JPH03294259A - New compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [C is OH or OSO3H; one of Y and Z is OSO3H and the other is H; R1 is H or lower alkyl; when Y is H, one of R2 and R3 is H and the other is lower alkyl or group shown by formula II (R5 and R6 are lower alkyl); when Z is H, R2 is H; both R2 and R3 show lower alkyl or one of R2 and R3 is H and the other is lower alkyl or group shown by formula II]. EXAMPLE:6-Methyl-1,4-heptanediol-4-sulfate. USE:Showing enhancing effects on actions of beta-adrenergic drug and useful as a cardiac. Having bronchodilatory action and useful as a drug for asthma. Usable as a substitute for musk which is difficult to obtain. PREPARATION:For example, 2,3-dihydrofuran is hydrolyzed, reacted with Grignard reagent, tritylated, sulfonylated and detritylated to give an example compound among compounds shown by formula I.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to novel compounds, and more particularly to novel compounds.

The present invention relates to a novel compound that has the effect of enhancing the action of β-adrenergic drugs.

(Prior Art) In Japan, licorice is used in Chinese medicine as one of the raw materials for cardiotonic drugs such as Kiōgan, Seikōgan, and Rokujingan, and its effects have been studied. The mechanism of action of Ilka's cardiotonic effect is β
- It was known to potentiate the action of adrenergic drugs. However, no other substance is known to have such an effect.

Furthermore, the component that enhances the action of β-adrenergic drugs in aroma has not been isolated or identified.

In recent years, the population of brown deer in the People's Republic of China has decreased;
In order to prevent extinction, the import of mandarin incense is prohibited by the Washington Convention, so it is virtually not imported at this time, and l.
As it became difficult to obtain 1 liter of citrus, there was a need for a substance that had a similar function to that of depressant.

(Problems to be Solved by the Invention) As a result of intensive research based on the prior art, the present inventors have found that
We isolated and identified a new compound that enhances the action of β-adrenergic drugs in depression, and also found that a new compound with a similar structure has a similar effect. It was discovered that a new compound that enhances the action of sex drugs also enhances the activity of protein kinase C, leading to the completion of the present invention.

(Means for Solving the Problems) According to the present invention, there is thus provided a novel compound that enhances the action of β-adrenergic drugs.

The compounds of the present invention are.

Formula 1: Y [X is OH: HAOS O3H, Y, Z, one is 0503H1, the other is a hydrogen atom, R1 represents a hydrogen atom or a lower alkyl group. When Y is a hydrogen atom, one of R2 and R3 represents a hydrogen atom, and the other represents a lower alkyl group or -CHR5 (R5 and R66 represent a lower alkyl group). When Z is a hydrogen atom, R2 is a hydrogen atom , R2 and R3 both represent a lower alkyl group, or one represents a hydrogen atom and the other represents a lower alkyl group or -CHRs (R5 and R6 represent a 6 lower alkyl group), Preferably, a compound in which Y is OS O3H in the formula (1), more preferably a compound in the general formula (%).

CH3CN(CH3)CH(O503H) (CH2)
6-methyl-2, with m structure of 2CH(OH)Clh
5-hebutadiol-5-sallefuate (hereinafter referred to as musclide AI).

CIhCHCCH3)CH2CHCO5(hH) (C
H2) 7-methyl-2,5-octadiol-5 sulfate (hereinafter referred to as musclide B) having the structure 2cH(OH)CH3.

CH3CN(CHz)CH2CHCO5O3H) (C
H2) 6- having the structure of 41II structure of yOH
Methyl-1,4-heptanediol-4-sulfate (hereinafter referred to as musclide A2), CHiCH(CH3)CH(O5(hH)(CH2)2
6-methyl-2 with the structure cH(O5(hH)CL
, 5-hebutadiol-2゜5-disulfate (hereinafter referred to as 1 synthetic product 1), CHiCH(CH3)CH(O5
(hH) 6-methyl- with the structure (CH2)40H
1.5 Hebutadiol-5-sulfate (hereinafter referred to as 5
(referred to as synthetic product 2).

These exemplified substances can be chemically synthesized. The method for chemically synthesizing the compound of the present invention is not particularly limited.

