JPH0380154B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to lactone derivatives. The lactone 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, A is

[Formula] Group or

[Formula] group, R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom,
hydroxyl group, lower alkanoyloxy group or tri(lower alkyl)silyloxy group, R ³ is a hydrogen atom,
Each represents a lower alkanoyloxy group or a tri(lower alkyl)silyloxy group. However, R ¹ ,
Except when R ² and R ³ are both hydrogen atoms. ] In this specification, the lower alkanoyloxy group defined as R ² and R ³ includes a group having 1 to 1 carbon atoms, such as formyloxy, acetoxy, propionyloxy, butyryloxy, tert-butyryloxy, pentanoyloxy, hexanoyloxy group, etc.
6 alkanoyl groups are mentioned. Examples of the tri(lower alkyl)silyloxy group include trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, tri-tert-butylsilyloxy, tripentylsilyloxy,
Trihexylsilyloxy, dimethyl-tert-butylsilyloxy, dimethyl-propylsilyloxy, dimethyl-pentylsilyloxy, diethyl-hexylsilyloxy, methyl-ethyl-
tert-butylsilyloxy, methyl-propyl-
Examples include trialkylsilyloxy groups having three alkyl groups having 1 to 6 carbon atoms, such as tert-butylsilyloxy groups. The compound of the present invention has an effect of increasing myocardial contractility (septal inotropic effect) and is useful as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. The compounds of the invention have little effect on heart rate. In addition, conventional cardiotonic agents such as digitalis have a narrow safety margin, and electrocardiogram abnormalities such as digitalis toxicity, premature contractions, and atrioventricular block, as well as side effects on the gastrointestinal system and nervous system, have been observed. It has the characteristic that the side effects mentioned above are extremely weak compared to conventional cardiotonic agents such as digitalis. The compound of the present invention can be produced by various methods, and a preferred example thereof is the method shown in Reaction Scheme-1 below. [In the formula, R ¹ , R ² and R ³ are the same as above. R ⁴ represents a hydroxyl group or an oxo group. ] The reaction shown in the above reaction scheme-1 is a novel reaction discovered by the present inventors, and the compound () of the present invention can be produced by reacting the compound represented by the general formula () with peracid. be done. That is, the compound of general formula () may be dissolved in a suitable inert solvent, and then an organic peracid may be added to this solution to carry out an oxidation reaction with the organic peracid. As the organic solvent, a wide range of organic solvents can be used without particular limitation as long as it can dissolve the treated compound 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, the organic peracid can be widely used without particular limitation, and examples thereof include perbenzoic acids such as perbenzoic acid, metachloroperbenzoic acid, metanitroperbenzoic acid, p-nitroperbenzoic acid, and 3,5-dinitroperbenzoic acid. , performic acid, peracetic acid and the like. The amount of organic peracid to be used is usually 1 to 5 times, preferably 2 to 3 times, the amount of compound (). In the present invention, 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
The oxidation reaction proceeds suitably at the reflux temperature of the solvent, preferably at room temperature to 70°C, and is generally completed in 20 minutes to 40 hours. In the case of a compound in which R ² in the above general formula () is a lower alkanoyloxy group or a tri(lower alkyl)silyloxy group, the compound is dissolved in water, a lower alcohol such as methanol, ethanol, or a mixed solvent thereof, hydrochloric acid, In the presence of inorganic acids such as sulfuric acid and aluminum chloride, organic acids such as acetic acid and formic acid, inorganic bases such as sodium bicarbonate, sodium hydroxide, sodium carbonate, potassium hydroxide, and potassium carbonate, and organic bases such as ammonia and triethylamine. By treating normally at about 0 to 100°C, preferably around 0 to 50°C for about 10 minutes to 48 hours, a compound in which R ² in the above general formula () is a hydroxyl group (hereinafter referred to as "compound (-A)") can be prepared. ) can be converted to Further, a compound in which R ² in the above general formula () represents a lower alkanoyloxy group can be obtained by acylating the compound (-A). The acylation reaction is performed using an acylating agent having a carbon number of 1, for example.
