JPH0469152B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to cardenolide derivatives. Disclosure of the Invention 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 (). [In the formula, R ¹ is -NHR ³ group (R ³ is hydroxy lower alkyl group, 1 to 1 lower alkoxy group as a substituent)
A lower alkyl group having two groups, a carboxy lower alkyl group, a lower alkylamino lower alkyl group, a lower alkylthio lower alkyl group, a lower alkyl group having a morpholino group or a 1-pyrrolidinyl group as a substituent, a hydroxyl group as a substituent on the phenyl ring. (a phenyl group that may have a phenyl group or a pyridyl group that may have a lower alkoxy group as a substituent on the pyridine ring) or a lower alkoxycarbonyl group. R ² is -NHR ⁴ group (R ⁴ is a hydroxy lower alkyl group, a lower alkyl group having 1 to 2 lower alkoxy groups as a substituent, a carboxy lower alkyl group, a lower alkylamino lower alkyl group, a morpholino group or A lower alkyl group having a 1-pyrrolidinyl group, a lower alkoxy lower alkoxy lower alkyl group, or a lower alkanoyl group which may have a phenoxy group as a substituent) or a lower alkoxycarbonyl group. However, when R ¹ represents a -NHR ³ group, R ² represents a lower alkoxycarbonyl group, and when R ¹ represents a lower alkoxycarbonyl group, R ² represents a -NHR ⁴ group. do. Also, R ¹ and R ² are bonded to each other.

[Formula] Group or

[Formula] may represent a group (R ³ and R ⁴ are the same as above). R ⁵ represents a hydrogen atom. Furthermore, R ¹ and R ² are combined with each other

[Reaction scheme-1]

[One of R ¹ ' and R ² ' represents a -CHO group, and the other represents a lower alkoxycarbonyl group. R ¹ ″ and R ² ″ represent a -NHR ³ group and R ² ″ a lower alkoxycarbonyl group, or R ^{1 ″} represents a lower alkoxycarbonyl group and R ² ″ represents a −
Indicates the NHR ⁴ ′ group. A is

[Formula] Group or

[Reaction scheme-2]

[ ^R5 is the same as above. C is a group

[Formula] or group

[Formula] is shown. A′ is the base

【Formula】Also is the base

[Reaction scheme-3]