For example, musclide A2 can be obtained by hydrolysis and Grignard reaction of -2,3-dihydrofuran, followed by tritylation, sulfonylation, and detritylation.

In addition, musklide A1. Muskride A2, musklide B, etc. can be extracted from natural products, such as mustard. The WH method for extracting the compound of the present invention from natural products is not particularly limited. For example, extraction with water or organic solvents, liquid chromatography. It can be extracted and purified by combining thin-layer chromatography.

The so-called Magnus method, which examines the response of β-adrenergic drugs to the mammary M muscle of the heart of cats and guinea pigs, has shown that if the novel compound of the present invention is added to a β-adrenergic drug, such as isoproterenol, the mammary muscle enforcement reaction will be strengthened. This shows that the novel compounds of the present invention enhance their action as cardiotonic agents, similar to depressants.

Further, - in formula I, Y is OS O3H.

Compounds where X is OH also enhance protein kinase C activity. The activity of protein kinase C was determined by the enzyme solution [γ-
By adding 32P)-ATP, it can be measured as the amount of P uptake per unit protein/minute.

(Effects of the Present Invention) Thus, according to the present invention, a novel compound represented by formula I above, which enhances the action of a β-adrenergic drug, is provided.

The novel compound of the present invention can also be synthesized and used as a material for cardiotonic drugs, and as a substitute for licorice, which has become difficult to obtain. Although other substances have been proposed as substitutes for mandarin incense, the novel compound of the present invention is the active ingredient in mandarin incense itself, or a similar substance thereof, and is particularly preferable as a substitute. Since its action enhances the action of β-adrenergic drugs, it is expected to have a bronchodilating action, and is expected to be used as an asthma drug.

Furthermore, among the novel compounds of the present invention, in general formula I, X
Since a compound in which is OH and Y is OS O3H also enhances the activity of protein kinase C, it can be expected that various physiological activities involving protein kinase C can be regulated.

(Example) The present invention will be described in more detail with reference to Examples below.

Example 1 Extraction, isolation, and identification of active ingredients from mandarin orange 31.4 g of mandarin incense was mixed with diethyl ether 47 (la
After extracting three times with 9, the residue was extracted four times with 300 ml of ethanol, the ethanol extract was evaporated under reduced pressure, and further,
Extracted 3 times with 120% pure water, removing the insoluble part of 0.12%,
The extract was dried under reduced pressure to obtain 2.9 g of extract. Next, 1.96 g of this extract was dissolved in a small amount of methanol,
Iatro beads (manufactured by Yatron) 200g column (3
, 5X 40c■) and sequentially elute with chloroform, methanol-chloroform (1:4), and methanol-chloroform (i:t) each at 200-mL, and the methanol-chloroform (1:1) eluate was eluted under reduced pressure. The solvent was distilled off to obtain 829 Otori. Of that, 397 g of intestine was melted into 20x2
0cm, 0.25mm) using eight sheets, developing solvent (ethyl acid: acetone: methanol: pure water = 10:10:1
:1), and the portion with Rf of 0.45 to 0.8 was extracted with methanol-chloroform (3N).

An extracted fraction of 320 m was obtained. 3 to 100 cm of this active fraction
Dissolve IIIg in methanol, using methanol as the solvent.

Flow rate 5-/ using G5-310 column (Asahi Kasei ml)
■in, subjected to recycling HPLC with detector RI. Two large peaks were observed in the first shield, the inner edge peak was removed, and 5 d fractions were collected from the start of the sixth shield peak, and the solvent of the second fraction was distilled off under reduced pressure.
85 mg of musklide was obtained. In addition, 14.6 mg of other fractions were combined and the solvent was distilled off under reduced pressure, and 14.6 mg was dissolved in methanol-water (1:4).
4) as a solvent and ODS 120T column (21,5 m
flow rate 3+a12/win, using
The peak and retention were subjected to HPLC using the detector RI, and the retention time was approximately 27 minutes.

The peak at a time of about 32 minutes was collected, the solvent was distilled off under reduced pressure, and the peak was extracted with musklide Al (retention time at about 27 minutes).
At 4.3 seconds, musklide A2 (retention time approximately 32 minutes) was obtained.