It is carried out according to a conventional method using alkanoic acid halides and alkanoic anhydrides of 6 to 6. The reaction using an acid halide is carried out at -50 to 150°C in an inert solvent, using a dehydrohalogenating agent if necessary, such as amines such as triethylamine, diisopropylethylamine, pyridine, and N,N-diethylaniline. It takes about 1 to 24 hours within a temperature range. Further, the reaction using an acid anhydride is carried out in an inert solvent at a temperature ranging from room temperature to 200°C for about 1 to 10 hours. Inert solvents in each of the above reactions include, for example, aromatic hydrocarbons such as nitrobenzene and benzene chloride; amines such as pyridine and N,N-dimethylaniline; ethers such as methyl ether and ethyl ether; dichloromethane, dichloroethane, Halogenated hydrocarbons such as chloroform can be confiscated. The ratio of the acylating agent to compound (-A) in the above is usually 1 mol or more, preferably 1 to 5 mol, of the latter to 1 mol of the former. In the above general formula (), R ² is tri(lower alkyl)
A compound exhibiting a silyloxy group is a compound (-
It can be obtained by tri(lower alkyl)silylation of A). This tri(lower alkyl)silylation reaction is carried out using silylating agents such as trialkylsilyl lower alkanesulfonates having 1 to 6 carbon atoms such as dimethyl-tert-butylsilyl trifluoromethanesulfonate, and 1 to 1 carbon atoms such as trimethylsilyl chloride. -6 trialkylsilyl halides and the like can be exemplified. The reaction is carried out in an inert solvent in the presence of a basic catalyst at a temperature range of -30 to 50°C for about 10 minutes to 15 hours. Inert solvents used in the above reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; ethers such as dioxane, diethyl ether, and tetrahydrofuran;
Examples include aromatic hydrocarbons such as benzene, xylene, and toluene, dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the basic catalyst include organic bases such as pyridine, quinoline, lutidine, and imidazole. The amount of the silylating agent to be used is usually at least equimolar, preferably equimolar to 3 times the molar amount of compound (-A). A compound in which R ³ in the above general formula () represents a lower alkanoyloxy group has the general formula [In the formula, R ¹ and R ² are the same as above. ] can be obtained by acylating the compound represented by Acylation of the compound of general formula () can be carried out under the same reaction conditions as for the acylation of compound (-A). The compound of the general formula () used above is a new compound that has not been published in any literature, and the compound is, for example, a compound of the general formula (In the formula, R ¹ , R ² and R ⁴ are the same as above.) It is produced by reacting a compound represented by the formula () with a peracid.The reaction between the compound of the general formula () and a peracid is as follows:
The reaction can be carried out under the same reaction conditions as the reaction between the compound of general formula () and a peracid. Furthermore, a compound in which R ³ in the above general formula () represents a tri(lower alkyl)silyloxy group can be obtained by tri(lower alkyl)silylation of the compound of the above general formula (). Tri(lower alkyl) silylation of the compound of general formula () is the tri(lower alkyl) silylation of the compound (-A).
It can be carried out under reaction conditions similar to those for silylation. The target compound of the present invention thus obtained can be easily isolated from the reaction mixture by conventional isolation means such as recrystallization, solvent extraction, column chromatography such as high performance liquid chromatography, and distillation. Separated and purified. Incidentally, the present invention naturally also includes optical isomers. The compound of general formula () is usually used in the form of a common pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, pills, powders, liquids, suspensions, emulsions,
Examples include granules, capsules, suppositories, injections (solutions, suspensions, 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 control agents such as white sugar, 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, 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 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 kg per 1 kg of body weight per day, although it is selected as appropriate depending on gender and other conditions, the severity of the disease, etc.
It is better to use mg. Further, it is preferable that the dosage unit form contains 0.01 to 25 mg of the active ingredient. Examples, reference examples, pharmacological test results, and formulation examples are listed below. Example 1 5β,14β,-dihydroxy-caldo-20(22)-
0.208 g of enolide-3-one is dissolved in 5 ml of dry chloroform, 0.138 g of m-chloroperbenzoic acid (MCPBA) is added thereto, and the mixture is stirred at room temperature for 32 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in a solvent of chloroform: methanol = 1:1, applied to Sephadex LH-20 (100 ml), developed with chloroform: methanol = 1:1, and the excess was removed.
Remove MCPBA. 0.237 g of the obtained MCPBA-free oxidation product was subjected to silica gel column chromatography (eluent: benzene: acetone =
2:1) and recrystallized from benzene-acetone to obtain A-homo= represented by the following formula (a).
0.082 g of 5,14-hydroxy-3-oxa-5β,14β-caldo-20(22)-enolide-3a-one (hereinafter referred to as "compound (a)") is obtained. mp.260−262℃ UV λ ^McOH _nax ; 216 nm (ε14200) [α] ²⁵ _D ; 33.7° (c=0.17, methanol) IR ν ^KBr _nax ; 3525, 3425, 3345, 2955, 1720, 1705, 1620, 1435 , 1410, 1310, 1293, 1194, 1175, 1140, 1130, 1070, 1055, 1028, 1015, 950, 910, 895, 860cm ^-1 MS m/z; 386 (M ⁺ -18) ¹ H-NMR (400MHz ) CDCl ₃ , δ; 5.90 (1H, br.s) 4.96 (1H, d, J = 18.0Hz) 4.80 (1H, d, J = 18.0Hz) 4.26 (1H, dd, J = 13.2Hz, 10.7Hz) 4.07 (1H, dd, J = 13.2Hz, 5.3Hz) 3.46 (1H, d, J = 13.7Hz) 2.81 (1H, dd, J = 9.0, 5.6Hz) 5.49 (1H, d, J = 13.7Hz) 1.00 (3H, s) 0.90 (3H, s) Elemental analysis value (as C ₂₃ H ₃₂ O ₆ ) C (%) H (%) Calculated value 68.29 7.97 Analysis value 68.12 8.14 Example 2 Ditoxin-16-acetate 1.021 g Dissolve in 8 ml of dry chloroform and add MCPBA0.509 to this.