[In the formula, B is

[Formula] Group or

[Formula] represents a group. R ⁵ is the same as above. One of R ¹ and R ² represents a hydroxyl group, and the other represents a -COOR ⁶ group. R ⁶ represents a lower alkyl group. R ¹ ′′′′′ and R ² ′′′′′
One side represents an amino group and the other side represents a COOR ⁶ group (R ⁶ is the same as above). ] When reacting digitoxygenin represented by formula () with a peracid to obtain a compound of general formula (), digitoxygenin is dissolved in a suitable inert solvent, and then an organic peracid is added to this solution. , a reaction using an organic peracid may be carried out. As the organic solvent, a wide range of organic solvents can be used without particular limitation as long as it can dissolve the compound to be treated and the organic peracid. Specific examples thereof include halogenated hydrocarbons such as chloroform, methylene dichloride, carbon tetrachloride, and trichloroethylene, and aromatic hydrocarbons such as benzene and toluene. In addition, it can be widely used as an organic peracid without particular limitation, such as perbenzoic acid, metachloroperbenzoic acid, metanitroperbenzoic acid, p-nitroperbenzoic acid, 3,5-
Examples include perbenzoic acids such as dinitroperbenzoic acid. The amount of organic peracid to be used is preferably 1 to 3 times the molar amount, preferably 1.2 to 1.5 times the molar amount of digitoxygenin. The organic peracid may be added as it is, or may be added dissolved in a solvent in advance. As the solvent used here, the same organic solvents as mentioned above can be mentioned. The above oxidation reaction is usually carried out at room temperature to the reflux temperature of the solvent, preferably 60 to 70°C.
The oxidation reaction progresses suitably and is generally completed in 20 minutes to 24 hours. In this way, a compound of general formula () is produced. Alcoholysis of the compound of the general formula () is carried out in the presence of a basic catalyst ^or an acid catalyst without a solvent or in an inert solvent.
This is carried out by reacting an alcohol represented by the formula (in which R ⁶ is the same as above). The basic catalysts used include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium bicarbonate, and sodium hydroxide, or triethylamine, pyridine, picoline, diethylamine, dipropylamine, collidine, etc. Examples include organic bases, and examples of acid catalysts include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid. The amount of such catalyst to be used is usually about 0.1 to 1 mol per 1 mol of compound ().
Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, ethers such as methyl ether and ethyl ether, dimethyl sulfoxide, and acetonitrile. The amount of the alcohol to be used is not particularly limited and can be appropriately selected within a wide range, but when the above reaction is carried out without a solvent, the amount of alcohol to be used is at least equimolar to the compound (). It is usually best to use an excess amount, and when carrying out the above reaction in an inert solvent, the alcohol should be used in at least an equimolar amount, usually 3 to 10 times the molar amount of the compound (). Good. The reaction temperature of this reaction is
The temperature is usually within the range of room temperature to 100°C. In this way, a compound of general formula () is produced. An oxidizing agent is added to the compound represented by the general formula () in an inert solvent, usually at 0 to 100°C, preferably at 15 to 60°C.
When the reaction is carried out in a temperature range of about 100%, a compound of the general formula () is obtained. As the oxidizing agent, a wide variety of conventionally known oxidizing agents can be used, including chromic acid compounds such as potassium dichromate, sodium dichromate, pyridine dichromate, pyridinium chlorochromate, potassium permanganate, and manganese dioxide. Examples include manganese oxides such as, bromine, etc. The amount of the oxidizing agent to be used is usually 1 to 2 mol per 1 mol of the compound (). Examples of the inert solvent include ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as chloroform and dichloromethane, and esters such as ethyl acetate and methyl acetate. A method for obtaining a compound of general formula () from a compound of general formula () is carried out by reacting the compound of general formula () with an ammonium salt and a reducing agent in an inert solvent. This reaction can be carried out under the same reaction conditions as the reductive amination reaction between compound () and compound () in Reaction Scheme-1. The reaction to obtain the compound of the general formula () by ring-closing the compound of the general formula () is carried out in the reaction scheme -
