JPS60204777A - Cardenolide derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is -NHR<3> (R<3> is phenyl-lower alkyl which may have hydroxyl group as substituent group on phenyl ring, or lower alkyl), or lower alkoxycarbonyl; R<2> is -NHR<4> (R<4> is lower alkyl, cycloalkyl, etc. having 5- or 6-membered unsaturated heterocyclic residue) or lower alkoxycarbonyl; when R<1> is -NHR<3>, then R<2> is lower alkoxycarbonyl, and when R<1> is lower alkoxy carbonyl, then R<2> is -NHR<4>; R<1> and R<2> may together from the group of formula II or formula III]. EXAMPLE:4-Furfurylamino-14-hydroxy-2,4-sequo-3-nor-5beta,14beta-cardo-20( 22 )-enolide-2-carboxylic acid methyl ester. USE:A cardiotonic agent. PREPARATION:The titled compound can be prepared by the reductive amination reaction of the compound of formula IV (R<1>' is CHO; R<2>' is lower alkoxycarbonyl) with R<3>NH2.

Description

[Detailed description of the invention] Technical field The present invention relates to cardenolide derivatives.

Structure and effect of defense The cardenolide derivative of the present invention is a novel compound that has not been described in any literature, and has the following general formula H [wherein R1 is -NHR3 group (R3 has a hydroxyl group as a substituent on the phenyl ring] represents a phenyl lower alkyl group or a lower alkyl group) or a lower alkoxycarbonyl group.

R2 is a -NHR' group (R4 is a group selected from a hydroxyl group and a lower alkoxy group as a substituent on the phenyl ring)
A phenyl lower alkyl group that may have ~3 members, a lower alkyl group having a 5- or 6-membered unsaturated heterocyclic residue,
Indicates a cycloalkyl group or a lower alkyl group. ) or lower alkoxycarbonyl group. However, R1 is -NH
R'' group, R2 shall represent a lower alkoxycarbonyl group, and when R1 represents a lower alkoxycarbonyl group, R2 shall represent an -NR4 group. Also, R1 and R2 shall represent a -NR4 group. , may each represent 0 (R3 and R4 are the same as above).

In this specification, lower alkoxycarbonyl groups include linear chains having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. Or a branched alkoxycarbonyl group can be exemplified.

Examples of the phenyl lower alkyl group which may have 1 to 3 hydroxyl groups or groups selected from hydroxyl groups and lower alkoxy groups as substituents on the phenyl ring include benzyl, 2-
13- or 4-hydroxybenzyl, 2-(2-hydroxyphenyl)ethyl, 1-(3-hydroxyphenyl)ethyl, 3-(4-hydroxyphenyl)propyl, 4-(2-hydroxyphenyl)butyl, 5- (3
-hydroxyphenyl)pentyl, 6-(4-hydroxyphenyl)hexyl, 2,4-dihydroxybenzyl, 2-(2,3-dihydroxyphenyl)ethyl,
1-(2,5-dihydroxyphenyl)ethyl, 3-(
2,6-dihydroxyphenyl)propyl, 4-(3
,4-dihydroxyphenyl)butyl, 3,4.5-trihydroxybenzyl, β-7enethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-13- or 4- Methoxybenzyl, 2-13- or 4-ethoxybenzyl, 2-
13- or 4-propoxybenzyl, 2-butoxybenzyl, 3-pentyloxybenzyl, 4-hexyloxybenzyl, 2-(2-methoxyphenyl)ethyl, 1
-(3-ethoxyphenyl)ethyl, 3-(4-propoxyphenyl)propyl, 4-(2-butoxyphenyl)butyl, 5-(3-pentyloxyphenyl)pentyl, 6-(4-hexyloxyphenyl) Hexyl, 2,4-dimethoxybenzyl, 2-(2,3-dimethoxyphenyl)ethyl, 1-(2,5-dimethoxyphenyl)ethyl, 3-(2,6-dimethoxyphenyl)
Hydroxyl group or hydroxyl group as a substituent on the phenyl ring such as propyl, 4-(3,4-dimethoxyphenyl)butyl, 2.4-dimethoxybenzyl, 3.4-dimethoxybenzyl, 3.4.5-trimethoxybenzyl group, etc. and 1 to 3 carbon atoms in the alkyl moiety, which may have 1 to 3 groups selected from linear or branched alkoxy groups having 1 to 6 carbon atoms.
An example is a phenylalkyl group having 6 to 6 phenylalkyl groups.

Lower alkyl groups include methyl, ethyl, propyl,
Examples include straight or branched alkyl groups having 1 to 6 carbon atoms such as isopropyl, butyl, tert-butyl, isobutyl, pentyl, and hexyl groups.

Examples of the lower alkyl group having a 5- or 6-membered unsaturated heterocyclic residue include furfuryl, (3-furyl)methyl, 2-
(3-furyl)ethyl, 1-(2-furyl)ethyl,
3-(3-furyl)propyl, 4-(2-furyl)butyl, 5-(3-furyl)pentyl, 6-(2-furyl)hexyl, (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)methyl, 1-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 3-(4-
pyridyl)propyl, 2-(2-pyridyl)ethyl,
4-(3-pyridyl)butyl, 5-(4-pyridyl)
Pentyl, 6-(2-pyridyl)pentyl, thenylmethyl, 1-(2-pyrazinyl)ethyl, 2-(2-pyrimidinyl)ethyl, 3-(3-pyrazinyl)propyl, (2-pyrrolyl)methyl, (2- imidazolyl)methyl, (2-chenyl)methyl, 2-(3-pyrazolyl)
Examples include those having 1 to 2 nitrogen atoms, oxygen atoms, or sulfur atoms, such as ethyl, 1-(2-pyrrolyl)ethyl, (3-isothiazolyl)methyl, and 2-(3-isoxazolyl)ethyl groups.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

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

The compound of the present invention can be produced, for example, by the method shown in Reaction Scheme-1 below.

[Reaction Scheme-1] (H) (Ia) (1b) [R1' and R2F, one represents a 10HO group and the other represents a lower alkoxycarbonyl group.

R "and R2" mean that R1" is -NHR" group, R11
"represents a lower alkoxycarbonyl group, or R1"
is a lower alkoxycarbonyl group, R2" is -NHR'
Indicates the group. In A, R11 and R4 are the same as above. ] The reaction between the compound of general formula (I[) and the amine of general formula (If) is called a reductive amination reaction, and is carried out, for example, in an inert solvent in the presence of a reducing agent. Examples of inert solvents include water, alcohols such as methanol, ethanol, and propanol, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, diethylene glycol, and dimethyl ether, and aromatic hydrocarbons such as benzene, toluene, and xylene. Or a mixed solvent thereof can be exemplified.

