JPH0451553B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to cardenolide derivatives. Structure and Effects of the Invention The cardenolide derivative of the present invention is a novel compound described in the literature and has the following general formula: [In the formula, R ¹ is a -NHR ³ group (R ³ represents a phenyl lower alkyl group or a lower alkyl group that may have a hydroxyl group as a substituent on the phenyl ring.)
Or it represents a lower alkoxycarbonyl group. ^R2 is
-NHR ⁴ group (R ⁴ is a phenyl lower alkyl group which may have 1 to 3 groups selected from hydroxyl and lower alkoxy groups as substituents on the phenyl ring, a 5- or 6-membered unsaturated heterocyclic ring) represents a lower alkyl group, cycloalkyl group, or lower alkyl group having a residue) or a lower alkoxycarbonyl group. However, when R ¹ represents -NHR ³ group,
^R2 shall represent a lower alkoxycarbonyl group, and when ^R1 represents a lower alkoxycarbonyl group, ^R2 shall represent a ^-NR4 group. Furthermore, R ¹ and R ² are bonded to each other.

[Formula] Group or

[Reaction formula-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 ″ are R ¹ ″ represents a −NHR ³ group and R ² ″ represents a lower alkoxycarbonyl group, or R ¹ ″ represents a lower alkoxycarbonyl group and R ² ″ represents an −NHR ⁴ group. shows. A is

[Formula] Group or

[Formula] represents a group. R ³ and R ⁴ are the same as above] The reaction between the compound of the general formula () and the amine of the general formula () is called a reductive amination reaction, and is carried out, for example, in an inert solvent in the presence of a reducing agent. This is done by Here, the inert solvent is
Examples include water, alcohols such as methanol, ethanol, and propanol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol, and dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, and mixed solvents thereof. can. Examples of the reducing agent include sodium cyanoborohydride, sodium borohydride, boron compounds such as diborane, lithium aluminum hydride, and the like. The amount of the amine of the above general formula () to be used is usually at least equimolar, preferably about 1 to 6 times the molar amount of the compound (), and the amount of the reducing agent to be used is The amount is usually equivalent to 3 times the molar amount of the compound (). The reaction is usually carried out at 0°C to 100°C, preferably room temperature to 60°C, and generally for 30 minutes to 5 minutes.
The reaction completes in about an hour. In this way, a compound of general formula (Ia) can be obtained. When using a boron compound, the reaction proceeds advantageously by adding an acid such as acetic acid. When using lithium aluminum hydride, it is preferable to use ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether as a solvent. The reductive amination reaction can also be carried out in the presence of a catalytic reduction catalyst, preferably in a solvent. Examples of the solvent used here include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran,
Acetic acid etc. can be used. Examples of the catalytic reduction catalyst include Raney nickel, platinum, platinum oxide, palladium-carbon, and palladium-black. The amount of catalyst used is usually about 0.2 to 0.5 times the weight of the compound of general formula (). The reaction is
Temperature is usually 0°C to 200°C, preferably 0°C to 150°C
Normally, under conditions where the hydrogen pressure is usually 1 to 30 atm.
Finishes in 0.5-10 hours. The reaction of ring-closing the compound of general formula (Ia) to obtain the compound of general formula (Ib) is usually carried out in an inert solvent.
This is carried out by heating the compound (Ia) to about 50 to 200°C, preferably about 100 to 160°C, usually for about 1 to 10 hours. Examples of inert solvents used here include aromatic hydrocarbons such as toluene, xylene, and anisole, N,N-dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethylsulfoxide, etc., or mixed solvents thereof. etc. can be exemplified. Further, ring closure can also be carried out in a suitable solvent in the presence of an acid. The solvent used here is
Alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene, toluene and xylene, hexane,
Examples include aliphatic hydrocarbons such as cyclohexane, pyridine, etc., and mixed solvents thereof. Examples of acids used include organic acids such as P-toluenesulfonic acid and acetic acid, and Lewis acids such as trialkylaluminum, boron trifluoride, boron tribromide, zinc chloride, iron chloride, and silver chloride. The amount of acid to be used is usually a catalytic amount, preferably 0.01 to equimolar amount to the compound of general formula (Ia). The reaction is usually completed at room temperature to 150°C, preferably room temperature to 100°C, in about 0.5 to 5 hours. The target compound thus obtained can be isolated by conventional isolation methods, such as recrystallization, solvent extraction, column chromatography such as high performance liquid chromatography,
easily isolated from the reaction mixture by means such as distillation;
Can be purified. The compound of general formula () is a new compound, and can be obtained, for example, by the method shown in Reaction Scheme-2 below. [In the formula, B is

[Formula] Group or

[Formula] Indicates a group. One of R ¹ and R ² has a hydroxyl group,
The other shows -COOR ⁵ groups. R ⁵ represents a lower alkyl group. ) To obtain a compound of general formula () by reacting digitoxygenin represented by formula () with a peracid, digitoxygenin is suitably dissolved in an 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 dioxide, 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 performed by converting the compound of the general formula () into the compound of the general formula R ⁵ OH in the presence of a basic catalyst or an acid catalyst without a solvent or in an inert solvent.
