JPS5948500A - Novel 14-aminosteroid, preparation and therapeutical use - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention, carried out in the laboratory of C.ERES (European Scientific Research Center), relates to novel steroid derivatives, more specifically, 14-
Concerning aminosteroids, their preparation and use in therapy.

Haiga Patent Application No. 2,464,270 describes compounds of the 14-aminosteroid type, in particular hydroxyl derivatives of 14-aminoantrostane and 14-amino-21-norpregnane. Furthermore, the 14th position was substituted with an amino group.

Pregnane steroid-based and anthrostane steroid-based alkaloids P are known. For example, x --7
, x, Astier (A, Astier) et al., Bu
ll, Soc.

Ghim, A9-IO, I), 1581-15
82 (1976), 14β-amino-roβ, 20α-
Pregnanediol is listed. Furthermore, Astea et al., Tetrahearon, Vol.
p. 1481-1486 (1978), another 14
β-Aminopregnane and 14β-aminoandroscune are described. However, the use of the above derivatives in pharmacological substances and therapy is not described.

Furthermore, therapeutically effective amine derivatives of atheroids are known. For example, Haiga Patent Application Nos. 2,494,697 and 2,494.698 include 6(5α)-amino-17α, 20-pregnanediol, 3(5α)
-Amino-19-nol-20-pregnanols and amine derivatives are described as having immunotherapeutic properties and can be used as treatment agents for autoimmune diseases due to the absence of certain lymphocytes.

The applicant's research has surprisingly revealed that novel amine derivatives of steroid P, more specifically, substituted at the 14-position with an amine group, substituted at the 6-position with a sugar residue, and, in some cases, 2 with a complementary and roxyl group at the 12th position
0-pregnanol derivatives and 21-nol-20
- It has been found that pregnanol derivatives have positive inotropic and antiarrhythmic properties.

The object of the present invention is therefore new 14-aminosteroid derivatives in the 6-position with sugar derivatives and their salts with inorganic or organic acids.

A further object of the present invention is to convert 14-aminosteroids with one 6-position substitution with sugar derivatives into 6゜20-dihydroxy-14-aminosteroids or 3,12.20-aminosteroids.
-trihydroxy-14-aminosteroid F.

The present invention further provides a novel monomer substituted at the 6-position with a sugar derivative.
Pharmaceutical compositions containing as active substances 4-aminosteroids and one or more of the novel 14-aminosteroid derivatives or pharmacologically acceptable salts in combination with one or more optional adjuvants. It relates to use in the treatment of humans and animals as a treatment agent for diseases.

The novel 14-aminosteroid derivative according to the present invention is
General formula (I) (wherein Rt/'i represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R1 is
represents an optionally substituted sugar residue, R2 represents a hydrogen atom, a hydroxyl group or -OR, where:
R3 represents a sugar residue that can be substituted depending on the case).

The novel 14-aminosteroid derivative of general formula (1) has a large number of asymmetric carbon atoms in its molecule, especially 3,
It has carbon at the 5, 14, 17, and 21 positions, and is rounded, R
When 2 is not a hydrogen atom, it has carbon at the 12th position, and therefore can exist in various stereoisomeric forms. The invention thus relates to new products of general formula (1) in the form of single isomers or mixtures.

The invention furthermore relates to 14 of the 14-aminosteroids of the general formula (1), in particular the salts obtainable by reaction with inorganic or organic acids according to known methods. The acids used are hydrochloric acid, oxalic acid, tartaric acid, Shima A [,12,1,1
f>2. p) Luenesulfonic acid, formic acid, beautifying hydrogen acid,
It can be selected from maleic acid, sulfamic acid, etc.

In the above general formula (11), R is preferably a hydrogen atom or a methyl group.

The sugar residue represented by H in the general formula (1) may be a monosaccharide residue, an oligosaccharide residue, or a polysaccharide residue that can be converted into 4 in some cases.

R, may be, for example, a monosaccharide residue, in particular for example 2-desoxyhexoso, 6-desoxyhexose, 2,6-didesoxyhexose, 2-desoxyhexose, 2-desoxyhexose, 2-desoxyhexose, 2-desoxyhexose, 2-desoxyhexose,
amine hexose, 6. ．． 7 denxy 6-amine hegysose, 6-dexy 6-methoxyhexose, 2,
From forming 3,6-tridesoxyhexose, 4,6-didesoxy-4-methoxyhegysose, 2,3,6-tridesoxy-2,5-didehydrohexose, etc.
It may optionally be a modified or (substituted) pentose or hexose.

Examples of monosaccharides that can be used in the present invention include, among others:
Glucose, rhamnose, fructose, galactose, mannose, arachinose, digitose, cimarose, xylose, liquinose, ligose, digitalose, 6-desoxyglucose, glucosamine, 4-amino-2,4,6-denxylyxohexquinyranose,
4-amino-4,6-ditesoxy2 licobylanose, 2
, 6-didesoxyrhamnobilanose, 4-methoxy=4
．． Examples include 6-dydenxyramnobilanose. The β-D or α-L anomer is preferred. Additionally, disaccharides (eg, zatucarose, maltose, lactose) or various polysaccharides can also be used.

