DE1270555B - Process for the preparation of steroid guanylhydrazones - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY GERMAN #fW PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

A61k; C07d

German classes: 12 ο - 25/02, 6, 25/01, 25/04, 25/05, 25/06; 30 h-2/10; 12p-2; 12q-24, 26

Number: 1 270 555

File number: P 12 70 555.4-42

Filing date: April 16, 1964

Opening day: June 20, 1968

The action of aminoguanidine on steroid ketones that contain only one carbonyl function is has been described in two cases (J. B a r η e 11 and C. J. O. R. M ο r r i s, Biochemical Journal, 40, 450 [1946], and M. P e s e z, J. B a r t s, J. M a t h i e η and J. Va 11 s, Bull. Soc. Chim. France [1958], 488). In both cases, ketones are reacted with the carbonyl group in the 3- or 17-position and the Reaction products have been used for physical measurements.

The subject of German patent 1175 228 is the production of condensation products from steroids of the androstane and pregnane series with more than one carbonyl function and aminoguanidine or its salts; these condensation products are heart-working. It has now been found that compounds with a cardiac effect can also be used when you get steroids that contain one or more sugar-like residues plus one or contain several keto or aldehyde carbonyl groups into the corresponding substituted or unsubstituted guanylhydrazones, which may still contain free keto or aldehyde carbonyl groups, caught.

Sugar-like residues of the type mentioned should include aliphatic residues with three or more hydroxyl groups, which can also be acylated or etherified, are understood, these sugar-like residues also exist in the heterocyclic furanose or pyranose form and still contain carbalkoxy groups can.

The mentioned sugar-like radicals with three or more hydroxyl groups can be used directly or via Ether, ester, amide, carbonic acid ester and carbammic acid ester groups bound to the steroid structure be.

The new compounds are prepared according to the invention by a steroid, the one or several aliphatic radicals with three or more hydroxyl groups, which are also acylated or etherified can be, these sugar-like aliphatic radicals also in the heterocyclic furanose or pyranose form and may also contain carbalkoxy groups, and that in addition one or contains several keto or aldehyde carbonyl groups, in a manner known per se, either

a) with an aminoguanidine of the general formula H ₂ NNC-NHB

E NA
or a salt of such or a process for the preparation
of steroid guanyl hydrazones

Applicant:

Paint factories Bayer Aktiengesellschaft, 5090 Leverkusen

Named as inventor:

Dr. Karlheinz Meyer,

Dr. Hans Krätzer,

Dr. Siegismund Schütz,

Dr. Kurt Stoepel, 5600 Wuppertal-Elberfeld; Dr. Hans-Günther Kroneberg, 5600 Wuppertal-Vohwinkel

b) with an S-alkylisothiosemicarbazide of the general formula

H ₂ NNC = NA

E S-alkyl

react and an amine of the general formula on the condensation product

H ₂ NB

can act or

c) with a hydrazine of the general formula

H ₂ N - NH

condensed and then with a cyanamide of the general formula.

NCHN - B

or an S-alkylisothiourea of the general formula

N / A

Alkyl - S - C - NHB

reacted, where A and E are hydrogen or a branched, unbranched or alicyclic alkyl chain with 1 to 6 carbon atoms, which can be substituted by one or more hydroxyl groups, B Hydrogen, a branched branch which is substituted or unsubstituted by one or more hydroxyl groups

801 560 537

or unbranched or alicyclic chain with 1 to G atoms, which also, optionally via a heteroatom, such as N, Q or S, can be connected to A, a nitro or an amino group or a basic radical of the general formula D

D = -

(CH ₂ ) "- N

where η = 0 to 8 and / = 1 or 2, and R and R ₁ each represent hydrogen, for identical or different, with one or more OH groups substituted or unsubstituted, branched, unbranched or alicyclic alkyl groups up to 6 C atoms which, if appropriate also via a hetero atom such as N, S or O, can be connected to one another.

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, naphthalene-1,5-disulfonic acid, phosphoric acid or hydrochloric acid, acting on the heart.

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

30 (Androst ^ -en-S-on-17-yl) -N-methyl-

N-1 '- (1' -deoxyglukosyO-carbamic acid ester, (AndrosM-en-S-on-17-yl) -N-2 '- (2'-deoxy-

glucosyl) carbamic acid ester, (AndrosM-en-S-on-17-yl) -N-1 '- (1' -deoxy-

glucosyl) carbamate,
(AndrosM-en-S-on-17-yl) -N-1 '- (1' -deoxy-

sorbityl) carbamate,
(Androst-4-en-3-one-17-y I) -N-1 '- {T-deoxyarabityl) -carbamate,

(Androst-4-en-3-on-17-yl) -N-T- (T-deoxyxylityl) -

carbamate,
(Androst-5-en-17-on-3-yl) -N-methyl-

N-T- (I '-deoxyglucosylj-carbamate. (Androst-5-en-17-on-3-yl) -N-2 '- (2'-deoxy-

glucosyl) carbamate,
(Androst-5-en-17-on-3-yl) -N-1 '- (1' -deoxy-

glucosyl) carbamate,
(Androst-5-en-17-on-3-yl) -N- T- (I '-deoxyarabityl) -carbamate,

(Androst-5-en-17-on-3-yl) -N- T- (I '-deoxyxylityl) -

carbamate,
(Pregn-4-en-3-on-20-yl) -N-methyl-

N-l '- (r-deoxyglucosyl) carbamate. (Pregn-4-en-3-on-20-yl) -N-2 '- (2'-deoxyglucosyl) -

carbamate,
(Pregn-4-en-3-on-20-yl) -NT- (1'-deoxyglucosyl) -

carbamate,
(Pregn-4-en-3-on-20-yl) -NT- (T-deoxyarabityl) -carbamate,

(Pregn-4-en-3-on-20-yl) -N-1 '- (1' -deoxyxylityl-

carbamate,
(Pregn-5-en-20-on-3-yI) -N-methyl-N-1 '- (1' -deoxy-

glucosyl) carbamate,
(Pregn-5-en-20-on-3-yl) -N-2 '- (2'-deoxyglucosyl) -

carbamate,
(Pregn-5-en-20-on-3-yl) -N-1 '- (T-deoxyglucosyl) -carbamate,

(Pregn-5-en-20-on-3-yl) -N-1 '- (1' -deoxyarabityl) -

carbamate,
(Pregn-5-en-20-on-3-yl) -NT- (T-deoxyxylityl) -

carbamate,
(Androst-4-en-3,11-dion-17-yl) -N-methyl-

N-T- (T-deoxyglucosyl) -carbamate, (androst-4-en-3,11-dion-17-yl) -N-2 '- (2'-deoxy-

glucosyl) carbamate *, i
(Andr ost-4-en-3,11-dion-17-yl) -N-1 '- (1' -deoxyglucosyl) -carbamate,

(Andr ost-4-en-3,11 -dione-17-y I) -N- T- (I '-deoxyarabityl) -carbamate,

(Androst-4-en-3,11-dion-17-yl) -N-1 '- (1' -deoxyxylityl) -carbamate,
(Pregn-4-en-3,20-dion-21-yl) -N-methyl-

