JPS60161983A - Novel cardenolide derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [A is formula V (R is 1-12C alkyl, cycloalkyl or phenyl which may have mercapto as a substituent group) or formula VI]. EXAMPLE:A-Homo-3a-aza-14-hydroxy-3-methylthio-5beta, 14beta-carda-3( 3a )-20( 22 )-dienolide. USE:A cardiotonic agent, having action of increasing the myocardial contractive force (positive inotropic action), and useful for treating cardiopathy, e.g. congestive failure, and very weak side effects, e.g. abnormal electrocardiograph, as compared with those of the conventional digitalis cardiotonic agent. PREPARATION:A compound expressed by formula IIa is reacted with a sulfonyl halide expressed by formula III (X is halogen; R<1> is aryl, etc.; R<2> is alkyl) in the presence of a dehydrohalogenating agent in an inert organic solvent to give a reaction product, which is then subjected to the Beckmann rearrangement reaction with an aluminum sulfide reagent expressed by formula IV to afford the aimed compound expressed by formula I a.

Description

[Detailed description of the invention] 1-1-circle-1 The present invention relates to cardenolide derivatives.

The cardenolide derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (I).

vinegar. Here, R represents an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group, or a phenyl group that may have a mercapto group as a substituent. ] In this specification, examples of the alkyl group having 1 to 12 carbon atoms that may have a mercapto group as a substituent include methyl, ethyl, 2-mercaptoethyl, propyl, isopropyl, 3-mercaptopropyl, butyl, tert. -butyl, 4-mercaptobutyl, pentyl, 5-mercaptopentyl, hexyl, 6-mercaptohexyl, octyl, decyl, undecyl, dodecyl groups, etc., and cycloalkyl groups include, for example, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cycloalkyl groups having 3 to 8 carbon atoms.

The compounds of the present invention have the effect of increasing myocardial contractility (positive inotropic effect) and are useful as cardiotonic agents for the treatment of heart diseases such as congestive heart failure. The compounds of the invention have little effect on heart rate. In addition, conventional cardiotonic agents such as digitalis have a narrow safety margin, and electrocardiogram abnormalities such as digitalis toxicity, premature contractions, and atrioventricular block, and side effects on the gastrointestinal system and nervous system have been observed. It has the characteristic that the side effects mentioned above are extremely weak compared to conventional cardiotonic agents such as digitalis.

The compound of the present invention can be produced by various methods, and a preferred example thereof is, for example, by the method shown in Reaction Scheme-1 below.

Reaction Scheme-1 0H(...D) (from) (In the formula, R1 represents an aryl group or an alkyl group, R2 represents an alkyl group, and X represents a halogen atom.

R is the same as above. ) That is, compound (Ia) or compound (Ib) is compound (Ia) or compound (Ib).
[a) or compound (IIb) is first treated with sulfonyl halides (1) in the presence of a dehydrohalogenating agent in an inert organic solvent.
) to give the oxime sulfonate, which was then treated with aluminum sulfide reagent (IV
) is produced by Beckmann rearrangement reaction.

Compound (I[a) and compound (nb) used as starting materials are known compounds. Sulfonyl halides (m) are also known compounds, such as alkanesulfonyl chlorides such as methanesulfonyl chloride and ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-
Examples include arylsulfonyl chlorides such as mesitylenesulfonyl chloride and p-acetamidosulfonyl chloride. The amount of sulfonyl halides (1) to be used is not particularly limited and can be appropriately selected within a wide range, but usually compound (IIa) or (I[tl
) per mole (approximately 1 mole, preferably 1
It is preferable to set the amount to about 3 mol.

Examples of inert solvents used include aromatic hydrocarbons such as benzene, toluene, xylene, anisole, and chlorobenzene, ethyl ether, tetrahydrofuran,
Examples include ethers such as dioxane and 1,2-dimethoxyethane, and halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane. Further, as the dehydrohalogenating agent, for example, amines such as triethylamine, pyridine, picoline, N,N-dimethylaniline, etc., and inorganic bases such as sodium bicarbonate, anhydrous sodium carbonate, anhydrous potassium carbonate, etc. can be widely used.