[In the formula, R ⁵ is the same as above. ] is carried out by reacting an alcohol represented by The basic catalysts used are 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 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, specifically 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. The compound of the general formula () thus obtained is used as a starting material for 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, warming 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 such as lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin Examples include adsorbents such as , bentonite and colloidal silicic acid, and lubricants such as sugar talc, stearate, boric acid powder, and 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 a pill, 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, 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 () 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 may be carried out in a manner 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% of the active ingredient. Reference Examples, Examples, Pharmacological Tests, and Pharmaceutical Products Reference Examples, Examples, Pharmacological Tests, and Pharmaceutical Pharmaceutical Products are listed below. Reference example 1 Synthesis of digitoxigenin 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 hydrocarbon 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
For chromatography using a chloroform solvent system as a developing solvent and increasing the ethyl acetate concentration sequentially. 70% ethyl acetate-chloroform elution yields 946 mg of a mixture of lactones with a melting point of 225-235°C
(83.0%). This mixture is A-homo-2a-
Oxa-14-hydroxy-5β,14β-caldo-20
(22)-enolide-3-one (hereinafter referred to as "compound (Va)") and A-homo-3a-oxa-14-
Hydroxy-5β,14β-caldo-20(22)-enolide-3-one (hereinafter referred to as “compound (Vb)”)
and in a ratio of about 1:1, respectively. Digitoxigenin 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 (logε) = 218.0 (4.16). Reference example 2 Compound (Va) and compound (Vb) obtained in Reference example 1
Dissolve 8.78 g (22.6 mmol) of the lactone mixture in 700 ml of methanol to obtain 1.56 g of anhydrous potassium carbonate.
(11.3 mmol) was added and stirred at room temperature for 80 minutes.
The mixture was neutralized with 5% hydrochloric acid under ice cooling, 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-dihydroxy-2,
4-seco-3-nor-5β,14β-caldo-20 (22)
Crude crystals of -enolide-2-carboxylic acid methyl ester (hereinafter referred to as "compound (a)") were obtained. The crude crystals were recrystallized from ethyl acetate-methanol-petroleum ether to yield 3.55 g of compound (a).
Obtained. 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), 2,14-dihydroxy-2,4-seco-3-nor-5β,14β-
Cardo-20(22)-enolide-4-carboxylic acid methyl ester (hereinafter referred to as "compound (b)")
3.3g of was obtained. Furthermore, the developing solution was changed to dichloromethane:acetonitrile=2:1 and the compound (
b) Obtained 0.77g. Physical properties of compound a 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- _b6 , 400MHz, δ): 0.77 (3H, s, 18- _CH3 ), 0.86 (3H, s, 19- _CH3 ), 2.21 (1H, bt, J=11.4, 4.4, 2- Ha), 2.34 (1H, dt, J = 11.4, 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 (Ib) 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-d ₆ , 400MHz, δ): 0.76 (3H, s, 18-CH ₃ ), 0.95 (3H, s, 19-CH ₃ ), 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-Hd), 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 3 420 mg of compound (a) was added to a solution in which 323 mg of pyridinium chlorochromate (hereinafter abbreviated as PCC) was suspended in 30 ml of anhydrous methylene chloride, and the mixture was stirred at room temperature in an argon atmosphere for 1.5 hours. Remove the insoluble matter and distill off the liquid to obtain a dark brown caramel-like substance.
470 mg was obtained, and this product was purified by column chromatography using 12 g of silica gel. Elute with methylene chloride-acetonitrile (12%) to obtain 2-oxo-14hydroxy-2,4-seco-3-nor-
5β,14β-Caldo-20(22)-enolide-4-carboxylic acid methyl ester (hereinafter referred to as “compound (
340 mg of colorless crystals of a) 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, 1785, 1750, 1720 (sh), 1719, 1618. NMR (CDCl ₃ , δ): 0.88 (3H, s), 1.29 (3H, s), 2.20 (1H, dd, J = 15.0, 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 (b) 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-20 (22). 310 mg of colorless needle-like crystals of -enolide-2-carboxylic acid methyl ester (hereinafter referred to as "compound (b)") was 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), 5.89 (1H, t, J = 1.9), 9.76 (1H, d, J = 3.2). [α] ²⁰ _D = −2.5° (C = 0.56, CHCl ₃ ). Example 1 Compound (b) 600 mg, furfurylamine 697 mg
Dissolve 0.5 ml of acetic acid in 20 ml of methanol, and add 150 mg of sodium cyanoborohydride while stirring at room temperature.
A solution of 5 ml of methanol was added dropwise to the mixture, and the mixture was reacted at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, 20 ml of saturated brine was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was dried over Glauber's salt and then evaporated under reduced pressure to obtain 780 mg of a residue. This product was purified by column chromatography using 30 g of silica gel and CHCl ₃ -MeOH (5%), and 4-furfurylamino-14-hydroxy-2,4-seco-3-nor-
480 mg of a colorless caramel of 5β,14β-caldo-20(22)-enolide-2-carboxylic acid methyl ester (Ic) was obtained. Trituration with ethyl acetate-diethyl ether gave colorless powdery crystals. Melting point 161-163℃. Mass (m/e): 499 (M ⁺ ), 467. IR (KBr, cm ^-1 ): 3515, 1800, 1750, 1620. NMR (CDCl ₃ , δ): 0.84 (3H, s), 0.91 (3H, s), 2.50 (1H, dd, J = 11.2, 3.4), 2.63 (1H, t, J = 11.2), 2.76 (1H, dd, J = 9.5, 5.8), 3.64 (3H, s), 3.72 (1H, d, J = 14.6), 3.78 (1H, d, J = 14.6), 4.78 (1H, dd, J = 18.0, 1.4) , 4.97 (1H, dd, J = 18.0, 1.4), 5.85 (1H, t, J = 1.4), 6.16 (1H, dd, J = 3.1, 0.8), 6.29 (1H, dd, J = 3.1, 0.8) , 7.33 (1H, dd, J = 1.7, 0.8), Example 2 570 mg of compound (b), 335 mg of p-hydroxybenzylamine and 0.1 ml of acetic acid were added to 25 ml of methanol.