N-T- (T-deoxyglucosyl) -carbamate, (Pregn-4-en-3,20-dion-21-yl) -N-T- (T-deoxy-

glucosyl) carbamate,
(Pregn-4-en-3,20-dion-21-yl) -N-2 '- (2'-deoxy-

glucosyl) carbamate,
(Pregn-4-en-3,20-dion-2 l-yl) -N-1 '- (1' -deoxy-

arabityl) carbamate,
(Pregn-4-en-3,20-dione-21 -yl) -N-1 '- (1' -deoxyxylityl) -carbamate

(Pregn-4-en-3,20-dion-6-yl) -N-methyl-N-1 '- (1 '-deoxyglucosylj-carbamate, (Pregn-4-en-3,20-dion-6-yl) -N-2' - (2'-deoxyglucosyl) -carbamate,

(9fi-fluoro-l 1 ß, 17a-dihydroxy-pregn-4-en-3,20-dion-2 l-yl) -N-methyl-NT- (1'-deoxyglucosyl carbamate,
(9u-fluoro-l ifiA 7u-dihydroxy-pregn-4-en-3,20-dione-

21 -yl) -N-2 '- (2'-deoxyglucosyl) -carbamate, (9u-Fluor-11 / i, 17tt-dihydroxy-pregn-4-en-3,20-dione-

21 -yl) -N-1 '- (1' -deoxyglucosyl) -carbamate, (9a-fluoro-1 l / i, 17a-dihydroxy-pregn-4-en-3,20-dione-

21 -y I) -N-1 '- (1' -deoxyarabityl) -carbamate, (9a-Fluör-ll / i, 17 "-dihydroxy-pregn-4-en-3.20-dione-

21 -yl) -N-1 '- (1' -deoxyxylityl) -carbamate, (17 «-Hydroxy-pregna-1,4-diene-3,11,20-trione-21-yl) -

N-methyl-N-1 '- (1' -deoxyglucosyl) carbamate. ( 11β, 17u-Dihydroxy-pregna-1,4-diene-3.20-dione-21 -yl) -N-methyl-N-1 '- (1' -deoxyglucosyl) -carbamate.
(17ü-Hydroxy-pregn-4-en-3,11.20-trion-21-yl) -

N-methyl-N-1 '- (1' -deoxyglucosyl) -carbamate, (1 IfiA 7u-dihydroxy-pregn-4-en-3.20-dion-21-yl) -

N-T- (I '-deoxyglucosylj-carbamate. (17 "-Hydroxy-pregna-1,4-diene-3.11, 20-trion-21-yl) -

N-1 '- (1' -deoxyglucose O-carbamate. (17 «-Hydroxy-pregna-1,4-diene-3,11,20-trione-21-y I) -

N-2 '- (2'-deoxyglucosyl) carbamate. (17a-Hydroxy-pregna-1,4-diene-3.11.20-trion-21-yl) -

N-T- (T-deoxyarabityl) carbamate. (17 «-Hydroxy-pregna-1,4-diene-3.11.20-trione-21-y1) -

N-I '- (1' -deoxyxylityl) carbamate. Testosterone-17- ( _/ iD-glucoside).
Testosterone 17 - (, VD-glucoside-tetraacetate). Androsterone-3 - (, iD-glucoside).
Androsteron-3 - (/ iD-glucoside-tetraacetate), deoxycorticosterone ^ li / iD-glucoside). . ■ Deoxycorticosterone ^ W ^ -D-glucoside-tetraacetate), 16-dehydropregnenolone-3- (D-glucoside-tetraacetate),

Deoxycorticosteron ^ l-lmaltosid-heptaacetat). Desoxycorticosterone-2I - (^ - maltoside). Testosterone 17 - (^ - maltoside heptaacetate), Testosterone-17 - (/) '- maltoside), ■

Deoxycorticosteron ^ 1 - (2,3,4-triacetyl-D-glucuron-

acid methyl ester),
Cortisone ^ li ^^ - triacetyl-D-glukopyranosyluron-

acid methyl ester),
Reichstein's substance S-21- (2,3,4-triacetyl-

D-glucuronic acid methyl ester),
Prednisone-21- (2,3,4-triacetyl-D-glucopyranosyl-

uronic acid methyl ester),
Hydrocortisone-21 - (2,3,4-triacetyl-D-glucuronic

acid methyl ester),
Dehydroepiandrosterone-3 - (/ iD-glucoside-

tetraacetate),
Dehydroepiandrosterone-3- (2,3,4-triacetyl-

D-glucuronic acid methyl ester),
Testosterone 17- (2,3,4-triacetyl-D-glucuronic

acid methyl ester),

Pregnenolone-3 - (/ ^ - D-glucoside-tetraacetate),
Pregnenolone-3 - (/ iD-glucoside).

The compounds mentioned are only examples of substances suitable as starting steroids. In addition, steroids are generally suitable which have one or more aliphatic radicals with three or more OH groups and which have one or more in the core in any position and / or in side chains Contain keto or aldehyde carbonyl groups as starting compounds for the process according to the invention. The steroids used as starting substances can be either saturated or mono- or polyunsaturated compounds. As far as the steric relationships are concerned, they can be cis-linked or trans-linked on rings A / B, BC and C / D. The starting steroids can be homo-, nor- and cyclo-compounds, and individual carbon atoms of the steroid structure can be replaced by heteroatoms, such as N.O or S. The structure of the steroids can also be in any position by radicals such as OH, O-alkyl. O-acyl, O-sulfonyl, phosphoryl. Epoxy. O-NO, 0-NO ₂ . NO. NO ₂ . CN. Halogen, alkyl, alkenyl, alkynyl. Acyl, cycloalkyl. Aryl, SH, S-alkyl. S-acyl, amido or sulfonamides can be substituted, or cycloaliphatic, aromatic or heterocyclic rings can be fused on in any positions.

Adrenal steroids and progesterone have already had effects on the heart muscle found (cf. Journ. Pharmacol, exp. Therapy. 131. P. 56 [1961] and 124. p. 59 [1958] and Can. Journ. Med. Sci .. 30. p. 325 [1952]).

The positive inotropic effects of these compounds on the heart or certain parts of the heart muscle (Atrium, papillary muscles) are very weak and only in relatively high concentrations and to be demonstrated under special experimental conditions. As a result, stands by her therapeutic use the specific hormone effect on the electrolyte metabolism or the uterine mucosa in the foreground. The pharmacologically verifiable and apparently beneficial effect of the heart does not appear in practical use. In contrast, it has now been shown that by introducing the guanylhydrazone residues into the steroid molecule according to the invention in the case of the starting substances, at best, indicated cardiac effect is considerably strengthened and qualitatively and is changed quantitatively so favorably that the products of the process can be used as medicaments for the therapy of heart diseases is possible.

The positive inotropic cardiac muscle effect of the products of the method according to the invention could can be demonstrated in the following pharmacological test arrangements:

1.Isolated spontaneously beating auricle specimen from guinea pigs, method see H ο 11 z,

P. and E. Westermann, Naunyn-Schmiedebergs Ach. exp. Path, and Pharmak., 225, 421 (1955), as well as G. K.roneberg and K. Stoepel, Naunyn-Schmiedebergs Arch. Exp. Path. and Pharmak., 249, 394 (1964).