It can be carried out under the same reaction conditions as the ring-closing reaction of the compound of general formula (a) in 1. Reaction scheme-4 The compound of the present invention represented by formula (a) is produced by Beckmann rearrangement reaction of a compound represented by formula (), and the compound of the present invention represented by formula (b) is produced by Beckmann rearrangement reaction of a compound represented by formula (). Manufactured by reaction. The compounds represented by formula () and formula () used as starting materials are both known compounds. When carrying out the Beckman rearrangement reaction, various methods can be employed as long as they are gentle methods that do not eliminate the hydroxyl group at the 14-position of the compound represented by the above formula () or (). More specifically,
This reaction is carried out in an appropriate solvent at a reaction temperature of 0 to 100°C.
The reaction preferably proceeds under temperature conditions of room temperature to 50°C, and the reaction is generally completed in about 10 minutes to 6 hours. The above reaction can be carried out in the presence of an acidic catalyst or a basic catalyst, and more preferably, it can be carried out mildly by adding a reagent that reacts with the hydroxyl group of the compound () or the oxime of the compound () to form a leaving group. It can also be carried out under reaction conditions. Examples of the basic catalyst 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 acids such as sulfuric acid, trifluoroacetic acid, phosphorus pentoxide, formic acid, and methanesulfonic acid. As a reagent for forming a leaving group, 2-mesitylenesulfonyl chloride, p-
Examples include aromatic or aliphatic halides such as toluenesulfonyl chloride, benzenesulfonyl chloride, p-acetamidosulfonyl chloride, ethanesulfonyl chloride, and it is preferable to add a common basic compound to this reaction to make a dehydrohalogenating agent. Reactivity is obtained. Examples of solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, ethers such as ethyl ether, tetrahydrofuran, and dioxane, chlorides such as chloroform, methylene chloride, and carbon tetrachloride, and tertiary compounds such as pyridine, triethylamine, and picoline. Examples include amines. The amount of the catalyst or sulfonyl halide used relative to the compound of formula () or formula () is not particularly limited and can be appropriately selected from a wide range, but is usually an excess amount, preferably an equimolar amount to 3 times the molar amount. It is better to do so. The compound of the general formula () thus obtained is used as a starting material in the reaction scheme-1 to produce the compound of the present invention. The compound of the present invention represented by the general formula () is usually used in the form of a common pharmaceutical preparation. The formulation contains commonly used fillers, extenders, binders, wetting agents, disintegrants,
It is prepared using diluents or excipients such as surfactants and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( liquid,
suspending agents, etc.). When forming tablets, a wide variety of carriers known in this field can be used, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid. agent, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch,
Disintegrants for lactose agents, disintegration inhibitors such as sucrose, stearin, cocoa butter, and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, and kaolin. Examples include adsorbents such as bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, and lubricants such as polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, or multilayer tablets. When forming into a pill form, 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, powdered tragacanth,
Examples include binders such as gelatin and ethanol, and disintegrants such as laminar agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, including 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 () to be contained in the pharmaceutical formulation of the present invention is not particularly limited and can be appropriately selected within a wide range, but usually 1 to 70% in the pharmaceutical formulation.
% by weight, preferably from 1 to 30% by weight. There are no particular restrictions on the method of administering the above pharmaceutical preparations, and the administration method is determined depending on the various preparation forms, age, sex and other conditions of the patient, and the severity of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally. In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and furthermore, if necessary, it is administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally. Suppositories are administered rectally. The dosage of the cardiotonic agent of the present invention depends on the usage, the age of the patient,