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 amines of the above general formula (I[) to be used is compound (IF)
Usually at least equimolar, preferably equimolar -6
The amount of the reducing agent used is preferably about twice the molar amount, and the amount of the reducing agent to be used is usually from equimolar to three times the molar amount of the compound (IF). The reaction is usually carried out at a temperature of 0-100°C, preferably a room temperature of 60°C, and generally at a temperature of 30°C.
The reaction is completed in about minutes to 5 hours. Thus, the general formula (I
Compound a) 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, tetrahydrofuran, 1,2-dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether are preferably used.

The reductive amination reaction can also be carried out in an appropriate solvent in the presence of a catalytic reduction catalyst. Examples of the solvent used here include water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as dioxane and tetrahydrofuran, acetic acid, and the like. Examples of the catalytic reduction catalyst include Raney nickel, platinum, platinum oxide, palladium-carbon, and palladium-black. The amount of catalyst to be used is usually 0.2 to 0.2 to
The range is about 0.5 times the weight. The reaction is carried out under conditions where the temperature is usually 0°C to 200°C, preferably around 0°C to 150°C, and the hydrogen pressure is usually 1 to 3 Qatl.
Finish in time.

The reaction to obtain the compound of general formula (Ib) by ring-closing the compound of general formula (Ia>) is carried out generally at 50 to 200°C in a total active solvent.
The compound (I
This is carried out by heating a) usually for about 1 to 10 hours. Inert solvents used here include aromatic hydrocarbons such as toluene, xylene, anisole, N,
Examples include -dimethylformamide, N-methylpyrrolidone, hexamethylphosphoric triamide, dimethylsulfoxide, and mixed solvents thereof.

Further, ring closure can also be carried out in a suitable solvent in the presence of an acid. Solvents used here include alcohols such as methanol, ethanol and propatool, ethers such as tetrahydrofuran and diethyl ether, halogenated hydrocarbons such as chloroform and dichloromethane, and aromatic hydrocarbons such as benzene, toluene and xylene. Examples include hydrogen, aliphatic hydrocarbons such as hexane and cyclohexane, pyridine, and mixed solvents thereof. Examples of acids used include organic acids such as P-toluenesulfonic acid and acetic acid;
Examples include Lewis acids such as trialkyl aluminum, boron trifluoride, boron tribromide, zinc chloride, iron chloride, and tin 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 easily isolated and purified from the reaction mixture by conventional isolation methods such as recrystallization, solvent extraction, column chromatography such as high performance liquid chromatography, and distillation.

The compound of general formula (II) is a new compound, and can be obtained, for example, by the method shown in Reaction Scheme-2 below.

(Reaction Scheme-2) CPI) (V) 0 0 One of R11 and R2#F represents a hydroxyl group, and the other represents a 100OR'' group. R5 represents a lower alkyl group. Digitoxygenin represented by formula (IV) is reacted with peracid to form the general formula ( In order to obtain the compound V), digitoxigenin is dissolved in a suitable inert solvent, and then an organic peracid is added to this solution to cause a reaction with the organic peracid.As the organic solvent, Any material can be used without particular limitation as long as it can dissolve the compound to be treated and the organic peracid.Specific examples include chloroform, methylene dichloride, carbon tetrachloride, halogenated hydrocarbons such as trichlorethylene, benzene, etc. , aromatic hydrocarbons such as toluene, etc. Also, organic peracids can be widely used without particular limitation, such as perbenzoic acid, metachloroperbenzoic acid, metanitroperbenzoic acid, varanitroperbenzoic acid, 3 Examples include perbenzoic acids such as .5-dinitroperbenzoic acid.The amount of organic peracid to be used is 1 to 3 times the molar amount of organic peracid relative to digitoxygenin, preferably 1.2 to 3 times the molar amount of organic peracid to digitoxygenin. It is preferable to use 1.5 times the molar amount.The organic peracid may be added as it is, or it may be added dissolved in a solvent in advance.The solvents used here include the above-mentioned organic solvents and The above oxidation reaction is usually carried out at room temperature to the reflux temperature of the solvent.
Preferably it proceeds at a temperature of 60 to 70°C, and generally at a temperature of 20°C.
The oxidation reaction is completed in minutes to 24 hours. Thus, the general formula (
A compound of V) is produced.

Alcoholysis of the compound of the general formula (V) is carried out by converting the compound of the general formula (V) into a compound of the general formula R50H [wherein R5 is the same as above] in the presence of a basic catalyst or an acid catalyst without a solvent or in an inert solvent. ] is carried out by reacting an alcohol represented by 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 (v). Examples of inert solvents include aromatic hydrocarbons such as benzene and toluene, ethers such as methyl ether and ethyl ether,
Examples include dimethyl sulfoxide and acetonitrile. The amount of the alcohol to be used is not particularly limited and can be appropriately selected from 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 compound (V). It is usually best to use an excess amount, and when the above reaction is carried out in an inert solvent, alcohol is used in at least an equimolar amount, usually 3 to 10 times the molar amount of compound (V). It is better to do so.

The reaction temperature for this reaction is normally room a! The temperature is preferably within the range of ~100°C.

In this way, a compound of general formula (Vl) is produced.

When a compound represented by general formula (Vl) is treated with an oxidizing agent in an inert solvent at a temperature range of usually 0 to 100°C, preferably about 15 to 60°C, a compound of general formula (It) 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 used is usually 1 to 2 mol per 1 mol of 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 (II) 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 of general formula (I) 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.
Typical examples include tablets, emulsions, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids,
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, propatool, 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 , thorium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrants such as lactose, white sugar, stearin,
Disintegration inhibitors such as cocoa butter and hydrogenated oils, absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose,
Examples include adsorbents such as kaolin, bentonite, and colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming into an emulsion, a wide variety of conventionally known carriers can be used, such as excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, and talc, powdered gum arabic, powdered tragacanth, and gelatin. , a binder such as ethanol, and a disintegrant such as laminaran agar. When forming into a suppository, a wide variety of conventionally known carriers can be used, such as polyethylene glycol,
Examples include cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides. 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 to prepare an isotropic solution may be included in the pharmaceutical preparation, and usual solubilizing agents, buffers, soothing agents, etc. may be added. It's okay. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals may be included in the pharmaceutical preparation, if necessary.

The amount of the compound of general formula (I) to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected from a wide range, but is usually 1 to 70 Il%, preferably 1 to 70 Il% in the pharmaceutical preparation. It is 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, emulsions, 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 further, if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. Suppositories are administered rectally.

The dosage of the cardiotonic agent of the present invention is appropriately selected depending on the usage, the age, sex and other conditions of the patient, the degree of disease, etc., but the amount of the compound of general formula (I), which is the active ingredient, is usually per kiloliter of body weight per day. It is preferable to set it to about o,,ooi~1■Q. Also, the amount of active ingredient in the dosage unit form is 0.01 to 25%.
It is preferable to include s+o.

, theory Reference examples, examples, pharmacological tests, and formulation examples are listed below.

