JPH02145574A - Medicine for reduction of blood viscosity containing diterpene alkaloids as active component - Google Patents

Abstract

NEW MATERIAL:Diterpene alkaloid represented by formula I (Bz is -COC6H6; R is methyl or ethyl). USE:A medicine for reduction of blood viscosity effective for remedy of thrombosis, encephalopathy and heart failure. A medicine for reduction of blood viscosity containing one or more compounds selected from a group of compounds composed of a novel diterpene alkaloid of formula I, benzoylmesaconine of formula II where R1 and R2 are respectively CH3 and OH, benzoylaconine of formula II where R1 and R2 are respectively CH2CH3 and OH, benzoylhypaconine of formula II where R1 and R3 are respectively CH3 and H and ignavine of formula III as the active components. PREPARATION:For example, a treated aconite root is extracted with a mixture solvent composed of water, ethanol, etc., and distributed using aqueous ammonia- chloroform to obtain the chloroform layer. To the resultant chloroform layer n-hexane is added and the n-hexane-insoluble part is subjected to the column chromatography and after elution the eluting solvent is removed, thus obtaining the objective compound of formula I and the compounds used as the active components.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a blood viscosity-lowering agent for fT as a pharmaceutical product.

[Prior Art and Issues] Brain diseases such as encephalomalacia and cerebral infarction, and heart diseases such as myocardial infarction are the leading causes of death in Japan and most other countries around the world, and their prevention and treatment are essential. This has become a big problem worldwide.

Thrombosis is one of the causes of brain disease and heart disease, but in order to prevent or treat blood coagulation within blood vessels such as thrombosis, it is necessary to improve the fluidity of the blood itself flowing within the blood vessels. In other words, it is important to reduce blood viscosity, and there has been a desire to develop a drug that has such medicinal effects.

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present invention provides a blood viscosity-lowering agent that reduces blood viscosity and is effective in treating thrombosis, brain disease, and heart disease. As a result of extensive research,
We focused on the fact that Shujifushi, which is used in Chinese medicine prescriptions such as Hachimijiogan and Keishika AL-Fukuba, has a blood viscosity-lowering effect.

Shujitsushi is a member of the Ranunculaceae family (Ranunculaceae).
) is a herbal medicine prepared by autoclaving the tuberous roots of plants belonging to the genus Tricapto, and is used for the purposes of pain relief, activation of metabolism, etc.

This Shujibushi contains many diterpene alkaloids, and the Ministry of the Invention and others screened the Shujibushi component for its blood viscosity-lowering effect, and found that it has the following formula I (wherein Bz is - We found that novel diterpene alkaloids, benzoylmethaconine, penzoylaconine, penzoylhibaconine, and ignabine, represented by COCs H5, R represents a methyl group or an edyl group, exhibit a strong blood viscosity-lowering effect. Ta.

That is, the present invention is based on this knowledge, and is based on a novel diterpene alkaloid represented by formula I (hereinafter referred to as compound of formula 1) and a group of compounds consisting of benzoylmethaconine, penzoylaconine, penzoylhypaconine and ignabine (hereinafter referred to as compound of formula 1). This is a blood viscosity-lowering agent containing as an active ingredient at least one compound selected from active ingredient compounds.

The structural formulas of benzoylmethaconine, penzoylaconine, penzoylhypaconine, and ignabine are each represented as follows.

(In the formula, Bz represents -GOCsHs.) Ignabine (In the formula, Bz represents -COCaHal.) The compound of formula (1) and the active ingredient compound can be obtained from Shujibushi, for example, as follows.