The amount of the compound of general formula (), which is the active ingredient, is usually about 0.001 to 1 mg per 1 kg of body weight per day, although it is selected appropriately depending on gender, other conditions, degree of disease, etc.
It is better to Further, it is preferable that the dosage unit form contains 0.01 to 25 mg of the active ingredient. Reference Examples Examples, Pharmacological Tests, and Formulation Examples Reference Examples, Examples, Pharmacological Tests, and Formulation Examples are listed below. Reference example 1 Synthesis of digitoxygenin lactone 1.10 g of digitoxigenin in anhydrous chloroform 15
ml solution, add 1.00 g of metachloroperbenzoic acid,
Stirred under reflux for 24 hours. The reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, and then the solvent was distilled off to obtain 1.24 g of a residue. Ethyl acetate on 100g of silica gel
Chromatography was performed using a chloroform solution system as a developing solvent while increasing the ethyl acetate concentration sequentially. From the 70% ethyl acetate-chloroform eluate,
946mg of a mixture of lactones with a melting point of 225-235℃
(83.0%). This mixture is A-homo-2a-
Oxa-14-hydroxy-5β,14β-caldo-20
(22)-enolide-3-one (hereinafter referred to as "compound (A)")
) and A-homo-3a-oxa-14-hydroxy-5β,14β-caldo-20(22)-enolide-
3-one (hereinafter referred to as "compound (B)") in a ratio of approximately 1:1. Digitoxygenin lactone mixture Melting point: 225-235℃ IR (KBr, cm ^-1 ): 3500, 2975, 2900, 1790, 1745, 1735,
1625, 1455, 1310, 1295, 1190, 1165, 1130,
1070, 1035. UV (λmax, MeOH): nm (log ε) = 218.0 (4, 16). Reference Example 2 8.78 g (22.6 mmol) of the lactone mixture of compound (A) and compound (B) obtained in Reference Example 1 was added to 700 ml of methanol.
1.56g (11.3mmol) of anhydrous potassium carbonate dissolved in
was added and stirred at room temperature for 80 minutes. 5% on ice
The mixture was neutralized with hydrochloric acid, and methanol was distilled off under reduced pressure. The residue was dissolved in ethyl acetate 2, washed with water, and the solvent was distilled off to obtain 9.35 g of colorless crystalline powder. This colorless crystalline powder was dissolved in 300 ml of ethyl acetate and 4,14-hydroxy-2,4
-Seco-3-nor-5β,14β-caldo-20(22)-
Crude crystals of enolide-2-carboxylic acid methyl ester (hereinafter referred to as "compound (C)") were obtained. The crude crystals were recrystallized from ethyl acetate-methanol-petroleum ether to obtain 3.55 g of compound (C). Next, the solvent of the remaining mother liquor in the fractional crystallization method was distilled off under reduced pressure, and the residue was subjected to column chromatography (φ4.3 cm x 30 cm, dichloromethane as eluent:
acetonitrile = 4:1) to give 2,14-dihydroxy-2,4-seco-3-nor-5β,14β-
Caldo-20(22)-enolide-4-carboxylic acid methyl ester (hereinafter referred to as "compound (D)") at 3.3
I got g. Further, the mixture was developed by changing the developing solution to dichloromethane:acetonitrile=:1 to obtain 0.77 g of compound (D). Physical properties of compound C Melting point: 194-196°C. IR (KBr, cm ^-1 ): 3420, 2935, 2870, 1800, 1730, 1705, 1610,
1430, 1380, 1310, 1250, 1220, 1180, 1160,
1020, 960. NMR (DMSO- _d6 , 400MHz, δ: 0.77 (3H, s, 18- _CH3 ), 0.86 (3H, s, 19- _CH3 ), 2.21 (1H, dt, J=11.4, 4.4, 2-Ha ), 2.34 (1H, dt, J = 11.4.4, 2-Hb), 2.72 (1H, m, 17-H) 3.40 (2H, m, 4H), 3.58 (3H, s, OCH ₃ ), 4.09 ( 1H, s, 14-OH), 4.27 (1H, t, J = 4.9, 4-OH), 4.88 (1H, dd, J = 18.7, 2.0, 21-Ha), 4.97 (1H, dd, J = 18.7 , 2.0, 21-Hb), 5.91 (1H, 22-H). Mass (m/e): 420 (M ⁺ ), 402, 388, 370, 352, 315, 297,
285, 269, 235, 217, 199, 187, 171, 163 (100
%), 159, 145, 131, 119, 105, 91, 79, 67,
55, 41. [α] ²⁰ _D = +39.5° (C = 0.51, CHCl ₃ ) Physical properties of compound (D) Melting point 180-182°C IR (KBr, cm ^-1 ): 3440, 3400, 3000, 2975, 2900, 1790, 1775,
1755, 1740, 1700, 1630, 1620, 1450, 1380,
1305, 1200, 1150, 1070, 1040, 1020, 940,
890. NMR (DMSO- _d6 , 400MHz, δ): 0.76 (3H, s, 18- _CH3 ), 0.95 (3H, s, 19- _CH3 ), 1.29 (1H, m, 1-Ha), 1.54 (1H , m, 1-Hb), 1.78 (1H, m, 5-H), 2.38 (2H, m, 4-H), 2.72 (1H, m, 17-H), 3.43 (2H, m, 2-H ), 3.59 (3H, s, OCH ₃ ), 4.09 (1H, s, 14-OH), 4.25 (1H, t, 2-OH, J = 4.9), 4.88 (1H, dd, J = 18.7, 2.0, 21-Ha), 4.97 (1H, dd, J = 18.7, 2.0, 21-Hb) 5.91 (1H, s, 22-H). Mass (m/e): 420 (M ⁺ ), 402, 388, 291, 278, 235, 217,
207, 194 (100%), 175, 147, 134, 119, 111,
107, 93, 79, 67, 55, 41. [α] ²⁰ _D = +33.1° (C = 0.42, CHCl ₃ ) Reference Example 3 Add 420 mg of compound (C) to a solution in which 323 mg of pyridinium chlorochromate (hereinafter abbreviated as PCC) was suspended in 30 ml of anhydrous methylene chloride. , in an argon stream,
The mixture was stirred at room temperature for 1.5 hours, insoluble matter was removed, and the liquid was distilled off to obtain 470 mg of a dark brown caramel-like substance, which was purified by column chromatography using 12 g of silica gel. Eluted with methylene chloride-acetonitrile (12%), 2-oxo-14-