Reference Example 1 Synthesis of digitoxigenin lactone Anhydrous chloroform 15- of digitoxigenin 1.10a
1.00Q of metachloroperbenzoic acid was added to the solution, and the mixture was 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 the l solvent was distilled off to obtain 1.24 g of a residue. This product was subjected to chromatography on silica gel 100Q using an ethyl acetate-chloroform solvent system while increasing the ethyl acetate concentration sequentially. A mixture of lactones 94610 (83.0%) having a melting point of 225 to 235°C was obtained from the 70% ethyl acetate-chloroform eluate. This mixture is A-
Homo-2a-oxa-14-hydroxy-5β, 14β
- Caldo 20(22)-Efride-3-one (hereinafter referred to as "Compound (Va)J") and A-homo-3a-oxa-14-hydroxy-5β,14β-Caldo 20 (
22)-Efride-3-one (hereinafter referred to as "Compound (Vb)")
J) in a ratio of approximately 1:1.

Digitoxigenin lactone mixture Melting point: 225-235°C IR (KBr, cm”): 3500.2975.2900, 1790°1745.
1735.1625.1455゜1”310..129
5,1190.1185°1130, 1070,10
35°UV' (λ-ax, MeOH): i-(log
ε) −218,0(4,16).

Reference Example 2 8.780 (22,61i+ol) of the lactone mixture of Compound (Va) and Compound (Vb) obtained in Reference Example 1 was dissolved in 700 g of methanol to make 1.56 g of anhydrous potassium carbonate.
0 (11.3 g 1 iol) was added thereto, and the mixture was stirred at room temperature for 80 minutes. The mixture was neutralized with 5% hydrochloric acid while cooling with water, and methanol was distilled off under reduced pressure. The residue was dissolved in 2Q ethyl acetate, washed with water, and the solvent was distilled off to obtain colorless crystalline powder 9.350.

This colorless crystalline powder was dissolved in 300 WIJ of ethyl acetate and subjected to fractional crystallization using 4,14-dihydroxy-2,4-seco-3-true 5β,14β-caldo-20(22)-
Crude crystals of ephrid-2-carboxylic acid methyl ester (hereinafter referred to as "compound (Via) J") were obtained.

The crude crystals were recrystallized from ethyl acetate-methanol-petroleum ether to obtain 3.55 g of compound (Vla).

Next, the solvent of the remaining mother liquor in the fractional crystallization method was distilled off under reduced pressure, and the residue was placed in a column column (φ4.3C).
×30C■, dichloromethane:acetonitrile-4:1) as eluent, 2゜14-dihydroxy-2,
4-seco-3-true 5β, 14β-caldo 20 (
22)-Efride-4-carboxylic acid methyl ester (
Under IX, 3.30% of compound (referred to as compound (■b) J) was obtained. Further, the developing solution was changed to dichloromethane:acetonitrile-2:1 to obtain 0.770 of compound (VIb).

Physical properties of compound Vla Melting point: 194-196°C.

IR (KBr, cm”): 3420.2935.2870.1800°1730.
1705, 1610, 1430°1380.1310.
1250.1220゜1180.1160.1020,
960°NMR (DMS O-ds, 4
00 MHZ, δ): 0', 77 (3H,'S,
18-CH3), 0.86 <3H,s, 19-CHs
), 2.21 (IH, dt, J-11, 4, 4, 4
゜2-Ha), 2.34 (1H, dt, J-11,4,4,4゜2-
Hb), 2.72 (IH, m, 17-H), 3.40 (2H, m, 4H), 3.58 (3H, s, 0CHs), 4.09 (I
H, s, 14-0H), 4.27 (IH, t, J-4
, 9, 4-0H), 4.88 (1H, dd, J-18
,7,2,0゜2l-Ha) ,4.97 (IH,dd,J=18.7,2.0゜2l
-Hb), 5.91 (IH, 22-H).

Mass (m/e): 420 (M”), 402, 388, 370° 352
．． 315,297,285,269°235.217,
199,187,171°163 (100%), 159
, 145.1'3'1.

119.105,91,79,67.55°41°0 [α), -+39.5° (C-0,51°CHCQ,
) Physical properties of compound (Ib) Melting point 180-182°C IR (KBr, cr'): 3440.3400, 3000.2975°290.0
,1790,1775.1755゜1740.1700
．． 1630.1620゜1450.1380.1305
．． 1200°1150.1070.1040.1020
゜940.890゜NMR(DMS O-de, 400M
Hz, δ): 0', 76 (3H, 8, 180H3
), 0.95 (3H,s, 19 CHa ), 1.2
9 (IH, m, 1-Ha), 1.54 (IH, m, 1-Hb), 1.78 (1)-1, m, 5-H), 2.38 (2
H, 'm, 4-H), 2, 72 (IH, m, 17-H), 3.43 (
2H, m, 2-H), 3.59 (3)1. s, OCH3), 4.09 (
11-1, s, 14-0H), 4.25 (1H, t
, 2-OH, J-4, 9>, 4.88 (IH, dd,
J-18,7,2,0°2l-Ha), 4.97 (IH,dd, J-18,7,2,0°2l
-Hb), 5.91 (IH, s, 22-H).

Mass (m/e): 420 (M”), 402, 388, 291° 278
．． 235,217,207.194 (100%), 17
5,147,134°119.111,107.93.
79.67°55.41°0 (α), -+33.16 (C=0.42°CHC(I
s)'.

Reference Example 3 Compound (Via) 420-0 was added to a solution of pyridinium chlorochromate (hereinafter abbreviated as PCC) 323io suspended in anhydrous methylene chloride 30- and stirred at room temperature in an argon stream for 1.5 hours. , insoluble matter was removed by sieving off, and the furnace liquid was distilled off to obtain 470 g of a dark brown caramel-like substance;
The crystals were purified by column chromatography using silica gel 120.

Elute with methylene chloride-acetonitrile (12%),
-Oxo-14-Hydroxy-2,4-Seco-3-Tulu-5β,14β-Caldo 20(22)-Efride-
4-carboxylic acid methyl ester (hereinafter referred to as [compound (I[
A colorless crystal 3401G (referred to as J) was obtained. Recrystallization from methylene chloride-ether gave colorless needles.

Melting point: 167-169°C.

Mass (m/e): 418 (M”), 400,386゜I R (KBr
, cta-'n; 3550.1785, 1750.1720 (sh)1
719.1618°NMR (CDC(ls', δ): 0.88 (3H, s), 1.29 (3H, s), 2.20 (IH? dd, J-15,0,2,1> ,
2.42 (IH, dd, J-5, 0), 2.45 (
IH, dd, J-15,0,2,1), 2.48 (I
H, dd, J-15, 0, 2, 1), 3.65 (3H
, s), 4.80 (IH, dd, J-18, 0, 1, 5), 4
．． 97 (IH, dd, J-18, 0, 1, 5), 5.
87 (IH, t, J-1, 5), 9.88 (IH,
dd, J-3,7,2,1).

