DE1263762B - Process for the preparation of steroid guanylhydrazones - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C 07c

German class: 12 ο -25/02

Number: 1263 762

File number: F 42668IV b / 12 ο

Filing date: April 20, 1964

Open date: March 21, 1968

Subject of the German patent 1 227 015 and the German patent application F 42053 IV b / 12 ο (German Auslegeschrift 1 257 139) are processes for the production of resin-active guanylhydrazones of 20 keto steroids.

It has now been found that compounds with a cardiac effect are also obtained when using steroids, which contain a keto or aldehyde group in the 17-position side chain, with the exception of the 20-position is converted into a guanylhydrazone.

Steroids which contain a keto or aldehyde group in the 17-position side chain should be understood here as meaning saturated and unsaturated nor-, homo- and cyclo-compounds which, as far as the steric relationships are concerned, on rings A / B, ß / C and C / D can be cis- or trans-linked, the individual carbon atoms of the steroid structure can be replaced by heteroatoms, such as N, O or S, which are in any position by radicals such as OH, O-alkyl, O-acyl, O-sulfonyl, phosphoryl, epoxy, O - NO, O - NO ₂ , NO, NO ₂ , CN, halogen, alkyl, alkenyl, alkynyl, acyl, cycloalkyl, aryl, SH, S-alkyl, S- Acyl, amido or sulfonamido, or can have fused-on cycloaliphatic, aromatic or heterocyclic rings in any positions, and the 17-position of the steroid molecule has a saturated or unsaturated branched or unbranched alkyl chain of any length with a keto or aldehyde group, with the exception of 20 Position, included. This chain can be interrupted by heteroatoms such as N, S or O and substituted by substituents such as OH, O-acyl, cycloalkyl or aryl.

According to the invention, the new compounds are prepared by using a steroid which is present in the 17 th Side chain contains a keto or aldehyde group, with the exception of the 20-position, in an in a known manner either a) reacts with aminoguanidine or a salt thereof or b) with a S-alkylisothiosemicarbazide react and let act on the condensation product ammonia.

The substances which can be prepared according to the invention are nontoxic as such or in the form of their salts with organic or inorganic acids, e.g. B. acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid, Succinic acid, tartaric acid, citric acid, salicylic acid, naphtharine-1,5-disuhonic acid, phosphoric acid or hydrochloric acid, acting on the heart.

Suitable starting materials for the process according to the invention are, for. B .:

24-keto-cholesterol, 3/3-acetoxy- ^ d ^s -cholen-24-al,
3Ä, 12 "-dihydroxy-cholan-24-al,

Process for the production of
Steroid guanyl hydrazones

Applicant:

Paint factories Bayer Aktiengesellschaft,

5090 Leverkusen

Named as inventor:

Dr. Karlheinz Meyer,

Dr. Siegismund Schütz,

5600 Wuppertal-Elberfeld;

Dr. Kurt Stoepel, 5600 Wuppertal-Vohwinkel;

Dr. Hans-Günther Kroneberg,

5600 Wuppertal-Elberfeld

3 /? - formoxy-zl ⁵ -cholen-24-al,
3/9-Hydroxy-24-keto-24-p-anisyl- / l ⁶ -cholen,
3 ^ -Hydroxy-24-keto-24-phenyl-Zl ⁶ -cholen,
3-acetoxy-bisnor-Zl ⁵ -cholenaldehyde,
3-methoxy-bisnor-J ⁵ -cholenaldehyde,
3-benzyloxy-bisnor- / l ⁵ -cholenaldehyde,
24-ketone of 28-nor-cycloeucalenol,
24-ketone of 28-nor-euphorbols,
3-acetoxy-20-acetyl-Zl ⁵ -pregnen,
16,22-epoxynorcoprostan-3 «-ol-25-one,
16,22-epoxynorcoprostan-3 «-acetoxy-25-one,
16,22-epoxycholan-3'-acetoxy-24-al.