An extract of Shujifuji is obtained using at least one mixed solvent selected from water, methanol, ethanol, acetone, ethyl acetate, ether, methylene chloride, benzene, n-hexane, and petroleum ether. After concentrating this extract, it was distributed with 3% ammonia water and chloroform. , the obtained chloroform layer was concentrated, n-hexane was added, and n-hexane was added.
- Separate into hexane soluble part and n-hexane insoluble part. The resulting n-hexane insoluble portion was mixed with water, aqueous ammonia, diethylamine, methanol, ethanol, acetonitrile, tetrahydrofuran, acetone, ethyl acetate, ether,
alumina, silica gel, using at least one solvent selected from chloroform, methylene chloride, benzene, n-hexane, cyclohexane, and petroleum ether as an elution solvent;
By subjecting the product to column chromatography once or several times using reverse phase silica gel, cellulose, etc. as a carrier, confirming the components of the eluted fractions, combining the fractions containing the target compound, and distilling off the solvent. A compound of formula 1 and an active ingredient compound are obtained.

Further, if necessary, purification may be performed by recrystallization using a commonly used appropriate solvent.

Specific examples of the production of active ingredient compounds are listed below.

Concrete example! 10 kg of Shuji Tsushi was extracted with methanol 40σ five times for 24 hours at room temperature, and the methanol extract was concentrated under reduced pressure. 1.1 kg of the obtained methanol extract was dissolved in 2Q of 3% aqueous ammonia, and partitioned and extracted five times with 2 g of chloroform.

The obtained chloroform layer was dehydrated with sodium sulfate, and the solvent was distilled off to obtain 88.8 g of chloroform extract. Dissolve this chloroform extract in a small amount of chloroform,
512 was added dropwise into n-hexane and separated into an n-hexane soluble portion and an n-hexane insoluble portion. The solvent in the n-hexane insoluble portion was distilled off to obtain a residue of 29.79 g. This residue was subjected to alumina column chromatography (Merck Aluminum Oxide 90. Neutral, the same applies hereinafter), and ethyl acetate, ethyl acetate-methanol (10:1, 5:1°1
:l) and methanol were eluted in this order.

Fraction 7.59 eluted with 12 od of ethyl acetate-methanol (l O:l) was subjected to medium pressure silica gel column chromatography (CIG column, 45 mm φ x 400
Among the fractions eluted with benzene ethyl acetate-methanol (2:2:l), thin layer chromatography (developing solvent: cyclohexane: ethyl acetate: diethylamine - 5:5:1) was performed. The fractions containing only components exhibiting an Rf value of 0.24 were combined and dried under reduced pressure to obtain a white powder of 3.09.

The chemical properties of this white powder are known from the literature [Sakai et al., Pharmaceutical Journal;
104, 222 (1984)].

Properties: White powder Specific rotation = [α]o +16.9° (c = l, l3, ClIC13) Mass spectrum (E I - M S ) m/z: 589 (M
”), 558 (IO0%).

540.105 Infrared absorption spectrum νCMCI 3α゛1:370
0~3300.1714 Ultraviolet absorption spectrum λ22? HMl(logε):
227(4,03) Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 3.30(3
H,s), 3.3 1(3H,s).

3.70 (31-1, s).

4.1 5 (I H, d, J = 8 Hz).

4.6 2 (I H, d, J = 6 Hz).

4.9 7 (II-1, d, J = 5 Hz
).

7.27-8.06 (5H, m) Carbon nuclear magnetic resonance spectrum (δ ppm in CDCl5): a 1.2 (t), 35.9 (t), 41.4 (d) 4
2.2(q), 43.4(s), 45.0(d)45.
2(d), 47.8(d), 50.3(s).

50.7(t), 55.9(q), 58.0(q).

59.2(q), 61.2(q), 64.4(d).

70.9(d), 74.7(s), 77.2(t)78
．． 2(s), 79.5(d), 81.6(d).

8t, 7(d), 82.4(d), 9o, 5(d).

128.5(d), 129.9(d).

129.9 (s), 133.0 (cl).

466.3(s) 2.5 5 (3H, s), 3.2 9 (3H, s).