0 (Qri, -+14.1° (C=0.66°CHCQo
).

Reference Example 4 Compound (Vlb) 420+g and PCC323mo were reacted in the same manner as in Reference Example 3 to obtain 4-oxo-14-hydroxy-2,4-seco-3-true 5β, 14β-caldo 20 (22)-ephrid 310 mg of colorless needle-like crystals of -2-carboxylic acid methyl ester (hereinafter referred to as "Compound (Ib) J)" was obtained.

Melting point: 165-167°C.

Mass (m/e): 418 (M”), 400,390,386゜IR
(KBr, cr'): 3500.1790,1730,1620°NMR(C
DC12a, δ): 0.88 (3H, s), 1.00 (3H, s), 2.87 (1H, dd, J=9.7.5.9), 3.
68 (3H, s), 4.80 (IH, dd, J=18.1, 1.9), 4
．． 96 (IH, dd, J=18.1, 1.9), 5.
89 (1H, t, J=1.9), 9.76 (1H,
d, J-3, 2).

[α]6°−−2.5°(C=0.56°CHC(la
).

Example 1 Compound (I[b) 60011117, 697 mg of furfurylamine, and 0.5-acetic acid were dissolved in 20 ml of methanol, and 1 ml of sodium cyanoborohydride was dissolved under stirring at room temperature.
A solution of 50 .mu.C dissolved in 5 parts of methanol was added dropwise, and the mixture was reacted at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, and 20% of saturated brine was added to the residue, followed by extraction with chloroform.

After drying the chloroform layer with Glauber's salt, it was distilled off under reduced pressure to leave a residue of 780 m! I got a 7. Crystal silica gel 30G, CH
Purified by column chromatography with C93-MeOH (5%) to give 4-furfurylamino-14-hydroxy-2,4-seco-3-true 5β, 14β-cardo 2
480 mg of a colorless caramel of (22)-ephrid-2-carboxylic acid methyl ester (Ic) was obtained. Trituration with ethyl acetate-diethyl ether gave colorless powdery crystals.

Melting point: 161-163°C.

Mass (m/e): 499 (M÷), 467°IR (KBr, cm-'): 3515.1800.1750.1620°NMR (C
DC (la, δ): 0.84 (3H, s), 0.91 (3H, s), 2.50 (IH, dd, J-11, 2, 3, 4), 2
．． 63 (IH, t, J-11, 2), 2.76 (I
H, dd, J=9.5.5.8), 3.64 (3H,
s), 3.72 (IH, d, J=14.6), 3.78 (
IH, d, J = 14.6), 4.78 (IH, dd,
J-18, 0, 1, 4), 4.97 (IH, dd, J
-18,0,1,4), 5.85 (IH,t,J-1
, 4), 6.16 (I H, dd, J-3, 1, 0,
8), 6.29 (IH, dd, J=3.1, 0.8)
, 7.33 (IH, dd, J-1, 7, 0, 8).

Example 2 570 mo of compound (IIb), 335 mo of p-hydroxybenzylamine and 0.1 mo of acetic acid were added to 25 mo of methanol.
The mixture was subjected to reductive amination and treatment in the same manner as in Example 1 using 150 mg of sodium cyanoborohydride to obtain 14-hydroxy-4-(p-hydroxybenzylamino)-2,
4-seco-3-true 5β, 14β-callido-20 (
22) A colorless caramel of -efrid-2-carboxylic acid methyl ester (Id) 700ma was obtained.

Mass (m/e): 493 (M+-32), 416,401°387.1
07° IR (Nujol, C'l): 3450.1780.1735, 1620° 1600° NMR (DMSO-66, δ): 0.75 (3H, s), 0.85 (3H, s), 2. 71 (IH, dd, J=9.4, 5.4>, 3.
56 (3H, s), 3.66 (3H, br, s), 4.08 (IH, s), 4.83 (IH, d, J-18,7), 4.96 (
IH, d, J-18, 7), 5.90 (IH, S), 6.69 (2H, d, J-8, 4), 7.14 (
2H, d, J-8, 4>, 9.27 (IH, br,
s).

Example 3 600 g of compound (IIb), 880 ml of 2-(2-aminoethyl)pyridine) and 0.5-ml of acetic acid were dissolved in 25 w1 J of methanol with 150 g of sodium chloride, 7 noborohydride.
Using reductive amination and treatment in the same manner as in Example 1 using
Colorless caramel of β-caldo 20 (22)-efrid-2-carboxylic acid methyl ester (Ie) 670
I got gma.

Mass (m/e): 524 (M÷), 492 (M+-32).

IR (KBr, cs+-'): 3450.1780, 1740.1735 (sh).

1620.1600°NMR (CDC9g, δ): O゛, 87 (3H, s), 0.97 (3H, s), 2.77 (2H, m), 2.90 (IH, t, J=11 .7) , 3.14
(IH, m), 3.27 (IH, m), 3.65 (3H, s), 4.80 (IH, dd, J-18, 1, 1, 6), 4
．． 97 (IH, dd, J-18, 1, 1, 6), 5
．． 87 (IH, t, J-1, 6), 7.19-7.
26 (2H, m), 7.66 (IH, 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 1.20 and acetic acid 0.25-
14-hydro±Nt A -(') /
Q A 62-1 k-at7T-n, 1] ethylamino-2,4-seco-3-true 5β.

Colorless powder of 14β-caldo 20 (22)-efrid-2-carboxylic acid methyl ester (If) 530■9
I got it.

Mass (m/e): 583 (M+), 553,446,432゜IR
(CHCQs, CI-'): 3500.1790
, 1740.1620°NMR (CDCQa, δ): 0.85 (3H, s), 0.93 (3H, S), 3.66 (3H, s), 3.79 (3H, s), 3. 88 (3)1. s), 4.01 (IH, d, J=13.0), 4.79 (
IH, d, J-18, 4), 4.96 (IH, d, J
= 18.4), 5.87 (IH, t, J = 1.6),
6.74 (IH, d+:, J-8, 6, 1, 9 P;
-74A (1)-1-d, Ix”+016.80
(IH, d, J-8, 6).

Example 5 Compound (I[b) 695-o, 1.44 g of 2,4-dimethoxybenzylamine hydrochloride, and 280 μO of sodium chloride 7 noborohydride were subjected to reductive amination and treatment in the same manner as in Example 1 in methanol 20111Q. and 14-hydroxy-4-(2,4-dimethoxybenzyl)amino-2
, 4-seco-3-true5β.

A colorless powder of 14β-kaldo 20 (22)-efrid-2-carboxylic acid methyl ester (In, 660 Ω) was obtained.

Mass (m/e): 569 (M÷), 551 (M÷-18).

537 (M+-32).