Muskride A1. The analysis results of A2 and B are shown below.

Muskrite A1: Composition formula Cs H+ g Os 5n
e(active ion FAB-MS m/z
: 225 (A-H)-:positive
ion FAB-MS m/z: 271 (
M+2Na-H)";'H-NMR(in CD3
0D) δ: 0.94 (3H, d.

J=7.0Hz, 1sopropyl), 0.95
(3H, d, J=7.0)lz.

1sopropylL 1.16 (3H+ d, J
=6.1Hz, ::CHCl1t)y2.06 (
IH, Otori, -CH (CH3h), 3.72
(1B, intestine.

-C1l-OH), 4.18 (1)1. -C
t[-0S(hH); "R to C-N (in CD3
0D) δ: 18.84 (q, 7-Cor 8-C
).

19.12 (q, ?-Cor &-C), 2
4.28 (qt 1-C).

28.84 (t, 4-C), 32.95
(d, 8-C), 38.78 (t.

3-C), 69.69 (d, 2-C),
86.34 (d, 5-C).

Muskride A2; Composition formula C# H+ e Os Sn
aggressive ton PAB-MS m/z: 2
25 (NH)-;'H-NNR(in CD30D
) δ: 0.92 (38, d.

J=6.7Hz, fsopropylL 0.94
(3Ht dy J”6.7)!zyisopropy
1L 3-58 (2H, Otori, -0M2-OR
), 4.44(IH,ys, -C1-O5(hH
) ; 13C-NMR (in CD30D) δ: 2
3.92 (q, ?-Cor 8-C), 24.1
13 (q, 7-Cor 8-C), 26-3
3 (d, 6-C), 29.73 (t,
3-C).

32.91 (t, 2-C), 45.76 (t,
5-c), 83.87 (t.

1-C), 79.92 (d, 4-C).

Muskride B: Composition formula C9H2g Os Snega
tive ion FAB-MS s/z: 239
(M-H)-;'H-NMR (in CD30D) δ:
0.92 (38, d.

J=8.5Hz, fsopropyl), 0.94
(3)1. d, J=6.5Hz.

1sopropylL 1.15 (3Ht dv J
4.3Hzt-CH-C7lz), 1.82 (1)
! , nonet, J=6.5Hz.

-C1i-(CH3)2), 3.74 (LH,5e
xtet, J=6.2Hzt-CI-0)1), 4
．． 45 (18, *, -Ctl-OSO3H);
13C-NMR (in C(hOD) δ: 2
3.92 (q, 8-Cor 9-C).

24, IB (q, 8-Cor 9-C), 24-
30 (q, I-C).

26.30 (d, 7-C), 32.57 (t,
4-C), 35.71 (t.

3-C), 45.83 (t, e-C), 69.26
(d, 2-C).

79.93 (d, 5-C).

From these results, musclide A1 is 6-methyl-2,5-hebutadiol-5-sulfate, musclide A2 is 6-methyl-1,4-hebutanediol-4-sulfate, and musclide B is 7-methyl-2. , 5-octadiol-5-sulfate.

Example 2 Synthesis of active ingredients (1) Synthesis of musklide A1 LiAl2Ha14 was added to anhydrous THF150-, stirred under water cooling, and (CH3bCCH(CtbhCOCL I
Og was added dropwise.

After the dropwise addition, the mixture was heated under reflux for 3 hours, and one reaction solution was gradually added to ice water to complete the reaction. Suction was carried out using Celite-545, and the filtrate was concentrated under reduced pressure and extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Remove the residue with silica gel 2
Subjected to 50 g column chromatography, eluted with chloroform, purified to obtain an oily substance (C) 13) 2 cc) l
38 g of (CH2)2cH(OH)CI was obtained.

After thoroughly washing NaH (80% oil 1, 8 g) with anhydrous ether, dimethylformamide 5 was added under water cooling.
〇-(CH3)2CCH(CH2)2CH(OH)C
H38K was dissolved and added, and while stirring, benzyl bromide (3.55 ndl) was added dropwise, and the mixture was stirred overnight at room temperature. Ice water was added to the reaction solution, and the mixture was extracted with ether. The extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on 120 g of silica gel and eluted with methane dichloride to give an oily substance (CHx)2CC)1(CH2)2CH(OCH2Cs
Hs) CFI: +4.1 g was obtained.