As mentioned above, the 14-aminosteroid derivative according to the present invention can exist in the form of various stereoisomers since a large number of asymmetric carbon atoms are present in the steroid 1' skeleton. In the general formula (11) according to the present invention, the substituent -OR at the 6-position jffj
,,5 hydrogen atom, the group B2 at the 12th position, the group -NH2 at the 14th position and the substituent -C; HRO)1 at the 17th position preferably have a β-vertical configuration. This configuration is limited; for example, a 5-position hydrogen atom may have an α configuration. When R is an alkyl group, 20
The 10H group in position can have a 1, α or β configuration.

The present invention particularly relates to 14-aminosteroid I'am substituted as follows. 3-0-(α-L-rhamnopyranosyl)-14β-amino-21-nol-5β-pregna/-roβ,20-diol, 3-0-(α-L-rhamnopyranosyl)-14β-amino-5β- Pregnane
Roβ, 20α diol and its 20β isomer, 3-0
-(β-D-digitoxocyl)-14β-amino-5β
-pregnane-6β, 20α diol, 3-O-(4-
Amino-2,ro,6-tridesoxyalpha-sylixohequinpyranosyl)-14β-amino-5β-biregnane-6β,20α-diol,6-〇-(α-munopyranosyl)-14λ-amino-21- Nor-5β-
Pregnane β.

12β,20-)liol,ro-0-(α-L-rhamnopyranosyl)-14β-amino-5β-pregnane-6
β, 12β, 20β-triates and their 20α
Isomer, 6-〇-(β-D-digitoxocyl)-14β
-amino-5β-pregnane-6β, 12β, 20β-
triol and its 20α isomer, 3.12-0-(
α-L-rhamnopyranosyl)-14β-amino-5β-
Pregnane-6β, 12β, 20β-trio-nod.

The novel 14-aminosteroid visiting conductor of the general formula (1) has the following general formula (■) (wherein R represents a hydrogen atom or a lower alkyl group (preferably a methyl group), R/2
is a hydrogen atom and a hydroxyl group.
The 4-amino steroid is protected by protecting the group -NH at the 14-position and the group -OH at the 20-position, and optionally further protecting the group -NH at the 14-position and the group -OH at the 20-position.
The group -OH at the 14 position represented by 4 is also protected, and then the general formula R, -X (wherein R.

has the above-mentioned meaning, X represents a halogen atom or an acetyl group) with an activated sugar, and then,
In some cases, it can be prepared by removing the protecting group.

Activated sugars include, for example, tri-0-acetyl digitoxose, tri-0-acetyl-α-L-rhamnosyl bromide, and tri-0-benzoyl-2,4°6-tridesoxy4.
-Trifluoroacetamide-α,β-L-rigisohexopyranoside acetyl, 2,6-di-O-acetyl-4
, 6-didesoxy 4-trifluoroacetamidoglycopyranosyl, tetra-0-acetyl-α-D-licosyl, and the like.

The group -NH at the 14th position and the group -OH at the 20th position are protected by a conventional method. For example, the group -NH.

is reacted with trinoroacetic anhydride in the presence of triethylamine to form a trifluoroacetamide group -NHC
OC:F, or can be converted to formamide F groups by reaction with acetic anhydride in formic acid. The group -OH is
Acetylation can be achieved by reaction with acetic anhydride in a suitable solvent (eg pyridine).

It is preferable that the functional groups of the sugar derivative are protected before the conjugation reaction with the 14-aminosteroid. The hydroxyl groups of the sugar derivatives can be protected in conventional ways, in particular by acylation or benzoylation. For example, the hydroxyl group of digitoxose or rhamnose can be converted to an acetoxy group by acetylation with acetic anhydride.

As sugar protection methods, in particular, Chem, Ber, yr,
53 T), 2662 (1920), described by E. Flscher et al. In some cases, the amino groups present in the sugar derivative are also protected beforehand by an acyl group (preferably a trifluoroacetyl group).

After binding the sugar derivative and the 14-amino steroid,
The protecting group is removed by conventional methods (eg, by heating in a basic medium).

The coupling reaction is carried out in a suitable solvent with the preprotected sugar derivative at the level of the asymmetric carbon atom and 1 with protective groups introduced at the level of the 1h'' substituents at the 14 and 20 positions.
This is carried out by reacting the hydroxyl group at the 6-position of a 4-aminosteroid.

Generally, equivalent amounts of sugar derivatives are used, but excesses can also be used. For example, 1.5 to 2.5 moles of sugar derivative may be used per mole of 14-aminosteroid.