g and stirred under reflux for 12 hours. then
Add 0.509 g of MCPBA and 2 ml of dry chloroform, and stir under reflux for an additional 12 hours. After cooling the reaction solution and removing precipitated crystals, the solution is concentrated. The obtained residue was mixed with chloroform:methanol=
Dissolved in 1:1 solvent, Sephadex LH-20
(200 ml) and developed with the same solvent to obtain the oxidized product.
Obtain 0.856g. The obtained oxidation product was purified by silica gel column chromatography (eluent; benzene:ethyl acetate = 1:1 → 1:2), and then fractionated by high performance liquid chromatography (Waters, model 440). do. The column is
Using LS410 (ODS diameter 10 mm x 30 cm, manufactured by Toyo Soda Kogyo Co., Ltd.), elution was carried out at a rate of 3 ml per minute using acetonitrile:methanol:water=1:5:9 as a developing solvent. Detection was performed using an ultraviolet absorption meter (254 nm) and a differential refractometer, and 8.4 mg of A-homo-14-hydroxy-16-acetyloxy-3-oxa-5β,14β,16β-caldo- expressed by formula (b) was detected. 20 (22)
-enolide-3a-one (hereinafter referred to as “compound (
b)'') and 4.1 mg of A-homo-14-hydroxy-16-acetyloxy-3a-oxa-5β,14β,16β-caldo-20 of formula (c)
(22)-enolide-3-one (hereinafter referred to as “compound (
c). Compound (b): mp.240-242℃ UV λ ^MeOH _nax ; 213.5 nm (ε13800) IR ν ^KBr _nax ; 3525, 3470, 2950, 2880, 1790, 1740, 1728, 1634, 1443, 1382, 1364, 1282, 1258, 1242, 1188, 1160, 1110, 1078, 1063, 1030, 978, 891cm ^-1 MS m/z; 404 (M ⁺ ) ¹ H-NMR CDCl ₃ , δ; 5.99 (1H, br, s) 5.49 ( 1H, ddd, J = 9.3, 8, 8, 2.7Hz) 4.97 (1H, dd, J = 18.1, 1.5Hz) 4.84 (1H, dd, J = 18.1, 1.5Hz) 4.26 (1H, dd, J = 13.2 , 10.8Hz) 4.08 (1H, dd, J = 13.2, 5.1Hz) 3.20 (1H, d, J = 8.8Hz) 3.10 (1H, br, t, J = 13.7Hz) 2.74 (1H, dd, J = 15.6 , 9.3Hz) 2.25 (1H, d, J = 13.7Hz) 1.98 (3H, s) 1.01 (3H, s) 0.96 (3H, s) Compound (c): mp.255-257℃ UV λ ^MeOH _nax ; 214nm (ε14300) IR ν ^KBr _nax ; 3525, 2950, 2890, 1793, 1740, 1710, 1612, 1445, 1368, 1351, 1302, 1290, 1269, 1248, 1187, 1168, 1120, 1091, 1068, 1059 ,1040, 1020, 989, 946, 895, 875 cm ^-1 MS m/z; 446 (M ⁴ ) ¹ H-NMR CDCl ₃ , δ; 6.00 (1H, br.s) 5.49 (1H, ddd, J = 9.3, 8.8, 2.8Hz) 4.96 (1H, dd, J = 18.1, 2.0Hz) 4.84 (1H, dd, J = 18.1, 2.0Hz) 4.58 (1H, dd, J = 13.2, 10.3Hz) 3.94 (1H, br.d, J = 13.2Hz) 3.20 (1H, d, J = 8.8Hz) 2.73 (2H) 2.42 (1H, dd, J = 14.6, 7.3Hz) 1.98 (3H, s) 1.02 (3H, s) 0.96 (3H, s ) Example 3 0.105 g of 12,14-dihydroxy-5β,12β,14β-caldo-20(22)-enolide-3-one was dissolved in 2 ml of dry chloroform and added to it.
Add 0.088 g of MCPBA and stir at room temperature for 16 hours.