This substance was dissolved in anhydrous THF 17a9 and stirred under water cooling.
After the solution was added dropwise to the solution, the mixture was returned to room temperature and stirred overnight at room temperature.

After adding ice water to the reaction solution and decomposing excess reagent, 3NN
aOH21,5aQ, then '35% H2O218,l
- was added and stirred for 2 hours under ice cooling. After neutralizing the reaction solution with 5% HclI under water cooling, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with saturated saline,
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by applying it to a column chromatograph using 150 g of silica gel and eluting with methane dichloride.

CH3CN(CH3)CH(OH)(CH2)2cH(
Obtained 3.4 g of OCH2C6H5)CH3.

Dissolve this substance 1, tax in THF 25-,
Pyridine sulfur trioxide complex 1. ．． 02g was added thereto, and the mixture was stirred overnight at room temperature. After passing the reaction solution, the solvent was distilled off under reduced pressure, the residue was dissolved in 25 mg of methanol, a catalytic amount of 10% Pd/C was added, hydrogen was passed through the solution, the mixture was stirred at room temperature for 4 hours, the catalyst was removed, and the solution was dissolved under reduced pressure. The solvent was distilled off.

The residue was subjected to column chromatography using 40 g of silica gel and eluted with methanol-chloroform (1:19).
It was purified to obtain 0.92 g of musklide A1, 'H-
The structure was confirmed by NMR.

(2) Synthesis of musklide A2 While stirring 0 and IM salt 1125- under water cooling, 2,
3-Dihydrofuran 5- was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with methane dichloride, washed with saturated sodium hydrogen carbonate, and dried over magnesium sulfate.
The solvent was evaporated under pressure. 3.4 g of magnesium are suspended in dry ether 20- and isobutyl bromide 11.
Grignard reagent III was added by dropping 8 g. The residue was dissolved in 40++ dl of anhydrous ether, Grignard reagent was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture to decompose excess Grignard SC*. After drying with magnesium, the solvent was distilled off under reduced pressure. Remaining, 74,7.
was subjected to column chromatography on 100 sections of silica gel, eluted with ethyl acetate-hexane (3N), purified, CH2Cl(CH3)CH2Cl(OH) (CTo
→30) Obtained 12.7K.

Dissolve 2.6 g of this substance in 18-dimethylformamide and prepare 1091 g of 4-N,N-dimethylaminopyridine.
.

4.4 g of triethylamine was added, and further 5.4 g of trityl chloride was added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with 5% Hα under ice cooling, extracted with ether, and the extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Section 4.6 of the residue was subjected to column chromatography on silica gel lOO, eluted with methane dichloride,
Purify and substance.

CH2Cl(CH3) CH2Cl(OH) (CL2)
34.8 g of 30c (Cabs) was obtained.

72 cm of this substance was dissolved in 2 d of anhydrous THF, 83 cm of pyridine sulfur trioxide was added, and the reaction solution was stirred overnight at room temperature. After passing the reaction solution, the solvent was distilled off under reduced pressure.
Dissolve the residue in 5+1 g of methanol and add 10% P of the catalytic amount.
d/C was added. After stirring at room temperature for 1 hour through hydrogen,
The catalyst was separated, the solvent was distilled off under reduced pressure, and the Jl residue was mixed with a developing solvent (ethyl acid: acetone: methanol: pure water: =
10:10:1:1) and expand with l? f is 0.45
~0.6 fraction was extracted, purified, and musclide A2
L5 was obtained and its structure was confirmed by 'H-NMR.

Moreover, the melting point of this substance was 133-136°C.