Hydroxy-2,4-seco-3-nor-5β,14β
340 mg of colorless crystals of -caldo-20(22)-enolide-4-carboxylic acid methyl ester were obtained. Recrystallization from methylene chloride-ether gave colorless needles. Melting point 167-169℃. Mass (m/e): 418 (M ⁺ ), 400, 386. IR (KBr, cm ^-1 ): 3550, 1885, 1750, 1720 (sh), 1719, 1618. NMR (CDCl ₃ , δ): 0.88 (3H, s), 1.29 (3H, s), 2.20 (1H, dd, J = 15.2.1), 2.42 (1H, dd, J = 5.0), 2.45 (1H, dd, J=15.0, 2.1), 2.48 (1H, dd, J=15.0, 2.1), 3.65 (3H, s), 4.80 (1H, dd, J=18.0, 1.5), 4.97 (1H, dd, J= 18.0, 1.5), 5.87 (1H, t, J=1.5), 9.88 (1H, dd, J=3.7, 2.1). [α] ²⁰ _D = +14.1° (C = 0.66, CHCl ₃ ) Reference Example 4 420 mg of compound (D) and 323 mg of PCC were reacted in the same manner as in Reference Example 3 to obtain 4-oxo-14-hydroxy-2, 4-seco-3-nor-5β,14β-caldo-
310 mg of colorless needle-like crystals of 20(22)-enolide-2-carboxylic acid methyl ester were obtained. Melting point 165-167℃. Mass (m/e): 418 (M ⁺ ), 400, 390, 386. IR (KBr, cm ^-1 ): 3500, 1790, 1730, 1620. NMR (CDCl ₃ , δ): 0.88 (3H, s), 1.00 (3H, s), 2.87 (1H, dd, J = 9.7, 5.9), 3.68 (3H, s), 4.80 (1H, dd, J = 18.1, 1.9), 4.96 (1H, dd, J = 18.1, 1.9), 5.86 (1H, t, J = 1.9), 9.76 (1H, d, J = 3.2). [α] ²⁰ _D = −2.5° (C = 0.56, CHCl ₃ ). Reference example 5 (E)-14-hydroxy-3-oximino-5β,
371 mg of 14β-caldo-20(22)-enolide (compound of formula ()), 0.182 ml of triethylamine and 2
- 241 mg of mesitylene sulfonyl chloride in 5 ml of dry methylene chloride at 0°C for 30 minutes, then at room temperature.
Stir for 30 minutes. The reaction mixture was added to 30 ml of methylene chloride-saturated brine (2:1), and the organic layer was separated. The organic layer was dried over Na ₂ SO ₄ and evaporated to give an oil. This oily substance was adsorbed onto 10 g of alumina and eluted with 30 ml of methanol. The colorless oil obtained by distilling off methanol was subjected to silica gel column chromatography and eluted with methylene chloride-acetone to obtain 300 mg of the compound of formula (a) as colorless crystals. The crystals were recrystallized from methylene chloride-ethyl acetate and had a melting point of 252-255°C. NMR ( _CDCl3 ): 0.888 (3H, s), 0.997 (3H,
s), 2.21 (1H, dd, J15.1, 8.6), 2.55 (1H,
dd, J15.1, 11.1), 2.75 (1H, ddd, J14.9, 7.3,
0.8), 2.78 (1H, m), 3.73 (1H, ddd, J14.9,
10.5, 3.8), 4.80 (1H, dd, J17.8, 1.4), 4.97
(1H, dd, J17.8, 1.4), 5.88 (1H, s), 5.98
(1H, s) Mass; m/e, 387 (M ⁺ ), 369, 290, 277, 262,
234, 220, 206, 193, 178, 165, 147, 134,
122, 112, 105, 91, 85, 67, 55, 41
(Calculated value as C ₂₃ H ₃₃ NO ₄ 387, 2409) IR (KBr); 3502, 3207, 3102, 1799, 1727,
1674, 1642, 1617, 1465, 1402, 1340, 1265,
1162, 1134, 1064, 1024, 897, 730, 690, 645 Reference example 6 (Z)-14-hydroxy-3-oximino-
The same procedure as in Example 1 was carried out except that 371 mg of 5β,14β-caldo-20(22)-enolide (compound of formula ()) was used to obtain 310 mg of the compound of formula (b) as colorless crystals. The melting point of the crystals recrystallized from methylene chloride-methanol is 270℃ (decomposition)
It was hot. NMR ( _CDCl3 ): 0.888 (3H, s), 1.00 (3H, s),
2.06 (1H, d, J = 15.1), 2.79 (1H, m), 2.98
(1H, dd, J15.1, 11.6), 3.08 (1H, ddd,
J14.3, 7.5, 5.2), 3.23 (1H, ddd, J14.3, 9.2,
5.4), 4.80 (1H, dd, J18.4, 1.6), 4.98 (1H,
dd, J18.4, 1.6), 5.83 (1H, s) Mass; m/e, 387 (M ⁺ ), 369, 290, 277, 262,
334 (100), 220, 206, 193, 178, 165, 147,
122, 105, 91, 85, 67, 55, 41 (calculated as C ₂₃ H ₃₃ NO ₄ 387, 2409) IR (KBr); 3362, 3352, 1797, 1734, 1622,
1497, 1462, 1452, 1382, 1359, 1342, 1259,
1192, 1132, 1029, 897, 859, 730, 645 Example 1 2-oxo-14-hydroxy-2,4-seco-
3-nor-5β,14β-caldo-20(22)-enolide-4-carboxylic acid methyl ester 220 mg and 2
- Dissolve 190 mg of methoxyethylamine in 5 ml of methanol and add 0.086 ml of acetic acid, then 60 mg of sodium cyanoborohydride (NaBH ₃ CN).
Dissolve in 3 ml of methanol and add dropwise. Stir overnight at room temperature. Thereafter, methanol was distilled off under reduced pressure, 15 ml of water was added to the resulting residue, and the mixture was extracted with ethyl acetate. After drying the ethyl acetate layer with sodium sulfate,
Distill under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform containing 5% methanol) to obtain 142 mg of 2-(2-
methoxyethyl)amino-14-hydroxy-2,
4-seco-3-nor-5β,14β-caldo-20 (22)
-enolide-4-carboxylic acid methyl ester is obtained. Colorless powder mp.167-169℃ IR (KBr); 3503, 1800, 1750, 1723, 1630cm ^-1 Mass (m/e); 413 (M ⁺ ), 445, 415, 400, 388,
235, 194, 117 NMR (CDCl ₃ ) δ; 0.87 (s, 3H), 1.02 (s,
3H), 2.39 (2H, m), 2.65 (td, J=11.6Hz,
4.9Hz), 2.71 (td, J=11.6Hz, 4.9Hz), 2.77
(m, 1H), 2.83 (2H, td, J=5.1Hz, 1.1Hz),
3.36 (s, 3H), 3.52 (2H, t, J=5.1), 3.67
(3H, s), 4.79 (1H, dd, J=18.1Hz, 1.6
Hz), 4.97 (1H, dd, J=18.1Hz, 1.6Hz), 5.87
(1H, t, J=1.6Hz) Using appropriate starting materials in the same manner as in Example 1, the following compound is obtained.