Binding condition V'1, the usual method, e.g. Niekerk (N
The combination method of Ekerk et al.
aA 2B1), 123 (1972), Meyer et al.
m, Ber, s, lQ4 p, 1 (1971)
) can be selected based on 2,6-didenoxyhexose or 4-amino-2゜4.6-to'J
When using desoxyhequinose, use the Boa pin (Boa pin)
ivin) et al.'s method ('retrahearonLet
It is advantageous to carry out the combination according to Fersp.

The binding reaction is carried out at room temperature in a solvent (penzeno, toluene,
The reaction can be carried out in acetonitrile, methylene chloride, dioxane, or a mixture thereof according to the above method, but depending on the reactants used, it may be advantageous to activate the reaction by heating.

The coupling reaction is preferably carried out with the hydroxyl group at the 6-position of the 14-aminosteroid, which is protected at the 14- and 20-positions, but unprotected at the 12-position. That is, the reactivity of the hydroxyl ν1 at the 6-position is, in some cases, much greater than the reactivity of the hydroxyl group at the 12-position. The 6- and 12-position sugar derivatives formed as secondary products during the conjugation reaction can be easily separated. In order to form a sugar derivative mainly at the intermediate position and the first position at the 12th position, it is sufficient to react with an excess of the sugar derivative.

The 14-aminosteroid of the general formula (Il+ in which the island is a hydrogen atom) used as a starting material is 17
A 3,14-dihydroxysteroid P containing an acyl group -COR (where R represents a hydrogen atom or an alkyl group) at the position is reduced and acetylated to form a
6°14.20-trihydroxysteroids acetylated at the 0 position and the product treated with a hydronitridic acid/'boron trifluoride complex followed by reduction with metal hydrides or by catalytic hydrogenation. It can be prepared by: General formula (■) (in the formula, R't'
The 14-amino steroids (i-hydroxyl group) can be prepared from 12,20-trihydroxy steroids in a similar manner as described in our Haiga patent application No. 83.10031.

For example, general formula (■) (wherein, R is a methyl group, R
'2 is a hydrogen atom) 14β-amino-
5β-pregnane-6β,20α-diol is 20-
Oxo-5β-pregnane-6β.

The 14β-diol was reduced with potassium borohydride and then acetylated with acetic anhydride in pyridine to give 6,20
-G-O-acetyl-5β-gredanan-3β, 14β
, 20β-triol by treating the product with hydronitridic acid in the presence of an ethereal distillate of boron trifluoride and then reducing it with a lithium hydride/aluminum hydride mixture. Can be prepared. Furthermore, the method of Asteir et al.
34 p., 1481-1486 (1978)) can also be used.

It is represented by general formula (1). The 14-aminosteroid derivatives have, as already mentioned, advantageous drug effects, in particular positive inotropic and antiarrhythmic properties, and can be used in the treatment of heart diseases in humans and animals.

The invention will be explained in detail in the following examples.

Example 1 3-0-C//-D-digitoxocyl)-14β-amino-21-nol-5β-pregnane-6β, 14β-amino-21-nol-5 in 40 ml of 20-diolpyridine
A solution in which 3.2 g of β-pregnane-3β,20-diol was dissolved was cooled to 0°C, and while stirring, acetic anhydride i
me was added.

After stirring for 30 min at 0°C, a low-cost aqueous sodium bicarbonate solution was added to the reaction mixture and stirred for an additional 10 min.
After that, it was extracted with methylene chloride and dried under vacuum.

The residue (3,62f) was crystallized in a benzene/hexane mixture to give 20-〇-acetyl-14β-amino-2
1-nol-5β-pregnane-3β.

20-diol was obtained (yield: 8%).

'2 derivative 6.661 in anhydrous methylene chloride 100rn
1. To the melt, which had been dissolved in water and cooled to 0° C., 3.4 m5 of triethylamine and 3.1 ml+ of trifluoroacetic anhydride were added with magnetic stirring. The mixture was stirred for 20 minutes, returned to room temperature, and then dried under vacuum. The residual aroma was dissolved in methylene chloride, and the resulting solution was dissolved in 6.1 O(]1(
Washed with sodium carbonate solution and water, then dried in vacuo. 600% of the obtained product is methyl alcohol.
meK intoxication (7, then filter O filled with resin lR45
It was passed slowly through the 0me column for 5 hr (OH stage).

Pure, uncrystallized 2O-O-acetyl-
14β-trifluoroacetamide-21-nol-5
4.52f of β-pregnane-roβ,20-diol was obtained.

The above derivative 0.339 and tri-acetyl 0.4
In a solution of 0f dissolved in 50 mt of benzene, anhydrous p
-) 0.35f of luenesulfonic acid was added. After stirring for 111 r at room temperature, saturated sodium bicarbonate solution was added to the reaction product and extracted with methylene chloride. Residue (0,
67) was chromatographed (silica: Merck H60, eluent: Hexano 75/ACOEt25).