(3) Synthesis of musklide B (CL)2CCH(CHp)2cH (OCLCsHs) synthesized in the same manner as in (1)
2.3 g of CL and 1.7 g of trimethylamine-N-oxide dihydrate were dissolved in 250 g of acetone and 25 d of pure water, and cooled to 10° C. under light shielding. 0sO of IN
After adding a t-butanol solution 5-, the mixture was stirred at room temperature overnight. 6. Add 20% sodium bisulfite solution to the reaction solution.
After stirring at room temperature for 30 minutes, the solvent was distilled off under reduced pressure, extracted with chloroform, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. 3 g of the residue was subjected to column chromatography using 100 g of silica gel, eluted with methanol chloroform (1:19), and purified.
LC(CH3)(OH) CH(OH)(CH2)2
C)I (OCH2C6H5)CH31,8δ was obtained.

After dissolving 1.37 g of this material in dioxane 76-
Add a solution of 71.56 g of HIO dissolved in 7- of pure water,
Stirred at room temperature for 4 hours. The reaction solution was extracted with ether, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was developed with chloroform using a Merck Kieselgel GF2SJ plate, and the portion with Rf of about 0.8 was extracted and purified.

CHO(CH2)2CH(OCH2C6H5)CH37
10 mg was obtained.

Magnesium 148B was suspended in dry ether 10-, and 6211 g of isobutyl bromide dissolved in dry ether IO was added dropwise, stirred at room temperature for 2 hours, and heated under reflux for 30 minutes to prepare a Grignard reagent. After cooling this reagent with water, a solution of 4-benzyloxypentanal 694 dissolved in 10 liters of dry ether was added dropwise, and the mixture was stirred at room temperature for 1 hour. Add ice water to the reaction solution, decompose excess reagent, and extract with ether.
After drying with magnesium sulfate, the solvent was distilled off under reduced pressure. 20. Pour the residue into silica gel. The product was purified by column chromatography and eluted with methane dichloride.

CHyCll(CH3)CH2C)l(OR)(CH2
)2cH(OCLCsHs)CHt 617g was obtained.

CH:1CH(CH3>CfhCH(OK>((:F1
2) 2CH(OCH2CeH5)CLδOmg anhydrous T
70 mg of pyridine-sulfatrioxide complex was added to the solution in HF2-, and the reaction solution was stirred at room temperature overnight. After filtration, the solvent was distilled off under reduced pressure, and the residue was dissolved in methanol 2III.
A catalytic amount of 10% Pd/C was added. After stirring under hydrogen for 4 hours at room temperature, the catalyst was removed, the solvent was distilled off under reduced pressure, and the residue was purified by Merck Kieselgel GF25.
Using a J plate, develop solvent (ethyl acetate: acetone:
It was developed with methanol:pure water = 10:10:1:1), extracted from the part with Rf of about 0.5, purified to obtain musklide B4O-, and its structure was confirmed by 'H-NMR. .

(4) Synthesis of synthetic product 1 CHaC(CH3)CH(CL)2cOcH36.3g
was dissolved in 48 all of anhydrous THF, and added dropwise to a 1,0 aborane THF clamp 121 which was being stirred under water cooling.

After dropping, stir overnight at room temperature, add ice water to decompose excess reagent, and add 60 dl of 3N NaOH, 35% 820250-
was added, stirred for 2 hours under ice-cooling, and added with 5% Hcl under water-cooling.
The solvent was distilled off under reduced pressure. The residue was extracted with chloroform, the extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was purified by column chromatography on 120 g of silica gel, eluting with methanol-dichlormethane (1:4), and purified with CH2Cl(CH3)CH(OH)(CH
2) Obtained 6.3 g of 2CH(OH)C)13CH3CH
(CH3)CH(OH)(CH2)2cH(0)1)C
Dissolved in H31,,44geTHF50-, pyridine.
95 g of sulfur trioxide complex 'L was added and stirred overnight at room temperature.

After passing the reaction solution, the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography using Iatro beads (100 g), and methanol-chloroform (2:3) 150
- After elution with methanol-chloroform (1:1)
It eluted at 150-. Methanol-chloroform (1
:l) The eluted fraction was solvent distilled off under reduced pressure.