14-
Colorless caramel of hydroxy-4-(p-hydroxybenzylamino)-2,4-seco-3-nor-5β,14β-caldo-20(22)-enolide-2-carboxylic acid methyl ester (Id) 700 mg I got it. Mass (m/e): 493 (M ⁺ -32), 416, 401, 387, 107. IR (nujiyor, cm ^-1 ): 3450, 1780, 1735, 1620, 1600. NMR (DMSO- _d6 , δ): 0.75 (3H, s), 0.85 (3H, s), 2.71 (1H, dd, J=9.4, 5.4), 3.56 (3H, s), 3.66 (3H, br. s), 4.08 (1H, s), 4.83 (1H, d, J = 18.7), 4.96 (1H, d, J = 18.7), 5.90 (1H, s), 6.69 (2H, d, J = 8.4), 7.14 (2H, d, J=8.4), 9.27 (1H, br.s). Example 3 600 mg of compound (b), 880 mg of 2-(2-aminoethyl)pyridine and 0.5 ml of acetic acid were mixed with 25 ml of methanol.
ml, using 150 mg of sodium cyanoborohydride, reductive amination and treatment in the same manner as in Example 1 to obtain 14-hydroxy-4-[2-(2-pinidylethyl)]amino-2,4-seco-3. −nor−5β,
Colorless caramel of 14β-caldo-2-(22)-enolide-2-carboxylic acid methyl ester (Ie)
Obtained 670 mg. Mass (m/e): 524 (M ⁺ ), 492 (M ⁺ −32). IR (KBr, cm ^-1 ): 3450, 1780, 1740, 1735 (sh), 1620, 1600. NMR (CDCl ₃ , δ): 0.87 (3H, s), 0.97 (3H, s), 2.77 (2H, m), 2.90 (1H, t, J = 11.7), 3.14 (1H, m), 3.27 (1H , m), 3.65 (3H, s), 4.80 (1H, dd, J = 18.1, 1.6), 4.97 (1H, dd, J = 18.1, 1.6), 5.87 (1H, t, J = 1.6), 7.19 ~ 7.26 (2H, m), 7.66 (1H, dt, J = 7.69, 1.86), 8.46 (1H, dq, J = 8.46, 5.13, 1.86, 1.16). Example 4 Compound (b) 680 mg, 2-(3,4-dimethoxyphenyl)ethylamine 1.2 g and acetic acid 0.25 ml
14-hydroxy-4-[2-
(3,4-dimethoxyphenyl)]ethylamino-
2,4-seco-3-nor-5β,14β-caldo-20
530 mg of colorless powder of (22)-enolide-2-carboxylic acid methyl ester (If) was obtained. Mass (m/e): 583 (M ⁺ ), 553, 336, 432. IR ( _CHCl3 , cm ^-1 ): 3500, 1790, 1740, 1620. NMR (CDCl ₃ , δ): 0.85 (3H, s), 0.93 (3H, s), 3.66 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 4.01 (1H, d, J = 13.0), 4.79 (1H, d, J = 18.4), 4.96 (1H, d, J = 18.4), 5.87 (1H, t, J = 1.6), 6.74 (1H, dd, J = 8.6, 1.9), 6.744 (1H, d, J = 1.9), 6.80 (1H, d, J = 8.6). Example 5 695 mg of compound (b), 1.44 g of 2,4-dimethoxybenzylamine hydrochloride, and 280 mg of sodium cyanoborohydride were reductively aminated and treated in the same manner as in Example 1 in 20 ml of methanol to obtain 14-hydroxy- 660 mg of colorless powder of 4-(2,4-dimethoxybenzyl)amino-2,4-seco-3-nor-5β,14β-caldo-20(22)-enolide-2-carboxylic acid methyl ester (Ig) was obtained. . Mass (m/e): 569 (M ⁺ ), 551 (M ⁺ -18), 537 (M ⁺ -32). IR ( _CHCl3 , cm ^-1 ): 3500, 1790, 1745, 1620. NMR (CDCl ₃ , δ): 0.85 (3H, s), 0.93 (3H, s), 3.66 (3H, s), 3.79 (3H, s), 3.88 (3H, s), 4.01 (1H, d, J = 13.0), 4.79 (1H, d, J = 18.4), 4.96 (1H, d, J = 18.4), 5.86 (1H, s), 6.47 (2H, m), 7.20 (1H, m). Example 6 Compound (b) 720 mg, methylamine hydrochloride 662
14-hydroxy-4-methylamino-2,4-seco-3-nor-5β,14β cardo by reductive amination and treatment in the same manner as in Example 1 with 280 mg of sodium cyanoborohydride in 5 ml of methanol. −
610 mg of colorless powder of 20(22)-enolide-2-carboxylic acid methyl ester (Ih) was obtained. Mass (m/e): 403 (M ⁺ -30). IR (KBr, cm ^-1 ): 3470, 1790, 1720, 1610. NMR (DMSO- _d6 , δ): 0.77 (3H, s), 0.89 (3H, s), 1.58 (1H, m), 2.59 (3H, s), 2.70 (1H, d, J=11.8), 2.74 (1H, m), 3.10 (1H, t, J = 11.8), 3.60 (3H, s), 4.16 (1H, s), 4.89 (1H, d, J = 18.7), 4.76 (1H, d, J = 18.7), 5.92 (1H, s), 7.94 (1H, br.s). Example 7 660 mg of compound (b) and 646 mg of n-propylamine hydrochloride were reductively aminated and treated in the same manner as in Example 1 with 280 mg of sodium cyanoborohydride in 20 ml of methanol to obtain 14-hydroxy-4-