Specific Example 2 In the medium pressure silica gel column chromatography of Specific Example 1, benzene-ethyl acetate-methanol (2:2:
Among the fractions eluted in 1), the Rf value was 0.37 in thin layer chromatography (developing solvent, cyclohexane:ethyl acetate:diethylamine-5:5:l).
Fraction 2.09 containing the component shown was subjected to alumina column chromatography and eluted with chloroform and chloroform-methanol (100:1) in this order.

Chloroporum-methanol (100:l) elution part 650
M9 was further subjected to medium pressure silica gel column chromatography (CI G column, 22ffffiφ x 300mm).
and benzene-ethyl acetate-methanol (l:1:
1) The eluate was dried under reduced pressure to obtain 170 tsg of white powder.

The physicochemical properties of this white powder are described in the literature [A, Katz et al.
11elv, Chim, Acta, Volume 87, 2017
(1984)] was consistent with the physicochemical properties of penzoylaconine.

Properties: Shiramura powder Specific optical rotation: Uα. +7. l.

(c = 0.98, EtO) mass spectrum (EI-MS) m/z: 6
03(M'), 588,572 (100%).

554 468 438.105 Infrared absorption spectrum νcI3 cll-+37
00～3300.1720 Ultraviolet absorption spectrum λu+buy” 71ffi (I
Ogε) = 229 (4,09) Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.11 (3H,t, J = 7 Hz) 3.25
(3H, s), 3.29 (31-1, s).

3.31(31(,s), 3.71(3H,s).

4.08 (IH, dd, J=6.IHz) 4.54 (
IH, m).

5.01 (l H, d, J = 5 Hz).

7.36-8.06 (5H, m) carbon nuclear magnetic resonance spectrum (δ ppm + in CDCl5) 13.3(q), 33.1(t), 36.1(t).

42.0(d), 43.0(s), 46.2(d)47
．． 7(t), 48.6(d), 48.9(t)50.5
(s), 55.8(q), 58.0(q).

59.1 (q), 61.0 (d), 61.7 (
q) 72.0 (d), 74.9 (s), 77.4 (t)
78.7(s), 79.9(d), 81.9(d).

82.5(d), 83.5(d), 90.8(d)12
8.5Cd), 129.9Cd) 129.9(s), 133.1(d) 166.3(s) Specific example 3 Specific example! In the 10th alumina column chromatography, ethyl acetate-methanol (10:1) 300
Fraction 740119 eluted with - was again subjected to alumina column chromatography and eluted with chloroform and chloroform-methanol (50:l) in this order to obtain 360 ml of fraction eluted with chloroporum-methanol (50:l). This chloroporum-methanol eluate was further subjected to alumina column chromatography and eluted with a mixed solvent of ethyl acetate and methanol. The obtained eddy acetate-methanol (50:l) eluate was dried under reduced pressure to obtain 147 m9 of white powder.

This white powder has been found in the literature [Sahara et al., Tohoku J, exp, Med, vol. 128,
175 (1979)] was determined to be penzoylhypaconin.

Properties: White powder Specific optical rotation: [α]o +13.9° (c = 1.04, ELO II) Mass spectrum (E I - M S ) rn/z: 5
73 (M”), 542 (l O0%) 524.105 Infrared absorption spectrum C: Old 13 α3700-3
200 1720 Ultraviolet absorption spectrum λ22υ n, m (logε)
.

228 (4,12) Proton nuclear magnetic resonance spectrum (δ ppm in CDC1a): 2.40(31(,s).

3.29 (6H, s), 3.30 (3H0s).

3.68 (3H, s).

4.05 (IH, d, J=7Hz) 4 54 (IH, d, J=6Hz).

5.02 (IH, d, J = 5Hz).

7.38-8.04 (5H, m) carbon nuclear magnetic resonance spectrum (δ ppm in CDCl5)- 26.0 (t), 34.1 (t), 36.8 (t).

39.2(s), 42.0(d), 42.8(q)46
．． 5(cl), 47.4(d), 47.9(d).