5.68 g of crudely purified product was obtained. Using a Merck Kieselgel GF25J plate, the following 700 m of the crude W product was coated with developing solvent (chloroform: methanol: pure water = 6 = 4
= 1), and the portion with Rf of approximately 0.2 was extracted and purified to obtain 220 g of an amorphous substance. This substance was analyzed by 'H-NMR (CDaOD), I3C-NMR (
CD30D) and synthesized product 1. That is, 6-methyl-2,5-hebutadiol-2,5-disulfate, CHaCH(CH3)CH(O503H) (CH2)
It was confirmed that it was 2CH(OSO3H)CH3. The analysis results are shown below.

negative ion FAB-MS m/z:
305 (1'l-old-;'H-NMR(i,n C
D30D) δ: 0.94 (3N, d
.

J=5.7Hz, CH3), 0.95 (38,d,
J: 5.8Hz, C)13).

1.33 (3H, d, J=6.1Hz, CHz),
2.11 (IH, m.

-C(CH3)2), 4.21 (1M, rx,
-CH-05O3H), 4.52 (IH, m, -1
4-OSO3H): 13C-NMR (in CD
30D) δ: 18.67 (q, 7-Cor
8-C), 19.08 and 19.00
(Q.

7-Cor 8-C), 21.75 and 2
1.86 (q, 1-C).

27.78 and 27.42 (t, 4-C
), 32.63 and 32.71 (d, 6-C
), 33.94 and 34.24 (t, 3
-C), 77.96 and 78.35 (d, 2
-C), 85.88 and 86.29 (d
.

5-C).

(5) Synthesis of Synthesis Product 2 30g of δ-valerolactone was dissolved in 600ml of anhydrous methanol, 1O2 concentrated sulfuric acid was added, the mixture was heated under reflux for 7 hours, and after cooling with water, KHC (h was added to 3 and stirred for 10 minutes). , and the solvent was distilled off under reduced pressure.The residue was extracted with chloroform, and the extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude ester 29.3. NaH
(80% oil, 2.42 g) was thoroughly washed with anhydrous ether, and then a solution of 14.5 g of the crude ester dissolved in dimethylformamide +00 was added under water cooling, and the solution was dissolved in chloromethyl methyl ether 1015 with stirring. was added dropwise, and the mixture was stirred at room temperature overnight. Ice water was added to the reaction solution, and the mixture was extracted with ether.

The extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. 50% silica gel of the residue
0g column chromatography, eluting with methane dichloride to prepare IW, CH30CH20(CH2)4cOOcHt 12.
3g was obtained.

LiAQHj to anhydrous THF 120++tQ under water cooling
Add 6g and stir, CIh0CH20(CH2)-C
12 g of OOC)It was dissolved in 50% of anhydrous THF and added dropwise. After the dropwise addition was completed, the mixture was heated under reflux for 5 hours, ice water was added to decompose the excess reagent, and the mixture was extracted with ethyl acetate. After drying the extract over magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and methanol-
Elute with chloroform (3:97) and obtain oily CH30C.
H20(CH2)sOH6-31 was obtained.

After thoroughly washing NaH (80% o it 2 g) with anhydrous ether, CH30CH20 (CH
2) A solution of 6.3 g of sOH dissolved in 50 mm of dimethylformamide was added, and while stirring, benzyl bromide was added dropwise, and the mixture was stirred overnight at room temperature. Add ice water to the reaction solution,
Extracted with ether. The extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was purified by column chromatography on 200 g of silica gel and eluted with methane dichloride, resulting in an oily substance C).
1i0CH20(CH2)sOcHpcaHs7.7g
I got it.

Add this substance to 30 aQ of methanol - 1-1 of pure water and 0.0 aq of concentrated hydrochloric acid.
4all was added and heated under reflux for 8 hours. After the reaction solution was neutralized with Na2COx under water cooling, the solvent was distilled off under reduced pressure.

The residue was extracted with chloroform, the extract was washed with saturated brine, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on 200 g of silica gel and eluted with chloroform to obtain an oily substance HO(CH2)SOCH2C8H54,79K.

2.4 g of HO(CH2)sOCH2Cs)Is was dissolved in methane dichloride, and pyridium chlorochromate was added.
The reaction mixture was stirred at room temperature for 1.5 hours, and after passing through the reaction mixture, the solvent was distilled off under -1 di pressure. The residue was purified by column chromatography using 40 g of silica gel and eluted with methane dichloride to obtain 3 g of CHO(CH2)aOcH2ceHsl.