2. Isolated frog heart according to Sträub, method see H. Fühner, detection and determination of poisons by biological means. Urban and Schwarzenberg, Berlin-Vienna, 1911, pp. 123 bis 129.

3. Measurement of the steepness of the intracardial pressure rise. For method see J. Hamacher, Naunyn-Schmiedebergs Arch. Exp. Path, and Pharmak., 244, 429 (1963).

Investigation results

Hydrochloride des (Pregn-5-en-20-guanylhydrazone-3 / ^ - y l) -N-methyl-N-1 '- (1' -deoxyglucosyl) ~ carbamate

Toxicity mouse: 12.5 to 16.0 mg / kg i.v. v.

Atrium guinea pigs:

Positive inotropic cardiac muscle effect from concentrations of 10 ~ ⁵ g / ml. Turnover to negative inotropic effect with contracture of the heart muscles at concentrations of 10 ~ ⁴ g / ml.

Frog heart:

Positive inotropic cardiac muscle effect with systolic cardiac arrest from concentrations of 1: 30000.

AndrosM-en ^ -guanylhydrazone-17 // - y hydrochloride l) -N-methy 1-N-1 '- (1' -deoxyglucosyl) -carbamate

Toxicity mouse: 3.0 to 4.0 mg / kg i.v. v.

Atrium guinea pigs:

Positive inotropic cardiac muscle effect from concentrations of 3 ■ 10 ~ ⁵ g'ml. Reversal to negative inotropic effect with myocardial contracture at concentrations of 10 ~ ⁴ g / ml.

Frog heart:

Positive inotropic cardiac muscle effects and systolic cardiac arrest from concentrations of 1: 10,000.
Intracardiac pressure rise steepness in the cat:

After infusions of 1.3 mg / kg iv, the • ^s? Pressure rise steepness from normal 4300 to 4480 Torr see. The animal only dies at 10.4 mg kg iv.

Dihydrochloride des (Pregn ^: 4-en-3,20-bisguanyl-

hydrazone-21 -yl) -N-methyl-N-1 '- (1 '-deoxyglucosyl) carbamate

Toxicity mouse: 0.6 to 0.8 mglcg i. v. Atrium guinea pigs:

Positive inotropic myocardial effect from concentrations of 3 · 10 " ⁷ gml. Change to negative inotropic effects with myocardial contracture from concentrations of 3 K)" ⁶ g / ml.

7 8

Frog heart: Intracardiac pressure rise steepness in the cat: Positive inotropic cardiac muscle effect and systo-.

lic cardiac arrest from concentrations of after i. v. infusions of 3.6 mg / kg takes the

j. 5 QQQ steepness of pressure rise from normal 2780 am

Intracardiac pressure rise steepness in the cat: ⁵
After iv infusions of 1.5 mg / kg, the frog heart takes:
Pressure rise steepness from normal 3380 to

5440 torr / sec. The death of the animal only occurs. Positive inotropic cardiac muscle action with systo-

after infusions totaling 4.4 mg / kg. lic cardiac arrest from concentrations of

ίο 1: 5000.
3 - [(1 '-deoxy-D-sorbityl-r) -imino] -

pregn-4-en-20-guapylhydrazone hydrochloride des 3 /? - (D-glucosyloxy) -pregn-5-en-

Toxicity mouse: 12.5 to 16.0 mg / kg i.v. 20-guanylhydrazone

Atrium guinea pigs:, ₅ atrium guinea pigs:

Positive inotropic myocardial effect from concentrations - Positive inotropic myocardial effect from concentrations of 3 · 10 g / ml. Envelope to negative trations of 3 x 10 " ⁵ g / ml,
inotropic effect with myocardial contracture
Concentrations of 3 x 10 " ⁵ g / ml. Hydrochloride des (19-nor-androst-4-en-3-guanyl-

Intracardial pressure increase steepness in the cat: 20 hydrazone-17 /? - yl) -N-methyl-

After i. v. infusions of 0.34 mg / kg takes the N-l '- (r-deoxyglucosyl) -carbamate

^On pressure increase slope l _A ™ ^r ™ ^{1 21} ® ^au f toxicity mouse: 8 to 12.5 mg / kg iv
2340 Torr / sec. The animal does not die until _{,, x,,} . ,

after 3.0 mg / kg. Atrium guinea pigs:

Positive inotropic cardiac muscle effect from concentration

Dihydrochloride of [pregn-5-en-20 - (/ i-diethylamino concentrations of 10 ^-4 g / ml to negative envelope

.. ".,, It. j \ τ ,, η XT ^ t. 1 inotropic effect with contracture of the cardiac

ethyl-guanylhydrazone) -3 /? - yl] -N-methyl-. * ,, . " ⁶ ... _ _irv _ _4,,

'",",,,,,., Musculature at concentrations of 3 x 10 6 g / ml.

N-I - (I -deoxyglucosyl) -carbamate _

Frog heart:

Toxicity mouse: 20 to 25 mg / kg iv ₃₀ Positive inotropic cardiac muscle effect with systo-

Atrium guinea pigs: lischem cardiac arrest from concentrations of

Positive inotropic cardiac muscle effect from concentration 1:10 000.

trations of 3 × 10 ~ ⁷ g / ml. Envelope to negative dihydrochloride of 21- (D-glucosyloxy) -pregn-

Motropic effect with contracture of the cardiac 4-en-3,20-bisguanylhydrazone

muscles at concentrations of 10 g / ml. 35

Toxicity mouse: 2.0 to 3.0 mg / kg i.v.

Frog heart: atrium guinea pigs:

Positive inotropic cardiac muscle effect and systo-

cardiac arrest from concentrations of positive inotropic cardiac muscle effect from concentration

1:10 000. 40 trations of ΙΟ " ⁵ g / ml. Envelope too negative

Hydrochloride des (Spirostan-12-guanylhydrazone- inotropic effect with contracture of the heart

3 /? - yl) -N-methyl-N-l '- (l'-deoxyglucosyl) -carbamate muscles from concentrations of 3 ■ 10 g / ml.

Toxicity mouse: 60 to 80 mg / kg i.V. frog heart

Auricle of guinea pigs: 45 positive inotropic cardiac muscle effects with systo-

Positive inotropic cardiac muscle effect in the case of concentrated cardiac arrest from concentrations of

trations of 10 "^ g / ml. Envelope to negative 1: 10,000.

inotropic effect with myocardial contracture

Concentrations of 3 × 10 ~ ^s g / ml. Intracardiac pressure rise steepness at

Frog heart ⁵ ° guinea pigs:

Positive inotropic cardiac muscle effect with systo- ^{Die by} l, l, l-trifluor-2-chloro-2-bromo-ethane loading

lic cardiac arrest from concentrations of ^{load to} H00 Torr / sec reduced pressure

1 ■ 50 000 steepness of increase is indicated by i. m.-apphcation of

0.1 mg / kg increased to 3065 torr / sec.

Hydrochloride des (Pregn-5-en-20-guanylhydrazone- ⁵⁵ ", _{T 4.} ,,,

3i? -Yl) -N-2 '- (2'-deoxyglucosyl) -carbamate dihydrochloride of 21- (D-tetraacetylglukosyloxy) -

pregn-4-en-3,20-bisguanylhydrazone
Toxicity mouse: 5.0 to 6.5 mg / kg iv

,. .,,. . Toxicity mouse: 1.8 to 2.5 mg / kg i.V.