50.4(s), 56.6(q), 56.7(t).

58.0(q), 59.1(q), 61.5(q).

63.0(d), 74.9(s), 78.5(s).

79.9(d), 80.2(t), 81.9(d).

83.2(d), 85.0(d), 91.1(d).

128.4(d), l　29.9(d).

1 3 0.0 (s), 1 3 3.1 (d).

166.3 (s) Specific Example 4 Fraction 1.59 eluted with 500-ethyl acetate-methanol (5:1) in the first alumina column chromatography of Specific Example 1 was subjected to alumina column chromatography again, and acetic acid Elution was carried out in the order of ethyl and ethyl acetate/methanol (50:I). The obtained ethyl acetate-methanol (50:l) elution fraction 49019 was further subjected to alumina column chromatography, and the fraction eluted with chloroform-methanol (50:l) was crystallized from acetone to give colorless needle crystals 1603. ! I
I got an F.

The physicochemical properties of this colorless needle crystal were consistent with the physicochemical properties of ignabine described in the literature [Takayama et al., Pharmaceutical Journal, Vol. 102, 525 (1982)].

Properties: Dicolorless needle crystals Melting point: 225-228°C Specific rotation: [α]D +85.2° (c = 1,03, EtOIl) Mass spectrum (E I-MS) m/z: 449 (M”) ,432,
327 (100%).

310.105 Infrared absorption spectrum Shini: i' 1 cM-1;
3600-3200.1722 Ultraviolet absorption spectrum λmad' y+m(logε
) 230 (4,06) Proton nuclear magnetic resonance spectrum (δ ppm in CD, OD): 1.17 (3H, s).

3.65 (l H, d, J = 2Hz).

3.99 (l　H, brs), 5.00 (2H, m).

5.39 (l H, ddd, J = 4.4.2 H
z).

7.45-8.05 (5H, m) carbon nuclear magnetic resonance spectrum (δ ppm in CD5OD): 25.8(t), 25.9(q), 30.1(t).

34.4(t), 36.4(d), 39.8(t).

42.3(s), 43.2(d), 45.4(s).

51.6(d), 52.2(s), 62.5(t).

6 5.8(d), 7 1. 4(d), 7 3.0(
d).

7 4.9(d), 7 5.9(d), 8 0.2(s
).

1 1 0.2 (t), 1 2 9.8 (d).

1 3 0.3 (d), 1 3 1. 4(s).

1 34.5 (d), 1 5 5.9 (s).

166.9(s) Next, the fact that the compound of formula I and the active ingredient compound have a blood viscosity-lowering effect will be explained with reference to experimental examples.

Experimental Example Blood was collected from the abdominal aorta of male Wistar rats (10 to 12 weeks old) pre-housed for one week under ether anesthesia, and 40% ethylenediaminetetraacetic acid dipotassium [(E D T A.2K)
Physiological saline was added at a rate of 3 times per 1 day. Blood is centrifuged #! (3000 rpm, 4°C, 5 minutes) to separate the supernatant and red blood cell layer. This supernatant was further centrifuged (3000 rpm, 4° C., 15 minutes), and the resulting supernatant was used as plasma. The red blood cell layer and plasma are
Measure the hemadcrit value (hereinafter referred to as 14T value) of the red blood cell layer for several animals each, and set the HT value to 45%.
The sample was adjusted to 100% and then used for measuring blood viscosity.

50% of the compound or active ingredient compound was added to l- of blood for measurement to a final concentration of 4.8XlO-'M.
% ethanol in physiological saline, 50 sides of this solution was added to a tLid for measuring blood viscosity, and incubated at 37°C for 60 minutes. Then incubated blood 0.5
Separate the dai and use a viscosity meter to measure the rubbing speed at 7.53-'
The viscosity was measured using the following formula, and the degree of blood viscosity reduction was calculated using the following formula.