【table】

【table】

[Table] Example 16 2-(2-methoxyethyl)amino-14-hydroxy-2,4-seco-3-nor-5β,14β-caldo-20(22)-enolide-4-carboxylic acid methyl ester 440 mg Dissolved in 4 ml of anisole-dimethylformamide (4:1) mixed solvent,
Heat and stir at 155°C for 4 hours. The solvent is distilled off under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: dichloromethane containing 15% acetonitrile). Recrystallized from ethyl acetate-diethyl ether to give 210 mg of A-homo-
3-(2-methoxyethyl)-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20
(22) − Obtain the enolide. Colorless needle crystals mp.175-176℃ IR (KBr): 3425, 1790, 1750, 1618cm ^-1 Mass (m/e): 445 (M ⁺ ), 430 (M ⁺ -15), 413,
400, 372, 354, 260 NMR (CDCl ₃ ): δ0.88 (3H, s), 0.96 (3H, s),
2.09 ( 1 Hd, J=14.2Hz), 2.78 (1H, m), 3.04
(1H, dd, J = 14.2Hz, 12.0Hz), 3.14 (1H,
dd, J=15.5Hz, 7.3Hz), 3.32 (3H, s), 3.48
(m, 4H ), 3.58 (1H, dd, J=15.5Hz, 7.3
Hz), 4.80 (1H, dd, J=18.1Hz, 1.3Hz), 4.99
(1H, dd, J = 18.1Hz, 1.3Hz), 5.87 (1H, t,
J=1.3Hz) The following compound is obtained in the same manner as in Example 16 using appropriate starting materials.