Atrium guinea pigs: ₆ , _Γ »τ ·

Positive inotropic cardiac muscle effect from the concentration of the auricle in guinea pigs:
concentrations of 3 x 10 ^-5 g / ml. Positive inotropic effect from concentrations of

10 ~ ⁵ g / ml. Change in negative inotropic effect

Hydrochloride of (androst-4-en-3-guanylhydrazone- ^with contracture of the heart muscles at concentrations

17 /? - yl) -N-2 '- (2'-deoxyglucosyl) -carbamate _6j trations of 3-10 g / ml.

Atrium guinea pigs: frog heart:

Positive inotropic cardiac muscle effect from concentration positive inotropic effect with systolic heart

tralions of 10 ~ ⁵ g / ml. standstill from concentrations of i: 10000.

Dihydrochloride of 21- (D-maltosyloxy) -pregn-4-en-3,20-bisguanylhydrazone

Atrium guinea pigs:
Positive inotropic effect from concentrations of ΙΟ " ⁵ g / ml.

Frog heart:

Positive inotropic effects with systolic cardiac arrest at concentrations from 1: 10000 to 1: 20000.

Dihydrochloride of 21- (D-heptaacetylmaltosyloxy) -pregn-4-en-3,20-bisguanylhydrazone

Atrium guinea pigs:

Positive inotropic cardiac muscle effect from concentrations of 10 ~ ⁵ g / ml.

Frog heart:

Positive inotropic cardiac muscle effect with systolic cardiac arrest from concentrations of 1: 10000.

B e i s ρ i e 1 1

1 g of pregn-5-en-3 / i-ol-20-one is dissolved in 200 ml of benzene and 50 ml of tetrahydrofuran, phosgene is passed through the solution for 1 hour and left to stand at room temperature for 1 hour. Then air is passed through the solution for 2 hours and evaporated to dryness in a vacuum. The remaining residue is recrystallized from methanol. This gives 1 g of pregn-5-en-20-one-3 /? - yl-chlorameisensäureester, mp 150 ⁰ C (decomposition)..

This substance is dissolved in 25 ml of acetone and a solution of 1 g of N-methylglucamine in 7 ml of water is added. The mixture is heated under reflux for 3 hours, evaporated to dryness in vacuo, the residue that remains is triturated with a little water and the crystals formed are filtered off with suction. By reprecipitating from methanol-ether, 0.7 g of the starting compound (Pregn-5-en-20-one-3 /? - yl) -N-methyl-N-1 '- (1' -deoxyglucoxyl) - carbamats, m.p. 128 ^° C. (decomposition).

0.5 g (Pregn-5-en-20-one-3 / ° -yl) -N-methyl-N-l'-O'-deoxyglucosyl D-carbamate are dissolved in 30 ml of methanol and with a solution (pH 2) of 140 mg of aminoguanidine hydrogen carbonate in methanolic Hydrochloric acid added. The mixture is left to stand under nitrogen at room temperature for 2 days and is stirred in ether, sucks off the resulting precipitate, boils it several times with acetone and precipitates out Alcohol — acetone around.

0.3 g of hydrochloride of (pregn-5-en-20-guanylhydrazone - 3/3 - yl) - N - methyl - N -1 '- (1' - desoxyglukosyl) carbamate, m.p. 208 ⁰ C (decomposition). .

Example 2

55

Analogously to Example 1, the hydrochloride of (androst-4-en-3) is obtained from (androst-4-en-3-one -1 7β- yl) - N - methyl - N - Γ - (1 '- deoxyglucosyl) carbamate -guanylhydrazone -1 7 β - yl) - N - methyl - N - Γ - (1 '- deoxyglucosyl) carbamate, m.p. 164 ° C (decomposition).

Example 3

Analogously to Example 1, starting from androst-5-en-3/5-ol-17-one, the androst-5-en-17-one-3 / i-yl-chloroformic acid ester is obtained, melting point 108 "C (decomposition) , therefrom by reaction with N-methyl-glucamine serving as the starting compound (androst-5-en-17-one-3 // - yl) -N-methyl-N-l '- (r-deoxyglucoxyl) - carbamate, m.p. 170 ^° C., and from this, by condensation with aminoguanidine, the hydrochloride of (androst-5-en-17-guanylhydrazone-3 /? - yl) -N-methyl-N-l '- (r-deoxyglucosyl) carbamate, m.p. 254 ⁰ C (decomposition).

Example 4

Analogously to Example 1, starting from pregn-4-ene-20 / i-ol-3-one, the pregn-4-en-3-one-20 /? - ylchlorameisensäureester, mp 140 ⁰ C (decomposition). therefrom serving as the starting compound (Pregn-4-en-3-on-20/3-yl) -N-methyl-N-l '- (l'-deoxyglucosyl) -carbamate, melting point 80 to 85 ° C, and from it the hydrochloride of (Pregn-4-en-3-guanylhydrazone-20 /? - yl) -N-methyl-N-1 '- (1' -deoxyglucosyl) carbamate, melting point 170 to 172 ° C (decomposition) .

Example 5

To 160 Analogously to Example 1 are obtained starting from pregn-4-en-21-ol-3,20-dione, the pregn-4-ene-3,20-dione-21-yl-chlorameisensäureester, mp. 162 ⁰ C to (Decomposition), and from it the starting compound (Pregn - 4 - en - 3,20 - dione - 21 - yl) - N - methyl-N-l '- (l'-deoxyglucosyl) -carbamate, mp. 82 bis 84 ⁰ C (decomposition).

370 mg of aminoguanidine hydrogen carbonate are dissolved in methanolic hydrochloric acid until the pH value = 2 dissolved and with a solution of 500 mg (Pregn-4-en-3,20-dion-21-yl) -N-methyl-N-l '- (r-deoxyglucosyl) -carbamate added to 25 ml of alcohol. The mixture is stirred for 24 hours at room temperature under nitrogen, sucks off the precipitated crystals, boils them with alcohol and washes them with ether. 0.6 g of dihydrochloride des (Pregn-4-en-3,20-bisguanylhydrazon-21-yl) -N-methyl-N-l '- (r-deoxyglucosyl) carbamate, Mp. 212 ° C (decomposition).

Example 6

0.5 g (Pregn - 5 - en - 20 - one - 3β - yl) - N - methyl-N-l '- (r-deoxyglucosyl) carbamate are dissolved in 10 ml of ethanol with a solution of 250 mg 1 - (/ 3-diethylamino-ethyl) -3-aminoguanidine hydrochloride is added to methanolic hydrochloric acid and stored for 24 hours at room temperature. It is stirred into ether, the precipitated substance is suctioned off and boiled several times with acetone. 0.4 g of dihydrochloride of [Pregn - 5 - en - 20 - (β - diethylamino - ethyl - guanylhydrazons-3 /? - yl)] - N-methyl-Nr- (r-deoxyglucosyl) carbamate, melting point 190 ° C.

Example 7

Analogously to Example 6, from (androst-5-en-17-one - 3/9 - yl) - N - methyl - N -1 '- (1' - deoxyglucosyl) carbamate and l - (/ 3-diethylamino- ethyl) -3-aminoguanidine hydrochloride the dihydrochloride of [Androst-5 - en -17 - (β - diethylamino - ethyl - guanylhydrazone) -3 / i-yl] -N-methyl-N-l '- (l'- desoxyglucosyl) carbamate, m.p. 193 ° C.