The amount of such a dehydrohalogenating agent to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually about an equimolar amount to 3 times the molar amount of compound (Ia) or (I[b)]. It is better to do so. The reaction proceeds either under cooling or at room temperature, but usually proceeds suitably at about -30° C. to room temperature, and is generally completed in about 0.5 to 3 hours.

Oxime sulfonate is produced by boiling in this way, but in the present invention, oxime sulfonate may be isolated from the reaction mixture and subjected to the next reaction, or this reaction mixture may be used as it is to the next reaction.

Aluminum sulfide reagent (IV
), for example, diisobutylaluminum methanesulfide, diisobutylaluminum propyl sulfide, diisobutylaluminum hexyl sulfide, diisobutylaluminum phenyl sulfide, diisobutylaluminum hexyl sulfide, diisobutylaluminum dodecyl sulfide, diisobutylaluminum cyclohexyl sulfide, diisobutylaluminum (6- mercaptohexyl sulfide, diisobutylaluminum cyclohexyl sulfide, diisobutylaluminum methane sulfide, etc. These can be prepared by combining a corresponding aluminum compound such as dialkylaluminum hydride or trialkylaluminium with a corresponding sulfur compound such as disulfide or thiol in a conventional manner. It can be easily prepared by reacting according to the following. In the present invention, aluminum sulfide sample 1 (IV) may be used after being isolated from the reaction mixture of the aluminum compound and sulfur compound, or may be used as it is without being isolated from the reaction mixture.

The amount of aluminum sulfide reagent (IV) to be used is not particularly limited and may be appropriately selected within a wide range.
It is preferable that the amount is at least equimolar, preferably equimolar to 3 times the molar amount. The reaction proceeds either under cooling, at room temperature, or under heating, but usually -8
The reaction proceeds suitably at a temperature of about 0 to 50°C, and is generally completed in about 10 minutes to 3 hours.

The target compound thus obtained can be easily isolated and purified from the reaction mixture by conventional isolation methods such as recrystallization, solvent extraction, column chromatography such as high performance liquid chromatography, and distillation.

The compound of general formula (I) is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders,
It is prepared using diluents or excipients such as binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, full-fill formulations, injections (liquids, suspending agents, etc.). When forming tablets, a wide variety of carriers known in the art can be used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose,
Excipients such as silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dried starch, sodium alginate , end of Kanten,
Laminaran powder, sodium bicarbonate, calcium carbonate,
Disintegrants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, quaternary ammonium bases, sodium lauryl sulfate, etc. absorption enhancers, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. I can give an example. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, melt-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming an emulsion, a wide variety of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic,
Examples include tragacanth powder, gelatin, binders such as ethanol, and disintegrants such as laminar agar. When molding into a fully opened form, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. When prepared as injections, solutions and suspensions are preferably sterilized and isotonic with blood, and when forming these solutions, emulsions, and suspensions, this agent is used as a diluent. All those commonly used in the field can be used, including water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like.

In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary.

The amount of the compound of general formula (I) to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1% by weight in the pharmaceutical preparation.
~30% by weight.

There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration may be carried out in accordance with the various preparation forms, the patient's age, cardiac sex and other conditions, the severity of the patient, and the like. For example, tablets, emulsions, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, it may be used alone or with glucose,
It is administered intravenously in a mixture with a normal replacement fluid such as an amino acid, and if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. If fully dilated, it is administered rectally.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but the amount of the compound of general formula (I), which is the active ingredient, is usually 1 kg (1 kg) of body weight per day. It is preferable that the amount of the active ingredient is about 0.001 to 111 J per unit.It is also preferable that the dosage unit form contains 0.01 to 25 parts of the active ingredient.

Reference Examples, Examples, pharmacological test results, and formulation examples are listed below.