IR(CHCQs, C1-'): 3500.1
790.1745.1620°NMR(CDC(ls)
, δ): 0.85 (3H, S), 0.93 (3H, s), 3.66 (3H, S) > 3.79 (3H, s), 3.88 (3H, s), 4 .0.1 (IH, d, J-13,0), 4.79
(IH, d, J-18, 4), 4.96 (IH,
d, J=18.4), 5.86 (IH, s), 6.47 (2H, m), 7.20 (IH, m).

Example 6 Compound (IIb) 720Jl, methylamine hydrochloride 66
2Peng O was subjected to reductive amination and treatment in the same manner as in Example 1 with 280 mg of sodium cyanoborohydride in methanol 5- to give 14-hydroxy-4-methylamino-2,
4-seco-3-true 5β.

6101 g of colorless powder of 14β-callido-20(22)-efrid-2-carboxylic acid methyl ester (Ih)
I got it.

Mass (m/e): 403 (M+-30).

I R (KBr, cl″): 3470.1790, 1720, 1610°N M R
(DMSO-ds, δ): 0.77 (3
H,s), 0.89 (3H,s), 1.58 (IH,m), 2.59 (3H,s>, 2.70 (IH,d, J-11,8), 2.74 (
IH, m), 3.10 (IH, t, J-11,8), 3.60 (
3H, s), 4.16 (IH, S), 4.89 (IH, d, J-18, 7), 4.76 (
IH, d, J = 18.7), 5.92 (IH, s)
, 7.94 (IH, br, s).

Example 7 Compound (I[b) 660-O% n-propylamine hydrochloride 646 Jl was mixed with Example 1 and xy-4-n in 280 μU of sodium cyanoborohydride in 20 g of methanol.
-propylamino-2,4-seco-3-turu-5β,1
Colorless powder 486■a of 4β-carlide-20(22)-efrid-2-carboxylic acid methyl ester (Process 1) was obtained.

Mass (m/e): 461 (M÷＞, 447,430,400゜I R(
CHCQs, cm-'): 3450.1790
．． 1740, 1620°NMR (CDC93, δ): 0.69 (3H, s), 0.82 (3H, S), 0.82 (3H, t, J=6.0), 2.21 (2
H, t, J-7, 6), 2.61 (2H, m>, 2.67 (2H, t, J-7, 6), 2.87 (I
H, t, J-12, 5), 3.51 (3H, s), 4.68 (IH, dd, J-18, 3, 1, 5), 4
．． 87 (IH, dd, J-18, 3, 1, 5), 5-
68 (IH, t, J-1, 5>.

Example 8 Compound (I[b) 630 mg, isopropylamine 51
Example 1
Reductive amination and treatment in the same manner as in
- Colorless powder of carboxylic acid methyl ester (Ij) 610
1g of 1I was obtained.

Mass (m/e): 461 (M”), 446,430゜I R (CHC
Qa, cr'): 3450.1740, 1620° NMR (CDC+ls, δ): 0.88 (3H, s), 0.97 (3H, s), 1.28 (3H, d, J=5.9 ), 1.30 (3
H, d, J-5,9), '2.88 (IH, m), 3.12 (IH, m), 3.67 (3H, s), 4.83 (I H, dd, J- 17, 8, 1, 4),
5.00 (I H, dd, J=17.8, 1.4),
5.88 (IH, t, J=1.4).

Example 9 Compound (Ib) 7001B, n-hexylamine 700
1G and acetic acid 0.2511111 were reductively aminated and treated with sodium cyanoborohydride 2801+117 in methanol 20-2 as in Example 1 to give 14-bedroxy-4-n-hexylamino-2,(4- Seco
450 m (J) of colorless powder of 3-true 5β, 14β-caldo 20(22)-efrid-2-carboxylic acid methyl ester (Ik) was obtained.

Mass (m/e,): 503 (M+), 472,453゜I R (CHC
Qa, cm-'): 2950.1795.175
0.1630°NMR (CDCQs, δ): 0.87 (3H, s), 0.88 (3H, t, J=1.0), 0.94 (3
H, s), 2.77 (IH, m), 3.67 (3H, s>, 4.80 (IH, dd, J=18.1, 1.6),
4.98 (1H, dd, J=18.1, 1.6),
5.87 (IH, t, J-1, 6).

Example 10 Compound (I[b) 712IQ, cyclohexylamine 7
14-hydroxy-4-cyclohexylamino-2,4-seco- Colorless powder of 3-true 5β, 14β-caldo-20(22)-efrid-2-carboxylic acid methyl ester (■1) 6
70m! ;I was obtained.

Mass (m/e): 501 (M+), 415,265゜I R (CHC
Qa, C "1): 3500.1790, 1740, 1620°NMR (C
DC123, 6): 0.99 (3H, S), 1.01 (3H, s), 3.70 (3H, s), 4.86 (IH, d, J-17, 8), 5.00
(IH, d, J=17.8), 5.91 (IH, s
).

Example 11 Compound (I[a) 500 mg, p-hydroxyhensylamine 30011G and acetic acid 0.1- were mixed with methanol 20
- Medium Sodium Cyanoborohydride 140111g
was subjected to reductive amination and treatment in the same manner as in Example 1 using
Colorless crystals 6101G of 4-hydroxy-2-(p-hydroxybenzyl)amino-2,4-seco-3-true 5β,14β-caldo 20 (22)-efrid-4-carboxylic acid methyl ester (Im) were obtained. Ta.

Melting point 188-195°C (recrystallized from ethyl acetate-diethyl ether) Mass (m/e): 525 (M”), 433,419°IR (KBr
, cr'): 3500.3425, 1790, 1730° 1615° NMR (DMSO-de, 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 (IH, d, J-18,9 > , 4.96
(IH, d, J=18.9), 6.78 (2H, d
, J-8,2) ,7.31 (2H,d, J=8.2
), 8.78 (IH, br, s), 9.66 (IH, br, s).

Example 12 Compound (I[a) 725io, n-propylamine hydrochloride 763■O was reductively aminated and treated with sodium cyanoborohydride 280-〇 in methanol 5I112 in the same manner as in Example 1 to obtain 14- Hydroxy-2-n-propylamino-2,4-seco-3-true 5β, 14β
- Colorless powder 612+no of Caldo 20 (22)-ephrid-4-carboxylic acid methyl ester (In) was obtained.

Mass (m/e): 461 (M÷), 446,433.4000IR (C
HCQ3, cm-'): 3450.2980.1790, 1750° 1620° NMR (CDCI23.6): 0.87 (3H, s), 1.00 (3H, t, J=6.0), 1. 03 (3
H, s), 2.82 (IH, m), 3', 69 (3H, S), 4.80 (IH, d, J-18, 1), 4.97 (
IH, d, J=18.1), 5.89 (IH, S)
.

0 [α]. -+189.2° (C-0,54°0HCQ
a).