Example 8

Analogously to Example 6, from (androst-4-en-3-one-17 / i-yl) -N-methyl-N-l '- (l'-deoxyglucosyl) carbamate and l - (/ f-diethylamino- ethyl) -3-aminoguanidine hydrochloride the dihydrochloride of [androst-4 - en - 3 - {β - diethylamino - ethyl - guanylhydrazone) -17 / ^ - yl] - N-methyl-Nr- (r-deoxyglukosyn-carbamate, M.p. 78 ° C.

809 560,537

Example 9

2 g of hecogenin are dissolved in 100 ml of dioxane. Phosgene is passed through the solution for 1 hour, then lets stand for 1 hour at room temperature, passes air through the solution for 2 hours and evaporates in the Vacuum to dryness. The solid residue is recrystallized from ethyl acetate. 1.6 g Spirostan-12-on-3 /? - yl-chloroformic acid ester, Mp. 186 ° C (decomposition).

The substance is dissolved in 60 ml of acetone and 1.3 g of N-methylglucamine are added. Afterward water is added until a clear solution is obtained. The mixture is refluxed for 3 hours, the pull Acetone in vacuo, cools the aqueous suspension and sucks the crystals off. 0.9 g (Spirostan-12-on-3 // - yl) -N-methyl-N-l '- (r-deoxyglucosyl) -carbamate, Mp. 154 ° C.

This starting material is dissolved in 20 ml of methanol, mixed with an acidic solution of 250 mg of aminoguanidine hydrogen carbonate in methanolic hydrochloric acid and stored for 3 days at room temperature. It is stirred into ether, decanted, the viscous residue is dissolved in ethanol and again stirred into ether. The crystals are suctioned off and washed with ether. 0.5 g hydrochloride of (Spirostan -12 - guanylhydrazone - 3 β - yl) -N - methyl - N - Γ - (Γ - deoxyglucosyl) - carbamate, melting point 178 ° C (decomposition).

Example 10

30th

1 g of Pregn-5-en-20-on-3 / i-yl-chloroformic acid ester is dissolved in 40 ml of acetone with the solution of 1.15 g of glucosamine hydrochloride and 210 mg of sodium hydroxide are added in 5 ml of water and 10 minutes heated to reflux. Some acetone is evaporated off, stirred for 1 hour at room temperature, The precipitate is suctioned off and recrystallized from methanol. 1.2 g (Pregn-5-en-20-on-3 / J-yl) -N-2 '- (2'-deoxyglucosyl) -carbamate, Mp 205 ° C (decomposition).

This substance serving as the starting steroid is dissolved in 25 ml of methanol, the acidic solution of 350 mg of aminoguanidine hydrogen carbonate in methanolic hydrochloric acid is added and the mixture is stirred for 3 days under nitrogen at room temperature. The precipitate is filtered off with suction, washed with ethanol and boiled with acetone. 1 g hydrochloride of (Pregn-5 - en - 20 - guanylhydrazone - 3 / i - yl) - N - 2 '- (T - deoxyglucosyl) carbamate, melting point 254 ° C (decomposition).

Example 11

240 mg of aminoguanidine hydrogen carbonate are dissolved in methanolic hydrochloric acid to pH = 2, with a solution of 0.8 g of (androst-4-en-3-one-17 / S-yl) -N-2 '- ( 2'-deoxyglucosyl) carbamate is added to 25 ml of methanol and stored for 3 days at room temperature. The ether is stirred in, the flakes which precipitate are filtered off with suction, they are boiled with acetone and precipitated from alcohol — acetone. 0.5 g of the hydrochloride of the (androst-4-en-3-guanylhydrazone Eat -1 - yl) - N - 2 '- (T - desoxyglukosyl) - carbamate, m.p. 246-250 ⁰ C (decomposition)..

Example 12

1 g of 17 / i- [D-tetraacetylglukosyloxy] -androst-4-en-3-one are dissolved in 50 ml of absolute dry spirit. The methanolic solution of the free aminoguanidine base, made up of 200 mg of aminoguanidine hydrochloride and 100 mg of Na in 30 ml of absolute methanol, is added and the clear, light yellow reaction mixture is refluxed for 12 hours. After stirring for a further 48 hours at room temperature, the solution is concentrated to dryness in vacuo, the residue is triturated well with water and dried in vacuo. The free base is then dissolved in a lot of ethanol, carefully acidified with methanolic HCl and stirred in dry ether. The precipitate is filtered off with suction and washed with ether. 0.6 g of hydrochloride of the 17jtf- [D-Glukosyloxy] androst-4-en-3-guanylhydrazons, mp. 196-203 ⁰ C.

Example 13

Analogously to Example 12, 3 /? - [D-Tetraacetylglukosyloxy] -pregn-5-en-20-one is obtained the hydrochloride of 3 / i- [D-glucosyloxy] -pregn-5-ene-20-guanylhydrazone with a melting point of 277 ° C (decomposition).

For example, 14

Analogously to Example 12, 3 / i- (D-tetraacetylglukosyloxy) -pregnan-20-one is obtained the hydrochloride of 3 /? - (D-glucosyloxy) -pregnan-20-guanylhydrazone, Mp. 250 ° C.

Example 15

3 g of 19-nor-testosterone are dissolved in 100 ml of benzene. Phosgene is passed through the solution for 1 hour, kept at room temperature for 1 hour, air is blown through the solution for 2 hours and evaporated to dryness in vacuo. The residue is recrystallized from acetone — H _{2 O.} 3.2 g of 19-nor-androst-4-en-17 / i-yl-chloroformic acid ester, m.p. 70 ^c C.

1.4 g of ^ -Nor-androst ^ -en-S-on-n / i-yl-chloroformic acid ester are dissolved in 25 ml of acetone, the solution of 1.6 g of N-methylglucamine in 2 ml of H ₂ O and heated under reflux for 3 hours. It is evaporated to dryness in vacuo, the residue is triturated with H ₂ O, decanted, the viscous oil is dissolved in CHCl ₃ and dried over Na ₁ SO ₄ . After distilling off, the starting compound (19-nor-androst-4-en-3-one-17 / i-yl) -N-methyl-N-1 '- (Γ-deoxyglucoside carbamate) remains as a colorless powder is dissolved in 20 ml of methanol without further purification, the solution of 400 mg of aminoguanidine hydrogen carbonate in methanolic HCl (pH 2) is added and the reaction _{solution is stored for 3 days at room temperature under N 2.} The mixture is stirred in ether, the precipitate is suctioned off and falls several times from alcohol-ether. 1.3 g of hydrochloride of 17 / i- (19-nor-androst-4-en-3-guanylhydrazone-17jtf-yl) -N-methyl-N-1 '- (1 '-desoxyglukosyl) carbamate, mp. 24O ⁰ C (decomposition).