Reference example 1 (E)-14-hydroxy-3-oximino-5β,
14β-kaldo 20 (22)-enolide 500■
9 (1,35 mmol), triethylamine 0.285
So (2.03 mmol) and methanesulfonyl chloride 0.115 ml (1.48 mmol) were dissolved in 10 Illl of methylene chloride, stirred and reacted at -20°C for 1 hour, diluted with about 30 m of methylene chloride, and then Wash sequentially with 1 mol/Q hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine. After drying with sodium sulfate, it was concentrated under reduced pressure to obtain (E)-14-hydroxy-3-methanesulfonyloxyimino-5β,14β-caldo 2 as a colorless powder.
0 (22)-enolide 628 mg (yield approximately 10
0%) was obtained.

111 85-88℃ IR (KBr): 3430.1780, 1740゜16200m-'' HNMR (CDCQa) δ; 0.89 (s, 3) 1) 0.98 (s, 3H) 2.56 (t, J-13.8Hz, IH) 2.7
8 (1,1 day) 3.05 (d, J-16,2Hz, IH)3.
13 (s, 3H) 4.80 (dd, J-1, 6, 18, 1Hz, IH
)4.98 (dd, J-1,6,18,1Hz,I
H) 5.88 (t, J-1,6Hz, IH) MS
(i/z)369 (M”-96) Reference Example 2 (Z)-14-hydroxy-3-oximino-5β,
14β-caldo 20 (22)-enolide 1.0g
Colorless powder (Z
)-14-hydroxy-3-methanesulfonyloxyimino-5β,14β-caldo 20 (22)-enolide 1.26 g (yield approximately 100%) was obtained.

Peng p 115-119℃ IR (KBr): 3450, 1787.1745゜16
30cr'' H-NMR (CDC(is) δ: 0.89
(s, 3H) 1.00 (s, 3H) 2.28 (dd, J-13,2,15,9Hz.

IH) 2.80 (dd, J-5, 4, 9, 5Hz, IH)
2.90 (ddd, J-2,1,4,0,15,9
H2, IH) 3.14 (s, 3H) 4.81 (dd, J-1,6,17,8Hz, IH
)4.98 (dd, J-1,6,17,8Hz,I
H) 5.89 (t, J-1,6H2, IH) MS
(-/z)369 (M"-96) Example 1 Diisobutylaluminum hydride-toluene solution 2.
Dimethyl disulfide 1.49 mmol (0,134
1Q) was added at 0°C, and the mixture was stirred at the same temperature for 30 minutes.

(E)-14-hydroxy-3-methanesulfonyloxyimino-5β obtained in Reference Example 1.

14β-kaldo 20 (22)-enolide 635
mg was dissolved in 1411 g of methylene chloride, and the aluminum-toluene mixture obtained above was added to this mixture after cooling to -78°C. After reacting at 0°C for 1 hour, 924 g of sodium fluoride and 0.0 g of water were added. Add 3- and roughly boil at 0℃
Run the reaction for 0 minutes.

Insoluble matter was separated in a furnace, and the furnace solution was concentrated under reduced pressure, subjected to silica gel chromatography, and isolated with an eluent of ethyl acetate-methylene chloride (ethyl acetate 10% to 50%) to obtain A-homo, which is the compound of the present invention. -38-aza-14-hydroxy-3
-Methylthio-5β.

14β-Caldo3(3a)-20(22)-genolide 29811J (yield 53%) was obtained. This compound will hereinafter be referred to as "compound A."

-p201 ~206℃ [αID 19.4° (C=0.16.C; HCQ*
)IR(KBr) ;3480,1 782. 1
743°1630cr'' H-NMR (CDC12s) δ: 0.88
(s, 3H) 0.95 (s, 3H) 2.24 (s, 3H) 2.55 (dd, J-10,3,15,5Hz.

IH) 2.78 (-, IH) 3.57 (d, J-14,6Hz, 1H) 3.8
6 (dd, J-9,9,14,6Hz, IH)4
．． 80 (dd, J-1,7,18,1Hz, IH)
4.98 (dd, J-1,7,18,1Hz, IH
)5.87 (t, J-1,7Hz, IH) MS
(m/z)417 (M”) Mass spectrometry value (02A
Hs 's Os N) Actual value -/z 417.23
38 Calculated value -/z 417.2338 Example 2 The compound of the present invention, A-homo-3a-aza-14-hydroxy-, was prepared in the same manner as in Example 1 except that n-propylthiol was used instead of dimethyl disulfide. 3-
Propylthio-5β.