Dissolve 500 μm of magnesium in 5-5% of anhydrous ether,
A reagent prepared by dropping 2 g of isopropyl bromide was slowly added dropwise to a solution in which 1 g of CHO(CH2)aOcH2ceHs was dissolved in 1.3 mm of anhydrous ether under water cooling.

After the dropwise addition, the mixture was stirred for 12 hours under water cooling and for 1 hour at room temperature. After adding ice to decompose the excess reagent, the mixture was extracted with ether. The extract was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. 1.1 g of the residue was subjected to column chromatography using 40 g of silica gel, eluted with methane dichloride, and purified.
CH2Cl(CH3)CI(OH)(CH2)aOcL
c; Hs572 was obtained.

CH2Cl(CH3)CH(0 old(CH2)aOcH2
ca) 15,168 mg was dissolved in anhydrous THF, 148 mg of pyridine sulfur trioxide complex was added, and the mixture was dissolved overnight at room temperature.

The reaction solution was passed through, and the solvent of the passed solution was distilled off under reduced pressure.

The residue was dissolved in methanol 6- and a catalytic amount of 10% Pd/
After adding C, hydrogen was bubbled through the mixture and the mixture was stirred at room temperature for 3 hours.

The catalyst was separated and the solvent was distilled off under reduced pressure. Merck removes the residue.
Using Kiesel Gel/GF2sj plate, developing solvent (
#Ethyl acid: acetone: methanol: pure water = 10:1
0:1:1), and the portion with Rf of about 0.5 was extracted and purified to obtain 20IIg of an amorphous substance. This substance was analyzed by H-NMR (CD30D) and was found to be synthetic product 2, namely 6-methyl-1,5-heptadiol-5-sulfate, CH3CH(CH3)C)I (OSO3H) (CH
2) It was confirmed that it was tOH. The analysis results are shown below.

'H-NNR (iri CD30D) δ: 0.93
(3H, d.

J Near, 0)1z, Cl-C11t), 0.95
(3H, d, J=6.7)1z.

CH-Cjlt), 2.07 (IH,m, CH-
CH3), 3.55 (28°t, J=6.4Hz,
CH2-0H), 4.18 (LH, q, J=6
．． 1Hz.

CH-OSO3H).

Example 3 Measurement of papillary muscle retraction by the Magnus method Hartley guinea pig (male, 210-520 years old, 4-8 weeks old)
1) The heart was removed and rebs-Henseleit 5olu saturated with 95% 02.5% CO2 mixed gas.
tion (1, 18, 4mM Na (JL 4.
69mM K (JL 2.0!IM Cann
2.1.16+wM MgCJL2, 1.1811
1'l KH2PO4-24,911N Na)l
cOr.

5.0 mM glucose). Papillary muscles with a diameter of 0.5 to LOm and a length of 3 to 4 mm were cut out from the right and left ventricles, kept warm at 30±1° C., and a 95% 02.5% CO 2 mixed gas was aerated. Krebs-)1enseleij
It was suspended in a 2.5 d capacity Magnus tank filled with 5 oluj:ion. An initial tension of 0.5 g was applied.

Electrical stimulation was applied to the papillary muscles using a bipolar platinum electrode at IOV, 0.8 milliseconds, and a cycle of 0.1 Hz. Isomet;rie transduc of papillary muscle contraction tension
er (ShinkohTsushin, υ-Ga
ge, Type I le 2-240),
It was allowed to stabilize for 30 minutes to 1 hour.

Musclide A1 was added to the Krebs-Henseleit 5 solution in a Magnus tank at a concentration of 30 μg/barrel.
No positive inotropic effect was observed. Ten minutes later, di-isoproterenol hydrochloride (manufactured by Kaken Pharmaceutical Co., Ltd.) was administered, and from 2.02n to 258r+?
The positive inotropic effect was measured and compared to administration of -dl-isoproterenol hydrochloride alone without addition of the sample.