n-propylamino-2,4-seco-3-nor-
486 mg of colorless powder of 5β,14β cardo-20(22)-enolide-2-carboxylic acid methyl ester (Ii) was obtained. Mass (m/e): 461 (M ⁺ ), 447, 430, 400. IR ( _CHCl3 , cm ^-1 ): 3450, 1790, 1740, 1620. NMR (CDCl ₃ , δ): 0.69 (3H, s), 0.82 (3H, s), 0.82 (3H, t, J = 6.0), 2.21 (2H, t, J = 7.6), 2.61 (3H, m) , 2.67 (2H, t, J = 7.6), 2.87 (1H, t, J = 12.5), 3.51 (3H, s), 4.68 (1H, dd, J = 18.3, 1.5), 4.87 (1H, dd, J = 18.3, 1.5), 5.68 (1H, t, J = 1.5). Example 8 Compound (b) 630 mg, isopropylamine 516
14-hydroxy-4-isopropylamino-2,4-seco-3-
nor-5β,14β caldo-20(22)-enolide-2
- Colorless powder of carboxylic acid methyl ester (Ij)
Obtained 610 mg. Mass (m/e): 461 (M ⁺ ), 446, 430. IR ( _CHCl3 , cm ^-1 ): 3450, 1740, 1620. NMR (CDCl ₃ , δ): 0.88 (3H, s), 0.97 (3H, s), 1.28 (3H, d, J = 5.9), 1.30 (3H, d, J = 5.9), 2.88 (1H, m) , 3.12 (1H, m), 3.67 (3H, s), 4.83 (1H, dd, J = 17.8, 1.4), 5.00 (1H, dd, J = 17.8, 1.4), 5.88 (1H, t, J = 1.4 ). Example 9 Compound (b) 700mg, n-hexylamine 700mg
14-hydroxy-
4-n-hexylamino-2,4-seco-3-nor-5β,14βcaldo-20(22)-enolide-2-
Colorless powder of carboxylic acid methyl ester (Ik) 450
I got mg. Mass (m/e): 503 (M ⁺ ), 472, 453. IR ( _CHCl3 , cm ^-1 ): 2950, 1795, 1750, 1630. NMR (CDCl ₃ , δ): 0.87 (3H, s), 0.88 (3H, t, J = 1.0), 0.94 (3H, s), 2.77 (1H, m), 3.67 (3H, s), 4.80 (1H , dd, J = 18.1, 1.6), 4.98 (1H, dd, J = 18.1, 1.6), 5.87 (1H, t, J = 1.6). Example 10 Compound (b) 712 mg, cyclohexylamine
700 mg of acetic acid and 0.25 ml of acetic acid were reductively aminated and treated in the same manner as in Example 1 using 280 mg of sodium cyanoborohydride in 5 ml of methanol to obtain 14-hydroxy-4-cyclohexylamino-2,4-seco-3-nor. 670 mg of colorless powder of -5β,14β caldo-20(22)-enolide-2-carboxylic acid methyl ester (Il) was obtained. Mass (m/e): 501 (M ⁺ ), 415, 265. IR ( _CHCl3 , cm ^-1 ): 3500, 1790, 1740, 1620. NMR (CDCl ₃ , δ): 0.99 (3H, s), 1.01 (3H, s), 3.70 (3H, s), 4.86 (1H, d, J = 17.8), 5.00 (1H, d, J = 17.8) , 5.91 (1H, s). Example 11 500 mg of compound (a), 300 mg of p-hydroxybenzylamine and 0.1 ml of acetic acid were added to 20 ml of methanol.
Reductive amination and treatment were carried out in the same manner as in Example 1 using 140 mg of sodium cyanoborohydride.
14-hydroxy-2-(p-hydroxybenzyl)
610 mg of colorless crystals of amino-2,4-seco-3-nor-5β,14β caldo-20(22)-enolide-4-carboxylic acid methyl ester (Im) were obtained. Melting point: 188-195°C (recrystallized from ethyl acetate-diethyl ether) Mass (m/e): 525 (M ⁺ ), 433, 419. IR (KBr, cm ^-1 ): 3500, 3425, 1790, 1730, 1615. NMR (DMSO- _d6 , δ): 0.77 (3H, s), 0.94 (3H, s), 2.39 (2H, m), 2.74 (2H, m), 2.83 (1H, m), 3.59 (3H, s) ), 3.96 (2H, s), 4.88 (1H, d, J = 18.9), 4.96 (1H, d, J = 18.9), 6.78 (2H, d, J = 8.2), 7.31 (2H, d, J = 8.2), 8.78 (1H, br.s), 9.66 (1H, br.s). Example 12 725 mg of compound (a) and 763 mg of n-propylamine hydrochloride were reductively aminated and treated with 280 mg of sodium cyanoborohydride in 5 ml of methanol in the same manner as in Example 1 to obtain 14-hydroxy-2-n.