3-0-(zi〇-lo, 4-acetyl)-20-0-acetyl-14β-trifluoroacetamide-21-nol-5β-pregnane-6β, 20-diol and 3-
0-(β-D-digitoxocyl)=20-0-acetyl-14β-trifluoroacetamido-21-nol-5β-pregnane-6β, 0.4y of a mixture with 20-diol was obtained.

To a solution of the above mixture dissolved in 16 ml of methyl alcohol, 4-5N caustic soda was added with stirring, and 2.5
Heat the addition to reflux for hr. The obtained product (0°27 mm) was subjected to chromatography (silica: Merck H60,
Eluent: CHz Ge 293 /MeOH7/N
H4OH[], 4). Next, the β-D derivative was crystallized in a mer/ether mixture.
．． 151 and α-D anomers o, iir were obtained.

Melting point F=198-199℃ (β-D anomer) 226
°C (α-D anomer) 1αD+−31° (G = i, CHC-IJs)
NMR spectrum (CDC&) δ-0,93 (CH3-19) 0.98 (CHs
18) 1.60 (GHs (S') 4.87 (H-
1') ppHl (β-D anomer) δ-0,95 (CH319) 1.00 (CHs 18
) 1.31 (CH36') 4.99 (Hi') ppm
(C1-D7 nomer) Example 2 3-0-(α-L-rhamnopyranosyl)-14β-amino-21-nol-5β-pregnane-6β.

20-diol 20-acetyl-14β prepared as described in Example 1
-trifluorosetamyl-21-/--5β-zolecnan-6β, 2o-diol 4°62 and 2,3.
To a solution of 6.951 ml of 4-tri0-acetel-α-L-rhamnosyl bromide dissolved in 235 ml of 7-tonitrile was added 96 ml of mercury cyanide/L. After stirring at room temperature for 1 hour, the mixture was diluted with methylene chloride, extracted, and washed with a saturated sodium carbonate solution. The obtained crude product (7
, 82r) was chromatographed (silica: Merck H60, eluent: CH2G4/MeOH0,3
X).

Uncrystallized pure 6β-0-(2,3,4-tri〇-acetyl-α-L-rhamnopyranosyl)-20-〇-acetyl-14β-trinoroacetamide-21
-nol-5β-pregnane-6β, 20-diol 5
．． 369 was obtained.

To a bath solution in which the above derivative 4.61 was dissolved in 130ml of methyl alcohol, 5N caustic powder 32g was added, and 4f
Heat the addition under IR reflux. Then j:+! Diluted with methylene chloride and washed with water followed by unsaturated sodium chloride solution (retaining sufficient methyl alcohol acidity).

Treated with thin layer chromatography and treated with methyl alcohol/
Crystallization in an ether mixture gave 62 products.

Melting point t゛-244℃ laDl =-53° (G = 1, CHC-g
s80/MeOH20) NMR spectrum (GDG1
3s) δ=L1.90(CH319)0.95(CHa
18) 1. 20(CH3-6')4.82(I(-
1') I)pm Example 6 2O-O-acetyl-14β-trifluoroacetamide-21=nor- prepared as described in Example 1
To a benzene solution containing 0.61 F of 5β-pregnane-6β,20-diol, 0.657 F of mercury 77 and 0.24 F of mercury bromide were added. 2,6-acetyl-4°6-didesoxy-4-trifluoroacetamide 1 glucopyranosyl bromide is added to benzene 6d while reducing.
A solution containing 277 particles was added. After 1 hour of slow boiling,
A bath solution in which 0.279 bromine sugar was dissolved was added to 6 ml of benzene, and after 1 hour, 4 ml of benzene was added. A solution in which 0.27 r of bromo sugar was dissolved was added. The mixture was refluxed for 2.5 hours, cooled, diluted with methylene chloride, and extracted with saturated sodium bicarbonate solution. Evaporate the organic solvent and remove the residue (
1,05F) was chromatographed (silica:
Merck H60, eluent: CH, Ce2/MeOH
0.4%).

0.46 r of pure product was obtained which crystallized in an acetone/hexane mixture.

Add 5 ml of 5N caustic soda to a bath solution in which the above product was dissolved in 1/4 ml of methyl alcohol, heat under reflux for 3 hr, then dilute with water, and dissolve in methylene crystallized Extracted with. 0.182% of product was obtained which crystallized in the ethyl alcohol/ether mixture.

Melting point F = 233°C 1 aDl −-34° (G = 1, C)
]C,,&3) Example 4 3-○-(4-amino-2,4,6-trigsoquine-α
-L-lyxohexopyranosyl) -14β-amino-
21-nol-5β-pregnane-6β,20-diol 1 described in Example 6 of Haiga Patent No. 2.464,270
4β-amino-21-nol-5β-pregnane-3β
, 20-diol 1. To a solution of F3f in 39.6 rnl of formic acid was added 24-acetic anhydride at room temperature. The mixture was heated to 60°C for 30 min 7 Iu and then to 100°C. Next, 8 m of acetic anhydride! , and reacted at 100° C. for about 1 hr.