example 1

1.65 g of 3-hydroxy-bisnor- / I ⁵ -cholenaldehyde are dissolved in 20 ml of absolute methanol, and a solution of 750 mg of aminoguanidine hydrogen carbonate in methanolic hydrochloric acid is added. The clear reaction _{solution is stirred under N 2} at room temperature for hours and then added dropwise to dry ether. The colorless, crystalline precipitate is filtered off with suction and redissolved once from methanol ether. The Guanylhydrazonhydrochlorid of 3-hydroxy-bisnor- / l ^s -cholenaldehyds melts at 27O ⁰ C.

Example 2

8.5 g of lanosterol, dissolved in 300 ml Essigester and ml of pyridine, at -23 ⁰ C ozonized (101 O ₂ per

809 519/694

3 4

Hour flow rate; Duration 60 minutes for adrenal steroids and for progesterone

= 1440 mg O ₃ ). After washing out the pyridine, effects on the heart muscle by means of water were found to be the solution with 1 g of Pd / CaCO ₃ and (cf. Journ. Pharmacol, exp. Therapy, 131 hydrogenated at room temperature. Der Kata- [1961], p 56 and 124 [1958], p. 59, as well as Can. Journ. Lysator is then filtered off and the solution up to 5 Med. Sci. 30 [1952], p. 325).

Concentrated dry in vacuo. What remains is the positive inotropic effects of these compounds

greasy, light yellow residue containing the 25,26,27-Trisnor- /! ^S -lano- sections (atrium, papillary muscles) are, however, very sten-24-al contained and which is dissolved in 150 ml of absolute metha weakly and only in relatively high concentrations and nol. After adding 2 g of aminoguanidinio under special experimental conditions after hydrogen carbonate in methanolic HCl one falls to assign. As a result, its therapeutic is pending colorless, crystalline substance. The suspension is stirred for about 60 hours at room temperature using the specific hormone effect. The depleted electrolyte metabolism or the uterine mucous membrane in the suctioned precipitate is not the desired pro-fore. The pharmacologically proven product. The filtrate is stirred into ether. Only a bare and apparently beneficial effect of the heart occurs with a small amount of brownish, flaky substance. of practical application is not apparent. The ether solution is concentrated to dryness. In contrast, it has now been shown that a semi-solid, yellow substance remains, which is reprecipitated from the introduction of a guanylhydrazone-methanol ether according to the invention and for the analysis remains in the 17-position side chain of the Steroid mol is boiled twice with acetone. The light · 20 küls these at best yellow, crystalline hydrochloride of 25,26,27-Trisnor-. interpreted cardiac effect is considerably strengthened and quali- Δ ⁸ -lanosten-24-guanylhydrazons has a fixed point tatively and quantitatively so favorably changed from 264 ⁰ C _.; that a use of the process products as

For the production of the starting compound, drugs for the therapy of heart diseases are used protection 25 is not possible within the scope of the present invention.

desired. The compounds prepared according to the invention

τ,. -ίο showed in pharmacological investigations

^{e 1 s} P * fish cardiac effects in the sense of the contraction

5.2 g of 3 ", 12" -Diformoxy-Zl ⁵ -cholen-24-al will have an increasing effect on the heart muscles.
20 ml of absolute methanol dissolved and a solution 30. 1.6 g of aminoguanidine H ₂ CO ₃ in methanolic HCl on the isolated spontaneously beating atrial preparation could be added to this positive inotropic myocardial effect. The light yellow solution is stirred for 60 hours to be able to detect the guinea pig. Method at room temperature. When the solution is added dropwise, see Holtz, P. and E. Westermann, Naunynin dry ether, a tough, dark yellow Schmiedebergs Arch. Path. u. Pharmak., 225 Substance which was caused to crystallize by repeated rubbing with 35 (1955), p. 421, as well as G. Kroneberg and K. S t o e ether. The Sub- (1955), p. 421, as well as G. Kroneberg and K. S tο e stanz was dissolved in concentrated water and with pel, Naunyn-Schmiedebergs Arch. Exp. Path. and concentrated NaOH solution added. Der flockige Pharmak., 249 (1964), p. 394.