14β-Caldo3(3a)-20(22)-genolide 27611 (yield 46%) was obtained. This compound will hereinafter be referred to as "compound B."

■p 101~105℃ [(Z] 17.3° (C-0,15,CHC(is
)IR(KBr);3450.1783.1745
゜1630c■-1' H-NMR (CDCQs) δ: 0.88 (s, 3H) 0.94 (s, 3H) 0.98 (t, J-7, 3Hz, 3) 1) 1, 6
1 (qt, J-7, 3) 1z, 2) 1) 2.2
1 (dd, J-6,9,16,8Hz, IH)2,
55 (dd, J-11,2,16,8Hz.

IH) 2.78 (1,1H) 2.82 (t, J-7,3Hz, 2H) 3.54
(d, J-14,2Hz, IH) 3.85 (d
d, J-10,8,14,2Hz.

IH) 4.80 (dd, J-1,7,18,5Hz, IH
)4.98 (dd, J=1.7.18.5Hz, I
H) 5.88 (t, J-1,7Hz, IH) MS
(1/Z) 445 (M+) Mass spectrometry value (C2e
Ha o NOs ) Actual measured value ■/z 445.26
48 Calculated value -/Z 445.2651 Example 3 A-homo-38-aza-14-hydroxy, a compound of the present invention, was prepared in the same manner as in Example 1 except that n-hexylthiol was used in place of dimethyl disulfide. -3-
Hexylthio-5β.

14β-Caldo3(3a)-20(22)-genolide 309Q (yield 47%) was obtained. This compound will hereinafter be referred to as "compound C."

[αIJ)28.9@(C-0,19,CHCQs
) IR (KBr): 3470.1784, 1748° 1632 cm' H-NMR (CDC (ls) δ; 0.87
<t, J-7,1Hz, 3H) 0.88 (s,
3H) 0.95 (s, 3H) 2.83 (w, 1) 1) 3.54 (d, J-14, 2Hz, IH) 3,
84 (dd, J-10, 13, 7Hz, IH) 4
．． 79 (dd, J-1,6,16,4Hz, IH)
4.90 (dd, J-1,6,16,4Hz, IH
)5.88 (t, J-1,6H2,IH)MS(m
/z)487(M÷) Mass spectrometry value (CQoHasOsN) actual measurement value
a/z 487.3113 Calculated value 嘗/z 487.3120 Example 4 A-homo-3a-aza-14, a compound of the present invention, was prepared in the same manner as in Example 1 except that thiophenol was used in place of dimethyl disulfide. -Hydroxy-3-phenylthio-5β,14β-caldo-3(3a)-20(
246 layers (yield 38%) of 22)-genolide were obtained. Hereinafter, this compound will be referred to as "compound DJ."

■p 130~135℃ [αID 25.3° (C=0.15.CHCQs
)IR(KBr): 3440.1785.1745
゜1650cm-'' HNMR (CDC9s) δ: 0.88 (s, 3H) 0.95 (s, 3H) 2.32 (ddd, J-1,6,10,0゜16.
7Hz, IH) 2.55 (dd, J-10,0,16,7Hz.

IH) 2.78 (■, 1 day) 3,49 (d, J-15,, OHz, IH
)3゜83 (ddd, J-1,6,11,1゜15
．． 0Hz, IH) 4.80 (dd, J-1, 9, 18, 1Hz, IH
)4.98 (dd, J-1,9,18,1Hz, 1
)1) 5.87 (t, J-1,9Hz, IH)7
．． 36 and 7.48 (gg, 5H) MS (m/z)
479 (M÷) Example 5 Compound A of the present invention was prepared in the same manner as in Example 1 except that trimethylaluminum was used instead of diisobutylaluminum hydride and 1,6-hexanedithiol was used instead of dimethyl disulfide. -Homo-3
8-aza-14-hydroxy-3-(6-mercaptohexyl)thio-5β,14β-caldo 3 (3a)
-20(22)-genolide 25910 (yield 37%
). This compound will hereinafter be referred to as "Compound E."