-propylamino-2,4-seco-3-nor-
612 mg of colorless powder of 5β,14β cardo-20(22)-enolide-4-carboxylic acid methyl ester (In) was obtained. Mass (m/e): 461 (M ⁺ ), 446, 433, 400. IR ( _CHCl3 , cm ^-1 ): 3450, 2980, 1790, 1750, 1620. NMR (CDCl ₃ , δ): 0.87 (3H, s), 1.00 (3H, t, J = 6.0), 1.03 (3H, s), 2.82 (1H, m), 3.69 (3H, s), 4.80 (1H , d, J=18.1), 4.97 (1H, d, J=18.1), 5.89 (1H, s). [ ^20D = 189.2 _° (C = 0.54, _CHCl3 ). Example 13 Compound (a) 700mg, isopropylamine 530mg
14-hydroxy-
2-isopropylamino-2,4-seco-3-nor-5β,14βcaldo-20(22)-enolide-4-
Colorless needle-like crystals of carboxylic acid methyl ester (Io)
Obtained 513 mg. Melting point: 103-105°C (recrystallized from ethyl acetate-diethyl ether). Mass (m/e): 461 (M ⁺ ), 446, 430. IR (KBr, cm ^-1 ): 3500, 3000, 1790, 1740, 1620. NMR (CDCl ₃ , δ): 0.86 (3H, s), 1.02 (3H, s), 1.09 (6H, d, J = 6.0), 2.77 (1H, m), 2.84 (1H, qq, J = 6.0, 6.0), 3.67 (3H, s), 4.80 (1H, dd, J = 18.1, 1.7), 4.98 (1H, dd, J = 18.1, 1.7), 5.87 (1H, t, J = 1.7). Example 14 Compound (a) 670mg, n-hexylamine 700mg
14-hydroxy-
2-n-hexylamino-2,4-seco-3-nor-5β,14βcaldo-20(22)-enolide-4-
Colorless powder of carboxylic acid methyl ester (Ip) 630
I got mg. Mass (m/e): 503 (M ⁺ ), 488, 471, 446, 432, 400. IR ( _CHCl3 , cm ^-1 ): 3500, 2980, 1795, 1620. NMR (CDCl ₃ , δ): 0.86 (3H, s), 0.89 (3H, t, J = 6.5), 1.04 (3H, s), 2.70 (1H, m), 3.68 (3H, s), 4.81 (1H , dd, J = 18.1, 1.7), 4.98 (1H, dd, J = 18.1, 1.7), 5.88 (1H, t, J = 1.7). [α] ²⁰ _D = +35.7° (C = 0.68, CHCl ₃ ). Example 15 630 mg of the compound (Im) obtained in Example 11 was dissolved in 50 ml of anhydrous methylene chloride and 3 ml of anhydrous pyridine, and 2.06 ml of a hexane solution of 19% AlMe ₃ was added dropwise under an argon atmosphere and stirring under ice cooling, and then It was refluxed for 3 hours. The reaction solution was cooled with ice to decompose the complex with 3N hydrochloric acid, and extracted with methylene chloride. The organic layer was dried with MgSO ₄ and evaporated to give a colorless caramel.
Obtained 530mg. This product was purified by column chromatography using 12 g of silica gel and chloroform-methanol (5%) as an eluent. 330 mg of colorless powdery crystals of -caldo-20(22)-enolide were obtained. Melting point: 167-170°C (recrystallized from ethyl acetate-diethyl ether). Mass (m/e): 493 (M ⁺ ), 387, 344. IR (KBr, cm ^-1 ): 3430, 1780, 1740, 1620, 1600 (sh). NMR (DMSO-d ₆ , δ): 0.76 (3H, s), 0.84 (3H, s), 1.87 (1H, d, J = 13.9), 2.18 (1H, m), 2.72 (1H, dd, J = 9.8, 5.4), 2.88 (1H, dd, J = 15.6, 7.1), 3.50 (1H, dd, J = 15.6, 11.2), 4.11 (1H, d, J = 14.2), 4.59 (1H, d, J = 14.2), 4.88 (1H, dd, J = 18.3, 1.4), 4.96 (1H, dd, J = 18.3, 1.4), 5.90 (1H, t, J = 1.4), 6.69 (2H, d, J = 8.5) , 7.03 (2H, d, J=8.5), 9.27 (1H, s). [α] ²⁰ _D = +21.8° (C = 0.77, MeOH). In the same manner as in Example 15, the following compounds of Examples 16 to 28 were obtained using appropriate starting materials. Example 16 In the general formula (Ib) above, A is

A compound having the formula [Formula] was obtained. Melting point: 270-272°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 429 (M ⁺ ), 414, 396. IR (KBr, cm ^-1 ): 3400, 2930, 1785, 1740, 1610. NMR (CDCl ₃ , δ): 0.89 (3H, s), 0.96 (3H, s), 1.04 (3H, d, J = 6.8), 1.09 (3H, d, J = 6.8), 2.11 (1H, d, J=14.9), 2.79 (1H, m), 3.00 (1H, d, J=15.9), 3.02 (1H, dd, J=14.9, 6.2), 3.25 (1H, dd, J=15.9, 10.3), 4.81 (1H, dd, J=18.1, 1.9), 4.84 (1H, qq, J=6.8, 6.8), 4.99 (1H, dd, J=18.1, 1.9), 5.88 (1H, d, J=1.9), [ α〕 ²⁰ _D = +14.9° (C = 0.36, chloroform). Example 17 In the general formula (Ib) above, A is