The residue obtained by concentrating under reduced pressure was dissolved in chloroform:
Dissolve in a small amount of methanol=1:1 solvent, apply to Sephadex LH-20 (50 ml), and develop with the same solvent to obtain 0.076 g of oxidized product. The obtained oxidation products are fractionated by high performance liquid chromatography (Waters Model 440). LS410 (ODS diameter 10 cm x 30 cm, manufactured by Toyo Soda Kogyo Co., Ltd.) is used as a column, and acetonitrile:methanol:water=1:6:9 is used as a developing solvent.
Detection was performed using an ultraviolet absorber (254 nm) and a differential refractometer, elution was performed at a rate of 4 ml per minute, and the developing solvent was changed to acetonitrile: methanol: water = 1:2:9 and high performance liquid chromatography was performed again. ,
8.8 mg of A-homo-12 of formula (d),
14-dihydroxy-3-oxa-5β, 12β, 14β
-Caldo-20(22)-enolide-3a-one (hereinafter referred to as "compound (e)") and 9.8 mg of the formula (
e) A-homo-12,14-dihydroxy-3a-oxa-5β,12β,14β-caldo-20
(22)-enolide-3-one (hereinafter referred to as “compound (
e). Compound (d); mp.255−257°C [α] ²⁸ _D 44.8° (c=0.13, methanol) UV λ ^MeOH _nax ; 217 nm (ε16100) IR ν ^KBr _nax ; 3530, 2950, 2875, 1740, 1715, 1628 , 1440, 1400, 1293, 1280, 1252, 1180, 1170, 1100, 1088, 1066, 1028, 1011, 960, 900, 860cm ^-1 MS m/z; 404 (M ⁺ ) ¹ H−NMR CDCl ₃ , δ ; 5.95 (1H, br.s) 4.90 (1H, dd, J = 18.1, 1.7Hz) 4.82 (1H, dd, J = 18.1, 1.7Hz) 4.25 (1H, dd, J = 13.2, 10.5Hz) 4.09 ( 1H, dd, J = 13.2, 6.3Hz) 3.43 (1H, m) 3.32 (1H, dd, J = 9.5, 6.4Hz) 3.08 (1H, dd, J = 13.9, 12.5Hz) 2.26 (1H, d, J = 13.9Hz) 1.02 (3H, s) 2.83 (3H, s) Compound (e): mp.295-298℃ (decomposition) [α] ²⁸ _D 52.1゜ (c = 0.13, methanol) UV λ ^MeOH _nax ; 217nm (ε14600) IR ν ^KBr _nax ; 3575, 3500, 2950, 2880, 1790, 1732, 1634, 1400, 1300, 1291, 1265, 1254, 1180, 1140, 1110, 1067, 1052, 1020, 955, 890, 8 49cm ^{- 1} MS m/z; 404 (M ⁺ ) ¹ H−NMR CDCl ₃ , δ; 5.96 (1H, br.s) 4.89 (1H, dd, J=18.1, 1.7Hz) 4.81 (1H, dd, J=18.1 , 1.7Hz) 4.55 (1H, dd, J = 12.9, 9.5Hz) 3.95 (1H, d, J = 12.9Hz) 3.46 (1H, m) 3.32 (1H, dd, J = 9.8, 6.6Hz) 2.71 (1H , dd, J = 14.2, 13.4Hz) 2.43 (1H, dd, J = 14.2, 7.3Hz) 1.04 (3H, s) 0.83 (3H, s) Example 4 12-acetyloxy-14-hydroxy-5β,
12β,14β-caldo-20(22)-enolide-3-
On 0.7g, MCPBA 0.605g and methylene chloride 15
ml mixture is stirred at room temperature for 12 hours. The reaction solution is diluted with methylene chloride, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over sodium sulfate. After concentrating the solvent, the residue was purified by silica gel column chromatography (eluent: benzene-ethyl acetate = 1:1 → 1:4),
It is then fractionated by high performance liquid chromatography (Waters Model 440). LS410 (diameter 4.6 mm x 30 cm) was used as the column, methanol:water = 1:1 was used as the developing solvent, and a UV detector (240 nm) was used for detection. A-homo-12-acetyloxy-14-hydroxy-3a-oxa-5β, 12β,