After cooling, it was diluted with water, extracted with dichloroethane, washed with aqueous bicarbonate, dried over sodium sulfate, and evaporated.

2.17 t of the resulting mixture of two neutral products +
42 ml of a 0025N methyl alcohol solution of caustic soda cooled to 5° C. was added. After standing at room temperature for 1 hr, it was diluted with water, extracted with methylene chloride, and washed to obtain a foamy residue 2.28F.

2.18 f of the above product to 12 m7 of pyridine! The solution was cooled to -15°C in a water bath. Acetic anhydride 0.5
5 F was added, and the temperature was raised to room temperature over 2 hours without taking it out from the water bath. Then, at -15°C, 0.1 acetic anhydride
6f was applied twice. The temperature was increased after each addition.

120ml of water was added. It was extracted with benzene, washed with a 5% aqueous citric acid solution, and then washed with water.

The crude product thus obtained was chromatographed (column: silica, centrifugal agent dichloromethane 98/
Methyl alcohol 2). Crystallized in a benzene/isopropyl ether mixture to give 20-acetyl-14β-
Formylamino-21-nol-5β-predanane-6
β,20-nol 1.23F was obtained (yield 60%).

The above product 0.60? and 3-0-benzoyl2.
4.6-) lysotuxi 4-trifluoroacet 7°miP-α, β-L-lyxohexopyranoside acetyl i,
, anhydrous p-)luenesulfone eO15P was added to a mixture of 50/j4fL of benzene/j4fL of methylene and 80% of a mixture thereof, cooled, and stirred at room temperature for 3 hr iW. Add
Extracted with methylene chloride. Balled crude product (1,66
9) was subjected to chromatography treatment (silica: Merck H60, releasing agent: 3 hexane/1 part acetone) to obtain α-L-
Anomer/β-L-anomer mixture 0.84 F was obtained. 0.50 y of pure α-L-anomer was isolated by crystallization in an acetone/hexane mixture.

α-L-ammer was dissolved in methyl alcohol 2411Le, 6 rnl of 5N caustic soda was added, and the mixture was heated under reflux for 1 hr. It was diluted with water and extracted with chloroform. Thus, the protecting group was removed and crystallization in a methyl alcohol/ether mixture gave the desired product 0.369.

Melting point F = 219-220°C 1αDI = -91°CG = 1, OH(J3)NM
R spectrum (CDCts) δ-0,96 (CH319) 1.00 (CHs
18) 1.17(CH36')4.91(H-1')p
pm Example 5 3-0-(β-D-digitoxocyl)-14β-amino-5β-pregnane-6β,20α-diol Based on the method described in Example 1, 14β-amino-5
β-pregnane = β, 20α-diol 1.71 was treated with acetic anhydride and the product obtained (amorphous state)
was reacted with trifluoroacetic anhydride and crystallized in an ether/'hexane mixture to give 20-○-acetyl-1
4β-trifluoroacetamibia 5β-pregnacy 6β,20α-diol 2.42 was obtained.

Similar to Example 1, the above product 0692 was reacted with 1 of tri-O-acetylnogitoxose in 120 rrL of benzene in the presence of 0.81 of anhydrous p-toluenesulfonic acid.
．． 1y was reacted.

After washing and extraction, treat with caustic soda while heating under reflux,
After purification, the β-D-anomers o, ssr and a were crystallized in a methyl alcohol/diethyl ether mixture.
-D--7/? -0,269 was obtained.

Melting point F = 208℃ (β-D-ano de-) 1αD+
--26° (C=1.5, CHC73) Example 6 Ro-0-(α-L-rhamnopyranosyl)-14β-amino-5β-pregnane-Roβ,20α-diol Operated in the same manner as Example 5 . However, in this case, in acetonitrile and in the presence of mercury cyanide, 2.5.4
-1-R-O-acetyl-α-R-rhamnosyl.

After reaction at room temperature for ihr, diluted with salt 1 himethylene, treated with saturated bicarbonate solution and purified by chromatography on a silica column, 6β-O~
(2,3,4-tri0-acetyl-α-L-rhamnopyranosyl)-20-0-acetyl-14β-trifluoroacetamide-5β-zoregnan-3β,20α-diol was obtained.

To the above product dissolved in methyl alcohol was added 5N caustic soda and heated under reflux for 8 hours. 6-0-(α-L-rhamnopyranosyl)-14β-amino-5β-pregnane-6β, diluted with water, extracted with methylene chloride, and crystallized in an ethyl alcohol/diethyl ether mixture.
, 20α-diol was obtained.