■p 101~105℃ 6 [αID 11.8° (C=0.17.0HCQ@)
IR (KBr): 3500.3440.1783゜1
742.1630c■1' HNMR (CDCQs) δ: 0.88 (s, 3H) 0.94 (s, 3H) 2.52 (■, 3 days) 2.78 (-, 3H) 3.53 (d , J-14, 3Hz, IH) 3.8
4 (dd, J-10,5,14,3Hz.

IH) 4.80 (dd, J-1,6,18,1Hz, IH
) 4.98 (dd, J-L, 6.18.1Hz, I
H) 5.87 (t, J-1,6Hz, IH) MS
(m/z) 519 (M÷) Mass spectrometry value (C2* Has On NSe) Actual value -/z 519.2826 Calculated value Sono/z 519.2841 Example 6 n-dodecylthiol in place of dimethyl disulfide The compound of the present invention, A-homo-3a-aza-14-hydroxy-3-
Dodecylthio-5β.

447ma (yield 58%) of 14β-caldo3(3a)-20(22)-genolide was obtained. This compound will hereinafter be referred to as "compound F."

-p 34 to 37℃ [α] 2 hours 35.3° (C=0.17.0HCQ m
)IR(KBr):3550,3470.3410
゜17B0,1760.1735゜1632c■1' H-NMR (CDCQs) δ:0.87 (t
, J-7,3Hz, 3H) 0.88 (s, 3H
) 0.94 (s, 3H) 2.18 (dd, J-8,6,15,6Hz, IH
)2.57 (dd, J-10,3,15,6Hz.

IH) 2.77 (m, IH) 2.82 (i, 2H) 3.53 (d, J-14,3Hz, IH) 3.8
4 (dd, J-10,0,14,3Hz.

IH) 4.80 (dd, J-1,6,18,1Hz, IH
)4.99 (dd, J-1,6,18,1Hz,I
H) 5.86 (t, J-1,6Hz, IH) MS
(-/z)571 (M”) Mass spectrometry value (Ca
s Hs y NOs S) Actual measurement value ■/z 571.
3888 Calculated value ■/z 571.4059 Example 7 The compound of the present invention, A-homo-38-aza-14-hydroxy-, was prepared in the same manner as in Example 1 except that cyclohexylthiol was used instead of dimethyl disulfide. 3
-cyclohexylthio-5β,14β-caldo3 (
3a)-20(22)-dienolide 32711J(
A yield of 50% was obtained.

This compound is hereinafter referred to as "compound G."

5p114~120℃ [αID 17.1° (C=0.42.0HCQs
) IR (KBr): 3540.3470.3410°1780; 1740°1630cm'' H-NMR (CDCQs) δ: 0.88 (s, 3H) 0.93 (s, 3H) 2.52 (dd, J -11,0,16,2Hz.

IH) 2.77 (■, 1 day) 3.47 (Hasumi, 1H) 3.52 (d, J-14,0) 1z, IH) 3.
83 (dd, J-9,8,14,0Hz, IH)
4.80 (dd, J-1,5,18,0Hz, IH
)4.98 (dd, J#-1,5,18,0Hz,
IH) 5.87 (t, J-1,5Hz, IH)
MS (m/z)485 (M”) Mass spectrometry value (
02$I Ha s NOs S) Actual measurement value Ken/z 4
85.2955 Calculated value gi/2 485.2964 Example 8 (Z)-14-hydroxy-3-methanesulfonyloxyimino-5β,14β-caldo 20 obtained in Reference Example 2
The compound of the present invention, A-homo-3-aza-
14-hydroxy-3a-methylthio-5β,14β-
Kaldor 3(3a)-20(22)-genolide 2
2011J (yield 39%) was obtained. This compound is referred to as “
It is called "Compound H".