Precipitation is absorbed in butanol, which The positive inotropic basic effect of cardiac

Solvent stripped off, the residue in metha is dissolved, according to recent studies, from Nolian HCl and stirred in ether. The bright K. Repke and HJ Portius, Experientia, 19 yellow, crystalline hydrochloride des 3 <x, 12a-dihydroxy- (1963), p. 452, sinters on the inhibition of the transport ATPase Δ ^s -cholen-24-guanylhydrazone from 95 ⁰ C. in the heart muscle cell. This inhib

could have an effect on those produced according to the invention

Example ^{4 4S} compounds can also be detected. Win

tion of the K ⁺ , Na ⁺ , Mg ⁺⁺ -activatable transport

1.7 g of 3-hydroxy-bisnor-Zl ⁵ -cholenaldehyde are dissolved in ATPase from guinea pig hearts according to T. K ο η ο 25 ml of absolute ethanol, with a solution of and SP C ο 11 ο wick, Arch. Biochem. Biophys., 0.7 g of S-methyl-isothiosemicarbazide hydrochloride in 93 (1961), pp. 520 to 533. Determination of the enzyme methanolic hydrochloric acid added and 5 ° activity for 24 hours according to JV Auditore, Proc. Soc. exp. stirred under nitrogen at room temperature. Then Biol. Med., 110 (1962), pp. 595 to 597. Specification of the one drips into dry ether, sucks the low effectiveness of a preparation in percent inhibition of the blow and washes with ether. Output activity.

1.5 g hydrochloride of 3-hydroxy-bisnor-zl ^s -cho-

len-22- (S-methyl-isothiosemicarbazons), m.p. 165 to 55,.

68 ⁰ C (decomposition). Examination results:

This substance is dissolved in 30 ml of ethanol, with 3-hydroxy-23,24-bisnor-ZI «-cholen-

70 ml of alcoholic ammonia solution added 22-guanylhydrazone hydrochloride

and refluxed for 12 hours. Then steams

if you dry it in a vacuum, rub the back 60 Tc-xrzität Mouse:
stood with little water and separates the insoluble. 12 to 16 mg / kg iv

This is after drying in a little ethanol overall _TT ". ,

dissolves, with essential hydrochloric acid up to the just acidic atrium, guinea pigs:
Reaction is added and the solution is stirred into ether. ? ^osativ ™ * «> pe cardiac muscle effect from concentration

The colorless, crystalline precipitate is sucked off 65 nations of 10 " ⁶ g / ml. Envelope to negative and once redissolved from methanol ether. Inotropic effect with myocardial contracture at

0.8 g hydrochloride of 3-hydroxy-bisnor-zl ⁵ -cholen- concentrations of 10- * g / ml.

22-guanylhydrazone, m.p. 267-69 ° C. ATPase inhibition: 1 x IO- ⁵ m - 61% inhibition.

Claims (1)

5 6 3,12-dihydroxy-Zi ^B -cholen-24-guanylhydrazone- claim: hydrochloride process for the production of steroid guanyl hydrazones, characterized Toxicity mouse: that a steroid is found in the 17-page page 30 to 40 mg / kg i.p. v. 5 chain contains a keto or aldehyde group, where the 20 position is excluded in itself Atrium guinea pigs: as is known, either a) with aminoguanidine positive inotropic cardiac muscle effect from concentrations or a salt thereof or b) with concentrations of 3 · 10 ~ ^e g / ml. Change to negative reaction to an S-alkylisothiosemicarbazide and inotropic effect with myocardial contracture at io on the condensation product ammonia a concentrations of 10 ~ ^s g / ml. works. 809 519/694 3.68 © Bundesdruckerei Berlin