Melting point F = 265°C lαD+ = -49° (C = Q, 8. GHGts 80
/MeOH20) NMR spectrum (CDC1, +CD40) δ-0,
96 (CH319) 1.00 (CH318) 1.0
6 (OH5-21) 1.28 (CH3-6'), 4
．． 90(H-1')1)l)m Example 7 3--0- (α-L-rhamnopyranosyl)-14β~
Amino-5β-norgnan-6β,20β-diol As in Example 1, 14β-amino-5β-pregnacy β,20β-diol was reacted with acetic anhydride, and then trifluoroacetic anhydride was reacted to give 20 -Acetoxy-14β-trifluoroacetamide-5β-pregnathic β,20β-diol was prepared.

Based on the coupling procedure described in Example J2, the above product was converted to the bromide of 2.3.4-) ly○-acetyl-α-L-dimnosyl in acetonitrile in the presence of mercuric cyanide. he reacted. After treatment with caustic soda in methyl alcohol with heating under reflux and crystallization in ethyl alcohol, 10-(α-L-rhamnopyranosyl)-14β-amino-5β-pregnane-6β,
20β-diol was obtained.

Melting point F = 265-264°C 1αDI = -52° (c = 0.7, CHCts 3
Q/MeOH20) NMR spectrum (CDC, t3+ CD40) δ-
[J, 95 (CH319) 1.16 (28318) 1.
30 (CH312) 1.30 (CH36') 4.
83 (H-1')ppm Example 8 3-0-(α-L-Rhamnopyranonl)-14β-amino-6β,20α-pregnanediol The same procedure as in Example 6 was carried out. However, in this case, 14β-amino-5β-
Instead of pregnane-6β, 20α-diol, the proton at the 5-position takes on the entire 5α configuration, 14β-amino-6
The β,20α-pregnane-diol isomer was combined with the bromide of 2°3,4-tri0-acetel-α-L-rhamnosyl under the same conditions.

After treatment with a solution of caustic soda in methyl alcohol while heating under reflux, it is crystallized in an ethyl alcohol/I-5-ol mixture to give the filter β-0-(α-L-rhamnobi').
Thank you for the (lanosyl)-14β-amino-20α-pregnanol.

Melting point F=271℃ NMR spectrum (CDCt3+CD<O) δ=0.7
8 (CH3-19) 0.98 (C; Ha 18) 1.
05 (CH321) 1.25 (C:Ha 6') 4.
76(f(-1')ppm Example 9 3-O-(4-amino-2,4,6-) rhizotuxic α
-L-lyxohexovidinosyl)-14β-amino5
β-pregnane-roβ,20α-diol The same procedure as in Example 4 was carried out. However, in this case, 14β-
Amino-21-nol-5β-pregnane-6β, 20
-14β-amino-5β-pregnane-6β,20α-diol was used instead of diol and crystallized in a methyl alcohol/ethyl ether mixture to give the desired product.

Melting point F = 224°C 1 CD +---79° (C = 1, CHC), 3
) Example 10 6-○-(α-L-rhamnobi°lanosyl)-14β-amino-5β-lugnan-67, 12β, 20β-triol 14β-amino-5β-pregnane-roβ, 12β.

20β-triol 3.5y) 7501:tl
While stirring, 1 me of acetic anhydride was added to the solution which had been dissolved in water and cooled to 0°C. Approximately 3 (3rpin) at 0℃
After reaction with stirring, 0° C. sodium bicarbonate solution was added. After 10 min, it was extracted with methylene chloride and the solvent was removed by evaporation.

Thus, 20-〇-acetyl-14β-amino-5β-pregnane-6β which can be prepared by crystallization
, 12β, 20β-triol 3.72 were obtained.

The above product was dissolved in 100 m6 of +=f himethylene at 0°C, then 3.5 m6 triethylamine and 3.1 WLle of trifluoroacetic anhydride were added. The reaction mixture was stirred for approximately 20 min, then the solvent was evaporated off.

The residue thus obtained was dissolved again in methylene chloride and diluted with N.
and then washed with sodium bicarbonate solution as usual. 20-○-acetyl-14β was dissolved in methyl alcohol and passed through a column packed with resin IR45.
-trifluoroacetamide-5β-pregnane-6β
, 12β, 20β-triol 4.62 were obtained.

The above derivatives 6v and 2,3.4-1-0-acetyl-L-rhamnoflu 2.7y were dissolved in acetonitrile'+60
1.92 mercury cyanide was added to the solution dissolved in rnl. After stirring for 1 hour at room temperature, the mixture was diluted with methylene chloride, extracted, and washed with saturated sodium acid solution.

Chromatographically treated silica: Merck H60,
Release agent: methylene chloride 98.5/methyl alcohol 1
．． 5), 6-O-(2,3,4-tri〇-acetyl-
α-L-rhamnoviranosyl)-20-0-7 cetyl-1
4β-trifluoroacetamide-5β-pregnane-
6β, 12β, 20β-triol 61 was obtained.

