DE1132921B - Process for the preparation of therapeutically effective 3, 16-diacylates of pregnan-3 or allopregnan-3ª ‰, 16ª ‡ -diol-20-one - Google Patents

Description

A large number of active ingredients have already been extracted from the adrenal glands. This is what the inventors intend to do For a few years together with T. Reichstein, among other things, aldosterone was isolated.

It was known that in a particular form of the familial congenital adrenogenital syndrome major Salt losses occur. The hypothesis up for discussion was that due to the hyperplased adrenal gland a sodium-eliminating factor is produced in excess. Other authors opposed it the cause is adrenal insufficiency with insufficient production of sodium-retaining steroids, like aldosterone. The inventors then proceeded from the assumption that a sodium excretory Factor was present, and have been systematically looking for such an active ingredient since 1955. In difficult work Using special isolation and testing methods, it was possible to find a substance in pure To isolate crystallized form with a melting point of 258 to 260 ° C, the sodium excreting Has properties.

When the new active ingredient was isolated for the first time, 1 mg of the new compound can be obtained in pure crystallized form. On the basis of further findings, the content of this active ingredient can be estimated at around 30 mg per 1000 kg of adrenal glands. Apparently this gland is out of the question as a starting material for the new active ingredient as a remedy for the sick to provide. Attempts have therefore been made to determine the constitution of the pure crystallized compound to clarify, in order to open up new ways of producing them. Surprisingly showed that the new active ingredient forms mono- and diesters. It was then found that this new Process for the preparation of therapeutically active 3,16-diacylates of the Pregnan or allopregnan-3 / 3.16 a-diol-20-ons

Applicant: CIBA Aktiengesellschaft, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney, Hamburg 36, Neuer Wall 10

Claimed priority:

Switzerland of July 8, December 20, 1957 and June 4, 1958 (No. 48 098, No. 54 027 and No. 60 206)

Dr. Albert Wettstein, Riehen,

Dr. Robert Neher, Binningen,

and Dr. Pierre-Antoine Desaulles, Oberwil (Switzerland),

have been named as inventors

Further experiments showed that the 5 /? - isomer of the active ingredient, the Pregnan-3 / ?, 16a-diol-20-one of the formula

CH ₃

CH, CO

Compound and its esters
16 £ x-diol-20-one of the formula

the allopregnan-3 ^,

HO

OH

OH

HO

or represent its esters.

or its esters have a sodium eliminating effect.

The present invention now relates to a process for the production of therapeutically active substances 3,16-diacylates of pregnan-3 or aliopregnan-3 / 3,16a-diol-20-one, which is characterized in that a 3-monoacylate of the Pregnan- or allopregnan-3 / S, 16'-diol-20-one, in which the acyl radical has more than 2 carbon atoms, with acylation

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agents that have at most 2 carbon atoms, in an 86, suppl. to issue 37, p. 1060 [1956]) is implemented in a known manner. Test conditions. Those are particularly valuable The acylating agents mentioned are, for. B. those esters whose acyl radical is a water-solubilizing agent which differ from saturated or unsaturated alipha group, such as the carboxyl group, or an amino table or cycloaliphatic, from aromatic 5 group, such as the remainder of glutaric acid, tetra or Derive heterocyclic carboxylic acids. Beethophthalic acid or primarily the amber games such acids are formic acid, acetic acid, acid. They can be used as a remedy like to manufacture Chloroacetic acid, trifluoroacetic acid, carbamic acid, the disturbed sodium balance, especially in Alkoxycarboxylic acids, propionic acid, butyric acids, retention of sodium, e.g. edema, circulatory lactic acid, Valeric acids, such as n-valeric acid, or io disorders including hypertension, use Trimethyl acetic acid, diethylacetic acid, caproic acids, find.

like | S-trimethyl-propionic acid, Oenanth-, Capryl-, For the application in the human or veterinary pelargon, Capric, undecylic acids, e.g. B. Undecylene medicine are used mixtures of the esters mentioned acid, lauric, myristic, palmitic or stearic pregnan-3jS, 16 "-diol-20-ones with solid or liquid acids, e.g. B. oleic acid, crotonic acid, undecanoic acid, 15 excipients. For parenteral, enteral or Cyclopentyl, cyclohexyl or phenylacetic acids topical application come such pharmaceutical or propionic acids, hexahydrobenzoic acid, benzoic, organic or inorganic carrier acid, Phenoxyalkanoic acids, such as phenoxyacetic acid, materials in question with the process products ρ-chloro-phenoxyacetic acid, 2,4-dichloro-phenoxyacetic acid do not react, e.g. B. water, vegetable oils, benzylic acid, 4-tert-butyl-phenoxyacetic acid, 3-phenoxy-pro 20 alcohols, polyethylene glycols, gelatine, milk sugar, pionic acid, 4-phenoxy-butyric acid, furan-2-carbon starch, magnesium stearate, talc, petrolatum, cholesterol acid, S-tert-butyl-furan ^ -carboxylic acid, 5-bromo-fu or other excipients. For the parenteral ran-2-carboxylic acid, nicotinic, isonicotinic acid, further administration are preferably solutions, Dicarboxylic acids, such as oxalic, succinic, maleic, primarily oily or aqueous solutions, also Glutar, dimethylglutar, pimeline, acetone dicarbon, suspensions, emulsions or implants for which Phthal, tetrahydrophthal, hexahydrophthal, endo-enteral application analogously to tablets or dramethylene tetrahydrophthalic, Endomethylene hexahydro- goes, for topical application ointments or creams, phthalic, endoxyhexahydrophthalic, endoxytetrahydro- which are optionally sterilized or with auxiliaries, such as phthalic acid, camphoric acid, cyclopropanedicarboxylic, preservative, stabilizing, wetting or emulsic acid, Cyclobutanedicarboxylic acid, diglycolic acid, ethy- 30 gierungsmittehi, salts to change the osmotilen bisglycolic acid, Polyäthylenbisglykolsäuren, Chin- see pressure or buffers are added. Of the oline, cinchomeronic acid, and the polyethylene glycol active ingredient content of an ampoule or tablet monoalkyl ether half esters of the above dicarboxylic acids is 0.1 to 200 mg.