Example 13 Compound (IIa) 700 g1 isopropylamine 53
0mo and 0.25IQ of acetic acid in methanol 511Q,
Example 1 with 280 mg of sodium chloride 7 noborohydride
Reductive amination and treatment in the same manner as in
-Colorless needle crystals of carboxylic acid methyl ester (process 0) 51
I got 3ia.

Melting point: 103-105°C (recrystallized from ethyl acetate-diethyl ether).

Mass (m/e): 461 (M+), 446,430゜I R (KBr
, CI-'): 3500.3000, 1790.1740°1620°NMR (CDC9a, δ): 0.86 (3H,S), 1.02 (3H,S'), 1.09 (6H,d, J-6,0), 2.77 (
IH, m), 2.84 (IH, QQ, J=6.0.6.0), 3
．． 67 (3H, s), 4.80 (IH, dd, J=18.1.1.7),
4.98 (IH, dd, J-18, 1, 1, 7),
5.87 (IH, t, J-1, 7).

Example 14 Compound (IIa) 670Jl, n-hexyl/l/7min 70010 and acetic acid 0.25-meta/-/lz 5
Sodium cyanoborohydride 280111 in wJ
11 was subjected to reductive amination and treatment in the same manner as in Example 1 to obtain 1.
4-Hydroxy-2-n-hexylamino-2,4-seco-3-true 5β,14β-caldo 20(22)-
Efride-4-carboxylic acid methyl ester (Ip)
Colorless powder 63011111 was obtained.

Mass (m/6): 503 (M+n, 488.471.446
゜432,400゜IR(CHC9s,cyg-'):,,3500
．． 2980, 1795.1620°NMR (CDCQs
, δ): 0.86 (3H, s), 0.89 (3H, t, J=6.5), 1.04 (
3H,s), 2.70 (IH,m), 3.68 (3H,s), 4.81 (IH,dd, J-18,1,1,7),
4.98 (IH, dd, J-18, 1, 1, 7),
5.88 (IH, t, J=1.7).

(α)”-+35.7°(C-0,68°CHC(ls
).

Example 15 Compound (Im) 63011J obtained in Example 11 was dissolved in 50 m of anhydrous methylene chloride, anhydrous and lysine 3-, and 19% AQMes in hexane 812.06- was added dropwise and then refluxed for 3 hours. The complex of the reaction solution was decomposed with 3N hydrochloric acid while cooling with water, and the mixture was extracted with methylene chloride. The organic layer is M gS
After drying at Ot, 530 eg of colorless caramel-like substance was obtained by distillation.
I got it. The crystals were purified by column chromatography using silica gel 12Q1 eluent chloroform-methanol (5%), and A-homo-3-aza-3a-oxo-3-(
p-hydroxy)benzyl-5β,14β-caldo2
330 ma of colorless powdery crystals of 0 (22)-enolide was obtained.

Melting point: 167-170°C (recrystallized from ethyl acetate-diethyl ether).

Mass (m/e): 493 (M”), 387,344゜I R (KBr
, cr'): 3430.1780, 1740.1620°1600(
sh).

NMR(DMSO-ds, δ): 0.7
6 (3H,s), 0'', 84 (3H,s), 1.87 (IH,d, J-13,9), 2.18 (
IH, m), 2.72 (IH, dd, J-9, 8, 5, 4), 2.
88 (I H, dd, J-15, 6, 7, 1), 3.
50 (IH, dd, J-15, 6, 11, 2), 4.
11 (IH, d, J-14, 2), 4.59 (IH
, d, J-14, 2), 4.88 (IH, dd, J-
18, 3, 1, 4), 4.96 (IH, dd, J-1
8, 3, 1, 4), 5.90 (IH, t, J=1.4
), 6.69 (2H, d, J-8, 5>, 7.03
(2H, d, J-8, 5), 9.27 (IH, s)
.

[α)”-+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 113C"CH2 A compound which is a group was obtained.

Melting point: 270-272°C (recrystallized from ethyl acetate-diethyl ether, colorless needles).

Mass (m/e): 429 (M+), 414,396゜I R (KBr
, cg+-'): 3400.2930.1785.1740°1610°NMR (CDC9s, δ): 0.89 (3, H S), 0.96 (3H, s), 1.04 (3H, d, J-6,8), 1.09 (3
H, d, J-6, 8), 2.11 (IH, d, J-1
4,9), 2.79 (IH, m), 3.00 (IH, d, J=15.9), 3.02 (
IH, dd, J-14, 9, 6, 2), 3.25 (I
H, dd, J-15, 9, 10, 3), 4.81 (I
H, dd, J-18, 1, 1, 9), 4”, 84 (I
H, 'qq, J-6.8, 6.8), 4.99 (IH
, dd, J-18, 1, 1, 9), 5.88 (IH,
d, J-1, 9).

0 (α) −+14.9° (C-0,36, chloroform).

Example 17 The base compound was obtained in the form of a colorless powder.

Mass (m/e): 471 (M÷), 456,442,414゜400゜I R (KBr, c--'): 3400.2930.1780, 1740゜1620゜NMR (CDC (is, δ) : 0.88 (3H, t, J-7, 3), 0.89 (3
H,s), 0.97 (3H,s), 2.09 (IH,d, J-14,9), 2.79 (
IH, m), 3.00 (2H, m) - 3,25 (IH, dt, J-14,9,7,6), 3.
40 (IH, -dt, J-14,9,7,6), 3.
46 (IH, dd, J-14, 5, 10, 8), 4.
81 (IH, dd, J-18, 1, 1, 6), 4.9
8 (IH, dd, J-18, 1, 1, 6), 5.88
(IH, t, J-1, 6).

[α] 2°-+30.1° (C-0,79, chloroform).

Example 18 A compound which is a group was obtained.

Melting point: 213-215°C (recrystallized from ethyl acetate, colorless needles).

Mass (m/e): 467 (M+), 449,439,399°3”8
6,357,273,246,81°IR (KBr,
cm''): 3400.3350.1785.1740°1640
(sh), 1630° NMR (CDCQs, δ): 0.87 (3H, s), 0.92 (3H, s), 2.27 (IH, dd, J-15, 1, 8, 4), 2
．． 62 (IH, dd, J-15, 1, 12, 1), 2
．． 77 (IH, m), 2.88 (IH, d, J-15, 1), 3.89 (
IH, dd, J-15, 1, 10, 3), 4.48 (
IH, d, J-15, 4), 4.59 (IH, (1,
J-15, 4), 4.79 (IH, dd, J-18,
0,1,8>, 4.97 (IH, dd, J-18,0
, 1, 8), 5.88 (IH, t, J ■ 1.9), 6
．． 24 (IH, dd, J-3, 3, O,, 7), 6
．． 32 (IH, dd, J-3, 3, 1, 8), 7.3
5 (IH, dd, J-1, 8, 0, 7).