■p 230~235℃ [α12073.1” (C=0.35.0HC(is
)IR(KBr):3540.3460,3410
゜1780.1738,163B.

i e i scr'' H-NMR (CDCQs)6:0.8B(s,
3H) 0.96 (s, 3H) 1,92 (d, J-15,3Hz, IH)
2, 27 (brs, 3H) 2.78 (i, IH) 3.08 (dd, J-12, 2, 15, 3H2.

IH) 3.62 (dd, J-9, 2, 14, 3Hz, IH
) 3.71 (dd, J-8, 2, 14, 3Hz, I
H) 4.80 (dd, J-1, 8, 18, 3Hz,
I H) 4.97 (dd, J-1, 8, 18, 3Hz
, IH)5.88 (t, J-1,8)1z, I
H) MS (-/z) 417 (M÷) Mass spectrometry value (C2A Ha s NOs N) actual value
■/z 417.2338 Calculated value l/z 417.2338 Example 9 A-homo-3-aza, a compound of the present invention, was prepared in the same manner as in Example 8 except that n-dodecylthiol was used instead of dimethyl disulfide. -14-hydroxy-3a-
Dodecylthio-5β.

3241 g (yield: 42%) of 14β-caldo 3 (3a)-20(22)-genolide was obtained. Hereinafter, this compound will be referred to as "Compound ■".

■p 80~84℃ [α]2186° (C=0.15.0HC(ls)
IR (KBr): 3450, 1760.1735°1
630cm' H-NMR (CDC(Is) δ: 0.87
(t, J-7,3Hz, 3H)0.88 (8,3
H) 0.94 (s, 3H) 1.88 (d, J-15,5Hz, IH) 2.14
(-, 2 days) 2.77 (s, 1H) 2.83 (t, J-7,3Hz, 2H) 3.04
(dd, J-12,0,15,5Hz.

IH) 3.59 (dd, J-8, 6, 14, 2Hz, 1H
) 3.67 (dd, J-8, 2, 14, 2Hz, I
H) 4.80 (dd, J-1,7,18,1Hz,
IH) 4.98 (dd, J-1, 7, 18, 1Hz
, 1H) 5.87 (t, J-1,7Hz, IH)
MS (m/z) 571 (M÷) Mass spectrometry value (Cs l5Hs y Not S) Actual value m/z 571.4059 Calculated value m/z 571.4059 Example 10 Cyclohexylthiol in place of dimethyl disulfide The compound of the present invention, A-homo-3-aza-14-hydroxy-38, was prepared in the same manner as in Example 8 except that A-homo-3-aza-14-hydroxy-38 was used.
-cyclohexylthio-5β,14β-caldo3 (
3a)-20(22)-dienolide 347go (yield 53%) was obtained.

This compound will hereinafter be referred to as "Compound J."

■p 114~120℃ [α']2183.6° (C-0,33,CHCQs
)IR(KBr):3450.1780.1740
゜1622cr'' HNMR (CDCQs) δ: 0.87 (s, 3H) 0.94 (s, 3H) 1.84 (d, J-15,4Hz, IH)2.
77 (m, IH) 3,04 (dd, J-12,4,15,4H2.

IH) 3.46 (Conference, 1H) 3.57 (dd, J-8,9,14,8Hz, IH
)3.65 (dd, J-8,9,14,8Hz, I
H) 4.80 (dd, J-1, 8, 18, 4Hz,
IH) 4.97 (dd, J-1, 8, 18, 4Hz
, IH) 5.87 (t, J-1,8Hz, IH)
MS (m/z) 485 (M+) Example 11 A-homo-3-aza-14, a compound of the present invention, was prepared in the same manner as in Example 8 except that 1,6-hexanedithiol was used in place of dimethyl disulfide. -Hydroxy-
38-(6-mercaptohexyl)thio-5β, 14β
260 g (yield 37%) of Kaldor 3(3a)-20(22)-genolide was obtained. This compound will hereinafter be referred to as "compound K."