Example 16

2.1 g of 21 ^ - [D-tetraacetylglukosyloxy] -3,20-dioxo-J ⁺ -pregnene are dissolved in 50 ml of absolute methanol. The methanolic solution of the free aminoguanidine base, made up of 750 mg of aminoguanidine hydrochloride and a sodium methylate solution, is added and the pale yellow, clear reaction mixture is refluxed for 24 hours. A milky, cloudy solution gradually forms, which is concentrated to dryness. The solid residue is digested with water, filtered off with suction and dried in vacuo. The amorphous, light yellow substance is dissolved in ethanol-dimethylformamide (1: 1)

dissolved, the solution acidified with methanolic hydrochloric acid and stirred in ether. The colorless precipitate is filtered off with suction and boiled several times with ethanol. 1.2 g of dihydrochloride of 21β- [D-glucosyloxy] -I ⁴ -pregnen-3,20-bisguanylhydrazone with a melting point of 240 ° C. (decomposition).

Example 17

2 g of 17 / J- [D-tetraacetylglukosyloxy] -androst-4-en-3-one are dissolved in 50 ml of absolute methanol and added to a methanolic solution of 1- [/ i-pyrrolidino-ethyl] -3-aminoguanidine. The clear reaction mixture is refluxed for 24 hours, then concentrated to dryness, dissolved in absolute methanol and acidified with methanolic hydrochloric acid. When stirred into ether, an almost colorless, amorphous precipitate separates out, which is filtered off with suction and 1 ml is recrystallized from dry spirit. The dihydrochloride of the 17 /} - [D-Glukosyloxy] -4-androst-en-3- [l '- (/ i-pyrrolidino - ethyl) - guanylhydrazons] had a melting point of 178 ⁰ C..

Example 18

Analogously to Example 17, 3 / i- [D-tetraacetylglukosyloxy] -pregn-5-en-20-one with 1- (/ i-pyrrolidinoethyl) -3-aminoguanidine gives the dihydrochloride of 3 /: J- [D -Glukosyloxy] pregn-5-en-20- [r - (/ i-pyrrolidinoäthyl) -guanylhydrazons] with the melting point of 28O ⁰ C (decomposition)..

Example 19

2.14 g of 3 / ^ - [D-tetraacetylglucosyloxy] -pregn-5-en-20-one are dissolved in 350 ml of absolute methanol and with a solution of 360 mg of aminoguanidine hydrochloride added in 20 ml of absolute methanol. The pH of the solution is adjusted with methanolic Hydrochloric acid to ~ 4.5. The mixture is stirred for 24 hours at room temperature. The concentrated methanolic The solution is stirred in ether, the precipitate which has been suctioned off is triturated twice with water and dried and falls over from methanol-ether. The hydrochloride des 3 / ^ - [D-tetraacetylglucosyloxy] -pregn-5-ene-20-guanylhydrazone has a mp of 178 "C.

B e i s ρ i e 1 20

Analogously to Example 19, the hydrochloride of 17 / i- [D-tetraacetylglukosyloxy] -androst-4-en-3- is obtained from 17 / i- [D-tetraacetylglukosyloxy] -androst-4-en-3-one with aminoguanidine hydrochloride guanylhydrazone, m.p. 185 ^: C.

Example 21

_{Analogously to Example 19, the dihydrochloride of 21 /} i- [D-tetraacetylglukosyloxy] -J ⁴ -pregnen-3,20- is obtained from 2V- [D-tetraacetylglukosyloxy] -I ⁴ -pregnen-3,20-dione with aminoguanidine hydrochloride bisguanylhydrazone, m.p. from 240 to 248 "C.

Example 22

2.5 g of S ^ -iJD-tetraacetylglukosyloxyj-pregn-S-en-20-one are dissolved in 100 ml of absolute dimethylformamide and 20 ml of absolute methanol. A solution of 1.1 g of 1 - \ _ ß- pyrrolidino-ethyl] -3-aminoguanidine trihydrochloride 111, 20 ml of absolute methanol, is added and the mixture is stirred at room temperature for 40 hours. The substance that precipitates out during the Einfebge-Ί d ' ¹ ' solution is removed.

45 sucks (NaCl) and the filtrate is stirred in ether. The light yellow, crystalline substance is filtered off with suction, dissolved in concentrated form in methanol, acidified with a little methanolic hydrochloric acid and stirred in ether. The trihydrochloride of 3ß - [d - tetraacetylglucosyloxy] - prepregn - 5 - en - 20 - [Γ - (ß - pyrrolidino - ethyl) - guanylhydrazones] has a melting point of 196 to 212 ° C.

Example 23

Analogously to Example 22, 17 / f- [D-Tetraacetylglukosyloxy] -androst-4-en-3-one is obtained with l - [/ i-pyrrolidino-ethyl] -3-aminoguanidine trihydrochloride in absolute methanol the trihydrochloride of 17 / i- [D-tetraacetylglukoxyloxy] -androst-4-en-3- [l '- (/ i-pyrrolidino-ethyl) -guanylhydrazone] with a m.p. of 182 to 188 ° C.

Example 24

Analogously to Example 22, the hexahydrochloride of 21 / i- is obtained from 21 / i- [D-tetraacetylglukosyloxy] - J ⁴ - pregnen - 3.20 - dione with 1 ■ iß - pyrrolidino - ethyl] - 3 - aminoguanidine - trihydrochloride in methanol [D-Tetraacetylglucosyloxy] -J ⁴ -pregnen-3,20-bis- [l '- (/ ^ - pyrrolidino-ethyl) -guanylhydrazone] with a melting point of 200 ° C.

Example 25

2.2 g of 21 / i- [D-tetraacetylglucosyloxy] -. l ⁴ -pregnen-3,20-dione are dissolved in 125 ml of absolute methanol and the methanolic solution of l - (/ i-pyrrolidino-ethyl) -3-aminoguanidine from 1.9 g of the corresponding hydrochloride with sodium methylate is added. After 48 hours of refluxing, the solution is concentrated to dryness, the residue is digested with water, filtered off with suction and dried. It is then taken up in absolute dimethylformamide, acidified with methanolic hydrochloric acid and stirred into dry ether. The pale yellow crystalline substance which precipitates is reprecipitated twice more from methanol-ether. The tetrahydrochloride des21 / f- [D-Glukosyioxy] -J ⁴ -pregnen-3,20-bis- [1 '- (β- pyrrolidino-ethyl) -guanylhydrazone] has a melting point of 88'C (decomposition).

Example 26

1.5 g of 21 ^ - [D-heptaacetylmaltosyloxy] - ^{I 4} -pregnen-3,20-dione are dissolved in 50 ml of absolute methanol. A methanolic solution of the free aminoguanidine base, made up of 400 mg of aminoguanidine hydrochloride and a sodium methylate solution, is added and the clear reaction solution is refluxed for 18 hours methanolic hydrochloric acid acidified and stirred in dry ether. The dihydrochloride of 21 ^ - [D-maltosyloxy] -. L ⁴ -pregnen-3,20-bisguanylhydrazone has a melting point of 217 "C.

27

iieispie

1.5 g of 21 _/ i- [D-heptaacetylmaltosyloxy] -I ⁴ -pregnen-3.20-dione are dissolved in 75 ml of absolute methanol and 400 mg of aminoguanidine hydrochloride in 25 ml of absolute methanol are added. The pH of the reaction solution is adjusted to 4.5 using 2 drops of methanolic hydrochloric acid. Stir for 40 hours at room temperature, then stir in dry ether, suck off the precipitate, twice

Digest with water and dry. The dihydrochloride of the 21 / i- [D-Heptaacetylmaltosyloxy] -J ⁴ -pregnen-3,20-bisguanylhydrazons has the mp. 180 ⁰ C (decomposition).

