DE1078573B - Process for making new 21-oxysteroids - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of new 21-oxysteroids in general formula

OH

C C Hn

Method of manufacture
new 2i-oxysteroids

wherein R ₁ and R _{2 are} free or functionally modified oxy groups and R _{3 is} a pyridyl-2'- or piperidyl- (2 ') nucleus, their derivatives unsaturated in the 4, S or 5,6 position and their am heterocyclic radical N-substituted derivatives or quaternary compounds and their salts. A functionally modified oxy group is in particular an oxy group esterified with an aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic acid, thionecarboxylic acid, thiolcarboxylic acid or sulfonic acid. Examples of acids are: acetic acid, chloroacetic acid, trifluoroacetic acid, propionic acid, butyric acids, valeric acids, trimethyl acetic acid, diethyl acetic acid, caproic acids, oenanthic acids, capric acids, palmitic acid, crotonic acid, undecanoic acid, lactic acid, carboxylic acid, maleic acid, maleic acid, maleic acid -Cyclopentylpropionic acid, benzoic acid, phenylacetic acid, cyclohexylacetic acid, furan-2-carboxylic acid, methanesulphonic acid and toluenesulphonic acids. The oxy groups in the 20- and 21-position can be freely or functionally modified, e.g. B. be esterified with the above acids.

N-substituents are particularly lower alkyl radicals or the acyl radicals of lower fatty acids, benzoic acid ^, or simple aryl fatty acids, especially the methyl or acetyl radical.

The lower alkylammonium compounds should be mentioned as quaternary compounds.

The new compounds are characterized by a coronary-expanding activity on the isolated rabbit applicant *.

CIBA Aktiengesellschaft, Basel (Switzerland)

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

Claimed priority:
Switzerland from October 3, 1956

Dr. Karl Hoffmann and Dr. Julius Heer,

Bmningen {Switzerland),
have been named as inventors

heart and can therefore be used as a medicine. Which already from the article in Jour. Amer, Chem. Soc, Vol. 73, 1951, p. 8S3, and 21-unsubstituted 20-oxy-20-pyridyl-pregnane known from US Pat. No. 2 7S0 380 have an antagonistic effect on the heart-accelerating epinephrine. However, they also seem to have a coronary- widening effect, which, however, lags behind that of the present process products, such as e.g. B. the comparison of S ^ l-diacetoxy ^ O-hydroxy ^ O-piperidyl - (2 ') - allopregnens with the 3 β -acetoxy - 20 - hydroxy - 20 - piperidyl - selected as a representative of the above 21-unsubstituted compounds (2 ') shows allopregnan. As can be seen from the table below, the former substance is more effective than the latter with regard to coronary dilation in the isolated rabbit heart, while both compounds show practically the same small decrease in heart activity (frequency and amplitude) from 10- ^β . A modification of the Massische Langendorff-

Coronary flow

frequency

amplitude

Percentage change after flow 10-β Comparative product 10- « 909 7fi8 / 437 with solutions from + 149 "/» ' in concentrations of + 29% Process product Φ : -S in concentrations of ■ -3OV » + 11% -29% 10- ' φ + U ⁰ U ' -5% Φ. -li »/ o

see method used. The flow-through solution was under constant pressure and constant temperature (Lock solution) the coronary flow as well as the frequency and the amplitude of the heart activity registered at the same time.

. The new compounds are obtained when using a 20-oxopregnane of the general formula

CO-CH ₂ -R ₂

10

15th

in which R ₁ and R _{2 represent} free or functionally modified oxy groups or radicals which can be converted into such groups and in which a double bond, starting from carbon atom 5, can also be present, is reacted in a known manner with pyridyl (2) metal compounds, if desired, the 20-oxy-20-pyridyl compounds obtained are treated with the pyridine ring reducing agents in a manner also known, and. in a known manner at any stage in a free or functionally modified oxy- ^a 5 group convertible groups in the 3- and 21-position converted into such and, if desired, in any order according to known methods in compounds obtained in 4,5- or 5, 6-position introduces a double bond and / or saturates a double bond starting from carbon atom 5, functionally modifies free oxy groups or releases functionally modified oxy groups and / or compounds obtained N-substituted and / or quaternized, N-acylated compounds saponified and / or bases obtained in their salts or salts obtained are converted into the free bases.