The above product was dissolved in 60 ml of total methyl alcohol and I
A total of 6 liters of ON caustic soda was added. After heating under reflux for 6 hours, it was diluted with water and extracted with methylene chloride. The crude 3-0-(α-L-rhamnopyranosyl)- thus obtained
14β-amino-5β-pregnane-6β,12β,2
0β-triol 17 was chromatographed (
Silica: Narc H60, bath release agent: methylene chloride 80/
Methyl alcohol 20/ammonia 2 mixture Va).

The hydrochloride salt was prepared by reaction with concentrated hydrochloric acid in methyl alcohol.

Melting point F=260℃ NMR spectrum (GDGt34/CD30D 1
) δ−0,93 (S , Me19) 1.06 (E
3, Me18) 1.26 (d, j=7.M821)
1.27 (d, j-6.

Me! 6') 3.28 (m, Hi2) 4.7
8 (m, Hi)99m Example 11 3.12-0-(α-L-rhamnopyranoturu)-14β
-amino-5β-pregnane-6β.

12β,20β-diol 20-0-acetyl- prepared as described in Example 10
14β-trifluoroacetamide-5β-pregnane-6β, 12β, 20β-triol 32 and 2,
3,4-) L-O-acetyl-L-rhamnosyl4.
6.22 of mercury cyanide was added to a solution of 42 dissolved in 160 ml of acetonitrile.

The ihr reaction was carried out at room temperature with stirring, diluted with methylene chloride, extracted, and washed with shearized sodium bicarbonate solution. The resulting product and proboscis were treated with 100 mJ of methyl alcohol.
and 10 ml of 1ON caustic soda was added. about 6
The mixture was heated to reflux for hr to vaporize the coloring agent, and 50 mg of water was added. The precipitate formed was filtered and collected in a mixture of 90% methylene chloride/10% methyl alcohol.

After extraction, drying and evaporation in the usual manner, purification by crystallization in absolute ethyl alcohol afforded the desired product 6.12.

Melting point F=240℃ IR spectrum (Nujol method) ν=3.440, 3°370, 3.260, 1
．． 620.

1.590c=i' It has been found from experiments that the 14-aminosteroid derivative of general formula (I) has positive variability and antiarrhythmic properties.

More specifically, the derivatives according to the invention have positive inotropy that is superior to known control compounds (eg alapain, digoxin).

The variability was investigated by measuring the contraction amplitude of each administered hL in the auricle of a rat under normal measurement conditions and comparing it with the control area.

Table 1 below shows the relationship between the increase in contractile force and the concentration for digoxin (comparative sample) and the products according to the invention as described in Examples 6 and 7.

Table 1 Compounds 2X10-7 1O-62X-66X10
-6 10-5 Digoxi 7 +38% +100X
+114% +128% +128% implementation seconds 6
- +43% +63F' +146
% +148% Example 7 +50% +97%
+178 -+-233% +206% As is clear from the above results, the product tit according to the present invention increases the contractile force more strongly than digoxin in certain sudden changes of the rod.

Furthermore, the 14-aminosteroid derivative according to the present invention is
It has a molecular membrane-based inhibitory ability against adenone triphosphatase that is equivalent to or higher than that of the control novokimon or ouabain.

As an example, Table 2 shows the results for the derivatives of Examples 2 and 6.7 and the results for a comparative sample consisting of ouabain and digoxin.

In the table, the value DB.50 is the dose that shows 50% inhibition.

Table 2 DE5Q Ouabain 3.6X 10-'M Digoxin 5.3X 10-9M Example 2 1.
3X10″OM 夾h'D Visu6
1.8X 10-10M Example 7 7.0X
10-10M The derivative according to the present invention has a score of 44, indicating that it has less phlegmic properties than known digitalis derivatives (eg, digoxin, ouanoin).

For example, the derivative of Example B can increase myocardial contractility by 150% in anesthetized dogs without exhibiting toxicity. On the other hand, with digoxin, toxicity appears when the increase is about 50% under the same experimental conditions. Furthermore, the hexagenicity of the derivatives according to the invention is reversible. That is, if administration is discontinued, the abnormality appearing in the electrocardiogram disappears.

As is clear from the above results, the derivative according to the present invention is
In particular, it can be used in the treatment of humans and animals as a therapeutic agent for heart diseases.

The derivatives of general formula (1) and pharmacologically acceptable salts thereof may be prepared in the usual form, i.e. in the form of tablets, capsules, herbal medicines, injections, syrups etc. diluted with suitable pharmacologically acceptable carriers. It can be administered with

For example, the key agent is -+iz2(1)'s 2nd exclusive use of the salt and several solid diluents (e.g.
It can be prepared by mixing with l'i:z magne/12 mu, talc). I'm giving it to you...l:Tetet
Yes, the 1tl substance acts gradually - 4 [1 as the core of the agent? N, it is possible to stratify all of the affected layers. The coating layer can be composed of polyvinyl acetate, carboxymethyl cellulose, and cellulose acetofucroate.

Tablets corresponding to the above formulation were reviewed.

