JPS6042381A - Novel cardenolide derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (A is group shown by the formula II or formula III). EXAMPLE:A compound shown by the formula IV. USE:A cardiac for remedying a heart disease such as congestive heart failure. PREPARATION:A compound wherein A is group shown by the formula II in the formula I is obtained by Beckmann rearrangement of a compound shown by the formula V, or a compound wherein A is group shown by the formula III in the formula I is obtained by Beckmann rearrangement of a compound shown by the formula VI. The Beckmann rearrangements are carried out under such a mild condition that the hydroxyl group at the 14-position of the compound shown by the formula V of formula IV is not eliminated, for example, it is completed in a proper solvent at 0-100 deg.C, preferably at room temperature-50 deg.C reaction temperature usually for 10min-6hrs. The rearrangement can be done in the presence of an acidic catalyst (e.g., sulfuric acid) or basic catalyst (e.g., alumina), preferably a reagent to be reacted with a hydroxyl group of oxime of the compound shown by the formula V or formula VI to form an elimination group is added to the reaction system and the reaction can be carried out under mild conditions.

Description

[Detailed description of the invention] The present invention is directed 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).

shows. The compound of the present invention has an effect of increasing myocardial contractility (inotropic effect) and is useful as a cardiotonic agent for a variety of heart diseases such as congestive heart failure. The compounds of the present invention have almost no effect on heart rate. Furthermore, conventional cardiotonic drugs such as digitalis have a narrow safety margin, and have been associated with cardiac abnormalities such as digitalis poisoning, premature contractions, and dizziness, as well as side effects on the intestinal and nervous systems. However, the compound of the present invention is characterized in that the above-mentioned side effects are extremely weak compared to conventional cardiotonic drugs 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 The compound of the present invention represented by formula (Ia) is represented by formula (II)
The compound of the present invention represented by formula (Ib) is produced by Beckmann rearrangement reaction of a compound represented by formula (I[[)]. Formula (IF) used as starting material
and the compound represented by formula (Iff) are all known compounds. When carrying out the Beckmann rearrangement reaction, as long as it is an acceptable method that does not remove the water f'lt group at position 14 of the compound represented by the above formula (II) or formula (I[I). You can use any method you like. More specifically, this reaction is carried out in a suitable solvent at a reaction temperature of O~
The reaction proceeds suitably at a temperature of 100°C, preferably room temperature to 50°C, and is generally completed in about 10 minutes to 6 hours. The above reaction is acidic Pil! ! It can be carried out in the presence of a medium or a basic catalyst, and more preferably in the presence of a compound (n
) or the hydroxyl group of the oxime of the compound (I [

Examples of chlorinated catalysts include metal oxides such as alumina, and tertiary amines such as collidine, lutidine, N,N-diethylaniline, triethylamine, pyridine, and picoline. Examples of acidic catalysts include r'I such as sulfuric acid, trifluoroacetic acid, phosphorus pentoxide, formic acid, and methanesulfonic acid.

Reagents for forming a dislocating group include aromatic or aliphatic HL halides such as 2-mesidilenesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, p-a is doamidosulfonyl chloride, ethanesulfonylchloride, and ido. can be exemplified, and for this reaction i
By adding ff+ a common basic compound and using a dehydrohalogenating agent, a preferable reactivity can be obtained. Examples of solvents include (2) aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as ethyl ether, tetrahydrofuran, and dioxane, chloroborum, methylene chloride,
Chlorides such as carbonaceous tetrachloride, pyridine, triethylamine,
Examples include tertiary amines such as picoline. The above catalyst (formula i of sulfonyl halides) or the compound of formula <1> is not particularly limited and can be selected from a wide range, but usually m? I m, preferably equimolar to 3 (preferably 8 molar).

The target compound 17 thus obtained can be easily prepared as a single compound from the reaction mixture by conventional single fjJ methods, such as recrystallization, solvent extraction method, column chromatography such as high performance liquid chromatography, and Tsubame Rudan's method. Ru.