14β-caldo-20(22)-enolide-3-one (hereinafter referred to as "compound (f)") and 169mg of A-homo-12-acetyloxy-14-hydroxy-3-oxa represented by formula (g) −5β, 12β,
14β-caldo-20(22)-enolide-3a-one (hereinafter referred to as "compound (g)") is obtained. Compound (f): mp.254−256°C [α] ¹⁸ _D 63.8° (c = 0.61, chloroform) IR ν ^KBr _nax ; 3600, 1782, 1732, 1632 cm ^-1 MS m/z; 446 (M ⁺ ) ¹ H-NMR (400MHz) CDCl ₃ , δ; 0.91 (3H, s) 1.02 (3H, s) 2.11 (3H, s) 2.42 (1H, dd, J = 15.1, 8.4Hz) 2.72 (1H, t, J = 13.8Hz) 2.90 (1H, m) 3.94 (1H, d, J = 13.5Hz) 4.56 (1H, dd, J = 10.0, 13.5Hz) 4.64 (1H, dd, J = 4.3, 12.2Hz) 4.77 (1H, dd, J=1.9, 18.1Hz) 4.87 (1H, dd, J=1.9, 18.1Hz) 5.86 (1H, s) Compound (g): mp.164−166℃ [α] ¹⁸ _D 63.1° (c=0.59 , chloroform) IR ν ^KBr _nax ; 3480, 1781, 1732, 1630cm ^-1 MS m/z; 446 (M ⁺ ) ¹ H−NMR (400MHz) CDCl ₃ , δ; 0.90 (3H, s) 1.00 (3H, s ) 2.09 (3H, s) 2.90 (1H, m) 3.09 (1H, t, J = 14.3Hz) 4.07 (1H, dd, J = 6.5, 13.3Hz) 4.28 (1H, dd, J = 10.0, 13.3Hz) 4.61 (1H, dd, J = 4.3, 11.9Hz) 4.78 (1H, dd, J = 1.6, 18.1Hz) 4.88 (1H, dd, J = 1.6, 18.1Hz) 5.86 (1H, s) Example 5 16- Acetyloxy-14-hydroxy-5β,
4β,16β-Caldo-20(22)-enolide-3-one 1.0g, MCPBA 0.762mg and methylene chloride 20ml
The mixture is stirred at room temperature for 12 hours. The reaction solution was diluted with methylene chloride, washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (eluent: benzene:ethyl acetate = 1:1) and then fractionated by high performance liquid chromatography (Waters Model 440). The column is LS410 (diameter 4.6mm x 30
cm), methanol:water =
1:1, 360 mg of A-homo-16-acetyloxy-14-hydroxy-3a-oxa-5β,14β,16β-caldo-20 of formula (h)
(22)-enolide-3-one (hereinafter referred to as “compound (
h)'') and 385 mg of A-homo-16-acetyloxy-14-hydroxy-3-oxa-5β,14β,16β-caldo-20 of formula (i)
(22)-enolide-3a-one (hereinafter referred to as "compound (i)") is obtained. Compound (h): mp.251-252℃ [α] ¹⁸ _D 6.92゜ (c=0.65, chloroform) IR ν ^KBr _nax ; 3530, 1800, 1745, 1718, 1619cm ^-1 MS m/z; 446 (M ⁺ ) ¹ H-NMR (400MHz) CDCl ₃ , δ; 0.95 (3H, s) 1.02 (3H, s) 1.97 (3H, s) 2.41 (1H, dd, J = 7.8, 14.3Hz) 2.71 (1H, dd, J = 9.5, 15.7Hz) 2.73 (1H, t, J = 14.3Hz) 3.19 (1H, d, J = 9.5Hz) 3.93 (1H, d, J = 13.2Hz) 4.58 (1H, dd, J = 10.0, 13.2Hz) 4.84 (1H, dd, J = 1.6, 18.4Hz) 4.95 (1H, dd, J = 1.6, 18.4Hz) 5.47 (1H, d, J = 2.8, 9.5Hz) 5.99 (1H, s) Compound ( i): mp.148−151℃ [α] ¹⁸ _D 11.1゜ (c=0.64, chloroform) IR ν ^KBr _nax ; 3480, 1780, 1740, 1632cm ^-1 MS m/z; 446 (M ⁺ ) ¹ H− NMR (400MHz) CDCl ₃ , δ; 0.95 (3H, s) 1.01 (3H, s) 1.98 (3H, s) 2.24 (1H, d, J = 13.0Hz) 2.74 (1H, dd, J = 9.1, 15.4Hz ) 3.11 (1H, t, J = 13.0Hz) 3.20 (1H, d, J = 9.1Hz) 4.07 (1H, dd, J = 5.4, 13.0Hz) 4.26 (1H, dd, J = 10.8, 13.0Hz) 4.84 (1H, dd, J=1.4, 18.1Hz) 4.97 (1H, dd, J=1.4, 18.1Hz) 5.48 (1H, td, J=2.7, 9.1Hz) 5.99 (1H, s) Example 6 12, 14 12,14-dihydroxy- obtained by oxidizing -dihydroxy-5β,12β,14β-cardo-20(22)-enolide-3-one in the same manner as in Example 3.