However, A: blood viscosity when formula I or the active ingredient compound is not included B: blood viscosity when formula I or the active ingredient compound is included The results are shown in Table 1.

From the results shown in Table 1 onwards, it was confirmed that the compound of formula I and the active ingredient compound had a blood viscosity lowering effect.

Next, an acute toxicity test of the compound of formula I and the active ingredient compound was conducted using ddY male mice. The L D of each compound after intraperitoneal administration is shown below.

The compound of formula I and the active ingredient compound may also include hydrochloride,
It can also be used as a pharmaceutically acceptable salt such as iodate or bromate.

Next, the dosage and formulation of the compound of formula I and the active ingredient compound will be described.

The compounds of formula I and the active ingredient compounds can be administered to animals and humans either neat or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and can be selected and used as required, including tablets, capsules, granules,
Examples include oral preparations such as fine granules and powders, and parenteral preparations such as injections and suppositories.

In order to exert the desired effect as an oral agent, the amount of the compound of formula I and the active ingredient compound for an adult is usually 5 to 50% by weight, although it varies depending on the patient's age, body weight, and severity of the disease.
It seems appropriate to take 0 m9 divided into two daily doses.

Oral preparations are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboquine methylcellulose, cornstarch, inorganic salts, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin,
Hydroquine propyl starch, methyl cellulose, sodium carboxyl methyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the invention can also be administered as suspensions, emulsions, syrups, elixirs,
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, although it varies depending on the patient's age, weight, and degree of disease, the compound of the present invention must be administered at a static dose of 0.5 to Injection, intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

Next, the present invention will be explained in more detail by giving Examples, but the present invention is not limited thereto.

Example 1 In the first alumina column chromatography of Example 1, 1.0 g of the fraction eluted with 800-ethyl acetate was subjected to alumina column chromatography again, and n-hexane-ethyl acetate (I:1), acetic acid Ethyl was eluted in this order. Among the fractions eluted with n-hexane ethyl acetate (1:I), a fraction containing a component showing an Rf value of 0.41 in thin layer chromatography (developing solvent, cyclohexane: ethyl acetate: diethylamine χ5:5:1) 360 M9 was further subjected to alumina column chromatography, and the fraction eluted with benzene-ethyl acetate (1:1) was crystallized from ethyl acetate to obtain colorless prism product 13019.

This colorless prism crystal has the physical and chemical properties shown below.
16-nipypyromesaconitine or 14α-benzoyloxy-3α, having the structure:

I3-dihydroxy-1a,6a,16a-trimethoxy-4-methoxymethyl-20-methylaconitan-1
It was decided to be 5-on.

Properties: Colorless prism product Melting point: 174-176°C Specific rotation = [α]o 104.7° (c = 1.
05, ELOII) Mass spectrum (El-MS) ra/z: 571 (
M'), 540 (100%).

522.105 Elemental analysis C5rH-+N Oe ・X Hto: Calculated value: C, 64, 23, H, 7, 13, N, 2.42 Actual value: C, 64, 39, H, 7, 17; N, 2.36 Infrared absorption spectrum C:H213a-':3700
~3300.1714 Ultraviolet absorption spectrum λ2:':' ym (Iog
ε): 229(4,13) Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.88 (L H, ddd, J = 16.6, 11.4, 2.
3Hz).

2.29 (IH, s).

3.04 (IH, dd, J=16.6, 7.1 Summer (
2).

3.05 (IH, dd, J=10.0, 6.7Hz) 3
．． 26 (3H', s), 3.27 (31-1, s).

3.30 (3H, s).

(l H, ddd, J = 11.8.5.4,!
, 3 l-1z).

3.70 (lH, d, J = 9.3 Hz).

3.75 (IH, d, J = 9.3Hz) 3.80 (3H
,s).

3.87 (l I-1, dd, I = 2.3, 1.9)
(z).

3.90 (11(, d, J = 6.6 Hz).