A compound having the formula [formula] was obtained in the form of a colorless powder. Mass (m/e): 471 (M ⁺ ), 456, 442, 414, 400. IR (KBr, cm ^-1 ): 3400, 2930, 1780, 1740, 1620. NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 7.3), 0.89 (3H, s), 0.97 (3H, s), 2.09 (1H, d, J = 14.9), 2.79 (1H, m) , 3.00 (2H, m), 3.25 (1H, dt, J = 14.9, 7.6), 3.40 (1H, dt, J = 14.9, 7.6), 3.46 (1H, dd, J = 14.5, 10.8), 4.81 (1H , dd, J = 18.1, 1.6), 4.98 (1H, dd, J = 18.1, 1.6), 5.88 (1H, t, J = 1.6), [α] ²⁰ _D = +30.1° (C = 0.79, chloroform ). Example 18 In the general formula (Ib) above, A is

A compound having the formula [Formula] was obtained. Melting point: 213-215°C (recrystallized from ethyl acetate, colorless needles). Mass (m/e): 467 (M ⁺ ), 449, 439, 399, 386, 357, 273, 246, 81. IR (KBr, cm ^-1 ): 3400, 3350, 1785, 1740, 1640, (sh), 1630. NMR (CDCl ₃ , δ): 0.87 (3H, s), 0.92 (3H, s), 2.27 (1H, dd, J = 15.1, 8.4), 2.62 (1H, dd, J = 15.1, 12.1), 2.77 ( 1H, m), 2.88 (1H, d, J = 15.1), 3.89 (1H, dd, J = 15.1, 10.3), 4.48 (1H, d, J = 15.4), 4.59 (1H, d, J = 15.4) , 4.79 (1H, dd, J = 18.0, 1.8), 4.97 (1H, dd, J = 18.0, 1.8), 5.88 (1H, t, J = 1.9), 6.24 (1H, dd, J = 3.3, 0.7) , 6.32 (1H, dd, J = 3.3, 1.8), 7.35 (1H, dd, J = 1.8, 0.7). [α] ²⁰ _D = 38.4° (C = 1.32, chloroform). Example 19 In the general formula (Ib) above, A is The base compound was obtained in the form of a colorless powder. Mass (m/e): 493 (M ⁺ ), 475, 384, 368, 107. IR (KBr, cm ^-1 ): 3450, 1785, 1740, 1620, 1600 (sh). NMR (CDCl ₃ , δ): 0.87 (3H, s), 0.92 (3H, s), 2.32 (1H, dd, J = 14.3, 8.8), 2.66 (1H, t, J = 14.3), 2.73 (1H, d, J = 15.6), 2.77 (1H), 3.83 (1H, dd, J = 15.6, 10.3), 4.35 (1H, d, J = 14.7), 4.58 (1H, d, J = 14.7), 4.79 (1H , dd, J = 18.3, 1.5), 4.96 (1H, dd, J = 18.3, 1.5), 5.88 (1H, t, J = 1.5), 6.79 (2H, d, J = 8.2), 7.09 (2H, d , J = 8.2). [α] ²⁰ _D = +40.6° (C = 0.54, chloroform). Example 20 In the general formula (Ib) above, A is The hydrochloride of the base compound was obtained. Melting point: 167-170°C (recrystallized from methanol-diethyl ether, colorless needles). Mass (m/e): 492 (M ⁺ ), 474, 459, 106. IR (KBr, cm ^-1 ): 3420, 1780, 1740, 1620. NMR (CDCl ₃ , δ): 0.88 (3H, s), 0.91 (3H, s), 2.78 (1H, m), 2.89 (1H, d, J = 13.6), 3.11 (1H, m), 3.19 (1H , m), 3.69 (1H, m), 3.84 (1H, m), 4.05 (1H, m), 4.80 (1H, dd, J=18.0, 1.5), 4.97 (1H, dd, J=18.0, 1.5) , [α] ²⁰ _D = +26.5° (C = 0.57, methanol). Example 21 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 188-190°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 551 (M ⁺ ), 523, 400. IR (KBr, cm ^-1 ): 3450, 2950, 1782, 1740, 1630. NMR (CDCl ₃ , δ): 0.88 (3H, s), 0.92 (3H, s), 2.57 (1H, dd, J = 14.6, 11.9), 2.65 (1H, d, J = 15.1), 3.78 (2H, m), 3.57 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 4.79 (1H, dd, J = 18.1, 1.6), 4.96 (1H, dd, J = 18.1, 1.6), 5.89 (1H, d, J = 1.6), 6.75 (1H, dd, J = 8.6, 2.0), 6.76 (1H, d, J = 2.0), 6.80 (1H, d, J = 8.6). [α] ²⁰ _D = +32.1° (C = 0.63, chloroform). Example 22 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 225-226°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 537 (M ⁺ ), 519, 506, 363. IR (KBr, cm ^-1 ): 3350, 2960, 1790, 1740, 1630. NMR (CDCl ₃ , δ): 0.86 (3H, s), 0.91 (3H, s), 2.26 (1H, dd, J = 14.7, 8.5), 2.64 (1H, dd, J = 14.7, 12.2), 2.76 ( 1H, m), 2.82 (1H, d, J = 15.3), 3.79 (6H, s), 3.81 (1H, dd, J = 15.3, 10.0), 4.46 (1H, d, J = 14.7), 4.54 (1H , d, J = 14.7), 4.78 (1H, dd, J = 18.0, 1.5), 4.95 (1H, dd, J = 18.0, 1.5), 5.87 (1H, t, J = 1.5), 6.43 (1H, d , J=2.4), 6.44 (1H, dd, J=8.9, 2.4), 7.15 (1H, d, J=8.9). [α] ²⁰ _D = +19.4° (C = 0.84, chloroform). Example 23 In the general formula (Ib) above, A is