3-oxa-5β, 12β, 14β-caldo-20(22)-
Enolide-3a-one and 12,14-dihydroxy-3a-oxa-5β,12β,14β-caldo-20
200 mg of a mixture of (22)-enolide-3-ones, 2,
A mixture of 0.085 ml of 6-lutidine, 0.145 ml of dimethyl-tert-butylsilyltrifluoromethanesulfonate and 5 ml of methylene chloride is stirred at 0°C for 10 minutes. The reaction solution is washed with a saturated aqueous sodium hydrogen carbonate solution and then dried. After concentration, the obtained residue was purified by silica gel column chromatography (eluent: benzene: ethyl acetate = 1:1), and then high performance liquid chromatography (manufactured by Waters,
Model 440). The column is
Using Lichrosorb Si60 (diameter 4.6mm x 30cm),
Methylene chloride: Acetonitrile = as developing solvent
4:1, 57 mg of A-homo-12-dimethyl-tert-butylsilyloxy-14-hydroxy-3a-oxa-5β,12β,
14β-caldo-20(22)-enolide-3-one (hereinafter referred to as "compound (j)") and 70 mg of A-homo-12-dimethyl- represented by formula (k)
tert-butylsilyloxy-14-hydroxy-3
-oxa-5β,12β,14β-caldo-20(22)-enolide-3a-one (hereinafter referred to as "compound (k)") is obtained. Compound (j): mp.227−229℃ [α] ¹⁸ _D 27.1゜(c=0.68, chloroform) IR ν ^KBr _nax ; 3460, 1740, 1620cm ^-1 MS m/z; 461 (M ⁺ −57) ¹ H-NMR (400MHz) CDCl ₃ , δ; 0.05 (3H, s) 0.08 (3H, s) 0.81 (3H, s) 0.91 (9H, s) 1.02 (3H, s) 2.42 (1H, dd, J = 8.1 , 15.1Hz) 2.70 (1H, t, J = 10.0Hz) 3.18 (1H, dd, J = 5.7, 9.5Hz) 3.37 (1H, dd, J = 4.3, 11.3Hz) 3.94 (1H, d, J = 13.0 Hz) 4.55 (1H, dd, J = 9.7, 13.0Hz) 4.77 (1H, dd, J = 1.4, 17.8Hz) 4.86 (1H, dd, J = 1.4, 17.8Hz) 5.89 (1H, s) Compound (k ): mp.207−209℃ [α] ¹⁸ _D 21.0゜ (c=0.84, chloroform) IR ν ^KBr _nax ; 3490, 1750, 1720 1620cm ^-1 MS m/z; 461 (M ⁺ −57) ¹ H− NMR (400MHz) CDCl ₃ , δ; 0.03 (3H, s) 0.07 (3H, s) 0.81 (3H, s) 0.90 (9H, s) 1.01 (3H, s) 2.25 (1H, d, J = 13.2Hz) 3.08 (1H, t, J = 13.2Hz) 3.17 (1H, dd, J = 5.4, 9.5Hz) 3.36 (1H, dd, J = 4.3, 11.1Hz) 4.08 (1H, dd, J = 5.7, 13.2Hz) 4.24 (1H, dd, J = 10.3, 13.2Hz) 4.78 (1H, dd, J = 1.6, 17.5Hz) 4.87 (1H, dd, J = 1.6, 17.5Hz) 5.89 (1H, t, J = 1.6Hz) Example 7 A-homo-14,16- obtained by oxidizing 14,16-dihydroxy-5β,14β,16β-caldo-20(22)-enolide-3-one in the same manner as in Reference Example 1 below
Dihydroxy-3-oxa-5β,14β,16β-caldo-20(22)-enolide-3a-one and A-
homo-14,16-dihydroxy-3a-oxa-5β,
14β,16β-caldo-20(22)-enolide-3-
A mixture of 1.0 g of a mixture of 1.0 g, 532 mg of dimethyl-tert-butylsilyl chloride, 493 mg of imidazole and 10 ml of dimethylformamide is stirred at room temperature for 12 hours. After concentrating the reaction mixture, the residue was subjected to silica gel column chromatography (eluent: benzene:
After purification with ethyl acetate = 1:1), high performance liquid chromatography (Waters, Model 440)
Fractionate by The column is Lichrosorb Si60 (diameter
410 using methylene chloride:acetonitrile = 4:1 as the developing solvent.