Tablet A Adjuvant (as required) 100η (Adjuvant: Ami-F), talc, lactose, magnesium stearate) Tablet B 3-(α-L-rhamnopyranosyl)-14β-amino-5β-pregnane-6β, 20β-diol 6■
Adjuvant (required number) 100■ (Adjuvant: amino, talc, lactose, magnesium stearate) Furthermore, the derivative according to the present invention can be added to water or glycerin with a derivative of the general formula (■) or a pharmacologically acceptable A syrup prepared by dissolving its salts can also be administered in the form of a soluble solution. In this case, additives (
For example, sweeteners, antioxidants) can also be added.

Injectable solutions can be prepared in a conventional manner, for example by dissolving the derivative of general formula (I) or a pharmacologically acceptable salt thereof in double-distilled water, aqueous alcohol, propylene glycol solution, or a mixture of the above-mentioned solvents. It can be constructed from a solution of

Optionally, suitable additives (eg preservatives) can be added.

The dosage is determined depending on the dosage form, degree of disease, duration of treatment, etc. For example, for oral administration in humans, for the derivative of Example 2, 6.7, 0.05 to 2 m9 /
h can be administered. In some cases, the dosage is 4 additional doses. For example, the dose of the derivative of Example 10 is 0.00
It is preferable to set it as 1-0.05Wg/Kr.

Claims (1)

[Scope of Claims] 1) General formula (■) (in the formula, Ell represents a hydrogen atom + or a lower alkyl group having 1 to 4 carbon atoms; Htltj represents a sugar residue which is optionally converted into 4) represents a group. R2 is a hydrogen atom, a hydroxyl group or a group -0L-t
, >, where R3 represents a sugar residue that may be replaced by 1) 14-Aminosteroid derivatives and acid salts thereof represented by i. 2) JT (1 piece of h gas as described in item 1 of the scope of patent df # sought, characterized in that it represents a hydrogen atom or a mepool group.) ``Samurai R'' characterized in that R7 is a saccharide residue and R7 is a hydrogen atom or a tJ hydroxyl group [Claim 1 or 2]
Derivatives described in Section. 4) R+ but optionally V', modified yet pentose residue 'tJ grafted'! It is characterized by the fact that it is a false source! [1] Derivative according to claim 6. 5) R1 is a glucose residue, a rhamnose residue, a rhamnose residue, where R1 is optionally replaced by V'', V! The derivative according to claim 4, characterized in that it does not represent a lactose residue, a fucose residue, or a toxose residue. 6) 3-0-(α-L-rhamnobi'lanosyl)-14β
-amino-21-nol-5β-pregnane-roβ,2
0-dimer, 3-0-<α-L-lano-nopyranosyl)=14β-amino-5β-pregnane-6β, 20α
-mil)A-le and its 20β isomer, 3-0-(β-
1]-Digitoxocyl)-14β-amino-5β-zoledanane-6β,20α-diol, Ro-0=(4-amino-2,3,6-tridesoxyα-L-lyxohexinoviranosyl)-14β-amino- 5β-zoregnane-roβ, 20α-diol, 5-0-(α-L-rhamnopyranosyl)-14β-amino-21-nol-5β-pregnane-roβ, 12β, 20-1 Rimer, 6-O-(
(me-L-lano, noviranosyl)-14β-amino-5
β-zoregnan-roβ, 12β. 20β-trimer and its 20α isomer, Ro-(,
1-(β-D-digitoxocyl)-14β-amino-5
β-pregnane-6β, 12β. 20σ−+・Riolu Asairo, 12−G〇−(α
-L-rhamnopyranosyl)-14β-amino-5β-zoregnane-12β-20β-triol. 7) In the method for preparing a 14-aminosteroid derivative according to claim 1, the general formula (11) (wherein R
, represents a hydrogen atom and a lower alkyl group] ~, R'2
is a hydrogen atom or iJ represents a hydroxyl group -j) 14-aminostero fl- represented by
:, Meho m I, after ft, general formula 〇 , -X ('L
Inside, Rt Id, represents a sugar residue,
A method characterized in that j4 is subjected to a bonding reaction with an active wild sugar sugar having an acetyl group (1), and then, if necessary, one or more groups (11) are removed. 8) Patent W characterized in that sugar derivatives of the general formulas R and -X are added in excess [described in item 7 of claim ψIJ1, section 7]. 9) The group -NH, at the 14th position is 1. Anhydrous trifluoro c+ l'+'++ #i in the presence of amine
The group -OH at the 20-position was previously protected by substitution with a fluoroacedobumido group or by reaction with acetic anhydride in formic acid to convert it to a formamyl group, and the -OH group at the 20-position was 8. Process according to claim 7, characterized in that the protection is carried out beforehand by acetylation with acetic anhydride in pyridine/. Medicament characterized in that it contains a 14-aminosteroid derivative according to one of claims 1 to 6 as active substance in combination with one or more pharmacologically acceptable adjuvants. Composition.