【table】

【table】

【table】

【table】

【table】

[Table] Example 46 2-[2-(N,N-dimethylamino)ethyl]
Amino-14-hydroxy-2,4-seco-3-nor-5β,14β-caldo-20(22)-enolide-4
- 400 mg of carboxylic acid methyl ester are dissolved in 20 ml of dry methylene chloride, and 1.41 ml of a 19% solution of trimethylaluminum in n-hexane is added dropwise. Thereafter, the mixture was heated and stirred for 2.5 hours under an argon stream. After the reaction is complete, add 20 ml of methylene chloride to the reaction solution, add 0.5N hydrochloric acid under ice cooling, make alkaline with saturated aqueous sodium bicarbonate, and separate the methylene chloride layer. The aqueous layer is further extracted with a methylene chloride layer, added to the methylene chloride layer, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform containing 10% methanol) and recrystallized from methanol-diethyl ether to give 154 mg.
A--homo-3-[2-(N,N-dimethyl)ethyl]-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide is obtained. mp.193−195℃ Colorless prismatic crystal IR (KBr): 3370, 1775, 1745, 1630cm ^-1 Mass (m/z): 458 (M ⁺ ), 413, 389, 348, 305,
260, 71, 58 NMR ( _CDCl3 ): 0.88 (3H, s), 0.97 (3H, s),
2.08 (1H, d, J = 14.7Hz), 2.29 (6H, s),
2.44 (2H, m), 2.79 (1H, m), 3.04-3.05
( 2H , m), 3.35 (1H, dt, J = 14.0Hz, 7.0Hz),
3.54 ( 2H dd, J=15.1Hz, 10.0Hz), 3.62 ( 1H ,
dt, J = 14.0Hz, 7.9Hz), 4.80 (1H, dd, J =
18.0Hz, 1.5Hz), 4.98 ( 1H , dd, J=18.0Hz,
1.5Hz), 5.87 (1H, t, J=1.5Hz) Using appropriate starting materials in the same manner as in Example 46, the compounds of Examples 16 to 18 and 20 to 45 are obtained. Example 47 2-[2-(pyrrolidin-1-yl)ethyl]amino-14-hydroxy-2,4-seco-3-nor-5β,14β-caldo-20(22)-enolide-4-
Carboxylic acid methyl ester 690mg methylene chloride
50 ml and 3 ml of pyridine, add 2.4 ml of 19% trimethylamminium n-hexane solution, and heat under reflux for 3 hours under an argon atmosphere. The following treatment and purification were carried out in the same manner as in Example 46, recrystallized from methanol-diethyl ether, and 450 mg of A-homo-3-[2-
(pyrrolidin-1-yl)ethyl]-3-aza-
3a-Oxo-14-hydroxy-5β,1β-caldo-20(22)-enolide is obtained. mp.220−221.5℃ Colorless needle crystal IR (KBr): 3450, 2960, 2880, 1790, 1740,
1620cm ^-1 Mass (m/z): 467, 412, 396, 386 NMR (DMSO-d ₆ ) δ: 0.78 (3H, s), 0.91
(3H, s), 1.58 (1H, m), 1.84 (1H, d, J
= 14.6Hz), 2.75 (1H, dd, J = 9.5Hz, 5.0Hz),
3.04 (1H, dd, J=15.5Hz, 7.3Hz), 3.15 (1H,
t, J = 14.6Hz), 3.60 (1H, dd, J = 15.5Hz,
11.1Hz), 3.81 (1H, dt, J = 13.7Hz, 6.9Hz),
4.14 (1H, s), 4.89 (1H, dd, J=18.1Hz, 1.3
Hz), 4.97 (1H, dd, J=18.1Hz, 1.3Hz), 5.92
(1H, t, J=1.3Hz) In the same manner as in Example 47, using appropriate starting materials, the compounds of Examples 16 to 20 and 22 to 45 are obtained. Example 48 2-oxo-14-hydroxy-2,4-seco-
Add 720 mg of 3-nor-5β,14β-caldo-20(22)-enolide-4-carboxylic acid methyl ester, 810 mg of ethylenediamine, and 0.3 ml of acetic acid to 5 ml of methanol.
Sodium cyanoborohydride dissolved in ml
Add 280 mg and stir at room temperature for 13 hours. After the reaction is complete, add 10 ml of saturated saline to the reaction solution and extract with chloroform. After drying the chloroform layer with sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent:
Purified with chloroform containing 20% methanol,
Recrystallized from ethyl acetate to give 265 mg of A-homo-
2,3-(1-azapropano)-3-aza-3a-
Oxo-14-hydroxy-5β,14β-caldo-20
(22) − Obtain the enolide. The structural formula of this compound is shown below. mp.300℃ or higher Colorless needle crystals IR (KBr): 3400, 2950, 1780, 1750, 1600 cm ^-1 Mass (m/z): 428 (M ⁺ ), 410, 385, 358, 341 NMR (DMSO-d ₆ ) δ: 0.78 (3H, s), 0.99 (3H, s), 1.44 (1H, dd, J=14.3Hz, 9.3
Hz), 1.86 (1H, d, J = 14.3Hz), 1.96 (1H,
d, J=17.2Hz), 2.84 (1H, dd, J=17.2Hz,
11.8Hz), 3.05 (1H, m), 3.15 (1H, dd, J=10.3Hz, 7.4
Hz), 3.25 (1H, dd, J = 10.3Hz, 7.4Hz), 4.21 (1H,
d, J = 9.3Hz), 4.88 (1H, dd, J = 18.2Hz,
1.5Hz), 4.96 (1H, dd, J = 18.2Hz, 1.5Hz), 5.91 (1H, t, J = 1.5Hz) Example 49 17 mg of 50% sodium hydride was suspended in 0.5 ml of dry dimethylformamide and A-homo-3-oxo-3a-aza-14-hydroxy-5β,14β-
A solution of 100 mg of caldo-20(22)-enolide in 2 ml of dimethylformamide is added. After stirring at room temperature for 30 minutes, 510 mg of 15-crown and 62μ of methoxymethyl chloride were added, and the mixture was stirred at room temperature for 12 hours. After the reaction is complete, the reaction solution is poured into ice water and extracted with ethyl acetate. Dry over sodium sulfate, then evaporate the solvent. The residue was purified by preparative thin layer chromatography (silica gel, developing solution: methylene chloride:acetone = 50:50) to obtain 90 mg of A-homo-3a-(methoxymethyl)-3-oxo-3a-. Aza-14-hydroxy
5β,14β-caldo-20(22)-enolide is obtained. mp.84-87℃ Colorless crystal IR (KBr): 3450, 1785, 1743, 1640 cm ^-1 Mass (m/z): 431 (M ⁺ ) NMR (CDCl ₃ ) δ: 0.89 (3H, s), 0.99 ( 3H,
s), 2.66 (1H, dd, J=12.2Hz, 14.3Hz),
2.78 (1H, m), 2.98 (1H, d, J = 15.7Hz)
3.29 (3H, s), 3.89 (1H, dd, J=10.8Hz,
15.7Hz), 4.67 (1H, d, J = 9.7Hz), 4.80 (1H,
dd, J=1.4Hz, 18.1Hz), 4.83(1H, d, J=
9.7Hz), 4.97 (1H, dd, J=1.4Hz, 18.1Hz),
5.89 (1H, t, J=1.4Hz) In the same manner as in Example 49, using appropriate starting materials, the compounds of Examples 16 to 25, 27 to 45 and the following compounds are obtained.