Example 28

2.7 g (Pregn-5-en-20-on-3 /} - yl) -N-methyl-N-l '- (r-deoxyglucosyl) carbamate are dissolved in 10 ml of ethanol and treated with a solution of 0.8 g of S-methylisothiosemicarbazide hydrochloride added in methanolic hydrochloric acid. It is kept under for 24 hours Nitrogen at room temperature and then stirred into ether. The precipitate is filtered off with Ether washed and reprecipitated from alcohol — ether. 3 g hydrochloride of [Pregn-5-en-20- (S-methylisothiosemicarbazol-Sjtf-ylQ-N-methyl-N-r-tr-deoxyglucosyl) carbamate, Mp. 168 to 171 ° C (decomposition).

This substance is dissolved in 30 ml of ethanol and stirred with ether. The light yellow, crystalline substance is redissolved from ethanol. The dihydrochloride of 21 β - [d - glucosyloxy] - 5α - pregnane - 3.20 - bisguanylhydrazone has a melting point of 228 ° C. (decomposition); 1.1g yield.

Example 31

Analogously, from 21 /? - [D-tetraacetylglukosyloxy] -5 /? - pregnan-3,20-dione, which can be prepared from 5 / i-pregnan-3,20-dione-21-ol analogously to Example 30 can, the dihydrochloride of 21 /? - [D-glucosyloxy] -5 / i-pregnan-3,20-bisguanylhydrazone, Mp 179-185 ° C (decomposition).

Example 32

5 g lo-Cyan-pregn-S-en ^ O-on-S-ol are in 200 ml dissolved in absolute benzene, added 8.5 g of freshly precipitated silver carbonate and a solution of 11.25 g 100 ml of an alcoholic ammonia solution is added 20 acetobromoglucose in 200 ml of absolute benzene and refluxed for 6 hours. Then steamed dripped. About 200 ml of benzene are slowly distilled

it is evaporated to dryness in vacuo, the residue is triturated with a little water and the insolubles are separated off. After drying, this is dissolved in ethanol, ethereal hydrochloric acid is added until the reaction is acidic and the solution is stirred into ether. The precipitate is filtered off with suction, boiled with acetone and reprecipitated from alcohol-acetone. 1.8 g of the hydrochloride des (Pregn-5-en-20-guanylhydrazon-3 / J-yl) azeotrope, allowed to stir under reflux for a further 15 hours, the catalyst is filtered off and the solution is concentrated to dryness. The viscous substance is chromatographed on a silica gel column, and in this way colorless, amorphous 3 / i- [D-tetraacetylglucosyloxy] -16-cyano-pregn-5-en-20-one, which serves as the starting material, is obtained.
3.25 g 3 / J- [D- tetraacetylglucosyloxy] -16 - cyano-

N-methyl-N-r ~ (l'-deoxyglucosyl) carbamate, m.p. 206 30 pregn-5-en-20-one are dissolved in 20 ml of absolute me-

up to 207 ⁰ C (decomposition).

Example 29

Analogously to Example 28, 1 g of “(androst-4-en-3'-one-17 ^ -yl) -N-methyl-N-l '- (l'-deoxyglucosyl) carbamate is obtained and 300 mg S-methyl-isothiosemicarbazide hydrochloride 1.2 g hydrochloride of [Androst-4-en-S-iS-methyl-isothiosemicarbazon-n / J-ylfl-N-methyl-N-r- (l'-deoxyglucosyl) carbamate, Mp. 99 to 101 ° C (decomposition) and from it by reaction with alcoholic Ammonia 0.5 g hydrochloride of (androst - 4 - en - 3 - guanylhydrazone -17/3 - yl) - N - methyl-N-r- (r-deoxyglucosyl) -carbamate, Mp 162-164 ° C (decomposition).

Example 30

2.5 g of 5a-pregnan-21-ol-3,20-dione are dissolved in 150 ml of absolute benzene, 4.5 g of silver carbonate are added and, with slight azeotropic distillation, a solution of 6 g of acetobromoglucose in 150 ml of absolute benzene dripped. The mixture is then stirred under gentle reflux for a further 15 hours, the catalyst is filtered off and the solution is concentrated to dryness. The viscous residue is taken up in ether and allowed to crystallize in the refrigerator. 1.9 g 21 / i- [D-Tetraacetylglukosyloxy] -5 'pregnan-3,20-dione, mp. 160 ⁰ C.

Dissolved ethanol, mixed with a solution of 600 mg of aminoguanidine hydrochloride in absolute methanol and brought to a pH of 4.5 to 5 with methanolic hydrochloric acid. After stirring for 60 hours at room temperature, the clear solution is added dropwise to dry ether. The colorless, crystalline precipitate is digested once with a little water, filtered off with suction and dried; 2.5 g hydrochloride of S ^ D-tetraacetylglucosyloxyl-lo-cyano-pregn-S-en-20-guanylhydrazone, m.p. 190-193 ° C (decomposition). For further characterization, the obtained hydrochloride of 3 / S- [D-tetraacetylglukosyloxy] -16-cyano-pregn-5-en-20-guanylhydrazone is dissolved in aqueous methanol and mixed with dilute sodium hydroxide solution. The precipitate is filtered off with suction, dried, dissolved in dry spirit and acidified with methanolic hydrochloric acid. The acidic solution is stirred into dry ether and the colorless crystalline precipitate is filtered off with suction. The hydrochloride of the 3 / 7- [D-GIukosyloxy] -16 - cyan - pregn - 5 - en - 20 - guanylhydrazones melts at 195-200 ⁰ C (decomposition).

Example 33

From 1.7 g of pregn-5-en-7,20-dione-3-ol, in a manner analogous to Example 32, 600 mg of 3 / i- [D-tetraacetylglukosyloxy] -pregn-5-en-7,20- dion, Mp 198-200 ° C. 250 mg of this as starting material serving sugar derivative are in 50 ml of absolute

1.9 g of the starting compound used
21 / i- [D-tetraacetylglukosyloxy] -5tt-pregnan-3,20-di- 60 methanol dissolved, 100 mg of aminoguanidine hydrochloride are dissolved in 30 ml of absolute methanol and added in methanol and the solution with methano with the methanolic solution of Aminoguanidine,
from Ig aminoguanidine hydrochloride with sodium methylate added. After 20 hours of heating under
The reflux is concentrated to dryness and 65 is digested
the residue with water, filtered off with suction and dried.

Take up in absolute dimethylformamide, acidify with methanolic hydrochloric acid and in dry

Lischer hydrochloric acid adjusted to pH 4. After stirring for 24 hours, it is added dropwise to dry ether, and the precipitate is filtered off with suction and digested
little water. Vacuuming and drying. That
hydrochloride of 3ß- [d-Tetraacetylglukosyk
pregn-5-en-7,20-bisguanylhydrazone melts
up to 213 C (decomposition); 250 mg yield. \ j

Example 34

510 mg of 3 /? - [D-tetraacetylglukosyloxy] -pregn-5-en-7,20-dione (Example 33) are reacted with 340 mg of aminoguanidine hydrochloride in absolute methanol with sodium methylate analogously to Example 30. The dihydrochloride of 3 / - [D-Glukosyloxy] pregn-5-en-7,20-bisguanylhydrazons melts at 205-210 ⁰ C (decomposition)?; 200 mg yield.