[Formula] A compound which is a group was obtained. Melting point: 266-267°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 401 (M ⁺ ), 386, 356, 248. IR (KBr, cm ^-1 ): 3350, 2950, 1780, 1740, 1640. NMR (CDCl ₃ , δ): 0.89 (3H, s), 0.97 (3H, s), 2.60 (1H, dd, J = 15.1, 12.4), 2.71 (1H, d, J = 15.1), 2.78 (1H, m), 2.95 (3H, s), 4.02 (1H, dd, J = 15.1, 10.3), 4.80 (1H, dd, J = 18.1, 1.6), 4.97 (1H, dd, J = 18.1, 1.6), 5.89 (1H, t, J = 1.6). [α] ²⁰ _D = +39.0° (C = 0.73, chloroform). Example 24 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 232-233°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 429 (M ⁺ ), 414, 400, 276. IR (KBr, cm ^-1 ): 3400, 2970, 1795, 1730, 1630. NMR (CDCl ₃ , δ): 0.89 (3H, s), 0.90 (3H, d, J = 7.3), 0.97 (3H, s), 2.73 (1H, d, J = 15.4), 2.79 (1H, m) , 3.30 (2H, m), 3.94 (1H, dd, J = 15.4, 10.0), 4.80 (1H, dd, J = 18.1, 1.6), 4.97 (1H, dd, J = 18.1, 1.6), 5.89 (1H , t, J = 1.6), [α] ²⁰ _D = +44, 8° (C = 0.42, chloroform). Example 25 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 276-278°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 429 (M ⁺ ), 414, 396, 386. IR (KBr, cm ^-1 ): 3500, 2990, 1790, 1760, 1620. NMR (CDCl ₃ , δ): 0.89 (3H, s), 0.96 (3H, s), 1.05 (3H, d, J = 6.9), 1.08 (3H, d, J = 6.9), 2.59 (1H, dd, J=14.6, 12.9), 2.77 (1H, d, J=15.5), 2.78 (1H, m), 3.62 (1H, dd, J=15.5, 10.3), 4.80 (1H, qq, J=6.9, 6.9) , 4.80 (1H, dd, J = 18.1, 1.3), 4.98 (1H, dd, J = 18.1, 1.3), 5.89 (1H, t, J = 1.3). [α] ²⁰ _D = +41.4° (C = 0.51, chloroform). Example 26 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 213-241.5°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 471 (M ⁺ ), 453, 442, 428, 400. IR (KBr, cm ^-1 ): 3450, 2950, 1790, 1730, 1620. NMR (CDCl ₃ , δ): 0.88 (3H, t, J = 6.0), 0.89 (3H, s), 0.97 (3H, s), 2.58 (1H, dd, J = 14.9, 11.9), 2.73 (1H, d, J = 15.7), 2.79 (1H, m), 3.32 (2H, dd, J = 8.6, 6.5), 3.93 (1H, dd, J = 15.7, 10.0), 4.80 (1H, dd, J = 18.1, 1.6), 4.97 (1H, dd, J = 18.1, 1.6), 5.89 (1H, t, J = 1.6). [α] ²⁰ _D = +33.2° (C = 0.12, chloroform). Example 27 In the general formula (Ib) above, A is A compound which is a group was obtained. Melting point: 228-229°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 469 (M ⁺ ), 454, 440, 426, 412. IR (KBr, cm ^-1 ): 3500, 2950, 1780, 1740, 1630. NMR (CDCl ₃ , δ): 0.89 (3H, s), 0.95 (3H, s), 2.60 (1H, t, J = 14.3), 2.79 (1H, m), 2.82 (1H, d, J = 15.1) , 3.64 (1H, dd, J = 15.1, 9.7), 4.38 (1H, tt, J = 11.9, 3.2), 4.80 (1H, dd, J = 17.8, 1.9), 4.97 (1H, dd, J = 17.8, 1.9), 5.89 (1H, t, J = 1.9). [α] ²⁰ _D = +39.8° (C = 0.12, chloroform). Example 28 In the general formula (Ib) above, A is A basic compound was obtained. Melting point: 259-260°C (recrystallized from ethyl acetate-diethyl ether) Mass (m/e): 429 (M ⁺ ), 414, 396, 386. IR (KBr, cm ^-1 ): 3400, 2950, 1780, 1740, 1630. NMR (CDCl ₃ , δ): 0.88 (3H, s), 0.89 (3H, t, J=7.6), 0.97 (3H, s), 2.79 (1H, m), 3.01 (2H, m), 3.22 (1H , dt, J = 14.9, 7.6), 3.39 (1H, dt, J = 14.9, 7.6), 3.47 (1H, dd, J = 15.4, 10.5), 4.81 (1H, dd, J = 18.1, 1.6), 4.99 (1H, dd, J=18.1, 1.6), 5.88 (1H, t, J=1.6). [α] ²⁰ _D = +189.2° (C = 0.54, CHCl ₃ ). Example 29 612 mg of (In) obtained in Example 12 was dissolved in 5 ml of dimethylformamide:anisole (1:3), and the mixture was heated and stirred at 150 to 160° C. for 6 hours under an argon stream. The solvent was distilled off under reduced pressure, and the residue was mixed with 16 g of silica gel.