5.43 (f H, d, J = 5.1 Hz).

7.40-8.01 (5H, m) Carbon nuclear magnetic resonance spectrum (δ ppm in CDC1z) 32.8 (t), 34.2 (t), 38.8 (d) 40
．． 8(d), 42.1(q), 43.9(s) 44.8
(d), 48.0(d), 49.3(d) 49.8(d
), 51.9(s), 56.4(q).

57.8(q), 59.2(q), 62.3(q)62
．． 9(d), 71.8(d), 76.8(t)77.5
(s), 78.5(d), 83.7(d).

84.0(d), 86.2(d), 128.6(d).

129.4 (s), 129.7 (d) 133
．． 6(d), 1.66.1(s).

211.5 (s) Example 2 In the first alumina column chromatography of Example I, the fraction 1.09 eluted with ethyl acetate 80077 was subjected to alumina column chromatography again, and n-hexane-ethyl acetate (l :1) and ethyl acetate were eluted in this order. n-hexane ethyl acetate (1:1)
Among the fractions eluted with , fraction 69 containing a component showing Rf (tmo, 48) in thin layer chromatography (developing solvent, cyclohexane/ethyl acetate:diethylamine-5:5:l) was purified by medium pressure silica gel chromatography ( CIG column, 22φX300.
) to obtain 22 m9 of n-hexane-ethyl acetate (3:I) elution fraction. This n-hexane-ethyl acetate elution fraction was crystallized from ethyl acetate to obtain colorless needle-like crystals 7,01!9. Based on the physical and chemical properties shown below, this colorless needle crystal has the following structure: I6 epi-pyraconitine, 14α-benzoyloxy-2
-ethyl-3α, 13-dihydroxy-1α, 6α, 1
It was determined to be 6α-trimethoxy-4-methoxymethylaconitan-15-one.

Properties: Colorless needle crystals Melting point: l7l-173°C Specific rotation: [α]a 113.7° (c = 0
．． 73, EtOH) Mass spectrum (EI-MS) m/z: 5
85 (M”), 570,554 (100%).

536.105 Elemental analysis Cs*tl 43N Oa calculated value: C, 6
5,62, H, 7,40, N 2.39 Actual value: C,
65,25;H,7,32;N,2.34 Infrared absorption spectrum νC1+(+3 α3700-3300
1714 Ultraviolet absorption spectrum λ2t011 n, (log
ε) 230(4,18) proton nuclear magnetic resonance spectrum (δppn in CDC13) 1.05 (3H,t, J = 7.1 Hz).

1.82 (l H, ddd, J = 15.7, I l, 5
．． 2.51-12) 3.04 (I H, dd, J =
15.7.7.6Hz).

3.05 (I H, dd, J= I O, 8, 6, 3H
z).

3.25 (6H, s), 3.30 (3H, s) 3.68
(l H, dd, J = I 2.2, 5.1 Hz)
3. 6 9 (I H, d, J
= 9. 3 Hz).

3.75 (lH, d, J = 9.3 Hz).

3.81 (3H, s).

3.86 (IHdd, J=2.5.21Hz).

3.9 0 (l H, d, J = 6.71
-1z).

5.4 2(l H,d, J =
5.1 Hz) 7.4 0-8.0 1 (5H,
m) Carbon nuclear magnetic resonance spectrum (δ ppm in CDCl5) 13.4(q), 32.9(t), 34.1(t).

38.7(d), 41.8(d), 43.7(s).

44.8(d), 47.4(t), 48.6(d).

49.0(t), 49.4(d), 51.2(s).

56.1 (q), 57.8 (q), 59.2 (q).

61.6(d), 62.3(q), 71.8(d).

76.7(t), 77.4(s), 78.5(d).

83.6(d), 84.1(d), 86.1(d).

128.7(d), 129.5(s).

129.7(d), l 33. e(d).

166.1 (s), 211.6 (s).