A-homo-14-hydroxy-16-dimethyl-tert-butylsilyloxy-3a-oxa-5β,14β,16β-caldo-20 expressed by the formula (l) in mg
(22)-enolide-3-one (hereinafter referred to as “compound (
A-homo-14-hydroxy-16-dimethyl- of the formula (m) and 390 mg of A-homo-14-hydroxy-16-dimethyl-
tert-butylsilyloxy-3-oxa-5β,
14β,16β-caldo-20(22)-enolide-3a-
(hereinafter referred to as "compound (m)"). Compound (l): mp.130-134℃ [α] ¹⁹ _D 26.9゜ (c = 0.62, dichloroform) IR ν ^KBr _nax ; 3480, 1780, 1740 1619cm ^-1 MS m/z; 461 (M ⁺ -57 ) ¹ H-NMR (400MHz) CDCl ₃ , δ; 0.02 (3H, s) 0.05 (3H, s) 0.84 (9H, s) 0.95 (3H, s) 1.01 (3H, s) 1.66 (1H, dd, J = 1.6, 14.6Hz) 2.39 (1H, dd, J = 7.6, 13.5Hz) 2.49 (1H, dd, J = 7.6, 14.6Hz) 2.73 (1H, t, J = 13.5Hz) 3.05 (1H, d, J = 7.6Hz) 3.93 (1H, dd, J = 0.8, 12.7Hz) 4.59 (1H, dd, J = 9.7, 12.7Hz) 4.64 (1H, td, J = 1.6, 7.6Hz) 5.00 (2H, s) 5.87 (1H, t, J = 2.2Hz) Compound (m): mp.260-261℃ [α] ¹⁹ _D 34.7゜ (c = 1.24, chloroform) IR ν ^KBr _nax ; 3490, 1800, 1730 1612cm ^-1 MS m /z; 461 (M ⁺ −57) ¹ H−NMR (400MHz) CDCl ₃ , δ; 0.02 (3H, s) 0.06 (3H, s) 0.85 (9H, s) 0.96 (3H, s) 1.00 (3H, s) 1.70 (1H, dd, J = 1.6, 14.9Hz) 2.03 (1H, dd, J = 5.9, 15.9Hz) 2.24 (1H, d, J = 13.2Hz) 2.50 (1H, dd, J = 7.6, 14.9 Hz) 3.04 (1H, d, J = 7.6Hz) 3.12 (1H, t, J = 13.2Hz) 4.06 (1H, dd, J = 5.7, 13.5Hz) 4.26 (1H, dd, J = 10.8, 13.5Hz) 4.64 (1H, td, J = 1.6, 7.6Hz) 5.00 (2H, s) 5.87 (1H, t, J = 2.2Hz) Reference example 1 14,16-dihydroxy-5β,14β,16β-caldo-20 (22 )-enolide-3-one (0.904 g) was dissolved in 5 ml of dry chloroform and added to it.
Add 0.754 g of MCPBA and stir at room temperature for 3 hours.
The precipitated crystals were removed, the liquid was concentrated under reduced pressure, the resulting residue was dissolved in a small amount of chloroform:methanol=1:1 solvent, and Sephadex LH-
20 (200ml), chloroform:methanol=
Expanding 1:1 (0.35) yields 0.874 g of oxidation product. The obtained oxidation product was subjected to silica gel column chromatography (eluent: benzene:acetone =
2.5:1) and then fractionated by high performance liquid chromatography (Waters Model 440). The column is LS410 (ODG diameter 10mm x 30
cm, manufactured by Toyo Soda Kogyo Co., Ltd.), and the developing solvent was acetonitrile:methanol:water=1:6:
Use 9. The elution rate is 4 ml/min.
0.149g of A-homo-14 represented by formula (a),
16-dihydroxy-3-oxa-5β, 14β, 16β
- caldo-20(22)-enolide-3a-one (hereinafter referred to as "compound (a)") and 0.153 g of A-homo-14,16-dihydroxy-3a-oxa-5β of formula (b), 14β, 16β-caldo-
20(22)-enolide-3-one (hereinafter referred to as "compound (b)") is obtained. Compound (a): mp.233-235℃ [α] ³⁰ _D 58.1゜ (c=0.18, chloroform) UV λ ^MeOH _nax ; 217.5nm (ε13600) IR ν ^KBr _nax ; 3500, 2950, 2880 1800, 1760, 1743 1720, 1630, 1455 1440, 1385, 1300 1280, 1269, 1248 1175, 1109, 1099 1080, 1060, 1030 894, 699cm ^-1 MS m/z; 404 (M ⁺ ) ¹ H-NMR (400MHz) CDCl ₃ , δ; 5.98 (1H, t, J = 1.7Hz) 5.05 (1H, dd, J = 18.1, 1.7Hz) 4.92 (1H, dd, J = 18.1, 1.7Hz) 4.55 (1H, ddd, J = 8.3, 7.1 ,6.2Hz)4.25
(1H, dd, J = 13.4, 10.5Hz) 4.07 (1H, ddd, J = 13.4, 6.3, 1.2Hz) 3.12 (1H, dd, J = 14.2, 13.2Hz) 2.98 (1H, br.d, J = 8.3Hz) 2.96 (1H, d, J = 7.1Hz) 2.41 (1H, dd, J = 14.6, 6.2Hz) 2.33 (1H, br.s) 2.26 (1H, d, J = 14.2Hz) 2.04 (1H, dd, J=16.7, 6.4Hz) 1.89 (1H, d, J=14.6Hz) 1.01 (3H, s) 0.97 (3H, s) Compound (b): mp.211−213℃ [α] ³⁰ _D 52.8° (c=0.11, chloroform) UV λ ^MeOH _nax ; 217.5 nm (ε14600) IR ν ^KBr _nax ; 3450, 2950, 2855 1790, 1758, 1630 1450, 1400, 1343 1305, 1212, 1180 1120, 1086, 1065 103 0,945 , 899cm ^-1 MS m/z; 404 (M ⁺ ) Reference example 2 50 mg of mixture of compound (h) and compound (Ii)
Dissolve in 4 ml of methanol and add 2 ml of 10% hydrochloric acid to this.