(α)”-+38.4° (C-1., 32.chloroform).

Example 19 In the general formula (Ib), 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, cr'): 34'30.1785.1740.1620°1600
(sh).

NMR (CDCQs, δ): 0.87 (3H, s), 0.92 (3H, s), 2.32 (IH, dd, J-14, 3, 8, 8), 2
．． 66 (IH,t,J-14,3),2,,'73
(IH, d, J-15, 6), 2.77 (IH), 3.83 (IH, dd, J-15, 6, 10, 3),
4.35 (IH, d, J=14.7), 4.58
(IH, d, J-14, 7), 4.79 (IH, d
d, J-18,3,1,5), 4.96 (IH, d
d, J-18,3,1,5), 5.88 (IH,t
, J=1.5), 6.79 (2H,d, J=8.2
), 7.09 (2H, d, J-8, 2).

[α)2'=+40.6° (C=0.54.Chloroform).

Example 20 In the general formula (Ib), 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, CI'): 3420, 1780. 1740. 1620゜NM
R (CDCQa, δ): 0.88 (3H, s), 0.91 (3H, s), 2.78 (1)1. m), 2.89 (1H, d, J-13,6), 3, 1
1 (IH, m), 3.19 (IH, m>, 3.69 (1H, m), 3.84 (IH, m), 4.05 (IH, m), 4.80 (IH, dd , J=18.0.1.5),
4.97 (IH, dd, J=18.0.1.5),
[α]6°-+26.5° (C=0.57.methanol).

Example 21 In the general formula (Ib), 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
, c+a-'): 3450.2950.1782, 1740° 1630° NMR (CDCQa, δ): 0.88 (3H, s), 0.92 (3H, s>, 2.57 (IH, dd, J -14,6,11,9),
2.65 (11-1, d, J=15.1), 3.78
(2H, m), 3.57 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 4.79 (IH, dd, J-18, 1, 1, 6 ), 4
．． 96 (IH, dd, J-18, 1, 1,, 6), 5
．． 89 (IH, d, J-1, 6), 6.75 (IH
, dd, J-8, 6, 2, 0), 6.76 (IH,
d, J-2,0), 6.80 (IH, d, J-8,
6).

[α)”-+32.1° (C-0,63, chloroform).

Example 22 In the general formula (Ib), 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, c'l): 3350.2960.1790,1740°1630°NM,, R (CDC9s, δ): 0.86 (3H,S), 0.91 (3H,s), 2.26 (IH , dd, J-14, 7, 8, 5), 2
．． 64 (IH, dd, J=14.7.12.2), 2
．． 76 (IH, m), 2.82 (1H, d, J-15, 3), 3.79 (
6H,s), 3.81 (1) (, dd, J=15.3.10.0)
, 4.46 (IN, d, J=14.7), 4.54
(IH, d, J-14, 7), 4.78 (IH, dd
, J=18.0.1.5> , 4.95 (IH, dd
, J-18,0,1,5) ,5.87 (IH,t,
J=1.5), 6.43 (IH, d, J=2.4)
, 6.44 (IH, dd, J=8.9.2.4) ,
7.15 (IH, d, J-8, 9).

0 [α]. -+19.4° (C-0,84, chloroform).

Example 23 Melting point: 266-267°C (recrystallized from ethyl acetate-diethyl ether, colorless needles).

Mass (m/e): 401 (M+), 386,356.248°I R
(KBr, cm-'): 3350.2950.1780.1740°1640°NMR (COCO2, δ): 0.89 (3H, s), 0.97 (3H, S), 2.60 (IH, dd , J-15,1,12,4)2
．． 71 (IH, d, J=15.1), 2.78 (I
H, m), 2.95 (3H, s), 4.02 (IH, dd, J=15.1, 10.3 in 4
．． 80 (IH, dd, J-18, 1, 1, 8), 4.
97 (1H, dd, J=18.1, 1.6), 5.8
9 (IH, t, J=1.6).

0 [α), = +39.0° (C-0,73, chloroform).

Example 24 In the general formula (Ib), eight is N- 11 0(CH2)2CH3 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”), 414.4=OO, 276°IR
(KBr, cr'): 3400.2970.1795, 1730° 1630° NMR (CDCQs, δ): 0.89 (3H, s), 0.90 (3H, d, J-7,3), 0. 97 (3
H,s>, 2.73 (IH,d, J-15,4), 2.79 (
IH, m), 3.30 (2H, m), 3.94 (IH, dd, J-15,4,10,0),
4.80 (IH, dd, J-18, 1, 1, 6), 4
．． 97 (IH, dd, J-18, 1, 1, 6), 5.
89 (IH, t, J-1, 6).

0 (α), −+44.8° (C=0.42.chloroform).

Example 25 In the general formula (Ib>), A is M- A basic compound was obtained.

Melting point: 276-278°C (recrystallized from ethyl acetate-diethyl ether, colorless needles).

Mass (m/e): 429 (M”), 414,396.386゜I R
(KBr, cr'): 3500.2990.1790.1760°1620°NMR (CDC(13, 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 (IH, dd,
J = 14.6, 12.9), 2.77 (IH, d, J
-15,5>, 2.78 (IH, m), 3.62 (IH, dd, J-15,5,10,3)4
．． 80 (IH, QQ, J-6, 9, 6, 9), 4.8
0 (IH, dd, J-18, 1, 1, 3), 4.9
8 (IH, dd, J-18, 1, 1, 3), 5.8
9 (IH, t, J-1, 3).

0 [α), -+41.4° (C-0,51, chloroform).

Example 26 In the general formula (Ib), A is N- A compound which is a group was obtained.

la 213-214.5°C (recrystallized from ethyl acetate-diethyl ether, colorless needles).

Mass (m/e): 471 (M÷), 453,442.428°400°IR (KBr, cr'): 3450.2950,1790,1730°1620°NMR (CDCQa, δ): 0.88 ( 3H,t, J-6,0), 0.89 (3
)1. s), 0.97 (31(,s), 2.58 (IH, dd, J-14,9,11,9)2
．． 73 (IH, d, J-15, 7), 2.79 (I
H, m), 3.32 (2H, dd, J=8.6, 6.5), 3.
93 (IH, dd, J-15,7,10,0), 4.
80 (IH, dd, J=18.1, 1.6), 4.9
7 (IH, dd, J-18, 1, 1, 6), 5.89
(1H, t, J-1, 6).

(α)”-+33.2° (C-0,12, chloroform).

Example 27 In the general formula (Ib), 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"): 3500.2950.1780.1740° 1630° NMR (CDC (ia, δ): 0 .89 (3H,S), 0.95 (3H,s), 2.60 (IH,t, J-14,3), 2.79 (
IH, m), 2.82 (IH, d, J-15,1), 3.64 (
IH, dd, J-15, 1, 9, 7), 4.38 (I
H, tt, J=11.9.3.2), 4.80 (IH
, dd, J-17, 8, 1, 9), 4.97 (IH,
dd, J-17, 8, 1, 9), 5.89 (IH, t
, J-1,9>.