Example 35

6.2 g prednisone
17 «, 21-diol) are dissolved in 450 ml of absolute dioxane and 100 ml of absolute benzene; in addition 10 g of silver carbonate and 15 g of acetobromoglucose in 300 ml of benzene. About half of the reaction volume is allowed to distill off within 2 hours. Then 15 hours of heating under reflux, filtering off the catalyst and concentrating to dryness. After chromatography on a silica gel column, 21β- [D-tetraacetylglucosyloxy] -pregna-1,4-dien-17a-ol-3, l 1,20-trione is obtained as an amorphous, colorless substance which serves as the starting material. Analogously to Example 32, the dihydrochloride of 21β- [D-tetraacetylglukosyloxy-pregna-1,4-dien-17u-ol-II-one-3,20-bisguanylhydrazone, melting point 185 to 190 ° C., is obtained therefrom.

Example 36

3.4 g 21 /? - [D-Tetraacetylglukosyloxy] -pregn-4-en-3,11,20-trione, Mp. 170 to 172 ° C, represented analogously Example 30 from Pregn-4-en-21-ol-3, ll, 20-trione are reacted analogously to Example 30 with aminoguanidine. The dihydrochloride of 21 /? - [D-glucosyloxy] -pregn-4-en-II-one-3,20-bisguanylhydrazone has a melting point of 245 ° C; 2.1g yield.

Example 37

2.1 g 21 / i - [d - Tetraacetylglukosyloxy.] - pregna-4,6-diene-3,20-dione, mp 170 to 173 ⁰ C, prepared analogously to Example 30 from pregna-4,6-dien-21-ol -3,20-dione are reacted analogously to Example 30 with aminoguanidine in methanol. The dihydrochloride of 21/9 [D-glucosyloxy] -pregna-4,6-diene-3,20-bisguanylhydrazone melts at 231 ° C. (decomposition); 1.2g yield.

Example 38

3 g 2lß - [D- Tetraacetylglukosyloxy] -. Pregnal, 4-diene-3,20-dione, mp 163 ⁰ C, prepared analogously to Example 30 from pregna-l, 4-dien-21-ol-3,20-dione are reacted analogously to Example 30 with aminoguanidine in methanol. The dihydrochloride of 21 / i- [D-glucosyloxy] - pregna - 1,4 - diene - 3,20 - bisguanylhydrazone melts at 210 to 215 ° C (decomposition); 1.5g yield.

Example 39

2.2 g of 21 / i- [D-tetraacetylglukosyloxy] -pregn-4-en-17 «-ol-3,20-dione, Mp. 165 ° C, prepared from Pregn-4-en-17 ", 21 -diol-3,20-dione (Reichstein-S-alcohol) analogous to Example 30, are analogous to Example 30 with aminoguanidine implemented in methanol. The dihydrochloride of 21 / i- [D-glucosyloxy] -pregn-4-en-17u-ol-3,20-bisguanylhydrazone melts at 258 "C (decomposition); 1.0 g yield.

Example 40

2.5 g 21 /? - [d - Tetraacetylglukosyloxy] - pregn-4-en-110-ol-3,2O-dione, melting point 175 ° C, prepared analogously to Example 30 from Pregn-4-en-II / ?, 21-diol-3, 20-dione are reacted analogously to Example 30 with aminoguanidine in methanol. ? The dihydrochloride of 21 / - [d-G1ukosyloxy] pregn-4-en-11 .beta.-ol-3,20-bisguanylhydrazons has a melting point of 230 ⁰ C (decomposed);. 1.05 g yield.

Example 41

5 g of (Pregn-5-en-20-on-3 / i-yl) -N-methyl-N-l '- (l'-deoxyglucosyl) carbamate are dissolved in 100 ml of ethanol with 1.5 ml of hydrazine hydrate for 30 minutes heated to reflux. It is concentrated to about 20 ml, the precipitate is filtered off with suction after adding a little water, it is dissolved in ethanol after drying, ethanolic hydrochloric acid is added until the reaction is acidic and the solution is stirred into ether. The precipitate is filtered off with suction, washed with ether and dissolved in 100 ml of iso-amyl alcohol. After adding 1 g of cyanamide, the mixture is refluxed for 12 hours. Then it is evaporated to dryness in vacuo, the residue is dissolved in a little ethanol and stirred into ether. The resulting precipitate is filtered off with suction, boiled several times with acetone and reprecipitated from alcohol-ether. 0.4 g of hydrochloride of (pregn-5-en-20-guanylhydrazone-3 /? - yl) -N-methyl-N- V- (I '-desoxyglukosyl) carbamate, m.p. 205 to 208 ⁰ C (dec. ).

Example 42

1.1g of l- (ß- pyrrolidino - ethyl) - 3 - aminoguanidine hydrochloride is dissolved in methanolic hydrochloric acid and the solution 1 g of (Pregn-4-en-3,20-dion-21-yl) -N-methyl- N-l '- (l'-deoxyglucosyl) - carbamate in 50 ml of ethanol. The mixture is stirred for 24 hours at room temperature, the precipitate is filtered off and boiled with acetone. 1.2 g of tetrahydroethyl) guanylhy drazon] -21-yl} -N-methyl-N-1 '- (1' -deoxyglucosyl) carbamate, melting point 200 ° C. (decomposition).

Claims (1)

Claim: Method of making steroid guanyl hydrazones, characterized in that a steroid is one or more aliphatic Residues with three or more hydroxyl groups, which can also be acylated or etherified, where these sugar-like aliphatic residues also in the heterocyclic furanose or pyranose form are present and can still contain carbalkoxy groups, and additionally one or contains several keto or aldehyde carbonyl groups, either in a manner known per se a) with an aminoguanidine of the general formula H ₂ NNC-NHB E NA or a salt of such converts or b) with an S-Alkylisothiosemicarbazid der general formula H ₂ NNC = NA
E S-alkyl react and an amine of the general formula on the condensation product H ₂ N - B can act or
c) with a hydrazine of the general formula H ₇ N -NH condensed and then with a cyanamide of the general formula NCNH-B. or an S-alkylisothiourea of the general formula N / A Il Alkyl - S - C - NHB converts, where A and E are hydrogen or a branched, unbranched or alicyclic Alkyl chain with 1 to 6 carbon atoms, which are substituted by one or more hydroxyl groups can, stand, B hydrogen, one substituted or unsubstituted with one or more hydroxyl groups, branched or unbranched or alicyclic chain with 1 to 6 carbon atoms, the also, optionally via a heteroatom, such as N, O or S, can be connected to A, a Nitro or an amino group or a basic radical of the general formula D. (CH ₂ ) ,, - N where η = 0 to 8 and / = 1 or 2, and R and R ₁ each represent hydrogen, for identical or different, with one or more OH groups substituted or unsubstituted, branched, unbranched or alicyclic alkyl groups up to 6 C atoms, which, if appropriate, can also be connected to one another via a hetero atom such as N, S or O, are present.