2, R3, R4, R5 are as defined above, treated with a quinone dehydrating agent in an inert water-miscible solvent, and after decomposing the excess reagent, the hydroxymethyl derivative of formula 1 is obtained.