【table】

[Table] <Pharmacological test> Blood perfusion isolated papillary muscle specimen Adult mongrel dogs weighing 8 to 12 kg are anesthetized by intravenously administering pentobarbital sodium salt at a dose of 30 mg/kg. heparin sodium salt
After intravenous administration at a dose of 1000U/Kg, the patient was killed by exsanguination.
Remove the heart. The specimen consists mainly of papillary muscles and ventricular septum, and is perfused with blood from a donor dog at a constant pressure of 100 mmHg through a cannula inserted into the anterior septal artery. Donor dogs weighing 14 to 30 kg were anesthetized in advance by intravenous administration of 30 mg/kg of pentobarbital sodium salt, and then treated with heparin sodium salt.
1000U/Kg is administered intravenously. Using bipolar electrodes, the papillary muscles are stimulated with a square wave at a voltage 1.5 times the threshold (0.5 to 3 V), a stimulation width of 5 msec, 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 in the anterior septal artery is measured using an electromagnetic flowmeter. Records of developed tension and blood flow were recorded on an ink recorder. Details of this method have already been reported by Endo and Hashimoto (Am.J.Phgsiol. No. 218
Volume, pp. 1459-1463, 1970, Naunyn-
Schmie−deberg′s Achieves of
Pharmacology, Volume 278, Pages 135-150, 1973
year: atrial muscle specimen). The test compound was administered intra-arterially in a volume of 10-30 μ over 4 seconds. The inotropic effect of the test compound was expressed as a % change in the tension generated before drug administration. The test compounds used are as follows. Test compound No. 1 A-homo-3-(2-methoxyethyl)-3-
Aza-3a-oxo-14-hydroxy-5β,14β
-Caldo-20(22)-enolide. 2 A-homo-3-[2-(morpholin-1-yl)ethyl]-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide. 3 A-homo-3-(2-hydroxyethyl)-3
-aza-3a-oxo-14-hydroxy-5β,
14β-caldo-20(22)-enolide. 4 A-homo-3-[2-(N,N-dimethyl)ethyl]-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide. 5 A-homo-3-[2-(pyrocidin-1-yl)ethyl]-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide. 6 A-homo-3-[2-[carboxyethyl]-
3-aza-3a-oxo-14-hydroxy-5β,
14β-Caldo-20(22)-enolide potassium salt. 7 A-homo-3-[3-(morpholin-1-yl)ethyl]-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide. 8 A-homo-3-(p-hydroxyphenyl)-
3-aza-3a-oxo-14-hydroxy-5β,
14β-caldo-20(22)-enolide. 9 A-homo-3-(3-methylthiopropyl)-
3-aza-3a-oxo-14-hydroxy-5β,
14β-caldo-20(22)-enolide. 10 A-homo-3-(6-methoxypyridine-1
-yl)-3-aza-3a-oxo-14-hydroxy-5β,14β-caldo-20(22)-enolide. 11 A-homo-2,3-(1-azapropano)-3
-aza-3a-oxo-14-hydroxy-5β,
14β-caldo-20(22)-enolide. 12 A-Homo-3a-[2-(morpholin-1-yl)ethyl]-3-oxo-3a-aza-14-hydroxy-5α,14β-caldo-20(22)-enolide. 13 A-homo-3a-(2-hydroxyethyl)-
3-oxo-3a-aza-14-hydroxy-5β,
14β-caldo-20(22)-enolide. 14 A-homo-3a-[2-(N,N-dimethyl)
ethyl]-3-oxo-3a-aza-14-hydroxy-5β,14β-caldo-20(22) enolide. 15 A-Homo-3a-[2-(pyrrolidin-1-yl)ethyl]-3-oxo-3a-aza-14-hydroxy-5β,14β-caldo-20(22)-enolide. 16 A-homo-3a-[3-(morpholin-1-yl)propyl]-3-oxo-3a-aza-14-
Hydroxy-5β,14β-caldo-20(22)-enolide. 17 A-Homo-3a-(2,2-dimethoxyethyl)-3-oxo-3a-aza-14-hydroxy-5β,14β-caldo-20(22)-enolide. 18 A-homo-3a-(methoxymethyl)-3-oxo-3a-aza-14-hydroxy-5β,14β-
Caldo-20 (22)-enolide. 19 A-homo-3a-[(2-methoxyethoxy)
methyl]-3-oxo-3a-aza-14-hydroxy-5β,14β-caldo-20(22)-enolide. 20 A-Homo-3a-(N,N-dimethylaminomethyl)-3-oxo-3a-aza-14-hydroxy-5β,14β-caldo-20(22)-enolide. 21 A-homo-3a-acetyl-3-oxo-3a
-aza-14-hydroxy-5β,14β-caldo-
20 (22) - enolide. The results are shown in Table 1.

【table】

[Table] Formulation Example 1 Compound of Example 37 0.025 mg Starch 132 mg Magnesium Stearate 18 mg Lactose 50 mg Total: Approximately 200 mg Tablets of the above composition were manufactured in a conventional manner. Formulation Example 2 Compound of Example 18 0.25mg Starch 130mg Magnesium Stearate 20mg Lactose 50mg Total: Approximately 200mg Tablets containing the above composition were prepared in a conventional manner. Formulation Example 3 Compound of Example 19 12.5 mg Polyethylene glycol 0.3 g (Molecular weight: 4000) Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 1000ml The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water at 80°C with stirring. The resulting 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 adjust the final volume. , sterilized by sterilization using a suitable filter paper.
Prepare injection by dispensing ml into ampoules.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is -NHR ³ group (R ³ is hydroxy lower alkyl group, 1 to 1 lower alkoxy group as a substituent)
A lower alkyl group having two groups, a carboxy lower alkyl group, a lower alkylamino lower alkyl group, a lower alkylthio lower alkyl group, a lower alkyl group having a morpholino group or a 1-pyrrolidinyl group as a substituent, a hydroxyl group as a substituent on the phenyl ring. (a phenyl group that may have a phenyl group or a pyridyl group that may have a lower alkoxy group as a substituent on the pyridine ring) or a lower alkoxycarbonyl group. R ² is -NHR ⁴ group (R ⁴ is a hydroxy lower alkyl group, a lower alkyl group having 1 to 2 lower alkoxy groups as a substituent, a carboxy lower alkyl group, a lower alkylamino lower alkyl group, a morpholino group or A lower alkyl group having a 1-pyrrolidinyl group, a lower alkoxy lower alkoxy lower alkyl group, or a lower alkanoyl group which may have a phenoxy group as a substituent) or a lower alkoxy carbonyl group. However, when R ¹ represents a -NHR ³ group, R ² represents a lower alkoxycarbonyl group, and when R ¹ represents a lower alkoxycarbonyl group, R ² represents a -NHR ⁴ group. do. Furthermore, R ¹ and R ² may be bonded to each other to represent a [formula] group or a [formula] group (R ³ and R ⁴ are the same as above). R ⁵ represents a hydrogen atom. Further, when R ¹ and R ² are bonded to each other to represent a [Formula] group, R ⁵ and R ³ may be bonded to each other to represent a -NH-(CH ₂ ) ₂ - group. ] A cardenolide derivative represented by.