The compound of general formula (I) is usually used in the form of a general 11-drug. The agent is prepared using commonly used fillers, extenders, binders, wetting agents, disintegrants, surfactants, brighteners, diluents or excipients. As for the preparation, various forms can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, 'a' preparations, oral preparations, emulsions, n-granules, capsules, suppositories, Note 0.1
The culm (liquid, suspension agent, etc.) is harvested. When forming into a tablet, a wide variety of carriers known in this field can be used, such as lactose, sucrose, thorium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc. Excipients, water, ethanol, propatool, simple syrup, grape liquid, starch liquid, geratin solution, carboxymethylcellulose, Kerac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, alginic acid Thorium, agar powder, laminaran powder, charcoal 111 hydrogen sl/lium, calcium carbonate, polyoxyethylene sorbitan fat r! Disintegrants such as fuesters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc., disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., 4th string ammonium base, promotion of drying of sodium lauryl sulfate caps humectants such as glycerin, starch, starch, lactose, kaolin, bentonite,
Examples include colloidal CaP M adsorbent, purified talc, stearin fi21M, boron cocoon powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into an emulsion, a wide variety of conventionally known carriers can be used, such as excipients such as glucose-lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth, and gelatin. , a binder such as ethanol, and a disintegrant such as laminaran agar. When molding into a band layer, a wide variety of conventionally known carriers can be used, such as polyethylene glycol, )J'A'Y,
ft, higher alcohols, esters of higher alcohols,
Gelatin, semi-synthetic glyhylide, etc. can be mentioned. When prepared as an injection, the liquid preparation and suspension agent are preferably sterilized and mixed with blood. All agents commonly used in this field can be used, such as water, ethyl alcohol, pyrene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be mentioned.

In addition, the pharmaceutical preparation may contain enough salt, glucose, or glycerin to prepare this isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You may. Furthermore, if necessary, other medical products such as coloring agents, preservatives, perfumes, flavors, sweeteners, etc. may be included in the Heiko Mulberry preparation.

General formula (I) to be contained in the pharmaceutical i7J agent of the present invention
The amount of the compound is not particularly limited and can be appropriately selected from a wide range, but it is 1 to 70,000%, preferably 1 to 30% in the mulberry preparation. It is Q6.

There is no particular restriction on the administration method of the above-mentioned medicine, and each fii
-'1 Administer by a method depending on the dosage form, patient's age, gender, condition, patient's severity, etc. For example, tablets, emulsions,
Liquid preparations, 5-yen tablets, emulsions, granules, and capsules are administered orally. In the case of injections, they can be administered intravenously alone or during regular fluid replacement such as glucose or amino acid, and if necessary, they can also be administered intramuscularly, intravenously, or intravenously.
It is administered subcutaneously or intrathecally. It is administered rectally into the disc of the zona.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, the age, gender and other conditions of the patient, the degree of dementia, etc. J is approximately 0.001 to 1 mg per kilogram of body weight per day.
Yes. In addition, 0.01 to 2
It is better to contain 5111g.

Examples, ritual test results, and 11th layer are listed below.

Example 1 (E)-14-hydro-4-cy-3-oximino-5β
, 14β-caldo20 (22)-enolide (formula (
Compound I) 371 mg, 1-liedylamine 0.1
82w+2 and 2-mesidilenesulfonyl chloride 2
41 mg was dissolved in 5 mQ of dry 93R methylene at 0°C for 30 min.
for 30 minutes, then at room temperature for 30 minutes.

The reaction mixture was diluted with methylene chloride-saturated saline (2:1).
The right (1st layer) was added to 30mQ, and the right (1st layer was removed by 1 molecule.) The right nth layer was dry-bombed over Na25Oa and distilled off to obtain 1r''I of oily material.

This oily substance was adsorbed on alumina 10 (+) and eluted with 30mG of methanol. The colorless oily substance obtained by distilling off the methanol was subjected to silica gel column chromatography, and eluted with dimethylated methylene-acetate. and the formula (I
Compound 3001111J of a) was obtained as colorless crystals. The crystals were recrystallized from methylene chloride-ethyl acetate and had a melting point of 252-255°C.

The IR spectrum of the obtained compound is shown in FIG. 1, the mass spectrum is shown in MS2 diagram, and the NMR spectrum is shown in FIG. 3.

NMR (CDCQ3): Q, 888 (3H1S),
0,997 (3)1. s ), 2.21 (11-
1, dd.

J15.1.8.6), 2.55 (IH, dd.

, ) 15. 1. 1 1. 1), 2. 75
(IH.

ddd, J14.9.7.3.0.8), 2, 78
(it(,m), 3.73 (1H,ddd.

J14.9.1°0.5, 3.8), 4.80 (11
-1, dd, J17.8.1.4), 4.97 (IH,
(+(+, J 17.8.1.4), 5.88(1H,
s ), 5.9'8 (IH, s ) Mass : m/
e, 387 (M”), 3-69.290.277.26
2.234.2201206.193.178.165
．． 147.134.122.112.105.91.8
5.67.55.41 (0238a 3'NO & calculated value 387.2409) IR (KBr): 3502.3207.3102.1
799.1727.1674.1642.1617.1
465.1402.1340.1265.1162.1
134.1064.1024.897.730.690
．． 645 Example 2 (Z)-14-human Oxy3-oximino=5β,
14β-caldo20 (22)-enolide (formula (I
The compound of formula (Ib) was treated in the same manner as in Example 1 except that 371 rag was used, and the compound of formula (Ib) was converted into colorless crystals with a colorless crystal of 310 mo blue. The crystals were recrystallized from methylene chloride-methanol and had a melting point of 270°C (decomposed).