Example 3 ■Corn starch 449 ■Crystalline cellulose 40g ■Carboxymethylcellulose calcium 59 ■Light anhydrous silicic acid 0.59■Magnesium stearate 0.59■ Compound obtained in body side 1
10y, total 100g According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain tablets of 200 Rfl each.

This tablet-tablet contains the compound 20JI9 obtained in Example I, and is taken by adults in 185 to 25 tablets divided into several doses.

Example 4 ■Crystalline cellulose 84.59■Magnesium stearate 0.59■Calcium carboxymethyl cellulose 5g Compound obtained in Example 2 1O Total 100g Parts of ■, ■, and ■ were uniformly mixed according to the above recipe, After compression molding, the mixture was pulverized, and the remaining amounts of (1) and (2) were added and mixed, and the mixture was compression molded using a key press to obtain tablets weighing 200 x 9 each.

These tablets contain the compound 2゜j19 obtained in Example 2, and adults should take 5 to 25 tablets a day in several doses.

Example 5 ■ Crystalline cellulose 49.59 ■ 10% hydroxypropyl cellulose ethanol solution 359 ■ Carboxymethyl cellulose calcium 59 ■ Magnesium stearate 0.59 ■ Compound obtained in Example 3 to9 Total 1009 ■, ■ and ■ according to the above recipe After homogeneously mixing the ingredients, neutering them using a conventional method, granulating them using an extrusion granulator, drying and crushing them, mix them with ■ and ■, and compression-mold them using a key press to make one tablet of 200 R9. Got the tablets.

This tablet contains 20 compounds obtained in the specific example, and is taken by adults in 185 to 20 tablets divided into several doses.

Example 6 Example 7 ■Corn starch 849■Magnesium stearate 0.59■Carboxomethyl cellulose calcium 59 ■Light silicic anhydride 0.59■Compound obtained in specific example 4 +017 total 1009 ■~■ were homogenized according to the above recipe After compression molding with a compression molding machine, the mixture was crushed with a crusher and sieved to obtain granules.

1 g of this granule contains the compound l00R9 obtained in specific example 4.
Adults should take ~10g in several doses per day.

■Crystalline cellulose 559 ■10% hydroxypropyl cellulose ethanol solution/&359 ■Example! Compound IO total 1009 obtained in 1 to 2 were uniformly mixed according to the above recipe and made into a paste. After granulation using an extrusion granulator, it was dried and sieved to obtain granules.

This granule 19 contains the compound obtained in Example 1 + oox9
It contains 1 to 49 doses per day for adults, divided into several doses.

Example 8 ■Corn starch 89.5y■Light silicic anhydride 0.5g■Compound obtained in Example 2
109 Total 100g Mix ■～■ uniformly according to the above recipe, and mix 200 m
y was filled into a No. 2 capsule.

This capsule contains compound 20R9, and adults should take 5 to 20 capsules a day in several doses.

Example 9 ■ Distilled water for injection 89,59 ■ Soybean oil
59 ■ Soybean phospholipid 2.59 ■ Glycerin
2g ■ Compound obtained in Example I 1g Total amount 100v Dissolve ■ in ■ and ■ according to the above recipe, and add ■ to this.
The solutions of (1) and (2) were added and emulsified to obtain an injection.

Claims (2)

[Claims] (1) A new diterpene alkaloid represented by the following formula I ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ I (However, in the formula, Bz represents -COC_6H_5, and R represents a methyl group or an ethyl group.) (2) Benzoylmesaco, a new diterpene alkaloid represented by the following formula I ▲ Numerical formulas, chemical formulas, tables, etc.▼ I (However, in the formula, Bz represents -COC_6H_5 and R represents a methyl group or an ethyl group.) A blood viscosity-lowering agent containing as an active ingredient at least one compound selected from the group of compounds consisting of nin, benzoylaconine, benzoylhypaconine, and ignabine.