[αID 23.2° (C=0.22.CHCQa
) IR (CHC12a): 3350.1785°17
50.1623cr'' H-NMR (CDCQs) δ; 0.88 (s, 3H) 0.95 (s, 3H) 1.87 (d, J-15,3Hz, 1) 1) 2.
52 (ad, J-2,4,7,3Hz, IH)2
．． 67 (t, J-7, 3, IH) 3.06 (dd
, J-12,0,15,3Hz.

1) 1) 3.63 (i, 2H) 4.78 (dd, J-1,5,17,9Hz, IH
)4.99 (dd, J-1,5,17,9Hz, I
H) 5.88 (t, J-1,5Hz, 1) 1) M
S(gz/-z)519(M÷) Pharmacological test〉 Blood perfusion isolated papillary muscle specimen Mongrel adults weighing 8 to 12 kg are anesthetized by intravenously administering bendoparbital sodium salt at a dose of 30112/kill. . 1000 tons of heparin sodium salt
After intravenous administration at a volume of J/klJ, the animals were bled to death and the heart was removed. The specimen mainly consists of papillary muscles and ventricular septum;
The cannula inserted into the anterior septal artery is perfused with blood led from the blood donor hole at a constant pressure of 100 g + ml - 1 g.

The blood donor hole was anesthetized in advance by intravenous administration of pendoparbital sodium salt 30.9/kg, and 1000 U/kc+ of heparin sodium salt was administered intravenously. Using bipolar electrodes, a threshold of 1.5
Double voltage (0.5~3V), stimulation width of 5ssec,
Papillary muscles are stimulated with a square wave with a stimulation frequency of 120 times per minute.

The resting tension of the papillary muscles is 1.5 g, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of developed tension and blood flow were recorded on an ink recorder. The details of this method have already been reported by Endo and Hashimoto (As, J.
Phosiol, Volume 218, Pages 1459-1463, 1970, Naunyn-8chsiedebe
ra's Achieves ofp har-a
vol. 278, pp. 135-150, 1
973: Atrial muscle specimen). The test compound is 10-30μQ
It was administered intra-arterially in a volume of 4 seconds.

The inotropic effect of the test compound was expressed as a percent change in the tension generated before drug administration.

Table 1 shows the results.

Table 1 Formulation example 1 Compound A O,025i.

Starch 132■Q Magnesium stearate 1B10 Breasts 50■ Total approximately 200g Tablets of the above composition were manufactured in a conventional manner.

Formulation example 2 Compound B O, 2519 Starch 130g Magnesium stearate 20g Sugar 501G Total approximately 200g Tablets of the above composition were manufactured in a conventional manner.

Formulation Example 3 Compound CI2.5 polyethylene glycol (molecular weight: 4000) 0.3a Sodium chloride 0.9a Polyoxyethylene sorbitan monooleate 0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.020 Distilled Water for Injection 100 - Dissolve the above parabens, sodium metabisulfite and sodium chloride in III water at 80°C with stirring.

The obtained solution was cooled to 40°C, the compound of the present invention, polyethylene glycol and polyoxyethylene sorbitan monooleate were sequentially dissolved therein, and then distilled water for injection was added to the solution to make the final volume of IIIL/ The mixture is sterilized by sterile filtration using an appropriate filter vapor, and then dispensed into ampoules to prepare injections.

[Brief explanation of drawings]

Figure 1 is the IR spectrum of Compound A, Figure 2 is the NMR spectrum of Compound A, Figure 3 is the IR spectrum of Compound A, Figure 4 is the NMR spectrum of Compound E, and Figure 5 is the NMR spectrum of Compound E. IR spectrum diagram, Figure 6 shows compound E
(DNMR spectrum diagram, Figure 7 is an IR spectrum diagram of compound G, Figure 8 is an NMR spectrum diagram of compound G, Figure 9 is an IR spectrum diagram of compound H, and Figure 10 is an NMR spectrum diagram of compound H. .

Claims (1)

[Claims] ■ General formula. Here, R represents an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group, or a phenyl group that may have a mercapto group as a substituent. ] A cardenolide derivative represented by