Control the average contraction tension in the absence of drug (0
%), and the maximum value of the contraction tension when each concentration of isoproterenol hydrochloride is added is set as 100%, and the maximum value of the contraction tension when adding each concentration of isoproterenol hydrochloride is positive. It was expressed as the % response of inotropic action. The increase in positive inotropic response % (Δresponse %) relative to the control at each concentration is shown in FIG. From this result, it was confirmed that musclide A1 enhances the action of isoproterenol hydrochloride.

The same procedure was performed except that each sample was used in place of musclide A1, and the maximum value of contractile tension when 258 nM isoproterenol hydrochloride was added was measured as the % positive inotropic response. The results are shown in Table 1.

These results showed that the compound of the present invention enhances the inotropic effect of β-adrenergic agonists.

Example 4 Activation of Protein Kinase C Method of Nishizuka et al. (Journal of Biochemical J, Bi
ochem, 89.1851-1654 (1981
)), the influence of the sample on the action of protein kinase C was investigated.

After killing a guinea pig (male, 330-470 mm), the heart was taken out and treated with Tris-HCl buffer (201A Tris-HCl, 0.25M sucrose, 21A EDTA,
Dissect the ventricular myocardium in 10 wet M EGTA, pH 7,5) and homogenize on ice using a Teflon glass homogenizer for 2 min in 10 times the wet weight of Tris-HCl buffer at +100,100 x 60 The mixture was centrifuged for a minute, and the supernatant was collected as an enzyme solution.

5μ layer 01 tris-hydrochloric acid (PH7,5), 1.25μ■
01 IP acid magnesium, 81 histone 50 μg,
2.5 nmol [γ-32P)-ATP
(approximately 250,000epm/tube), 20μ of phosphatidylserine & 104μ of enzyme solution. Ca at various concentrations
A 0.25+d reaction solution containing the sample and sample was incubated at 30°C for 3 minutes, and the reaction solution was dropped onto the paper to stop the reaction. The remaining 32 pji was measured with a scintillation counter, the protein amount of the enzyme solution was determined by the Lowry method, and the amount of P taken up per minute was expressed per gram of protein.

Musklide A1 was used as a sample at O, Z, 4.8tjI
Figure 112 shows the amount of P uptake in the reaction solution containing 0.0.5. It was shown to be activated.

Similarly, using four other samples, the amount of P uptake in the reaction solution containing 2° of Ca was measured. The results are shown in Table 1 as protein kinase C activation %, with the amount of P uptake taken as 100% when the same measurement was performed except that no sample was included as a control.

From this result, it was found that among the novel compounds of the present invention, the compound represented by the following formula activates the action of protein kinase C.

No. table

[Brief explanation of drawings]

Figure 11!1 shows the degree of positive inotropic effect of musklide Al, and Figure 2 also shows the degree of activation of protein kinase C by musklide A1.

Claims (1)

[Claims] 1. General formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [X is OH or OSO_3H, one of Y and Z is OSO_3H, the other is a hydrogen atom, R'_1 is Represents a hydrogen atom or a lower alkyl group. When Y is a hydrogen atom, one of R_2 and R_3 represents a hydrogen atom, and the other represents a lower alkyl group or ▲There are numerical formulas, chemical formulas, tables, etc.▼ (R_5 and R_6 represent lower alkyl groups). If Z is a hydrogen atom,
R_2 represents a hydrogen atom, R_2 and R_3 both represent a lower alkyl group, or one represents a hydrogen atom and the other represents a lower alkyl group, or ▲There are mathematical formulas, chemical formulas, tables, etc.▼(R_5,
R_6 represents a lower alkyl group]. 2. The compound according to claim 1, wherein Y in general formula I is OSO_3H. 3. The compound according to claim 2, wherein in the general formula I, X is OH. 4, CH_3CH(CH_3)CH(OSO_3H)(
A compound having the structure CH_2)_2CH(OH)CH_3, CH_3CH(CH_3)CH_2CH(OSO_3H
)(CH_2)_2CH(OH)CH_3, and CH_3CH(CH_3)CH_2CH(OSO_3H
)(CH_2)_3OH compound according to claim 3.