was added and left at room temperature for 20 hours. 10 of the reaction solution
After neutralizing with aqueous sodium hydroxide solution, methanol was distilled off, and then ethyl acetate and water were added at 20% each.
ml and after stirring thoroughly, separate the ethyl acetate layer, extract the aqueous layer with 20 ml of ethyl acetate, combine with the ethyl acetate layer, wash with water, dehydrate, and concentrate.
The obtained residue was dissolved in 1 ml of methanol and subjected to high performance liquid chromatography under the same conditions as in Reference Example 1 to obtain 4.5 mg of compound (a) (mp.233-
235℃) and compound (b) 2.0mg (mp.211-213
℃) is obtained. Reference example 3 Mixture of compound (h) and compound (i) 20
mg was dissolved in 5 ml of methanol, 0.5 ml of 5% aqueous sodium bicarbonate solution was added thereto, and the mixture was left at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to remove methanol, 10 ml each of ethyl acetate and water were added thereto, thoroughly stirred, the ethyl acetate layer was separated, and the aqueous layer was further extracted with 10 ml of ethyl acetate. The mixture is combined with the ethyl acetate layer, washed with water, dehydrated, and concentrated. The obtained residue was dissolved in 0.15 ml of methanol and subjected to high performance liquid chromatography under the same conditions as in Reference Example 1 to obtain 0.4 mg of compound (a).
(mp.233-235℃) and compound (b) 0.3mg
(mp.211−213℃) is obtained. <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 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. Stimulate the papillary muscles using a bipolar electrode with a square wave at a voltage 1.5 times the threshold (0.5-3 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,
Vol. 278, pp. 135-150, 1973: 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. Table 1 shows the results.

[Table] Formulation Example 1 Compound (a) 0.025 mg Starch 132 mg Magnesium Stearate 18 mg Lactose 50 mg Total approximately 200 mg Tablets of the above composition were prepared in one tablet by a conventional method. Formulation Example 2 Compound (b) 0.25 mg Starch 130 mg Magnesium stearate 20 mg Lactose 50 mg Total approximately 200 mg Tablets containing the above composition were prepared in a conventional manner. Formulation example 3 Compound (a) 12.5mg polyethylene glycol (molecular weight: 4000)
0.3g Sodium chloride 0.9g Polyoxyethylene sorbitan monooleate
0.4g Sodium metabisulfite 0.1g Methyl-paraben 0.18g Propyl-paraben 0.02g Distilled water for injection 100ml 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.

[Brief explanation of drawings]

Figure 1 is an NMR spectrum diagram of compound (a), Figure 2 is an IR spectrum diagram of compound (a),
Figure 3 is an NMR spectrum diagram of compound (b),
Figure 4 is an IR spectrum diagram of compound (b), Figure 5 is an NMR spectrum diagram of compound (c), Figure 6 is an IR spectrum diagram of compound (c), and Figure 7 is an IR spectrum diagram of compound (c).
The figure shows the NMR spectrum of compound (d), No. 8
The figure is an IR spectrum diagram of compound (d), Figure 9 is an NMR spectrum diagram of compound (e), and Figure 10 is a diagram of the NMR spectrum of compound (e).
The figure is an IR spectrum diagram of compound (e), No. 11
The figure is an NMR spectrum diagram of compound (f), 1st
Figure 2 is an NMR spectrum diagram of compound (g), Figure 13 is an NMR spectrum diagram of compound (h),
Figure 14 is an NMR spectrum diagram of compound (i), Figure 15 is an NMR spectrum diagram of compound (Ij), Figure 16 is an NMR spectrum diagram of compound (k), and Figure 17 is an NMR spectrum diagram of compound (l). Figure 18 is an NMR spectrum diagram of compound (m).

Claims (1)

[Claims] 1. General formula [In the formula, A is a [formula] group or a [formula] group, R ¹ is a hydrogen atom or a hydroxyl group, R ² is a hydrogen atom,
hydroxyl group, lower alkanoyloxy group or tri(lower alkyl)silyloxy group, R ³ is a hydrogen atom,
Each represents a lower alkanoyloxy group or a tri(lower alkyl)silyloxy group. However, R ¹ ,
Except when R ² and R ³ are both hydrogen atoms. ] A lactone derivative represented by.