(α) 20-+39.8° (C-0,12, chloroform).

Example 28 In the general formula (Ib), eight is -C- A compound which is a group was obtained.

Melting point 259-260°C (recrystallized from ethyl acetate-diethyl ether - Makushubachi Bakuraku) Lylass (m/e): 429 (M+), 414.396, 386°I R (K
Br, cm-'): 3400, 2950. 1780. 1740°163
0°NMR (CDC(ls, δ): 0.88 (3H, s), 0.89 (3H, t, J-7,6), 0.97 (
3H, s), 2.79 (IH, m), 3.01 (2H, m), 3.22 (IH, dt, J-14,9,7,6),
3.39 (1)1. dt, J=14.9.7.6)
, 3.47 (IH, dd, J-15, 4, 10, 5)
, 4.81 (IH, dd, J-18, 1, 1, 6)
, 4.99 (IH, dd, J-18, 1, 1, 6)
, 5.88 (IH, t, J-1, 6).

0 (α), -+189.2° (C-(154°CHCQ
a,).

Example 29 (In)612io obtained in Example 12 was dissolved in dimethylformamide:anisole (1:3) 5- and 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 purified by column chromatography using silica gel 16Q1 eluent chloroform-methanol (10%) to obtain A-homo-3-aza-3a-oxo-3-propyl-5β,14β-caldo. 20 (22)
- 485 mQ of colorless needles of the enolide are obtained.

Melting point: 259-260°C (recrystallized from ethyl acetate-diethyl ether, colorless needles).

Mass (m/e): 429 (M÷), 414,396.386゜IR (KB
r, c--'): 3400.2950, 1780.1740° 1630° NMR (CDC12a-δ): 0.88 (3H, s), 0.89 (3H, t, J-7, 6), 0 .97 (3
H,s), 2,, 79 (I H,m), 3.01 (2H,m),.

3.22 (IH, dt, J-14, 9, 7, 6), 3
．． 39 (IH, dt, J-14, 9, 7, 6), 3
．． 47 (IH, dd, J-15, 4, 10, 5), 4
．． 81 (IH, dd, J-18, 1, 1, 6), 4
．． 99 (IH, dd, J-i8.1, 1.6), 5
．． 88 (IH, t, J-1, 6).

(α)”-+189.2° (C-0,54°CHCQs
).

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 Mongrel adults weighing 8 to 12 kO are anesthetized by intravenously administering bendoparbital sodium salt at a dose of 30 g/kg. 1000U/ko of heparin sodium salt
After intravenous administration at a volume of 100 ml, the animals were bled to death and the heart was removed.

The specimen mainly consists of papillary muscles and the ventricular septum, and is perfused with blood drawn from the blood donor hole through a cannula inserted into the anterior septal artery at a constant pressure of 100118 (+).The blood donor hole has a body weight of 1
The animals weighing 4 to 30 kg were anesthetized in advance by intravenously administering 30 g/ko of bendoparbital sodium salt, and 1000 LI/ko of heparin sodium salt was administered intravenously. Using bipolar electrodes, a voltage of 1.5 times the threshold (0,5
~3V), stimulate the papillary muscles with a square wave with a stimulation width of 5 m5ec and a stimulation frequency of 120 times per minute. The resting tension of the papillary muscles is 1.50, and the generated tension of the papillary muscles is measured via a force displacement exchanger. The blood flow in the anterior septal artery is measured using an electromagnetic flowmeter. Records of developed tension and blood flow were recorded on an ink recorder. The details of this method have been previously reported by Endo and Hashimoto (Agi, J., Phos.
iol, Volume 218, Pages 1459-1463, 197
Year 0, Naunyn -3chg+iedeberg's
Achieves ofPharmacology
, Vol. 278, pp. 135-150, 1973: Atrial muscle specimen). The test compound was intraarterially administered in a volume of 10 to 30 μQ for 4 seconds.

The inotropic effect of the test compound is based on the tension generated before drug administration.
Expressed as % change.

The test compounds used are as follows.

1, A-homo-3-oxo-3a-aza-3a-(2,
4-dimethoxybenzyl)-5β.

14β-caldo 20(22)-enolide (Example 2
2).

2, A-homo-3-oxo-3a-aza-3a-n-propyl-5β,14β-caldo 20(22)-enolide (compound of Example 24).

3, A-homo-3-aza-3a-oxo-3-isopropyl-5β,14β-caltod-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-ox/-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-calthod-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 1 Formulation Example 1 Compound of Example 15 0.025+ea Starch 13
2a+g Magnesium Stearate 18m.

Milk sugar 50■Q Total about 200+.

Tablets of the above composition were manufactured in a conventional manner.

Formulation example 2 Compound of Example 20 0.25+g Starch 130+a Magnesium stearate 201g Milk sugar 50mg Total approximately 200,112 Tablets of the above composition were manufactured in a conventional manner.

Formulation Example 3 Compound of Example 23 12.510 Polyethylene glycol (molecular weight: 4000) 0.3a Sodium chloride 0.9° Polyoxyethylene sorbitan monooleate 0.4Q Sodium metabisulfite 0. IQ Methyl-paraben 0.18g Propyl-paraben 0.02a Distilled water for injection ioom The above parabens, sodium metabisulfite and sodium chloride are dissolved in distilled water at 80°C with stirring. The obtained solution was cooled to 40°C, and the compound of the present invention,
Polyethylene glycol and polyoxyethylene sorbitan monooleate are sequentially dissolved, the solution is then adjusted to the final volume by adding distilled water for injection, and sterilized by sterile filtration using a suitable filter paper to obtain 11I2. Dispense each into ampoules and make 11 injections.

(That's all) Continued from page 1 ■Int, CI,' Identification code Internal office reference number 313:
00) 6tj4U-4(.

Claims (1)

[Claims] ■ In the general formula C, R1 is a -NHR3 group (R3 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 a lower Indicates an alkoxycarbonyl group. R2 is -NHR' group (R
A is a phenyl lower alkyl group which may have 1 to 3 groups selected from a hydroxyl group and a lower alkoxy group as a substituent group on the phenyl ring, or a lower phenyl group having a 5- or 6-membered unsaturated heterocyclic residue; Indicates an alkyl group, a cycloalkyl group, or a lower alkyl group. ) or lower alkoxycarbonyl group. However, when R1 represents -NHR3 group, R
2 represents a lower alkoxycarbonyl group, and R
When 1 represents a lower alkoxycarbonyl group, R2
represents a -NHR' group. Also, R1 and R2
may be bonded to each other to represent a -NR3-C-I group or a -0-NR'- group (R3 and RA are the same as in 1 above). ] A cardenolide derivative represented by .