FIG. 4 shows the IR spectrum, FIG. 5 shows the mass spectrum, and FIG. 6 shows the NMR spectrum of the compound obtained.

NMR (CDC123): 0.888 (3H,s
).

1.00 (3H, s >, 2.06 (IH, d.

J15.1), 2.79 <IH,m), 2.98
(IH, dd, J15.1.11.6), 3, 08 (
IH, ddd, J 14. 3. 7. 5゜5.
2), 3.23 (iH, ddd, J 14.3°9
．． 2, 5.4), 4.80 (IH, dd, 'J 18
．． 4, 1.6), 4.98 (IH, dd.

, ) 18. 4. 1. 6), 5. 83 (
IH, S)Mass; m/e, 387 (M
稍, 369.290.277.262.334 (10'
O), 220.206.193.178.165.14
7.122.105.91.85.67.55.41
(Silver value as C23H33NOa: 387.2409
) IR (KBr): 33G2, 3352,
1 797.1734.1622.1497.1462
．． 1452.1382.1359.1342.1259
．． 1192.1132.1o29.897.859.7
30.645 Kureishimon〉 Blood group flow Extracted papillary muscle (7 body m 8 ~ 12 kg miscellaneous [5 Adult dogs were anesthetized by intravenously administering Beni, barbiturate, and storium di at the mouth of the river at 30 ma/kn) 100% sodium salt of heparin
After intravenous administration at a volume of 0 U/kll, the animals were sacrificed by defacement and the hearts were removed. The specimen consists mainly of papillary muscles and the interventricular septum, and is flushed out at a constant pressure of 100+nmTL with blood introduced from the blood donor hole through a cannula inserted into the anterior mediocircular filJ pulse. The IC11 dog weighed 14-30kq and was pre-treated with bendoparbital sodium j? The animals were anesthetized by intravenous administration of 30 mg/ko, and 1000 U/k of heparin protein (J) was administered intravenously.
), using a voltage 1.5 times the F1 value (0.5 to 3 V)
, the papillary muscles were stimulated with a square wave with a stimulation width of 5 m5ec and 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 9 in the anterior Nakata artery is determined using a current loss flow meter. The generated tension and blood flow m are recorded in ink.
I recorded ten. Details of this method have already been reported by Endo and Hashimoto (Am, J, r'l+gsio1.
No. 218Q, RT pages 1459-1463, 1970,
Naunyn-5chn+iedeberg's A
chieves of Pbarmacolooy, No. 2789. pp. 135-150, 1973: Atrial muscle specimen). The test compound was intraarterially administered in 8 doses of 10 to 30 μQ over 4 seconds.

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

Table 1 shows the results.

Table 1 Formulation example 1 Compound (Ia) 0.025m.

Starch 132ma Magnesium stearate 1- 18+++a Lactose 5
01110 Total: Approximately 200m+1 T! I played 4i.

Formulation example 2 Flower stand (Ib) 0.25mq Starch 130+11(1 Magnesium stearate 20II1g Lactose 50
mG total: approximately 200,111 (1) Tablets of the above composition were manufactured in a conventional manner.

1'l drug example 3 Compound (Ia) 12.5m.

Polyethylene glycol (molecular weight: 4000) 0.3° Sodium chloride 0.9 (1) Polyoxyethylene sorbitan monooleate 0.41 J Sodium metabisulfite 0.1 g Methyl-paraben 0.18. (+ 5 Propyl-paraben 0 .02゜Retained water for injection 100FQ Add the above paraben n1 metal nitrous sulfur 1~lium and sodium sodium chloride to distilled water at 80°C with stirring.
do. 11. The compound of the present invention, polyethylene glycol, and polyoxyethylene sorbitan monomer 1-1 were dissolved in the cold FJI L solution to 40°C, and then distilled water for injection was added to the solution. D Hiiragi no 8
Using a suitable filter paper, reduce the volume by dipping the mixture into ampoules and dispense 1 mQ into ampoules to prepare 1 drug.

Figures 1 and 4 are IR spectra of the compound of the present invention;
2 and 50 are mass spectrograms of the compound of the present invention,
No. 30 and No. 60 (4) NMR spectra of the invention compounds.

) Agent: Patent Attorney Eiji Sanae

Claims (1)

[Claims] No basis shown. ] Represented by 6jJ Rudenoride induced suspension.