The reactions, such as hydrolysis, to be carried out if necessary in the steroid residue or on nitrogen an acyloxy group, N-acylation, N-alkylation, Hydrolysis of an N-acyl group, introduction or saturation of a double bond, quaternization, etc. are used in the usual way, possibly with the protection of others, not for the implementation of specific groups carried out.

The new compounds will vary depending on the reaction conditions obtained in the form of the free amine or ammonium bases or their salts. The free Bases can be converted into their salts in the usual way, while the latter can be converted into known way can release the bases. Such inorganic or organic acids come as salts into consideration such. B. of hydrohalic acids, sulfuric acid, nitric acid, phosphoric acid, Rhodanic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, malic acid, Methanesulfonic acid, ethanesulfonic acid, oxyethanesulfonic acid, benzene or toluenesulfonic acid or of therapeutically effective acids.

The new compounds can be used as medicaments, for example in the form of pharmaceutical preparations find which they or their salts in a mixture with one for enteral or parenteral administration contain suitable pharmaceutical organic or inorganic carrier material. For education the same substances come into question that do not react with the new compounds, such as. B. Water, gelatin, lactose, starch, magnesium stearate, tallow, vegetable oils, benzyl alcohol, gum, Polyalkylene glycols, petrolatum, cholesterol, or other known excipients. The pharmaceutical Preparations can e.g. B. as tablets, coated tablets, or in liquid form as solutions, suspensions or Emulsions are present. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, Stabilizing, wetting or emulsifying agents, salts to change the osmotic Pressure or buffer. They can also contain other therapeutically valuable substances.

The invention also includes those embodiments of the method in which one is on any Compounds obtainable at the stage of the process are used as starting materials and the missing process steps carries out or terminates the process at any of its stages.

The starting materials are known or can be obtained by processes known per se.

The invention is described in the following example. The temperatures are in degrees Celsius specified.

. example

A solution of 10.4 g is added over 30 minutes at -30 to -40 ° to a pyridyl-lithium solution of 2.1 g of lithium, 200 ml of ether, 24 g of bromobenzene and 24 g of 2-bromopyridine in 100 ml of benzene A ⁵ S ß, 21-diacetoxy-pregnen-20-one and then stirred for 3 hours at -40 °. After adding 2N hydrochloric acid and, if necessary, methanol to dissolve it, the base is precipitated from the acidic solution with aqueous ammonia. The A ⁵ -3 β, 20,2ί-Τή- hydroxy-20-pyridyl- (2 ') - obtained in this way is acetylated in the usual way using 50 ml of pyridine and 15 ml of acetic anhydride, the zl ⁵ -3 / ?, 21-diacetoxy-20-hydroxy-20-pyridyl- (2 ') - pregnen is formed. From methanol it crystallizes in flakes with a melting point of 159 to 160 °; [α] ff = -46 ° ± 4 (c = 0.888 in chloroform).

4.95 g of ⁵ -3 ^, 21-diacetoxy-20-hydroxy-20-pyridyl- (2 ') - pregnen are hydrogenated in 80 ml of glacial acetic acid in the presence of 300 mg of platinum oxide. After 900 ml of hydrogen have been taken up, the catalyst is filtered off, the filtrate is evaporated in vacuo and isolated by adding aqueous ammonia 3 / ?, 21-diacetoxy ^ O-hydroxy ^ O-piperidyl- (2 ') -allopregnane. The base is converted directly into the hydrochloride; F. = over 260 °.

Claims (2)

Patent claims: 1. Process for the production of new 21-oxysteroids, characterized in that there is a 20-oxopregnane of the formula CO-CH ₉ -R ₅ . where R ₁ and R _{2 represent} free or functionally modified oxy groups or radicals which can be converted into such groups and in which a double bond starting from carbon atom 5 can also be present, reacts in a known manner with pyridyl (2) metal compounds, if desired, the 20-oxy-20-pyridyl compounds obtained are also treated in a known manner with the pyridine ring reducing agents, and in a known manner at any stage into a free or functionally modified oxy group Transferable groupings in 3- and 21-position converted into such and, if desired, in any order according to known methods in obtained compounds in 4,5- or 5,6-position introduces a double bond and / or one from Carbon atom saturates 5 outgoing double bond, functionally modifies free oxy groups or functionally modified oxy groups sets and / or obtained compounds N-substituted and / or quaternized, N-acylated compounds saponified and / or the bases obtained are converted into their salts or the salts obtained are converted into the free bases. 2. The method according to claim 1, characterized in that one pyridyl (2) lithium as Pyridyl metal compound used. A priority document was displayed when the registration was announced.