Ketocarboxylic acids, such as jS-keto carboxylic acids, e.g. B. The method according to the invention is used in the following

Acetoacetic, Propionylessig-, Butyrylessig- or Capro- 35 explained in more detail in the following examples. The tempe-

noyl acetic acid, amino acids such as diethylamino acetic acid are given in degrees Celsius,
acid.

These esters can be prepared according to Example 1, which is known per se
Establish methods. So you can get a 3-monoacylate

of the active ingredient, in which the acyl radical has more than 2 carbon atoms 40 50mg Allopregnan-Sftlöa-diol ^ O-on-SjS-mono-

with acids containing at most 2 carbon atoms are benzoate in 0.5 cm ^{3 of} pyridine and 0.2 cm ⁸

point, or their functional derivatives, such as their acetic anhydride for 20 hours at 20 ° -

Halides, anhydrides, thiol derivatives and ketetones. After adding a little water,

with the formation of diesters, the acyl radicals of which evaporate the pyridine and acetic acid in vacuo

are divorced. 45 the residue is dissolved in ether, washed with water,

The above-mentioned Pregnan-3 / 3,16a-diol-20-ones are thin hydrochloric acid and sodium hydrogen carbonate

New. Their 3β- acetates and the 3 / 3.16 "-di solution are known to have been washed neutral. After removing the

acetate. Their production was carried out by reducing solvent, which is converted from ether-hexane.

the corresponding 3jS-acetate-16 "-benzyl ether and crystallized residue of pure allopregnan-3j8,16" -

Action of acetylating agents on the formed 50 diol ^ O-on-S / S-benzoate-loa-acetate. IR absorption band

deten Pregnan-3 (S, 16a-dioxy-20-on-3/3-acetate den at 5.75 to 5.88 μ (complex band), 7.90 and

(H. Hirschmann et al., J. Org. Chem., 20, p. 572 8.16 µ.

[1955]; J. of Am. Chem. Soc, 78, p. 3755 [1956]). The allopregnant used as the starting material

However, it was not known that these acetates 3 / 3,16'-diol-20-one-3 | 8-monobenzoate can have a therapeutic effect. It was not possible to suspect that allopregnan-3 / 3,16'-diol-20-one was placed in connection with the sodium excreted in any zoyl chloride, as described in patent 1102145.
Factor related to the adrenal gland. Example 2

The new esters can be used as intermediates

Preparation of the Pregnan-3 / ?, 16a-diol-20-ones or 60 80 mg Allopregnan-3 _i ö, 16 <x-diol-20-one-3/3-mono serve for their purification. But they also have, like the trimethylacetate, in 0.5 cm ^{3 of} pyridine and 0.3 cm ^{3 of} new active ingredient, sodium-eliminating action of acetic anhydride for 36 hours at 20 °, the rat without any significant effect on the potassium Evaporation of the pyridine and acetic acid excreted during the duration of the experiment, the residue in ether becomes urine. The determination of the electrolyte deposit was recorded, washed neutral with dilute hydrochloric acid, cold soda (sodium and potassium) and the water separating solution and water. The after manure takes place z. B. according to the residue obtained in the publication of drying and distilling off P. Desaulles and R. Meier (Switzerland. Med. Wschr., Supplies, recrystallized from ether-hexane, Allopreg-

nan- 3β, 16α-diol-20-one-3/3-trimethylacetate-16α-acetate. IR absorption bands at 5.78, 5.87 and 8.12 µ.

The AUopregnan-3ß, 16 <x - diol - 20 - one - 3/5 - monotrimethylacetate used as starting material can be obtained by reacting allopregnan-3 / 3,16 "-diol-20-one with trimethyl acetic acid chloride, as in patent 1 102 145 described.

Example 3

In the above examples, the allopregnan-3 / ?, 16a-diol-20-one replaced by pregnan-3 (ö, 16 «-diol-20-one, one obtains the corresponding esters, e.g. the 3 /? - Benzoate-16a-acetate of Pregnan-3 / ?, 16a-diol-20-one. IR absorption bands at 5.75 to 5.90 µ (unresolved), 7.85, 8.05 and 8.70 µ.

Claims (1)

PATENT CLAIM: Process for the preparation of therapeutically active 3,16-diacylates of pregnan-3j8,16a-diol-20- one, characterized in that a 3-monoacylate of pregnan-3 or allopregnan-3 / S, 16a is used -diol-20-one, in which the acyl radical has more than 2 carbon atoms, is reacted in a manner known per se with acylating agents which have at most 2 carbon atoms. © 209 619/430 7.62