Purified by column chromatography using chloroform-methanol (10%) as an eluent, A-homo-3
-Ather 3a-oxo-3-propyl-5β,14β-
Colorless needle crystals of Caldo-20(22)-enolide 485mg
get. Melting point: 259-260°C (recrystallized from ethyl acetate-diethyl ether, colorless needles). Mass (m/e): 429 (M ⁺ ), 414, 396, 386. IR (KBr, cm ^-1 ): 3400, 2950, 1780, 1740, 1630. NMR (CDCl ₃ , δ): 0.88 (3H, s), 0.89 (3H, t, J=7.6), 0.97 (3H, s), 2.79 (1H, m), 3.01 (2H, m), 3.22 (1H , dt, J = 14.9, 7.6), 3.39 (1H, dt, J = 14.9, 7.6), 4.47 (1H, dd, J = 15.4, 10.5), 4.81 (1H, dd, J = 18.1, 1.6), 4.99 (1H, dd, J=18.1, 1.6), 5.88 (1H, t, J=1.6). [α] ²⁰ _D = +189.2° (C = 0.54, CHCl ₃ ). Thereafter, in the same manner as in Example 29, the compounds of Examples 15 to 28 were obtained using appropriate starting materials. <Pharmacological test> Blood perfusion isolated papillary muscle specimen An adult mongrel dog weighing 8 to 12 kg is anesthetized by intravenously administering pentobarbital sodium salt at a dose of 39 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, stimulate the papillary muscles with a square wave at a voltage 1.5 times the threshold value (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-Schmiedeberg's Achieves of
Pharmacology, Volume 278, Pages 135-150, 1973
Year: Atrial muscle specimen). The test compound was intra-arterially administered in a volume of 10-30 μl 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. 1 A-homo-3-oxo-3a-aza-3a-
(2,4-dimethoxybenzyl)-5β,14β-caldo-20(22)-enolide (compound of Example 22). 2 A-homo-3-oxo-3a-aza-3a-n
-Propyl-5β,14β-caldo-20(22)-enolide (compound of Example 24). 3A-homo-3-aza-3a-oxo-3-isopropyl-5β,14β-caldo-20(22)-enolide (compound of Example 16). 4 A-homo-3-aza-3a-oxo-3-n
-hexyl-5β,14β-caldo-20(22)-enolide (compound of Example 17). 5 A-homo-3-oxo-3a-aza-3a-furfuryl-5β,14β-caldo-20(22)-enolide (compound of Example 18). 6 A-homo-3-aza-3a-oxo-3-n
-Propyl-5β,14β-caldo-20(22)-enolide (compound of Example 28). 7 A-homo-3-oxo-3a-aza-3a-methyl-5β,14β-caldo-20(22)-enolide (compound of Example 23). 8 A-homo-3-aza-3a-oxo-3-(4
-hydroxybenzyl)-5β, 14β-caldo-
20(22)-enolide (compound of Example 15). Table 1 shows the results.

[Table] Formulation Example 1 Compound of Example 15 0.025 mg Starch 132 mg Magnesium Stearate 18 mg Lactose 50 mg Total about 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 2 Compound of Example 20 0.25 mg Starch 130 mg Magnesium Stearate 20 mg Lactose 50 mg Total about 200 mg Tablets of the above composition were manufactured in a conventional manner. Formulation Example 3 Compound of Example 23 12.5 mg Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0.9 g Polyoxyethylene sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 100ml Dissolve the above parabens, sodium metabisulfite and sodium chloride 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 a -NHR ³ group (R ³ represents a phenyl lower alkyl group or a lower alkyl group that may have a hydroxyl group as a substituent on the phenyl ring.)
Or it represents a lower alkoxycarbonyl group. ^R2 is
-NHR ⁴ group (R ⁴ is a phenyl lower alkyl group which may have 1 to 3 groups selected from hydroxyl and lower alkoxy groups as substituents on the phenyl ring, a 5- or 6-membered unsaturated heterocyclic ring) represents a lower alkyl group, cycloalkyl group, or lower alkyl group having a residue) or a lower alkoxycarbonyl group. However, when R ¹ represents -NHR ³ group,
^R2 shall represent a lower alkoxycarbonyl group, and when ^R1 represents a lower alkoxycarbonyl group, ^R2 shall represent a ^-NR4 group. 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). ] A cardenolide derivative represented by.